Textbook of Clinical Neuropsychiatry

qxd 3/10/08 5:51 PM Page i
Textbook of Clinical Neuropsychiatry

This page intentionally left blank
lims.qxd 3/10/08 5:51 PM Page iii
Textbook of Clinical
Neuropsychiatry
Second edition
David P Moore MD
Associate Clinical Professor, Department of Psychiatry, Associate
Clinical Professor, Department of Neurosurgery (Division of Physical
Medicine and Rehabilitation), University of Louisville School of
Medicine, Louisville, Kentucky, USA
PART OF HACHETTE LIVRE UK

lims.qxd 3/10/08 5:51 PM Page iv
First published in Great Britain in 2001 by Arnold

This second edition published in 2008 by Hodder Arnold,
an imprint of Hodder Education, part of Hachette Livre UK,
338 Euston Road, London NW1 3BH
http://www.hoddereducation.com
Copyright © 2008 David P Moore
All rights reserved. Apart from any use permitted under UK copyright law,
this publication may only be reproduced, stored or transmitted, in any
form, or by any means with prior permission in writing of the publishers
or in the case of reprographic production in accordance with the
terms of licences issued by the Copyright Licensing Agency. In the
United Kingdom such licences are issued by the Copyright Licensing
Agency: 90 Tottenham Court Road, London W1T 4LP.
Whilst the advice and information in this book are believed to be true
and accurate at the date of going to press, neither the author nor the
publisher can accept any legal responsibility or liability for any errors or
omissions that may be made. In particular (but without limiting the
generality of the preceding disclaimer) every effort has been made to
check drug dosages; however it is still possible that errors have been
missed. Furthermore, dosage schedules are constantly being revised and
new side-effects recognized. For these reasons the reader is strongly
urged to consult the drug companies’ printed instructions before
administering any of the drugs recommended in this book.
British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
ISBN-13 978 0 340 93953 6
1 2 3 4 5 6 7 8 9 10
Commissioning Editor: Philip Shaw

Project Editor: Amy Mulick
Production Controller: Karen Tate
Cover Design: Helen Townson
Typeset in 10/12 pt Minion by Charon Tec Ltd

(A Macmillan Company), Chennai, India
www.charontec.com
Printed and bound in Great Britain
What do you think about this book? Or any other Hodder Arnold
title? Please visit our website: www.hoddereducation.com
lims.qxd 3/10/08 5:51 PM Page v
Dedication
This book is dedicated to my wife, Nancy G Moore, PhD, my children, Ethan, Nathaniel, and Joshua, and to James W
Jefferson, MD, for whose example and guidance I remain ever thankful. I also wish to express my gratitude to Professors
Raymond Faber, Michael R Trimble and Elden Tunks, whose kind words made this second edition possible.
‘Scribere actum fidei est’

Contents
Preface xiii
PART I DIAGNOSTIC ASSESSMENT 1

1 Diagnostic assessment 3
1.1 Diagnostic interview 3
1.2 Mental status examination 5
1.3 Neurologic examination 10
1.4 Neuroimaging 17
1.5 Electroencephalography 21
1.6 Lumbar puncture 31
PART II SIGNS, SYMPTOMS, AND SYNDROMES 43

2 ‘Cortical’ signs and symptoms 45
2.1 Aphasia 45
2.2 Alexia 49
2.3 Agraphia 50
2.4 Acalculia 51
2.5 Gerstmann’s syndrome 51
2.6 Hypergraphia 52
2.7 Aprosodia 53
2.8 Apraxia 55
2.9 Agnosias 57
2.10 Neglect 62
3 Abnormal movements 72
3.1 Tremor 72
3.2 Myoclonus 75
3.3 Motor tics 77
3.4 Chorea 78
3.5 Athetosis 81
3.6 Ballism 82
3.7 Dystonia 83
3.8 Parkinsonism 87
3.9 Akinesia 91
3.10 Akathisia 92
3.11 Catatonia 93
3.12 Asterixis 96
3.13 Mirror movements 97
3.14 Pathologic startle 98
4 Other signs and symptoms 117
4.1 Mutism 117
4.2 Akinetic mutism 118
lims.qxd 3/10/08 5:51 PM Page viii
viii Contents
4.3 Stuttering 119

4.4 Palilalia 120
4.5 Perseveration 121
4.6 Primitive reflexes 121
4.7 Pseudobulbar palsy 123
4.8 Emotional facial palsy 124
4.9 Le fou rire prodromique 125
4.10 Abulia 125
4.11 Environmental dependency syndrome 126
4.12 Kluver–Bucy syndrome 127
4.13 Alien hand sign 129
4.14 Balint’s syndrome 131
4.15 Phantom and supernumerary limbs 131
4.16 Depersonalization 132
4.17 Obsessions and compulsions 133
4.18 Reduplicative paramnesia 135
4.19 Confabulation 136
4.20 Amusia 136
4.21 Foreign accent syndrome 137
4.22 Cataplexy 137
4.23 Sympathetic storm 138
4.24 Catastrophic reaction 139
4.25 Flattened affect 139
4.26 Inappropriate affect 139
4.27 Mannerisms 140
4.28 Stereotypies 140
4.29 Echolalia and echopraxia 141
4.30 Hallucinations and delusions 142
4.31 Schneiderian first rank symptoms 146
5 Syndromes of cognitive impairment 162
5.1 Dementia 162
5.2 Mild cognitive impairment 173
5.3 Delirium 174
5.4 Amnesia 183
5.5 Mental retardation 187
6 Syndromes of disturbances of mood and affect 208
6.1 Depression 208
6.2 Apathy 214
6.3 Mania 215
6.4 Agitation 222
6.5 Anxiety 225
7 Other major syndromes 238
7.1 Psychosis 238
7.2 Personality change 244
7.3 Seizures and epilepsy 249
7.4 Stroke 275
7.5 Traumatic brain injury 288
7.6 Acute encephalitis 294
7.7 Somatoform disorders 296
7.8 Malingering and factitious illness 302
PART III SPECIFIC DISORDERS 333
8 Neurodegenerative and movement disorders 335

8.1 Alzheimer’s disease 335
8.2 Pick’s disease 340
8.3 Frontotemporal dementia 341
lims.qxd 3/10/08 5:51 PM Page ix
Contents ix
8.4 Amyotrophic lateral sclerosis 342

8.5 Parkinson’s disease 344
8.6 Diffuse Lewy body disease 350
8.7 Progressive supranuclear palsy 352
8.8 Corticobasal ganglionic degeneration 354
8.9 Multiple system atrophy 354
8.10 Huntington’s disease 356
8.11 Choreoacanthocytosis 358
8.12 FXTAS 358
8.13 Senile chorea 359
8.14 Benign hereditary chorea 360
8.15 Dentatorubropallidoluysian atrophy 360
8.16 Wilson’s disease 361
8.17 Spinocerebellar ataxia 362
8.18 Pantothenate kinase-associated neurodegeneration 364
8.19 Dopa-responsive dystonia 365
8.20 Primary torsion dystonia 366
8.21 Idiopathic cervical dystonia 366
8.22 Task-specific dystonia 367
8.23 Meige’s syndrome 368
8.24 Spasmodic dysphonia 368
8.25 Tourette’s syndrome 369
8.26 Myotonic muscular dystrophy 371
8.27 Cerebrotendinous xanthomatosis 373
8.28 Thalamic degeneration 374
8.29 Metachromatic leukodystrophy 374
8.30 Adrenoleukodystrophy 376
8.31 Kufs’ disease 377
8.32 Essential tremor 377
8.33 Hyperekplexia 378
9 Congenital, developmental, and other childhood-onset disorders 403
9.1 Sturge–Weber syndrome 403
9.2 Tuberous sclerosis 404
9.3 Von Recklinghausen’s disease (neurofibromatosis type 1) 405
9.4 Down’s syndrome 407
9.5 Klinefelter’s syndrome 408
9.6 Fragile X syndrome 409
9.7 Velocardiofacial syndrome 410
9.8 Lesch–Nyhan syndrome 411
9.9 Bardet–Biedl syndrome 412
9.10 Prader–Willi syndrome 412
9.11 Congenital rubella syndrome 413
9.12 Fetal alcohol syndrome 414
9.13 Rett’s syndrome 414
9.14 Autism 416
9.15 Attention-deficit/hyperactivity disorder 418
9.16 Developmental dysphasia 420
9.17 Developmental dyslexia 421
9.18 Developmental dysgraphia 422
9.19 Developmental dyscalculia 423
9.20 Developmental stuttering 423
10 Vascular disorders 433
10.1 Multi-infarct dementia 433
10.2 Lacunar dementia 434
10.3 Vascular parkinsonism 435
10.4 Binswanger’s disease 436
10.5 Cranial arteritis 437
lims.qxd 3/10/08 5:51 PM Page x
x Contents
10.6 Cerebral amyloid angiopathy 438

10.7 CADASIL 439
10.8 Granulomatous angiitis of the central nervous system 440
10.9 Polyarteritis nodosa 441
10.10 Wegener’s granulomatosis 442
10.11 Behçet’s disease 442
10.12 Hypertensive encephalopathy 443
10.13 Reversible posterior leukoencephalopathy syndrome 444
10.14 MELAS 445
10.15 Thrombotic thrombocytopenic purpura 446
10.16 Fat embolism syndrome 446
10.17 Multiple cholesterol emboli syndrome 447
10.18 Transient global amnesia 447
11 Trauma 454
11.1 Subdural hematoma 454
11.2 Diffuse axonal injury 455
11.3 Dementia pugilistica 456
11.4 Post-concussion syndrome 457
11.5 Radiation encephalopathy 458
12 Hypoxic disorders 462
12.1 Post-anoxic encephalopathy 462
12.2 Delayed post-anoxic leukoencephalopathy 463
12.3 Carbon monoxide poisoning 463
13 Nutritional, toxic and metabolic disorders 466
13.1 Vitamin B12 deficiency 466
13.2 Folic acid deficiency 468
13.3 Pellagra 468
13.4 Wernicke’s encephalopathy 469
13.5 Korsakoff’s syndrome 471
13.6 Manganism 472
13.7 Thallium intoxicaton 473
13.8 Arsenic intoxication 473
13.9 Bismuth intoxication 474
13.10 Tin intoxication 474
13.11 Lead encephalopathy 475
13.12 Mercury intoxication 476
13.13 Dialysis dementia 476
13.14 Dialysis disequilibrium syndrome 477
13.15 Hypoglycemia 478
13.16 Hyperviscosity syndrome 479
13.17 Central pontine myelinolysis 479
13.18 Uremic encephalopathy 481
13.19 Hepatic encephalopathy 481
13.20 Acquired hepatocerebral degeneration 482
13.21 Hepatic porphyria 483
13.22 Fahr’s syndrome 484
14 Infectious and related disorders 493
14.1 Acquired immunodeficiency syndrome (AIDS) 493
14.2 Cytomegalovirus encephalitis 495
14.3 Progressive multifocal leukoencephalopathy 496
14.4 Arbovirus meningoencephalitis 497
14.5 Herpes simplex encephalitis 498
14.6 Encephalitis lethargica 499
14.7 Infectious mononucleosis 500
14.8 Mumps 501
14.9 Varicella-zoster 502
14.10 Rabies 503
lims.qxd 3/10/08 5:51 PM Page xi
Contents xi
14.11 Acute disseminated encephalomyelitis 504

14.12 Subacute sclerosing panencephalitis 506
14.13 Subacute measles encephalitis 506
14.14 Progressive rubella panencephalitis 507
14.15 Neurosyphilis 508
14.16 Lyme disease 510
14.17 Tuberculosis 512
14.18 Whipple’s disease 513
14.19 Rocky Mountain spotted fever 514
14.20 Malaria 514
14.21 Toxoplasmosis 515
14.22 Fungal infections 516
15 Prion diseases 525
15.1 Creutzfeldt–Jakob disease 525
15.2 New-variant Creutzfeldt–Jakob disease 527
15.3 Gerstmann–Sträussler–Scheinker disease 528
15.4 Fatal familial insomnia 528
15.5 Kuru 529
16 Endocrinologic disorders 534
16.1 Cushing’s syndrome 534
16.2 Adrenocortical insufficiency 536
16.3 Hyperthyroidism 537
16.4 Hypothyroidism 539
17 Immune-related disorders 544
17.1 Multiple sclerosis 544
17.2 Systemic lupus erythematosus 548
17.3 Sjögren’s syndrome 551
17.4 Sneddon’s syndrome 552
17.5 Primary anti-phospholipid syndrome 552
17.6 Susac’s syndrome 553
17.7 Limbic encephalitis 553
17.8 Sarcoidosis 555
17.9 Hashimoto’s encephalopathy 556
17.10 Sydenham’s chorea 558
17.11 Chorea gravidarum 560
18 Sleep disorders 569
18.1 Somnambulism 569
18.2 REM sleep behavior disorder 570
18.3 Nightmare disorder 572
18.4 Night terrors 572
18.5 Nocturnal head banging 573
18.6 Enuresis 574
18.7 Narcolepsy 575
18.8 Sleep apnea 577
18.9 Pickwickian syndrome (obesity–hypoventilation syndrome) 579
18.10 Kleine–Levin syndrome 579
18.11 Restless legs syndrome 581
18.12 Periodic limb movements in sleep 582
18.13 Painful legs and moving toes 583
18.14 Circadian rhythm sleep disorder 584
18.15 Primary insomnia 585
18.16 Primary hypersomnia 587
19 Brain tumors and hydrocephalus 596
19.1 Brain tumors 596
19.2 Hydrocephalus 600
19.3 Normal pressure hydrocephalus 602
lims.qxd 3/10/08 5:51 PM Page xii
xii Contents
20 Idiopathic psychotic, mood, and anxiety disorders 606

20.1 Schizophrenia 606
20.2 Schizoaffective disorder 614
20.3 Delusional disorder 615
20.4 Post-partum psychosis 617
20.5 Bipolar disorder 618
20.6 Major depressive disorder 624
20.7 Premenstrual dysphoric disorder 629
20.8 Post-partum depression 630
20.9 Post-partum blues 631
20.10 Panic disorder 631
20.11 Agoraphobia 634
20.12 Specific (simple) phobia 635
20.13 Social phobia 636
20.14 Obsessive–compulsive disorder 638
20.15 Post-traumatic stress disorder 639
20.16 Generalized anxiety disorder 641
21 Substance use disorders 656
21.1 Stimulants 656
21.2 Cocaine 657
21.3 Hallucinogens 659
21.4 Phencyclidine and ketamine 660
21.5 Alcohol 661
21.6 Sedatives, hypnotics, and anxiolytics 667
21.7 Inhalents (solvents) 669
21.8 Cannabis 670
21.9 Opioids 671
21.10 Nicotine 673
21.11 Caffeine 675
21.12 Methanol 675
21.13 Isopropanol 676
22 Medication and substance-induced disorders 683
22.1 Neuroleptic malignant syndrome 683
22.2 Tardive dyskinesia 685
22.3 Supersensitivity psychosis 688
22.4 Rabbit syndrome 689
22.5 Serotonin syndrome 689
22.6 Anticholinergic delirium 690
22.7 Cholinergic rebound 691
22.8 Alcoholic dementia 692
22.9 Alcohol hallucinosis 693
22.10 Alcoholic paranoia 694
22.11 Marchiafava–Bignami disease 694
22.12 Inhalent-induced dementia 695
Index 703
lims.qxd 3/10/08 5:51 PM Page xiii
Preface
This second edition of the Textbook of Clinical and readers will find references to the works of such
Neuropsychiatry, like the first, is a practical, clinically oriented physicians as Alzheimer, Binswanger, Bleuler, Hughlings
text that is designed to equip readers to diagnose and treat Jackson, Kraepelin, and Kinnier Wilson. In all, over 5000
the multitude of neuropsychiatric disorders they encounter. references are included, thus providing readers not only
It is divided into three parts: Part 1 describes the diagnostic with ready access to further detail on any particular subject,
assessment of patients and details the interview, mental but also with a window on the literature as a whole.
status examination, neurologic examination and ancillary I am deeply indebted to the reviewers of the first edition,
investigations; Part 2 provides a thorough description of the and to many other readers who have offered comments,
various signs, symptoms and syndromes that are seen in critiques, and suggestions: they have enabled me to write a
neuropsychiatric practice; and Part 3 presents virtually all second edition, which, I believe, is far stronger than the first.
of the specific disorders seen in neuropsychiatric practice, Neuropsychiatry is a rapidly growing specialty, and it is my
in each instance detailing clinical features, course, etiology, hope that this text will not only help solidify the field but
differential diagnosis, and treatment. also enable the reader to practice it successfully. As with the
The literature devoted to neuropsychiatric disorders is first edition, so too with this second one, I invite both
vast, encompassing, as it does, much of both neurology and newcomers and established practitioners to try using it in
psychiatry, and I have attempted to cull from this their own practices, as I think they may well find it as
tremendous reservoir those references that are of most use indispensable as I do.
to the clinician. Although the preponderance of references David P Moore
are from the recent past, classic authors are not neglected September 2007
p 01.qxd 3/10/08 9:33 AM Page 1
PART I
DIAGNOSTIC ASSESSMENT
1 Diagnostic assessment 3
p 01.qxd 3/10/08 9:33 AM Page 3
1
Diagnostic assessment
1.1 Diagnostic interview 3 1.5 Electroencephalography 21

1.2 Mental status examination 5 1.6 Lumbar puncture 31
1.3 Neurologic examination 10 References 34
1.4 Neuroimaging 17
1.1 DIAGNOSTIC INTERVIEW sets aside a sufficient amount of time to take the history,
which may range from less than half an hour in uncompli-
Lord Brain (1964) noted that ‘in the diagnosis of nervous cated cases related by cooperative patients to well over an
diseases the history of the patient’s illness is often of greater hour when the history is long and complex or the patient is
importance than the discovery of his abnormal physical unable to cooperate fully. There is debate as to whether the
signs’, a sentiment echoed by Russell DeJong (1979) who physician should take notes during the interview: some feel
asserted that ‘a good clinical history often holds the key to it is distracting, both to the patient and the physician,
diagnosis’. whereas others recommend it in order to ensure accuracy,
Obtaining the history, however, as noted by DeJong especially when the interview is lengthy. I agree with Victor
(1979), ‘is no simple task [and] may require greater skill (Victor and Ropper 2001) who feels that the practice is ‘par-
and experience than are necessary to carry out a detailed ticularly recommended’. The idea is not to make a transcript
examination’. The acquisition of this skill is, for most, no but simply to jot down key points and dates, and to do so in
easy matter, requiring, above all, practice and supervision. a way that allows the physician to maintain his or her atten-
Certain points, however, may be made regarding the set- tion on what the patient is saying.
ting of the interview, establishing rapport, eliciting the
chief complaint, the division of the interview itself into
Establishing rapport
non-directive and directive portions, concluding the inter-
view, and the subsequent acquisition of collateral history
DeJong (1979) noted that ‘interest, understanding, and
from family or acquaintances. Even these general points,
sympathy’ are essential to the successful conduct of the
however, allow exceptions depending on the clinical situa-
interview: patients who experience a sense of rapport with
tion, and the physician must be flexible and prepared to
their physicians are more likely to be truthful and forth-
exercise initiative.
coming; hence establishing rapport is of great importance.
First impressions carry great weight here: after introduc-
ing themselves, physicians should clearly relate their role in
Setting the case and then, as suggested by DeJong (1979), display
‘kindness, patience, reserve, and a manner which conveys
The interview should ideally be conducted in a quiet and
interest’ throughout the interview. Provided with such a
private setting, set apart from distractions and anything
forum, most patients will, with only minor help, provide the
that might inhibit patients as they relate the history.
history required to generate the appropriate differential
Importantly, that means that family and friends should be
diagnosis.
excused during the interview, as patients may feel reluctant
to reveal certain facts in their presence. If the interview
takes place at the bedside, the physician should be seated; Eliciting the chief complaint
standing implies that time is short, and some patients,
picking up on this cue, may skip over potentially valuable ‘It is well’, noted Lord Brain (1964), ‘to begin by asking the
parts of the history in order not to waste the physician’s patient of what he complains’. The chief complaint is the
time. In this regard, it is also important that the physician epitome of the patient’s illness: lacking such a focus,
p 01.qxd 3/10/08 9:33 AM Page 4
4 Diagnostic assessment
digressions are almost inevitable, and the history obtained ‘question-and-answer’ approach used by many. The prob-
may be of little diagnostic use. Thus, once introductions lem with the ‘question-and-answer’ approach is that many
are out of the way the first question put by the physician patients will lose the initiative to speak, and simply await
should focus on what brought the patient to the hospital. questions from the physician, which is all well and good
Critically, as some patients may be reluctant to reveal the unless, of course, the physician fails to ask the ‘right’ ques-
actual reason for their coming to the hospital, it is neces- tions, in which case potentially critical aspects of the his-
sary to weigh the chief complaint offered by the patient and tory may remain unrevealed.
ask oneself whether, in fact, it sounds like a plausible rea- Gentle shepherding may be required in cases when
son to seek medical attention. If not, gentle probing is in patients digress or take off at a tangent. One should not, of
order and should generally be continued until the actual course, rudely pull the patient back to task, but rather tact-
chief complaint is revealed. Importantly, the physician fully suggest that refocusing on the illness that prompted
should never accept at face value a diagnosis offered by a admission might be more appropriate.
patient: as Bickerstaff (1980) pointed out, ‘it must be made Once the essential points have been covered, it is appro-
absolutely clear what the patient means by his description priate to summarize briefly what the patient has said in
of his symptoms. By all means put it down in his words order to be sure that the history, as understood by the
first, but do not be content with that . . . “Black-outs” may physician, is correct. Patients should be invited to correct
mean loss of consciousness, loss of vision, loss of memory, any misapprehensions and once the history is complete the
or just loss of confidence’. physician should move on to the directive portion of the
Occasionally, it may not be possible to establish a chief interview.
complaint during the interview, as may occur with patients
who are delirious, demented, psychotic, or simply hostile
and uncooperative. In such cases, persisting overly long in
the pursuit of a chief complaint may become counterpro- The directive portion of the interview
ductive as patients may become resentful, and it is gener-
ally more appropriate to move on to the ‘directive’ portion The directive portion of the interview should be introduced
of the interview described below, always being alert, how- to the patient as a series of perhaps ‘routine’ questions relat-
ever, to the possibility that the patient may ‘slip in’ the ing to the patient’s overall health. Here, one obtains infor-
chief complaint at an unexpected moment. mation regarding the medications that the patient is taking,
allergies, the past medical history, a review of systems, the
family medical history and, finally, the mental status exam-
The non-directive portion of the interview ination (discussed in Section 1.2). In this regard, two points
deserve special emphasis. First, when interviewing hospital-
Once a chief complaint has been established, the patient, as ized patients it is essential to obtain an absolutely accurate
noted by Brain (1964), ‘should be allowed to relate the list of medicines that the patient was taking at home, prior
story of his illness as far as possible without interruption, to admission: medication changes often provide the clue to
questions being put to him afterwards to expand his state- otherwise puzzling syndromes, such as delirium, which
ments and to elicit additional information’. Some patients, may occur during the hospital stay. Second, given the
once asked to expand on the chief complaint, may, with lit- increasing importance of genetics in neuropsychiatric prac-
tle or no prompting, provide the ‘perfect’ history, covering tice, it is essential to obtain a detailed family history regard-
each of the following essential points: ing any neuropsychiatric illness.
During the directive portion of the interview, although
● onset, including approximate date and mode of onset a question-and-answer approach is generally appropriate
(acute, gradual, or insidious) the physician must always be ready to adopt a non-directive
● presence or absence of any precipitating factors approach should the patient report a symptom or illness
● temporal evolution of various signs and symptoms potentially pertinent to the chief complaint. For example,
● presence or absence of any aggravating or alleviating if during the review of systems the patient affirms that
factors headaches have been present it is appropriate to stop and
● treatment efforts and their results ask the patient to elaborate on this, with an eye towards
● pertinent positives and negatives obtaining information regarding each of the essential points
● any history of similar experiences in the past. described earlier.
Questions regarding alcohol/drug use and suicidal/
Most patients will require, however, either encourage- homicidal ideation must be directly pursued if not already
ment or some gentle shepherding at various times. When covered in the non-directive portion of the interview.
patients begin to falter in their history, or seem to be leaving These are, of course, delicate areas, but, if approached in a
items out, it is appropriate to encourage them to talk by straightforward and non-judgmental way, it is remarkable
asking ‘open-ended’ questions such as ‘Tell me more about how forthcoming, and indeed relieved, some patients may
that’. Such a method is much to be preferred over the be at being given an opportunity to speak of them.
p 01.qxd 3/10/08 9:33 AM Page 5
Concluding the interview stroke (or whatever illness the patient feels comfortable
discussing) often have difficulties here’. Should patients
Once the directive portion of the interview has been com- remain uncooperative, it may at times be possible to infer
pleted it is appropriate to give the patient an opportunity their cognitive status indirectly; for example, during his-
to speak freely again. If asked whether they have anything tory taking, by asking the date of a recent event brought up
else to add, many patients will offer important information by the patient.
that they may have either withheld or simply not recalled As noted below, abnormalities on the mental status
earlier. Asking patients whether they have anything they examination typically indicate the presence of one of the
wish to ask the physician is also appropriate, as the major syndromes, such as dementia (Section 5.1), delirium
patients’ questions may reveal much about the concerns (Section 5.3), amnesia (Section 5.4), depression (Section
that brought them to the hospital in the first place. 6.1), apathy (Section 6.2), mania (Section 6.3), anxiety
(Section 6.5), psychosis (Section 7.1), and personality
change (Section 7.2), especially the frontal lobe syndrome.
Collateral history
According to Brain (1964), ‘the history obtained from the Grooming and dress
patient should always be supplemented, if possible, by an
account of his illness given by a relative or by someone who Good habits of grooming and dress may suffer in certain
knows him well’. This is especially the case when patients illnesses, sometimes with diagnostically suggestive results.
are confused or suffer from poor memory: it is remark- Depressive patients may find that hopelessness, fatigue,
able how often a collateral history will change a diagnostic and anhedonia make them give up all hope of maintaining
impression, guide further testing or alter proposed treat- their appearance, with the result that grooming and dress
ments. In obtaining the collateral history, particular attention are left in a greater or lesser degree of disarray. Manic
should be paid to establishing the patient’s pre-morbid patients, overflowing with exuberance, may truly make a
baseline ability to perform such routine activities of daily spectacle of themselves with decorations of make-up and
living as bathing, dressing, cooking, feeding, doing house- garish clothing. Patients with psychosis, especially schizo-
work, shopping, driving or using public transportation, phrenia (Section 20.1) may be quite unkempt and at times
and paying bills. Inquiry should also be made regarding dirty, and their clothing may be bizarre, as, for example,
hobbies, such as playing cards or chess, or doing crossword with multiple layers and a woollen cap, even in the sum-
puzzles. In cases characterized by cognitive deficits, the loss mer; overall dishevellment may also be seen in frontal lobe
of these abilities may serve to establish the onset of the cur- syndrome, dementia, or delirium. Rarely, one may see evi-
rent illness. dence of neglect wherein dress and grooming suffer on
Some have expressed concern that interviewing the fam- only one side of the body (Section 2.1).
ily or acquaintances may violate patient confidentiality but
this is simply not the case, provided that the contact knows
already that the patient is in the hospital and that the physi- General description
cian reveals nothing about the patient while interviewing
the collateral contact. No confidentiality is breached by An overall and general description of the patient’s behavior
introducing oneself as the patient’s physician or by asking is essential, and gives room for the exercise of whatever lit-
collateral contacts what they know about the patient. erary talents the physician may possess.
Finally, it is also essential to review old records. This is Comments should be made on the relationship of the
sometimes a tedious task but, as with interviewing collat- patient to the interviewer, noting, for example, whether the
eral sources, it may reveal critical information. patient is cooperative or uncooperative, guarded, evasive,
hostile, or belligerent. The overall quality of the relation-
ship may also be of diagnostic importance. For example, as
1.2 MENTAL STATUS EXAMINATION noted by Bleuler (1924), in schizophrenia, there is often a
‘defect in . . . emotional rapport’ (italics in original), such
The mental status examination constitutes an essential part that ‘the joy of a schizophrenic does not transport us, and
of any neuropsychiatric evaluation and, at a minimum, his expressions of pain leave us cold’. By contrast, in
should cover each of the items discussed below. Many of mania, as noted by Kraepelin (1921), ‘the patient feels the
these may be determined during the non-directive portion need to get out of himself, to be on more intimate terms
of the interview; however, some, especially those concern- with his surroundings’, such that the physician, willingly or
ing cognition (e.g., orientation, memory), require direct not, often feels engaged, in one fashion or another, with
testing. As some patients may object to cognitive testing, it the patient; in the case of a euphoric manic it is the rare
is important to smooth the way by indicating that these are physician who can keep from smiling, and in the case of an
‘routine’ questions to test ‘things such as memory and irritable manic most physicians will find themselves
arithmetic’, perhaps adding that ‘patients who have had a becoming, at the very least, on edge.
p 01.qxd 3/10/08 9:33 AM Page 6
During the interview, one may also find evidence of cer- wherein patients repeatedly engage in the same behaviors,
tain discrete personality changes. Perseveration, disinhibi- to no apparent purpose (Section 4.28). Echopraxia is said
tion, and a tendency to puerile, silly puns or jokes may to be present when patients involuntarily mimic what others,
suggest frontal lobe syndrome, and in epileptics one may such as the examining physician, do (Section 4.29) Although
find evidence of the interictal personality syndrome with an each of these disturbances may be seen in schizophrenia,
overall ‘viscosity’ or ‘adhesiveness’, such that patients are they are also present in other disorders such as dementia.
unable to manage changing the subject or switching tasks.
Evidence of the Kluver–Bucy syndrome (Section 4.12) may
also be apparent should patients repeatedly put inedible Mood and affect
objects in their mouths or engage in indiscriminate sexual
activity. Mood is constituted by an individual’s prevailing emotional
Consideration should also be given to the overall level ‘tone’. When this is within the broad limits of normal, one
of the patient’s verbal and motor behavior, noting whether speaks of ‘euthymia’ or a euthymic mood; significant mood
there is either psychomotor hyperactivity or retardation. disturbances may tend toward depression, euphoria, anxi-
Psychomotor hyperactivity may manifest with agitation ety, or irritability. Depressed mood may be characterized
(Section 6.4) or mere restlessness, and the activity itself by ‘a profound inward dejection and gloomy hopelessness’
may or may not be purposeful. For example, hyperactivity (Kraepelin 1921); in contrast, euphoria is characterized
may be quite purposeful in mania: as pointed out by by an ‘overflowing contentment’ (Griesinger 1882), such
Kraepelin (1899), the manic patient ‘feels the need to come patients being ‘penetrated with great merriment’ (Kraepelin
out of his shell [and] to have livelier relations with those 1921). Anxious patients are beset with apprehensions, may
around him’. By contrast, in excited catatonia (Section 3.11) plead for help, and may complain of tremor and palpita-
behavior is typically purposeless and bizarre: Kraepelin tions. Irritable patients are typically ‘dissatisfied, intolerant
(1899), in commenting on this difference between mania [and] fault-finding’ (Kraepelin 1921), often quick to react
and catatonia, noted that ‘the catatonic’s urge to move to any perceived slight or criticism.
often takes place in the smallest space, i.e. in part of the In the case of euphoria or irritability, one should also
bed, whereas the manic looks everywhere for an opportu- note whether or not the mood is ‘heightened’, that is to say
nity to be active, and runs around, occupies himself with whether or not it is so abundant and at such a level that its
other patients, follows the doctor and gets into all kinds of display in strong affect is simply inevitable: for example,
mischief’. patients with a heightened sense of irritability may be hos-
Psychomotor retardation may range from an almost tile, argumentative, and uncontrollably angry, whereas other
total quietude and immobility to a mere slowing of speech patients whose irritability is not heightened might present
and behavior. Various conditions may underlie such a a picture of mere sullenness and withdrawal.
change. Mere exhaustion may slow patients down, but the Affect has been variously defined as representing either
response to rest is generally robust. Apathetic patients, the combination of the immediately present emotion and
lacking in motivation, may evidence little speech or behav- its accompanying expression in tone of voice, gesture,
ior; depressed patients may appear similar but here one facial expression, etc. or, less commonly, as only the emo-
also sees a depressed mood. In akinesia (Section 3.9) there tional expression itself. Although in general there is a con-
may also be a generalized slowing of all behavior; however, gruence between the experienced emotion and the facial
here one also fails to see a depressed mood. Abulia (Section expression, disparities may arise, as in ‘inappropriate affect’
4.10) is distinguished from akinesia by the response to (Section 4.26), sensory aprosodia (Section 2.7), emotional
supervision: in contrast with patients with apathy, depres- facial palsy (Section 4.8), and ‘emotional incontinence’ (as
sion, or akinesia, the abulic patient performs at a normal seen in pseudobulbar palsy [Section 4.7]). In each of these
rate when supervised. Delirium may be characterized by conditions patients report a substantial difference between
quietude and inactivity but is distinguished by the presence what they are feeling and what is ‘showing’ on their faces.
of confusion and deficits in memory and orientation. This is perhaps most dramatic in emotional incontinence
Catatonia of the stuporous type (Section 3.11) may be (or, as Wilson [1928] called it, ‘pathological laughing and
characterized by profound immobility; however, here one crying’), which is characterized by an uncontrollable affective
typically finds distinctive associated signs, such as waxy flex- display that occurs in the absence of any corresponding
ibility, posturing, and negativism. Finally, one should never feeling. Thus ‘incontinent’ of affective display, patients
forget hypothyroidism, wherein, as noted by Kraepelin may burst forth into laughter or tears upon the slightest of
(1899), it may take patients ‘an incredibly long time to do stimuli and be unable to control themselves despite the
the simplest things, to write a letter [or] to get dressed’. lack of any sense of mirth or sadness.
Other behavioral disturbances may occur during the Given that, as with mood, affect may be depressed,
interview and examination, including mannerisms, stereo- euphoric, anxious, or irritable it may appear academic to
typies, and echopraxia. Mannerisms represent more or less distinguish between the two; however, disparities between
bizarre transformations of speech, gesture, or other behav- mood and affect may arise. Mood is enduring, whereas
iors (Section 4.27). Stereotypies are a kind of perseveration affect is relatively changeable: in a sense, mood is to climate
p 01.qxd 3/10/08 9:33 AM Page 7
as affect is to weather. Thus, patients suffering from a the mental status examination, then a diagnosis of aphasia
depressed mood that has generally endured for weeks, of the ‘sensory’ type should be considered (Section 2.1).
months, or longer may at times during the day experience There has been much ink spilt on whether it is possible to
a normal, or near-normal affect, and in such cases if the reliably distinguish the incoherence seen in schizophrenia
physician depended solely on observation of the patient’s (known as ‘loosening of associations’) from that seen in
affect and did not inquire of the overall enduring mood an sensory aphasia; however, of the many articles written on
important clinical finding might be missed. this subject only two studies actually compared the speech
Affect, in addition to being depressed, euphoric, anx- of patients with schizophrenia with that of patients with
ious or irritable, may also be flattened or labile. Flattened sensory aphasia secondary to stroke (Faber et al. 1983;
(or ‘blunted’ as it is also known) affect is characterized by a Gerson et al. 1977), and the results, although promising,
lifeless and wooden facial expression, accompanied by an were not definitive. In general, patients with loosening of
absence or diminution of feeling. As such, it may be distin- associations spoke freely and at length and, although what
guished from motor aprosodia (Section 2.7), wherein they said made little sense, they had no trouble in finding
patients do in fact still experience feelings, although speaking words. By contrast, patients with aphasia often had at least
in a monotone as if they had no feelings. The ‘hypomimia’ some difficulty in finding words, and their responses to
seen in parkinsonian conditions, such as Parkinson’s disease questions were typically brief. Furthermore, whereas
or antipsychotic-induced parkinsonism, is distinguished in patients with loosening of associations had little or no
the same way: although these patients’ facial movements recognition of their incoherence, the aphasic patients often
are more or less frozen and devoid of expression they still seemed at least somewhat aware of their difficulty. It has
may have strong feelings. Some investigators believe flat- been this author’s experience that these differences,
tened affect is also present in severe depression; however, although often present, are not sufficiently reliable to make
in my experience there is little difficulty in distinguishing a the differential between loosening of associations and
flattened from a depressed affect. Flattened affect is found aphasia, and that it is much more useful to look for the
very commonly in schizophrenia (Andreasen et al. 1979); it presence of more or less bizarre delusions, which are typi-
may also occur in some secondary psychoses (Cornelius cally present in any patient with loosening of associations
et al. 1992) and, rarely, in dementia secondary to infarction but absent in those with aphasia.
of the mesencephalon or thalamus (Katz et al. 1987). Circumstantiality is said to be present when, perhaps in
Labile affect is characterized by swift, and sometimes response to a question, patients take the cognitive ‘long way
violent, changes in both felt and expressed emotion. round’, traversing superfluous details and dead-ended
Disturbances of mood are seen in a large number of con- digressions until finally getting around to the answer. In
ditions, as discussed in the chapters on depression, mania, listening to such patients, the interviewer often has to
and anxiety. Furthermore, it must be stressed that changes suppress the urge to tell them to ‘get to the point’.
in mood, and especially affect, are also very common in Tangentiality differs from circumstantiality in that the
dementia and delirium. This is particularly important to patient’s thought, although coherent, takes off on a ‘tan-
keep in mind, given that effective treatment of delirium typ- gent’ from the initial question, never in fact getting ‘to the
ically results in a normalization of affect without the need point’. Both of these signs are diagnostically non-specific
for treatment with antidepressants or other medications. but may be seen in the same conditions as incoherence.
Flight of ideas is, according to Kraepelin (1921), charac-
terized by a ‘sudden and abrupt jumping from one subject
Incoherence and allied disturbances to another’: before any given thought is fully developed,
the patient’s attention lights on another thought that is
Normally the thoughts we put into words are coherent, there to stay for only a short time before moving on yet
focused, and goal-directed: abnormalities here include again. This differs from incoherence in that, although
incoherence, circumstantiality and tangentiality, and flight incomplete, the development of the subject is coherent
of ideas. before the patient jumps to the next. Such a flight of ideas
Incoherent speech is characterized by a disconnected- is classic for mania.
ness and disorganization of words, phrases, and sentences
such that what the patient says, to a greater or lesser degree,
‘makes no sense’. Incoherence may be found in a number Other disturbances of thought or speech
of different syndromes, and it is the presence of other signs
and symptoms that alerts the clinician to which syndromal Poverty of thought is characterized by a dearth of thoughts:
diagnosis should be pursued: cognitive deficits indicate the such patients, lacking anything to say, speak very little. By
presence of dementia or delirium; heightened mood, pressure contrast, patients with poverty of speech may speak much.
of speech, and hyperactivity suggest mania; and bizarre Their speech, however, is ‘empty’, being filled with so
behavior, hallucinations, or delusions point to a psychosis, many stock phrases and repetitions that little is actually
such as schizophrenia. In cases characterized primarily by ‘said’. Both these disturbances may be found in schizo-
incoherence but with few, if any, other abnormalities on phrenia and in certain cases of aphasia.
p 01.qxd 3/10/08 9:33 AM Page 8
Thought blocking is characterized by an abrupt termi- just went out or that they are in the walls or that they speak
nation of speech, sometimes in the middle of a sentence, as through invisible apparatus’.
if the train of thought had suddenly been ‘blocked’. This is Certain auditory hallucinations are included among the
not a matter of simply running out of things to say, but Schneiderian first rank symptoms (Section 4.31), and
rather an uncanny experience wherein thoughts suddenly should routinely be sought. They include: audible thoughts
stop appearing. When present to a marked degree, this (i.e., hearing one’s own thoughts ‘out loud’, as if they were
experience is typically accompanied by one of the being spoken and as if others could also hear them), hear-
Schneiderian first rank delusions, namely ‘thought with- ing voices that comment on what the patients themselves
drawal’ (Section 4.31). are doing, and hearing voices that argue with one another.
Pressure of speech is experienced by the patient as an Although classically associated with psychosis, halluci-
‘urge to talk’ that is so imperious that, as described by nations are just as common in delirium and dementia.
Kraepelin (1899), ‘he cannot keep quiet for long, chatters
and shouts out loud, yells, roars, bawls, whistles [and]
speaks overhastily’. To be in the presence of such patients Delusions
is akin to standing in front of a dam bursting with words
and thoughts. Although classically seen in mania, such a A delusion, according to Lord Brain (1964), ‘is an erroneous
disturbance may also be seen in schizophrenia, schizo- belief which cannot be corrected by an appeal to reason
affective disorder, and, occasionally, in dementia. and is not shared by others of the patient’s education and
Perseveration of speech (Section 4.5) is said to be pres- station’. Thus, whereas for a Russian in the middle part of
ent when patients either supply the same answer to succes- the twentieth century to be convinced that the telephones
sive questions or merely, and without prompting, repeat were routinely ‘bugged’ would not, prima facie, be a delusion;
the same words or phrases over and over. This abnormality for a Canadian of the twenty-first century to be so convinced
is most commonly seen in dementia or delirium. Palilalia, would be suspect. Although at times it may be difficult to
sometimes confused with perseveration, is characterized decide whether or not a belief is delusional, it is in most
by an involuntary repetition of the last phrase or word of a cases quite obvious: for example, the belief that a small rep-
sentence, with these repetitions occurring with increasing tilian creature sits inside one’s external auditory canal and
rapidity, but diminishing distinctness (Section 4.4). inserts thoughts is simply not plausible in any culture.
Echolalia is characterized by an involuntary repetition Delusions are generally categorized according to their
by the patient of words or sentences spoken by others, and content or theme. Thus, there are delusions of persecution,
may be seen in a large number of disorders, such as demen- grandeur, erotic love, jealousy, sin, poverty, and reference.
tia, aphasia, catatonia, and Tourette’s syndrome. Delusions of reference are said to be present when patients
Obsessions are distinguished from normal thoughts by believe that otherwise unconnected events in some way or
the fact that they repeatedly and involuntarily come to other refer or pertain to them. Thus, patients with a delu-
mind despite the fact that the patient finds them unwanted sion of persecution who believed that they were under sur-
and distressing. veillance might, upon reading a newspaper article about
undercover police, hold that the article, in fact, was a kind
of ‘warning’ or ‘message’ that they could not escape.
Hallucinations Certain delusions are also counted among the
Schneiderian first rank symptoms, and these include
Patients are said to be hallucinated when they experience beliefs that one is directly controlled or influenced by out-
something in the absence of any corresponding actual side forces, that thoughts can be withdrawn, or alterna-
object; such hallucinations may occur in the visual, audi- tively inserted, and that thoughts are being ‘broadcast’
tory, tactile, olfactory, or gustatory sphere. Thus, a patient such that they can be ‘picked up’ and known by others.
who ‘saw’ a group of people or who ‘heard’ people mur- Delusions, like hallucinations, may be seen not only in
muring in the next room when the room was in fact empty psychosis, but also in delirium or dementia.
and silent would be considered hallucinated. Hallucinated
patients may or may not retain ‘insight’: that is to say, they
may or may not recognize that their experience is not ‘real’. Other disturbances of thought content
For example, whereas one patient might say, ‘I hear some
people next door, but I know that it’s just my imagination Phobias are fears that patients admit are irrational. Seen
and they’re not really there’, another might be surprised to in the condition known as specific phobia (Section 20.12),
hear that the physician did not hear them also. In cases they may occasionally manifest during the interview, as, for
where insight is lacking, it is generally useless to disagree example, in claustrophobia when the patient may object to
with patients or try and ‘talk them out of it’. As Bleuler the door being closed.
(1924) pointed out, ‘it is of no avail to try to convince the Depersonalization is characterized by an uncanny sense
patient by his own observation that there is no one in the of detachment on the patient’s part from what is currently
next room talking to him; his ready reply is that the talkers going on. Patients may complain of feeling detached, as if
p 01.qxd 3/10/08 9:33 AM Page 9
they weren’t ‘there’, and, although doing things, were some- are oriented perfectly in all these three spheres then one
how removed and observing. As discussed in Section 4.16, may simply note ‘oriented times three’ in the chart. If they
this may occur not only in ‘depersonalization disorder’, are not, it is critical to note their exact responses: simply
but also in other conditions such as epilepsy. noting ‘oriented times two’ fails to capture important infor-
Compulsions are characterized by irrational and over- mation, including, as it does, the patient who believes it is
whelming urges to do things; obsessions are thoughts that 1948 and the patient who is off the date by only a few days.
come to mind involuntarily and do so repeatedly despite In cases when patients are disoriented, it is appropriate
patients’ attempts to stop them. Discussed further in to subsequently, and gently, state the correct orientation.
Section 4.17, these phenomena may occasionally be evi- This not only ensures that they have been told the correct
dent during the interview, as, for example, with a compul- orientation at least once, but also opens the door to the iden-
sion to arrange things ‘just so’ on the desk or bedside table tification of the rare syndrome of reduplicative paramnesia
or with the obsessive recurrence of a fragment of a song. (Section 4.18) (also known as ‘delusional disorientation’)
wherein, for example, patients may correctly identify the
name of the hospital but insist that the hospital is in a
Level of consciousness distant city.
Some authors also recommend checking orientation in
Note should be made of whether or not patients are alert. If a ‘fourth’ sphere, namely orientation to situation. This is
not, attempts should be made to arouse them, ranging from typically determined during the non-directive portion of
calling the patient’s name, to shaking the shoulder, to, if the interview, when it becomes clear whether or not
necessary, painful stimuli, such as a sternal rub. The response patients recognize that they are ill, and in a hospital for
to these maneuvers should be noted. Terms such as ‘stu- treatment, etc. It is akin to ‘insight’ (discussed later in this
por’, ‘torpor’, or ‘obtundation’ are best avoided as they are chapter) and is probably appropriate.
used differently by different authors. Disorientation may be seen in delirium, dementia,
amnesia, and psychosis.
Presence or absence of confusion

Memory
Confused patients may appear to be in a daze, and some
may report feeling ‘fuzzy’ or ‘cloudy’: they have difficulty Memory is discussed in detail in Section 5.4 and, as noted
ordering their own thoughts and a similar difficulty in there, the most important type of memory from a clinical
attending to events around them. An evocative synonym point of view is memory for events and facts, and it is this
for confusion is ‘clouding of the sensorium’. This is a par- that is tested in the mental status examination.
ticularly important clinical finding given that the differen- Traditionally, three aspects of memory are tested: imme-
tial diagnosis between delirium and dementia rests, in large diate, short-term, and long-term memory. Immediate recall
part, on its presence or absence. is tested by using ‘digit span’. Here, the patient is given a
list of random digits, slowly, one second at a time, and then
immediately asked to recall them forwards, from first to
Orientation last. One starts with a list of three digits, and if the patient
recalls these correctly, moves to a list four digits long, pro-
Orientation is traditionally assessed for three ‘spheres’ – ceeding to ever longer lists until the patient either errs in
person, place and time – and patients who can properly recall or reaches seven digits; normal individuals can recall
place themselves in each sphere are said to be ‘oriented lists of five to seven digits in length. Once this has been
times three’. Orientation to person may be determined by accomplished, ‘backward’ digit recall is checked by giving a
asking patients for their full names; such orientation is list two digits long and immediately asking the patient to
only very rarely lost. Orientation to place is checked by ask- recall them in reverse order. If this is done correctly one
ing patients to identify where they are, including the name proceeds to longer lists, again until errors are made or the
of the city and of the building. In cases where patients hes- patient performs within the normal range of spans of three
itate to answer, perhaps because they are unsure, it is to five digits.
important to encourage them to take a guess. Should they Short-term recall is tested by telling the patient that you
misidentify the building, inquire further as to what kind of will give a list of three words and that you would like him
building it is. Some patients may betray a degree of con- or her to memorize them because in a few minutes you will
creteness here, for example, by replying ‘a brick building’ ask that they be recalled. Three unrelated words are then
and, if they do, gently press further by offering some provided (e.g., ‘rock, car, pencil’) and the patient is asked
choices, for example, ‘a hotel, hospital or office building’, to repeat them once to make sure that he or she ‘has’ them.
and ask them to choose one. Orientation to time is deter- Once it is clear that the patient ‘has’ them, wait 5 minutes
mined by asking patients the date, including the day of the and then ask the patient to recall them. Importantly, dur-
week, the month, day of the month, and year. If patients ing this 5-minute interval, the interviewer should stick to
p 01.qxd 3/10/08 9:33 AM Page 10
neutral topics (e.g., some innocuous ‘review of systems’ a theatre?’. In many instances, however, it is appropriate to
questions) and avoid any emotionally laden subjects that pose situations more relevant to the patients’ lives; thus,
might upset the patient. Normally, all three words are one might ask a police officer what should be done if a sus-
recalled. pect refused to answer questions.
Long-term memory should be checked both for per- Insight, for the purposes of the mental status examina-
sonal and public events. This is often assessed informally tion, refers not to some sophisticated appraisal of one’s sit-
during the non-directive portion of the interview as one uation, but rather, simply, to whether or not patients
ascertains whether the patient recalls what happened in the recognize that they are ill or that something is wrong. This
days leading up to admission, during recent holidays, or is identical to ‘orientation to situation’ as discussed earlier
recalls where he or she worked/went to school. Recall of in this chapter and, if already noted, no further comment is
public events may be checked by asking about recent news- required.
worthy events or, in a somewhat more quantitative way, by Judgment or insight may be lost in delirium, dementia,
asking the patient to recall the names of the last four prime or a personality change such as frontal lobe syndrome.
ministers or presidents. Insight may also be lost when anosognosia (Section 2.9) is
Deficits in immediate recall are typically accompanied present, as, for example, when a patient with hemiplegia is
by confusion and generally indicate a delirium. In addition unable to recognize the deficit.
to delirium, deficits in short- and long-term memory may
also be seen in dementia and amnesia. In some cases, either
during testing for long-term memory or during the inter- 1.3 NEUROLOGIC EXAMINATION
view, one may find evidence of confabulation (Section 4.19),
wherein the answers that patients provide are clearly false. Bleuler (1924), in his classic Textbook of Psychiatry, insisted
that ‘a minute physical and especially neurological examina-
tion must not be omitted’ (italics in original) and the
Abstracting ability reader is urged to take this admonition to heart.
Over the decades, the neurologic examination has
Abstracting ability is traditionally assessed by asking patients ‘thinned down’ somewhat and of the dozens of abnormal
to interpret a proverb, such as ‘Don’t cry over spilled milk’. reflexes that used to be de rigeur only a few survive today.
Responses to proverb testing may be ‘abstract’ or ‘concrete’, The scheme presented here constitutes a ‘middle-of-the-
as, for example, if a patient replied, ‘Well, it’s already spilled.’ road’ approach and, although it may be found skimpy by
At times, the abnormality on proverb interpretation will some, others may consider it overly detailed. I plead guilty
consist of a bizarre response instead of a concrete reply, such on both accounts, but urge the reader to try this approach
as ‘Alien milk has no taste’. Concrete responses may be and then to reshape it in light of future experience and
seen in delirium or dementia and typically indicate frontal wide reading. Although, in most cases, the examination
lobe dysfunction. Bizarre responses suggest a psychosis, may be conducted in the order suggested here, flexibility
such as schizophrenia. must be maintained, especially with fatigued, agitated, or
uncooperative patients. Bear in mind that even with a
completely uncooperative patient, much may be gathered
Calculating ability by a simple observation of eye and facial movements,
speech, movement of the extremities, gait, etc.
Calculating ability is traditionally assessed with the ‘serial For most findings, further detail on, and a consider-
sevens’ test, wherein patients are asked to subtract seven ation of, the differential diagnosis of the finding may be
from 100, then seven from that number, and are then found in the appropriate chapter, as noted below.
asked to keep on subtracting seven until they can go no
further. Fewer than one-half of normal individuals are able
to do this perfectly, most making two or three errors General appearance
(Smith 1962). In cases in which patients are unable to do
serial sevens at all, it is appropriate to ask them to attempt In some cases, the overall appearance of the patient may
simpler mathematical tasks, such as adding four plus five, immediately suggest a possible diagnosis. Examples
or subtracting eight from 12. As discussed in Section 2.4, include the moon facies of Cushing’s syndrome (Haskett
deficits in calculating ability may occur in a number of 1985; Spillane 1951), the puffy facial myxedema and thin-
conditions, including dementia and delirium. ning hair of hypothyroidism (Akelaitis 1936; Nickel and
Frame 1958) and the massive obesity of the Bardet–Biedl
and Prader–Willi syndromes (Rathmell and Burns 1938;
Judgment and insight Robinson et al. 1992) or the Pickwickian syndrome (Meyer
et al. 1961).
Judgment has traditionally been assessed with test ques- Facial appearance, including facial dysmorphisms, may
tions such as ‘What would you do if you smelled smoke in also be diagnostically suggestive (Wiedemann et al. 1989),
p 01.qxd 3/10/08 9:33 AM Page 11
as, for example, the port wine stain of Sturge–Weber syn- available at the bedside, such as toothpaste. There are also
drome, the adenoma sebaceum of tuberous sclerosis or commercially available tests of the ‘scratch and sniff’ vari-
the high forehead, large ears, and prognathism of fragile X ety, which, although much more detailed, have not as yet
syndrome. found a place in routine clinical practice. Unilateral anos-
mia may occur secondary to compression of the olfactory
bulb or tract by a tumor, such as a meningioma of the olfac-
Handedness tory groove; bilateral anosmia may be seen in neurodegen-
erative diseases, such as Alzheimer’s or Parkinson’s disease
Inquire as to handedness and observe as patients handle (Mesholam et al. 1998), and may also be seen after head
implements such as a pen; if there is doubt, ask which hand trauma, with rupture of the olfactory filaments as they pass
the patient uses to throw a ball or which foot is used to through the cribriform plate.
kick with.
CRANIAL NERVE II
Pupils The optic nerve is tested not only for acuity, but also for
visual fields. Visual acuity may be informally tested by ask-
The pupils are normally round in shape, regular in outline ing the patient to read text from a newspaper or, more for-
and centered in the iris. Their diameter should be mea- mally, by use of a Snellen chart. If the patient has glasses or
sured and their reactions to light and to accommodation contact lenses, vision should be tested both with and with-
should be noted. The pupillary reaction to light is tested out them. The visual fields may be assessed by confronta-
first by shining a penlight into one eye and observing the tion testing: while facing each other, the physician and
reaction, not only of that pupil but also in terms of the con- patient are separated by about a meter, each fixing vision on
sensual reaction in the opposite pupil. After a short wait, the other’s nose; the physician then brings a small object
the other eye should be tested in the same fashion. The (e.g., the tip of a reflex hammer) in from outside the patient’s
accommodation or convergence reaction is then tested by peripheral field, instructing the patient to say ‘yes’ as soon
asking the patient to focus on the examiner’s finger as it is as it comes into view, and bringing the target in not only
slowly moved along the midline toward a spot midway from either side, but also from above and below. Impor-
between the patient’s eyes: normally, as the eyes converge, tantly, in cases where the patient fails to respond to an
both pupils undergo constriction. A preserved reaction to object in one hemi-field, one must consider not only the
accommodation in the face of an absent or sluggish reac- possibility of an hemianopia, but also the possibility of left
tion to light is known as an Argyll Robertson pupil and is visual neglect (see Neglect, p. 16).
very suggestive of neurosyphilis.
While examining the pupils, the corneal limbus should
also be examined for a Kayser–Fleischer ring, as seen in CRANIAL NERVES III, IV, AND VI
Wilson’s disease. This is a golden brown discoloration of The oculomotor, trochlear, and abducens nerves are tested
the limbus, which typically begins at the 12- and 6 o’clock by having the patient follow the physician’s finger as it
regions from where it gradually expands medially and lat- moves to either side and both upward and downward
erally to eventually form a ring around the cornea. while the patient’s head is kept stationary. Eye movements
should be full and conjugate in all directions of gaze, and
without nystagmus. The oculomotor nerve also innervates
Funduscopic examination the upper eyelid; thus, the presence or absence of ptosis
should be noted. In cases where there is limitation of vol-
After examining the optic fundus for any hemorrhages or
untary up-gaze, or, more importantly, down-gaze, one
exudates, attention should be turned to the optic disk, which
should further test the patient with the ‘doll’s eyes’ maneu-
should be flat and sharply demarcated from the surround-
ver to determine if the vertical gaze palsy is either
ing fundus. The depth of the optic cup should be noted, as
supranuclear, nuclear, or infranuclear. To perform this
should the presence or absence of venous pulsations.
first lightly grasp the patient’s head and then flex and
extend it at the neck, watching how the eyes move. If eye
Cranial nerves movements are full then the lesion responsible for the vol-
untary vertical gaze palsy is supranuclear, as may be seen in
CRANIAL NERVE I disorders such as progressive supranuclear palsy.
The olfactory nerve is tested by first occluding one nostril CRANIAL NERVE V
and then bringing an aromatic substance, such as ‘a little
powdered coffee’ (Brain 1964), to the patent’s nostril, The trigeminal nerve has both motor and sensory compo-
inquiring as to whether any odor is appreciated, and if nents. Masseter muscle strength is checked by lightly plac-
so, what it is. In a pinch one may use a substance readily ing one’s fingers on the patient’s cheeks and then
p 01.qxd 3/10/08 9:33 AM Page 12
instructing the patient to bite down. Sensory testing, to Rinne testing, air conduction is better than bone conduc-
both light touch and pin-prick, is checked in all three divi- tion bilaterally.
sions, namely the ophthalmic, maxillary, and mandibular.
The corneal reflex, which tests both the cranial nerves V CRANIAL NERVES IX AND X
and VII, may also be performed by lightly touching a wisp
of cotton to the patient’s cornea, after which there should The glossopharyngeal and vagus nerves are tested with the
be a bilateral blink. gag reflex and by observation for symmetric elevation of
the palate during phonation.
CRANIAL NERVE VII
CRANIAL NERVE XI
The facial nerve is first tested for voluntary facial move-
ments by asking the patient to wrinkle the forehead and The spinal accessory nerve is tested by having patients shrug
subsequently to show the teeth. In cases of unilateral vol- their shoulders against the resistance of the physician’s
untary facial paresis note must be made of which divisions hand and by turning the head to one side or the other while
of the facial nerve are involved: the upper (controlling the physician exerts contrary pressure on the jaw.
forehead wrinkling), the lower (controlling elevation of the
side of the mouth), or both. At times facial weakness may CRANIAL NERVE XII
be quite subtle, manifesting perhaps only with a slight flat-
tening of the nasolabial fold on one side. The hypoglossal nerve is tested first by asking the patient to
After voluntary movements have been tested, the physi- open the mouth and then observing the tongue, as it rests
cian must then test for involuntary or ‘mimetic’ facial in the oropharynx, for any atrophy or fasciculations. Once
movements. This may be accomplished by telling a joke, this has been accomplished, the patient is asked to protrude
or, if the physician is in less than a humorous mood, by the tongue as far as possible, noting especially whether it
simply observing the patient for any spontaneous smiling. protrudes past the lips and also whether it deviates to one
Voluntary and involuntary facial movements are quite dis- side or the other.
tinct neuroanatomically and thus both should be tested for
(Hopf et al. 1992). Voluntary facial palsy affecting only the
lower division indicates a lesion of the pre-central gyrus or Sensory testing
corticobulbar fibers, whereas emotional facial palsy (Section
4.8) indicates a lesion in the supplementary motor area, Elementary sensory testing involves light touch, pin-prick,
temporal lobe, striatum, or pons. and vibration. Light touch may be assessed by using a wisp
of cotton, or simply by a light touch with one’s finger, and
CRANIAL NERVE VIII pin-prick sensation is tested using a disposable safety pin.
Vibratory sensation is tested by touching a vibrating tun-
The vestibulocochlear nerve is generally tested by gently ing fork to a bony structure (such as a finger joint, the lat-
rubbing the fingers together about 30 cm from the patient’s eral malleolus, or the great toe) and asking the patient
ear and asking whether anything is heard; alternatively, whether he or she can tell if it is vibrating; if so, the tuning
one may bring a ticking watch in from a distance and ask fork is held in place and the patient is asked to say when the
the patient to indicate when it is first heard. If there are any vibration ceases, with the physician taking note, in a rough
abnormalities, both Weber and Rinne testing should be sort of way, of how much the tuning fork is still vibrating at
performed to determine whether the hearing loss is of the that point. If there are any abnormalities in elementary
conduction or sensorineural type. sensation it is critical to determine whether or not they
In the Weber test, a vibrating tuning fork is placed are bilateral. In general, it is sufficient to test sensation
square on the midline of the patient’s forehead and the at both hands and both feet, reserving more detailed test-
patient is asked whether it sounds the same on both sides ing for cases in which the history suggests a more focal
or is heard louder on one side than on the other. In the sensory loss.
Rinne test, a vibrating tuning fork is placed against the sty- Graphesthesia and two-point discrimination tests also
loid process and the patient is asked to indicate when the constitute part of the sensory examination but these
sound vanishes, at which point the tines of the tuning fork should only be used if elementary sensation is intact.
are immediately brought in close approximation to the ear Agraphesthesia is said to be present when patients, with
and the patient is asked whether it can now be heard. With their eyes closed, are unable to identify letters or numerals
conductive hearing loss, the Weber lateralizes to the side traced on their palms by a pencil or dull pin. Two-point
with the hearing loss, and on Rinne testing, bone conduc- discrimination may be tested by ‘bending a paperclip to
tion (i.e., with the tuning fork against the styloid process) different distances between its two points . . . [starting]
is louder than air conduction (i.e., with the tines of the fork with the points relatively far apart . . . [then] approximated
vibrating in the air just outside the ear). With sensorineu- until the patient begins to make errors’ (Dejong 1979). As
ronal loss, the Weber lateralizes to the ‘good’ side and, on two-point discriminatory ability varies on different parts
p 01.qxd 3/10/08 9:33 AM Page 13
of the body (from 2 to 4 mm at the fingertips to 20–30 mm If they are comfortable with these instructions then the test
on the dorsum of the hand), what is most important here is can be carried out, observing the patients for perhaps half a
to compare both sides to look for a difference. minute to see whether or not any swaying develops once
Agraphesthesia and diminished two-point discrimina- the eyes are closed. A ‘positive’ Romberg test indicates a
tion suggest a lesion in the parietal cortex; elementary sen- loss of position sense, as may be seen with a peripheral
sory loss, especially to pin-prick, is also seen with parietal neuropathy or damage to the posterior columns.
cortex lesions but in addition may occur with lesions of the Gait is tested by asking the patient to walk a straight
thalamus, brainstem, cord, or of the peripheral nerves. line down a hall, then walking ‘heel to toe’ in a tandem
walk, and, finally, if these are done adequately, by
asking the patient to walk ‘on the outside of your feet, like
Cerebellar testing a “cowboy”’.
An ataxic gait, seen in cerebellar disorders, is wide based
In addition to observing the patient’s gait for ataxia, as dis- and staggering: steps are irregular in length, the feet are
cussed below, cerebellar testing also involves finger-to- often raised high and brought down with force, and the
nose and heel-to-knee-to-shin testing, testing for rapid overall course is zigzagging. In a ‘magnetic’ gait, as seen in
alternating movements and observing for dysarthria. hydrocephalus or bilateral frontal lesions, the feet seem
In the finger-to-nose test, patients are instructed to stuck to the floor as if magnetized or glued to it. In a step-
keep their eyes open, extend the arm with the index finger page gait, seen in peripheral neuropathies, the normal dorsi-
outstretched, and then to touch the nose with the index flexion of the feet with walking is lost and patients raise
finger. In the heel-to-knee-to-shin test, patients, while their feet high to avoid tripping on their toes. In a spastic
seated or recumbent, are asked to bring the heel into con- gait, seen with hemiplegic patients, the affected lower
tact with the opposite knee and then to run that heel down extremity is rigid in extension and the foot is plantar
the shin below the knee. In both tests one observes for evi- flexed: with each step, the leg is circumducted around and
dence of dysmetria (as, for example, when the nose is the front of the foot is often scraped along the floor. In very
missed in the finger-to-nose test) and for intention tremor, mild cases of hemiplegia, the gait, to casual inspection, may
wherein, for example, there is an oscillation of the finger not be abnormal; however, when patients walk ‘on the out-
and hand as it approaches the target (in this case the nose, side’ of their feet, one often sees dystonic posturing of the
with this tremor worsening as the finger is brought pro- upper extremity on the involved side. Parkinsonian gait is
gressively closer to the nose). described in Abnormal movements, p. 14.
Rapid alternating movements also assess cerebellar func-
tion. Here, while seated, patients are asked to pronate the
hand and gently slap an underlying surface (e.g., a tabletop Strength
or the patient’s own thigh) and then supinate the same hand
and again gently slap the underlying surface. Once they Strength may, according to Brain (1964), be graded as
have the hang of it, patients are then asked to repeat these follows: 0, no contraction; 1⫹, a flicker or trace of move-
movements as quickly and carefully as possible. Decompo- ment; 2⫹, active movement providing that gravity is elim-
sition of this movement, known as dysdiadochokinesia, if inated; 3⫹, active movement against gravity; 4⫹, active
present, is generally readily apparent on this test. movement against some resistance; and 5⫹, full strength.
Dysarthria may also represent cerebellar dysfunction In the process of assessing muscular strength one should
and may be casually assessed by simply listening carefully also observe for any atrophy, fasciculations, or myotonia.
to the patient’s spontaneous speech, noting any evidence of Myotonia is sometimes apparent in a handshake, as
slurring. In doubtful cases one may ask the patient to patients may have trouble relaxing their grip, and may also
repeat a test phrase, such as ‘Methodist Episcopal’ or ‘Third be assessed by using a reflex hammer to lightly tap a mus-
Riding Artillery Brigade’ (DeJong 1979). Importantly, cle belly, such as at the thenar eminence, and watching for
dysarthria may also be seen with lesions of the motor cor- distinctive myotonic dimpling.
tex or associated subcortical structures. Common patterns of weakness include monoparesis, if
only one limb is involved, hemiparesis if both limbs on one
side are weak, paraparesis if both lower extremities are
Station, gait, and the Romberg test weak, and quadriparesis (or, alternatively, tetraparesis), if
all four extremities are weakened. In cases when strength ⫽ 0
Station is assessed by asking patients to stand with their then one speaks not of paresis but of paralysis, and uses the
feet normally spaced, and observing for any sway or loss of terms monoplegia, hemiplegia, paraplegia, or quadri-
balance. At this point, if station is adequate, one should plegia. When weakness is present, note should be made
perform the Romberg test by telling patients that you will whether the proximal or distal portions of the limb are pri-
ask them to put their feet close together, as if ‘at attention’, marily involved; in cases of hemiparesis in which both
and then to close their eyes, reassuring them that you will limbs are not equally affected, the limb that is more
have your hands close by and that you will not let them fall. affected should be noted.
p 01.qxd 3/10/08 9:33 AM Page 14
Drift patient carries out an intended action, as, for example,

touching the index finger to the nose. Other forms are also
A positive pronator drift test may be the first evidence of possible, for example, Holmes’ tremor, which has both
hemiparesis. This test, according to DeJong (1979), is postural and intention elements. Tremor is further char-
accomplished by asking patients (with their eyes closed) to acterized in terms of amplitude (from fine to coarse) and
fully extend their upper extremities, palms up, and then frequency (ranging from slow [3–5 cps] to medium
maintain that position: a positive test consists of ‘slow [6–10 cps] to rapid [11–20 cycles per second, cps]).
pronation of the wrist, slight flexion of the elbow and fin- Myoclonus (Section 3.2) consists of ‘a shock-like mus-
gers, and a downward and lateral drift of the hand’. cular contraction’ (Brain 1964) and may be focal, segmen-
tal, or generalized, occurring either spontaneously in
response to some sudden stimulus (e.g., a loud noise) or as
Rigidity ‘intention’ or ‘action’ myoclonus that appears upon inten-
tional movement. This is an especially valuable sign and
Rigidity should, at a minimum, be assessed at the elbows, the physician should remain alert to its occurrence
wrists, and knees by passive flexion and extension at the throughout the interview and examination.
joint, with close attention to the appearance of spastic, lead Motor tics (Section 3.3) are sudden involuntary move-
pipe, or cogwheel rigidity. Spastic rigidity, seen with upper ments that, importantly, resemble purposeful movements,
motor neuron lesions, is most noticeable on attempted such as shoulder shrugs, facial grimaces, or head jerks.
extension of the upper extremity at the elbow and Unlike myoclonus, tics involve ‘a number of muscles in
attempted flexion of the lower extremity at the knee. their normal synergic relationships’ (Brain 1964).
Furthermore, in spasticity, one may see the ‘clasp knife’ Chorea (Section 3.4), according to Brain (1964), is
phenomenon. Here, on attempted rapid extension of the characterized by ‘quasi-purposive, jerky, irregular, and
upper extremity at the elbow, an initial period of minimal non-repetitive’ movements that are very brief in duration,
resistance is quickly followed by a ‘catch’ of increased generally erupting randomly on different parts of the body.
resistance, which, in turn, is eventually followed by a loos- Athetosis (Section 3.5) ‘consists of slow, writhing move-
ening, with the whole experience reminiscent of what it ments’ (Brain 1964) that are generally most evident in the
feels like to open the blade on clasp knife. Lead pipe rigid- distal portions of a limb; they are persistent and seem to
ity, seen in parkinsonism, is, in contrast with spastic rigid- flow into one another in a serpentine fashion.
ity, characterized by a more or less constant degree of Ballismus (Section 3.6), which is generally unilateral,
rigidity throughout the entire range of motion, much as if consists of ‘wild flaillike, writhing, twisting or rolling move-
one were manipulating a thick piece of solder. Cogwheel ments that may be intense and may lead to exhaustion’
rigidity, also seen in parkinsonism, may accompany lead (DeJong 1979). In severe cases the flinging movements of
pipe rigidity or occur independently. This is best appreci- the extremity may actually throw the patient off the chair
ated by gently holding the patient’s elbow in the cup of or bed.
your hand while pressing down on the patient’s biceps ten- Dystonia (Section 3.7), in contrast with ballismus, con-
don with your thumb. Once the arm is thus supported, sists of slow and sustained movements that variously twist
with your other hand gradually extend the arm. When cog- or contort the involved body part. It may be focal (e.g.,
wheeling is present, a ‘ratcheting’ motion will be appreci- moving the head to one side or ‘cramping’ the hand), seg-
ated with your thumb, much as if there were a ‘cogwheel’ mental (e.g., spreading to an adjacent body part, as with
inside the joint. the head turning and the shoulder elevating), or general-
After testing for these forms of rigidity, one should then ized (e.g., in severe cases, creating a human ‘pretzel’).
test for gegenhalten at the elbow by repeatedly extending Parkinsonism (Section 3.8), when fully developed,
and flexing the arm, feeling carefully for any increasing stamps patients with a distinctive clinical picture. A flexion
rigidity. Evidence for this generally indicates frontal lobe posture is evident, with the patient being stooped over with
damage. the arms and legs held in flexion, and a rhythmic ‘pill-rolling’
rest tremor of the hands may be seen, especially with the
hands resting on the lap. The face is often ‘masked’ and
Abnormal movements expressionless, and bradykinesia is evident in the slowness
with which all movements are executed. Gait is shuffling
Tremor (Section 3.1) is generally of one of three types: rest, and one may also see festination wherein the patient seems
postural, or intention. Rest tremor is most noticeable when to hurry ‘with small steps in a bent attitude, as if trying to
the extremity is at rest, as for example when the patient is catch up [with] his center of gravity’ (Brain 1964).
seated with the hands resting in the lap. Postural tremor Akathisia (Section 3.10) is typified by an inability to
becomes evident when a posture is maintained, as, for keep still. If standing, patients may rock back and forth or
example, when the arms are held straight out in front with ‘march in place’ and, if seated, there may be a restless
the fingers extended and spread. Intention tremor (as fidgeting, with crossing and uncrossing of the arms or legs.
described in Cerebellar testing, p. 13) appears when the In severe cases, the compulsion to move is irresistible, and
p 01.qxd 3/10/08 9:33 AM Page 15
patients may constantly pace back and forth. Characteristi- by lightly dragging a blunt object across the sole of the
cally, the restlessness is worse when lying down or seated, patient’s foot: beginning at the heel, proceeding along the
and most patients find some relief upon standing or mov- lateral aspect of the sole and then turning medially to cross
ing about. under the ball of the foot. One then observes for the ‘plan-
Catatonia (Section 3.11) of the stuporous type (Barnes tar response’ of the toes, noting whether it is ‘flexor’ or
et al. 1986) is characterized by varying degrees of immobility, ‘extensor’. The normal response is ‘flexor’, wherein the
mutism, and a remarkable phenomenon known as waxy toes undergo flexion. An ‘extensor’ response is considered
flexibility (or catalepsy), wherein, as noted by Kraepelin abnormal and constitutes the Babinski sign, which, when
(1899), the limbs, after being passively placed in any posi- fully present, consists of dorsiflexion of the great toe and
tion, ‘retain this position until they receive another impetus fanning of the rest. The presence of the Babinski sign is a
or until they follow the law of gravity as a result of extreme reliable indicator of damage to the corticospinal tract.
muscular fatigue’.
Asterixis (Section 3.12) (Leavitt and Tyler 1964) is tested
for by having patients hold their upper limbs in full exten- Primitive reflexes
sion, with the hands being held in hyperextension: asterixis,
if present, appears as a precipitous loss of muscle tone, Certain reflexes present in infancy or early childhood nor-
such that the hands ‘flap’ down. When present, this may mally disappear. When these reappear in adult years they
appear immediately and recur frequently, or may be are known as ‘primitive reflexes’ (Section 4.6) and may
delayed for up to half a minute. indicate frontal lobe disease.
Heightened startle response (Section 3.14) (Saenz-Lope The palmomental reflex is tested for by repeatedly and
et al. 1984) is often precipitated by a sudden loud noise and rapidly dragging an object, such as the tip of a reflex ham-
may go beyond being simply excessively ‘jumpy’; some mer, across the thenar eminence: when the reflex is pres-
patients may actually be thrown to the ground during the ent, one sees ‘a wrinkling of the skin of the chin and slight
startle. retraction and sometimes elevation of the angle of the
mouth’ (DeJong 1979).
The snout reflex is said to be present when gentle tap-
Deep tendon reflexes ping or pressure just above the patient’s upper lip, in the
midline, is followed by a puckering or protrusion of the
At a minimum, the following deep tendon reflexes should
lips; in advanced cases, the reflex may be elicited by merely
be tested: biceps jerk, triceps jerk, supinator jerk, knee jerk,
‘sweeping a tongue blade briskly across the upper lip’
and ankle jerk (Brain 1964). The results may, according to
(DeJong 1979).
DeJong (1979), be graded as 0 for absent, ⫹ for present but
The grasp reflex may be elicited by laying one’s finger
diminished, ⫹⫹ for normal, ⫹⫹⫹ for increased, and
across the patient’s palm such that it may be readily dragged
⫹⫹⫹⫹ for markedly hyperactive. Hyperactive deep ten-
out between the patient’s thumb and index finger. If the
don reflexes may also be accompanied by ankle clonus.
reflex is present, the patient’s fingers will grasp the physi-
Testing for clonus is accomplished by placing your hand
cian’s finger as it is slowly dragged across the palm (Walshe
under the ball of the patient’s foot and then briskly dorsi-
and Robertson 1933).
flexing the foot. When clonus is present, the foot will then
The grope reflex may be elicited by simply lightly touch-
briskly and spontaneously undergo plantar flexion.
ing the patient’s hand with one’s finger: when present, the
Keeping a light upward pressure on the ball of the foot may
patient’s hand will automatically make groping move-
precipitate repetitive clonic jerking, and in some cases this
ments until the physician’s finger is found and grasped
may be self-perpetuating or ‘sustained’.
(Seyffarth and Denny-Brown 1948).
In those cases in which patients remain so tense that
their reflexes cannot be elicited, several maneuvers may
render the examination possible (Bickerstaff 1980): for the
Aphasia and mutism
upper limbs, the patient should clench his teeth tightly or
while one arm is being examined he should clench the fist
Aphasia represents a disturbance in the comprehension
of the other. For the lower limbs these measures can still be
and/or production of spoken language. Testing involves
used but the well-tried method of Jendressak is more reli-
listening to the patient’s spontaneous speech, giving simple
able; the patient interlocks the flexed fingers of the two
spoken commands, and determining whether the patient
hands and pulls one against the other at the moment the
understands them, and asking the patient to repeat a test
reflex is stimulated.
phrase, such as ‘No ifs, ands, or buts’.
As discussed in detail in Section 2.1, there are three
Babinski sign basic forms of aphasia: motor (also known as expressive or
Broca’s), sensory (also known as receptive or Wernicke’s),
The Babinski sign, considered by DeJong (1979) as ‘the and global. In motor aphasia, patients are able to follow
most important sign in clinical neurology’, may be elicited commands, although their speech, despite being coherent,
p 01.qxd 3/10/08 9:33 AM Page 16
is effortful, sparse, and often ‘telegraphic’, (i.e., lacking in mime, by providing the implement and asking the patient
prepositions and conjunctions). In sensory aphasia, in con- to make use of it. In ideational apraxia, both miming and
trast, patients have a greater or lesser degree of difficulty in actual use are defective, whereas with ideomotor apraxia
following oral commands, especially complex ones; fur- the patient, although unable to mime, has no trouble cor-
thermore, speech is quite fluent, even voluble, rather than rectly employing the actual implement.
being effortful: however, there is a greater or lesser degree Constructional apraxia is tested for by asking the patient
of incoherence such that what the patient says makes ‘no to draw a simple figure, such as a ‘stick person’, or to copy
sense’. Finally, the global type of aphasia represents a com- a geometric design (DeJong 1979) such as a cube.
bination of these two: patients have trouble following com- Dressing apraxia is casually assessed by observing the
mands, speech is effortful and sparse, and what the patient patient put on clothing: when present, patients may put
says is more or less incoherent. their arms in the wrong sleeve or perhaps attempt to put
Each of these three types may also occur as a ‘trans- their shirt on backwards (Hecaen et al. 1956).
cortical’ variant, and this is said to be present when
patients are able to repeat a test phrase accurately and
without effort. Other variants, less common, are also pos- Agnosias
sible and these are discussed Section 2.1.
Mutism (Section 4.1) is said to be present when there is Agnosia, as discussed in Section 2.9 exists in various forms: for
no speech. example, visual agnosia, tactile agnosia, and anosognosia. In
each form, despite the fact that relevant elementary sensory
abilities are intact there is an inability to recognize things.
Alexia and agraphia Visual agnosia, or the inability to recognize an object by
sight, is tested by pointing to a common object, such as a
Alexia (Section 2.2) and agraphia (Section 2.3) represent, comb, and asking patients not only to name it, but also to
respectively, difficulties in reading and writing, and although describe its use.
often seen in combination with aphasia, may also appear in Tactile agnosia represents an inability to recognize an
pure form. Testing is accomplished simply by asking the object by touch: with the eyes closed, the patient is given a
patient to read something, perhaps a headline, and then to common object, such as a key, and asked both to identify it
write something, such as an address. and to describe its use.
Anosognosia is said to be present when patients fail to
Aprosodia recognize a deficit, such as hemiparesis, or grossly mini-
mize it, for example, by characterizing a severely hemi-
Aprosodia (Section 2.7) represents a disturbance in the paretic limb as simply ‘stiff’.
production or comprehension of the ‘emotional’ and Other agnosias, also described in Section 2.9, which are
melodic aspects of speech (Ross 1981). Thus, the patient’s generally not routinely tested for, include color agnosia,
own speech may be monotone, lacking all prosodic ele- prosopagnosia (the inability to recognize faces), auditory
ments, or the patient may have difficulty in appreciating agnosia (the inability to recognize common sounds),
the emotional tone of another’s voice. A lack of prosody in topographagnosia (a loss of a sense of direction), simul-
the patient’s own speech is generally apparent as the his- tanagnosia (an inability to visually ‘grasp’ the whole of a
tory is related; testing for the patient’s ability to ‘compre- scene to see all of its parts simultaneously), and aso-
hend’ prosody may require that patients close their eyes matagnosia (a denial of the ‘ownership’ of a body part, as
and then listen as the physician repeats the same neutral may be seen in some cases of hemiparesis).
phrase repeatedly but with different intonations (e.g.,
happy, angry, or sad), asking each time what the tone was.
Aprosodia must be distinguished from flattened affect Neglect
and parkinsonian hypomimia, and this differential was
discussed above previously in this chapter under Mood Neglect, discussed in Section 2.10, is characterized by an
and affect. involuntary failure to attend to or notice phenomena on
one side or the other; this may be either visual or motor.
Visual neglect is tested by seating the patient squarely in
Apraxia front of a table, with the patient’s trunk kept parallel to the
edge of the table (Beschin et al. 1997). First, draw a line
Apraxia may be ideational/ideomotor, constructional, or horizontally across a piece of paper, at least 15 cm long
dressing. (Tegner and Levander 1991) and then place the paper
Ideational and ideomotor apraxia (DeJong 1979; Heilman directly in front of, and square to, the patient. The patient
1973) are tested by first asking the patient to mime using a is then asked to bisect the line. Next, draw numerous short
common implement, such as a comb or a pair of scissors, marks in a random fashion on a piece of paper, placing the
and then, if the patient has any difficulty in performing the paper squarely in front of the patient and asking the patient
p 01.qxd 3/10/08 9:33 AM Page 17
1.4 Neuroimaging 17
to mark or cancel out all the lines. Finally, position a blank of voxels and pixels with the result that, especially in the
piece of paper in front of the patient with the instruction to case of MRI, the scans are breathtakingly accurate repre-
draw a clock face on it, with all the numbers, from one to sentations of the intracranial contents.
twelve, on the drawing. These constitute, respectively, the The technology of CT scanning is similar to that utilized
line bisection, line cancellation, and clock-drawing tests, in traditional radiography and is thus conceptually easily
and visual neglect is said to be present if the line is bisected grasped by most physicians. MR scanning, however, relies
off the midline, a significant percentage of the random on a fundamentally different technology, which, for most,
lines on one side are not cancelled out, or the numerals on requires some getting used to.
the clock face are bunched to one side. This chapter will briefly discuss CT and MRI, and then
Motor neglect is tested by asking the patient to perform consider their relative merits for clinical neuroimaging.
a task that requires the use of both upper extremities, such
as fastening a button: when motor neglect is present, the
patient ‘underutilizes’ the ‘neglected’ side and attempts to
CT scanning
perform the task primarily with one hand, despite the fact
CT scanning, developed by Hounsfield (1972), is based
that with strong urging normal bilateral manual coordina-
upon determining the attenuation of an X-ray beam by any
tion is possible (Laplane and Degos 1983).
given voxel of tissue. The degree of attenuation is expressed
in Hounsfield units (Phelps et al. 1975): by convention,
Extinction these range from ⫺1000 (for air) to ⫹1000 (for bone), tis-
sues of biologic interest being assigned intermediate values,
Extinction, also discussed in Section 2.10, is considered a for example, 0 for water, ⬃30 for white matter, ⬃35 for
subtype of neglect, and, like neglect, may be either visual or gray matter, ⬃75 for freshly clotted blood, and ⬃150–200
tactile (Valler et al. 1994). for calcified gray matter. A gray scale is then created to
Visual extinction may be tested immediately after per- represent the various attenuation coefficients, very low-
forming confrontation testing of the visual fields. While attenuation (or ‘hypodense’) areas such as air in the sinuses
retaining the same position with respect to the patient, the appearing black, and very high-attenuation (or ‘hyper-
physician holds both hands outstretched laterally to the dense’) tissues, such as blood, bone, or other areas of heavy
edge of the peripheral fields and then simultaneously wig- calcification, appearing more or less white.
gles both index fingers, asking the patient to point to the CT scanning is most reliable for supratentorial struc-
finger/fingers that are moving. When visual extinction is tures: the posterior fossa is particularly likely to be obscured
present, the patient notes the motion of only one finger. by various artifacts (Mostrum and Ytterbergh 1986).
Tactile extinction may be tested during routine sensory Enhancement is accomplished by the intravenous injec-
testing. While the patient’s eyes are closed, the physician tion of an iodinated contrast material, which, as it has a
instructs the patient to report which hand or hands are high attenuation coefficient, makes the tissue into which it
being touched – touching first one hand, then the other extravasates appear more dense.
and then both simultaneously. When tactile extinction is Angiography may also be accomplished with CT scan-
present, only one hand will be reported as touched during ning; however, this requires a large injection of contrast
simultaneous stimulation. material.
MR scanning
1.4 NEUROIMAGING
The physics underlying MRI are complex (Edelman and
Computed tomography (CT) and magnetic resonance Warach 1993; Pykett 1982; Pykett et al. 1982), so what fol-
imaging (MRI) have revolutionized neuroimaging. Before lows is a very simplified, and very brief, general overview.
the advent of CT in 1972, physicians were limited to To begin, consider hydrogen atoms, their nuclei composed
skull radiographs, radionuclide scanning, and pneumo- of but one proton. Each proton spins at a very fast rate,
encephalography, none of which retains any use for imag- thus creating a magnetic field and, as it were, becoming a
ing the brain today. very small magnet itself. These proton ‘magnets’ are nor-
For both CT and MRI, imaging is accomplished on a mally arrayed in random directions, but if a very strong
voxel-by-voxel basis. A voxel (from volume element) is a external magnetic field is applied, they will all align them-
specific three-dimensional volume of tissue, each voxel selves parallel to the external magnetic field. In such a situ-
subsequently being represented on the scan by a pixel ation, if a radio pulse of appropriate frequency is fired at
(from picture element). Early-generation scanners allowed the protons, they will absorb this energy, with the result
for only a limited number of voxels; consequently, tissue that they begin to spin with an eccentric axis, no longer in
resolution was poor and the corresponding scan created by parallel alignment to the external magnetic field. Over a
the pixels was fuzzy and relatively unedifying. However, variable period of time, however, the protons fall back into
technical progress has allowed for a much higher number line, in so doing releasing the energy absorbed from the
p 01.qxd 3/10/08 9:33 AM Page 18
earlier radio pulse. The speed with which the protons extravasated have a much higher signal intensity and
undergo realignment is determined by various factors, appear much brighter.
including the availability of nearby tissues that may absorb Consideration should also be given to ordering diffu-
energy and the presence of any surrounding magnetic sion-weighted images (DWIs) (Schaeffer et al. 2000). DWI
inhomogeneities or tissues that, of themselves, have mag- is exquisitely sensitive to cytotoxic edema (Warach et al.
netic properties. The released energy may be measured and 1995) (somewhat less so to vasogenic edema), and, as dis-
constitutes the ‘signal’ of the voxel in question. cussed below, has become an essential tool in the diagnosis
Routine MRI imaging includes T1, T2, and FLAIR (fluid- of cerebral infarction (Fisher and Albers 1999; Neumann-
attenuated inversion recovery) sequences and, whenever Haefelin et al. 2000). In cases in which there is uncertainty
one is interested in documenting old bleeds, a gradient as to whether the increased signal intensity on a diffusion-
echo (or T2*) sequence should also be ordered. The appear- weighted image represents cytotoxic edema or vasogenic
ance of various tissues and abnormalities differs on each of edema, an ‘apparent diffusion coefficient’ (ADC) map
these sequences. On T1-weighted images, cerebrospinal should be ordered: on ADC mapping, areas of cytotoxic
fluid (CSF) appears black, gray matter is medium-gray in edema appear very dark, whereas areas of vasogenic edema
appearance, white matter is light-gray, and both edema have an increased signal intensity.
and gliosis are dark. On T2-weighted images, CSF appears Angiography may also be performed with MRI. Such
bright, gray matter is medium-gray, white matter is dark- magnetic resonance angiography (MRA) may be performed
gray, and both edema and gliosis are light-colored. On either with ‘time of flight (TOF) imaging’ or via ‘phase con-
FLAIR sequences, CSF is quite dark, gray matter is light- trast imaging’: of the two, the TOF technique produces
gray and white matter somewhat lighter, and edema and more informative images.
gliosis are quite bright. Overall, T1-weighted scans provide
the sharpest delineation of structures, but are less sensitive Clinical indications
to pathology. T2-weighted and FLAIR scans provide less
clear delineation of structures, but are far more sensitive to As with any diagnostic test, the decision to request either
pathology and, of these two, FLAIR is the most sensitive. CT or MRI should be guided by one’s diagnostic suspi-
Gradient echo scanning is reserved for situations wherein cions. Furthermore, it is critical to provide the radiologist
one suspects that the patient has had, in the distant past, with a brief summary of the history and findings, along
intracerebral hemorrhage. In this situation, blood has with one’s presumptive diagnosis, so that the best imaging
degraded to hemosiderin, and T2*-weighted scanning is parameters may be selected.
exquisitely sensitive for this, displaying an area of greatly MRI is preferable to CT in most clinical situations
reduced signal intensity. (Armstrong and Keevil 1991; Bradley et al. 1984; Haughton
The enhancement of MRI is accomplished by the injec- et al. 1986), with the exception of suspected intracranial cal-
tion of a paramagnetic substance such as gadolinium and is cification (Holland et al. 1985). However, MRI should not
best appreciated on T1-weighted scans (Berry et al. 1986; be utilized whenever the patient harbors a metallic object
Brant-Zawadzki et al. 1986): on such images, as illustrated that might undergo any potentially dangerous movement
in Figure 1.1, the tissues into which the gadolinium has during the application of the external magnetic field.
Examples include: aneurysmal clips, depth electrodes,
intracranial bullets or shrapnel, some CSF shunts, some
cochlear implants, cardiac pacemakers, transcutaneous
electrical nerve stimulation (TENS) units, some prosthetic
valves, some arterial stents, various orthopedic devices,
some penile implants, wire sutures, and, importantly, any
metallic object in the eye. This last contraindication deserves
special attention as some patients may not be aware of the
presence of a metallic ocular foreign body (e.g., a lathe
operator struck in the eye with a minute sliver of metal
decades earlier): if any doubt exists, plain films of the orbits
should be acquired first. Metallic objects that may be
removed include hearing aids, dentures, TENS units,
insulin pumps, and some intrauterine devices.
Some common indications (such as suspected cerebral
Figure 1.1 Both of these T1-weighted magnetic resonance (MR) infarction) for CT or MRI are discussed as follows.
scans are of the same patient with a high-grade glioma in the
right hemisphere; on the left, the tumor appears as an area of CEREBRAL INFARCTION
decreased signal intensity but, with enhancement, as seen in the
scan on the right, the tumor displays increased signal intensity Cerebral infarction demonstrates a definite evolution of
and ‘lights up’. (Reproduced from Gillespie and Jackson 2000.) pathologic stages, progressing from cytotoxic edema to
p 01.qxd 3/10/08 9:33 AM Page 19
1.4 Neuroimaging 19
vasogenic edema and finally to necrosis, with varying on the T2-weighted scan. The late subacute phase ensues
degrees of cavitation. and lasts for months; during this phase red blood cells rup-
On CT scanning (Bories et al. 1985; Johnson 1994) there ture and methemoglobin is released into the extracellular
is loss of definition of the gray-white boundary within the space, creating increased signal intensity on both T1- and
first 6 hours, and over the next 18 hours an area of slight T2-weighted scans. Finally, during the chronic stage, there
radiolucency develops in the appropriate vascular terri- is degradation of methemoglobin and chronic deposition
tory. After 24 hours, this area becomes better defined and, of hemosiderin, with low signal intensity on both T1 and
with the development of vasogenic edema, a mass effect on T2 scans and a virtual black hole on gradient echo scans.
surrounding structures develops, peaking at from 3–5 days. Although, as in the case of suspected ischemic infarc-
Edema gradually resolves over 2–4 weeks, and eventually tion, CT is routinely used initially in suspected intracere-
a fairly circumscribed area of radiolucency appears, bral hemorrhage, this again appears to be more a matter
corresponding to the residual encephalomalacia. Contrast of availability, given that MRI performed within the first
enhancement generally appears after 3 days, and resolves few hours appears just as sensitive (Kidwell et al. 2004;
in a matter of weeks. Schellinger et al. 1999). Furthermore, in evaluating patients
MRI with diffusion-weighted imaging (DWI) is exqui- months after suspected intracerebral hemorrhage there is
sitely sensitive to the cytotoxic edema of infarction, reveal- no question that MRI, utilizing gradient echo sequences, is
ing an increased signal intensity within the first few hours, far more sensitive than CT (Wardlaw et al. 2003).
and indeed, in some cases within minutes (Yoneda et al.
1999). T2-weighted and FLAIR images will reveal SUBARACHNOID HEMORRHAGE
increased signal intensity in the area of infarction within 6
hours and this tends to persist. Gadolinium enhancement Subarachnoid hemorrhage is routinely detected by CT
becomes apparent within a matter of days, and resolves in scanning as an area of hyperdensity corresponding to the
from 1 to 2 months. free blood within the subarachnoid space (van der Wee et al.
Although CT scanning is typically utilized first in cases 1995; van Gijn and van Dongen 1982). As in the case with
of suspected cerebral infarction, this is primarily due to its suspected ischemic infarction or intracerebral hemorrhage,
ease of use and availability, and to its efficacy in the detec- CT is generally used first in possible subarachnoid hemor-
tion of intracerebral hemorrhage. It is not because CT is rhage; however, MRI, using FLAIR sequence, may be just
superior to MRI in the detection of acute infarction; as accurate (Wiesmann et al. 2002).
indeed, there is no question that MRI is by far superior to
CT in this regard (Fiebach et al. 2001; Gonzalez et al. 1999; LACUNAR INFARCTIONS
Lansberg et al. 2000).
Chronic lacunar infarctions, often missed on CT scanning,
INTRACEREBRAL HEMORRHAGE appear on MR scanning as areas of decreased signal inten-
sity on T1-weighted scans and increased signal intensity on
On CT scanning (Dolinskas et al. 1977) intracerebral hem- T2-weighted scans (Brown et al. 1988). As with large corti-
orrhage is immediately apparent as an area of increased cal infarcts, DWI may reveal acute lacunar infarcts (Singer
radiodensity. Over the following weeks this gradually et al. 1998) and is especially helpful in indicating which
resolves to an area of isodensity and, eventually, after lacunae are ‘fresh’ (Oliveira-Filho et al. 2000); indeed, DWI
months, an area of radiolucency appears. may demonstrate the occurrence of lacunar infarctions
With MR scanning the evolution of the image is more despite the absence of any history of a clinical event (Choi
complex (Gomori et al. 1985; Patel et al. 1996). During the et al. 2000). Importantly, lacunae must be distinguished
‘hyperacute’ phase, when the hemoglobin in the red blood from prominent Virchow–Robin spaces (Heier et al. 1989;
cells is, for the most part, still in its oxyhemoglobin form, Jungreis et al. 1988), which, unlike lacunae, tend to be
there may be little definitive change on MR scanning. It bilaterally symmetric and quite regular in shape.
was initially felt that this hyperacute phase lasted several
hours; however, recent studies have indicated that intracel- BINSWANGER’S DISEASE
lular hemoglobin may begin to degrade to deoxy-
hemoglobin early on, within these first few hours. In the Binswanger’s disease, also known as subcortical arterioscle-
following acute phase, spanning the next few days, there is rotic leukoencephalopathy, is characterized by irregular,
unequivocal degeneration of intracellular oxyhemoglobin patchy and often confluent areas of more or less complete
into deoxyhemoglobin, and the bleed now appears as an demyelinization in the centrum semiovale and peri-
area of decreased signal intensity on T2-weighted scans. ventricular white matter. Although these patchy lesions may,
During the early subacute phase, which lasts roughly from in some cases, be seen on CT scans as ill-defined areas of
day three to day seven, the intracellular deoxyhemoglobin hypodensity, they are much better appreciated on MR
further degrades into methemoglobin and the lesion at this scanning as areas of decreased signal intensity on T1-weighted
point appears as an area of increased signal intensity on T1- scans and, most especially, as areas of increased signal
weighted scans, with persisting decreased signal intensity intensity on T2-weighted scans (Kinkel et al. 1985). These
p 01.qxd 3/10/08 9:33 AM Page 20
patchy lesions must be distinguished from certain normal decreased signal intensity on T1-weighted scans and
variants (Fazekas et al. 1991), such as bilaterally symmetric increased signal intensity on T2-weighted scans; active
and smoothly contoured periventricular ‘caps’ and ‘rims’, plaques demonstrate gadolinium enhancement. Serial MR
and what are known as unidentified bright objects (UBOs): scanning (Grossman et al. 1988; Guttmann et al. 1995;
scattered punctate foci of increased signal intensity on T2- Thompson et al. 1992) may be used to follow the progress
weighted images. of the disease and may indeed reveal clinically ‘silent’
lesions. Furthermore, recently activated plaques may be
INTRACRANIAL CALCIFICATION detected by gadolinium enhancement before there is any
clinical evidence of their presence (Kermode et al. 1990;
Intracranial calcification, as may be seen in Fahr’s syn- Miller et al. 1988). MRI has revolutionized the diagnosis of
drome, tuberous sclerosis, or Sturge–Weber syndrome, is multiple sclerosis and no evaluation of a patient suspected
better demonstrated on CT scanning, on which it is evident of harboring this dreaded disease is complete without it.
as an area of hyperdensity, than on MR scanning, where
it may be difficult to detect (Holland et al. 1985; Wasenko MESIAL TEMPORAL SCLEROSIS
et al. 1990).
Mesial temporal sclerosis, the most common cause of com-
plex partial seizures, is better detected by MRI than CT
TUMORS
(Franceschi et al. 1989). On MR scanning, mesial temporal
Tumors are, overall, better demonstrated by MR than CT sclerosis is apparent with atrophy (best seen on T1-weighted
scanning (Armstrong and Keevil 1991; Bradley et al. 1984; scans) and, on T2-weighted scans, increased signal inten-
Brant-Zawadzki et al. 1984). With both CT and MR scan- sity in the same area: importantly, these changes are gener-
ning, enhancement increases sensitivity (Sze et al. 1990) ally best seen on coronal images (Berkovic et al. 1991).
and, in the case of gliomas, the degree of enhancement may
serve as a guide to the malignancy of the tumor, with NEURONAL MIGRATION DISORDERS
increased enhancement indicating greater malignancy with
Neuronal migration disorders are a common cause of sim-
both CT (Tchang et al. 1977) and MR (Dean et al. 1990; Graif
ple or complex partial seizures and of grand mal seizures of
and Steiner 1986) scanning. In the case of meningiomas,
focal onset. For the most part, they manifest as subependymal
the administration of contrast is especially important
nodular heterotopias, either laminar or band heterotopias
(Vassilouthis and Ambrose 1979; Zimmerman et al. 1985):
in the white matter itself, or areas of cortical dysplasia or
on unenhanced CT scanning, the tumor, although often
microdysgenesis. Although CT scanning may detect
hyperdense, may be isodense, and on MR scanning there is
subependymal heterotopias (especially if they are calcified)
often no change at all in signal intensity on either T1- or T2-
MR scanning is superior, picking up not only these lesions,
weighted scans. With contrast, however, almost all menin-
but also band and laminar heterotopias (Altman et al.
giomas will enhance on both CT and MR scanning.
1988; Barkovich and Kjos 1992; Huttenlocher et al. 1994),
as illustrated in Figure 1.2.
TRAUMATIC BRAIN INJURY
AIDS DEMENTIA
Although CT is generally the first technique used in patients
with traumatic brain injury and is often the only one, it is AIDS dementia has imaging characteristics similar to those
clear that MRI is far superior in the detection of contu- described for Binswanger’s disease and is better imaged with
sions, and, especially, diffuse axonal injury (Jenkins et al. MRI than CT (Chrysikopoulos et al. 1990). Furthermore,
1986; Kelly et al. 1988; Mittl et al. 1994; Orrison et al. 1994; MRI is also more sensitive than CT for AIDS-related illnesses
Zimmerman et al. 1986). such as toxoplasmosis (Porter and Sande 1992) and pro-
gressive multifocal leukoencephalopathy (Guilleux et al.
MULTIPLE SCLEROSIS 1986; Krup et al. 1985).
Multiple sclerosis is characterized by plaques of demyelin- HERPES SIMPLEX VIRAL ENCEPHALITIS

ization that may be either active (with evidence of definite
inflammation) or chronic and inactive. CT scanning Herpes simplex viral encephalitis, the most common cause
(Hershey et al. 1979; Mushlin et al. 1993) demonstrates of sporadic encephalitis (and a very important diagnosis
plaques as areas of hypodensity, and active plaques may be given its amenability to treatment) is far better imaged by
identified by contrast enhancement. MR scanning is far MRI than CT (Gasecki and Steg 1991); indeed, CT scan-
more sensitive than CT scanning, even when CT scanning ning may be normal during the critical first few days
is carried out using double contrast (Mushlin et al. 1993; (Greenberg et al. 1981). Herpes simplex encephalitis usu-
Young et al. 1981). ally affects first the mesial temporal structures, producing
On MR scanning (Katz et al. 1993; Nesbit et al. 1991; an increased signal intensity on T2-weighted scanning
Ormerod et al. 1987), inactive plaques appear as areas of (Tien et al. 1993).
p 01.qxd 3/10/08 9:33 AM Page 21
should include at least 20 minutes of artifact-free record-

ing, followed, when appropriate, by the activating proce-
dures of hyperventilation, photic stimulation, and sleep,
which should itself last an additional 20 minutes.
In contrast with CT and MR scanning, there is nothing
‘intuitively’ obvious about an EEG tracing: anyone familiar
with neuroanatomy can almost immediately grasp an MR
scan. Looking at an EEG tracing is, however, like looking at
an electrocardiogram (ECG); without a considerable amount
of preparation on the part of the physician, the EEG trac-
ing is no more informative about the state of the brain than
the ECG is about the heart. Consequently, this section on
EEG is relatively longer than that on neuroimaging, as well
as more detailed.
Instrumentation
Electrodes are attached to the scalp and are connected via

wires to the EEG machine. Pairing of these wires, and the
electrodes from which they stem, allows one to construct
numerous different channels. In older, analog machines,
this pairing is performed utilizing ‘selector switches’: how-
ever, in the now standard digital machines, an analog-to-
digital-converter allows for the creation of channels at the
Figure 1.2 A T1-weighted magnetic resonance imaging scan touch of a keyboard. Within the EEG machine itself, one
demonstrates a laminar band heterotopia, as indicated by the finds amplifiers and filters that respectively amplify the
arrow, in exquisite detail. (Reproduced from Hopkins et al. 1995.) very weak electrical signals arising from the cortex and fil-
ter out as much as possible electrical activity that arises
PITUITARY ADENOMA from either extracerebral sources or from the brain, and
which is of little clinical interest.
Pituitary macroadenomas may be seen on both CT and MR The amplified and filtered electrical impulse of each
scanning; microadenomas, however, are generally seen only channel is then used, in analog machines, to cause a deflec-
with MR scanning (Levy and Lightman 1994), which, in the tion of the appropriate pen over a continuously moving
case of prolactinomas, may be used to monitor the results sheet of paper, thus creating the actual tracing (EEG). With
of treatment with bromocriptine (Pojunas et al. 1986). digital machines, there are, of course, no pens or paper
tracings; however, this terminology has stayed with us. In a
standard recording, the sheet moves at a constant rate of
1.5 ELECTROENCEPHALOGRAPHY 30 mm/s, and the sensitivity of the pen is set such that an
impulse of 50 μV causes a deflection of 7 mm.
The existence of cerebral electrical activity was demon- The specific arrangement of electrodes on the scalp is
strated in animals in 1875 by an English physician, Richard known as an array, and the international 10–20 system
Caton (1875), and the first human electroencephalogram described by Jasper (1958) remains a world-wide standard
(EEG) was reported by Hans Berger in 1929 (Berger 1929). (Epstein et al. 2006b). In this system, imaginary lines are
By the middle of the twentieth century, the EEG had become drawn on the head between specific landmarks (e.g., the
very important in the diagnosis of such intracranial lesions nasion and inion) and the electrodes are placed along them
as tumors but, with the advent of CT and MRI the indica- at certain fractional intervals, i.e., either 10 percent or 20
tions for electroencephalography have changed, and most percent of the total length of the imaginary line. These elec-
EEGs are currently obtained in the course of the diagnosis trodes are designated with letters that refer to their loca-
or management of seizures or epilepsy and in the evaluation, and with numbers that indicate whether they are on
tion of delirium. This chapter discusses EEG instrumenta- the left side of the head, the right side or in the sagittal mid-
tion, the normal EEG, various EEG abnormalities, activation line; thus, Fp ⫽ frontopolar, F ⫽ frontal, T ⫽ temporal,
procedures (e.g., hyperventilation), normal variants, and the O ⫽ occipital, C ⫽ central, P ⫽ parietal, and A ⫽ auricu-
various artifacts that may mimic pathologic abnormalities. lar; odd numbers indicate the left side of the head, even
As with any other diagnostic test, electroencephalogra- numbers the right side, and zero (‘z’) the sagittal midline.
phy must be properly performed to yield the most useful Figure 1.3 demonstrates these placements, and Table 1.1
data (Epstein et al. 2006a). In particular, the awake EEG provides the full name for each electrode. Note, however,
p 01.qxd 3/10/08 9:33 AM Page 22
sample the medial aspect of the temporal lobe (MacLean

1949). Sphenoidal leads are invasive, requiring a trochar to
Fp1 Fp2 place them through the masseter muscle and up posterior
to the zygomatic arch: these also attempt to sample the
F7 F8
F3 F4
medial aspect of the temporal lobe (Risinger et al. 1989).
Fz There is a debate over which one or combination of
supplemental leads is most appropriate for detecting tem-
A1 T3 C3 Cz C4 T4 A2 poral lobe foci. The addition of anterior temporal leads
provides more sensitivity than a routine 10–20 array, and it
appears that anterior temporal leads are either of roughly
Pz equivalent (Sperling and Engel 1985) or superior sensitiv-
P3 P4
ity (Sadler and Goodwin 1989) to nasopharyngeal leads. It
T5 T6 is not clear how anterior temporal leads compare in sensi-
O1 O2 tivity to sphenoidal leads: some studies find them equivalent
(Homan et al. 1988; Sadler and Goodwin 1989); however,
others find sphenoidal leads superior (Sperling et al. 1986).
Figure 1.3 Electroencephalography (EEG) electrode placement Whenever temporal lobe foci are sought, at the very least
according to the international 10–20 system (see text for details). ‘true’ anterior leads should be ordered with other supple-
mental leads held in reserve.
As noted earlier, the electroencephalography machine
Table 1.1 Electrode names in the 10–20 system allows electrodes to be paired in various ways, and the pat-
Name Position tern of such pairings is known as a montage. Three standard
montages are recommended: a referential montage and two
bipolar montages, namely a longitudinal bipolar montage
Fp1, Fp2 Prefrontal and a transverse bipolar montage (Epstein et al. 2006c).
F7, F8 Anterior temporal In a referential montage, each scalp electrode is paired
T3, T4 Mid-temporal with the same ‘reference’ electrode, usually the ipsilateral ear,
T5, T6 Posterior temporal producing channels such as F7⫺A1, T3⫺A1, and T5⫺A1.
O1, O2 Occipital The scalp electrode is commonly referred to as the ‘active’
F3, F4 Frontal electrode, in contrast with the reference electrode, which is
C3, C4 Central termed ‘indifferent’. However, this terminology is not
P3, P4 Parietal accurate because the ear electrode in fact picks up electrical
A1, A2 Auricular activity arising from the temporal lobe and is thus only
Fz Frontal midline ‘relatively’ indifferent. In some instances, other electrodes,
Cz Central vertex or combinations of electrodes, will be used instead of one
Pz Parietal midline ear: thus, the reference electrode may be found on the
angle of the mandible or an ‘average reference electrode’
may be produced by averaging the electrical activity of a
that clarification is needed regarding electrodes F7 and F8; large number of scalp electrodes (Goldman 1950).
although, logically, one might expect these to be called In a bipolar montage, scalp electrodes are paired in two
‘frontal’, they are commonly referred to instead as ‘ante- directions – longitudinal and transverse. In a longitudinal
rior temporal’ leads as, for the most part, they reflect activ- bipolar montage, the pairings proceed ipsilaterally, from
ity arising from the anterior portion of the temporal lobes. anterior to posterior, producing ‘chains’ of channels, such
This international 10–20 system may be extended and as Fp1⫺F3, F3⫺C3, C3⫺P3, and P3⫺O1. In a transverse
modified by adding more electrodes (Chatrian et al. 1985; bipolar montage, the chain proceeds across the scalp, from
Epstein et al. 2006b), and this may be resorted to in order left to right, for example F7⫺F3, F3⫺Fz, Fz⫺F4, F4⫺F8. It is
to improve localization or to increase spatial resolution appropriate to note here that in the chains of a bipolar
and allow for better computed EEG analysis. Supplemental montage one individual electrode may serve as the second
leads may also be added to better detect and localize foci in electrode in one channel and the first electrode of the next;
the temporal lobe. ‘True’ anterior temporal leads (to be for example, in the chain noted above, containing channels
distinguished from the admittedly misnamed F7 and F8 Fp1⫺F3, F3⫺C3, C3⫺P3, and P3⫺O1, note that electrode F3
electrodes) are placed by drawing a line between the exter- serves as the second electrode for the first channel
nal auditory canal and the lateral canthus, and placing the (Fp1⫺F3) and the first electrode for the next channel
electrode anterior to the external auditory canal one-third (F3⫺C3). As will be noted later in the discussion of inter-
of the way forward along, and 1 cm above, this line (Homan ictal epileptiform abnormalities, the commonality of one
et al 1988; Silverman 1960). Nasopharyngeal leads, as the electrode to two successive channels in a bipolar montage
name suggests, are inserted into the nostril in order to allows for a localization of epileptic foci.
p 01.qxd 3/10/08 9:33 AM Page 23
Normal EEG under 8 Hz) and ‘fast’ referring to any activity in the beta
range (i.e., over 13 Hz). Recurrent activity may also be rhyth-
The electrical activity recorded by the EEG arises from the mic and regular in occurrence, or arrhythmic and irregular.
apical dendrites of cortical pyramidal neurons (Humphrey The EEG will normally have a recognizable background
1968; Purpura and Grundfest 1956). Although the elec- activity that is more or less persistent and similar through-
trical activity associated with an action potential is too brief out the recording. Upon this background, one may at
to be recorded on an EEG (i.e., lasting less than 1 ms), times see isolated events that, for one reason or another,
activity derived from both inhibitory and excitatory post- stand out from the background, such events being referred
synaptic potentials lasts much longer (from 15 to 200 ms) to as ‘transients’. Transients may, in turn, consist either of
and it is this activity that is reflected in the EEG (Humphrey an isolated spike or wave, or a ‘complex’ of two or more of
1968). The electrical activity arising from one neuron is these. Complexes themselves are further described in terms
obviously too weak to affect the surface electrodes, so it is of whether they are isolated or recurrent, and if recurrent,
upon the summed activity of numerous neurons that the whether they recur irregularly or regularly. ‘Spindles’
EEG depends. Furthermore, it must be borne in mind that comprise a specific type of transient complex, consisting of
abnormal electrical activity occurring deep below the cor- a group of rhythmic waves that gradually increase in
tex may not ‘reach’ the scalp electrodes (Cooper et al. 1965) amplitude, and then just as gradually decrease.
and thus certain deep lesions, such as lacunar infarcts, may The normal adult awake EEG, as seen during relaxed
not cause any abnormality on the EEG although have pro- wakefulness with the eyes closed, contains an alpha rhythm
found clinical consequences (MacDonnell et al. 1988). and a beta rhythm. These two terms must not be used
Electroencephalographic activity may or may not be loosely: for example, although much EEG activity may
rhythmic and it appears that rhythmicity occurs secondary occur in the alpha frequency, the activity must fulfill certain
to the activity of the thalamus, which acts like a pacemaker other criteria to qualify as an alpha rhythm. In a minority
or ‘conductor’, exerting rhythmic control over the cortical of individuals, a mu rhythm may also be seen.
‘orchestra’, and bringing large groups of neurons into syn- The alpha rhythm consists of more or less regular sinu-
chrony (Dempsey and Morrison 1942; Steriade et al. 1990). soidal activity, ranging in amplitude from 20 to 60 μV
This dependence of cortical neurons upon the thalamus (averaging about 50), occurring in the alpha range and
for rhythmic firing was demonstrated by experiments in most prominent posteriorly. The alpha rhythm is generally
which the destruction of the thalamus abolished rhythmic ‘blocked’ by eye opening, being replaced by lower ampli-
cortical activity (Jasper 1949). tude, and faster/irregular activity. Although the frequency
The EEG consists of various waves that may differ in of the alpha rhythm is the same on each side, the actual
terms of morphology, amplitude, and duration. Thus, in waves themselves are generally out of phase. Further, there
terms of morphology, an individual wave may be monophasic, is also generally an amplitude difference between the two
diphasic, triphasic, or polyphasic, depending on how many sides, with the left side alpha being of lower amplitude than
times the ‘baseline’ is crossed by the wave in question. the right. Generally, this amplitude differential is no more
Amplitude is measured in microvolts from the crest to the than 20 percent; however, the range of normal here is wide,
trough of the wave: customarily, amplitudes under 20 μV with some normal individuals having differentials up to 50
are considered low, those between 20 and 50 μV, medium, percent. The alpha rhythm is best seen in a state of relaxed
and those over 50 μV, high (some electroencephalogra- wakefulness with the eyes closed. In a small minority of
phers will, however, rather than using this absolute scale, cases, variants of the alpha rhythm may occur (Goodwin
consider the amplitude of a given wave relative to the overall 1947), wherein the frequency of the sinusoidal activity is
amplitude of background activity: thus, if the background either in the 4- to 5-Hz range (‘slow’ alpha variant) or
activity were generally of 60 μV, a 30-μV wave, using this 16- to 20-Hz range (‘fast’ alpha variant). These variants
relative scale, might be considered low). It is therefore crit- represent ‘harmonics’ of the more typical alpha rhythm.
ical that the electroencephalographer specifies whether an The beta rhythm consists of bilateral beta activity of an
absolute or a relative scale is being used when reporting amplitude of 30 μV or less, seen best anteriorly, which is
amplitude. The duration of the wave is measured in mil- blocked unilaterally by contralateral tactile stimulation,
liseconds: waves lasting less than 70 ms are referred to as movement, or merely an intention to move. Although the
‘spikes’ and those lasting from 70 to 200 ms as ‘sharp waves are generally out of phase, the frequency is bilaterally
waves’; those lasting for over 200 ms are spoken of either as symmetric. An amplitude variance of up to 35 percent
‘slow waves’ or simply ‘waves’. from side to side is considered normal. Beta activity is
Waves may be isolated or recurrent. If recurrent, their often increased by sedatives such as benzodiazepines and
frequency is reported in cycles per second (Hz): by conven- barbiturates (Brown and Penry 1973; Frost et al. 1973;
tion, frequencies less than 4 Hz are termed ‘delta’, those Greenblatt et al. 1989).
from 4 to under 8 Hz ‘theta’, those from 8 to 13 Hz ‘alpha’, The mu rhythm represents another normal type of EEG
and those over 13 Hz as ‘beta’ waves. Some electroen- activity, one that is not seen as routinely as the alpha or beta
cephalographers also use the terms ‘slow’ and ‘fast’, ‘slow’ rhythms and is present in only about 10 percent of normal
referring to both delta and theta activity (i.e., anything adults. The mu rhythm consists of theta or alpha activity
p 01.qxd 3/10/08 9:33 AM Page 24
(ranging from 7 to 11 Hz) that appears as long transients transients, but with the appearance of K complexes, sleep
(‘trains’) lasting at least several seconds and appearing in spindles and POSTs. Stage III is characterized by further
the centroparietal region. Although these occur bilaterally, slowing (20–50 percent of the background activity being in
the trains are often not synchronous, with one side having a the delta range), an absence of vertex sharp transients, a fad-
train and then losing it, and then a train appearing a little ing out of K complexes and sleep spindles, but a persistence
later on the opposite side. The mu rhythm is generally of POSTs. Stage IV is identified by gross slowing (more
50 μV or less in amplitude. The mu rhythm, like the beta than 50 percent delta activity), an absence of vertex sharp
rhythm, may also be unilaterally blocked by contralateral transients and K complexes, and only rare sleep spindles
phenomena (Chatrian 1964; Chatrian et al. 1959) including and POSTs.
movement (Chatrian et al. 1959), intention to move (Klass The entire night’s sleep typically occurs in cycles, each
and Bickford 1957) and tactile stimuli (Magnus 1954). cycle lasting from 80 to 120 minutes. The first cycle begins
Each of these three normal rhythms may represent a as the patient drifts into stage I, progressing down through
kind of ‘idling’ of the underlying cerebral cortex. This stages II and III to stage IV and thence back up through
hypothesis, poetic as it might be, gains support from the stages III and II to stage I, from which REM sleep emerges.
various blocking maneuvers. For example, if the alpha The end of REM sleep signals the end of the first cycle and
rhythm represents an idling occipital cortex one would the beginning of the next. During one night’s sleep, sub-
expect it to be blocked when the occipital cortex is brought jects normally pass through three to five of these cycles,
into gear by visual stimuli. and with each successive cycle, the amount of time spent in
The normal adult sleep EEG demonstrates both REM stage IV sleep decreases.
(rapid eye movement) and non-REM (NREM: non-rapid
eye movement) sleep. REM sleep is, as the name suggests,
characterized by rapid, saccadic, conjugate eye movements EEG abnormalities
and is typically associated with dreaming. NREM sleep is
generally not associated with dreaming, and during such The various EEG abnormalities discussed here include
sleep, the eyes are either still, or slowly roving about. decreased amplitude, slowing (either focal or generalized),
NREM sleep may further be divided into four stages: I, II, interictal (‘epileptiform’) and ictal abnormalities, periodic
III, and IV, with each of these stages having a distinctive complexes, triphasic waves, and the burst-suppression
electroencephalographic signature (Erwin et al. 1984; pattern.
Rechtschaffen and Kales 1968). In order to identify the var-
ious stages one must be familiar with several different tran- DECREASED AMPLITUDE
sient events: vertex sharp transients, K complexes, sleep
spindles, and positive occipital sharp transients (POSTs). Low-amplitude EEG activity may result either from an
Vertex sharp transients (also known as ‘V waves’) are alteration in the media between the cortex and the record-
intermittently occurring, bilaterally symmetric sharp ing electrode or from decreased electrogenesis by the cor-
waves of high amplitude (rarely more than 250 μV) seen tex (Aird and Shimuzu 1970). For example, both grease
most prominently at the vertex. K complexes are very sim- and an abnormally thick skull (e.g., in Paget’s disease) act
ilar to vertex sharp transients, differing only in that they as insulators, and fluid collections, such as subgaleal,
generally consist of a diphasic slow wave. Sleep spindles are epidural, or subdural hematomas, act as ‘shunts’ that
transients lasting from half a second to several seconds, divert the electrical field away from the overlying electrode.
consisting of rhythmic activity in the 11- to 14-Hz range, Cortical electrogenesis may be reduced either because of
which, as with all spindles, demonstrates a gradual increase actual destruction, as in Alzheimer’s disease or tumors,
and decrease in amplitude, with a maximum of generally or decreased neuronal activity, as in metabolic deliria or
less than 50 μV. These sleep spindles occur simultaneously post-ictal states. Decreased amplitude may be either gener-
on both sides and, although maximal centrally, are wide- alized or focal.
spread. POSTs (Vignaendra et al. 1974) consist of sharp Generalized low-amplitude EEGs of from 20 to 10 μV
waves of positive polarity seen posteriorly in the occipital may be seen in 5–10 percent of normal adults; an ampli-
regions. They are monophasic and generally of no more tude of less than 10 μV is rare in normal subjects. When the
than 50 μV in amplitude; although they are seen bilaterally, general amplitude is reduced to below 20 μV, it is helpful to
they are not synchronous. Furthermore, they are not be able to compare the current record with past ones, or
rhythmic and can be seen at irregular intervals of anywhere to make serial recordings in order to determine whether
from several to one per second. the low amplitude is stable or worsening. It is also critical
With these various transients in mind, the four sleep to ensure that the recording is made during relaxed wake-
stages may now be defined. The onset of stage I is marked fulness: tense or anxious patients, or those engaging in
by ‘alpha dropout’, with slowing of the background some more or less demanding mental activity, will have
rhythm into the delta–theta range (2–7 Hz); soon there- low-amplitude recordings. A generalized decrease in ampli-
after vertex sharp transients appear. Stage II is character- tude may be seen in conditions characterized by wide-
ized by a persistence of the slowing and the vertex sharp spread cortical neuronal loss (e.g., Alzheimer’s disease,
p 01.qxd 3/10/08 9:33 AM Page 25
Huntington’s disease [Scott et al. 1972], Creutzfeldt–Jakob in metabolic or toxic delirium (Pro and Wells 1977; Romano
disease [Burger et al. 1972], post-anoxic encephalopathy, or and Engel 1944). Metabolic deliria accompanied by gener-
AIDS dementia [Harden et al. 1993]) or widespread neu- alized asynchronous slowing include hepatic encephalopa-
ronal dysfunction (e.g., metabolic deliria such as hepatic or thy and uremic encephalopathy, and the deliria occurring
uremic encephalopathy, or other conditions such as secondary to hyperglycemia, hypoglycemia, hypernatremia,
hypothyroidism, hypothermia, uncomplicated alcohol with- hyponatremia, hypercalcemia, or hypocalcemia. Toxic
drawal [Walker et al. 1956] or post-ictally after a grand deliria associated with similar slowing include those due to
mal seizure). phenytoin (Roseman 1961), valproate (Adams et al. 1978),
Focal low-amplitude EEGs may be seen in conditions and either carbamazepine or phenobarbital (Schmidt
that cause a unilateral increase in the media (e.g. subdural 1982). Generalized slowing may also be seen during alco-
hematoma [Lusins et al. 1976]) and either unilateral hol intoxication (Walker et al. 1956) and in Wernicke’s
neuronal destruction (e.g., infarction or tumor [Aird and encephalopathy. Interestingly, however, the delirium of
Shimuzu 1970]) or dysfunction (e.g., transient ischemic delirium tremens, rather than slowing, is accompanied by
attacks, migraine, and post-ictally after a partial seizure an increase of beta activity (Kennard et al. 1945; Schear
[Kaibara and Blume 1988]). 1985). The delirium seen with bacterial meningitis or viral
In evaluating amplitude asymmetries of the alpha encephalitis is also marked by generalized slowing. Various
rhythm, one must not forget that the left side normally has dementing disorders may also be accompanied by general-
an amplitude of up to 50 percent less than the right; it is ized asynchronous slowing, including Alzheimer’s disease
thus only when the alpha rhythm on the left is at least 50 (Deisenhammer and Jellinger 1974; Johannesson et al.
percent less than that on the right that one can declare with 1977), Binswanger’s disease (Caplan and Schoene 1978),
certainty that an abnormality is present. The beta rhythm Parkinson’s disease (Neufeld et al. 1988), diffuse Lewy
is generally bilaterally symmetric, but even here an ampli- body disease (Briel et al. 1999), progressive supranuclear
tude asymmetry is not unusual in normal individuals; thus, palsy (Su and Goldensohn 1973), normal pressure hydro-
for the beta rhythm, any asymmetry must be more than 35 cephalus (Wood et al. 1974), vitamin B12 deficiency (Walson
percent before it can be declared outside the normal range. et al. 1954), post-anoxic encephalopathy (Hockaday et al.
A unilateral reduction in amplitude of the beta rhythm 1965), AIDS dementia (Harden et al. 1993), and
indicates a frontal lesion. In general, a unilateral reduction Creutzfeldt–Jakob disease (Burger et al. 1972) (including
of the alpha rhythm suggests a lesion of the underlying the new-variant type [Zeidler et al. 1997]).
occipital cortex, but in the case of the alpha rhythm an A mild degree of generalized asynchronous slowing may
amplitude reduction may also be seen with distant lesions also be seen as a normal variant in a small minority of sub-
in the frontal or parietal cortices or the ipsilateral thalamus. jects; furthermore, occasional scattered theta transients are
Amplitude asymmetry may occasionally be spurious, as not at all abnormal in normal subjects over the age of 60
for example with ‘breach’ rhythms. Here, in conditions years (Kooi et al. 1964). Generalized slowing also, of course,
where the skull has been breached, for example with a burr occurs with sleep, and thus slowing in a drowsy patient who
hole or fracture (regardless of how much scar tissue has is slipping in and out of sleep is of little significance.
formed), an excessive amplitude is seen on the side with Synchronous bilaterally generalized slowing typically
the breach, making the normal amplitude activity on the occurs episodically, and in such cases is termed IRDA
other side appear low by comparison (Cobb et al. 1979). (intermittent rhythmic delta activity). In most adults,
IRDA is predominantly frontal, and is termed FIRDA
SLOWING (frontal intermittent rhythmic delta activity) (Zurek et al.
1985), whereas in children IRDA is generally occipital and
Slowing on the EEG may be either focal or generalized. referred to as OIRDA (Watemberg et al. 2007). Although
FIRDA was classically associated with deep midline lesions
Focal slowing (Daly et al. 1953), it has now become clear that FIRDA is
Focal slowing may consist of either theta or delta activity, most commonly seen in metabolic and toxic deliria
and is seen in a variety of focal conditions, including infarcts (Schaull et al. 1981), especially in patients with pre-existing
and tumors (Daly and Thomas 1958; Gastaut et al. 1979; ischemic lesions (Watemberg et al. 2002); FIRDA has also
Gilmore and Brenner 1981), subdural hematoma (Lusins been reported in association with diffuse Lewy body dis-
et al. 1976), post-ictally after a focal onset seizure (Gilmore ease (Calzetti et al. 2002), Creutzfeldt–Jakob disease
and Brenner 1981), after some migraine headaches (Wieser et al. 2004), and in association with high-dosage
(Hockaday and Whitty 1969), and early in herpes simplex antipsychotics (Koshino et al. 1993). There is one other,
encephalitis (Upton and Gumpert 1970). relatively rare, type of IRDA which is restricted to the tem-
poral areas: this TIRDA, rather than being seen in delir-
Generalized slowing ium, most commonly occurs in patients with complex
Generalized slowing appears in the theta or delta range and partial seizures (Normand et al. 1995), especially, as might
may be either bilaterally asynchronous or synchronous. be expected, in those with foci in the temporal lobes (Di
Asynchronous generalized slowing is most commonly seen Gennaro et al. 2003).
p 01.qxd 3/10/08 9:33 AM Page 26
INTERICTAL AND ICTAL EEG ABNORMALITIES activity itself. Most paroxysmal electrical discharges are
‘surface negative’ (Matsuo and Knott 1977), i.e., their elec-
In patients with seizures or epilepsy, abnormalities seen trical potential is negative with regard to the normal base-
between seizures are termed ‘interictal’, whereas those seen line. Furthermore, most of these discharges cover a fairly
during a seizure are designated as ‘ictal’. wide area: although the discharge may be ‘seen’ under only
one electrode, this is quite rare and in the vast majority of
Interictal activity cases it covers a wider area, subtending two or more adja-
Interictal activity consists of what are known as epilepti- cent electrodes. The electrical activity itself may be visual-
form discharges. These interictal epileptiform discharges ized as a landscape, which may in turn contain various
(IEDs) are paroxysmal transients that ‘shoot’ out from the topographic features: gently rolling electrical hills and val-
background rhythm (Pedley 1980). These paroxysmal leys represent the normal EEG background, whereas deep
transients may consist of isolated spikes or sharp waves or chasms can be likened to epileptiform discharges plunging
may appear as complexes, such as spike-and-sharp wave, down from the background. With this image in mind, one
spike-and-slow wave, sharp-and-slow wave, polyspikes, or can understand the changes produced on either a referen-
polyspike-and-wave discharges. Although epileptiform tial or bipolar montage.
activity may be seen in a very small percentage of subjects To take an example, consider an epileptiform discharge
who have never had a seizure (Ajmone-Marsan and Zivin producing an electrical ‘chasm’ on the left hemisphere that
1970; Gibbs et al. 1943; Gregory et al. 1993; Zivin and is large enough to subtend electrodes F3, C3, and P3, as
Ajmone-Marsan 1968), and may also occur as a side-effect illustrated in Figure 1.4. Keep in mind also that, in this
of certain medications (e.g., lithium [Helmchen and example, the ‘walls’ of the chasm, rather than going straight
Kanowski 1971], clozapine [Malow et al. 1994], meperidine up and down, instead gently slope down to the greatest
[Kaiko et al. 1983]), and in patients with autism (Kim et al. electrical depth. Thus, proceeding from Fp1 to F3 the depth
2006) or developmental dysphasia (Picard et al. 1998), they falls, from F3 to C3 it continues to fall to its nadir, from C3
are typically present only in patients with a history of to P3 it rises, and from P3 to O1 it continues to rise back to
seizures. Importantly, however, although most epileptic the surface. Assume, for the purpose of this example, that
patients will have interictal epileptiform abnormalities the gently rolling landscape exists at an electrical potential
(Goodin and Aminoff 1984), the absence of such a finding of ⫺25 μV, and that this is what electrodes Fp1, O1, and A1
on the first EEG does not rule out a diagnosis of epilepsy, as ‘see’. Furthermore, assume also that electrode F3, being
it may take up to four or more EEGs before an IED is over the gently downsloping wall of the chasm, sees a
‘caught’ (Salinsky et al. 1987). Furthermore, in evaluating a potential of ⫺50 μV, and that electrode C3, being over the
patient who has had a seizure, it is important to obtain the nadir of the chasm, sees a potential of ⫺100 μV. Electrode
EEG within the first 24 hours, as EEGs obtained later than P3, being over the following wall of the chasm, sees ⫺50 μV,
this are less likely to reveal IEDs (King et al. 1998). It must and electrode O1 encompasses the normal landscape of
be borne in mind, however, that in a very small minority of ⫺25 μV. Depending on whether a referential or bipolar
patients with unquestionable epilepsy routine EEGs will montage is used, the EEG recording of this same landscape
simply not display IEDs (Ajmone-Marsan and Zivin 1970; will look quite different.
Martins da Silva et al. 1984; Morris et al. 1988). As noted earlier, in a referential recording each scalp, or
Interictal epileptiform activity may be generalized, active electrode, is paired with the same reference electrode,
focal, or multifocal: in this example the ipsilateral ear; thus, in this example, as
Generalized bisynchronous IEDs indicate the presence
of one of the idiopathic generalized epilepsies, such as petit
mal epilepsy (either childhood or juvenile onset), juvenile
myoclonic epilepsy, or epilepsy with any tonic–clonic Fp1 Fp2
seizures. In petit mal epilepsy, one sees the classic, roughly F7 F8
3-Hz generalized and bisynchronous spike and dome dis- F3
Fz
F4
charges (Dalby 1969); in the other forms, the IEDs may be
spike-and-wave, polyspike or polyspike-and-wave in char-
acter (Betting et al. 2006) (importantly, in this latter group A1 T3 C3 Cz C4 T4 A2
⫺100 ␮V
a minority of patients displayed atypical findings, includ-
ing focal discharges). Pz
P3 ⫺50 ␮V
P4
Focal epileptiform activity strongly suggests an underly-
ing focal epileptogenic lesion (e.g., a tumor, scar, or area of T5 T6
⫺25 ␮V
cortical dysplasia), whereas multifocal epileptiform activ- O1 O2
ity, as might be expected, suggests widespread and multiple
lesions (e.g., subsequent to severe traumatic brain injury).
The task of localizing focal epileptiform activity is facili- Figure 1.4 Surface-negative epileptiform discharge, of greatest
tated by having in mind a spatial image of the electrical extent at electrode C3 (see text for details).
p 01.qxd 3/10/08 9:33 AM Page 27
illustrated in Figure 1.5, there are five channels to consider: ‘looking’ up, the pen goes up, but if one is ‘looking’ down
Fp1⫺A1, F3⫺A1, C3⫺A1, P3⫺A1, and O1⫺A1. Channel the pen likewise goes down.
Fp1⫺A1, with both electrodes ‘seeing’ the same potential, The situation with bipolar recordings is quite different:
would register no difference; channel F3⫺A1 would see a here, it is not amplitude that is important but a phenome-
difference of 25 μV (i.e., looking up from a depth of ⫺50 to non known as phase reversal (Knott 1985; Lesser 1985).
the surface, which is at ⫺25); channel C3⫺A1 would see a Take the same example of an electrical paroxysm as used
difference of 75 μV (looking up from a depth of ⫺100 to above, but this time cover it, as illustrated in Figure 1.6,
the surface at ⫺25); channel P3⫺A1 a difference of 25 μV with a longitudinal chain of electrodes, starting at Fp1 and
(looking up from ⫺50 to ⫺25), and the last channel, including, sequentially, F3, C3, P3, and O1. Then construct
O1⫺A1, with both electrodes seeing ⫺25 μV, would regis- the following channels: Fp1⫺F3, F3⫺C3, C3⫺P3, and,
ter 0. As seen in Figure 1.4, the greatest pen deflection is finally, P3⫺O1. Now consider what each channel will
seen in the channel containing the electrode, in this exam- record. For channel Fp1⫺F3, one looks down from Fp1 at
ple C3, which lies over the deepest part of the electrical ⫺25 to F3 at ⫺50, for a difference of ⫺25 μV. For the next
chasm. Thus, with referential recordings, it is the channel channel, F3⫺ C3, one continues to look down into the elec-
showing the greatest amplitude that serves to localize the trical chasm, now looking down from ⫺50 to ⫺100, for a
focus of the electrical paroxysm. difference of ⫺50 μV. At the next channel, C3⫺P3, how-
It may be noted that the pen deflections in channels ever, something very different happens; here, standing at
F3⫺A1, C3⫺A1, and P3⫺A1 are all positive, and this is the nadir of the chasm at ⫺100, one is looking ‘up’ to ⫺50,
according to the convention (Knott 1985) that whenever, for a difference of ⫹50 μV. Similarly, for the next channel,
in going from the first to second lead of any channel, one is P3⫺O1, one continues to look up, but here from ⫺50 to
⫺25, for a difference of ⫹25 μV.
Figure 1.6 shows the various pen tracings seen for each
channel. As may be noted, both channels Fp1⫺F3 and
Fp1 Fp2
F7 F8
F3 F4
Fz
Fp1 Fp2
A1 T3 C3 Cz C4 T4 A2 F7 F8
F3 F4
Fz
P3 Pz P4
A1 T3 C3 Cz C4 T4 A2
T5 T6
O1 O2
P3 Pz P4
T5 T6
O1 O2
Fp1–A1
F3–A1 Fp1–F3
C3–A1 F3–C3
P3–A1 C3–P3
O1–A1 P3–O1
Figure 1.5 Referential recording of the epileptiform discharge Figure 1.6 Bipolar recording of the epileptiform discharge
shown in Figure 1.4 (see text for details). shown in Figure 1.4 (see text for details).
p 01.qxd 3/10/08 9:33 AM Page 28
F3⫺C3 show a downward or negative pen deflection. What PERIODIC COMPLEXES

happens next, however, is most critical: the next two chan-
nels, C3⫺P3 and P3⫺O1, both show an upward or positive Periodic complexes generally consist of one or more sharp
deflection. It is apparent here that there has been a phase waves combined with one or more slow waves that recur
reversal as one goes from channel F3⫺C3 to channel on a regular basis, at intervals ranging from 1 to 15 sec-
C3⫺P3. This indicates that, in going from channel F3⫺C3 onds, often on a background of generalized slowing.
to channel C3⫺P3, one has ‘crossed’ over the depth of the Although they may begin with a focal predominance, they
electrical chasm; furthermore, as the electrode that both fairly soon become generalized and synchronous, often
these channels have in common is C3, it is now clear that with a frontal prominence. Such periodic complexes are
the depth of the chasm lies under that electrode; that is to often associated with myoclonus and are classically seen in
say phase reversal is seen at electrode C3. such disorders as subacute sclerosing panencephalitis
In some cases, focal epileptiform activity will not exhibit (Cobb 1966; Cobb and Hill 1950) and Creutzfeldt–Jakob
phase reversal with a bipolar montage. Specifically, when disease (Aguglia et al. 1987; Burger et al. 1972; Chiofalo et al.
the focus is either proximal to the start of the chain or dis- 1980; Levy et al. 1986; Steinhoff et al. 1996). Importantly,
tal to its end, phase reversal is not possible. For example, although almost all patients with Creutzfeldt–Jakob dis-
consider a longitudinal chain linking Fp1, F3, C3, P3, and ease eventually develop periodic complexes (Browne et al.
O1, and then imagine that the focus is located anterior to 1986) (generally within the first 3 months [Levy et al.
Fp1. In this case, all the pen deflections will be positive. 1986]), these may be absent (Bortone et al. 1994; Zochodne
Conversely, if the focus were distal to O1, all the pen deflec- et al. 1988), and this appears to be particularly the case with
tions would be negative. new-variant Creutzfeldt–Jakob disease (Will et al. 1996).
Periodic complexes have also been noted in various other
conditions, including herpes simplex viral encephalitis
Ictal activity (Upton and Gumpert 1970), post-anoxic encephalopathy
Ictal discharges consist of rhythmic activity that, unlike (Hockaday et al. 1965), Alzheimer’s disease and diffuse
interictal epileptiform discharges, is sustained, at the very Lewy body disease (Doran and Larner 2004; Tschampa et al.
least, for a matter of seconds, with most ictal discharges 2001), and baclofen intoxication (Hormes et al. 1988).
lasting minutes. These ictal discharges may be either gener- Triphasic waves constitute a specific kind of periodic
alized at the onset or display a focal onset. complex. These are slow waves that, as the name indicates,
Ictal discharges that are generalized from the onset are possess a triphasic morphology. They typically occur in a
typically seen in the idiopathic generalized epilepsies: generalized, bilaterally synchronous fashion, often with a
myoclonic seizures are typically accompanied by polyspike frontal predominance, either singly, in an isolated fashion,
or polyspike-and-wave sustained discharges, and petit mal or in longer bursts. Although they are classically associated
seizures by sustained spike-and-dome discharges very sim- with hepatic encephalopathy (Karnatze and Bickford 1984;
ilar to those seen interictally (Browne et al. 1974). Summerskill et al. 1956), they may be seen in other types of
Ictal discharges that are focal at the onset may remain so metabolic delirium (Fisch and Klass 1988) such as that of
for the duration of the seizure, and in most of these cases, uremia, hypercalcemia, hypoglycemia, hypernatremia, or
clinically one sees a simple partial seizure of one sort or the hyponatremia, and have also been noted in a toxic delir-
other. In cases when there is spread to a more or less focal ium secondary to lithium (Kaplan and Birbeck 2006).
area contralaterally a complex partial seizure is often seen, Periodic lateralized epileptiform discharges (PLEDS) con-
and in those cases when the generalization involves the stitute another specific form of periodic complex. These
entire cortex, a grand mal seizure is the typical accompani- consist of lateralized epileptiform discharges (either spikes
ment. Although in some cases in which there was some pre- or sharp waves) that occur with a fairly regular periodicity,
ceding interictal epileptiform activity the ictal discharges varying from once every half a second to every 5 seconds
may resemble the interictal ones, in most cases ictal dis- (Chatrian et al. 1964; Markand and Daly 1971). As described
charges are morphologically different (Blume et al. 1984; in two large studies (Garcia-Morales et al. 2002; Gurer et al.
Geiger and Horner 1978). In general, the ictal activity is 2004), in most cases PLEDS are associated with lesions
rhythmic and may occur at any frequency, from delta to affecting the cortex. Although subcortical white matter
beta; rarely, instead of primarily a change in frequency, one lesions may also be responsible, this is far less common; the
may see a change in amplitude, namely an ‘electrode- most common lesions are infarctions, followed by tumors,
cremental’ pattern in which the seizure is accompanied abcesses, and subdural hematomas. Other conditions include
only by a paroxysmal loss of amplitude. Creutzfeldt–Jakob disease, herpes simplex encephalitis,
Remarkably, in the case of partial seizures, the surface and post-anoxic encephalopathy and, rarely, alcohol with-
EEG may remain normal, even in the face of indisputable drawal (Chu 1980). In most cases, PLEDS occur during the
seizures. In the case of simple partial seizures (Cockerell et al. acute onset of these underlying lesions and then gradually
1996; Devinsky et al. 1989; Seshia and McLachlan 2005) this remit; in a small minority of cases, however, they may per-
is seen in the majority; however, with complex partial seizures sist chronically. Clinically, most patients will also have
it is noted in only a very small percentage (Lieb et al. 1976). seizures (Baykan et al. 2000); importantly, however, with
p 01.qxd 3/10/08 9:33 AM Page 29
rare exceptions (Singh et al. 2005), the PLEDS themselves do (Holmes et al. 2004), except in patients with treatment-
not constitute ictal discharges, but, from an electroencephalo- resistant focal seizures, in whom it occurred in one-quarter
graphic point of view, constitute innocent bystanders. of all patients (Guaranha et al. 2005).
Bilateral independent periodic lateralized epileptiform Hyperventilation is generally contraindicated in
discharges (BIPLEDS) constitute a variant of PLEDS, with, patients with sickle cell disease (Protass 1978) or those with
as the name suggests, the appearance of these lateralized significant cerebrovascular or cardiovascular disease.
epileptiform discharges first on one side, then the other.
This pattern may be seen in herpes simplex encephalitis or
anoxic encephalopathy (de la Paz and Brenner 1981), and PHOTIC STIMULATION
with bilateral infarctions of the frontal (Nicolai et al. 2001),
Photic stimulation is accomplished by positioning a stro-
or temporal lobes (Fushimi et al. 2003).
boscopic light about 30 cm from the patient’s face, the eyes
being either open or closed. The light is then flashed at var-
BURST-SUPPRESSION ious frequencies (e.g., 3, 5, 10, 13, 15, 17, 20, and 25 Hz),
each frequency being allotted about 10 seconds. In about
The burst-suppression pattern is characterized by bursts of
two-thirds of normal adults this stroboscopic illumination
generalized, bilaterally symmetric and synchronous delta
will produce the photic driving response, wherein bilater-
activity, lasting in the order of 1–3 seconds and occurring
ally symmetric and synchronous waves appear at a fre-
every 3–10 seconds, in between which the background
quency equal to either the stroboscopic frequency or some
activity is suppressed to a very low amplitude or, at a nor-
harmonic of it (Hughes 1960). Normally, although the
mal sensitivity, to a flat line. This pattern is seen in states of
photic driving is maximal occipitally, it may extend to the
severe cortical dysfunction, for example subacute scleros-
parietal or temporal area. Maximal photic driving is gener-
ing panencephalitis (Markand and Panzi 1975), viral
ally seen when the strobe frequency is close to the patient’s
encephalitis, or post-anoxic coma (Hockaday et al. 1965).
normal alpha rhythm and, as with the alpha rhythm, the
Although it is typically bilateral, it may occasionally be seen
amplitude of the photic driving response is often lower on
unilaterally, as for example after a very large infarction.
the left side. With very high-frequency stroboscopic activ-
ity the resultant wave forms may resemble spikes.
Abnormalities seen with photic driving include unex-
Activation procedures
pected amplitude asymmetries, photomyoclonic responses,
and photoparoxysmal responses. Amplitude asymmetries
Hyperventilation, photic stimulation, and sleep are all con-
wherein the left side has an amplitude of less than 50 per-
sidered to be activation procedures in that they may acti-
cent that of the right, or wherein the right side has an
vate certain abnormalities that would otherwise not be
amplitude less than that of the left, indicate a definite
apparent on the routine EEG. In patients suspected of hav-
abnormality. The photomyoclonic response (Meier-Ewert
ing reflex seizures, exposing the patient to the putative
and Broughton 1976) consists of a myoclonic twitching of
epileptogenic stimulus may also be considered in order to
the eyelids and, in severe cases, myoclonus of the head and
activate the focus.
neck; it may be seen in a very small minority of normal
individuals (Kooi et al. 1960) and more commonly in those
HYPERVENTILATION withdrawing from alcohol or sedative hypnotics (Fisch et al.
1989; Gastaut et al. 1958). The photoparoxysmal response
Hyperventilation is normally followed by a build-up of
consists of epileptiform changes (Bickford et al. 1952) and
generalized, bilaterally symmetric and synchronous high-
is most common in those with petit mal or one of the other
amplitude slow waves, maximal frontally in adults (Goldberg
idiopathic generalized epilepsies (Stevens 1962; Wolf and
and Strauss 1959). Abnormalities that may occur include
Gooses 1986). A minority of patients with the photoparox-
asymmetric or focal slowing and epileptiform abnormali-
ysmal response will experience a seizure during the photic
ties. Asymmetric or focal slowing has the same significance
stimulation (Seddigh et al. 1999).
as spontaneous slowing, as discussed previously in this
chapter. Epileptiform abnormalities are very common in the
case of petit mal seizures, with most of these patients show- SLEEP
ing typical 3-Hz spike-and-dome epileptiform changes
(Dalby 1969); indeed, in these patients hyperventilation is Sleep may activate epileptiform activity (Sammaritano et
a more sensitive diagnostic procedure than is a 6-hour al. 1991); indeed, IEDs are seen only during sleep in up to
recording (Adams and Lueders 1981). In the case of complex one-third of patients with complex partial seizures
partial seizures, however, only a small minority of cases (Niedermeyer and Rocca 1972). The sleep portion of the
will display activation (Adams and Lueders 1981; Gabor and recording should last at least 20 minutes and include both
Ajmone-Marsan 1969; Miley and Forster 1977; Morgan stages I and II of sleep. In some cases, patients will simply
and Scott 1970). In addition to IEDs, seizures may also be drift off to sleep on their own at the end of the awake
induced by hyperventilation but this is very uncommon recording session, whereas in others the administration of
p 01.qxd 3/10/08 9:33 AM Page 30
chloral hydrate will be required. Some authors recommend generally last about a minute and are most commonly seen
sleep deprivation not only to ensure that the patient falls with hyperventilation in the elderly.
asleep during the recording, but also in the belief that sleep Rhythmic mid-temporal discharges (Gibbs et al. 1963;
deprivation per se is activating: this is a controversial Klass and Westmoreland 1985), also known as rhythmic
notion, supported by some (Ellingson et al. 1984; Leach et theta bursts of drowsiness, consist of lengthy trains of
al. 2006; Mattson et al. 1965), but not all, studies (Pratt et rhythmic theta activity that occur in both temporal areas,
al. 1968; Veldhuizen et al. 1983). In interpreting a sleep either synchronously or independently. The trains them-
EEG it is important to distinguish epileptiform activity selves often last about 10 seconds but they may endure for
from normally occurring POSTs and vertex sharp waves. as long as a minute. This variant was once referred to as the
In addition to revealing epileptiform abnormalities, sleep psychomotor variant but this terminology has been aban-
recordings may, at times, reveal other abnormalities, for doned as there is no connection between rhythmic mid-
example the early onset of REM sleep as may be seen in temporal discharges and complex partial seizures.
narcolepsy or in alcohol or anxiolytic withdrawal (Kales Ctenoids, also known as ‘14- and 6-cps positive bursts’
et al. 1974). (Klass and Westmoreland 1985; Lombroso et al. 1966)
consist of brief trains, lasting half a second to one second,
REFLEX ACTIVATION
of 6- or 14-Hz rhythmic waves that occur in the temporal
regions either independently or in a bilaterally synchro-
In cases of definite or suspected ‘reflex’ epilepsy, it may be nous fashion. They are best seen during stages I and II of
appropriate, as discussed in Section 7.3 to expose the sleep, and the waves themselves have a distinctive arciform
patient to the triggering event itself. Thus, in ‘musicogenic’ morphology.
epilepsy, the appropriate tune may be played, and in ‘read- Wicket spikes (Klass and Westmoreland 1985; Reiher
ing’ epilepsy, the appropriate passage read, etc. Consider- and Lebel 1977) consist of brief trains of rhythmic activity
ation must, of course, be given to the risk of inducing a at a frequency of 6–11 Hz, which are most prominent in
seizure during the recording. the temporal regions where they may appear independ-
ently or in a bilaterally synchronous fashion. Like ctenoids,
the waves themselves have an arciform morphology. In
Normal variants some cases, rather than trains, wicket spikes may occur in
an isolated fashion: such isolated wicket spikes may be dis-
Normal variants may resemble epileptiform changes (e.g., tinguished from IEDs by the absence of a following slow
small sharp spikes [SSS]) or pathologic slow waves (e.g., wave (Krauss et al. 2005).
subclinical rhythmic EEG discharges of adults [SREDA]). Lambda waves (Barlow and Ciganek 1969; Evans 1953;
SSS, also known as benign epileptiform transients of Green 1957; Scott et al. 1967) are isolated, bilaterally syn-
sleep (BETS), are, as the name suggests, low-amplitude, chronous occipital waves that occur just after saccadic eye
very sharp spikes (i.e., less than 50 μV in amplitude and less movements made by patients as they scan a detailed scene
than 50 ms in duration) that are seen intermittently during or picture. The waves themselves are of 20–50 μV in ampli-
drowsiness in both temporal areas, either intermittently or in tude and 200–300 ms in duration; they have a characteris-
a bilaterally synchronous fashion (Klass and Westmoreland tic triangular or sawtooth-shaped morphology. These may
1985; White et al. 1977). be eliminated by having the patient stare at a blank sheet of
Phantom spike-and-wave (also known as 6-cps spike- paper, and this technique should be utilized and noted by
and-wave) (Klass and Westmoreland 1985; Thomas and the EEG technologist.
Klass 1968) is characterized by brief trains of rhythmic 6-
Hz activity that are generalized, bilaterally symmetric, and
synchronous, generally lasting no longer than a second or Artifacts
two. The name comes from the fact that the rhythmic
activity is composed of a peculiar spike-and-wave complex Artifacts may be grouped according to the EEG activity that
wherein the spike is of such relatively low amplitude and they most closely resemble, including interictal epilepti-
brevity that, next to the much more prominent wave, it, form discharges, slow waves, or decreased amplitude. There
like the ‘Phantom’, is rarely seen. is also a 60-cps artifact, which is usually readily identified as
‘Occipital spikes of blind persons’, an aptly named elec- it does not resemble any naturally occurring EEG activity.
trographic syndrome, may be seen in patients with con-
genital or acquired blindness and is characterized by RESEMBLING INTERICTAL EPILEPTIFORM DISCHARGES
intermittent spikes confined to the occipital area.
SREDA (O’Brien et al. 1998; Westmoreland and Klass Drip artifact (Linnenger et al. 1981) reflects the electrical
1981) is characterized by lengthy trains of rhythmic theta disturbance occurring each time a drip occurs in an intra-
or, less commonly, delta activity, seen best in the centro- venous line. It may appear so similar to an epileptiform
parietal areas. The trains themselves are often of abrupt discharge that its correct identification may depend on the
onset and may be preceded by some sharp waves. They EEG technician noting on the record when the drips occur.
p 01.qxd 3/10/08 9:33 AM Page 31
Electrode pop reflects, as it were, a sudden ‘spark’ at an head movements that occur either with respiration or,
individual electrode, often occurring secondary to some when present, tremor. The regularity of the resulting arti-
impurity. Although it strongly resembles an epileptiform fact, the identity of its frequency with the respiratory rate
spike the fact that it is restricted to one electrode betrays its or the tremor frequency, and its restriction to the occipital
artifactual nature, as true epileptiform spikes are almost leads all highlight its true nature.
always seen at more than one electrode. Glossokinetic artifact occurs with tongue movement.
Electrocardiography (ECG) artifact represents cardiac The tip of the tongue is negative, and its up and down
electrical activity picked up by the EEG. In the case of a reg- movement may produce slow waves in the frontal or tem-
ular cardiac rhythm, its artifactual nature is immediately poral areas. Asking the patient to say ‘la la la’ during the
obvious as epileptiform spikes simply do not occur with recording allows for ready identification of this artifact.
such monotonous regularity. When irregularly occurring Pulse artifact occurs in situations when an electrode is
premature ventricular contractions are present, however, accidentally placed over a relatively large scalp artery,
the distinction may be more difficult and indeed may which, with every passing pulse, slightly moves the elec-
depend on simultaneously recording the ECG. trode resting on it. The fact that the resulting artifact
Muscle artifact reflects electrical activity arising from occurs at a regular rate, identical to the cardiac rate, sug-
the contraction of the scalp musculature and may appear gests its true identity: in doubtful cases, a simultaneous
in any one of three ways: as isolated irregularly appearing ECG will reveal that the pulse artifact follows, after a slight
‘blips’, or as ‘blips’ superimposed on a ‘muddy’ black line, delay, every QRS complex, the delay reflecting the time
the blips occurring either arrhythmically or rhythmically. required for the pulse to travel from the heart to the scalp.
The key to the identification of muscle ‘blips’ is their Perspiration on the scalp, as may occur if the patient is
extreme brevity. febrile or anxious, both alters the resistance of the overly-
ing electrodes and allows for some slight slippage between
RESEMBLING SLOW WAVES the electrodes and the scalp: the resulting artifact consists
of very slow waves (e.g., 0.5 Hz) of very high amplitude,
Eye movements may induce artifacts (Peters 1967). In the which occur in a generalized, bilateral, but asynchronous
case of vertical movements, the artifact is seen in the fashion.
frontopolar leads and, if horizontal, in the anterior tempo-
ral leads. Heuristically, the eye may be considered to be a RESEMBLING DECREASED AMPLITUDE
‘battery’, the cornea being positive and the retina negative:
thus, whichever electrode the eye ‘looks’ toward becomes Increased electrode resistance may lead to what appears to
more positive, and whichever one the eyes ‘look’ away be decreased amplitude at one electrode. Its restriction,
from becomes, conversely, more negative. Consider, for however, to but one electrode betrays its artifactual nature
example, the results with a longitudinal bipolar montage as pathologic conditions capable of causing decreased
when the patient engages in horizontal eye movement amplitude are rarely so restricted in location that they will
looking to the left: F7 becomes more positive relative to T3, be reflected at only one electrode position.
and thus, in the channel F7⫺T3 the pen deflection is down- Defective calibration of one channel may result in a
wards; conversely, F8 becomes more negative relative to T4, decreased deflection of that channel’s pen. Its isolation to
and thus, in channel F8⫺T4, the pen deflection is up. Next, one pen suggests the correct diagnosis; furthermore, the
consider the situation with vertical eye movements, as fact that the same pen continues to show decreased deflec-
occurs during a blink (Matsuo et al. 1975), recalling that tion with changing montages confirms the diagnosis.
when a blink occurs, the eyes, in Bell’s phenomenon,
undergo upward rotation. In this case, both frontopolar SIXTY CYCLE PER SECOND ARTIFACT
electrodes, Fp1 and Fp2, become positive relative to their
immediate neighbors, F3 and F4, and thus channels Fp1⫺F3 A 60-Hz artifact occurs secondary to interference from a
and Fp2⫺F4 both show a negative deflection. Eye move- nearby alternating current source, typically appearing on
ment artifacts, whether horizontal or vertical, are sug- the EEG as a thick ‘muddy’ line. If there is any doubt as to
gested by their bilateral synchrony. In the case of the source of such a ‘muddy’ line, lowering the paper speed
horizontal movements, a further indication is the fact that to 15 mm/s will confirm the diagnosis by allowing the res-
the resulting pen deflections on either side are in opposite olution of the line into orderly 60-Hz deflections.
directions. In the case of vertical eye movements occurring
with blinking, the occurrence of eyelid flutter may make
identification a little more difficult because the resulting 1.6 LUMBAR PUNCTURE
artifact will appear similar to a bifrontal slow wave focus.
Movement artifact occurs when the electrodes are actu- In the not-too-distant past, lumbar puncture was a stan-
ally moved, as most commonly occurs when the occipital dard procedure and it was the rare neuropsychiatric
electrodes (pressed between the patient’s head and the patient admitted to hospital who escaped this procedure.
underlying pillow) are slightly dislodged by the minimal Although the need for this test has dropped dramatically
p 01.qxd 3/10/08 9:33 AM Page 32
with the advent of modern neuroimaging using CT and the appropriate area, the target may be marked by indent-
MRI, there are still certain clinical situations, as discussed ing the skin with a fingernail. The area is then prepped with
below, in which it is vital. This section will discuss the indi- betadine and alcohol, and sterile drapes are placed. Most
cations and contraindications for lumbar puncture, its physicians will then infiltrate the superficial tissues with
technique and complications, and the various tests, both half a cubic centimeter of a local anesthetic; however,
standard and otherwise, that may be ordered. some, on the theory that this puncture causes as much pain
as the actual lumbar puncture, will forgo it. In order to
reduce the risk of a post-lumbar puncture headache (Evans
Indications and contraindications et al. 2000), a 20- or 22-gauge needle should be used
(higher gauge needles, up to 26 gauge, are even safer in this
Lumbar puncture is indicated in cases of encephalitis or regard [Tourtellotte et al. 1972], but given their small size
meningitis, and in those uncommon cases wherein sub- the flow of CSF may be quite sluggish), and the bevel of the
arachnoid hemorrhage is strongly suspected although the needle should be parallel to the longitudinal axis of the
CT scan is negative. Lumbar puncture is also indicated patient, as this angle allows for separation, rather than lac-
when the following disorders are suspected: neurosyphilis, eration, of dural fibers. Atraumatic needles are even less
multiple sclerosis, Creutzfeldt–Jakob disease, certain cases prone to cause headache (Lavi et al. 2006; Strupp et al.
of vasculitis, and benign intracranial hypertension. 2001) but they are more difficult to use. The needle itself
Lumbar puncture is contraindicated when there is should be held perpendicular to the patient’s back and
infection of any of the tissues near the site of the proposed angled slightly cephalad, generally toward the patient’s
puncture. Conditions that present a risk of bleeding during umbilicus (with due regard for sagging umbilici in obese
the puncture also constitute contraindications, and these patients). The needle is then gently inserted: at a depth of
include thrombocytopenia (with platelet counts below from 4 to 5 cm, there is often a palpable ‘give’ as the dura is
50 000) and treatment with either heparin or warfarin. In pierced, followed by a less obvious ‘pop’ when the arach-
cases when puncture must be performed, consideration noid is punctured. Once these landmark events have tran-
may be given to use of platelet transfusion, protamine, or spired, the stylet should be slowly removed (rapid removal
vitamin K. Evidence of increased intracranial pressure is may suck a nerve rootlet into the lumen) and one should
often considered a contraindication, but this holds only watch to see if any fluid emerges. ‘Dry taps’ generally indi-
where there is a risk of herniation, whether subfalcine, cate improper placement and, if the patient is tolerating
uncal, transtentorial, or cerebellar. Thus, the presence of the procedure, the stylet should be replaced, the needle
mass lesions and acute infarctions generally argue against gently withdrawn, and another attempt made. As fluid
lumbar puncture. However, there are some cases of raised emerges, the patient may be allowed to relax and to slightly
intracranial pressure wherein the risk of herniation is low, extend the legs. In cases when an opening pressure is
as for example in benign intracranial hypertension and desired, a manometer is attached to the needle and the
some cases of subarachnoid hemorrhage; in these instances pressure of water read (in centimeters). Given that com-
lumbar puncture may be safely performed and indeed may pression of the abdomen may elevate the pressure, it is nec-
be carried out therapeutically. As a rule, imaging with essary for obese patients to relax their legs sufficiently to
either CT or MRI should be performed in every patient release any pressure on the abdomen before reading the
before lumbar puncture: the only exception here would be pressure. In any case, the CSF is then collected into three
when bacterial meningitis is strongly suspected and delay containers and these are then promptly sealed. When suffi-
could prove fatal. cient fluid has been obtained, the stylet is replaced, the nee-
dle is withdrawn, and firm pressure is applied to the
puncture site, followed by the application of an adhesive
Technique (Roos 2003) plaster. The patient may then be allowed to be up ad lib;
bed rest at this point does not decrease the risk of a post-
The patient is placed in the left lateral decubitus position lumbar puncture headache (Dieterich and Brandt 1985).
on a firm surface, with his or her back brought up to the Recently, it has become common to perform lumbar
edge of the bed or gurney. Pillows are placed under the puncture under fluoroscopic guidance, with the procedure
head and neck as well as between the legs, and the back is itself performed by a radiologist.
kept strictly vertical by assuring that the right shoulder and
hip are directly above the left shoulder and hip, respec-
tively. The patient is then helped into a fetal position by Complications
flexing the head and legs, thus opening the spaces between
the spinous processes. In adults, the needle should gener- The most common complication of a lumbar puncture is
ally be inserted in the L3⫺L4 interspace, a spot which may headache and this may occur in about one-quarter of all
be found by palpating the superior iliac crests and then cases. The headache occurs typically a day or two after the
drawing an imaginary line between them: the appropriate puncture, and may last from days to a couple of weeks: it
interspace generally lies just below this line. After palpating is generalized and may be either steady or throbbing in
p 01.qxd 3/10/08 9:33 AM Page 33
character, and is worse when sitting or standing and gener- be distinguished by centrifuging the first tube, and inspect-
ally relieved by recumbancy. Treatment involves bed rest ing the supernatant. In traumatic taps the supernatant is
and analgesics; caffeine sodium benzoate, in a dose of clear, whereas in subarachnoid hemorrhage the presence of
500 mg i.v., may also be used and is typically dramatically hemolyzed red cells creates xanthochromia. Importantly,
effective (Choi et al. 1996). If these fail, and the headache is however, xanthochromia may be absent early on, for, as
severe, a ‘blood patch’ may be placed by injecting about 10 noted above, hemolysis generally takes at least 8 hours
cubic centimeters (cm3) of the patient’s blood on to the to occur.
puncture site: this procedure, however, should not be rou-
tine for it may cause a radiculopathy in up to one-third of CELL COUNT AND DIFFERENTIAL
all cases. The mechanism underlying the headache involves
leakage of fluid through the dural hole, which allows the Normal CSF is free of red cells but may contain up to five
brain to ‘sag’, thus stretching pain-sensitive structures. white cells, either lymphocytic or mononuclear. Red cells
This sagging may also stretch cranial nerves, resulting in may be seen in subarachnoid hemorrhage and cases of either
tinnitus, deafness, or diplopia; rarely, these cranial nerve contusion or intracerebral/intraventricular hemorrhage.
palsies may occur in the absence of headache. A pleocytosis, i.e., increased number of white cells, is
Other complications include backache, subarachnoid seen in a large number of conditions. Note that a polymor-
bleeding, radiculopathy, and, as noted above, herniation. phonuclear predominance generally indicates a bacterial
infection: although viral, fungal, or tubercular infections
may initially display a polymorphonuclear predominance
Standard measurements a lymphocytic one is far more common, especially after the
infection has passed the acute stage.
A number of determinations are considered standard and When the CSF is frankly bloody, as in subarachnoid
should be requested in all cases. These include the appear- hemorrhage or with a traumatic tap, the CSF white blood
ance of the fluid, cell count and differential, total protein, count (WBC) is of course elevated by white cells derived
glucose, stain and appropriate culture, and tests for directly from the systemic circulation. As a rule of thumb,
syphilis. Measurement of the opening pressure was once one may correct for this by subtracting one white cell from
standard but is now rarely required. the total CSF count for every 1000 red cells.
Total protein
APPEARANCE
Most of the protein in the CSF consists of albumin; other
Normal CSF is crystal clear. A ‘ground glass’ appearance constituents include gamma-globulins, other globulins
may occur in the presence of 200 or more red blood cells (alpha and beta) and prealbumin. The total protein in nor-
(RBCs), whereas red counts over 1000 may impart a pink- mal CSF ranges from 15 to 45 mg/dL.
ish cast to the fluid. A hazy fluid may occur in the presence When the fluid is grossly bloody, the total protein is
of 200 or more white cells, and larger white counts may corrected by subtracting about 1 mg for each 1000 RBCs.
make the fluid cloudy in appearance.
Xanthochromia, or a yellowish discoloration, may Glucose
occur in any situation when the total protein is over Normally, CSF glucose runs anywhere from 50 to 65 per-
150 mg/dL. Such a discoloration may also occur in jaun- cent of serum glucose and hence normal CSF values range
dice (serum bilrubin ⬎6 mg/dL), cases of carotenemia and from 45 to 80 mg/dL. In all cases, the serum glucose should
in patients treated with rifampin. Another very important be measured, however, given that 2–4 hours are required
cause of xanthochromia is hemolysis (as may be seen eight for equilibration between serum and CSF, the timing of the
or more hours after a subarachnoid hemorrhage), wherein blood draw varies according to the fed state of the patient:
lysed red cells leak hemoglobin breakdown products, such when the patient is fasting, the blood draw may be just
as bilirubin, into the CSF. before the puncture; when the patient has eaten, however,
Frankly bloody CSF may occur either in cases of sub- the blood draw should be 2–4 hours before the scheduled
arachnoid hemorrhage or after a traumatic, or ‘bloody’, puncture.
tap. Traumatic taps occur in about 10 percent of lumbar Elevated CSF glucose is of no concern. Reductions in
punctures and, rather than reflecting poor technique, they CSF glucose may occur with hypoglycemia, in bacterial or
generally result from the accidental nicking of a vein in the fungal meningitides, or other inflammatory disorders.
epidural plexus. These two possibilities may be differenti-
ated by the ‘three-tube test’, wherein one simply watches Stains and cultures
for any change in appearance between the first, second, The CSF should always be Gram-stained and, whenever
and third tubes collected. In subarachnoid hemorrhage, tuberculosis is suspected, an acid-fast stain should also be
the fluid in the third tube is as bloody as that in the first, requested. An ‘India ink prep’ is traditional when crypto-
whereas in a traumatic tap there is substantial clearing of coccal infection is suspected; however, the availability of
the fluid by the third tube. These two conditions may also polymerase chain reaction (PCR) assays has made this
p 01.qxd 3/10/08 9:33 AM Page 34
almost superfluous. Appropriate cultures should also be Oligoclonal bands, that is to say anywhere from three to
requested, whether bacterial, tubercular, or fungal. five bands seen on electrophoresis, are seen in a number of
conditions, including multiple sclerosis, lupus, Behçet’s
Tests for syphilis syndrome, neurosarcoidosis, and infections, whether viral,
It is good practice to always request a CSF-VDRL test with bacterial, or fungal.
titer. Furthermore, in cases where the clinical picture is con- Myelin basic protein is found in diseases characterized
sistent with neurosyphilis but the CSF-VDRL is negative it is by myelin breakdown, such as multiple sclerosis. An
entirely appropriate to obtain a CSF-FTA, given that the increased myelin basic protein, however, is certainly not
CSF-FTA is a far more sensitive test than the CSF-VDRL specific for multiple sclerosis, being found in various other
(Davis and Schmitt 1989; Timmermans and Carr 2004). conditions, such as encephalitis, lupus, vasculitidies, and
recent infarction.
Opening pressure The 14-3-3 protein should be tested for in suspected
cases of Creutzfeldt–Jakob disease. Although this is very
Measurement of the opening pressure, although once con- sensitive for Creutzfeldt–Jakob disease, false-positives have
sidered standard, is rarely required in modern practice: one been noted in large number of conditions such as encephali-
exception consists of cases of suspected benign intracranial tis, recent infarction, multiple sclerosis, Hashimoto’s
hypertension. The normal opening pressure ranges from encephalopathy, paraneoplastic limbic encephalitis, astro-
6 to 20 cm of water; values of below 5 cm may be seen with cytoma, and even degenerative disorders such as Alzheimer’s
systemic dehydration, subarachnoid block, or following a disease, diffuse Lewy body disease, and amyotrophic lateral
prior lumbar puncture. Elevations of over 20 cm are seen scelerosis (Lemstra et al. 2000; Martinez-Yelamos et al. 2001;
in cases of benign intracranial hypertension, meningitis, Van Everbroeck et al. 2005).
cerebral venous occlusion, and with mass lesions, hemor-
rhages, or acute infarctions.
REFERENCES
Other determinations
Other determinations are requested depending on one’s Adams DJ, Lueders H. Hyperventilation and 6-hour EEG recording
diagnostic suspicions, and may include PCR assay and test- in evaluation of absence seizures. Neurology 1981;
ing for various antibodies and antigens: in these regards, 31:1175–7.
consultation with an infectious disease specialist, if not Adams DJ, Lueders H, Pippinger CH. Sodium valproate in the
already in the works, is always appropriate, given the rapid treatment of intractable seizure disorders: a clinical and
advances made in these fields. Other tests to consider electroencephalographic study. Neurology 1978; 28:152–7.
include the immunoglobulin G (IgG) index, oligoclonal Aguglia U, Farnarier G, Tinuper P et al. Subacute spongiform
bands, myelin basic protein and the 14-3-3 protein. encephalopathy with periodic paroxysmal activities: clinical
Polymerase chain reaction assay represents a rapid, sen- evaluation and serial EEG findings in 20 cases. Clin
sitive, and specific means for detecting various infections. Electroencephalogr 1987; 18:147–58.
Viruses detected include herpes simplex, varicella zoster, Aird RB, Shimizu M. Neuropathological correlates of low-voltage
Epstein-Barr, JC virus, HIV, and cytomegalovirus (CMV) EEG foci. Arch Neurol 1970; 22:75–80.
(Steiner et al. 2005). Furthermore, almost all bacteria may Ajmone-Marsan C, Zivin LS. Factors related to the occurrence of
also be identified (Poppert et al. 2005). Fungal and tuber- typical paroxysmal abnormalities in the EEG records of
cular infections may also be detected. epileptic patients. Epilepsia 1970; 11:361–81.
Antibodies to arboviruses, rabies virus, Borrelia burg- Akelaitis AJE. Psychiatric aspects of myxedema. J Nerv Ment Dis
dorferi and Coccidioides immitis may be tested for, as may 1936; 83:22–36.
antigens specific for Cryptococcus and Histoplasma, and Altman NR, Purser RK, Rost MJD. Tuberous sclerosis: characteristics
these should be ordered in the appropriate clinical setting. at CT and MR imaging. Radiology 1988; 167:523–32.
The IgG index provides a reliable measure of increased Andreasen NC. Affective flattening and criteria for schizophrenia.
production of IgG within the CNS. Elevations of total Am J Psychiatry 1979; 136:944–7.
IgG itself may represent a false-positive, given that the Armstrong P, Keevil SF. Magnetic resonance imaging. 2. Clinical
immunoglobulin level in the CSF reflects not only uses. BMJ 1991; 303:105–9.
intrathecal synthesis of globulin, but also transfer of globu- Barkovich AJ, Kjos BO. Gray matter heterotopias: MR
lins from the systemic circulation. Consequently, it is nec- characteristics and correlation with developmental and
essary to correct the CSF level by obtaining what is known as neurologic manifestations. Radiology 1992; 182:493–9.
the ‘IgG index’. The IgG index ⫽ (IgG[CSF]/IgG[serum])/ Barlow JS, Ciganek L. Lambda responses in relation to visual
(albumin[CSF]/albumin[serum]). IgG index values above evoked responses in man. Electroencephalogr Clin
0.65 indicate intrathecal synthesis. To calculate this, of Neurophysiol 1969; 26:183–92.
course, one must also obtain blood for a serum protein Barnes MP, Saunders M, Walls TJ et al. The syndrome of Karl
electrophoresis, and this should be done just before the Ludwig Kahlbaum. J Neurol Neurosurg Psychiatry 1986;
lumbar puncture. 49:991–6.
p 01.qxd 3/10/08 9:33 AM Page 35
References 35
Baykan B, Kinay D, Gokyigit A et al. Periodic lateralized Burger LJ, Rowan AJ, Goldensohn ES. Creutzfeldt–Jakob disease.
epileptiform discharges: association with siezures. Seizure An electroencephalographic study. Arch Neurol 1972;
2000; 9:402–6. 26:428–33.
Berger H. Uber das elektrenkephalogramm des menschen. Archiv Calzetti S, Bortone E, Negrotti A et al. Frontal intermittent
Psychiat Nervenkr 1929; 87:527–70. rhythmic delay activity (FIRDA) in patients with dementia with
Berkovic SF, Andermann F, Olivier A et al. Hippocampal sclerosis Lewy bodies: a diagnostic tool? Neurol Sci 2002; 23(suppl.
in temporal lobe epilepsy demonstrated by magnetic 2):S65–6.
resonance imaging. Ann Neurol 1991; 29:175–82. Caplan LR, Schoene WL. Clinical features of subcortical
Berry I, Brant-Zawadzki M, Osaki L et al. Gd-DTPA in clinical MR arteriosclerotic encephalopathy (Binswanger disease).
of the brain. 2. Extra-axial lesions and normal structures. AJR Neurology 1978; 28:1206–15.
1986; 147:1231–5. Caton R. The electrical currents of the brain. BMJ 1875; 2:278.
Beschin N, Cubelli R, Della Sala S et al. Left of what? The role of Chatrian GE. Characteristics of unusual EEG patterns: incidence,
egocentric coordinates in neglect. J Neurol Neurosurg significance. Electroencephalogr Clin Neurophysiol 1964;
Psychiatry 1997; 63:483–9. 17:471–2.
Betting LE, Mory SB, Lopes-Cendes I et al. EEG features in Chatrian GE, Petersen MC, Lazarte JE. The blocking of the rolandic
idiopathic generalized epilepsy: clues to diagnosis. Epilepsia wicket rhythm and some central changes related to
2006; 47:523–8. movement. Electroencephalogr Clin Neurophysiol 1959;
Bickerstaff ER. Neurological examination in clinical practice, 4th 11:497–510.
edn. Oxford: Blackwell Scientific, 1980. Chatrian GE, Shaw CM, Leffman H. The significance of periodic
Bickford RG, Sem-Jacobsen CW, White PT et al. Some lateralized epileptiform discharges in EEG: an electrographic,
observations on the mechanism of photic and photo-Metrazol clinical and pathological study. Electroencephalogr Clin
activation. Electroencephalogr Clin Neuropshysiol 1952; Neurophysiol 1964; 17:177–93.
4:275–82. Chatrian GE, Lettich F, Nelson PL. Ten percent electrode system
Bleuler E. Textbook of psychiatry, translated by Brill AA. New York: for topographic studies of spontaneous and evoked EEG
Macmillan, 1924. Reissued by Arno Press, New York, 1976. activities. Am J EEG Technol 1985; 25:83–92.
Blume WT, Young GB, Lemieux JF. EEG morphology of partial Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of
epileptic seizures. Electroencephalogr Clin Neurophysiol 1984; Cretuzfeldt–Jakob disease. Arch Neurol 1980; 37:143–5.
57:295–302. Choi A, Laurito CE, Cunningham FE. Pharmacologic management
Bories J, Derhy S, Chiras J. CT in hemispheric ischemic attacks. of postdural puncture headache. Ann Pharmacother 1996;
Neuroradiology 1985; 27:468–83. 30:831–9.
Bortone E, Bettoni L, Giorgi C et al. Reliability of EEG in the Choi SH, Na DL, Chung CS et al. Diffusion-weighted MRI in
diagnosis of Creutzfeldt–Jakob disease. Electroencephalogr vascular dementia. Neurology 2000; 54:83–9.
Clin Neurophysiol 1994; 90:323–30. Chrysikopoulos HS, Press GA, Grafe MR et al. Encephalitis caused
Bradley WG, Waluch W, Yadley RA et al. Comparison of CT and by human immunodeficiency virus: CT and MR imaging
MR in 400 patients with suspected disease of the brain and manifestations with clinical and pathological confirmation.
cervical spinal cord. Radiology 1984; 152:695–702. Radiology 1990; 175:185–91.
Brain W. Clinical neurology, 2nd edn. London: Oxford University Chu NS. Periodic lateralized epileptiform discharges with
Press, 1964. preexisting focal brain lesions: role of alcohol withdrawal and
Brant-Zawadzki M, Badami JP, Mills CM et al. Primary anoxic encephalopathy. Arch Neurol 1980; 37:551–4.
intracerebral tumor imaging: a comparison of magnetic Cobb WA. The periodic events of subacute sclerosing
resonance and CT. Radiology 1984; 150:435–40. panencephalitis. Electroencephalogr Clin Neurophysiol 1966;
Brant-Zawadzki M, Berry I, Osaki L et al. Gd-DTPA in clinical MR 21:278–94.
of the brain. 1. Intraaxial lesions. AJR 1986; 147:1223–30. Cobb WA, Hill D. Electroencephalogram in subacute progressive
Briel RC, McKeith IG, Barber WA et al. EEG findings in dementia encephalitis. Brain 1950; 73:392–404.
with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Cobb WA, Guiloff RJ, Cast J. Breach rhythm: the EEG related to skull
Psychiatry 1999; 66:401–3. defects. Electroencephalogr Clin Neurophsyiol 1979; 47:251–71.
Brown JJ, Hessellink JR, Rothrock JF. MR and CT of lacunar Cockerell OC, Rothwell J, Thomson PD et al. Clinical and
infarcts. Am J Neuroradiol 1988; 9:477–82. physiological features of epilepsia partialis continua. Cases
Browne P, Cathala F, Castaigne P et al. Creutzfeldt–Jakob disease: ascertained in the UK. Brain 1996; 119:393–407.
clinical analysis of a consecutive series of 230 Cooper R, Winter AL, Crown JJ et al. Comparison of subcortical,
neuropathologically verified cases. Ann Neurol 1986; cortical and scalp activity using indwelling electrodes in man.
20:597–602. Electroencephalogr Clin Neurophysiol 1965; 18:217–28.
Browne TR, Penry JK. Benzodiazepines in the treatment of Cornelius JR, Day NL, Fabrega H et al. Characterizing organic
epilepsy. Epilepsia 1973; 14:277–310. delusional syndrome. Arch Gen Psychiatry 1991; 48:997–9.
Browne TR, Penry JK, Porter RJ et al. Responsiveness before, Dalby MA. Epilepsy and three per second spike and wave rhythms.
during and after spike-wave paroxysms. Neurology 1974; A clinical electroencephalographic and prognostic evaluation
24:659–65. of 346 patients. Acta Neurol Scand 1969; 45(suppl. 40):1–180.
p 01.qxd 3/10/08 9:33 AM Page 36
Daly DD, Thomas JE. Sequential alterations in the Faber R, Abrams R, Taylor MA et al. Comparison of schizophrenic
electroencephalograms of patients with brain tumors. patients with formal thought disorder and neurologically
Electroencephalogr Clin Neurophysiol 1958; 10:395–404. impaired patients with aphasia. Am J Psychiatry 1983;
Daly DD, Whelan JL, Bickford RG et al. The electroencephalogram 140:1348–51.
in cases of tumor of the posterior fossa and third ventricle. Fazekas F, Schmidt R, Offenbacher H et al. Prevalence of white
Electroencephalogr Clin Neurophysiol 1953; 5:203–16. matter and periventricular magnetic resonance
Davis LE, Schmitt JW. Clinical significance of cerebrospinal fluid hyperintensities in asymptomatic volunteers. J Neuroimag
tests for neurosyphilis. Ann Neurol 1989; 25:50–5. 1991; 1:27–9.
Dean BL, Drayer BP, Bird CR. Gliomas: classification with MR Fiebach J, Jansen O, Schellinger P et al. Comparison of CT with
imaging. Radiology 1990; 174:411–15. diffusion-weighted RMI in patients with hyperacute stroke.
Deisenhammer E, Jelinger K. EEG in senile dementia. Neuroradiology 2001; 43:628–32.
Electroencephalogr Clin Neurophysiol 1974; 36:91–3. Fisch BJ, Klass DW. The diagnostic specificity of triphasic
DeJong RN. The neurologic examination, 4th edn. New wave patterns. Electroencephalogr Clin Neurophysiol 1988;
York:Harper & Row, 1979. 70:1–8.
Dempsey EW, Morrison RS. The production of rhythmically Fisch BJ, Hauser WA, Brust JCM et al. The EEG response to diffuse
recurrent cortical potentials after localized thalamic and patterned photic stimulation during acute untreated
stimulation. Am J Physiol 1942; 135:293–300. alcohol withdrawal. Neurology 1989; 39:434–6.
Devinsky O, Sato S, Kufta CV et al. Electroencephalographic Fisher M, Albers GW. Applications of diffusion-perfusion magnetic
studies of simple partial seizures with subdural electrode resonance imaging in acute ischemic stroke. Neurology 1999;
recordings. Neurology 1989; 39:527–33. 52:1750–6.
Dieterich M, Brandt T. Is obligatory bedrest after lumbar puncture Franceschi M, Triulzi F, Ferini-Strambi L et al. Focal cerebral
obsolete? Eur Arch Psychiatr Neurol Sci 1985; 235:71–5. lesions found by magnetic resonance imaging in cryptogenic
Di Gennaro G, Quarato PP, Onorati P et al. Localizing significance of nonrefractory temporal lobe epilepsy patients. Epilepsia 1989;
temporal intermittent rhythmic delta activity (TIRDA) in drug- 30:540–6.
resistant focal epilepsy. Clin Neurophysiol 2003; 114:70–8. Frost JD, Carrie JRG, Borda RP et al. The effects of Dalmane
Dolinskas C, Bilaniuk LT, Zimmerman RA et al. Computed (flurazepam hydrochloride) on human EEG characteristics.
tomography of intracerebral hematomas. I. Transmission CT Electroencephalogr Clin Neurophysiol 1973; 34:171–5.
observations of hematoma resolution. AJR 1977; 129:681–8. Fushimi M, Matsubichi N, Sekine A et al. Benign bilateral
Doran M, Larner AJ. EEG findings in dementia with Lewy bodies independent periodic lateralized epileptoform discharges. Acta
causing diagnostic confusion with sporadic Creutzfeldt–Jakob Neurol Scand 2003; 108:55–9.
disease. Eur J Neurol 2004; 11:838–41. Gabor AJ, Ajmone-Marsan C. Co-existence of focal and bilateral
Edelman RR, Warach S. Magnetic resonance imaging. N Engl J diffuse epileptiform discharges in epileptics. Epilepsia 1969;
Med 1993; 328:708–16. 10:453–72.
Ellingson RJ, Wilken K, Bennet DR. Efficacy of sleep deprivation as Garcia-Morales I, Garcia MT, Galan-Davila L et al. Periodic
an activation procedure in epilepsy patients. J Clin lateralized epileptiform discharges: etiology, clinical aspects,
Neurophysiol 1984; 2:83–101. seizures, and evolution in 130 patients. J Clin Neurophysiol
Epstein CM, Bej MD, Foldvary-Schaefer N et al. American Clinical 2002; 19:172–7.
Neurophysiology Society. Guideline 1: Minimum technical Gasecki AP, Steg RE. Correlation of early MRI with CT scan, EEG
requirements for performing clinical electroencephalography. and CSF: analyses in a case of biopsy-proven herpes simplex
J Clin Neurophysiol 2006a; 23:86–91. encephalitis. Eur Neurol 1991; 31:372–5.
Epstein CM, Bej MD, Foldvary-Schaefer N et al. American Clinical Gastaut H, Trevisan C, Naquet R. Diagnostic value of
Neurophysiology Society. Guideline 5: Guideline for standard electroencephalographic abnormalities provoked by
electrode position nomenclature. J Clin Neurophysiol 2006b; intermittent photic stimulation. Electroencephalogr Clin
23:107–10. Neurophysiol 1958; 10:194–5.
Epstein CM, Bej MD, Foldvary-Schaefer N et al. American Clinical Gastaut JL, Michael B, Hassan S et al. Electroencephalography in
Neurophysiology Society. Guideline 6: A proposal for standard brain edema (127 cases of tumor investigated by cranial
montages to be used in clinical EEG. J Clin Neurophysiol computerized tomography). Clin Neurophysiol 1979;
2006c; 23:111–17. 46:239–55.
Erwin CW, Somerville ER, Radtke RA. A review of Geiger LR, Horner RN. EEG pattern at the time of focal seizure
electroencephalographic features of normal sleep. Clin onset. Arch Neurol 1978; 35:276–86.
Neurophysiol 1984; 1:253–74. Gerson SN, Benson F, Frazier SH. Diagnosis: schizophrenia versus
Evans CC. Spontaneous excitation of the visual cortex and posterior aphasia. Am J Psychiatry 1977; 134:966–9.
association areas – lambda waves. Electroencephalogr Clin Gibbs FA, Gibbs EL, Lennox WG. Electroencephalographic
Neurophysiol 1953; 5:69–74. classification of epileptic patients and control subjects. Arch
Evans RW, Armon C, Frohman EM et al. Assessment: Prevention of Neurol Psychiatry 1943; 50:111–28.
post-lumbar puncture headaches. Neurology 2000; Gibbs FA, Rich CL, Gibbs EL. Psychomotor variant type of seizure
55:909–14. discharge. Neurology 1963; 13:991–8.
p 01.qxd 3/10/08 9:33 AM Page 37
References 37
van Gijn J, van Dongen KJ. The time course of aneurysmal Harden CL, Daras M, Tuchman AJ et al. Low amplitude EEGs in
hemorrhage on computed tomograms. Neuroradiology 1982; demented AIDS patients. Electroencephalogr Clin Neurophysiol
23:153–6. 1993; 87:54–6.
Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold, Haskett RF. Diagnostic categorization of psychiatric disturbance
2000. in Cushing’s syndrome. Am J Psychiatry 1985; 142:911–16.
Gilmore PC, Brenner RP. Correlation of EEG, computerized Haughton VM, Rimm AA, Sobocinski KA et al. A blinded clinical
tomography, and clinical findings: a study of 100 patients comparison of MR imaging and CT in neuroradiology.
with focal delta activity. Arch Neurol 1981; 38:371–2. Radiology 1986; 160:751–5.
Goldberg HH, Strauss H. Distribution of slow activity induced by Hecaen H, Penfield W, Bertrand C et al. The syndrome of
hyperventilation. Electroencephalogr Clin Neurophysiol 1959; apractagnosia due to lesions of the minor cerebral
11:615. hemisphere. Arch Neurol Psychiatry 1956; 75:400–34.
Goldman D. The clinical use of the ‘average’ reference electrode in Heier LA, Bauer CJ, Schwartz J et al. Large Virchow–Robin
monopolar recording. Electroencephalogr Clin Neurophysiol spaces: MR–clinical correlation. Am J Neuroradiol 1989;
1950; 2:209–12. 10:929–36.
Gomori M, Grossman RI, Goldberg HI et al. High field magnetic Heilman KM. Ideational apraxia – a re-definition. Brain 1973;
resonance imaging of intracranial hematomas. Radiology 96:861–4.
1985; 157:87–93. Helmchen H, Kanowski S. EEG changes under lithium treatment.
Gonzalez RG, Schaefer PW, Buonanno FS et al. Diffusion- Electroencephalogr Clin Neurophysiol 1971; 30:269.
weighted MR imaging: accuracy in patients imaged within 6 Hershey LA, Gado MH, Trotter JL. Computerized tomography in
hours of stroke symptom onset. Radiology 1999; 210:155–62. the diagnostic evaluation of multiple sclerosis. Ann Neurol
Goodin DS, Aminoff MJ. Does the interictal EEG have a role in the 1979; 5:32–9.
diagnosis of epilepsy? Lancet 1984; 1:837–9. Hockaday JM, Whitty CW. Factors determining the
Goodwin JE. Significance of alpha variants and their relationship electroencephalogram in migraine: a study of 560 patients,
to epileptiform syndrome. Am J Psychiatry 1947; 104:369–79. according to clinical type of migraine. Brain 1969;
Graif M, Steiner RE. Contrast-enhanced magnetic resonance 92:769–88.
imaging of the central nervous system: a clinical review. Br J Hockaday JM, Potts F, Epstein E et al. Electroencephalographic
Psychiatry 1986; 59:865–73. changes in acute cerebral anoxia from cardiac or respiratory
Green J. Some observations on lambda waves and peripheral arrest. Electroencephalogr Clin Neurophysiol 1965;
stimulation. Electroencephalogr Clin Neurophysiol 1957; 18:575–86.
9:691–704. Holland BA, Kucharcyzk W, Brant-Zawadzki M et al. MR imaging
Greenberg SB, Taber L, Septimus E et al. CT in brain biopsy-proven of calcified intracranial lesions. Radiology 1985; 157:353–6.
herpes simplex encephalitis. Early normal results. Arch Neurol Holmes MD, Dewaraja AS, Vanhatalo S. Does hyperventilation
1981; 38:58–9. elicit epileptic seizures? Epilepsia 2004; 45:618–20.
Greenblatt DJ, Ehrenberg BL, Gunderman J et al. Pharmacokinetic Homan RW, Jones MC, Rawat S. Anterior temporal electrodes in
and electroencephalographic study of intravenous diazepam, complex partial seizures. Electroencephalogr Clin Neurophysiol
midazolam, and placebo. Clin Pharmacol Ther 1989; 1988; 70:105–9.
45:356–65. Hopf HC, Muller-Forell W, Hopf NJ. Localization of emotional and
Gregory RP, Oates T, Merry RTG. EEG epileptiform abnormalities in volitional facial paresis. Neurology 1992; 42:1918–23.
candidates for aircrew training. Electroencephalogr Clin Hopkins A, Shorvon S, Cascino G. Epilepsy, 2nd edn. London:
Neurophysiol 1993; 86:75–7. Arnold, 1995.
Griesinger W. Mental pathology and therapeutics. New York: Hounsfield GN. Computerized transverse axial scanning
William Wood, 1882. (tomography). I. Description of the system. Br J Psychiatry
Grossman RI, Braffman BH, Brorson JR et al. Multiple sclerosis: 1972; 46:1016–22.
serial study of gadolinium-enhanced MR imaging. Radiology Hormes JT, Benarroch EE, Rodriguez M et al. Periodic sharp waves
1988; 169:117–22. in baclofen-induced encephalopathy. Arch Neurol 1988;
Guaranha MSB, Garzon E, Buchpiguel CA et al. Hyperventilation 45:814–15.
revisited: physiolgical effects and efficacy on focal seizure Hughes JR. Usefulness of photic stimulation in routine clinical
activation in the era of video-EEG monitoring. Epilepsia 2005; electroencephalography. Neurology 1960; 10:777–82.
46:69–7. Humphrey DR. Re-analysis of the antidromic cortical response: II.
Guilleux M-H, Steiner RE, Young IR. MR imaging in progressive On the contribution of all discharges and PSPs to the evoked
multifocal leukoencephalopathy. Am J Neuroradiol 1986; potential. Electroencephalogr Clin Neurophysiol 1968;
7:1033–5. 25:421–42.
Gurer G, Yemisci M, Saygi S et al. Structural lesions in periodic Huttenlocher PR, Taravath S, Mojjahedi S. Periventricular
lateralized epileptiform discharges (PLEDS). Clin EEG Neurosci heterotopia and epilepsy. Neurology 1994; 44:51–5.
2004; 35:88–93. Jasper H. Diffuse projection systems: the integrative action of the
Guttmann CRG, Abn SS, Hsu L et al. Evolution of multiple sclerosis thalamic reticular system. Electroencephalogr Clin
lesions on serial MRI. Am J Neuroradiol 1995; 16:1481–91. Neurophysiol 1949; 1:405–20.
p 01.qxd 3/10/08 9:33 AM Page 38
Jasper HH. The ten-twenty electrode system of the International tomographic, nuclear magnetic resonance, and clinical
Federation. Electroencephalogr Clin Neurophysiol 1958; correlation. Arch Neurol 1985; 42:951–9.
10:371–3. Klass DW, Bickford RG. Observations on the rolandic arceau
Jenkins A, Teasdale G, Hadley MD et al. Brain lesions detected by rhythm. Electroencephalogr Clin Neurophysiol 1957; 9:570.
magnetic resonance imaging in mild and severe head injuries. Klass DW, Westmoreland BF. Nonepileptogenic epileptiform
Lancet 1986; 2:445–6. electroencephalographic activity. Ann Neurol 1985; 18:627–35.
Johannesson G, Brun A, Gustafson I et al. EEG in presenile Knott JR. Further thoughts on polarity, montages and localization.
dementia related to cerebral blood flow and autopsy findings. J Clin Neurophysiol 1985; 2:63–75.
Acta Neurol Scand 1977; 56:89–103. Kooi KA, Thomas MH, Mortensen FN. Photoconvulsive and
Johnson MH. CT evaluation of the earliest signs of stroke. photomyoclonic responses in adults. An appraisal of their
Radiologist 1994; 1:189–99. clinical significance. Neurology 1960; 10:113–40.
Jungreis CA, Kanal E, Hirsch W et al. Normal perivascular spaces Kooi KA, Guvener AM, Tupper CJ et al. Electroencephalographic
mimicking lacunar infarction: MR imaging. Radiology 1988; pattern of the temporal regions in normal adults. Neurology
169:101–4. 1964; 14:1029–35.
Kaibara M, Blume WT. The postictal electroencephalogram. Koshino Y, Murata I, Murata T et al. Frontal intermittent rhythmic
Electroencephalogr Clin Neurophysiol 1988; 70:99–104. delta activity in schizophrenic patients receiving antipsychotic
Kaiko RF, Foley KM, Grabisnki PY et al. Central nervous system drugs. Clin Electroenphalogr 1993; 24:13–18.
excitatory effects of meperidine in cancer patients. Ann Neurol Kraepelin E. Manic–depressive insanity and paranoia, translated
1983; 13:180–5. by Barclay RM. Edinburgh: E&S Livingstone, 1921. Republished
Kales A, Bixler EO, Tan TL et al. Chronic hypnotic drug use. by Arno Press, New York, 1976.
Ineffectiveness, drug-withdrawal insomnia and dependence. Kraepelin E. Psychiatry. A textbook for students and physicians,
JAMA 1974; 227:513–17. 1899, translated by Metoui H, Ayed S. Canton, MA: Science
Kaplan PW, Birbeck G. Lithium-induced confusional states: History Publications, 1990.
nonconvulsive status epilepticus or triphasic encephalopathy? Krauss GL, Abdallah A, Lesser R et al. Clinical and EEG features of
Epilepsia 2006; 47:2071–7. patients with EEG wicket rhythm misdiagnosed with epilepsy.
Karnatze DS, Bickford RG. Triphasic waves: a reassessment of Neurology 2005; 64:1879–83.
their clinical significance. Electroencephalogr Clin Krup LB, Lipton RB, Swerlow ML et al. Progressive multifocal
Neurophysiol 1984; 57:193–8. leukoencephalopathy: clinical and radiographic features. Ann
Katz DI, Alexander MP, Mandell AM. Dementia following strokes Neurol 1985; 17:344–9.
in the mesencephalon and diencephalons. Arch Neurol 1987; Lansberg MG, Albers GW, Beaulieu G et al. Comparison of
44:1127–33. diffusion-weighted MR and CT in acute stroke. Neurology
Katz DI, Taubenberger JK, Cannella B et al. Correlation between 2000; 54:1557–61.
magnetic resonance imaging findings and lesion development Laplane D, Degos JD. Motor neglect. J Neurol Neurosurg Psychiatry
in chronic, active multiple sclerosis. Ann Neurol 1993; 1983; 46:152–8.
5:661–9. Lavi R, Yernitzky D, Rowe JM et al. Atraumatic Whitacre needle
Kelly AB, Zimmerman RD, Snow RB et al. Head trauma: for diagnostic lumbar puncture: a randomized trial. Neurology
comparison of MR and CT-experience in 100 patients. Am J 2006; 67:1492–4.
Neuroradiol 1988; 9:699–708. Leach JP, Stephen LJ, Salveta C et al. Which
Kennard MA, Beuding E, Wortis SB. Some biochemical and electroencephalography (EEG) for epilepsy? The relative
electroencephalographic changes in delirium tremens. Q J Stud usefulness of different EEG protocols in patients with possible
Alcohol 1945; 6:4–14. epilepsy. J Neurol Neurosurg Psychiatry 2006; 77:1040–2.
Kermode AG, Thompson AJ, Tofts P et al. Breakdown of the Leavitt S, Tyler H. Studies in asterixis. Arch Neurol 1964;
blood–brain barrier precedes symptoms and other magnetic 10:360–8.
resonance imaging signs of new lesions in multiple sclerosis. Lemstra AW, van Meegen MT, Vreyling JP et al. 14-3-3 testing in
Brain 1990; 113:1477–89. diagnosing Creutzfeldt-Jakob disease. A prospective study in
Kidwell CS, Chalela JA, Saver JL et al. Comparison of MRI and CT 112 patients. Neurology 2000; 55:514–16.
for detection of acute intracerebral hemorrhage. JAMA 2004; Lesser RP, Luders H, Dinner DS et al. An introduction to the basic
292:1823–30. concepts of polarity and localization. J Clin Neurophysiol
Kim HL, Donnelly JH, Tonay AE et al. Absence of seizures despite 1985; 2:45–61.
high prevalence of epileptiform EEG abnormalities in children Levy A, Lightman SS. Diagnosis and management of pituitary
with autism monitored in a tertiary care center. Epilepsia tumors. BMJ 1994; 308:1087–91.
2006; 47:394–8. Levy SR, Chiappa KH, Burke CJ et al. Early evolution and incidence
King MA, Newton MR, Jackson GD et al. Epileptology of the first of electroencephalographic abnormalities in Creutzfeldt–Jakob
seizure presentation: a clinical, EEG and MRI study of 300 disease. J Clin Neurophysiol 1986; 3:1–21.
consecutive patients. Lancet 1998; 352:1007–11. Lieb JP, Walsh GO, Babb TL et al. A comparison of EEF seizure
Kinkel W, Jacobs L, Polachini I et al. Subcortical arteriosclerotic patterns recorded with surface and depth electrodes in patients
encephalopathy (Binswanger’s disease): computed with temporal lobe epilepsy. Epilepsia 1976; 17:137–60.
p 01.qxd 3/10/08 9:33 AM Page 39
References 39
Linnenger AW, Volow MR, Gianturco DT. Intravenous infusion Morgan MH, Scott DF. EEG activation in epilepsies other than
artifact. EEG Technol 1981; 21:167–73. petit mal. Epilepsia 1970; 11:255–61.
Lombroso CT, Schwartz IH, Clark DM et al. Ctenoids in healthy Morris HH, Dinner DS, Luders H et al. Supplementary motor
youths: Controlled study of 14- and 6-per second positive seizures: clinical and electroencephalographic findings.
spiking. Neurology 1966; 16:1152–8. Neurology 1988; 38:1075–82.
Lusins J, Jaffe R, Bender MB. Unoperated subdural hematoma: Mostrum V, Ytterbergh C. Artifacts in computed tomography of
long-term follow-up study by brain scan and the posterior fossa: a comparative phantom study. J Comput
electroencephalography. J Neurosurg 1976; 44:601–7. Assist Tomogr 1986; 10:560–6.
MacDonnell RAL, Donnan GA, Baldin PF et al. The Mushlin AI, Detsky AS, Phelps CE et al. The accuracy of magnetic
electroencephalogram in acute ischemic stroke. Arch Neurol resonance imaging in patients with suspected multiple
1988; 45:520–4. sclerosis. JAMA 1993; 269:3146–51.
MacLean PD. A nasopharyngeal lead. Electroencephalogr Clin Nesbit GM, Forbes GS, Scheithauer BW et al. Multiple sclerosis:
Neurophysiol 1949; 1:110–12. histopathologic and MR and/or CT correlation in 37 cases at
Magnus O. The cerebral alpha-rhythm (‘rhythme en arceau’). biopsy and three cases at autopsy. Radiology 1991;
Electroencephalogr Clin Neurophysiol 1954; 6:349–50. 180:467–74.
Malow BA, Reese KB, Sato S et al. Abnormalities during clozapine Neufeld MY, Inzelberg R, Korczyn AD. EEG in demented and non-
treatment. Electroencephalogr Clin Neurophysiol 1994; demented parkinsonian patients. Acta Neurol Scand 1988;
91:205–11. 78:1–5.
Markand ON, Daly DD. Pseudo-periodic lateralized paroxysmal Neumann-Haefelin T, Moseley ME, Albers GW. New magnetic
discharges in electroencephalogram. Neurology 1971; resonance imagining methods for cerebrovascular disease:
21:975–81. emerging clinical applications. Ann Neurol 2000; 47:559–70.
Markand ON, Panzi JG. The electroencephalogram in subacute Nickel SN, Frame B. Neurologic manifestations of myxedema.
sclerosing panencephalitis. Arch Neurol 1975; 32:719–26. Neurology 1958; 8:511–17.
Martinez-Yelamos A, Saiz A, Sanchez-Valle R et al. 14-3-3 Nicolai J, van Putten MJ, Tavy DL. BIPLEDS in a kinetic mutism
protein in the CSF as prognostic marker in early multiple caused by bilateral anterior cerebral artery infarction. Clin
sclerosis. Neurology 2001; 57:722–4. Neurophysiol 2001; 112:1726–8.
Martins da Silva A, Aarts JH, Binne CD et al. The circadian Niedermeyer E, Rocca V. The diagnostic significance of sleep
distribution of interictal epileptiform EEG activity. electroencephalograms in temporal lobe epilepsy: a
Electroencephalogr Clin Neurophysiol 1984; 58:1–13. comparison of scalp and depth tracings. Eur Neurol 1972;
Matsuo F, Knott JR. Focal positive spikes in 7:119–29.
electroencephalography. Electroencephalogr Clin Neurophysiol Normand MM, Wszolek ZK, Klass DW. Temporal intermittent
1977; 42:15–25. rhythmic delta activity in electroencephalograms. J Clin
Matsuo F, Peters JF, Reilly EL. Electrical phenomena associated Neurophysiol 1995; 12:280–4.
with movements of the eyelid. Electroencephalogr Clin O’Brien TJ, Sharbrough FW, Westmoreland BF et al. Subclinical
Neurophysiol 1975; 38:507–11. rhythmic electrographic discharges of adults (SREDA)
Mattson RH, Pratt KL, Calverley JR. Electroencephalograms of revisited: a study using digital EEG analysis. J Clin
epileptics following sleep deprivation. Arch Neurol 1965; Neurophysiol 1998; 15:493–501.
13:310–15. Oliveira-Filho J, Ay H, Schaeffer PW et al. Diffusion-weighted
Meier-Ewart R, Broughton RJ. Photomyoclonic response of magnetic resonance imaging identifies the ‘clinically relevant’
epileptic and nonepileptic subjects during wakefulness, sleep, small-penetrator infarcts. Arch Neurol 2000; 57:1009–14.
and arousal. Electroencephalogr Clin Neurophysiol 1976; Ormerod IEC, Miller DH, McDonald WI et al. The role of NMR
23:301–4. imaging in the assessment of multiple sclerosis and isolated
Mesolham RI, Moberg PJ, Mahr RN et al. Olfaction in neurological lesions. Brain 1987; 110:1579–616.
neurodegenerative disease: a meta-analysis of olfactory Orrison WW, Gentry RL, Simac GK et al. Blinded comparison of
functioning in Alzheimer’s and Parkinson’s diseases. Arch cranial CT and MR in closed head injury evaluation. Am J
Neurol 1998; 55:84–90. Neuroradiol 1994; 15:351–6.
Meyer JS, Gotham J, Tazaki Y et al. Cardiorespiratory syndrome Patel MR, Edelman RR, Warach S. Detection of hyperacute
of extreme obesity with papilledema. Neurology 1961; primary intraparenchymal hemorrhage by magnetic resonance
11:950–8. imaging. Stroke 1996; 27:2321–4.
Miley CM, Forster FM. Activation of complex partial seizures by de la Paz D, Brenner RP. Bilateral independent periodic lateralized
hyperventilation. Arch Neurol 1977; 34:371–3. epileptiform discharges: clinical significance. Arch Neurol
Miller DH, Rudge P, Johnson G et al. Serial gadolinium enhanced 1981; 38:713–15.
magnetic resonance imaging in multiple sclerosis. Brain 1988; Pedley TA. Interictal epileptiform discharges: discriminating
111:927–39. characteristics and clinical correlations. Am J EEG Technol
Mittl RL, Grossman RI, Hieble JF et al. Prevalence of MR evidence 1980; 20:101–19.
of diffuse axonal injury in patients with mild head injury and Peters JF. Surface electrical fields generated by eye movements.
normal CT findings. Am J Neuroradiol 1994; 15:1583–9. Am J EEG Technol 1967; 7:27–40.
p 01.qxd 3/10/08 9:33 AM Page 40
Phelps ME, Hoffman EJ, Ter-Pogossian MM. Attenuation Salinsky M, Kanter R, Dashieff RM. Effectiveness of multiple EEGs
coefficients of various body tissues, fluids and lesions at in supporting the diagnosis of epilepsy: an operational curve.
photon energies of 18 keV to 136 keV. Radiology 1975; Epilepsia 1987; 28:331–4.
117:537–83. Sammaritano J, Gigli GL, Gotman J. Interictal spiking during
Picard A, Cheliout Hearaut F, Bouskraoui M et al. Sleep EEG and wakefulness and sleep and the localization of foci in temporal
developmental dysphasia. Dev Med Child Neurol 1998; lobe epilepsy. Neurology 1991; 41:290–7.
40:595–9. Schaeffer PW, Grant PE, Gonzalez RG. Diffusion-weighted MR
Pojunas KW, Daniels DL, Williams AL et al. MR imaging of imaging of the brain. Radiology 2000; 217:331–45.
prolactin-secreting microadenomas. Am J Neuroradiol 1986; Schaul N, Lueders H, Sachdev K. Generalized bilaterally
7:209–13. synchronous bursts of slow waves in the EEG. Arch Neurol
Poppert S, Essig A, Stoehr B et al. Rapid diagnosis of bacterial 1981; 38:690–2.
meningitis by real-time PCR and fluorescence in situ Schear HE. The EEG pattern in delirium tremens. Clin
hybridization. J Clin Microbiol 2005; 43:3390–7. Electroencephalog 1985; 16:30–2.
Porter SB, Sande MA. Toxoplasmosis of the central nervous Schellinger PD, Jansn O, Fiebach JB et al. A standardized MRI
system. N Engl J Med 1992; 327:1643–8. stroke protocol: comparison with CT in hyperacute
Pratt KL, Mattson RH, Weikers NJ et al. EEG activation of intracerebral hemorrhage. Stroke 1999; 30:765–8.
epileptics following sleep deprivation: a prospective study of Schmidt D. The influence of antiepileptic drugs on the
114 cases. Electroencephalogr Clin Neurophysiol 1968; electroencephalogram: a review of controlled clinical studies.
24:11–15. Electroencephalogr Clin Neurophysiol 1982 (suppl.); 36:
Pro JD, Wells CE. The use of the electroencephalogram in the 453–66.
diagnosis of delirium. Dis Nerv Syst 1977; 38:804–8. Scott DF, Groetheysen UC, Bickford RG. Lambda responses in the
Protass L. Hyperventilation in sickle cell disease. Arch Int Med human electroencephalogram. Neurology 1967; 17:770–8.
1978; 138:29. Scott DF, Heathfield KWG, Toone B et al. The EEG in Huntington’s
Purpura DP, Grundfest H. Nature of dendritic potentials and disease: a clinical and neuropathological study. J Neurol
synaptic mechanism in cerebral cortex of cat. J Neurophysiol Neurosurg Psychiatry 1972; 35:97–102.
1956; 19:573–95. Seddigh S, Thomke F, Vogt Th. Complex partial seizures provoked
Pykett IL. NMR imaging in medicine. Sci Am 1982; 246:78–88. by photic stimulation. J Neurol Neurosurg Psychiatry 1999;
Pykett SL, Newhouse JH, Buonanno BS et al. Principles of nuclear 66:801–2.
magnetic imaging. Radiology 1982; 143:157–68. Seshia SS. McLachlan RS. Aura continua. Epilepsia 2005;
Rathmell TK, Burns MA. The Laurence–Moon–Biedl syndrome 46:454–5.
occurring in a brother and a sister. Arch Neurol Psychiatry Seyffarth H, Denny-Brown D. The grasp reflex and the instinctive
1938; 39:1033–42. grasp reaction. Brain 1948; 71:109–83.
Rechtschaffen A, Kales A. A manual of standardized terminology, Singh G, Wright MA, Sander JW et al. Periodic lateralized
technique and scoring system for sleep stages of human epileptiform discharges (PLEDS) as the sole electrographic
subjects. Washington DC: US Government Printing Office, correlate of a complex partial seizure. Epileptic Disord 2005;
1968. 7:37–41.
Reiher J, Lebel M. Wicket spikes: clinical correlates of a previously Silverman D. The anterior temporal electrode and the ten-
undescribed EEG pattern. Can J Neurol Sci 1977; 4:39–47. twenty system. Electroencephalogr Clin Neurophysiol 1960;
Risinger MW, Engel J, Van Ness PC et al. Ictal localization of 12:735–7.
temporal lobe seizures with scalp sphenoidal recordings. Singer MB, Chong J, Lu D et al. Diffusion-weighted MRI in acute
Neurology 1989; 39:1288–93. subcortical infarction. Stroke 1998; 29:133–6.
Robinson WP, Bottani A, Yagang X. Molecular, cytogenetic, and Smith A. The serial sevens subtraction test. Arch Neurol 1962;
clinical investigations of Prader–Willi syndrome patients. Am J 17:78–80.
Hum Genet 1992; 49:1219–34. Sperling MR, Engel J. Electroencephalographic recordings from
Romano J, Engel GL. Delirium, I: electroencephalographic data. the temporal lobe: a comparison of ear, anterior temporal and
Arch Neurol Psychiatry 1944; 51:356–77. nasopharyngeal electrodes. Ann Neurol 1985; 17:510–13.
Roseman E. Dilantin toxicity: a clinical and Sperling MR, Mednius JR, Engel J. Mesial temporal spikes: a
electroencephalographic study. Neurology 1961; 11:912–21. simultaneous comparison of sphenoidal, nasopharyngeal and
Roos KL. Lumbar puncture. Semin Neurol 2003; 23:105–14. ear electrodes. Epilepsia 1986; 27:81–6.
Ross ED. The aprosdias: functional–anatomic organization of the Spillane JD. Nervous and mental disorders in Cushing’s syndrome.
affective components of language in the right hemisphere. Brain 1951; 74:72–94.
Arch Neurol 1981; 38:561–9. Steiner L, Budka H, Chaudhuri A et al. Viral encephalitis: a review
Sadler RM, Goodwin J. Multiple electrodes for detecting spikes in of diagnostic methods and guidelines for management. Eur J
partial complex seizures. Can J Neurol Sci 1989; 16:326–9. Neurol 2005; 12:331–43.
Saenz-Lope E, Herranz-Tanarro FJ, Masdeu JC et al. Steinhoff BJ, Racker S, Herrendorf G et al. Accuracy and reliability
Hyperekplexia: a syndrome of pathological startle responses. of periodic sharp wave complexes in Creutzfeldt–Jakob
Ann Neurol 1984; 15:36–41. disease. Arch Neurol 1996; 53:162–6.
p 01.qxd 3/10/08 9:33 AM Page 41
References 41
Steriade M, Gloor P, Llinas RD et al. Basic mechanisms of cerebral Walker A, Pescor FT, Fraser HF et al. Electroencephalographic
rhythmical activities. Electroencephalogr Clin Neurophysiol changes associated with chronic alcohol intoxication and the
1990; 76:481–508. alcohol abstinence syndrome. Am J Psychiatry 1956;
Stevens JR. Central and peripheral factors in epileptic discharge: 113:106–14.
clinical studies. Arch Neurol 1962; 7:330–8. Walshe FMR, Robertson EG. Observations upon the form and
Strupp M, Schueler O, Straube A et al. ‘Atraumatic’ Sprotte needle nature of the ‘grasping’ movements and ‘tonic innervation’
reduces the incidence of post-lumbar puncture headaches. seen in certain cases of lesions of the frontal lobe. Brain 1933;
Neurology 2001; 57:2310–12. 56:40–70.
Su P, Goldensohn ES. Progressive supranuclear palsy: Walson JM, Kiloh LG, Osselton JW et al. The electroencephalogram
electroencephalographic studies. Arch Neurol 1973; 29:183–6. in pernicious anemia and subacute combined degeneration of
Summerskill WHJ, Davidson EA, Sherlock S et al. The the spinal cord. Electroencephalogr Clin Neurophysiol 1954;
neuropsychiatric syndrome associated with hepatic cirrhosis 6:45–64.
and extensive portal circulation. Q J Med 1956; 25:245. Warach S, Gaa J, Stewart B et al. Acute human stroke studied by
Sze G, Milano E, Johnson C et al. Detection of brain metastases: whole echo-planar diffusion-weighted imaging. Ann Neurol
comparison of contrast-enhanced MR with unenhanced MR 1995; 37:231–44.
and enhanced CT. Am J Neuroradiol 1990; 11:785–91. Wardlaw JM, Keir SL, Dennis MS. The impact of delays in
Tchang S, Scotti G, Terbrugge K et al. Computed tomography as a computed tomography of the brain on the accuracy of
possible aid to histological grading of supratentorial tumors. J diagnosis and subsequent management in patients with minor
Neurosurg 1977; 46:735–9. stroke. J Neurol Neurosurg Psychiatry 2003; 74:77–81.
Tegner R, Levander M. The influence of stimulus properties on Wasenko JJ, Rosenbloom SA, Duchesneau PM et al. The
visual neglect. J Neurol Neurosurg Psychiatry 1991; 54:882–7. Sturge–Weber syndrome: comparison of MR and CT
Thomas JE, Klass DW. Six-per-second spike-and-wave pattern in characteristics. Am J Neuroradiol 1990; 11:131–4.
the electroencephalogram: a reappraisal of its clinical Watemberg N, Alehan F, Dabby R et al. Clinical and radiologic
significance. Neurology 1968; 18:587–93. correlates of frontal intermittent rhythmic delta activity.
Thompson AJ, Miller D, Youl B et al. Serial gadolinium-enhanced J Clin Neurophysiol 2002; 19:535–9.
MRI in relasping/remitting multiple sclerosis of varying disease Watemberg N, Linder I, Dabby R et al. Clinical correlates of
duration. Neurology 1992; 42:60–3. occipital intermittent rhythmic delta activity (OIRDA) in
Tien RD, Felsberg GJ, Osumi AK. Herpes virus infection of the CNS: children. Epilepsia 2007; 48:330–4.
MR findings. AJR 1993; 161:283–9. van der Wee N, Rinkel GJ, Hasan D et al. Detection of
Timmermans M, Carr J. Neurosyphilis in the modern era. J Neurol subarachnoid hemorrhage on early CT: is lumbar puncture still
Neurosurg Psychiatry 2004; 75:1727–30. needed after a negative scan? J Neurol Neurosurg Psychiatry
Tourtellotte WW, Henderson WG, Tucker RP et al. A randomized, 1995; 58:357–9.
double-blind clinical trial of post-lumbar puncture headache Westmoreland BF, Klass DW. A distinctive rhythmic EEG discharge
in normal individuals. Headache 1972; 12:73–8. of adults. Electroencephalogr Clin Neurophysiol 1981;
Tschampa HJ, Neumnn M, Zerr I et al. Patients with Alzheimer’s 51:186–91.
disease and dementia with Lewy bodies mistaken for White JC, Langston JW, Pedley TA. Benign epileptiform transients
Creutzfeldt–Jakob disease. J Neurol Neurosurg Psychiatry of sleep: clarification of the small sharp spike controversy.
2001; 71:33–9. Neurology 1977; 17:1061–8.
Upton A, Gumpert J. Electroencephalography in diagnosis of Wiedemann H-R, Kunze J, Grosse F-R et al. An atlas of clinical
herpes simplex encephalitis. Lancet 1970; 1:650–2. syndromes, 3rd edn. St Louis, MO: Mosby-Wolfe, 1989.
Valler G, Rusconi ML, Bignamimi L et al. Anatomical correlates of Wieser HG, Schwarz U, Blatter T et al. Serial EEG findings in
visual and tactile extinction in humans: a clinical CT scan sporadic and iatrogenic Creutzfeldt-Jakob disease. Clin
study. J Neurol Neurosurg Psychiatry 1994; 57:464–70. Neurophysiol 2004; 115:2467–78.
Van Everbroeck BRJ, Boons J, Cras P. 14-3-3 Isoform detection Wiesmann M, Mayer TE, Yousry I et al. Detection of hyperacute
distinguishes sporadic Creutzfeldt–Jakob disease from other subarachnoid hemorrhage of the brain by using magnetic
dementias. J Neurol Neurosurg Psychiatry 2005; 76:100–2. resonance imaging. J Neurosurg 2002; 96:684–9.
Vassilouthis J, Ambrose J. Computerized tomography scanning Will RG, Ironside JW, Zeidler M et al. A new variant of
appearances of intracranial meningiomas: an attempt to Creutzfeldt–Jakob disease in the UK. Lancet 1996;
predict the histological features. J Neurosurg 1979; 50:320–7. 347:921–5.
Veldhuizen R, Binnie CD, Beintema DJ. The effect of sleep Wilson SA. Modern problems in neurology. London: Edward
deprivation on the EEG in epilepsy. Electroencephalogr Clin Arnold, 1928.
Neurophysiol 1983; 55:505–12. Wolf P, Gooses R. Relation of photosensitivity to epileptic
Victor M, Ropper AH. Principles of neurology, 7th edn. New York: syndromes. J Neurol Neurosurg Psychiatry 1986;
McGraw Hill, 2001. 49:1386–91.
Vignaendra V, Mathews RL, Chatrian GE. Positive occipital sharp Wood JW, Bartlet D, James AE et al. Normal pressure
transients of sleep: relationships to nocturnal sleep cycle in hydrocephalus: diagnosis and patient selection for shunt
man. Electroencephalogr Clin Neurophysiol 1974; 37:239–46. surgery. Neurology 1974; 24:517–26.
p 01.qxd 3/10/08 9:33 AM Page 42
Yoneda Y, Tokui K, Hanihara T et al. Diffusion-weighted magnetic Zimmerman RD, Bilaniuk LT, Hackney DB et al. Head injury: early
resonance imaging: detection of ischemic injury 39 minutes results of comparing CT and high-field MR. Am J Neuroradiol
after onset in a stroke patient. Ann Neurol 1999; 45:794–7. 1986; 7:757–64.
Young IR, Hall AS, Pallis CA et al. Nuclear magnetic resonance Zivin L, Ajmone-Marsan C. Incidence and prognostic significance
imaging of the brain in multiple sclerosis. Lancet 1981; of ‘epileptiform’ activity in the EEG of non-epileptic subjects.
2:1063–6. Brain 1968; 91:751–79.
Zeidler M, Stewart GE, Barraclough CR et al. New variant Zochodne DW, Young GB, McLachlan RS et al. Creutzfeldt–Jakob
Creutzfeldt–Jakob disease: neurological features and disease without periodic sharp wave complexes: a clinical,
diagnostic tests. Lancet 1997; 35:903–7. electroencephalographic and pathologic study. Neurology
Zimmerman RD, Fleming CA, Saint-Louis LA et al. Magnetic 1988; 38:1056–60.
resonance imaging of meningiomas. Am J Neuroradiol 1985; Zurek R, Schiemann-Delgado J, Froescher W et al. Frontal
6:149–57. intermittent rhythmical delta activity and anterior
bradyarrythmia. Clin Electroencephalogr 1985; 16:1–10.
p 02.qxd 3/10/08 9:32 AM Page 43
PART II
SIGNS, SYMPTOMS, AND SYNDROMES
2 ‘Cortical’ signs and symptoms 45

3 Abnormal movements 72
4 Other signs and symptoms 117
5 Syndromes of cognitive impairment 162
6 Syndromes of disturbances of mood and affect 208
7 Other major syndromes 238
2
‘Cortical’ signs and symptoms
2.1 Aphasia 45 2.7 Aprosodia 53

2.2 Alexia 49 2.8 Apraxia 55
2.3 Agraphia 50 2.9 Agnosias 57
2.4 Acalculia 51 2.10 Neglect 62
2.5 Gerstmann’s syndrome 51 References 64
2.6 Hypergraphia 52
2.1 APHASIA Comprehension, or its lack, becomes apparent during

interaction with the patient. For example, during the neu-
Aphasia is a fascinating clinical phenomenon, as it repre- rologic examination it may appear that the patient has
sents a disruption of that most human of all characteristics, trouble understanding certain commands as, for example,
namely language. The classification of the various types of when one instructs the patient to take the index finger and
aphasia has a long and contentious history: although the touch the nose. If one suspects a perhaps more subtle
approach offered here is currently dominant, further deficit in comprehension, it is appropriate to present a
research may require a more or less substantial revision. more complex command, for example, ‘Now I want you to
touch your right knee with your left hand’.
Coherence, or, again, its lack, becomes apparent during
Clinical features conversation with the patient. In this regard, it is critical to
engage the patient in prolonged conversation, and to avoid
Aphasia is characterized by impairments in one or more a ‘yes–no’ format that denies the patient the opportunity to
aspects of spoken language. Assessment begins with obser- speak at length: all too often, physicians come away from a
vation of the patient’s spontaneous speech, with particular brief ‘yes–no’ interview without any sense of how incoher-
attention to fluency, comprehension, and coherence and ent their patient actually is. Incoherent speech is character-
also to the presence of what is known as paraphasia – ized by the presence of such disconnectedness and
a peculiar kind of misuse of words. Following this, one tests disorganization of words, phrases, and sentences that what
specifically for any improvement of speech with repetition the patient says ‘makes no sense’.
and for the patient’s ability to name objects. Paraphasias represent a specific distortion in word usage,
Fluency, or its absence, is immediately apparent. Fluent and come in one of two forms: phonemic (also known as
speech occurs at a normal, or perhaps even increased rate: literal) paraphasia, and semantic (also known as verbal)
phrases and sentences are present, and there is a normal paraphasia. In phonemic paraphasia, a letter or syllable is
complement of prepositions, conjunctions, adjectives, and replaced or added thus producing an incorrect word: for
adverbs. Non-fluent speech, by contrast, is effortful, slowed, example, rather than saying ‘put it on the table’, the patient
and ‘telegraphic’. Given that many readers have perhaps with a phonemic paraphasia may say ‘put it on the stable’.
never seen a telegraph, some words are in order regarding In semantic paraphasia, by contrast, an entire word is sub-
this descriptive term. The cost of a telegraph was appor- stituted: for example, rather than saying “the book is on
tioned according to its length, and hence efforts were the table”, the patient with a semantic paraphasia may say
made by telegraphers to omit as may words as possible ‘the book is on the mirror’.
while maintaining the sense of the original message. Repetition may have a remarkable effect in some cases
Consequently, telegraphs often lacked prepositions, con- of aphasia. As in some cases speech improves with repeti-
junctions, adverbs, and adjectives. Non-fluent aphasias tion, tell the aphasic patient that you are going to ask him
share this characteristic and, as this was first described in the to repeat something and then provide the patient with a
age of telegraphs, the term ‘telegraphic’ was applied. test phrase, such as ‘this is a hospital’. If the patient repeats
p 02.qxd 3/10/08 9:32 AM Page 46
46 ‘Cortical’ signs and symptoms
this correctly and without hesitation then give a more present, are rare. Repetition does not improve speech;
complex phrase, for example ‘to get out of the hospital, naming, although effortful, is generally preserved.
take the elevator to the first floor and then turn right’. Motor aphasia can be a very frustrating experience and
Finally, the ability to name things may be tested by patients tend to become irritable or depressed (Benson
pointing to an object in the room, such as a lamp, or per- 1973). Asking about the patient’s experience can be edify-
haps by holding up a pencil and asking the patient to name ing. Try, for example, saying to the patient ‘Some patients
it. If the patient does so correctly then proceed to parts of who have trouble speaking do so because they’re not clear
the object in question, such as the lampshade, light bulb, what they want to say, whereas others know exactly what
etc. If the patient has difficulty then provide cues, such as they want to say but can’t get the words out. Is that the kind
‘it’s something that provides light’ or ‘it begins with the of trouble you’re having? Do you know what you want to
letter L’. If cues are not helpful, tell the patient the name of say but can’t get it out?’ Patients with motor aphasia often
the object and ask whether or not that is the correct name. nod their heads vigorously, relieved that the physician
After making all these determinations, it is generally pos- understands their plight. Interestingly, emotionally laden
sible to classify the patient’s aphasia into one of the following speech, such as cursing, may be relatively unaffected, and
types (all described in detail below): motor, transcortical some patients may evidence a remarkably preserved ability
motor, sensory, transcortical sensory, global, transcortical to sing (Yamadori et al. 1977).
mixed, conduction, pure word deafness, and anomic. In most cases, the responsible lesion is seen to involve
Importantly, however, it must be borne in mind that this the posterior portion of the inferior frontal gyrus (Mohr
classificatory scheme is but an approximation: clinical real- et al. 1978; Naeser and Hayward 1978; Tonkonogy and
ity often overflows the nosologic boundaries we erect and Goodglass 1981). Given that most lesions extend beyond
atypical cases are not at all uncommon (Brown and the inferior frontal gyrus, it is very common to find associ-
Simonson 1957). One must also be prepared for surprises: ated deficits, such as a right-sided hemiparesis: indeed,
for example, in bilingual patients one may see a different although noted (Henderson 1985; Masdeu and O’Hara
aphasia for each language: in one case of a native Spanish 1983), it is very uncommon to find an isolated motor
speaker who had Hebrew as a second language, there was a aphasia without any accompanying deficits.
motor aphasia for Spanish and a sensory one for Hebrew Motor aphasia has also been noted with a thalamic
(Silverberg and Gordon 1979). lesion (Megens et al. 1992) and with infarction of the puta-
Each of the various types of aphasia is described further men and adjacent anterior limb of the internal capsule
below, with comments on its localizing value. Before pro- (Naeser et al. 1982).
ceeding, however, a word is in order regarding aphasia’s lat-
eralizing value. Roughly 90 percent of the general population TRANSCORTICAL MOTOR APHASIA
is right-handed and in 99 percent of these individuals the left
hemisphere is dominant for language. Among left-handers, Transcortical motor aphasia is essentially identical to
the majority also exhibit language dominance in the left motor aphasia, with the exception that repetition is pre-
hemisphere (Goodglass and Quadfasel 1954; Humphrey served. Transcortical motor aphasia is most often seen with
and Zangwill 1952), and among the remainder some form of lesions of the medial aspect of the left frontal lobe, as may
mixed dominance is generally present. Consequently, and occur with infarctions in the area of distribution of the
especially in right-handers, the presence of aphasia lateral- anterior cerebral artery (Alexander and Schmitt 1980;
izes the lesion to the left hemisphere. However, exceptions Bogousslavsky and Regli 1990; Freedman et al. 1984; Racy
to this rule in right-handers have been noted, and such cases et al. 1979; Rubens 1975). A syndrome similar to transcorti-
are referred to as ‘crossed aphasia’ (Bakar et al. 1996; Brown cal motor aphasia may also occur with lesions of the putamen
and Wilson 1973; Holmes and Sadoff 1966). Crossed apha- or thalamus (Alexander and LoVerme 1980; Ghika-Schmid
sia has been noted for motor aphasia (Hindson et al. 1984; and Bogousslavsky 2000; McFarling et al. 1982).
Trojanowski et al. 1980), transcortical motor aphasia
(Ghika-Schmid and Bogousslavsky 2000), sensory aphasia SENSORY APHASIA
(Alexander et al. 1989; Henderson 1983; Sweet et al. 1984),
global aphasia (Assal et al. 1981), and mixed transcortical Sensory aphasia, also known as Wernicke’s aphasia or
aphasia (Cappa et al. 1993). receptive aphasia, is characterized by fluent speech that is
more or less incoherent and contaminated by frequent
MOTOR APHASIA paraphasias; such patients also have difficulty compre-
hending commands, especially complex ones. In its most
Motor aphasia, also known as Broca’s aphasia or expressive severe form, one sees what as known as ‘jargon aphasia’, or
aphasia, is characterized by non-fluent, effortful speech speech that is almost totally incomprehensible.
that is laconic, often circumlocutory, and telegraphic. In some cases, patients may appear relatively uncon-
Comprehension is preserved and although one may miss cerned, despite a severe deficit. In other cases, patients may
hearing the expected prepositions, conjunctions, and the become agitated and suspicious, and some may develop
like, coherence is generally preserved and, paraphasias, if delusions of persecution (Benson 1973, Singer et al. 1989).
p 02.qxd 3/10/08 9:32 AM Page 47
2.1 Aphasia 47
Sensory aphasia may be seen with lesions involving the contrast with sensory aphasia, however, comprehension is
temporoparietal area (Naeser and Hayward 1978), espe- preserved. Furthermore, and remarkably so in light of the
cially Wernicke’s area on the posterior surface of the supe- preserved comprehension, patients are unable to repeat
rior temporal gyrus (Selnes et al. 1985); it may also be seen complex sentences.
with lesions of the white matter subjacent to Wernicke’s Conduction aphasia is classically associated with dam-
area (Naeser and Hayward 1978) and lesions affecting age to the arcuate fasciculus (Benson et al. 1973; Damasio
the putamen and adjacent posterior limb of the internal and Damasio 1980; Tanabe et al. 1987) but has also been
capsule (Naeser et al. 1982). noted with infarction of the caudate nucleus (Godefroy
et al. 1994).
TRANSCORTICAL SENSORY APHASIA
Transcortical sensory aphasia resembles sensory aphasia, PURE WORD DEAFNESS

except that repetition is intact. Transcortical sensory apha-
sia may be seen with lesions of the parietotemporal area that Pure word deafness is a remarkable syndrome characterized
spare Wernicke’s area (Selnes et al. 1985), or with lesions of by an isolated inability to comprehend spoken words and to
the left thalamus, principally the dorsomedial nucleus repeat phrases. Spontaneous speech is both fluent and
(Bogousslavsky et al. 1988a; Tuszynski and Petito 1988). coherent, and there are no paraphasias. One patient com-
mented, ‘Voice comes but no words . . . There is no trouble
at all with the sound. Sounds come. I can hear, but I cannot
GLOBAL APHASIA
understand it’ (Hemphill and Stengel 1940). Another
Global aphasia is characterized by a combination of speech patient, although able to recognize non-speech sounds such
that is effortful and sparse with an inability to follow as telephone rings or automobile horns, could not under-
complex commands. Coherence is diminished; however, stand spoken words: he commented, ‘I can hear you talking
this is often difficult to assess, given that many patients are but I can’t translate it’ (Kanshepolsky et al. 1973).
reduced to single words or over-learned stock phrases. Pure word deafness has been noted with bilateral dam-
Repetition does not improve their speech. age to the superior temporal gyrus (Coslett et al. 1984;
Global aphasia is most commonly seen with very large Kanshepolsky et al. 1973) and with bilateral damage to the
lesions involving the frontal, parietal, and temporal inferior colliculi (Meyer et al. 1996; Pan et al. 2004).
cortices (Bogousslavsky 1988; Naeser and Hayward 1978) Transcortical pure word deafness, wherein patients,
and, as such, is typically accompanied by a hemiparesis. although unable to understand the spoken word are yet
Exceptions to this rule do occur, however, and global apha- able to repeat it, may or may not occur in pure form: a pos-
sia secondary to cortical lesions may occur without hemi- sible case was noted with a lesion of the left angular gyrus
paresis when there are two distinct lesions – one in the (Heilman et al. 1981).
frontal, and one in the temporoparietal cortex; such a
scenario has been noted with multiple embolic infarctions
ANOMIC APHASIA
(Hanlon et al. 1996; Tranel et al. 1987; Van Horn and
Hawes 1982). Global aphasia has also been noted with a Anomic aphasia is characterized by a more or less isolated
lesion of the thalamus (Kumar et al. 1996) and of the puta- inability to correctly name objects. Speech, although over-
men and adjacent anterior and posterior limbs of the inter- all fluent and coherent, is marked by circumlocutions and
nal capsule (Naeser et al. 1982). a tendency to use indefinite nouns, such as ‘it’ or ‘thing’
when the correct word fails to come to mind. Com-
TRANSCORTICAL MIXED APHASIA prehension is preserved.
Although cueing is not effective, if the examiner pro-
This aphasia, which could also just as well be called ‘trans-
vides the correct name, the patient generally recognizes it.
cortical global aphasia’, is essentially identical to global apha-
Although isolated anomic aphasia does not have strong
sia except for the fact that speech improves with repetition.
localizing value, pathology in the temporal lobe may be
Transcortical mixed aphasia may be seen with lesions
suspected, especially as seen in frontotemporal dementia.
that, in one way or other, ‘isolate’ the posterior portion of
Anomic aphasia may also occur in the course of a delirium
the superior temporal gyrus and adjacent angular gyrus
and as a side-effect of certain medications, such as topi-
from the rest of the cortex, and has been reported with
ramate (Mula et al. 2003) and both tricyclic (Schatzberg et
watershed infarction (Bogousslavsky et al. 1988b) and
al. 1978) and monoamine oxidase inhibitor (Goldstein and
infarction of the medial aspects of the left frontal and pari-
Goldberg 1986) antidepressants.
etal cortices (Ross 1980).
CONDUCTION APHASIA ATYPICAL APHASIA
In conduction aphasia speech is fluent, but there is a degree Atypical aphasias are not uncommon and simply do not
of incoherence and paraphasias are present. In striking fit into the categories noted above. They are particularly
p 02.qxd 3/10/08 9:32 AM Page 48
associated with subcortical lesions (Ciemens 1970; worsens, a dementia eventually appears, thus betraying the
Damasio et al. 1982a). nature of the underlying process (Le Rhun et al. 2005).
Aphasia may also appear in the context of a pre-existing
dementia, and this may occur in each of the disorders,
noted above, that may also cause the syndrome of primary
Etiology progressive aphasia. In passing, it may be noted that, with
the exception of frontotemporal dementia, it is rare that
As noted above, the various different types of aphasia, these neurodegenerative disorders present with an isolated
although generally lateralizing to the left hemisphere, aphasia. Aphasia is also common in the midst of a delir-
localize, according to the type present, to multiple different ium, and here one typically finds elements of either a
areas of the cortex and, less commonly, subcortical struc- sensory or an anomic aphasia.
tures. Determining the nature of the underlying lesion is In children, aphasia may also be seen as part of the
facilitated by attending to the mode of onset of the aphasia, Landau–Kleffner syndrome (Hirsch et al. 1990; Mantovani
whether acute or gradual, and whether or not it is occur- and Landau 1980; Paquier et al. 1992) and the syndrome of
ring in a more or less isolated fashion or in the context of developmental dysphasia: in developmental dysphasia
another syndrome, notably either dementia or delirium. both motor (Sato and Dreifuss 1973) and sensory (Bartak
Aphasia of acute onset, in most cases, represents a stroke, et al. 1975; Cohen et al. 1989; Paul et al. 1983) types have
either ischemic or hemorrhagic. In this situation, it is not been described.
uncommon for the patient to initially present with mutism:
over time, as perilesional edema subsides, the mutism
resolves, leaving one of the classic aphasias in its wake Differential diagnosis
(Pedersen et al. 1995). Rarely, a similar onset may be seen
secondary to an emerging plaque in multiple sclerosis Motor aphasia must be distinguished from dysarthria.
(Achiron et al. 1992; Devere et al. 2000; Lacour et al. 2004; Dysarthric, or slurred, speech, may appear somewhat
Olmos-Lau et al. 1977). Aphasia of paroxysmal onset may effortful, but there are no word finding pauses or circum-
occur on an ictal basis, representing either a simple partial or locutions and, if one listens carefully one finds a normal
a complex partial seizure. In the case of simple partial complement of prepositions, adjectives, etc.
seizures, aphasia may be the sole symptom (Hamilton and Sensory aphasia must be distinguished from other
Mathews 1979; Labar et al. 1992) or may be accompanied by causes of incoherence, notably the loosening of associa-
some twitching of the right side of the face (Williamson et al. tions seen in schizophrenia and the rambling and variably
1985); when aphasia occurs as part of a complex partial incoherent speech seen in delirium and advanced cases of
seizure (Devinsky et al. 1994; Knight and Cooper 1986) one dementia. This differential is relatively easy if one pays
also finds other typical symptoms, such as confusion or attention to the clinical context and associated symptoms.
automatisms. Post-ictal states may also be characterized by Loosening of associations, in contrast with sensory
aphasia, and this strongly suggests that the seizure focus is in aphasia (Faber et al. 1983; Gerson et al. 1977), is generally
the left hemisphere (Gabr et al. 1989; Privitera et al. 1991). associated with more voluble speech; furthermore, patients
Aphasia of gradual onset may occur secondary to an with loosening of associations are also less concerned
appropriately situated tumor or abscess and has also been about their incoherence than are patients with sensory apha-
noted in progressive multifocal leukoencephalopathy sia: indeed, patients with loosening often are absolutely
(Astrom et al. 1958; Krupp et al. 1985): all of these condi- unconcerned in this regard. Although these points may be
tions are readily identified on MR scanning. Such gradual helpful in distinguishing loosening from sensory aphasia,
onsets may also occur in a condition known as primary they represent differences in degree only and may not be
progressive aphasia (PPA). PPA represents the effects of a that helpful clinically. In my experience it is far more use-
focal onset of various neurodegenerative disorders (Josephs ful to attend to the presence of associated symptoms, such
et al. 2006; Knibb et al. 2006), including Alzheimer’s as bizarre behavior, auditory hallucinations, and bizarre
disease (Clark et al. 2003; Galton et al. 2000; Green et al. delusions, which are almost universally present in cases of
1990; Greene et al. 1996), frontotemporal dementia schizophrenia associated with loosening of associations
(Mesulam et al. 2007; Turner et al. 1996), Pick’s disease and, by contrast, are absent in cases of sensory aphasia: as
(Graff-Radford et al. 1990; Karbe et al. 1993; Kertesz et al. noted above, delusions or persecution may be present in
1994; Wechsler et al. 1982), corticobasal ganglionic degen- patients with sensory aphasia but bizarre delusions are
eration (Geda et al. 2007; Ikeda et al. 1996), and progres- absent.
sive supranuclear palsy (Knibb et al. 2006); the syndrome Rambling and more or less incoherent speech is typical
has also been reported secondary to Creutzfeldt–Jakob dis- of delirium and advanced cases of dementia, and some
ease (Mandell et al. 1989). Clinically, most patients present might argue that the difference between this and sensory
with a motor or anomic aphasia or, less commonly, a sen- aphasia is moot and go on to simply say that this finding, in
sory aphasia (Clark et al. 2003; Mendez and Zander 1991). fact, represents a sensory aphasia. From a clinical point of
Over a long period of time, and as the aphasia gradually view, however, the important point is not to resolve this
p 02.qxd 3/10/08 9:32 AM Page 49
2.2 Alexia 49
debate but rather to note whether in patients with ram- this chapter, however, is concerned with alexia occurring
bling and incoherent speech there are associated cognitive in an isolated fashion, that is to say in patients who,
deficits, such as disorientation, confusion, short-term although still able to understand the spoken word and to
memory loss, etc. If these are present, then one pursues the speak fluently and coherently, are yet unable to compre-
differential as noted in Section 5.1 (dementia) and Section hend the written word.
5.3 (delirium).
Pure word deafness must be distinguished from deaf-
ness, and this may be accomplished by attending to the Clinical features
patient’s reaction to sounds other than speech. Patients
with pure word deafness, although unable to comprehend Alexia may or may not be accompanied by agraphia, or the
spoken words, nevertheless are able to respond appropri- inability to write: cases of alexia without agraphia are also
ately to other sounds, such as the ringing of a telephone of referred to as ‘pure’ alexia or ‘pure word blindness’.
the sound of a car horn (Coslett et al. 1984; Kanshepolsky The experience of alexia is quite remarkable. One patient
et al. 1973). Deaf patients, in contrast, fail to respond to with alexia without agraphia (Cohen et al. 1976), an English
these non-speech sounds (Bahls et al. 1988; Le Gros Clark teacher, in describing her situation, commented: ‘I can
and Russel 1938). write and I can see, but I can’t read.’ She went on to note
Isolated alexia (Section 2.2) or agraphia (Section 2.3) that ‘it was as if the writing were in a foreign language.’ She
must also be differentiated from aphasia, and this is readily attempted to cope with the deficit during class by memoriz-
accomplished if one keeps in mind that aphasia is primarily ing what she had written on the blackboard and the strategy
a disturbance in spoken language: although disturbances in would work, unless, of course, the memory faded – turning
written language typically accompany the disturbed speech back to the blackboard, she then found herself unable to
they do not appear in isolation, that is to say in the presence read what she’d written just minutes earlier.
of intact speech, as they do in alexia or agraphia. Remarkably, in alexia without agraphia, some patients,
although unable to read words, are still able to read indi-
vidual letters, and this preserved ability enables patients
Treatment with pure alexia to circumvent their deficit by utilizing a
‘letter-by-letter’ reading strategy. Here, patients read each
In addition to treatment, if possible, of the underlying con- letter out loud, and in hearing the letters, they reconstruct
dition, speech therapy and, controversially, drug treatment the word, which is then understood (Stommel et al. 1991;
may be considered. Warrington and Langdon 1994).
Speech therapy is generally reserved for cases of aphasia In cases of alexia without agraphia, one often, but not
secondary to stroke or other more or less static lesions; its always, finds a right hemianopia. In cases of alexia with
effectiveness in cases of aphasia secondary to disorders agraphia, one also typically sees elements of the Gerstmann’s
which, in the natural course of events tends to progress syndrome, such as finger agnosia, right–left disorientation
(e.g., tumors, neurodegenerative disorders), is not clear. and acalculia.
Drug therapy has been attempted with bromocriptine,
donepezil, and amphetamine, with inconclusive results.
Bromocriptine has been studied in the treatment of motor Etiology
aphasia secondary to stroke in four double-blind studies,
with one positive result (Bragoni et al. 2000) and three neg- A brief review of the visual pathways may be helpful in
ative ones (Ashtary et al. 2006; Gupta et al. 1995; Sabe et al. understanding the mechanisms involved in alexia. To
1995). In one double-blind study of patients with chronic begin, recall that fibers of the optic tract terminate in the
aphasia of various different types, donepezil was superior lateral geniculate body of the thalamus. From the lateral
to placebo on some measures (Bertheir et al. 2006). geniculate body, the geniculocalcarine tract arises and pro-
Dextroamphetamine, in one double-blind study (Walker- ceeds to the calcarine cortex, located on the medial aspect of
Batson et al. 2001), showed some short-term benefit in a the ipsilateral occipital cortex. Fibers from the left calcarine
group of patients with various aphasia types secondary to cortex proceed directly anteriorly toward the left angular
stroke but this benefit was not maintained to a statistically gyrus, whereas fibers from the right calcarine cortex must
significant degree over the long haul. Given these incon- first pass forward, and then cross in the splenium of the cor-
clusive results, prudence may dictate abstaining from drug pus callosum, after which they proceed laterally to an even-
treatment pending further studies. tual juncture with the fibers that originated in the left
calcarine cortex. These conjoined fibers then proceed ante-
riorly, to terminate finally in the left angular gyrus.
2.2 ALEXIA It appears that the left angular gyrus subserves both
reading and writing. Hence, lesions of the gyrus itself cause
As noted in the immediately preceding chapter, alexia (the the syndrome of alexia with agraphia. Lesions, however,
inability to read) may be seen in conjunction with aphasia; which spare the angular gyrus but which deprive it of visual
p 02.qxd 3/10/08 9:32 AM Page 50
afferents from both hemispheres cause ‘pure’ alexia, i.e., The term ‘alexia’, by convention, refers to cases of an
alexia without agraphia. acquired inability to read in those who had once mastered
This deprivation of the angular gyrus of visual afferents this skill. In cases characterized by an inability, despite ade-
from both hemispheres may occur via a number of differ- quate intelligence and educational opportunity, to acquire
ent mechanisms. First, and most commonly, one finds a this skill, one speaks of ‘developmental dyslexia’ (discussed
lesion in the splenium of the corpus callosum (which sev- in Section 9.17).
ers afferents from the right occipital cortex) in combina-
tion with a lesion of the medial aspect of the left occipital
cortex (which destroys afferents from the left occipital Treatment
cortex) (Ajax et al. 1977; Damasio and Damasio 1983).
This first mechanism occurs most commonly secondary to Speech therapy may also be considered in addition to treat-
an infarction in the area of distribution of the left posterior ment, where possible, of the underlying lesion.
cerebral artery, which nourishes both the splenium and the
medial aspect of the left occipital cortex. Second, there may
be a combination of a lesion affecting the left lateral genic-
2.3 AGRAPHIA
ulate body (thus depriving visual afferents from the left
Agraphia, or the inability to write, may be seen, as discussed
hemisphere) and one affecting the splenium (thus severing
in Section 2.1, in conjunction with aphasia; this chapter,
afferents from the right hemisphere) (Stommel et al. 1991).
however, is concerned with agraphia occurring in an iso-
Third, just subjacent to the angular gyrus there may be a
lated fashion, that is to say in patients who, despite being
lesion located in the white matter, which destroys the con-
unable to write, are able to both speak and understand the
joined fibers from both occipital lobes (Greenblatt 1976).
spoken word without significant difficulty.
As noted earlier, cases of alexia without agraphia may be
accompanied by a right hemianopia, and this occurs with
either the first or second mechanisms just described. In Clinical features
cases occurring via the third mechanism, however, the
visual fields remain unaffected. Agraphia may occur in one of two fashions, either in a
As in the case of spoken language, so too for written ‘pure’ form, or as part of Gerstmann’s syndrome, where
language the left hemisphere is dominant in almost all one also finds finger agnosia, right–left disorientation and
right-handers and in most left-handers also. Exceptions, acalculia.
however, do occur. For example, cases of ‘crossed’ alexia
have been noted in which right-handed patients suffered
alexia due to right hemisphere lesions (Fincham et al. 1975; Etiology
Henderson et al. 1985). Furthermore, there is also a case
report of a left-handed patient who developed alexia due to As might be expected, agraphia typically appears secondary
a right hemisphere lesion (Pillon et al. 1987). to lesions in the left hemisphere. Most cases occur second-
Most cases of alexia occur on the basis of stroke, as a result ary to lesions affecting the parietotemporal cortex (Rosati
of an ischemic infarction or, less commonly, an intracerebral and De Bastiani 1979), including either the supramarginal
hemorrhage. Other possible lesions include appropriately sit- or angular gyri (Roeltgen and Heilman 1984); cases have
uated tumors (Turgman et al. 1979; Vincent et al. 1977) or also been reported secondary to lesions in or near ‘Exner’s
plaques of multiple sclerosis (Day et al. 1987; Dogulu et al. area’ (in the posterior portion of the middle frontal gyrus)
1996; Mao-Draayer and Panitch 2004). (Anderson et al. 1990; Tohgi et al 1995) or in the dorsomedial
nucleus of the thalamus (Ohno et al. 2000).
Agraphia may also be confined to the left hand in right-
Differential diagnosis handed patients as part of a disconnection syndrome occur-
ring secondary to a lesion of the corpus callosum (Yamadori
Aphasia is distinguished by an inability to understand the et al. 1980)
spoken word. Agraphia typically occurs as part of a stroke syndrome,
Neglect may include a kind of alexia (often referred to secondary to either ischemic infarction or intracerebral
as ‘hemialexia’) wherein patients fail to attend to the left hemorrhage.
part of a word and thus misread it (Kinsbourne and
Warrington 1962). For example, a patient with left neglect
might, upon being presented with the written word ‘bird- Differential diagnosis
house’, read ‘house’.
Dementing disorders, such as Alzheimer’s disease Poor handwriting, as may be seen with tremor, dystonia,
(Arsland et al. 1993), may cause alexia but this is seen in the paresis or parkinsonian micrographia, is readily apparent,
context of other cognitive deficits, such as disorientation, provided one simply observes the patient’s attempt at
short-term memory loss, etc. writing.
p 02.qxd 3/10/08 9:32 AM Page 51
2.5 Gerstmann’s syndrome 51
Apraxia may lead to disturbed handwriting; however, Etiology

associated features typically suggest the correct diagnosis.
In ideational apraxia, one also sees difficulty in employing Isolated acalculia has been noted with lesions of the left
other ‘tools’, thus patients, in addition to difficulty in uti- parietal cortex (Lampl et al. 1994; Takayama et al. 1994),
lizing a pen or pencil, will also have difficulty in handling a especially the angular gyrus (Benson and Weir 1972;
comb, scissors, etc. In constructional apraxia, there will be Bernal et al. 2003), the posterior inferior frontal cortex
additional difficulties in copying geometric figures, draw- (Tohgi et al. 1995), striatum (Corbett et al. 1986), or ante-
ing stick figures, etc. rior thalamus (Mendez et al. 2003). In almost all cases,
Delirium and dementia may be accompanied by acalculia occurs as part of a stroke syndrome.
agraphia, but the correct syndromal diagnosis is immedi-
ately suggested by associated cognitive deficits, such as
confusion, disorientation, short-term memory loss, etc. Differential diagnosis
Agraphia may also occur on a developmental basis and
in these cases, it is referred to by convention as dysgraphia. Dementia or delirium is typically accompanied by acalcu-
Developmental dysgraphia, discussed in Section 9.18, is lia; however, here the associated cognitive deficits, such as
distinguished from acquired agraphia in that in develop- confusion, disorientation, short-term memory loss, etc.,
mental cases, writing skills, despite adequate intelligence suggest the correct syndromal diagnosis.
and educational opportunity, were simply never acquired, Aphasia is also typically accompanied by acalculia.
whereas in acquired agraphia, these skills were acquired, Perseveration, as may be seen with frontal lesions, may
only to be lost. pantomime acalculia. For example, perseveration in the
‘serial 7s’ test may lead to the following responses: ‘93, 83,
73, 63 . . .’.
Treatment In cases where patients are able to perform calculations
‘in their head’, but are unable to do so on paper, suspicion
Speech therapy should be considered in addition to treat- should be aroused for neglect or apraxia. In neglect,
ment, if possible, of the underlying lesion. patients may misread written numbers (e.g., reading ‘48’
for ‘1948’) and in apraxia they may be unable to properly
order written numbers on the page.
Acalculia occurring on a developmental basis (as dis-
2.4 ACALCULIA cussed in Section 9.19) is distinguished from acquired
acalculia in that in developmental cases patients are unable
Acalculia, that is to say an acquired inability to do to acquire mathematical skills despite adequate intelligence
arithmetic, may be seen as part of Gerstmann’s syndrome, and educational opportunity, whereas in acquired cases
wherein it is accompanied by finger agnosia, right–left dis- this ability was developed only to be subsequently lost.
orientation and agraphia, or it may occur in an isolated
fashion, and it is this isolated acalculia that is dealt
with here. Treatment
In addition, if possible, to treatment of the underlying

lesion, speech therapy may be considered. Hand-held cal-
Clinical features culators, of course, should also be utilized.
Acalculia may become obvious to patients when they
find themselves unable to make change or balance their 2.5 GERSTMANN’S SYNDROME
checkbooks or may only become apparent during the men-
tal status examination. Typically, on the mental status In 1924, Josef Gerstmann described a remarkable syn-
examination, the patient’s ability to do simple, one- or drome characterized by the tetrad of finger agnosia,
two-digit addition and subtraction is tested and, if these right–left disorientation, agraphia, and acalculia. Although
are done well, the patient is then asked to perform ‘serial there has been controversy in the past regarding whether
7s’. In this venerable test, the patient is asked to subtract 7 this occurs in ‘pure’ form or not, the case reports cited
from 100, then to subtract 7 from that number and to keep below indicate that, although rare, the pure syndrome does
on subtracting sevens until he or she can go no further: in fact occur.
making more than two or three errors is considered abnor-
mal (Smith 1962). If there is a clinical suspicion of acalculia
and these tests are done well, it is appropriate to then test Clinical features
the patient’s ability to do multiplication and division, as in
some cases the various computational processes may be In later papers in English, Gerstmann (1940, 1942, 1957)
differentially affected (Lampl et al. 1994). further described the syndrome. He noted that in finger
p 02.qxd 3/10/08 9:32 AM Page 52
agnosia the patient cannot name the fingers either of that goes beyond any social, occupational, or educational
his/her or the examiner’s hand, and that this deficit is usu- requirements. The text produced is for the most part coher-
ally more pronounced with regard to the index, middle, ent, and, rather than consisting of the mere perseverative
and ring fingers. Right–left disorientation may become reproduction of phrases, words or letters, displays a more
apparent when patients are instructed, say, to touch their or less complete working-up of various related themes.
right knee with their left hand: patients with this sign may
use the incorrect hand or may touch the ipsilateral knee.
Agraphia and acalculia are tested for by having the patient Clinical features
write a brief paragraph and then asking him or her to per-
form progressively more difficult calculations. In evaluating a patient’s written production for evidence of
As noted by Gerstmann (1940), it is not uncommon to hypergraphia, attention must be paid to the pre-morbid
see an associated right hemianopia and a degree of alexia. level of written output. Thus, for a patient who pre-
morbidly wrote very little, the appearance of a tendency to
write several pages a day would be clinically significant.
Etiology
Particular attention must also be made to the presence or
absence of perseveration: hypergraphic productions tend
Classically, Gerstmann’s syndrome, as pointed out by
to read like letters, articles or chapters, in that there are
Gerstmann himself (1940), localizes to the angular gyrus
more or less clear themes, which again are more or less
(Gold et al. 1995). The syndrome has also been noted with
fully elaborated in a more or less coherent fashion.
lesions of the white matter subjacent to the angular gyrus
(Mayer et al. 1999), and with lesions involving both the
angular and supramarginal gyri (Roeltgen et al. 1983;
Tucha et al. 1997). Although most cases are due to infarc-
Etiology
tion, Gerstmann’s syndrome has also been noted with
Hypergraphia may be seen in the interictal personality
tumors (Tucha et al. 1997), systemic lupus erythematosus
syndrome, mania, and in schizophrenia.
(Jung et al. 2001), trauma (Mazzoni et al. 1990), and sub-
The interictal personality syndrome (see Section 7.2),
dural hematoma (Maeshima et al. 1998). Although left-sided
seen in patients with chronic epilepsy typically includes
lesions are by far the most common cause, Gerstmann’s syn-
hypergraphia (Hermann et al. 1988; Okamura et al. 1993;
drome has been noted with a right-hemisphere lesion
Waxman and Geschwind 1974, 1975) and is suggested by
(Moore et al. 1991).
the history of chronic epilepsy and the appearance of other
Note that Gerstmann’s syndrome may also occur on a
aspects of the syndrome, such as deep and persistent affect,
developmental basis (Benson and Geschwind 1970;
verbosity, a pre-occupation with religious, ethical or philo-
PeBenito 1987; Suresh and Sebastian 2000).
sophical concerns, hyposexuality, and irritability.
Mania may be characterized by hypergraphia, wherein
Differential diagnosis it represents the written equivalent of pressured speech.
Kraepelin (1976) noted that manics may produce an
The various elements of the tetrad may occur in patients with ‘astonishing’ number of documents, all from ‘the pleasure
dementia or delirium; however, here the associated cognitive in writing’. The presence of other typical symptoms, such
deficits, such as confusion, disorientation and short-term as increased energy, pressured speech, a decreased need for
memory loss, will suggest the correct syndromal diagnosis. sleep, etc. indicate the correct diagnosis.
Certain neurodegenerative disorders, such as Alzheimer’s Schizophrenia may also lead to hypergraphia and
disease, may, albeit rarely, present in a ‘focal’ fashion, with Kraepelin (1971) commented on the ‘very numerous
the syndrome of ‘posterior cortical atrophy’, which, in addi- and monotonous’ documents that may appear, all marked
tion to elements of Gerstmann’s syndrome, also includes by neologisms, delusional thoughts, and a degree of
Balint’s syndrome, aphasia, apraxia, and neglect (Renner incoherence.
et al. 2004; Tang-Wei et al. 2004).
Differential diagnosis
Treatment
Hypergraphia must be distinguished from an appropriate
Consideration may be given to a course of speech therapy in
increase in written output and from mere perseverative
addition to treatment, if possible, of the underlying lesion.
writing. Increased written output is normal in professional
authors and others whose personal or professional lives
2.6 HYPERGRAPHIA require writing. With perseveration, when it appears in
written form, the written output itself consists of the same
Hypergraphia, as defined by Mungas (Hermann et al. phrase, word, or even letter written repeatedly again and
1988), is characterized by a tendency to excessive writing again, sometimes filling page after page. Here, there is no
p 02.qxd 3/10/08 9:32 AM Page 53
2.7 Aprosodia 53
theme evident and no elaborative working-up of ideas. Comprehension on the patient’s part of the prosody
This kind of graphic perseveration has been referred to as with which others speak may be difficult to assess during
‘automatic writing behavior’ and has been noted with a the interview, as most physicians have been trained to keep
right hemispheric tumor (Imamura et al. 1992), right a studied neutrality in their tone of voice. Consequently, it
hemisphere stroke (due to either infarction in the area is necessary to ask the patient if he has had any difficulty in
of distribution of the right middle cerebral artery or to understanding what others are feeling. When there is
putaminal hemorrhage) (Evyapan and Kumral 2001), and doubt, one may also ask friends or family members of the
in dementia characterized in part by a frontal lobe patient whether the patient seems to have had any trouble
syndrome (Frisoni et al. 1993; van Pugt et al. 1996). understanding what they are feeling. In some cases, others
may report that the only way to get across to the patient
what they are feeling is to state it explicitly, rather than
Treatment relying on tone of voice. Formal testing may be accom-
plished by telling the patient that you are going to say
Treatment is directed at the underlying condition.
something (e.g., as above, ‘I am going to the movies’) with
different tones of voice (e.g., happy, angry, or sad) and that
2.7 APROSODIA you want him to report what tone you are using. In per-
forming this test, one must stand behind the patient in
Prosody refers to the affective or emotional aspects of order to prevent the patient from seeing your facial expres-
speech, which are conveyed by the inflection, rhythm, and sions or gestures.
tone with which patients speak (Monrad-Krohn 1947a,b); A ‘mismatch’ between what the patient is feeling and
aprosodia, in turn, represents a defect either in speaking the prosody with which he speaks as he describes his feeling
with normal prosody or in comprehending the prosody may become apparent during the interview. For example,
with which others speak. In a sense, as will become appar- after the patient has described a traumatic experience,
ent below, aprosodia is to the right hemisphere as aphasia one may ask ‘how are you feeling now?’. If the patient says
is to the left hemisphere. The scheme presented here fol- ‘I’m feeling very sad,’ yet there is a lilt to his voice then a
lows closely that presented by Ross (Gorelick and Ross mismatch is present. Or conversely, after the patient has
1987; Ross 1981). described a gratifying experience, one may again ask how
Aprosodia, although not as obvious as aphasia, may he is feeling. If he says ‘Great, just great’ yet his tone of
have profound effects on a patient’s life. In many aspects of voice is somber and lugubrious then again one has demon-
life, it is not so much what we say that counts, as it is how strated that a ‘mismatch’ is present. Importantly, a monot-
we say it, and it is this aspect that is impaired in aprosodia. onous tone does not indicate a ‘mismatch’: to say that a
mismatch is present, there must be a dissonance between
what the patient says he is feeling and the tone with which
Clinical features he reports that feeling.
Repetition is tested by telling the patient that you are
In assessing patients for aprosodia, attention is paid to the going to say something with different tones of voice, and
following aspects of speech: the presence or absence of a that you want him to repeat what you said with the exact
monotonous voice; the ability of the patient to compre- tone in which you said it. One may then proceed with the
hend what another is feeling by simply hearing the intona- neutral phrase ‘I am going to the movies’, said first with a
tion in the other’s voice; the presence or absence of a happy tone, then a sad one and finally an angry one.
‘mismatch’ between what the patient says he is feeling and It should be noted that in aprosodia there is also often
the prosody with which he speaks; and, finally, for any an accompanying change in gesture and facial expression.
improvement in prosodic deficits by repetition. For example, if monotony is present, one may see an
Monotony is said to be present when the patient’s speech absence of gesturing and a lack of facial expression. This
is devoid of inflection or changes in tone – stripped, as it association is not invariable, however, and in many cases
were, of emotional valence. When there is doubt about this, gesture and expression will remain intact in the face of a
it may be appropriate, at some point during the interview, to significant disturbance of prosody.
ask an emotionally charged question and then to listen care- After the above assessment, it is generally possible to
fully to see whether the patient’s response remains monoto- categorize the patient’s aprosodia into one of the following
nous. If it does, then it is critical to ask the patient what he is categories: motor, transcortical motor, sensory, trans-
feeling during the response. Furthermore, one may simply cortical sensory, global, transcortical mixed, conduction, and
ask the patient if he has had any trouble in expressing him- pure affective deafness. Each is discussed below, with com-
self by his tone of voice. Formal testing may be accom- ments on its localizing value. Before proceeding, however,
plished by providing a neutral phrase, such as ‘I am going to it is appropriate to note, as indicated earlier, that in almost
the movies’, and asking the patient to speak that phrase on all cases, aprosodia indicates a right hemisphere lesion.
three successive occasions with three different intonations, Cases of ‘crossed’ aprosodia, in which right-handed
namely happy, angry, and sad. patients developed aprosodia secondary to a lesion in the
p 02.qxd 3/10/08 9:32 AM Page 54
left hemisphere, although reported (Darby 1993; Ross et al. GLOBAL APROSODIA
1989), are rare.
In global aprosodia, speech is monotonous and compre-
hension of other’s prosody is poor; repetition does not
MOTOR APROSODIA improve the patient’s prosodoic output. Global aprosodia
has been noted with lesions affecting both the frontal oper-
In motor aprosodia, speech is monotonous, but compre- culum and the posterior temporal cortex (Darby 1993;
hension is intact and there is no ‘mismatch’; repetition Ross 1981).
does not relieve the monotonous tone. The presence of
motor aprosodia may be quite disconcerting to patients.
One of Ross and Mesulam’s (1979) patients complained TRANSCORTICAL MIXED APROSODIA
that she had great difficulty in disciplining her children
Transcortical mixed aprosodia, which might just as well
because when she said to them that she was angry they
be called transcortical global aprosodia, is essentially identi-
didn’t respond, because she didn’t sound angry. She
cal to global aprosodia with the exception that the patient’s
eventually came up with a way to circumvent her motor
prosody improves with repetition. A case has been reported
aprosodia by adding a parenthetical statement, such as
with a lesion involving the frontoparietal cortex (Ross
‘God damnit, I mean it’ or ‘I am angry and I mean it,’ after-
1981).
ward, thereby getting across what she was feeling. Of note,
however, in this case, ‘even the parenthetical statement was
voiced in a complete monotone’. CONDUCTION APROSODIA
Motor aprosodia most commonly occurs secondary to
In conduction aprosodia spontaneous speech shows a nor-
lesions in the posterior frontal operculum (Gorelick and
mal range of intonation, and comprehension is intact.
Ross 1987; Ross 1981; Ross and Mesulam 1979); cases have
Remarkably, however, there is a ‘mismatch’ between the
also been reported with lesions in the internal capsule
patient’s statement as to how he is feeling and the tone with
(Ross et al. 1981) and basal ganglia (Speedie et al. 1993).
which that statement is made. Furthermore, and remark-
ably so in light of the preserved comprehension of prosody,
TRANSCORTICAL MOTOR APROSODIA patients are unable to repeat sentences with the prosody
spoken by the examiner. Conduction aprosody appears to
Transcortical motor aprosodia is essentially identical to be very rare; a case was reported with a lesion involving the
motor aprosodia except that the monotonous tone of temporoparietal cortex (Gorelick and Ross 1987).
voice disappears with repetition. A case was reported sec-
ondary to a lesion in the anterior limb of the internal
capsule (Ross 1981). PURE AFFECTIVE DEAFNESS
In this condition, spontaneous speech shows a normal range

SENSORY APROSODIA of intonation and there is no mismatch present. Despite
these preserved abilities; however, patients are unable to
In sensory aprosodia there is a normal range of intonation comprehend the prosody with which others speak.
in the patient’s spontaneous speech. Comprehension, Remarkably, however, patients are able to mimic the exam-
however, is impaired, and one finds mismatches; repeti- iner’s intonation upon repetition testing.
tion is also impaired in that when patients repeat the neu- Cases of pure affective deafness have been reported with
tral phrase, the intonation of their speech will not be the lesions affecting the posterior frontal and immediately
same as that of the examiner. subjacent temporal operculum (Gorelick and Ross 1987;
Sensory aprosodia has been noted with lesions affecting Ross 1981) and also with a large lesion affecting the occip-
the temporoparietal cortex (Darby 1993; Gorelick and itoparietal cortex (Gorelick and Ross 1987).
Ross 1987; Ross 1981); a case has also been reported sec-
ondary to a lesion of the thalamus and adjacent posterior
limb of the internal capsule (Wolfe and Ross 1987). Etiology
TRANSCORTICAL SENSORY APROSODIA Almost all reported cases of aprosodia have occurred as
part of a stroke syndrome, secondary to either ischemic
This aprosodia is similar to sensory aprosodia with the infarction or, much less commonly, intracerebral hemor-
exception that repetition is performed well, with the rhage. A case has also been reported of a gradually progres-
patient accurately mimicking the examiner’s tone of voice. sive motor aprosodia secondary to a progressive focal
Cases have been described secondary to a lesion of the atrophy of the right frontal lobe (Ghacibeh and Heilman
anterior temporal cortex (Ross 1981), and the striatum and 2003). Further, there is also a report of motor aprosodia
adjacent posterior limb of the internal capsule (Gorelick occurring paroxysmally as a simple partial seizure
and Ross 1987). (Bautista and Ciampetti 2003).
p 02.qxd 3/10/08 9:32 AM Page 55
2.8 Apraxia 55
Various forms of aprosodia may also be seen in demen- a monotone that the listener might well doubt whether the
tia, as for example Alzheimer’s disease (Perez-Trullen and patient was, in fact, really feeling any sadness.
Modrego Pardo 1996); however, here associated cognitive
deficits, such as disorientation and short-term memory
loss, will suggest the correct syndromal diagnosis. Treatment
Speech therapy may be helpful in addition to treatment, if

Differential diagnosis possible, of the underlying condition.
Motor aprosodia must be distinguished from flattened

affect and hypophonia. Flattened affect is typically accom- 2.8 APRAXIA
panied by a monotone voice; however, here there is also a
‘flattening’ of the patient’s feelings: patients with flattened Apraxia is said to be present when, despite preserved
affect typically report having no feelings and this is in strength, sensation, and coordination, patients are unable
contrast with motor aprosodia wherein patients, although to carry out purposeful activities. In the literature, there are
speaking in a monotone, still have feelings, sometimes a large number of different kinds of apraxia described;
quite strong ones. Hypophonia, as seen in parkinsonism, is in this chapter, four of these are considered: ideomotor,
a speech deficit characterized by whispering and low vol- ideational, constructional, and dressing.
ume, which stands in contrast with the normal volume
seen in motor aprosodia.
Sensory aprosodia must be distinguished from emotional Clinical features
incontinence and from inappropriate affect. Emotional
incontinence, as discussed in Section 4.7, is characterized Each of the four kinds of apraxia is described below.
by episodes of involuntary laughing or crying (accompa-
nied by, respectively, a mirthful or sad tone of voice) dur- IDEOMOTOR AND IDEATIONAL APRAXIA
ing which the patient has no feelings, except, perhaps, a
sense of consternation at being unable to control the emo- Ideomotor and ideational apraxia both have to do with the
tional display. This, superficially, is similar to the ‘misuse of tools, considered in a broad sense, such as combs,
match’ seen in sensory aprosodia; however, on closer knives and forks, and scissors. Bedside testing is readily
inspection there are differences. First, there is, in fact, no accomplished using either some plastic knives/forks from
actual ‘mismatch’ in the sense of a patient feeling one thing the hospital cafeteria or a plastic blunt-ended pair of scis-
and displaying a discordant tone of voice as he reports that sors carried discreetly in the pocket of one’s white coat.
feeling, for in emotional incontinence patients often are Begin first by asking the patient to pantomime the use of a
emotionally neutral during the episode. Second, in con- knife and fork, or perhaps a pair of scissors, and observe
trast with aprosodia, which in almost all cases is constant the performance. In some cases, the evidence for apraxia is
and more or less chronic, emotional incontinence occurs obvious, as patients appear perplexed and are unable to
in discrete episodes, in between which there is a congru- make any appropriate movements. In other cases, there
ence between what the patient feels and the tone with may be some doubt, as for example when patients use a
which that feeling is reported. body part as the tool itself. An example of this might be
Inappropriate affect is very similar to sensory aprosodia, when, in attempting to pantomime using scissors to cut an
in that in both these signs there is a mismatch between imaginary piece of paper, the patient moves the index and
what the patient feels and the tone of voice in which that middle fingers as if they were the blades of the scissors,
feeling is expressed. Differentiating between the two rather than making a repetitive, squeezing kind of motion
requires attention to comprehension of prosody, which is with the hand, as one does when the scissors are actually
present in patients with inappropriate affect, and absent in present. Some authorities consider this an example of
those with sensory aprosodia. apraxia; however, in this author’s experience normal indi-
Finally, aphasia must be clearly distinguished from viduals are as likely to use their fingers as scissors as not. If
aprosodia. Aphasia represents a disturbance in what is said, the patient does display significant difficulty in mimicking
aprosodia a disturbance in how it is said. Consider, for the use of a tool, the next step is to provide the tool and ask
example, two patients who are both grief-stricken over a the patient to use it; in this case, one pulls out the scissors
recent loss. The first one, having a motor aphasia (Broca’s and offers them, along with a piece of paper, and observes
aphasia), although restricted to simply repeating the word the response. In some cases, patients are able to pick up the
‘sad . . . sad . . . sad’ over and over again, might yet say it so tool and use it with little or no difficulty. In others, how-
lugubriously that the listener has no doubt about the depth ever, the perplexity persists: patients may pick up the scis-
of the patient’s grief. By contrast, the second patient, with sors by the wrong end, turn them upside down, or
a motor aprosodia, although able to say the words ‘I’ve otherwise hold them in a useless position. Cases wherein
never felt so sad in my entire life’, would say them in such patients are unable to pantomime use of a tool but then go
p 02.qxd 3/10/08 9:32 AM Page 56
on to use the actual tool without difficulty are considered diseases. Of the neurodegenerative diseases that can present
examples of ideomotor apraxia; cases wherein the diffi- with ideomotor or ideational apraxia, corticobasal gan-
culty with mimicking is followed by a significant difficulty glionic degeneration is the most important, and in such
in actually using the tool are considered examples of cases one typically finds an associated asymmetric parkin-
ideational apraxia. sonism (Riley et al. 1990; Rinne et al. 1994). Other neurode-
Ideomotor apraxia rarely, if ever, constitutes a chief generative disorders that may present with these apraxias
complaint, given that, in the normal course of events, most include Alzheimer’s disease (Ross et al. 1996) and Pick’s
individuals simply do not engage in pantomime. Ideational disease (Fukui et al. 1996). In all of these neurodegenerative
apraxia, however, may bring patients to clinical attention disorders the gradually progressive apraxia is eventually
as, for example, when patients who are unable to use a knife joined by a dementia.
and fork begin to eat with their hands, or those who are Isolated ideomotor (Kazui ad Sawada 1993) or ideational
unable to utilize a toothbrush develop severe bad breath. (Watson and Heilman 1983) apraxia may also occur as part
of a disconnection syndrome, wherein the apraxia is con-
CONSTRUCTIONAL APRAXIA fined to the left upper extremity. In these cases, a lesion of
the corpus callosum, by severing fibers running from the left
Constructional apraxia is said to be present when patients parietal cortex to the right parietal cortex, deprives the right
are unable to copy figures or to spontaneously draw them, parietal cortex of ‘guidance’ and hence purposeful move-
and bedside testing is performed with pencil and paper. ments of the left arm cannot be made.
First, draw some simple geometric forms, such as a trian- Ideomotor and ideational apraxia are very commonly
gle, and ask the patient to copy them. Next, ask the patient found in delirium and advanced dementia and in these cases
to draw a daisy, a house, and a stick figure. In assessing the constitute but one of a large number of cortical deficits
results, one is obviously not judging artistic merit, but accompanying the associated cognitive changes, such as
rather, attention is focused on any disorganization of the confusion, short-term memory loss, disorientation, etc.
drawn figure.
CONSTRUCTIONAL APRAXIA
DRESSING APRAXIA
Constructional apraxia is seen with lesions, generally
In dressing apraxia there is, as the name implies, a significant infarctions, of the right parietal cortex (Piercy et al. 1960);
difficulty in getting dressed, which cannot be accounted for rarely constructional apraxia may be seen with a right thal-
by weakness, fatigue, or clumsiness. One patient, described amic lesion (Motomura et al. 1986). Rarely, a disconnec-
by Hecaen et al. (1956) ‘mentioned spontaneously that he tion constructional apraxia may occur wherein, again
had had a great deal of trouble in dressing and that he must because of a callosal lesion, drawing with the right hand is
frequently be helped by his wife. “I get puzzled in dressing. I severely impaired, whereas drawing with the left hand is
get my clothes mixed.” He said he put his arms in the wrong relatively good by contrast (Giroud and Dumas 1995).
sleeve of his shirt or he put the back of his shirt in front’.
DRESSING APRAXIA
Etiology Dressing apraxia may be seen with lesions, again generally

ischemic infarctions, of the right parietal cortex (Brain
IDEOMOTOR AND IDEATIONAL APRAXIA 1941; Hacean et al. 1956).
Both ideomotor and ideational apraxia may occur in a

more or less isolated fashion, or they may be found in the Differential diagnosis
context of a larger syndrome such as delirium or dementia.
When occurring in an isolated fashion, the onset may be Sensory aphasia, given the overall difficulty with compre-
either acute or gradual. Acute onsets almost always occur as hension, may make it very difficult to test for ideomotor,
part of a stroke syndrome. In these cases, ideomotor apraxia ideational, or constructional apraxia.
may be seen with lesions in the left hemisphere, of either Visual agnosia may complicate testing for ideational
the parietal cortex (Heilman 1973), lentiform nucleus apraxia, in that patients may simply not recognize the tool
(Agostoni et al. 1983), or thalamus (Agostoni et al. 1983; that you are asking them to use. Consequently, if patients
Nadeau et al. 1994). Ideational apraxia, similarly, is also do display apparent ideational apraxia, it is necessary to ask
seen with left hemisphere lesions, including the parietal them to name the offered tool and if they have difficulty
cortex (De Renzi et al. 1988), lentiform nucleus (De Renzi with that one should go on to ask them to describe what
et al. 1986), and thalamus (De Renzi et al. 1986; Warren et the tool is used for in order to rule out mere anomia.
al. 2000). Gradual onsets may occur with mass lesions, such Anomic patients may not be able to say the name of the
as tumors, in the same locations; more commonly, how- tool, but can describe its use; agnosic patients, by contrast,
ever, gradual onsets are seen in certain neurodegenerative will neither be able to name it nor describe its use.
p 02.qxd 3/10/08 9:32 AM Page 57
2.9 Agnosias 57
Neglect of the left side, as may be seen with right parietal name it and they will be unable to say what it is used for.
lesions, may simulate constructional apraxia to a degree. In Interestingly, however, if they are given the object and
neglect, however, the deficient drawing is present only on allowed to handle it, they are able to recognize it by touch.
the left side of the figure, whereas the right side of the fig- Visual agnosia may be broken down into two subtypes:
ure is drawn more or less normally; in contrast, in con- apperceptive and associative. The clinical differentiation of
structional apraxia both the left and right halves of the these subtypes is based on the patient’s ability, after being
figure are poorly drawn. Left neglect may also simulate shown the object in question, to either draw it or pick it out
dressing apraxia, as patients may leave the left side of their from a photograph or drawing of a group of different
dressing unattended to, with the left shirt sleeve dangling objects (one of which is the object in question). In apper-
or the left shoe untied. Here, however, as with the differen- ceptive visual agnosia patients can neither make a drawing
tial with constructional apraxia, the clue to the diagnosis of of the object nor can they pick it out of a group of objects.
neglect is the presence of adequate dressing on the right In associative visual agnosia, however, patients are able to
side of the body. perform these tasks.
At a phenomenological level, it seems that when apper-
ceptive subtype patients are shown an object they do not
Treatment experience an image of it and, lacking such an image, have
no subsequent recognition and, of course, no ability to
Speech and occupational therapy should be considered in make a drawing. In associative visual agnosia, however, an
addition to treatment, if possible, of the underlying cause. image does occur, as evidenced by patient’s ability to make
a drawing of the object or to pick it out of a group of
objects. Despite the presence of an image, however, there is
2.9 AGNOSIAS an inability to make a connection between that image and
the concept of that object, and thus a failure to recognize it,
Agnosia is a condition characterized by a failure, despite name it, or say what it is used for.
adequate sensation, to recognize phenomena. There are a Of note, visual agnosia is typically more severe for small
number of different kinds of agnosia and these may be objects, such as a pair of scissors, than it is for large objects,
grouped as described below. such as chairs or desks, which patients are generally able to
Certain agnosias are distinguished by the sensory recognize and name. Furthermore, the presence of a larger
modality affected. Thus, in visual agnosia, there is a failure object may, by providing a context, allow a patient to rec-
to recognize an object by sight, in tactile agnosia, by touch, ognize a smaller object, which, if seen in isolation, he or she
and in auditory agnosia by the sound made by the object. would be unable to name. For example, if shown a pair of
Other agnosias are characterized by a specific kind of fea- scissors on a desk-top, the patient might be able to name it,
ture that cannot be recognized: in prosopognosia there is whereas if shown the scissors in isolation, perhaps by plac-
difficulty in recognizing faces, in topographagnosia land- ing them on the bed sheet, the patient would be unable
marks go unrecognized and patients get lost, and in color to do so.
agnosia patients cannot recognize various colors. Two
other agnosias are marked by an inability to recognize cer- ETIOLOGY
tain facts: in anosognosia, patients fail to recognize certain
signs and symptoms, as for example hemiparesis; in aso- Apperceptive visual agnosia has been noted with bilateral
matognosia patients fail to recognize that a body part, for infarction of the occipital lobes, which spare the striate
example a hemiparetic arm, belongs to them. Finally, there cortex but involve the secondary visual cortices; the adja-
is a form of agnosia, namely simultanagnosia, wherein cent temporal lobes are often also involved but only in
patients fail to simultaneously recognize all the objects in their more posterior extent (Benson and Greenburg 1969;
their view, as if one or more of them had actually disap- Ferreira et al. 1998; Shelton et al. 1994).
peared. Each of these agnosias is now discussed in turn. Associative visual agnosia may occur secondary to bilat-
eral infarction of the medial occipitotemporal cortex and
subcortical white matter, especially involving the lingual,
Visual agnosia fusiform, and parahippocampal gyri (Albert et al. 1979).
Cases have also been reported secondary to a left unilateral
Visual agnosia, or the inability to recognize and name occipitotemporal infarct coupled with infarction of the
objects by sight, is a rare disorder. splenium of the corpus callosum (Feinberg et al. 1994).
This latter mechanism represents a kind of ‘disconnection’
CLINICAL FEATURES syndrome wherein, although the right occipital lobe is
untouched, the lesion of the splenium disconnects it from
In visual agnosia, patients, despite adequate visual acuity, the left hemisphere.
are unable to recognize familiar objects by sight alone. Theoretically, it appears reasonable to say that in the
Thus, if shown a pair of scissors, they will be unable to apperceptive subtype the destruction of the secondary
p 02.qxd 3/10/08 9:32 AM Page 58
visual cortex prevents, as it were, the ‘working-up’ of the ETIOLOGY

raw visual experience into a coherent image. In the associa-
tive subtype, sparing of the secondary visual cortices allows Tactile agnosia generally occurs secondary to a lesion in the
for the development of an image, but destruction of the inferior parietal cortex (Caselli 1993), on either the right
more anterior occipitotemporal cortex renders impossible (Platz 1996) or the left (Reed et al. 1996).
an association between the image and the concepts that the
patient has regarding various objects. DIFFERENTIAL DIAGNOSIS
Astereognosia is similar clinically to tactile agnosia in that

DIFFERENTIAL DIAGNOSIS patients are unable to recognize objects by touch alone; the
difference lies in the fact that patients with astereognosia
Motor aphasia, when at all severe, is distinguished by the are unable to describe the shape of the object, whereas
effortful speech. In milder cases, characterized primarily by patients with tactile agnosia can.
a word-finding difficulty, the distinction is based on the Anomic aphasia may also appear similar to tactile
patient’s ability to ‘circumlocute’ and say what the object is agnosia in that anomic patients also are unable to name an
used for: in Broca’s aphasia, patients, when shown a pair of object by touching it. In contrast with tactile agnosia, how-
scissors, although unable to say the word ‘scissors’, yet are ever, patients with anomic aphasia are unable to name the
able to say it is used for cutting, whereas in visual agnosia object although they can describe its use (e.g., ‘it’s for
patients are unable to describe the use of the object. opening a lock’).
Anomic aphasia may be distinguished by the patient’s
response to being allowed to handle the object. The anomic
TREATMENT
patient, upon handling the pair of scissors, will still remain
unable to come up with the name, whereas the agnosic Except in the visually impaired, treatment is rarely required.
patient will recognize and name the object.
Auditory agnosia
TREATMENT
Auditory agnosia, or, more explicitly, environmental audi-
Speech/language and occupational therapy may be effec-
tory agnosia, is a very rare condition characterized by an
tive, especially with regard to helping patients develop
inability to recognize such environmental sounds as the
compensatory strategies.
ringing of a telephone or the honking of a horn, despite
normal hearing and a normal ability to understand the
Tactile agnosia spoken word (Vignolo 1982).
Tactile agnosia is characterized by an inability to recognize CLINICAL FEATURES

objects by touching and handling them, despite normal
Auditory agnosia may come to attention when patients fail
light touch, pin-prick, vibratory and two-point discrimi-
to answer the phone or perhaps, with potentially disastrous
natory sensation, and despite an ability to describe the
consequences, fail to respond to the honking of a car horn.
shape of the object in question (Platz 1996).
Bedside testing may be accomplished by standing behind
the patient and ringing a bell or perhaps snapping your fin-
CLINICAL FEATURES gers, and then asking the patient what he heard. In environ-
mental auditory agnosia, patients will acknowledge hearing
After making sure that the patient’s eyes are kept closed, something but they will be unable to say what it was.
place a common object, such as a key, in the patient’s hand
and ask the patient to identify it by touch alone. If the
ETIOLOGY
patient has any difficulty in doing so, ask for a description
of the object. In cases of tactile agnosia, although the Auditory agnosia has been reported with an infarction of
patient can describe the object’s shape (e.g., as having a ser- the posterior portion of the right temporal lobe (Fujii et al.
rated edge), there is an inability to name it or to describe its 1990); it has also been noted to evolve out of a syndrome of
function. At this point, ask the patient to take a look at the cortical deafness secondary to lesions affecting the auditory
object and name it: in tactile agnosia, the patient will be radiations of the retrolenticular portion of the internal
able to name it immediately by sight. capsule bilaterally (Taniwaki et al. 2000).
Importantly, because tactile agnosia may occur unilat-
erally in either hand it is necessary to test both hands, using DIFFERENTIAL DIAGNOSIS
a different object each time; furthermore, it is also neces-
sary to tell the patient to use only one hand at a time and Deafness is readily distinguished in that here there is no
not to palpate the object with both hands. response to any sound. Pure word deafness, as discussed in
p 02.qxd 3/10/08 9:32 AM Page 59
2.9 Agnosias 59
Section 2.1, is a form of aphasia in which patients are (Cohen et al. 1994; Landis et al. 1986, 1988; Rosler et al.
unable to comprehend the meaning of the word, although 1997; Wada and Yamamoto 2001). In all these cases, the
they are able to recognize environmental sounds and the prosopagnosia occurred as part of a stroke syndrome, gen-
spoken word as a word. erally secondary to ischemic infarction.
Prosopagnosia has also been noted secondary to resec-
TREATMENT tion of the posterior portion of the right temporal lobe
(Mesad et al. 2003) and after a right hemispherectomy
Speech/language therapy may enable the patient to develop (Sergent and Villemure 1989). There are also rare reports
compensatory strategies. of progressive prosopagnosia occurring secondary to pro-
gressive atrophy of the right temporal lobe (Evans et al.
1995; Joubert et al. 2003).
Prosopagnosia Interestingly, prosopagnosia may also occur on a parox-
ysmal basis as a simple partial seizure: in one case, a patient
The term prosopagnosia is derived from the Greek word with left occipitotemporal scarring had seizures character-
for face, ‘prosopon’, and refers to a remarkable condition in ized by a sense of ‘flickering lights’ followed by a brief
which patients are unable to recognize others by looking at episode of prosopagnosia (Agnetti et al. 1978).
their faces (Sergent and Poncet 1990). Finally, there are also rare reports of prosopagnosia
occurring on a developmental basis (Kress and Daum 2003).
CLINICAL FEATURES
Patients with prosopagnosia, although able to recognize DIFFERENTIAL DIAGNOSIS

faces as faces, and indeed able to describe accurately the
Anomic aphasia may render patients incapable of coming
facial features of others, are yet unable to identify the other
up with the name of another person; in such cases, however,
person (Tranel et al. 1988). Remarkably, these patients,
in contrast with prosopagnosia, there is no difficulty in rec-
although unable to identify others by their facial features,
ognizing the other person or in specifying the relationship
may be able to identify them by other features, such as their
that exists between the patient and the other person.
voice, dress, or characteristic gait (Damasio et al. 1982b).
Some examples may help to clarify this remarkable con-
dition. In one case, the patient, a party to a lawsuit, had TREATMENT
come to identify his own lawyer by the setting in which the
two of them generally met, namely the lawyer’s office; all Speech/language and occupational therapy may assist the
went well until trial, when the patient, unable to recognize patient in developing compensatory strategies.
people in the courtroom, went up to the opposing counsel
and began to discuss confidential details of the case ‘with
disastrous consequences’ (Pevzner et al. 1962). In another Topographagnosia
case, a patient had come to rely on his wife’s clothing as a
means of identifying her: at a party, he found himself At the outset, it should be noted that there is some debate
unable to recall what she had put on and although she regarding the definition of topographagnosia and, conse-
walked right by him he failed to recognize her (Hecaen and quently, the reader, in perusing journal articles, should pay
Angelergues 1962). In a similar vein, another patient ‘failed particular attention to the definition peculiar to the
to recognize a physician who had just examined him after authors of the article. In this text, topographagnosia refers
the doctor had substituted his suit jacket for his white coat’ to a condition in which patients, despite adequate memory
(Hecaen and Angelergues 1962). Finally, and most remark- and vision, are unable to find their way in surroundings
ably, some patients are not able to recognize themselves that had not previously caused any difficulty. This group of
when they look in the mirror (Damasio et al. 1980). patients may be further subdivided into two types, namely
As might be expected, such patients, in addition to one wherein the difficulty lies in an inability to recognize
being unable to recognize old acquaintances by their facial familiar landmarks (termed here ‘landmark agnosia’) and
features, are also unable to utilize facial features to recog- another wherein, despite a preserved ability to recognize
nize new acquaintances (Malone et al. 1982). landmarks, there is an inability to utilize these landmarks
in deciding which way to proceed (herein referred to as
‘topographical disorientation’).
ETIOLOGY
Prosopagnosia generally occurs secondary to bilateral CLINICAL FEATURES

lesions of the inferior occipitotemporal area (Cohn et al.
1986; Damasio et al. 1980, 1982b; Meadows 1974b; Finding one’s way depends both on recognizing landmarks
Pevzner et al. 1962); rarely prosopagnosia may occur sec- and on knowing which way to proceed upon encountering
ondary to a unilateral occipitotemporal lesion on the right those landmarks. Thus, if one’s accustomed route home
p 02.qxd 3/10/08 9:32 AM Page 60
from the office involves walking down Main Street to the DIFFERENTIAL DIAGNOSIS
Bank and then turning right, then in order to successfully
navigate this route one must first recognize the Bank as the Patients with amnesia may lose their way in unfamiliar sur-
landmark and then, second, know that at this landmark roundings. The basis for this, however, lies in an inability
one must turn right. to commit to memory features of the new environment,
In landmark agnosia, difficulty arises at the level of rec- and this stands in contrast with topographagnosia wherein
ognizing the Bank as a landmark. Although the patient memory is intact. Furthermore, patients with amnesia typ-
may recognize the building, and even describe it, it is not ically have no trouble finding their way in environments
recognized as a landmark and hence the patient is as likely that they have travelled in before, provided, of course, that
to walk past it as to turn. any retrograde amnesia has not obscured their recall.
In topographic disorientation, the situation is a little Patients with dementia or delirium often lose their way
different. Here, the patient does recognize the Bank as a and although this may be on the basis of memory loss (or,
landmark, but, having lost a ‘sense of direction’, the patient in the case of delirium, confusion), it can also occur in
is unable to figure out whether to turn to the right or left, patients with relatively preserved memory, and in these
or simply proceed onward. Some examples may flesh this cases it is perhaps appropriate to consider the topog-
out. In one case, a patient ‘had sudden difficulty finding raphagnosia as but one indicator of widespread cortical
her way out of a subway station she had used daily for damage or dysfunction. The existence of other cognitive
years. She had no difficulty recognizing the surrounding deficits, however, indicates the correct syndromal diagnosis.
buildings, but she was unable to find her way to work or to
her own home despite multiple attempts’ (Alsaadi et al.
TREATMENT
2000). In another case, the patient: ‘. . . suddenly lost his
way home, where he was going on foot. The buildings in Speech/language and occupational therapy may assist the
front of him were familiar to him, so he could recognize patient in developing compensatory strategies.
them right away. However, he did not know which direc-
tion his home was from there. Relying on cues from build-
ings, surrounding scenery and signs, but taking several
wrong turns along the way, he eventually arrived in front Color agnosia
of his own home, and knew immediately that it was in fact
his own home’ (Takahashi et al. 1997). CLINICAL FEATURES
In color agnosia, patients, despite normal color vision,

ETIOLOGY are unable to recognize and name the color of objects
(Kinsbourne and Warrington 1964; Meadows 1974a).
Landmark agnosia has been reported with infarction
involving the medial occipitotemporal area (primarily the
fusiform and lingual gyri, with some involvement of the DIFFERENTIAL DIAGNOSIS
parahippocampal gyrus), either unilaterally on the right or
bilaterally (Aguirre and D’Esposito 1999). An example was Color agnosia must be distinguished from acquired color
also reported as a sequela to herpes simplex encephalitis blindness or, as it is also known, central achromatopsia
wherein there was damage to both temporal lobes, with the (Damasio et al. 1980), this distinction being readily accom-
right side being much more severely involved (McCarthy plished with Ishihara plates. Whereas patients with achro-
et al. 1996). matopsia are unable to read the plates, patients with color
Topographical disorientation has also been reported agnosia are. The patient with achromatopsia exists in a
with infarction of the bilateral fusiform, lingual, and world of grays; by contrast, the patient with color agnosia,
parahippocampal gyri (Alsaadi et al. 2000), and also with although able to discern hues, cannot name them.
infarction of the right parahippocampal gyrus (Habib and
Sirigu 1987; Luzzi et al. 2000). Interestingly, cases have also
been reported secondary to infarction of the splenium ETIOLOGY
(Alsaadi et al. 2000) or right retrosplenial cortex (Takahashi
Color agnosia may occur with lesions of the splenium
et al. 1997).
and the medial portion of the left occipital cortex, and is
Further, there are also case reports of topographagnosia
often seen in association with alexia without agraphia
occurring on a transient basis, with episodes lasting from
(Geschwind and Fusillo 1966).
5 to 30 minutes (Stracciari et al. 1994). During these
episodes, apart from the topographagnosia, patients are
otherwise normal and recovery is complete. Most patients TREATMENT
were women in their middle or later years and, although
the etiology is unknown, it is speculated to be similar to Occupational therapy may assist in devising compensatory
that of transient global amnesia. strategies.
p 02.qxd 3/10/08 9:32 AM Page 61
2.9 Agnosias 61
Anosognosia right hemiparesis; furthermore, it is speculated that the

relative rarity of reports of anosognosia for right hemi-
Anosognosia, a term coined by Babinski in 1914, is paresis may actually be due to an associated sensory apha-
characterized by a failure to recognize neuropsychiatric sia, which makes testing for anosognosia very difficult
deficits. Although hemiparesis is the deficit most com- (Weinstein et al. 1969). Anosognosia for hemiparesis may
monly involved (and indeed anosognosia for hemiparesis is also be seen with infarction or hemorrhage of the following
very common in the first few months after stroke [Hier areas: right posterior limb of the internal capsule and adja-
1983a,b]), other deficits, as noted below, may also go cent lenticular nucleus (House and Hodges 1988), right
unrecognized. thalamus (Liebson 2000; Motomura et al. 1986), and the
pons, on either the right or the left side (Bakchine et al.
CLINICAL FEATURES 1997; Evyapan and Kumral 1999).
Anosognosia for hemianopia has been noted with uni-
The severity of the anosognosia may range from a mere ten- lateral infarction in the area of distribution of the posterior
dency to minimize the extent of the deficit to a strong denial cerebral artery (Celesia et al. 1997) and Anton’s syndrome,
that any deficit at all exists (Baier and Karnath 2005). Upon with bilateral infarctions in the area of distribution of the
questioning patients with anosognosia for hemiparesis, posterior cerebral arteries.
some patients may admit there is something wrong but Anognosia for chorea, as noted above, has been noted in
then go on to say that the paretic limb is only ‘a bit stiff’, or Huntington’s disease.
perhaps suffers from some ‘heaviness’ (Cutting 1978; Roth Cognitive and behavioral deficits are often denied in
1949); in other cases, ‘the patient behaves as though he patients with Alzheimer’s disease (Kashiwa et al. 2005;
knew nothing about his hemiplegia, as though it had not Starkstein et al. 1997), frontotemporal dementia (Eslinger
existed, as though his paralyzed limbs were normal’ et al. 2005), and traumatic brain injury (Sbordone et al.
(Gerstmann 1942). Even more remarkably, in some cases 1998; Flashman and McCallister 2002).
the patient may insist that the paralyzed limb, although
motionless, is in fact moving (Feinberg et al. 2000). DIFFERENTIAL DIAGNOSIS
Other deficits that may go unrecognized include hemi-
anopia, cortical blindness, chorea, and cognitive or behav- In all cases, anosognosia must be differentiated from emo-
ioral deficits. tionally motivated denial. This distinction must not be
Anosognosia for hemianopia after stroke was noted in based on the vehemence with which patients deny any dis-
over one-half of patients in one study (Celesia et al. 1997), ability, as some patients with anosognosia may be quite
a fact that emphasizes the absolute necessity of meticulous insistent in their assertion that nothing is wrong; rather it
visual field testing. should be based on the patient’s response to a display of
Anosognosia for cortical blindness, known as Anton’s sympathy from others. Whereas patients with anosognosia
syndrome, represents a most remarkable clinical phenom- are unmoved by sympathy, patients ‘in denial’ will often
enon (Bergman 1957; Redlich and Dorsey 1945; Symonds break down and tearfully discuss the fears aroused by their
and MacKenzie 1957). Patients, although blind, may insist disabilities.
that their vision is perhaps only slightly impaired, that the Anosognosia for cognitive deficits may be mimicked by
light is too dim, or they may flatly insist that there is noth- a frontal lobe syndrome, wherein disinhibition and jocu-
ing wrong with their vision at all; attempting to walk, they larity prevent patients from acting on any recognition they
predictably bump into things, trip, and fall. might have of their deficits.
Abnormal movements may also go unrecognized, and
this is particularly the case with chorea in Huntington’s TREATMENT
disease (Snowden et al. 1998), wherein patients often
stoutly maintain that there is absolutely nothing wrong. Patients should be seen in rehabilitation therapies and,
Cognitive and behavioral deficits may also be denied by pending resolution of the anosognosia, protective mea-
patients with dementia, who may insist on keeping their sures may be required.
own checkbooks or driving with disastrous results.
ETIOLOGY Asomatognosia
Anosognosia for hemiparesis is most typically seen as part In asomatognosia, patients with left hemiparesis fail to
of a stroke syndrome with infarction in the area of distri- experience the hemiparetic extremity as belonging to them.
bution of the superior division of the middle cerebral
artery involving both the parietal and frontal lobes. CLINICAL FEATURES
Although the vast majority of cases involve infarction of
the right hemisphere with left hemiparesis (Cutting 1978; In some cases, patients, in addition to denying that the
Roth 1949), cases have been reported of anosognosia for paretic arm is theirs, may go on to say that in fact the arm
p 02.qxd 3/10/08 9:32 AM Page 62
belongs to someone else, perhaps a family member (Brock watching the movie, ‘noted to her surprise and consterna-
and Merwarth 1957; Feinberg et al. 1990). This can lead to tion that the character she had been watching was suddenly
a rather bizarre interview: in one case (Sandifer 1946), a sent reeling across the room, apparently as a consequence
female patient with a left hemiplegia, when her paretic left of a punch thrown by a character she had never seen’.
hand was held up in front of her, indicated that it was not Bedside testing may be accomplished either by asking
hers but belonged to the physician. When the physician patients to describe everything they see in their room, or by
attempted to correct her by pointing out that the hand in showing them a picture or photograph of a complex scene,
question had her wedding ring on it, the patient and asking, again, for them to describe every object that
responded, ‘That’s my ring, you’ve got my ring, Doctor.’ they see.
In doubtful cases, it may be helpful to lift up the paretic
left arm, bring it over into the right hemispace and ask the
ETIOLOGY
patient whose arm it is (Feinberg et al. 1990).
Simultanagnosia has been noted with infarction of the
ETIOLOGY right temporo-occipital area (Cohen et al. 1994; Coslett
and Saffran 1991), and with bilateral infarction of the pos-
Most cases are due to infarction involving the right parietal terior occipitoparietal area (Rizzo and Hurtig 1987; Rizzo
cortex in the area of the supramarginal gyrus (Feinberg and Robin 1990). Cases have also been reported secondary
et al. 1990); cases have also been reported secondary to to progressive neurodegenerative conditions in the syn-
infarction involving the right striatum and adjacent inter- drome of posterior cortical atrophy (Tang-Wei et al. 2004).
nal capsule (Healton et al. 1982) and to hemorrhage in the Simultanagnosia may also occur as part of Balint’s syn-
right thalamus (Liebson 2000; Motomura et al. 1986). Rarely, drome (Section 4.14) and, given this, all patients with
asomatognosia may constitute the sole symptomatology of simultanagnosia should be tested for optic ataxia and optic
a simple partial seizure, wherein the seizure focus was in apraxia.
the right parietal lobe (So and Schauble 2004).
DIFFERENTIAL DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Hemianopia and visual neglect are experienced to only one
In the alien hand syndrome, although patients experience side in contrast with simultanagnosia, wherein objects may
the left arm as being under the control of some ‘alien’ be ‘lost’ from any point of the visual field.
entity, they still acknowledge that the arm is theirs; further-
more, in the alien hand syndrome the left arm is quite
active, whereas in asomatognosia the arm is paretic. TREATMENT
Speech/language and occupational therapy may enable

TREATMENT patients to develop compensatory strategies.
Rehabilitation therapies may be helpful.
2.10 NEGLECT
Simultanagnosia
In this aptly named syndrome, patients, in one fashion or
Simultanagnosia, first described by Wolpert in 1924, is a another, neglect or fail to attend to phenomena on one
remarkable syndrome in which patients, despite normal side, usually the left. Neglect may either be visual or motor:
visual acuity, intermittently fail to see all parts of their in visual neglect (also known as spatial neglect), as might
environment simultaneously, with certain objects literally be expected, objects are not attended to in one of the hemi-
falling out of view, as if they had become temporarily fields; in motor neglect, there is an ‘underutilization’ of the
invisible. limbs on one side, as if, in a sense, the patient ‘neglects’ to
use them.
CLINICAL FEATURES
Simultanagnosia may present clinically either because Clinical features

objects ‘disappear’ or, conversely, ‘appear’. In one case
(Coslett and Saffran 1991), a patient, while walking Both forms of neglect are considered in turn, beginning
through the apartment she had lived in for 25 years, ‘fell with visual neglect. Importantly, the physician must test
over her dining room table’ because she didn’t see it as she for both visual and motor neglect before concluding that
crossed the room. The same patient reported the converse neglect, per se, is, or is not, present. This is the case because
experience while watching a movie. In the movie, a charac- visual and motor neglect may occur independently of each
ter was having a heated argument, and the patient, while other (Laplane and Degos 1983).
p 02.qxd 3/10/08 9:32 AM Page 63
2.10 Neglect 63
VISUAL NEGLECT oriented at various and random angles, and then asks the
patient to simply mark off each line. In a positive test, the
Visual neglect may come to clinical attention in a variety of proportion of lines marked off to the left of the midline will
ways. Patients may fail to comb their hair, shave, or put on be substantially less than the proportion marked off to
make-up on the neglected side, and food on the neglected the right.
side of a dinner plate may go uneaten. In talking with a In the clock-drawing test, the patient is asked to draw a
group, patients may fail to speak with those on the large circle on the paper and then to put in all 12 numbers,
neglected side, and, if patients are looking for something, as on a clockface. In a positive test, the numbers will be
the may fail to find it if it is on the neglected side, even if it more or less ‘bunched up’ on the right side. In a similar
is in plain view. In one case (Cherington 1974) left neglect test, patients are asked to draw a daisy; in a positive test, the
ruined a patient’s chess game: although chess pieces on the petals of the daisy will end up being bunched on the right-
right side of the board were moved as always, those on the hand side. Importantly, patients should be asked to simply
left, neglected, remained in position, and were easy prey ‘draw a daisy’ and not given instructions to ‘arrange’ the
for his opponent. In another case (Frantz 1950), a patient, petals around a circle, because when patients are given
while driving, began to run into things (such as pedestrians) such an instruction, the neglect may ‘vanish’ as the petals
on the left. Importantly, as in all cases of visual neglect, are arranged, one by one, evenly around the circle (Ishiai
these collisions did not occur because of a hemianopia: the et al. 1997).
patient had full visual fields but simply did not attend to Importantly, each one of these tests must be performed
things to his left. before concluding that the bedside examination is negative,
Interestingly, visual neglect may also extend to imagined as some patients with neglect may ‘pass’ one, but not another
scenes. In one study, for example, patients with neglect (Azouvi et al. 2002; Binder et al. 1992; Ishiai et al. 1993).
were instructed to imagine that they were standing on one Another bedside test for visual neglect involves testing
side of a famous plaza and then describe what they saw: as for what is known as visual extinction. To test for visual
might be expected, in their description of the imagined extinction, establish first, with confrontation testing, that
scene, they failed to speak of things on the plaza that were the visual fields are full. Stand directly in front of the
located on the left of the imagined scene (Bisiach and patient, perhaps an arm’s length away, and spread your
Luzzatti 1978). arms to the sides such that your hands end up level with the
Bedside testing for visual neglect may be accomplished patient’s eyes and perhaps 30 cm in front of the patient.
with three ‘paper and pencil’ tests: line bisection, line can- Next, ask the patient to stare at your nose and to point to
cellation, and clock drawing. In order to obtain reliable the finger that wiggles, all the while continuing to look
results for these tests, the patient must be seated squarely in straight at your nose. To perform the test, wiggle one index
front of a table, the trunk parallel to the edge of the table finger at a time: if the patient points to each finger when it
and the piece of paper placed directly in front of the wiggles, then, at least on this confrontation testing, the
patient, such that the midline of the paper is continuous fields are full. At this point, while maintaining the same
with the patient’s midline. Although patients may move position, wiggle both fingers simultaneously: with a posi-
their head in any direction, and look in any direction, this tive test, the movement on the neglected side is ‘extin-
relative position of the paper and the patient’s trunk must guished’ and the patient points only to the movement on
be maintained. The reason why the position of the patient’s the unaffected side.
trunk is so important in these three tests is that if the trunk
is angled toward the neglected side the portion of the visual
field subject to neglect will shrink, to the point at which the MOTOR NEGLECT
tests may become falsely negative (Beschin et al. 1997;
Karnath and Hartje 1993). Motor neglect (Laplane and Degos 1983; Triggs et al. 1994)
In the line bisection test a single line is drawn lengthwise may come to clinical attention in a peculiarity of gait: on
on the piece of paper, with the middle of the line resting at the affected side, there may be reduced arm swing, and the
the midline of the piece of paper. The patient is then asked leg, generally being underutilized and ‘left behind’, is seen
to make a mark directly on the middle of the line. When to be ‘dragged’ along to keep up with the leg on the unaf-
left neglect is present, the mark made by the patient will be fected side. When patients are in a wheelchair, the arm on
to the right of the true midline. Importantly, the line the affected side may dangle down from the shoulder and
should be of the order of 10 cm or longer because if the line be dragged along passively on the floor as the wheelchair is
is substantially shorter than this, there may be a ‘crossover’ pushed forward; for patients in bed, the affected leg may be
effect, whereby the patient with left neglect will place the ‘left behind’, still stretched out on the bed, as the patient
mark not to the right but to the left of the true midline swings the leg on the unaffected side over the edge of the
(Anderson 1997; Tegner and Levander 1991). bed while attempting to rise. A more subtle form of motor
In the line cancellation test (Albert 1973) the examiner neglect may occur as patients neglect to chew on the neg-
places a large number of short, straight lines randomly on lected side, with food consequently dribbling out (Andre
the surface of the piece of paper, the different lines being et al. 2000).
p 02.qxd 3/10/08 9:32 AM Page 64
Bedside testing for motor neglect may be accomplished Motor neglect must be distinguished from hemiparesis,
by asking patients to clap their hands or fasten a button: and this distinction is made, as indicated earlier, on the
when motor neglect is present, the arm on the neglected basis of the response to vigorous encouragement. Patients
side will either not participate in the task or do so only with neglect eventually respond to vigorous direction,
minimally. Importantly, this is not the result of a lack of whereas patients with hemiparesis simply cannot.
strength or coordination: with strong urging, patients are
generally able to bring the affected arm into play such that
there is more or less full bimanual cooperation in the task Treatment
at hand.
Various rehabilitation techniques are helpful for visual
neglect, including prism adaptation (Frassinetti et al. 2002;
Etiology Keane et al. 2006), neck muscle vibration (Schindler et al.
2002), and visual scanning training.
As indicated earlier, left neglect, due to a lesion in the right
hemisphere, is clinically far more prominent than right
neglect. Although right neglect certainly does occur, it is REFERENCES
less common, less severe, and, in the case of stroke, less
enduring (Beis et al. 2004; Stone et al. 1991). Achiron A, Ziv I, Djaldetti R et al. Aphasia in multiple sclerosis:
Although neglect may occur secondary to both cortical clinical and radiologic correlation. Neurology 1992;
and to subcortical lesions, in the great majority of cases, it 42:2195–7.
is a lesion of the cortex that is responsible (Vallar and Agnetti V, Carreras M, Pinna L et al. Ictal prosopagnosia and
Perani 1986; Vallar et al. 1994). Cortical lesions capable of epileptogenic damage of the dominant hemisphere. Cortex
causing neglect may be found in the frontal lobe (primarily 1978; 14:50–7.
in the posterior portion of the inferior frontal gyrus Agostoni E, Coletti A, Orlando G et al. Apraxia in deep cerebral
[Daffner et al. 1990; Husain and Kennad 1996; Heilman lesions. J Neurol Neurosurg Psychiatry 1983; 46:804–8.
and Valenstein 1972; Maeshima et al. 1994; Stein and Aguirre GK, D’Esposito M. Topographical disorientation: a
Volpe 1983]), the parietal lobe (Bender 1945; Cherington synthesis and txonomy. Brain 1999;122:1613–28.
1974; Critchley 1949; Frantz 1950) (primarily in the infe- Ajax ET, Schenkenberg T, Kosteljanetz M. Alexia without agraphia
rior parietal lobule [Mort et al. 2003; Vallar and Perani and the inferior splenium. Neurology 1977; 27:685–8.
1986]), and in the temporal lobe (primarily the medial Albert ML. A simple test of visual neglect. Neurology 1973;
aspect of the parahippocampal gyrus [Mort et al. 2003]). 23:658–64.
Subcortical structures implicated include the caudate Albert ML, Soffer D, Silverberg R et al. The anatomic basis of
nucleus (Caplan et al. 1990; Kumral et al. 1999), the puta- visual agnosia. Neurology 1979; 29:876–9.
men (Hier et al. 1977), and the thalamus (Kumral et al. Alexander MP, LoVerme SR. Aphasia after left hemispheric
1995; Motomura et al. 1986; Watson et al. 1981). Rarely, intracerebral hemorrhage. Neurology 1980; 30:1193–202.
neglect has been noted with a lesion of the posterior limb Alexander MP, Schmitt MA. The aphasia syndrome of stroke in the
of the internal capsule (Bogousslavsky et al. 1988c; Ferro left anterior cerebral artery territory. Arch Neurol 1980;
and Kertesz 1984) and with a combined lesion of the 37:97–100.
medial aspect of the occipital lobe and the splenium Alexander MP, Fischette MR, Fischer RS. Crossed aphasias can be
(Chung Park et al. 2005). mirror image anomalous: case reports, review and hypothesis.
Although neglect is most commonly seen as part of a Brain 1989; 112:953–73.
stroke syndrome, it may also occur with other focal lesions Alsaadi T, Binder JR, Lazar RM et al. Pure topographic
(such as tumors) and may also be seen as but one sign in a disorientation: a distinctive syndrome with varied localization.
dementing disorder such as Alzheimer’s disease. Neurology 2000; 54:1864–6.
Anderson B. Pieces of the true crossover effect in neglect.
Neurology 1997; 49:809–12.
Differential diagnosis Anderson SW, Damasio AR, Damasio H. Troubled letters but not
numbers. Domain specific cognitive impairments following
Visual neglect must be distinguished from hemianopia and focal damage in the frontal cortex. Brain 1990; 113:
constructional apraxia. Hemianopic patients, of course, 749–66.
will fail to attend to objects in the hemianopic field, given Andre JM, Beis JM, Morin N et al. Buccal hemineglect. Arch
that they simply do not see them. Confrontational testing Neurol 2000; 57:1734–41.
for visual fields, done with sufficient vigor, however, Arsland D, Larsen JP, Hoien T. Alexia in dementia of the
reveals full fields in patients with neglect. In constructional Alzheimer’s type. Acta Neurol Scand 1993; 88: 434–9.
apraxia, drawing a clock face or daisy may be very difficult; Ashtary F, Janghorbani M, Chitsaz A et al. A randomized, double-
however, here one sees a random pattern of errors, rather blind trial of bromocriptine efficacy in nonfluent aphasia after
than a ‘bunching up’ on the unneglected side. stroke. Neurology 2006; 66: 914–16.
p 02.qxd 3/10/08 9:32 AM Page 65
References 65
Assal G, Perentes E, Deruaz J-P. Crossed aphasia in a right-handed Bisiach E, Luzzatti C. Unilateral neglect of representational space.
patient. Arch Neurol 1981; 38: 455–8. Cortex 1978; 14:129–33.
Astrom K-E, Mancall EL, Richardson EP. Progressive multifocal Bogousslavsky J. Global aphasia without other lateralizing signs.
leukoencephalopathy: a hitherto unrecognized complication of Arch Neurol 1988; 45:143.
chronic lymphatic leukaemia and Hodgkin’s disease. Brain Bogousslavsky J, Regli F. Anterior cerebral artery territory infarction
1958; 81:93–111. in the Lausanne stroke registry: clinical and etiologic
Azouvi P, Samuel C, Louis-Dreyfus A et al. Sensitivity of clinical considerations. Arch Neurol 1990; 47:144–50.
and behavioral tests of spatial neglect after right hemisphere Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical
stroke. J Neurol Neurosurg Psychiatry 2002; 73:160–6. syndromes, etiology, and prognosis. Neurology 1988a;
Babinski J. Contribution a l’etude des troubles mentaux dans 38:837–48.
l’hemiplegie organique cerebrale (anosognosie). Rev Neurol Bogousslavsky J, Regli F, Assal G. Acute transcortical mixed
1914; 27:845–7. aphasia: a carotid occlusion syndrome with pia and watershed
Bahls FH, Chatrian GE, Mesher RA et al. A case of persistent infarcts. Brain 1988b; 111:631–41.
cortical deafness: clinical, neurophysiologic, and neuro- Bogousslavsky J, Miklossy J, Regli F et al. Subcortical neglect:
pathologic observations. Neurology 1988; 38:1490–3. neuropsychological, SPECT, and neuropathological correlations
Baier B, Karnath H-O. Incidence and diagnosis of anosognosia with anterior choroidal artery territory infarction. Ann Neurol
for hemiplegia. J Neurol Neurosurg Psychiatry 2005; 1988c; 23:448–52.
76:358–61. Bragoni M, Altieri M, Di Piero V et al. Bromocriptine and speech
Bakar M, Kirshner HS, Wertz RT. Crossed aphasia: functional brain therapy in non-fluent chronic aphasia after stroke. Neurol Sci
imaging with PET or SPECT. Arch Neurol 1996; 53:1026–32. 2000;21:19–22.
Bakchine S, Ctassaro I, Seilhan D. Anosognosia for hemiplegia Brain WR. Visual disorientation with special reference to
after a brainstem haematoma: a pathological case. J Neurol lesions of the right cerebral hemisphere. Brain 1941;
Neurosurg Psychiatry 1997; 63:686–7. 64:244–72.
Bartak L, Rutter M, Cox A. A comparative study of infantile autism Brock S, Merwarth HR. The illusory awareness of body parts
and specific developmental receptive language disorders. I. The in cerebral disease. Arch Neurol Psychiatry 1957; 77:
children. Br J Psychiatry 1975; 126:127–45. 366–75.
Bautista RE, Ciampetti MZ. Expressive aprosody and amusia as a Brown JR, Simonson J. A clinical study of 100 aphasic patients:
manifestation of right hemisphere seizures. Epilepsia observations on lateralization and localization of lesions.
2003;44:466–7. Neurology 1957; 7:777–83.
Beis JM, Keller C, Morin N et al. Right spatial neglect after left Brown JW, Wilson FR. Crossed aphasia in a dextral: a case report.
hemisphere stroke: qualitative and quantitative study. Neurology 1973; 23:907–11.
Neurology 2004; 63:1600–5. Caplan LR, Schmahmann JD, Kase CS et al. Caudate infarcts. Arch
Bender MB. Extinction and precipitation of cutaneous sensations. Neurol 1990; 47:133–43.
Arch Neurol Psychiatry 1945; 54:1–9. Cappa SF, Perani D, Bressi S et al. Crossed aphasia: PET follow up
Benson DF. Psychiatric effects of dysphasia. Br J Psychiatry 1973; study of two cases. J Neurol Neurosurg Psychiatry 1993;
123:555–66. 56:665–71.
Benson DF, Geschwind N. Developmental Gerstmann syndrome. Caselli RJ. Ventrolateral and dorsomedial somatosensory
Neurology 1970; 20:293–8. association cortex damage produces distinct somesthetic
Benson DF, Greenberg JP. Visual form agnosia. A specific defect in syndromes in humans. Neurology 1993; 43:762–71.
visual discrimination. Arch Neurol 1969; 20:82–9. Celesia G, Brigell MG, Vaphiades MS. Hemianopic anosognosia.
Benson DF, Wier WF. Acalculia: acquired anarithmetria. Cortex Neurology 1997; 49:88–97.
1972; 8:465–72. Cherington MS. Single case study: visual neglect in a chess player.
Benson DF, Sheremata WA, Bouchard R et al. Conduction aphasia: J Nerv Ment Dis 1974; 159:145–7.
a clinicopathological study. Arch Neurol 1973; 28:339–46. Chung Park K, Jeong Y, Hwa Lee B et al. Left hemispatial visual
Bergman PS. Cerebral blindness. Arch Neurol Psychiatry 1957; neglect associated with a combined right occipital and
78:568–84. splenial lesion: another disconnection syndrome. Neurocase
Bernal B, Ardila A, Altman NR. Acalculia: an fMRI study with 2005; 11: 310–18.
implications with respect to brain plasticity. Int J Neurosci Ciemens VA. Localized thalamic hemorrhage: a case of aphasia.
2003; 113:1505–23. Neurology 1970; 20:776–82.
Berthier ML, Green C, Higueras C et al. A randomized, placebo- Clark DG, Mendez MF, Farag E et al. Clinicopathologic case report:
controlled study of donepezil in poststroke aphasia. Neurology progressive aphasia in a 77-year-old man. J Neuropsychiatr
2006; 67:1687–9. Clin Neurosci 2003; 15:231–8.
Beschin N, Cubelli R, Della Sala S et al. Left of what? The role of Cohen DN, Salanga VD, Hully W et al. Alexia without agraphia.
egocentric coordinates in neglect. J Neurol Neurosurg Neurology 1976; 26:455–9.
Psychiatry 1997; 63:483–9. Cohen L, Gray F, Meyrignal C et al. Selective deficity of visual size
Binder J, Marshall R, Lazar R et al. Distinct syndromes of perception: two cases of hemimicropsia. J Neurol Neurosurg
hemineglect. Arch Neurol 1992; 49:1187–94. Psychiatry 1994; 57:73–8.
p 02.qxd 3/10/08 9:32 AM Page 66
Cohen M, Campbell R, Yaghmai F. Neuropathological Evyapan D, Kumral E. Visuospatial stimulus-bound automatic

abnormalities in developmental dysphasia. Ann Neurol 1989; writing behavior: a right hemisphere stroke syndrome.
25:567–70. Neurology 2001; 56:245–7.
Cohn R, Neumann MA, Wood DH. Prosopagnosia: a Faber R, Abrams R, Taylor MA et al. Comparison of schizophrenic
clinicopathological study. Ann Neurol 1986; 20:177–82. patients with formal thought disorder and neurologically
Corbett AJ, McCosker EA, Davidson OR. Acalculia following a impaired patients with aphasia. Am J Psychiatry 1983;
dominant-hemisphere subcortical infarct. Arch Neurol 1986; 140:1348–51.
43:964–6. Feinberg TE, Haber LD, Leeds NE. Verbal asomatognosia.
Coslett HB, Saffran E. Simultanagnosia: to see but not two see. Neurology 1990; 40:1391–4.
Brain 1991; 114:1523–45. Feinberg TE, Schindler RJ, Ochoa E et al. Associative visual
Coslett HB, Brashear HR, Heilman KM. Pure word deafness after agnosia and alexia without prosopagnosia. Cortex 1994;
bilateral primary auditory cortex infarcts. Neurology 1984; 30:395–411.
34:347–52. Feinberg TE, Roane DM, Ali J. Illusory limb movements in
Critchley M. Phenomenon of tactile inattention with special anosognosia for hemiplegia. J Neurol Neurosurg Psychiatry
reference to parietal lesions. Brain 1949; 72:538–61. 2000; 68:511–13.
Cutting J. Study of anosognosia. J Neurol Neurosurg Psychiatry Ferreira CT, Ceccaldi M, Giusiano B et al. Separate visual
1978; 41:548–55. pathways for perception of actions and objects: evidence from
Daffner KR, Ahern GL, Weintraub S et al. Dissociated neglect a case of apperceptive agnosia. J Neurol Neurosurg Psychiatry
behavior following sequential stroke in the right hemisphere. 1998; 65:382–5.
Ann Neurol 1990; 28:97–101. Ferro JM, Kertesz A. Posterior internal capsule infarction
Damasio AR, Damasio H. The anatomic basis of pure alexia. associated with neglect. Arch Neurol 1984; 41:422–4.
Neurology 1983; 33:73–83. Fincham RW, Nibelink DW, Aschenbrenner CA. Alexia with left
Damasio AR, Yamada T, Damasio H et al. Central achromatopsia: homonymous hemianopia without agraphia. Neurology 1975;
behavioral, anatomic and physiologic aspects. Neurology 25:1164–8.
1980; 30:1064–71. Flashman LA, McCallister TW. Lack of awareness and its impact in
Damasio AR, Damasio H, Rizzo M et al. Aphasia with traumatic brain injury. Neurorehabilitation 2002; 17:285–96.
nonhemorrhagic lesion in the basal ganglia and internal Frantz KE. Amnesia for left limbs and loss of interest and
capsule. Ann Neurol 1982a; 39:15–20. alteration in left fields of vision. J Nerv Ment Dis 1950;
Damasio AR, Damasio H, Van Hoesen GW. Prosopagnosia: 112:240–4.
anatomic basis and behavioral mechanisms. Neurology 1982b; Frassinetti F, Angeli V, Meneghello F et al. Long-lasting
32:331–41. amelioration of visuospatial neglect by prism adaptation.
Damasio H, Damasio AR. The anatomical basis of conduction Brain 2002; 125:608–23.
aphasia. Brain 1980; 30:337–50. Freedman M, Alexander MP, Naeser MA. Anatomic basis of
Darby DG. Sensory aprosodia: a clinical clue to lesions of the transcortical motor aphasia. Neurology 1984; 34:409–17.
inferior division of the right middle cerebral artery? Neurology Frisoni GB, Scuatti A, Biancetti A et al. Hypergraphi and brain
1993; 43:567–72. damage. J Neurol Neurosurg Psychiatry 1993; 56:576–7.
Day JT, Fisher AG, Mastaglia FL. Alexia with agraphia in multiple Fuji T, Fukatsu R, Watabe S et al. Auditory sound agnosia without
sclerosis. J Neurol Sci 1987; 78:343–8. aphasia following a right temporal lesion. Cortex 1990;
De Renzi E, Lucchelli F. Ideational apraxia. Brain 1988; 26:263–8.
111:1173–85. Fukui T, Sugita K, Kawamura M et al. Primary progressive apraxia
De Renzi E, Faglioni P, Scarpa M et al. Limb apraxia in patients in Pick’s disease: a clinicopathologic report. Neurology 1996;
with damage confined to the left basal ganglia or thalamus. 47:467–73.
J Neurol Neurosurg Psychiatry 1986; 49:1030–8. Gabr M, Luders H, Dinner D et al. Speech manifestations in
Devere TD, Trotter JL, Cross AH. Acute aphasia in multiple lateralizaton of temporal lobe seizures. Ann Neurol 1989;
sclerosis. Arch Neurol 2000; 57:1207–9. 25:82–7.
Devinsky O, Kelley K, Yacubia EMT et al. Postictal behavior. Arch Galton CJ, Patterson K, Xuereb JH et al. Atypical and typical
Neurol 1994; 51:254–9. presentations of Alzheimer’s disease: a clinical, neuro-
Dogulu CF, Kansu T, Karabudak R. Alexia without agraphia in psychological, neuroimaging and pathological study. Brain
multiple sclerosis. J Neurol Neurosurg Psychiatry 1996; 61:528. 2000; 123:484–98.
Eslinger PJ, Dennis K, Moore P et al. Metacognitive deficits in Gerson SN, Benson DF, Frazier SH. Diagnosis: schizophrenia versus
frontotemporal dementia. J Neurol Neurosurg Psychiatry 2005; posterior aphasia. Am J Psychiatry 1977; 134:966–9.
76:1630–5. Gerstmann J. Fingeragnosie: eine umschriebene storung der
Evans JJ, Heggs AJ, Antoun N et al. Progressive prosopagnosia orientierung am eigenen korper. Wein Klin Wschr 1924;
associated with selective right temporal lobe atrophy: a new 37:1010–12.
syndrome? Brain 1995; 118:1–13. Gerstmann J. Syndrome of finger agnosia, disorientation for right
Evyapan D, Kumral D. Pontine anosognosia for hemiplegia. and left, agraphia and acalculia. Arch Neurol Psychiatry 1940;
Neurology 1999; 53:647–9. 44:398–408.
p 02.qxd 3/10/08 9:32 AM Page 67
References 67
Gerstmann J. Problem of misperception of disease and of impaired Heilman KM. Ideational apraxia – a re-definition. Brain 1973;
body territories with organic lesions: relation to body scheme 96:861–4.
and its disorders. Arch Neurol Psychiatry 1942; 48:890–913. Heilman KM, Valenstein E. Frontal lobe neglect in man. Neurology
Gerstmann J. Some notes on the Gerstmann syndrome. Neurology 1972; 22:660–4.
1957; 7:866–9. Heilman KM, Rothi L, McFarling D et al. Transcortical sensory
Geschwind N. Disconnexion syndromes in animals and man. Brain aphasia with relatively spared spontaneous speech and
1965; 88:585–644. naming. Arch Neurol 1981; 38:236–9.
Geschwind N, Fusillo M. Color-naming defects in association with Hemphill RE, Stengel E. A study on pure word deafness. J Neurol
alexia. Arch Neurol 1966; 15:137–46. Neurosurg Psychiatry 1940; 3:251–62.
Ghacibeh GA, Heilman KM. Progressive affective aprosodia and Henderson VW. Speech fluency in crossed aphasia. Brain 1983;
prosoplegia. Neurology 2003; 60: 1192–4. 106:837–57.
Ghika-Schmid F, Bogousslavsky J. The acute behavioral syndrome Henderson VW. Lesion localization in Broca’s aphasia. Impli-
of anterior thalamic infarction: a propsective study. Ann cations from Broca’s aphasia without hemiparesis. Arch Neurol
Neurol 2000; 48:220–7. 1985; 42:1210–12.
Giroud M, Dumas R. Clinical and topographical range of callosal Henderson VW, Friedman RB, Teng EL et al. Left hemisphere
infarction: a clinical and radiological correlation study. pathways in reading: inferences from pure alexia without
J Neurol Neurosurg Psychiatry 1995; 59:238–42. hemianopia. Neurology 1985; 35:962–8.
Godefroy O, Rousseaux M, Pruvo JP et al. Neuropsychological Hermann BP, Whitman S, Wyler AR et al. The neurological,
changes related to unilateral lenticulostriate infarcts. J Neurol psychosocial and demographic correlates of hypergraphia in
Neurosurg Psychiatry 1994; 57:480–5. patients with epilepsy. J Neurol Neurosurg Psychiatry 198;
Gold M, Adair JC, Jacobs DH et al. Right-left confusion in 51:203–8.
Gerstmann’s syndrome: a model of body centered spatial Hier DB, Davis KR, Richardson EP et al. Hypertensive putaminal
orientation. Cortex 1995; 31:267–83. hemorrhage. Ann Neurol 1977; 2:152–9.
Goldstein DM, Goldberg RL. Monoamine oxidase inhibition- Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after
induced speech blockage. J Clin Psychiatry 1986; 47:604. right hemisphere stroke. Neurology 1983a; 33:337–44.
Goodglass H, Quadfasel FA. Language laterality in left-handed Hier DB, Mondlock J, Caplan LR. Recovery of behavioral
aphasics. Brain 1954; 77:521–48. abnormalities after right hemisphere stroke. Neurology 1983b;
Gorelick PB, Ross ED. The aprosodias: further 33:345–50.
functional–anatomical evidence for the organization of Hindson DA, Westmoreland DE, Carroll WA et al. Persistent
affective language in the right hemisphere. J Neurol Neurosurg Broca’s aphasia after right cerebral infarction in a right-
Psychiatry 1987; 50:553–60. hander. Neurology 1984; 34:387–9.
Graff-Radford NR, Damasio AR, Hyman BT et al. Progressive Hirsch E, Marescaux C, Maquet P et al. Landau-Kleffner syndrome:
aphasia in a patient with Pick’s disease: a neuropsychological, a clinical and EEG study of five cases. Epilepsia 1990;
radiologic and anatomic study. Neurology 1990; 40:620–6. 31:756–67.
Green J, Morris JC, Sandson J et al. Progressive aphasia: a Holmes JE, Sadoff RL. Aphasia due to a right hemisphere tumor in
precursor of global dementia? Neurology 1990; 40:423–9. a right-handed man. Neurology 1966; 16:392–7.
Greenblatt SH. Subangular alexia without agraphia or House A, Hodges J. Persistent denial of hardship after infarction
hemianopia. Brain Lang 1976; 3:229–45. of the right basal ganglia: a case study. J Neurol Neurosurg
Greene JDW, Patterson K, Xuereb J et al. Alzheimer disease and Psychiatry 1988; 51:112–15.
nonfluent progressive aphasia. Arch Neurol 1996; 53: Humphrey ME, Zangwill OL. Dysphasia in left-handed patients
1072–8. with unilateral brain lesions. J Neurol Neurosurg Psychiatry
Gupta MR, Micoch AG, Scolaro C et al. Bromocriptine treatment 1952; 15:184–93.
of nonfluent aphasia. Neurology 1995; 45:2170–3. Husain M, Kennard C. Visual neglect associated with frontal lobe
Habib M, Sirigu A. Pure topographical disorientation: a definition infarction. J Neurol 1996; 243:652–7.
and anatomical basis. Cortex 1987; 23:73–85. Ikeda K, Akiyama H, Iritani S et al. Corticobasal degeneration with
Hamilton NG, Mathews T. Aphasia: the sole manifestation of focal primary progressive aphasia and accentuated cortical lesion in
status epilepticus. Neurology 1979; 29:745–8. superior temporal gyrus: case report and review. Acta
Hanlon RE, Lux WE, Dromerick AW. Global aphasia without Neuropathol 1996; 92: 534–9.
hemiparesis: language profiles and lesion distribution. J Neurol Imamura T, Yamadori A, Tsuburaya K. Hypergraphia associated
Neurosurg Psychiatry 1996; 66:365–9. with a brain tumor of the right cerebral hemisphere. J Neurol
Hecaen H, Angelergues R. Agnosia for faces (prosopagnosia). Arch Neurosurg Psychiatry 1992; 54:25–7.
Neurol 1962; 7:92–100. Ishiai S, Sugishita M, Ichikawa T et al. Clock-drawing test
Hecaen H, Penfield W, Bertrand C et al. The syndrome of and unilateral spatial neglect. Neurology 1993; 43:
apractagnosia due to lesions of the minor cerebral 106–10.
hemisphere. Arch Neurol Psychiatry 1956; 75:400–34. Ishiai S, Seki K, Koyama Y et al. Disappearance of unilateral
Healton EB, Navarro C, Bressman S et al. Subcortical neglect. spatial neglect following a simple instruction. J Neurol
Neurology 1982; 32:776–8. Neurosurg Psychiatry 1997; 63:23–7.
p 02.qxd 3/10/08 9:32 AM Page 68
Josephs KA, Duffy JR, Strand EA et al. Clinicopathological and Labar DR, Solomon GE, Wells CR. Aphasia as the sole
imaging correlates of progressive aphasia and apraxia of manifestation of simple partial status epilepticus. Epilepsia
speech. Brain 2006; 129:1385–98. 1992; 33:84–7.
Joubert S, Felician O, Barbeau E et al. Impaired configurational LacourA, de Seze J, Revenco E et al. Acute aphasia in multiple
processing in a case of progressive prosopagnosia associated sclerosis. Neurology 2004; 62:974–7.
with predominant right temporal lobe atrophy. Brain 2003; Lampl Y, Eshel Y, Gilad R et al. Selective acalculia with sparing of
126:2537–50. the subtraction process in a patient with left parietotemporal
Jung RE, Yeo RA, Sibbit WL et al. Gerstmann syndrome in systemic hemorrhage. Neurology 1994; 44:1759–61.
lupus erythematosus: neuropsychological, neuroimaging and Landis T, Cummings JL, Benson DF et al. Loss of topographic
spectroscopic findings. Neurocase 2001; 7:515–21. familiarity: an environmental agnosia. Arch Neurol 1986;
Kanshepolsky J, Kelley JJ, Waggener JD. A cortical auditory 43:132–6.
disorder: clinical, audiologic and pathologic aspects. Landis T, Regard M, Bliestle A et al. Prosopagnosia and agnosia for
Neurology 1973; 23:699–705. noncanonical views. Brain 1988; 111:1287–97.
Karbe H, Kertesz A, Polk M. Profiles of language impairment in Laplane D, Degos JD. Motor neglect. J Neurol Neurosurg Psychiatry
primary progressive aphasia. Arch Neurol 1993; 50:192–201. 1983; 46:152–8.
Karnath HO, Hartje W. Decrease of contralateral neglect by neck Leibson E. Anosognosia and mania associated with right thalamic
muscle vibration and spatial orientation of trunk midline. haemorrhage. J Neurol Neurosurg Psychiatry 2000;68:107–8.
Brain 1993; 116:383–96. Le Gros Clark WE, Russell WR. Cortical deafness without aphasia.
Kashiwa Y, Kitabayashi Y, Narumoto J et al. Anosognosia in Brain 1938; 61:375–83.
Alzheimer’s disease: association with patient characteristics, Le Rhun E, Richard F, Pasquier F. Natural histoy of primary
psychiatric symptoms and cognitive deficits. Psychiatry Clin progressive aphasia. Neurology 2005;65:887–91.
Neurosci 2005; 59:697–704. Luzzi S, Pucci E, Di Bella P et al. Topographical disorientation
Kazui S, Sawasa T. Callosal apraxia without agraphia. Ann Neurol consequent to amnesia of spatial location in a patient with
1993; 33:401–3. right parahippocampal damage. Cortex 2000; 36:427–34.
Keane S, Turner C, Sherrington C et al. Use of fresnel prism glasses Maeshima S, Funahashi K, Ogura M et al. Unilateral spatial
to treat stroke patients with hemispatial neglect. Arch Phys neglect due to right frontal lobe hematoma. J Neurol
Med Rehabil 2006; 87:1668–72. Neurosurg Psychiatry 1994; 57:89–93.
Kertesz A, Hudson L, Mackenzie IRA et al. The pathology and Maeshima S, Okumura Y, Nakai K et al. Gerstmann’s syndrome
nosology of primary progressive aphasia. Neurology 1994; associated with chronic subdural haematoma: a case report.
44:2065–72. Brain Inj 1998; 12:697–701.
Kinsbourne M, Warrington EK. A variety of reading disability Malone DR, Morris HH, Kay MC et al. Prosopagnosia: a double
associated with right hemisphere lesions. J Neurol Neurosurg dissociation between the recognition of familiar and
Psychiatry 1962; 25:339–44. unfamiliar faces. J Neurol Neurosurg Psychiatry 1982;
Kinsbourne M, Warrington EK. Observations on color agnosia. J 45:820–2.
Neurol Neurosurg Psychiatry 1964; 27:296–9. Mandell AM, Alexander MP, Carpenter S. Creutzfeldt–Jakob
Knibb J, Xuereb JH, Patterson K et al. Clinical and pathological disease presenting as isolated aphasia. Neurology 1989;
characterization of progressive aphasia. Ann Neurol 2006; 39:55–8.
59:156–65. Mantovani JF, Landau WM. Acquired aphasia with convulsive
Knight RT, Cooper J. Status epilepticus manifesting as reversible disorder: course and prognosis. Neurology 1980; 30:524–9.
Wernicke’s aphasia. Epilepsia 1986; 27:301–4. Mao-Draayer Y, Panitch H. Alexia without agraphia in multiple
Kraepelin E. Dementia praecox and paraphrenia. Huntington, NY: sclerosis: case report with magnetic resonance imaging
Robert E. Krieger, 1971. localization. Mult Scler 2004; 10:705–7.
Kraepelin E. Manic-depressive insanity and paranoia. NY: Arno Masdeu JC, O’Hara RJ. Motor aphasia unaccompanied by
Press, 1976. faciobrachial weakness. Neurology 1983; 33:519–21.
Kress T, Dau M. Developmental prosopagnoia: a review. Behav Mayer E, Martory M-D, Pegna AJ et al. A pure case of Gerstmann’s
Neurol 2003; 14:109–21. syndrome with a subangular lesion. Brain 1999; 122:1107–20.
Krupp LB, Lipton RB, Swerdlow ML et al. Progressive multifocal Mazzoni M, Pardossi L, Cantini R et al. Gerstmann syndrome: a
leukoencephalopathy: clinical and radiologic features. Ann case report. Cortex 1990; 26:459–67.
Neurol 1985; 17:344–9. McCarthy RA, Evans JJ, Hodges JR. Topographic amnesia: spatial
Kumar R, Masih AK, Pardo J. Globl aphasia due to thalamic memory disorder, perceptual dysfuncton, or category specific
hemorrhage: a case report and review of the literature. Arch semantic memory impairment? J Neurol Neurosurg Psychiatry
Phys Med Rehabil 1996; 77:1312–15. 1996; 60:318–25.
Kumral E, Kocaer T, Ertubey NO et al. Thalamic hemorrhage: a McFarling D, Rothi LJ, Heilman KM. Transcortical aphasia from
prospective study of 100 patients. Stroke 1995; 26: ischemic infarcts of the thalamus: a report of two cases.
964–70. J Neurol Neurosurg Psychiatry 1982; 45:107–12.
Kumral E, Evyapan D, Balkir N. Acute caudate vascular lesions. Meadows JC. Disturbed perception of colours associated with
Stroke 1999; 30:100–8. localized cerebral lesions. Brain 1974a; 97:615–32.
p 02.qxd 3/10/08 9:32 AM Page 69
References 69
Meadows JC. The anatomical basis of prosopagnosia. J Neurol Pan C-L, Kuo M-F, Hsieh S-T. Audiory agnosia caused by a tectal
Neurosurg Psychiatry 1974b; 37:489–501. germinoma. Neurology 2004; 63:2387–9.
Megens J, van Loon J, Goffin J et al. Subcortical aphasia from a Paquier PF, Van Dongen HR, Loonen CB. The Landau–Kleffner
thalamic abscess. J Neurol Neurosurg Psychiatry 1992; syndrome or ‘acquired aphasia with convulsive disorder’: long-
55:319–22. term follow-up of six children and a review of the recent
Mendez MF, Zander BA. Dementia presenting with aphasia: literature. Arch Neurol 1992; 49:354–9.
clinical characteristics. J Neurol Neurosurg Psychiatry 1991; Paul R, Cohen DJ, Caparulo BK. A longitudinal study of patients
54:542–5. with severe developmental disorders of language learning.
Mendez MF, Papasian NC, Lim GT. Thalamic acalculia. J Neuro- J Am Acad Child Adolesc Psychiatry 1983; 22:525–34.
psychiatry Clin Neurosci 2003; 15:115–16. PeBenito R. Developmental Gerstmann syndrome: case report
Mesad S, Laff R, Devinsky O. Transient postoperative proso- and review of the literature. J Dev Behav Pediatr 1987;
pagnosia. Epilepsy Behav 2003; 4:567–70. 8:229–32.
Mesulam M, Johnson N, Kreftt TA et al. Progranuin mutations in Pedersen PM, Jorgensen HS, Nakayama H et al. Aphasia in acute
primary progressive aphasia. The PPA1 and PPA3 families. Arch stroke: incidence, determinants, and recovery. Ann Neurol
Neurol 2007; 64:43–7. 1995; 38:659–66.
Meyer B, Kral T, Zentner J. Pure word deafness after resection of a Perez-Trullen JM, Modrego Pardo PJ. Comparative study of
tectal plate glioma with preservation of wave V of brain stem aprosody in Alzheimer’s disease and in multi-infarct dementia.
auditory evoked potentials. J Neurol Neurosurg Psychiatry Dementia 1996; 7:59–62.
1996; 61:423–4. Pevzner S, Bornstein B, Loewenthal M. Prosopagnosia. J Neurol
Mohr JP, Pessin MP, Finkelstein S et al. Broca aphasia: pathologic Neurosurg Psychiatry 1962; 25:336–8.
and clinical. Neurology 1978; 28:311–24. Piercy M, Hecaen H, de Ajuriaguerra J. Constructional apraxia
Monrad-Krohn GH. Dysprosody or altered ‘melody of language’. with unilateral cerebral lesions – left and right sided cases
Brain 1947a; 70:405–15. compared. Brain 1960; 83:225–42.
Monrad-Krohn GH. The prosodic quality of speech and its Pillon B, Bakchine S, Lhermitte F. Alexia without agraphia in a
disorders. Acta Psychiatr Neurol Scand 1947b; 22:255–69. left-handed patient with a right occipital lesion. Arch Neurol
Moore MR, Saver JL, Johnson KA et al. Right parietal stroke with 1987; 44:1257–62.
Gerstmann’s syndrome. Appearance on computed tomograph, Platz T. Tactile agnosia: causistic evidence and theoretical
magnetic resonance imaging, and single-photon emission remarks on modality-specific meaning representations and
computed tomography. Arch Neurol 1991; 48: sensorimotor integration. Brain 1996; 119:1565–74.
432–5. Privitera MD, Morris GL, Gilliam F. Postictal language assessment
Mort DJ, Malhorta P, Mannan SK et al. The anatomy of visual and lateralization of complex partial seizures. Ann Neurol
neglect. Brain 2003; 126:1986–97. 1991; 30:391–3.
Motomura N, Yamadori A, Mori E et al. Unilateral spatial neglect Racy A, Jannotta FS, Lehner LH. Aphasia resulting from occlusion
due to hemorrhage in the thalamic region. Acta Neurol Scand of the left anterior cerebral artery: report of a case with an old
1986; 74:190–4. infarct in the left rolandic region. Arch Neurol 1979;
Mula M, Trimble MR, Thompson P et al. Topiramate and word- 36:221–4.
finding difficulties in patients with epilepsy. Neurology 2003; Redlich FC, Dorsey JF. Denial of blindness by patients with
60:1104–7. cerebral disease. Arch Neurol Psychiatry 1945; 53:407–17.
Nadeau SE, Reltgen DP, Sevush S et al. Apraxia due to a Reed CL, Caselli RJ, Farah MJ. Tactile agnosia: underlying
pathologically documented thalamic infarction. Neurology impairment and implications for normal tactile object
1994; 44:2133–7. recognition. Brain 1996; 119:875–88.
Naeser MA, Hayward RW. Lesion localization in aphasia with Renner JA, Burns JM, Hou CE et al. Progressive posterior cortical
cranial computed tomography and the Boston diagnostic dysfunction. A clinicopathologic series. Neurology 2004;
aphasia exam. Neurology 1978; 28:545–51. 63:1175–80.
Naeser MA, Alexander MP, Helm-Estabrooks N et al. Aphasia with Riley DE, Lang AE, Lewis A et al. Cortical-basal ganglionic
predominantly subcortical lesion sites: description of three degneration. Neurology 1990; 40:1203–12.
capsular/putaminal aphasia syndromes. Arch Neurol 1982; Rizzo M, Hurtig R. Looking but not seeing: attention, perception,
39:2–14. and eye movements in simultanagnosia. Neurology 1987;
Ohno T, Bando M, Nagura Het al. Apraxic agraphia due to 37;1642–8.
thalamic infarction. Neurology 2000;54:2336–9. Rizzo M, Robin DA. Simultanagnosia: a defect of sustained
Okamura T, Fukai M, Yamadori A et al. A clinical study of attention yields insight on visual information processing.
hypergraphia in epilepsy. J Neurol Neurosurg Psychiatry 1993; Neurology 1990; 40:447–55.
56:556–9. Rinne JO, Lee MS, Thompson PD et al. Corticobasal degeneration:
Olmos-Lau N, Ginsberg MD, Geller JB. Aphasia in multiple a clinical study of 36 cases. Brain 1994; 117:1183–96.
sclerosis. Neurology 1977; 27:623–6. Roeltgen DP, Helman KM. Lexical agraphia. Further support for
Orton ST. ‘Word blindness’ in school children. Arch Neurol the two-system hypothesis of linguistic agraphia. Brain 1984;
Psychiatry 1925; 14:581–615. 107:811–27.
p 02.qxd 3/10/08 9:32 AM Page 70
Roeltgen DP, Sevush S, Heilman KM. Pure Gerstmann’s syndrome Shelton PA, Bowers D, Duara D et al. Apperceptive visual agnosia:
form a focal lesion. Arch Neurol 1983; 40:46–67. a case study. Brain Cogn 1994; 25:1–23.
Rosati G, De Bastiani P. Pure agraphia: a discrete form of aphasia. Silverberg R, Gordon HW. Differential aphasia in two bilingual
J Neurol Neurosurg Psychiatry 1979; 42:266–9. individuals. Neurology 1979; 29:51–5.
Rosler A, Lanquillon S, Dippel O et al. Impairment of facial Singer S, Cummings JL, Benson DF. Delusions and mood disorders
recognition in patients with right cerebral infarcts quantified in patients with chronic aphasia. J Neuropsychiatry Clin
by computer aided ‘morphing’. J Neurol Neurosurg Psychiatry Neurosci 1989; 1:40–5.
1997; 62:261–4. Smith A. The serial sevens subtraction test. Arch Neurol 1962;
Ross ED. Left medial parietal lobe and receptive language 17:78–80.
functions: mixed transcortical aphasia after left anterior Snowden JS, Craufurd D, Griffiths HL et al. Awareness of
cerebral artery infarction. Neurology 1980; 30:144–51. involuntary movements in Huntington disease. Arch Neurol
Ross ED. The aprosodias: functional–anatomic organization of the 1998; 55:801–5.
affective components of language in the right hemisphere. So EL, Schauble BS. Ictal asomatognosia as a cause of epileptic
Arch Neurol 1981; 38:561–9. falls. Simultaneous video EMG, and invasive EEG. Neurology
Ross ED, Mesulam M-M. Dominant language functions of the 2004; 63:2153–4.
right hemisphere: prosody and emotional gesturing. Arch Speedie LJ, Wertman E, Ta’ir J et al. Disruption of automatic
Neurol 1979; 36:144–8. speech following a right basal ganglia lesion. Neurology 1993;
Ross ED, Harney JH, deLacoste-Utamsing C et al. How the brain 43:1768–74.
interprets affective and propositional language into a unified Starkstein SE, Chemerinski E, Sabe L et al. Prospective longitudinal
behavioral function: hypothesis based on clinicoanatomic study of depression and anosognosia in Alzheimer’s disease. Br
evidence. Arch Neurol 1981; 38:745–8. J Psychiatry 1997; 171:47–52.
Ross ED, Anderson B, Morgan-Fisher A. Crossed aprosodia in Stein S, Volpe BT. Classical ‘parietal’ neglect syndrome after
strongly dextral patients. Arch Neurol 1989; 46:206–9. subcortical right frontal lobe infarction. Neurology 1983;
Ross SJM, Graham N, Stuart-Green L et al. Progressive biparietal 33:797–9.
atrophy: an atypical presentation of Alzheimer’s disease. J Stommel EW, Friedman RJ, Reeves AG. Alexia without agraphia
Neurol Neurosurg Psychiatry 1996; 61:388–95. associated with spleniogeniculate infarction. Neurology 1991;
Roth N. Disorders of body image caused by lesions of the right 41:587–8.
parietal lobe. Brain 1949; 72:89–111. Stone SP, Wilson B, Wroot A et al. The assessment of visuo-spatial
Rubens AB. Aphasia with infarction in the territory of the anterior neglect after acute stroke. J Neurol Neurosurg Psychiatry 1991;
cerebral artery. Cortex 1975; 11:239–50. 54:345–50.
Rumsey JM, Donohue BC, Brady DR et al. A magnetic resonance Stracciari A, Lorusso S, Pazzaglia P. Transient topographical
imaging study of planum temporale asymmetry in men with amnesia. J Neurol Neurosurg Psychiatry 1994; 57:1423–5.
developmental dyslexia. Arch Neurol 1997; 54:1481–4. Suresh PA, Sebastian S. Developmental Gerstmann’s syndrome: a
Sabe L, Salvarezza F, Garcia Cuerva A et al. A randomized, double- distinct clinical entity of learning disabilities. Pediatr Neurol
blind, placebo-controlled study of bromocriptine in nonfluent 2000; 22:267–78.
aphasia. Neurology 1995; 45:2272–4. Sweet EWS, Panis W, Levine DN. Crossed Wernicke’s aphasia.
Sandifer PH. Anosognosia and disorders of body scheme. Brain Neurology 1984; 34:475–9.
1946; 68:122–37. Symonds C, MacKenzie I. Bilateral loss of vision from cerebral
Sato S, Dreifuss FE. Electroencephalographic findings in a patient infarction. Brain 1957; 80:415–55.
with developmental expressive aphasia. Neurology 1973; Takahashi N, Kawamura M, Shiota J et al. Pure topographic
23:181–5. disorientation due to right retrosplenial lesion. Neurology
Sbordone RJ, Seranian GD, Ruff RM. Are the subjective complaints 1997; 49:464–9.
of traumatically brain injured patients reliable? Brain Inj 1998; Takayama Y, Sugishita M, Akiguchi I et al. Isolated acalculia due
12:505–15. to left parietal lesion. Arch Neurol 1994; 51:286–91.
Schatzberg AF, Cole JO, Blumer DP. Speech blockage: a tricyclic Tanabe H, Sawada T, Inoue N et al. Conduction aphasia and
side effect. Am J Psychiatry 1978; 135:600–1. arcuate fasciculus. Acta Neurol Scand 1987; 76:422–7.
Schindler I, Kerkhoff G, Karnath H-O et al. Neck vibration induces Tang-Wei DF, Graff-Radford NR, Boeve BF et al. Clinical, genetic,
lasting recovery in spatial neglect. J Neurol Neurosurg and neuropathlogic characteristics of posterior cortical
Psychiatry 2002;73:412–19. atrophy. Neurology 2004; 63:1168–74.
Selnes OA, Knopman DS, Miccum N et al. The central role of Taniwaki T, Tagawa K, Sato F et al. Auditory agnosia restricted to
Wernicke’s area in sentence repetition. Ann Neurol 1985; environmental sounds following cortical deafness and
17:549–57. generalized auditory agnosia. Clin Neurol Neurosurg 2000;
Sergent J, Poncet M. From covert to overt recognition of faces in 102:156–62.
prosopagnosia. Brain 1990; 113:989. Tegner R, Levander M. The influence of stimulus properties on
Sergent J, Villemure JG. Prosopagnosia in a right hemi- visual neglect. J Neurol Neurosurg Psychiatry 1991; 54:
spherectomized patient. Brain 1989; 112:975–95. 882–7.
p 02.qxd 3/10/08 9:32 AM Page 71
References 71
Toghi H, Saitoh K, Takahashi S et al. Agraphia and acalculalia lateral occipital region. J Neurol Neurosurg Psychiatry 2001;
after a left prefrontal (F1, F2) infarction. J Neurol Neurosurg 71:254–7.
Psychiatry 1995; 58:629–32. Walker-Batson D, Curtis S, Natarajan R et al. A double-blind,
Tonkonogy J, Goodglass H. Language function, foot of the third placebo-controlled study of the use of amphetamine in the
frontal gyrus, and rolandic operculum. Arch Neurol 1981; treatment of aphasia. Stroke 2001; 32:2093–8.
38:486–90. Warren JD, Thompson PD. Diencephalic amnesia and apraxia after
Tranel D, Biller J, Damasio H et al. Global aphasia without left thalamic infection. J Neurol Neurosurg Psychiatry 2000;
hemiparesis. Arch Neurol 1987; 44:304–8. 68:248.
Tranel D, Damasio AR, Damasio H. Intact recognition of facial Warrington EK, Langdon D. Spelling dyslexia: a deficit in the
expression, gender, and age in patients with impaired visual word-form. J Neurol Neurosurg Psychiatry 1994;
recognition of face identity. Neurology 1988; 38:690–6. 57:211–16.
Triggs WJ, Gold M, Gerstle G et al. Motor neglect associated with Watson RT, Heilman KM. Callosal apraxia. Brain 1983;
a discrete parietal lesion. Neurology 1994; 44:1164–6. 106:391–403.
Trojanowski JQ, Green RC, Levine DN. Crossed aphasia in a Watson RT, Valenstein E, Heilman KM. Thalamic neglect. Possible
dextral: a clinicopathological study. Neurology 1980; role of the medial thalamus and nucleus reticularis in
30:709–13. behavior. Arch Neurol 1981; 38:501–6.
Tucha O, Steup A, Smely C et al. Toe agnosia in Gerstmann Waxman SG, Geschwind N. Hypergraphia in temporal lobe
syndrome. J Neurol Neurosurg Psychiatry 1997; 63:399–403. epilepsy. Neurology 1974; 24:629–36.
Turner RS, Kenyon LC, Trojanowski JQ et al. Clinical, Waxman SG, Geschwind N. The interictal behavior syndrome of
neuroimaging, and pathologic features of progressive temporal lobe epilepsy. Arch Gen Psychiatry 1975; 32:
nonfluent aphasia. Ann Neurol 1996; 39:166–73. 1580–6.
Turgman J, Goldhammer Y, Braham J. Alexia, without agraphia, Wechsler AF, Verity A, Rosenschein S et al. Pick’s disease: a
due to brain tumor: a reversible syndrome. Ann Neurol 1979; clinical, computed tomographic, and histologic study with
6:265–8. Golgi impregnation observations. Arch Neurol 1982;
Tuszynski MH, Petito CK. Ischemic thalamic aphasia with 39:287–90.
pathologic confirmation. Neurology 1988; 38:800–2. Weinstein EA, Cole M, Mitchell MS et al. Anosognosia and
Vallar G, Perani D. The anatomy of unilateral neglect after right- aphasia. Arch Neurol 1969; 10:376–86.
hemisphere stroke lesions. A clinical/CT-scan correlation study Williamson PD, Spencer DD, Spencer SS et al. Episodic aphasia
in man. Neuropsychologia 1986; 24:609–22. and epileptic focus in the nondominant hemisphere: relieved
Vallar G, Rusconi ML, Bignamini L et al. Anatomical correlates of by section of the corpus callosum. Neurology 1985;
visual and tactile extinction in humans: a clinical CT scan 35:1069–71.
study. J Neurol Neurosurg Psychiatry 1994; 57:464–70. Wolfe GI, Ross ED. Sensory aprosodia with left hemiparesis from
Van Horn G, Hawes A. Global aphasia without hemiparesis: a sign subcortical infarction: right hemisphere analogue of sensory-
of embolic encephalopathy. Neurology 1982; 32:403. type aphasia with right hemiparesis? Arch Neurol 1987;
van Pugt P, Kees L, Cras P. Increased writing activity in 44:668–71.
neurological conditions: a review and clincial study. J Neurol Wolpert I. Die simultanagnosie-storung der gasamtauffassung.
Neurosurg Psychiatry 1996; 61:510–14. Z Ges Neurol Psychiatr 1924; 93:397–415.
Vignolo LA. Auditory agnosia. Phil Trans R Soc Lond Biol Sci 1982; Yamadori A, Osumi Y, Masuhara S et al. Preservation of singing in
298:49–57. Broca’s aphasia. J Neurol Neurosurg Psychiatry 1977;
Vincent FM, Sadowsky CH, Saunders RL et al. Alexia without 40:221–4.
agraphia, hemianopia or color-naming defect: a disconnection Yamadori A, Osumi Y, Ikeda H et al. Left unilateral agraphia
syndrome. Neurology 1977; 27:689–91. and tactile anomia: disturbances seen after occlusion of
Wada Y, Yamamoto T. Selective impairment of facial recognition the anterior cerebral artery. Arch Neurol 1980; 37:
due to a haematoma restricted to the right fusiform and 88–91.
p 03.qxd 3/10/08 9:32 AM Page 72
3
Abnormal movements
3.1 Tremor 72 3.9 Akinesia 91

3.2 Myoclonus 75 3.10 Akathisia 92
3.3 Motor tics 77 3.11 Catatonia 93
3.4 Chorea 78 3.12 Asterixis 96
3.5 Athetosis 81 3.13 Mirror movements 97
3.6 Ballism 82 3.14 Pathologic startle 98
3.7 Dystonia 83 References 99
3.8 Parkinsonism 87
3.1 TREMOR surface of the fingers, resembles the movements one would
make if one were rolling a pill back and forth in one’s hand.
Tremor is a more or less rhythmic oscillatory movement, Intention tremor comes to light during finger-to-nose
most commonly seen in the upper extremities, which testing. To perform this, ask the patient to extend the upper
occurs secondary to the rapidly alternating contraction of extremity, with the index finger extended out, and then to
agonist then antagonist muscles. bring the index finger in to touch the nose. Normally, the
movement is smooth throughout; when intention tremor is
present, however, an oscillatory movement develops as the
Clinical features index finger closes in on the target. Some authors refer to
this as a ‘kinetic’ tremor, indicating that it appears with
From a clinical point of view, it is most useful to distin- movement; however, this term has not gained currency and
guish three different types of tremor, namely postural, rest, the term ‘intention’ is used in this text.
and intention; other types (e.g., Holmes’ tremor) also Other tremors, far less common, include ‘task-specific’
occur and are discussed later in this chapter, but are far less tremors, orthostatic tremor, ‘rabbit’ tremor, Holmes’ tremor,
common. and ‘wing-beating’ tremor.
Postural tremor is most apparent when the patient ‘Task-specific’ tremors resemble postural tremors; how-
maintains a posture, as for example by extending the arms ever, they only appear when the patient is engaged in a spe-
straight forward, with the fingers outstretched and slightly cific activity, such as writing, throwing darts, etc.
spread apart. This tremor typically occurs at a frequency Orthostatic tremor (Heilman 1984), as the name sug-
of from 6 to 10 Hz, and ranges in amplitude from a fine gests, occurs when patients stand up. This is a rapid tremor
tremor (which may be almost unnoticeable to casual of the lower extremities, which patients often describe as a
inspection) to a coarse tremor (which may effectively pre- sense of quivering, which may cause a sense of unsteadi-
clude even the simplest of activities, such as bringing a cup ness or even cause patients to fall. As this tremor may be
of water to the lips). Some authors also refer to this tremor invisible, it is necessary to palpate the inner aspects of the
as an ‘action’ tremor, in that it occurs when the patient patient’s thighs immediately after the patient stands up to
takes an ‘action’, for example by extending the arms. Not assess its presence.
all authors are in agreement with this term, however, and ‘Rabbit’ tremor is a rest tremor confined to the jaw and
it is not used further here. presents an appearance similar to that of a rabbit chewing.
Rest tremor, as the name indicates, is seen when the Holmes’ tremor, named after Gordon Holmes who first
involved extremity is at rest as, for example, when, with the described it in 1904, is a slow frequency tremor (at a rate of
patient seated, the hands are resting in the lap. This tremor from 2 to 4 Hz) of the upper, and occasionally lower, extrem-
occurs at a frequency of from 3 to 5 Hz and is typically ‘pill- ity, with rest, intentional, and postural components. The
rolling’ in character, in that the oscillatory activity of the appearance of this tremor with sustained posture may be
thumb, sweeping back and forth in proximity to the ventral quite remarkable, with a rolling, sinuous motion of the upper
p 03.qxd 3/10/08 9:32 AM Page 73
3.1 Tremor 73
arm and a ‘flapping’ motion of the hand. In the past this (Kronfol et al. 1983), lithium (Gelenberg and Jefferson
tremor has been referred to as a ‘rubal’ or ‘midbrain’ tremor, 1995; Vestergaard et al. 1988), and valproic acid (Hyman
however these terms are discouraged, given that, as discussed et al. 1979) are especially important.
below, this tremor may occur in the absence of involvement Alcohol withdrawal is so commonly associated with
of the nucleus ruber or of any part of the midbrain. tremor that this condition is commonly referred to as ‘the
‘Wing-beating’ tremor involves the upper extremities, shakes’. This is probably one of the most commonly
which are flexed at the elbows: the tremor itself is primarily missed diagnoses, primarily either because the patient
proximal and results in an oscillation of the upper extrem- denies excessive use of alcohol or because the physician
ities that appears similar to the motions a bird makes as it simply does not inquire. The same ‘missed diagnosis’ may
flaps its wings. occur with tremor due to benzodiazepine or other seda-
tive-hypnotic withdrawal.
Metabolic and endocrinologic conditions are also
Etiology common causes. Hypoglycemia should be suspected
when tremor occurs in diabetics or post-prandially.
The various etiologies of each of the types of tremor discussed Hyperthyroidism should be suspected when the tremor is
above are summarized in Table 3.1, and discussed below. accompanied by diaphoresis, heat intolerance, proptosis,
etc. Pheochromocytoma-induced tremor is rare, and is
POSTURAL TREMOR suggested by associated paroxysms of hypertension.
Delirium may be accompanied by tremor, and in such
One of the most common causes of isolated postural cases the tremor is often coarse and quite prominent
tremor is drug toxicity, and of the various responsible (Jankovic and Fahn 1980). Delirium tremens (Latin for
mediations listed in Table 3.1 the tricyclic antidepressants ‘trembling delirium’) is, of course, the first consideration.
Table 3.1 Causes of tremor

Postural tremor Peripheral neuropathies
Medication-induced Mercury intoxication (Section 13.12)
Caffeine Tertiary neurosyphilis (Section 14.15)
Sympathomimetics (e.g., pseudoephedrine)
Rest tremor
Amphetamine
Parkinsonian conditions (e.g., Parkinson’s disease, diffuse
Theophylline
Lewy body disease [Section 3.8])
Antidepressants (tricyclics, SSRIs, venlafaxine)
Antipsychotic medications
Lithium
Valproic acid Intention tremor
Antipsychotics Disease of the cerebellar cortex, dentate nucleus or
Amiodarone outflow tracts
Alcohol and sedative hypnotic withdrawal (Sections 21.5 and 21.6) Toxicity
Alcohol intoxication
Metabolic and endocrinologic Sedative hypnotic intoxication
Hypoglycemia Lithium intoxication
Hyperthyroidism (Section 16.3)
Pheochromocytoma Other types of tremor
Task-specific tremors
Associated with delirium
Primary writing tremor
Delirium tremens (Section 21.5)
Neuroleptic malignant syndrome (Section 22.1) Orthostatic tremor
Serotonin syndrome (Section 22.5) Idiopathic orthostatic tremor
Other encephalopathies (uremic [Section 13.18], hepatic Secondary orthostatic tremor (e.g., head trauma,
[Section 13.19], etc.) hydrocephalus, pontine lesions)
Rabbit tremor
Associated with anxiety or depression
Rabbit syndrome (Section 22.4)
Generalized anxiety disorder (Section 20.16)
Depression (Section 20.6) Holmes’ tremor
Anxiety attacks (Section 6.5) Lesions of the dentate nucleus or its outflow tracts, the
thalamus or the pons
Other causes
Wing-beating tremor
Essential tremor (Section 8.32)
Wilson’s disease (Section 8.16)
Multiple sclerosis (Section 17.1)
SSRI, selective serotonin reuptake inhibitor.
p 03.qxd 3/10/08 9:32 AM Page 74
74 Abnormal movements
The serotonin syndrome should be suspected whenever a outflow tracts, and has been specifically reported with
delirium with tremor follows initiation of treatment with a lesions of the dentate nucleus (Krauss et al. 1995), superior
combination or serotoninergic agents, and the neuroleptic cerebellar peduncle (Krack et al. 1994; Krauss et al. 1995),
malignant syndrome whenever the syndrome is preceded by dorsal midbrain tegmentum (Krauss et al. 1995), the red
initiating treatment with an antipsychotic or by decreasing nucleus and adjacent structures (Holmes 1904; Remy et al.
or discontinuing a dopaminergic agent. Other ‘metabolic 1995), the posterior thalamus (Krauss et al. 1992; Miwa et al.
encephalopathies’ may also be accompanied by tremor, 1996; Tan et al. 2001), and the pontine tegmentum (Miyagi
including hepatic and uremic encephalopathy. et al. 1999; Shepherd et al. 1997).
Anxiety or ‘agitated’ depression may be characterized by Wing-beating tremor, although classic for Wilson’s dis-
persistent tremor, and anxiety attacks may also be accom- ease, is among the presenting signs of this disease in only a
panied by tremor, as may be seen in panic disorder. small minority of cases (Starosta-Rubinstein et al. 1987);
Of the other causes of postural tremor, among the late- this tremor, rarely, has also been reported with thalamic
to middle-aged and elderly, essential tremor is perhaps the infarction (Ghika et al. 1994).
most common. Multiple sclerosis, in addition to the more
commonly associated intention tremor, may also cause
postural tremor. Certain peripheral neuropathies, such as Differential diagnosis
chronic inflammatory demyelinating peripheral neuropa-
thy (CIDP) and Charcot–Marie–Tooth disease, may also A postural tremor often occurs in normal individuals and in
cause postural tremor but this is rare. Other rare causes these cases is referred to as a ‘physiologic tremor’. Normally,
include mercury intoxication and tertiary neurosyphilis this physiologic tremor is so fine that it is invisible to
(general paresis of the insane [GPI]). the naked eye. However, with fatigue, or during systemic
illnesses, it may become apparent.
REST TREMOR Myoclonus is distinguished from postural tremor in
that rather than being characterized by an oscillatory
Rest tremor is a cardinal sign of parkinsonism, and of the motion it consists of a ‘jerk’ followed by a relaxation phase.
multiple causes of parkinsonism discussed in Section 3.8 In tremor there is alternating contraction of agonist and
(under Parkinsonism), Parkinson’s disease, diffuse Lewy antagonist musculature, whereas in myoclonus there is
body disease and multiple system atrophy, along with only contraction of one group. Rhythmicity may also help
treatment with first-generation antipsychotics, stand out distinguish these two: tremor is always more or less rhyth-
as the most common. mic whereas myoclonus, although at times rhythmic, is
most often intermittent.
INTENTION TREMOR Asterixis may appear when the arms are outstretched,
Intention tremor is most commonly due to disease of the especially if the hands are somewhat dorsiflexed during
cerebellar cortex, the dentate nucleus or the outflow tracts this maneuver, and thus may be confused with postural
of the dentate nucleus. Consideration should be given to tremor. The differential rests, as with myoclonus, on the
degenerative conditions (e.g., alcoholic cerebellar degener- absence of oscillation. In asterixis, there is a sudden relax-
ation of one of the spinocerebellar ataxias [Section 8.17]), ation, such that the hands ‘drop’; this is then followed by a
multiple sclerosis (Section 17.1), and, especially in young slower, voluntary resumption of the dorsiflexed position.
adults, Wilson’s disease (Section 8.16). Severe intoxication Clonic movements, as may occur during a simple par-
with alcohol or sedative hypnotics (e.g., benzodiazepines) is tial motor seizure, may simulate postural tremor; however,
also typified by intention tremor, and this may also consti- here, again, there is no oscillation, but rather a rhythmic
tute one of the disabling sequelae of lithium intoxication. contraction of one muscle group followed by a relaxation.
Furthermore, and in contrast with postural tremor that is
OTHER TYPES almost always bilateral, simple partial motor seizures are
almost always unilateral.
Task-specific tremors are inherited conditions and appear ‘Dystonic tremor’ refers to a jerking motion of a dys-
to be associated with the more common task-specific dysto- tonic limb. Although the term has currency, this is not a
nias, such as ‘writer’s cramp’ (Bain et al. 1995; Klawans et al. true tremor but more of an intermittent jerk that typically
1982a; Soland et al. 1996a). disappears when the patient relaxes and gives way to the
Orthostatic tremor, as noted, may occur on either an developing dystonic spasm.
idiopathic basis or secondary to other causes, such as head Simulated tremor, as may occur in conversion disorder,
trauma, hydrocephalus or, rarely, lesions of the pons malingering or factitious illness, is suggested when the
(Benito-Leon et al. 1997). tremor changes markedly in frequency or amplitude, and
The rabbit syndrome (discussed further in Section 22.4) especially when this occurs with distraction. Weighting the
occurs as a side-effect of antipsychotics. involved limbs may also be diagnostically useful: in simu-
Holmes’ tremor, as pointed out by Holmes himself lated tremor, rather than a reduction of amplitude, one
(1904), localizes the lesion to the dentate nucleus or its often sees an increase (Deuschl et al. 1998).
p 03.qxd 3/10/08 9:32 AM Page 75
3.2 Myoclonus 75
Treatment other miscellaneous causes may be considered. Each of

these diagnostic possibilities is listed in Table 3.2 and
In the case of medication-associated tremor, dose reduc- discussed further below.
tion is often sufficient; when this is not practical, for exam- In patients with delirium, the presence of myoclonus
ple in lithium treatment, consideration may be given to strongly suggests the serotonin syndrome and a diligent
symptomatic treatment with propranolol (Lapierre 1976). search should be made for recent use of a combination of
Treatment is otherwise directed at the underlying cause, serotoninergic drugs. Hashimoto’s encephalopathy should
and most of these are discussed in the respective chapters. also be considered, especially in cases with ataxia or
For primary writing tremor, consideration may be given to seizures, and anti-thyroid antibodies should be tested for.
propranolol or primidone (Bain et al. 1995), botulinum Metabolic deliria associated with myoclonus include ure-
injections (Singer et al. 2005), or the use of a writing device mic encephalopathy and hyperosmolar non-ketotic hyper-
(Espay et al. 2005a). Orthostatic tremor may respond to glycemia, and these will be revealed on a chemistry profile.
clonazepam or gabapentin (Onofrj et al. 1998; Rodrigues Encephalopathic pellagra should be considered in alcoholics
et al. 2006), and Holmes’ tremor may respond to car- with delirium, especially when there is also an associated,
bidopa/levodopa (Remy et al. 1995; Samie et al. 1990; Tan albeit mild, parkinsonism. Baclofen withdrawal delirium, as
et al. 2001; Velez et al. 2002), clonazepam (Jacob and may occur when chronic, high-dose baclofen is abruptly
Pratap Chand 1998), trihexyphenidyl (Krack et al. 1994), discontinued, or when a baclofen pump malfunctions, is
or levetiracetam (Striano et al. 2007). characterized, in addition to delirium, by myoclonus and
fever, and in many respects, including treatment response,
resembles the serotonin syndrome. Myoclonus may play a
3.2 MYOCLONUS minor role in the overall clinical picture of an arbovirus
encephalitis or an episode of complex partial status epilep-
Myoclonus is an important diagnostic sign, and, in addi- ticus. Bismuth intoxication is rare but myoclonus plays a
tion to close observation during the interview and exami- prominent role in its symptomatology. Other intoxications
nation, patients should be questioned as to whether or not that may be characterized by myoclonus include those with
they have had any jerking motions. In patients with delir- leaded gasoline, bromide, or mercury.
ium the presence of myoclonus immediately suggests the In patients with dementia, myoclonus immediately sug-
serotonin syndrome or Hashimoto’s encephalopathy; in gests Creutzfeldt–Jakob disease; consideration should also
patients with dementia its presence immediately raises the be given to post-anoxic encephalopathy. Subacute scleros-
possibility of Creutzfeldt–Jakob disease. ing panencephalitis, in either children or adults, is rare but
is classically associated with myoclonus. A large number of
other disorders capable of causing dementia may also be
Clinical description associated with myoclonus (see Table 3.2); however, in
these the myoclonus plays only a very minor role in the
Myoclonus consists of sudden rapid muscular jerks, fol- overall clinical picture.
lowed by a slower relaxation phase. These myoclonic jerks Certain epilepsies are characterized by myoclonus, and in
may be focal, multifocal, or generalized, and they vary in patients with grand mal or petit mal seizures the presence
amplitude from being almost imperceptible to a gross of myoclonus should suggest the diagnosis of juvenile
movement that can, in severe cases, throw an arm up or myoclonic epilepsy or one of the progressive myoclonic
knock a patient off balance. Although occasionally rhyth- epilepsies, such as Unverricht–Lundborg disease, myoclonic
mic myoclonus may be seen, myoclonic jerks, in most cases, epilepsy with ragged red fibers, or Lafora body disease. In
occur at irregular intervals with a frequency varying from adults, the very rare Kufs’ disease should also be considered.
only several per day up to multiple occurrences every Medications that are capable of causing myoclonus are
minute. Although in most cases myoclonus occurs sponta- listed in Table 3.2 and of these the anti-epileptic drugs
neously, at times one may see stimulus-sensitive myoclonus gabapentin and lamotrigine stand out, as do the opioids
to either a sudden touch or a loud noise; furthermore, in meperidine and hydromorphone. With regard to the
some cases myoclonus only occurs with ‘action’, as for opioids, in some cases myoclonus may appear early on in
example when the patient extends the arms. treatment; however, in others it is only after prolonged treat-
ment that the myoclonus appears; in these cases it is
suspected that the myoclonus is occurring due to the accu-
Etiology mulation of toxic metabolites and not secondary to the par-
ent compound (Mercadante 1998). This same late evolution
In attempting to determine the cause of myoclonus, it is has also been noted with fluoxetine, with which years of treat-
useful to consider first whether the patient has a delirium ment may pass before myoclonus appears. Although little
or a dementia, or has epilepsy. If the cause is still unclear need be said regarding the other medications, some words are
then one should consider the possibility of medication in order regarding tardive myoclonus. Tardive myoclonus is
toxicity and, if the diagnosis remains obscure, a number of a rare variant of tardive dyskinesia and, like all the tardive
p 03.qxd 3/10/08 9:32 AM Page 76
Table 3.2 Causes of myoclonus

Associated with delirium Unverricht–Lundborg disease (Koskiniemi et al. 1974;
Serotonin syndrome (Feighner et al. 1990; Sternbach 1991) Magaudda et al. 2006)
Hashimoto’s encephalopathy (Castillo et al. 2006; Ghika-Schmid Myoclonic epilepsy with ragged red fibers (Berkovic et al.
et al. 1996) 1989)
Uremic encephalopathy (Mahoney and Arieff 1982) Lafora body disease (Yokoi et al. 1968)
Hyperosmolar non-ketotic hyperglycemia (Morres and Dire 1989) Kufs’ disease (Berkovic et al. 1988; Nijssen et al. 2002)
Encephalopathic pellagra (Serdaru et al. 1988)
Medications
Baclofen withdrawal (Meythaler et al. 2003)
Gabapentin (Zhang et al. 2005)
Arbovirus encephalitis (Kleinschmidt-DeMasters et al. 2004)
Lamotrigine (Crespel et al. 2005)
Encephalitis lethargica (Blunt et al. 1997; Walsh 1920)
Meperidine (Kaiko et al. 1983)
Complex partial status epilepticus (Kaplan 1996)
Hydromorphone (Hofmann et al. 2006)
Bismuth intoxication (Supino-Viterbo et al. 1977)
SSRIs (Barucha and Sethi 1996)
Leaded gasoline intoxication (Goldings and Stewart 1982)
Tricyclic antidepressants (Casas et al. 1987; DeCastro 1985;
Bromide intoxication (Obeso et al. 1986)
Garvey and Tollefson 1987; Lippmann et al. 1977)
Mercury intoxication (Roullet et al. 1994)
Trazodone (Garvey and Tollefson 1987; Patel et al. 1988)
Associated with dementing disorders Lithium (Caviness and Evidente 2003)
Creutzfeldt–Jakob disease (Brown et al. 1986) Buspirone (Ritchie et al. 1988)
Post-anoxic encephalopathy (Werharhan et al. 1997) Clozapine (Bak et al. 1995; Barak et al. 1996)
Subacute sclerosing panencephalitis (both child [Dawson 1934] Levodopa (Klawans et al. 1975)
and adult [Prashanth et al. 2006] onset) Amantadine (Matsunaga et al. 2001)
Diffuse Lewy body disease (Louis et al. 1997) Trimethoprim/sulfamethoxazole (Dib et al. 2004)
Corticobasal ganglionic degeneration (Rinne et al. 1994) Tardive myoclonus (Abad and Ovsiew 1993; Little and Jankovic
Multiple system atrophy (both striatonigral [Wenning et al. 1995] 1987; Wojick et al. 1991)
and olivopontocerebellar variants [Rodriguez et al. 1994])
Miscellaneous causes
Progressive supranuclear palsy (Collins et al. 1995)
Lance–Adams syndrome of post-anoxic action myoclonus
Huntington’s disease (both adult [Salt et al. 2006] and juvenile
(Lance and Adams 1963)
[Siesling et al. 1997] onset)
Infarction of the frontoparietal cortex (Sutton and Meyere
Alzheimer’s disease (Benesch et al. 1993; Chen et al. 1991)
1974) or thalamus (Kim 2001; Lehericy et al. 2001)
Dentatorubropallidoluysian atrophy (Becher et al. 1997)
Spinal cord lesions (De La Sayette et al. 1996; Hoehn and
Acquired immune deficiency syndrome (AIDS) dementia
Cherrington 1977; Keswani et al. 2002)
(Maher et al. 1997; Navin et al. 1986)
Paraneoplastic myoclonus (Bataller et al. 2001)
Dialysis dementia (Chokroverty et al. 1976; Garrett et al. 1988;
Whipple’s disease (Louis et al. 1996)
Lederman and Henry 1978)
Celiac disease (Tison et al. 1989)
Epilepsies Myoclonus dystonia (‘essential myoclonus’ [Mahloudji and
Juvenile myoclonic epilepsy (Jain et al. 1998; Panayiotopoulos Pikielny 1967])
et al. 1994; Pedersen and Petersen 1998)
SSRI selective serotonin reuptake inhibitor.
dyskinesia subtypes, occurs only after long exposure to myoclonus, typically affects the trunk and extremities.
antipsychotics; although tardive myoclonus may appear in Paraneoplastic myoclonus reflects autoimmune involvement
isolation, it is often accompanied by tardive dystonia. of the brainstem and is often accompanied by opsoclonus
Regarding the miscellaneous causes of myoclonus, several (Digre 1986). Rare causes of myolonus include Whipple’s
comments are in order. As noted earlier, myoclonus is char- disease and celiac disease. Finally, myoclonus may also
acteristic of post-anoxic dementia; however, an episode of occur on an inherited basis, namely as the syndrome of
anoxia may be followed by myoclonus alone and in such myoclonus–dystonia (Asmus et al. 2002; Doheny et al. 2002;
cases the term ‘Lance–Adams syndrome’ is used, in honor of Foncke et al. 2006; Grimes et al. 2002; Schule et al. 2004). This
Lance and Adams who first described it in 1963. Lesions, for syndrome, also known as ‘essential myoclonus’, is inherited
example infarction of the frontoparietal cortex or the thala- on an autosomal dominant basis with incomplete pene-
mus, may cause myoclonus and months or longer may elapse trance. Onset is in childhood or adolescence, and, in addition
between the infarct and the appearance of the abnormal to myoclonus there may also be cervical or task-specific dys-
movement. Lesions of the spinal cord, such as infarction, tonia (e.g., writer’s cramp). Of interest, there appears to be
myelitis or trauma, may cause myoclonus, which may be an association between myoclonus–dystonia and obsessive–
either focal, reflecting the segment involved, or generalized: compulsive disorder and alcoholism (Hess et al. 2007;
this generalized form, often referred to as propriospinal Saunders-Pullman et al. 2002).
p 03.qxd 3/10/08 9:32 AM Page 77
3.3 Motor tics 77
Differential diagnosis 3.3 MOTOR TICS

Asterixis is distinguished from myoclonus in that, rather Motor tics, although classically associated with Tourette’s
than consisting of a jerking motion, it is characterized by syndrome, may also occur as a side-effect to various med-
a sudden drop, or abrupt relaxation; furthermore, rather ications or in various other disorders (e.g., Sydenham’s
than occurring spontaneously, it appears only when the chorea).
outstretched hands are held in dorsiflexion. Some authors
consider asterixis to be a kind of myoclonus, namely ‘neg-
ative’ myoclonus, in that it consists of a sudden loss of Clinical features
muscle tonus rather than an active contraction. Given,
however, that the etiologies of asterixis and myoclonus are Motor tics are sudden, rapid movements that, to varying
not identical, it may be prudent, from a clinical point of degrees, resemble purposeful actions. They range from such
view, to keep the two separate. simple tics as brow-wrinkling, facial grimacing, head-
Tremor is distinguished from myoclonus by its contin- shaking, or shoulder-shrugging to more complex activities
uous nature. In tremor, there is an ongoing and alternating such as gesturing or rising from a chair. In most cases, the
contraction of agonist and antagonist muscles, producing actual tics are preceded by a ‘premonitory urge’ that rises
a persistent, oscillatory motion. By contrast, in myoclonus in intensity until it is finally relieved by the tic’s appear-
there is a distinct relaxation phase following each jerk: ance. Although some patients are able to suppress the tic
following the contraction of the agonist musculature, for a time, considerable effort is required to do so: Kinnier
rather than an immediately following contraction of Wilson (Wilson 1928) noted that ‘the strain in holding
the antagonist muscle, there is merely a relaxation of the back is as great as the relief in letting go’, and reported that
agonist musculature. one of his patients, in describing the experience, said that
Tics are characterized by premonitory urges and by ‘you can’t help it any more than you can sneezing’.
their temporary suppressibility by voluntary effort, Although in some cases there may be ‘focal’ tics, with
features which are not seen in myoclonus. Furthermore, the same tic recurring uninterruptedly over time, tics are
although some tics are quite simple in nature, and thus ‘multifocal’ in most instances, with different tics occurring
may appear similar to myoclonic jerks, they may also be at different locations.
complex, resembling fragments of voluntary activity, a
feature that, again, is not seen in myoclonus.
Choreic movements may be difficult to distinguish Etiology
from myoclonic jerks. One helpful feature is the ten-
dency of chorea to appear and disappear on different Table 3.3 lists the various causes of motor tics. The most
parts of the body with lightning-like fluidity; myoclonus common cause of tics, by far, is Tourette’s syndrome or a
is rarely so mercurial. Furthermore, in some cases cho- variant of Tourette’s, known as chronic motor tic disorder.
reic movements may be complex and, like some tics, may As noted in Section 8.25, the onset of Tourette’s and
resemble voluntary behaviors, thus distinguishing them- chronic motor tic disorder is usually in childhood; how-
selves from myoclonic jerks, which are always simple in ever, it must also be borne in mind that Tourette’s can go
nature. into remission, only to recur in later life; hence, in cases of
Hypnic jerks, also known as ‘sleep starts’, are myoclonic adult-onset tics it is critical to inquire as to a history of
jerks that occur during the transition from wakefulness to childhood tics (Chouinard and Ford 2000; Klawans and
stage I sleep; they are considered a normal variant. Barr 1985).
There is also a condition known as palatal myoclonus Tics may also occur as a side-effect to medications, albeit
(Lapresle 1986); however, the name itself may be a mis- rarely, and if Tourette’s appears to be an unlikely cause
nomer. In this condition there is a very rapid and rhythmic then the patient’s medication history should be scrutinized
movement of the palate, which may be appreciated by the for any of the stimulants, anti-epileptics, antidepressants,
patient as a kind of clicking. The movement itself is more or antipsychotics listed in Table 3.3, keeping in mind that
of a tremor than anything else and hence the name of this in some cases a long period of time may elapse between ini-
condition might better be ‘palatal tremor’. tiation of treatment with an offending medication and the
emergence of tics. As noted in Table 3.3, tics may also
occur after chronic treatment with antipsychotics, as a
Treatment subtype of tardive dyskinesia.
Tics may occur during the long-term course of various
Treatment is aimed, whenever possible, at the underlying choreiform disorders, such as Sydenham’s chorea,
cause, and this is discussed in the respective chapters. If Huntington’s disease, and choreoacanthocytosis; indeed,
symptomatic treatment is required, consideration may in the case of choreoacanthocytosis eventually over one-
be given to clonazepam, levetiracetam, or valproic acid half of patients will develop tics. Furthermore, albeit rarely,
(Van Zandijcke 2003). these choreiform disorders may actually present with tics,
p 03.qxd 3/10/08 9:32 AM Page 78
as has been noted in Sydenham’s chorea (Kerbeshian et al. Differential diagnosis

1990), Huntington’s disease (Angelini et al. 1998), and
choreoacanthocytosis (Feinberg et al. 1991). Tics must be distinguished from myoclonus, chorea, hemi-
Of the other causes of tics, consideration is given to facial spasm, tic douloureux, and stereotypies. One differ-
autism, and to a history of carbon monoxide poisoning, ential feature which distinguishes tics from each of these
traumatic brain injury, or encephalitis. Rare causes include differential possibilities is the premonitory urge, which is
pantothenate kinase-associated neurodegeneration, classic for a tic, but absent in all these other conditions.
infarction of the basal ganglia, Behçet’s syndrome and Myoclonus may resemble a simple tic but, in addition
peripheral injury. In the case of tics that are secondary to to lacking a premonitory urge, myoclonic jerks, unlike tics,
peripheral injury (e.g., trauma to the neck followed by a tic are not suppressible by voluntary effort.
of the head), the tics are persistently focal, occurring only Choreiform movements may be either simple in nature
in proximity to the site of the injury. Finally, in cases of or somewhat complex, resembling purposeful acts, and
adult-onset tics for which no cause may be determined, thus may be difficult to distinguish from tics. As in the case
consideration may be given to the possibility of an auto- of myoclonus, however, choreiform movements are neither
immune attack on the basal ganglia. associated with a premonitory urge nor are they suppress-
ible. Furthermore, whereas at times tics may be repetitive,
choreiform movements rarely are; rather they appear and
Table 3.3 Causes of motor tics
reappear on different parts of the body, typically with light-
Tourette’s syndrome (Cardoso et al. 1996; Lees et al. ning-like rapidity.
1984) Hemifacial spasm, again, lacks a premonitory urge and
Medications is non-suppressible. Furthermore, it is repetitive, involves
Cocaine (Cardoso and Jankovic 1993; Pascual-Leone and only musculature innervated by the facial nerve, and is
Dhuna 1990) confined, as the name suggests, to one side of the face.
Methylphenidate (Denckla et al. 1976) Tic douloureux is primarily a condition of painful
Pemoline (Bachman 1981; Mitchell and Mathews 1980) spasms of the face, immediately distinguishing it from tics,
Atomoxetine (Ledbetter 2005) which are not painful. Furthermore, the ‘tic’ of tic dolour-
Lamotrigine (Lombroso et al. 1999; Sotero de Menezes et al. eaux is more of a wince after the spasm of pain than a true,
2000) autonomous motor tic.
Carbamazepine (Robertson et al. 1993) Stereotypies, as with all these differential possibilities,
Phenobarbital (Burd et al. 1986) lack premonitory urges; furthermore, they are readily sup-
Escitalopram (Altindag et al. 2005) pressible and, in contrast with tics, patients find no difficulty
Sertraline (Altindag et al. 2005) in keeping the stereotypy suppressed.
Clomipramine (Moshe et al. 1994)
Fluoxetine (Eisenhauer and Jermain 1993) Treatment
Haloperidol (Gualtieri and Patterson 1986)
Thioridazine (Gualtieri and Patterson 1986) Treatment is directed at the underlying cause. When this is
Clozapine (Lindenmeyer et al. 1995) ineffective or not possible, consideration may be given to
Tardive tics (Bharucha and Sethi 1995; Stahl 1980) the use of low-dose second-generation antipsychotics.
Choreiform disorders
Sydenham’s chorea (Cardoso et al. 1997; Creak and Guttmann
3.4 CHOREA
1935)
Huntington’s disease (Jankovic and Ashizawa 1995)
Choreiform movements, classically seen in Huntington’s
Choreoacanthocytosis (Hardie et al. 1991)
disease, may also occur as a side-effect to various medica-
Other causes tions or as part of a host of other disorders.
Autism (Ringman and Jankovic 2000)
Carbon monoxide poisoning (Ko et al. 2004)
Traumatic brain injury (Krauss and Jankovic 1997)
Clinical features
Post-encephalitis (herpes zoster [Northam and Singer 1991],
Choreic movements consist of brief jerks, of greater or
varicella-zoster [Dale et al. 2003])
lesser complexity, which appear and disappear on different
Pantothenate kinase-associated neurodegeneration (Scarano
parts of the body with an amazing fluidity and rapidity,
et al. 2002)
often flitting like summer lightning; they may first appear
Infarction of the basal ganglia (Kwak and Jankovic 2002)
on the face, then the arm, or perhaps the leg, then again
Behçet’s syndrome (Budman and Sarcevic 2002)
showing up in the hand. Although they are purposeless,
With peripheral injury (Factor and Moltho 1997)
some patients may attempt to disguise a choreiform move-
Autoimmune conditions (Edwards et al. 2004)
ment by merging it into a purposeful one; thus, a choreic
p 03.qxd 3/10/08 9:32 AM Page 79
3.4 Chorea 79
jerk of the arm up to the head may be melded into a pur- medications or intoxicants (e.g., as seen in tardive dyskine-
poseful movement of the hand across the top of the head, sia or with oral contraceptives); those of gradual onset in
as if the movement, all along, had been meant to smooth late adolescence or adult years (of which Huntington’s dis-
back the hair. Gait is often disturbed in chorea, and may ease is the most important); those of childhood or early
become lurching: when severely affected the gait has a adolescent onset, such as Sydenham’s chorea; and, finally,
‘dancing and prancing’ quality to it; and it is from this that a miscellaneous group, of which stroke is probably the
the term ‘chorea’ (Latin for ‘the dance’) is derived. most important.
Of medications capable of causing chorea, perhaps the
most important group is the antipsychotics, which, after
Etiology chronic use, can cause tardive dyskinesia, which, in turn,
classically presents with chorea. Of note, and in contrast
The various causes of chorea are listed in Table 3.4. These with most other causes of chorea, the chorea seen in tardive
causes are divided into several groups: those secondary to dyskinesia, although it can be generalized, tends to remain
Table 3.4 Causes of chorea

Secondary to medications or intoxicants With onset in childhood or early adolescence
Tardive dyskinesia (Sachdev 2000) Sydenham’s chorea (Bland and Jones 1952; Cardoso et al. 1997;
Oral contraceptives (Gamboa et al. 1971; Green 1980; Nausieda Nausieda et al. 1980a)
et al. 1979) Cerebral palsy (Rosenbloom 1994)
Phenytoin (Kooiker and Sumi 1974; Nausieda et al. 1978) Lesch–Nyhan syndrome (Jankovic et al. 1988; Lesch and Nyhan
Valproic acid (Lancman et al. 1994) 1964; Nyhan 1972)
Gabapentin (Buetefisch et al. 1996; Chudnow et al. 1997) Pantothenate kinase-associated neurodegeneration (Dooling et al.
Phenobarbital intoxication (Lightman 1978) 1974)
Lamotrigine (Zesiewicz et al. 2006) Ataxia telangiectasia (Woods and Taylor 1992)
Cocaine (Daras et al. 1994) Benign hereditary chorea (Behan and Bone 1977; Fernandez
Amphetamine (Lundh and Tunving 1981) et al. 2001)
Methylphenidate (Extein 1978; Weiner et al. 1978)
Pemoline (Sallee et al. 1989)
Stroke (infarction of basal ganglia [Chung et al. 2004] or
Levodopa (Mones et al. 1971)
thalamus [Lera et al. 2000])
Baclofen (both during treatment [Crystal 1990] and upon
Acquired immune deficiency syndrome (AIDS) (Gallo et al. 1996;
discontinuation [Kirubakaren et al. 1984])
Pardo et al. 1998; Piccolo et al. 1999)
Lithium intoxication (Podskalny and Factor 1996)
Anti-phospholipid syndrome (Cervera et al. 1997; Sunden-
Neuroleptic malignant syndrome (Rosebush and Stewart 1989)
Cullberg et al. 1998; Paus et al. 2001)
Fluoxetine (Bharucha and Sethi 1996)
Systemic lupus erythematosus (Donaldson and Espiner 1971;
Paroxetine (Fox et al. 1997)
Fermaglich et al. 1973)
Trazodone (McNeill 2006)
Chorea gravidarum (Wilson and Preece 1932a,b)
Trihexyphenidyl (Nomoto et al. 1987)
Paraneoplastic syndrome (Croteau et al. 2001; Heckmann et al.
Alpha-interferon (Moulignier et al. 2002)
1997; Kinirons et al. 2003; Vernino et al. 2002)
Cimetidine (Kushner 1982)
Hyperosmolar non-ketotic hyperglycemia (Chang et al. 1996)
Leaded gasoline intoxication (Goldings and Stewart 1982)
Hypernatremia (Speracio et al. 1976)
With gradual onset in late adolescence or adult years Hyperthyroidism (Fidler et al. 1971; Van Uitert and Russakoff
Huntington’s disease (Heathfield 1967) 1979)
Huntington disease-like syndrome 1 and 2 (Stevanin et al. 2003) Post-hypoglycemic (Hefter et al. 1993; Lai et al. 2004)
Choreoacanthocytosis (Critchley et al. 1968; Hardie et al. 1991; Delayed post-anoxic encephalopathy (Davous et al. 1986; Hori
Sakai et al. 1981) et al. 1991; Schwartz et al. 1985)
McLeod syndrome (Danek et al. 2001; Jung et al. 2001) ‘Post pump’ chorea (Medlock et al. 1993)
Dentatorubropallidoluysian atrophy (Becher et al. 1997; Warner B12 deficiency (Pachetti et al. 2002)
et al. 1994, 1995) Polycythemia vera (Gautier-Smith and Prankard 1967)
Fahr’s syndrome (Manyam et al. 2001) New-variant Creutzfeldt–Jakob disease (McKee and Talbot 2003)
Acquired hepatocerebral degeneration (Finlayson and Superville Mercury intoxication (Snyder 1972)
1981; Victor et al. 1965) Cervical cord compression (Tan et al. 2002)
Wilson’s disease (Steinberg and Sternlieb 1984) Paroxysmal dystonic choreoathetosis (Demirkiran and Jankovic
Schizophrenia (Owens et al. 1982) 1995)
Senile chorea (Bourgeois et al. 1980; Delwaide and Desseilles Paroxysmal chorea with hyperthyroidism (Fishbeck and Layzer
1977; Klawans and Barr 1981; Varga et al. 1982) 1979)
p 03.qxd 3/10/08 9:32 AM Page 80
somewhat localized to the face. Oral contraceptives may disease, rarely, may present with chorea; however, other
cause chorea, and this is more likely to occur in females with abnormal movements (e.g., dystonia, tremor) are far more
a history of Sydenham’s chorea or with either systemic lupus common (Starosta-Rubinstein et al. 1987): nevertheless,
erythematosus or the anti-phospholipid syndrome. Of the given the tragic nature of missing the diagnosis of this
anti-epileptic drugs capable of causing chorea, phenytoin is treatable disease, it should remain prominent on the differ-
most commonly involved, with the others only rarely being ential. Schizophrenia may cause chorea but this is usually
at fault. Of the stimulants implicated in chorea, cocaine is quite mild and is far overshadowed, clinically, by the clas-
prominent, and chorea in these cases is often referred to as sic psychotic symptoms. Finally, in cases of late onset
‘crack dancing’. Of note, after repeated intoxication with ‘pure’ chorea, without associated features, consideration
either cocaine (Daras et al. 1994) or amphetamines (Lundh should be given to a diagnosis of ‘senile chorea’.
and Tunving 1981), the chorea, rather than subsiding with Of the childhood- or early adolescent-onset choreas,
abstinence, may persist. Levodopa-induced chorea may Sydenham’s chorea is by far the most common. Although
occur as either a ‘peak dose’ side-effect or, less commonly, it is often accompanied by other evidence of rheumatic
may be seen as the blood level rises and as it falls, with an fever, such as carditis or polyarthritis, the onset of the
interval ‘clear’ of chorea during peak blood levels. Baclofen, chorea may at times be delayed for so long that the other
as noted in Table 3.4, may cause chorea not only during signs of rheumatic fever have already gone into remission,
treatment, but also with discontinuation of chronic treat- leaving a case of ‘pure’ Sydenham’s chorea. The chorea is of
ment. Lithium may cause chorea but this is only with subacute onset, over weeks, and, although typically gener-
lithium intoxication at high blood levels: although in most alized, is often most prominent in the face and upper
cases the chorea clears as the blood level falls, in some cases extremities. In a small minority there may be only hemi-
it may persist for months (Zorumski and Bakris 1983). The chorea. Although Sydenham’s chorea may in some patients
neuroleptic malignant syndrome is a rare disorder seen with present solely with chorea, there are in the majority other
an abrupt diminution of dopaminergic tone, due either to neuropsychiatric features, most notably obsessions and
treatment with a dopamine blocker, such as an antipsy- compulsions (Swedo et al. 1993). In Sydenham’s chorea,
chotic, or to discontinuation of a dopaminergic agent, such the chorea, in almost all cases, eventually undergoes spon-
as levodopa: in addition to chorea, one also sees delirium, taneous remission, generally within 5–9 months. The other
diaphoresis, fever, tachycardia, and rigidity. Regarding the causes listed in Table 3.4, however, are chronic. Cerebral
other medications in Table 3.4 little need be said, except that palsy, of the ‘extrapyramidal’ type, may cause chorea and
chorea represents a very rare side-effect to them. its appearance may be delayed for several years after birth.
Of the choreas with gradual onset in late adolescence The Lesch–Nyhan syndrome is immediately suggested by
or early adult years, Huntington’s disease is the most the classic mutilative lip biting, which usually become
common cause: most patients fall ill in their thirties with apparent as soon as the child gets teeth. Pantothenate
the gradual onset of a progressively worsening chorea that kinase-associated neurodegeneration may cause chorea;
is eventually joined by a dementia; this is an autosomal however, this is usually accompanied by dystonia. Ataxia
dominant condition and sporadic cases are very rare. telangiectasia may also cause chorea but this is usually pre-
There are other neurodegenerative disorders that present ceded by ataxia. Finally, in cases of chronic childhood-
in a more or less similar fashion to Huntington’s disease, onset chorea when other disorders are unlikely, one may
and these must be considered in the differential diagnosis. consider the diagnosis of benign hereditary chorea.
Two of them are so similar, clinically, to Huntington’s that Of the miscellaneous causes of chorea, stroke and
they go by the name ‘Huntington disease-like syndrome’, acquired immune deficiency syndrome (AIDS) are among
types 1 and 2: the differential here often rests solely on the most common in a general hospital setting (Piccolo
genetic testing. Other disorders that come into the differ- et al. 1999). Infarction of the basal ganglia or thalamus may
ential often have distinguishing clincial features. Thus, cause either a hemichorea or, less commonly, generalized
both choreoacanthocytosis and the X-linked McLeod syn- chorea, and in many cases the onset of the chorea may be
drome are associated with elevated creatinine kinase (CK) delayed for months (Kim 2001a). In AIDS patients chorea
levels and acanthocytosis; choreoacanthocytosis may also may occur secondary either to opportunistic infections or
cause tics, dystonia, and, classically, mutilative lip biting. as part of an HIV encephalopathy. Chorea may also occur
Dentatorubropallidoluysian atrophy, another Huntington on an autoimmune basis, either as part of the anti-
‘look-alike’, is suggested by the presence of ataxia. Fahr’s phospholipid syndrome or systemic lupus erythematosus.
syndrome may present with chorea but this is usually Chorea gravidarum (Latin for ‘chorea of pregnant
accompanied by other abnormal movements, such as dys- women’) should obviously be suspected when chorea
tonia or parkinsonism, and computed tomography (CT) occurs during pregnancy, and in most of these cases the
scanning will immediately reveal calcification of the basal patient will have either the anti-phospholipid syndrome or
ganglia. Acquired hepatocerebral degeneration, seen only systemic lupus erythematosus, or will have a history of
in patients with longstanding hepatic disease and a history Sydenham’s chorea. Patients with a paraneoplastic syn-
of recurrent episodes of hepatic encephalopathy, in addi- drome may also present with chorea but this is soon joined
tion to chorea, may also cause tremor and ataxia. Wilson’s by other elements of a paraneoplastic syndrome, such as
p 03.qxd 3/10/08 9:32 AM Page 81
3.5 Athetosis 81
delirium, seizures, ataxia, and peripheral neuropathy. 3.5 ATHETOSIS

Metabolic causes of chorea include hyperosmolar non-
ketotic hyperglycemia and, very rarely, hypernatremia, and Athetosis, a term coined by Hammond in 1871, is derived
both of these are readily diagnosed by a chemical survey. from the Greek word athetos, and means ‘without fixed
Hyperthyroidism may cause a persistent chorea, and the position’.
diagnosis is suggested by the associated tremor, diaphore-
sis, and heat intolerance. Chorea may also occur as a
sequela to hypoxic coma or as part of a delayed post-anoxic Clinical features
encephalopathy, and, in children, may follow cardiac sur-
gery, the so-called ‘post pump’ chorea. Of the other etiolo- Athetosis is characterized by purposeless, slow, continuously
gies of persistent chorea listed in Table 3.4, little more need writhing movements that tend to flow, one into the other, in
be said except that they only very rarely cause choreiform an unceasing, serpentine pattern. They may be unilateral or
movements. Finally, note should be made of episodic, bilateral, and are typically seen in the extremities; more
paroxysmal chorea. This may occur as part of paroxysmal often the upper than the lower extremity, and more often on
dystonic choreoathetosis, wherein it is typically accompa- the distal portions of the involved extremity. The move-
nied by dystonia (discussed further in Section 3.7), and may ments, when seen in the hand, may mimic, in a grotesque
also, albeit very rarely, occur as part of hyperthyroidism. fashion, the movements of the fingers made when playing
the piano or, in some cases, may remind the observer of the
hand movements made by Balinese dancers.
Etiology
Choreiform movements must be distinguished from
myoclonus, tics, athetosis, and from the abnormal oro- The various causes of athetosis are listed in Table 3.5.
mandibular movements seen in edentulous patients. Cerebral palsy of the ‘dyskinetic’ type, due generally to
Myoclonic jerks are always simple in nature, and hence either hypoxia or, in the past, kernicterus, may leave
when choreic jerks are complex, as they sometimes may patients with bilateral or ‘double’ athetosis.
be, the differential is straightforward. Simple choreic Infarction of the lenticular nucleus or thalamus may
jerks, however, may be more difficult to distinguish from cause athetosis, and in some cases the emergence of this
myoclonic jerks. One clue is the ‘mercurial’ nature of abnormal movement may be delayed for weeks or months
chorea, with jerks appearing and disappearing, fluidly, after the stroke (Dooling and Adams 1975; Kim 2001a).
from one part of the body to another: myoclonic jerks Severe proprioceptive sensory loss, as may be seen with
rarely display such lightning-like changes. infarction of the parietal cortex or thalamus, or with
Tics, like choreic movements, may be either simple or lesions of the cervical cord or dorsal root ganglia, may also
complex, and thus complexity cannot be used to differen- be followed by athetosis. In the literature this is often
tiate them from choreic movements. Tics, however, like referred to as ‘pseudoathetosis’; however, given that clini-
myclonus, rarely display the mercurial transience of cho- cally these cases are essentially indistinguishable from
reic movements. Furthermore, tics are associated with a
Table 3.5 Causes of athetosis
premonitory urge and are, at least partially, suppressible;
these features are not characteristic of chorea. Cerebral palsy (‘double athetosis’) (Rosenbloom 1994)
Athetotic movements are longer lasting and more sus- Infarction of the basal ganglia or thalamus (Carpenter 1950;
tained in character than are choreic ones; furthermore, Papez et al. 1938; Spiller 1920)
rather than being jerky they are ‘slow and writhing in
Associated with proprioceptive sensory loss due to infarction
character’, as pointed out by Kinnier Wilson (Wilson 1955).
of the parietal cortex of thalamus or to lesions of the cervical
Edentulous patients may display oromandibular move-
cord or dorsal root ganglia (Ghika and Bogousslavsky 1997;
ments reminiscent of chorea; however, in this condition
Sharp et al. 1994)
there are no abnormal movements elsewhere on the body
and the tongue is not involved (Koller 1983). Miscellaneous causes
Acquired hepatocerebral degeneration (Finlayson and
Superville 1981)
Fahr’s syndrome (Manyam et al. 2001)
Treatment Pantothenate kinase-associated neurodegeneration (Rozdilsky
et al. 1968)
Treatment is directed at the underlying condition, as dis-
Medication side-effect (tiagabine [Tombini et al. 2006],
cussed in the respective chapters. In many cases this
donepezil [Tanaka et al. 2003])
involves symptomatic treatment with an antipsychotic,
Post-mercury intoxication (Snyder 1972)
and in this regard one of the second-generation anti-
Post-cyanide intoxication (Rosenow et al. 1995)
psychotics, for example risperidone, may be considered.
p 03.qxd 3/10/08 9:32 AM Page 82
those seen with infarction of the lenticular nuclei, this dis- Etiology
tinction may not be useful.
Of the miscellaneous causes of athetosis, consideration The various causes of ballism are noted in Table 3.6.
may be given to acquired hepatocerebral degeneration, Stroke, whether due to ischemic infarction or, less com-
Fahr’s syndrome and pantothenate kinase-associated neu- monly, intracerebral hemorrhage, is the most common cause
rodegeneration; however, in each of these conditions other of ballism (Vidakovic et al. 1994). Although the subthalamic
features often dominate the clinical picture: in acquired nucleus is most commonly involved, damage to related
hepatocerebral degeneration, chorea, tremor, and dystonia structures, such as the striatum, thalamus or, very rarely, the
may be seen; in Fahr’s syndrome, parkinsonism and calci- substantia nigra, may also cause ballism. In most cases, a
fication of the basal ganglia on CT scanning; and, in pan- hemiballism occurs, and, as might be expected, in most of
tothenate kinase-associated neurodegeneration, dystonia. these cases, the lesion is found in the contralateral hemi-
There are also single case reports of athetosis occurring sphere. However, exceptions to this lateralizing rule do occur
as a side-effect to either tiagabine or donepezil. Finally, and ipsilateral hemiballism has been noted with lesions of the
athetosis may occur as a sequela to intoxication with either subthalamic nucleus (Crozier et al. 1996; Moersch and
mercury or cyanide. Kernohan 1939) or the striatum (Borgohain et al. 1995).
Other focal lesions may also cause hemiballism, and
this has been noted in the subthalamic nucleus for
Differential diagnosis both metastatic tumors and multiple sclerosis plaques.
Of the miscellaneous causes of ballism, the most impor-
Choreiform movements, as noted in the preceding tant from a clinical point of view is non-ketotic hyperos-
chapter, tend to be jerky and to appear and reappear on molar hyperglycemia, as may be seen in elderly diabetics.
different parts of the body; in contrast, athetotic move- This syndrome may present with either generalized or
ments are writhing in character, sustained, and generally hemiballism; of note, in cases of hemiballism, T1-weighted
remain localized to a particular limb. MR scanning may reveal hyperintensity of the contralateral
Dystonic movements are relatively fixed in character, striatum. In all cases, the ballism resolves with restoration of
and lack the writhing quality of athetosis. euglycemia; however, it may take days or weeks for full
recovery to occur. Rarely, both systemic lupus erythemato-
sus and Sydenham’s chorea may cause ballism, presumably
Treatment on the basis of an autoimmune attack on the subthalamic
nucleus. Traumatic brain injury is another rare cause and,
Botulinum toxin has been utilized in the treatment of dou-
ble athetosis seen in cerebral palsy (Gooch and Sandell
1996); in cases of athetosis secondary to stroke, deep brain Table 3.6 Causes of ballism
stimulation has been utilized (Katayama et al. 2003). It is
Stroke (infarction or intracerebral hemorrhage)
not at all clear whether pharmacologic treatment with
Subthalamic nucleus (Carpenter 1955; Martin and Alcock
antipsychotics or other agents might be beneficial.
1934; Melamed et al. 1978; Pfeil 1952; Whittier 1947)
Striatum (Defebvre et al. 1990; Kase et al. 1981; Schwarz and
Barrows 1960; Srinivas et al. 1987)
3.6 BALLISM Thalamus (Antin et al. 1867; Dewey and Jankovic 1989;
Kulisevsky et al. 1993)
Ballism, or ballismus, comes originally from the Greek
Substantia nigra (Caparros-Lefebvre et al. 1994)
word ballismos, which means a jumping movement; it is
also related to the Latin ballista, which refers to an ancient Other focal lesions
military machine, similar to a catapult, used for throwing Tumors (Glass et al. 1984)
large stones. Multiple sclerosis (Riley and Lang 1988; Waubant et al. 1997)
Non-ketotic hyperglycemia (Chu et al. 2002; Lee et al. 1999;
Clinical features Lin and Chang 1994; Lin et al. 2001)
Systemic lupus erythematosus (Dewey and Jankovic 1989;
Ballistic movements involve the extremities: most com-
Vidakovic et al. 1994)
monly both the upper and lower extremities are involved
Sydenham’s chorea (Konagaya and Konagaya 1992)
on one side, producing hemiballism; occasionally one may
Traumatic brain injury with damage to the subthalamic
see monoballism (with involvement of only one extremity)
nucleus (Vakis et al. 2006)
or biballism (with bilateral, generalized involvement). The
Hyperthyroidism (Ristic et al. 2004)
proximal musculature is preferentially involved and the
Medications (phenytoin [Opida et al. 1978], oral contraceptives
movements are wild and flinging in nature, sometimes to a
[Driesen and Wolters 1986], bupropion [de Graaf et al. 2003])
degree that may throw patients off balance.
p 03.qxd 3/10/08 9:32 AM Page 83
3.7 Dystonia 83
in the case in question, there was damage, as might be agonist and antagonist muscles, and persists for variable
expected, to the subthalamic nucleus. Hyperthyroidism may periods of time. Some common varieties deserve to be
also cause ballism, albeit rarely, and there are isolated case mentioned. Dystonia of the cervical muscles may rotate or
reports of ballism occurring as a side-effect to phenytoin, twist the head in one direction or the other (torticollis),
oral contraceptives, and bupropion. pull it over to one side (lateralcollis), or forward (antero-
collis), or backward (retrocollis). Dystonic contraction of
the oromandibular musculature may cause a forced yawn-
Differential diagnosis ing type of movement, and when the orbicularis oculi mus-
cles undergo dystonic contracture blepharospasm occurs.
The hallmark of ballism is its wild, flinging nature, and it is The extraocular musculature may be involved, creating
this characteristic that distinguishes it from other abnor- what is known as an ‘oculogyric crisis’, with tonic conju-
mal movements, such as dystonia, athetosis and chorea. gate gaze deviation, generally superiorly and laterally.
Dystonic movements are fixed and more or less immobile; When the upper extremity is involved, the arm may be
although in athetosis there is some motility, it is slow and twisted, and in the hand the thumb may be adducted with
writhing in character. Choreic jerks, when severe, may the fingers hyperextended. Lower extremity involvement is
approach the flinging character of ballistic movements but typified by inversion and plantar flexion of the foot. The
choreic jerks appear and reappear on different parts of the axial musculature may also be involved resulting in vari-
body in contrast with the consistent presence of ballism on able contortions of the trunk. Finally, there are also cases
one or more limbs. where dystonia occurs only with specific movements. As
noted earlier, in some cases dystonia may be precipitated
by movement, and this may occur with non-specific move-
Treatment ments, such as turning the head, or lifting an arm. There
are, however, dystonias wherein only very specific activi-
Of the various symptomatic treatments for ballism, by far
ties, such as writing or typing, precipitate the dystonia.
the best established agents are the antipsychotics; among
Dystonias are often described with reference to the
these haloperidol (Davis 1976; Klawans et al. 1976a) has
number and contiguity of body parts involved. Thus, in
the longest track record. Other first-generation agents to
focal dystonia, only one body part is involved (e.g., the
consider include perphenazine (Johnson and Fahn 1977)
upper extremity alone), whereas in segmental dystonia,
and chlorpromazine (Klawans et al. 1976a). Of second-
two adjacent parts are affected (e.g., the neck and upper
generation antipsychotics, risperidone (Evidente et al.
extremity): ‘hemidystonia’ is a term reserved for a specific
1999), olanzapine (Mukand et al. 2005), and clozapine
segmental dystonia wherein the upper and lower extremity
(Stojanovic et al. 1997) have also been used. Regardless of
are both involved. In multifocal dystonia, two or more
which agent is chosen, it is appropriate to start with a low
non-adjacent parts are affected; in generalized dystonia,
dose (e.g., 1–2 mg of haloperidol or 0.25–0.5 mg of risperi-
bilateral involvement is seen.
done) and to gradually titrate the dose upward. Periodic
In some cases, patients may be able to relieve a dystonia
attempts should be made to taper and, if possible, discon-
by utilizing what is known as a ‘sensory trick’, or geste
tinue antipsychotics over the following months.
antagoniste. For example, by simply placing a hand gently
Other pharmacologic agents to consider include sertra-
on the cheek a patient with torticollis may abort the twist-
line (Okun et al. 2001), topiramate (Gatto et al. 2004), and
ing motion of the neck musculature, and a patient with a
divalproex (Chandra et al. 1982; Lenton et al. 1981)
generalized dystonia precipitated by walking may find
(although not all reports are favorable for divalproex [Lang
relief by walking backward.
1985]). In severe treatment-resistant cases, consideration
may be given to pallidotomy (Yamada et al. 2004), deep
brain stimulation of the thalamus (Tsubokawa et al. 1995),
or intrathecal baclofen (Francisco 2006).
Etiology
The various causes of dystonia are listed in Table 3.7, in

3.7 DYSTONIA which they are divided into several groups. The first group,
known as the primary dystonias, is composed of ‘pure’ dys-
Dystonia, a term coined by Oppenhiem in 1911, refers to a tonias that occur either idiopathically or on an inherited
more or less sustained contortion of one or more body parts. basis. The next group, known as the ‘dystonia plus’ syn-
dromes, is also characterized by inherited disorders; how-
ever, here the dystonia is accompanied by other abnormal
Clinical features movements, such as parkinsonism or myoclonus. Following
this are the secondary dystonias. This is a heterogeneous
Dystonic movements may arise either spontaneously or group, including medication-induced dystonias (e.g.,
when a patient begins a voluntary movement. The con- antipsychotics), those occurring as part of a neurodegenera-
tortion arises from the simultaneous contraction of both tive disorder, those occurring secondary to focal lesions
p 03.qxd 3/10/08 9:32 AM Page 84
Table 3.7 Causes of dystonia

Primary dystonias Multiple system atrophy (Boesch et al. 2002)
Primary torsion dystonia (Johnson et al. 1962; Marsden and Fahr’s syndrome (Manyam et al. 2001)
Harrison 1974; Schmidt et al. 2006) Dentatorubropallidoluysian atrophy (Warner et al. 1995)
Idiopathic cervical dystonia (Chan et al. 1991; Jankovic et al. 1991; Neuroacanthocytosis (Hardie et al. 1991)
Sorensen and Hamby 1966) Huntington’s disease (Louis et al. 2000)
Meige’s syndrome (Defazio et al. 1999; Tolosa 1981) Spinocerebellar ataxia (Nandagopal and Moorthy 2004)
Breughel’s syndrome (Gilbert 1996) Focal lesions
Spasmodic dysphonia (Brin et al. 1998) Infarction or hemorrhage of the basal ganglia, thalamus, or
Axial dystonia (Bhatia et al. 1997b) parietal cortex
Task-specific dystonia (Cohen and Hallett 1988; Sheehy and Mass lesions of the basal ganglia, frontal lobe, or
Marsden 1982) cerebellum
‘Dystonia plus’ syndromes
Dopa-responsive dystonia (Harwood et al. 1994;
Traumatic brain injury (Burke et al. 1980; Lee et al. 1994;
Nygaard and Duvoisin 1986; Nygaard et al.
Munchau et al. 2000)
1990; Sawle et al. 1991; Tassin et al. 2000)
Post-anoxic (Bhatt et al. 1993)
Myoclonus dystonia (Asmus et al. 2002; Doheny et al. 2002;
Central pontine myelinolysis (Maraganore et al. 1992;
Grimes et al. 2002; Schule et al. 2004)
Yoshida et al. 2000)
Rapid-onset dystonia parkinsonism (Zaremba et al. 2004)
Cyanide intoxication (Rosenow et al. 1995; Valenzuela
Lubag (Evidente et al. 2002)
et al. 1992)
Secondary dystonias Methanol intoxication (Quartarone et al. 2000)
Medication-induced Manganese intoxication (Lu et al. 1994)
Antipsychotics Post-encephalitic (encephalitis lethargica [Alpers and
Tardive dystonia (a variant of tardive dyskinesia) Patten 1927], Japanese encephalitis [Kalita and Misra
Levodopa (Cubo et al. 2001; Kidron and Melamed 1987; 2000, Murgod et al. 2001])
Melamed 1979; Nausieda et al. 1980b) Acquired immune deficiency syndrome (AIDS) (Factor et al.
Bupropion (Detweiller and Harpold 2002) 2003)
Fluoxetine (Dominguez-Moran et al. 2001) Creutzfeldt–Jakob disease (Hellmann and Melamed 2002)
Sertraline (Walker 2002) Tourette’s syndrome (Stone and Jankovic 1991)
Buspirone (LeWitt et al. 1993) Cerebral palsy (Saint Hilaire et al. 1991)
Carbamazepine (Stryjer et al. 2002) Cervical cord lesion (Cammarota et al. 1995)
Gabapentin (Pina and Modrego 2005, Reeves et al. 1996) Thoracic outlet syndrome (Quartarone et al. 1998)
Tiagabine (Wolanczyk and Grabowska-Grzyb 2001) Peripheral trauma (Schott 1985; O’Riordan and
Valproic acid (Oh et al. 2004) Hutchinson 2004)
Cocaine withdrawal (Choy-Kwong and Lipton 1989) Esophageal reflux (‘Sandifer syndrome’ [Shahnawaz et al.
MDMA (‘Ecstasy’) (Priori et al. 1995) 2001])
Lamivudine (Song et al. 2005)
Paroxysmal dystonias
Alpha-interferon (Atasoy et al. 2004)
Non-kinesigenic paroxysmal dystonic choreoathetosis
Flunarazine (Koukoulis et al. 1997)
Kinesigenic paroxysmal dystonic choreoathetosis
Cimetidine (Romisher et al. 1987)
Exercise-induced paroxysmal dystonic choreoathetosis
Neurodegenerative disorders Nocturnal paroxysmal dystonia
Wilson’s disease (Svetel et al. 2001; Walshe and Yealand 1992) Ictal dystonia (Kuba et al. 2003; Newton et al. 1992)
Lesch–Nyhan syndrome (Jankovic et al. 1988) Miscellaneous causes (multiple sclerosis [Waubant et al. 2001,
Pantothenate kinase-associated neurodegeneration (Hayflick Zenzola et al. 2001], Fahr’s syndrome [Volonte et al. 2001],
et al. 2003; Swaiman 1991) traumatic brain injury and infarction of the basal ganglia
Corticobasal-ganglionic degeneration (Litvan et al. 1997b; [Demerkirian and Jankovic 1995])
Riley et al. 1990; Rinne et al. 1994, Vanek and Jankovic 2001)
Progressive supranuclear palsy (Barclay and Lang 1997)
(e.g., infarctions of the basal ganglia), and those occurring Of the primary dytonias, the classic example is primary
secondary to a large number of miscellaneous causes. torsion dystonia, or ‘dystonia musculorum deformans’ as
Finally, there is a group of paroxysmal dystonias, character- it was originally named by Oppenheim (1911). This typi-
ized clinically by dystonia occurring only in discrete, brief cally has an onset in childhood or adolescence, presenting
episodes. In general clinical practice, dystonia is most with a focal dystonia, often of the lower extemity, and
commonly caused by one of the primary dystonias. gradual progression to generalized involvement. The other
p 03.qxd 3/10/08 9:32 AM Page 85
3.7 Dystonia 85
primary dystonias generally have an onset in adult years and Duggal 2006). Furthermore, it must be borne in mind
and typically remain more or less focal. Idiopathic cervical that other dopamine blockers, such as metoclopramide, may
dystonia, as the name clearly suggests, manifests with a also cause dystonia (Chistodoulou and Kalaitzi 2005). In
cervical dystonia; Meige’s syndrome is characterized by patients who are treated chronically with antipsychotics, tar-
blepharospasm, Breughel’s syndrome by oromandibular dive dystonia, a variant of tardive dyskinesia, may also occur:
dystonia, and spasmodic dysphonia, again as the name this generally presents with a focal dystonia affecting the
suggests, by dysphonia. Rarely, only the trunk may be neck or face, which may undergo segmental spread and,
involved, creating the syndrome of axial dystonia. As noted rarely, become generalized (Burke et al. 1982; Kiriakakis et al.
above, some dystonias occur only with specific activities, 1998; Wojick et al. 1991; Yassa et al. 1986), in which case it
and these are known as the ‘task-specific dystonias’: exam- may be disabling (Yadalam et al. 1990). Interestingly, should
ples include writer’s, typist’s, and musician’s cramp. mania occur, a pre-existing tardive dystonia may undergo
In considering the ‘dystonia plus’ syndromes, by far the substantial improvement (Kiriakakis et al. 1998; Yazici et al.
most important disorder to keep in mind is dopa-responsive 1991). As with acute dystonias, tardive dystonia may also
dystonia. This disorder has an onset in childhood with dys- rarely be seen with second-generation agents such as olanza-
tonia of the lower extremity, and thus figures in the differ- pine, although it is more common with first-generation
ential diagnosis of primary torsion dystonia. The reason agents (Gunal et al. 2001).
why it should always be considered is because, in contrast The most common offender of the other medications that
with primary torsion dystonia, it is eminently treatable, are capable of causing dystonia is levodopa, as utilized in the
often responding dramatically to low-dose levodopa. The treatment of Parkinson’s disease: in such cases dystonia may
other ‘dystonia plus’ syndromes are rare. Myoclonus– appear either as a peak-dose dyskinesia or, more commonly,
dystonia (discussed also in Section 3.2) has an onset in child- as an end-of-dose ‘wearing off’ phenomenon. The remaining
hood or adolescence and is characterized by myoclonus and medicines listed in Table 3.7 only rarely cause dystonia: most
dystonia, often a cervical or a task-specific dystonia. Rapid- references are limited to single case reports.
onset dystonia–parkinsonism presents in adult years Turning now to the neurodegenerative disorders capa-
acutely with a combination of dystonia and parkinsonism, ble of causing dystonia, the most important disorder to
with symptoms escalating over days or weeks and then keep in mind is Wilson’s disease, given that, unlike all the
stabilizing. Lubag (also known as X-linked dystonia– other disorders in this group, it is treatable. The onset of
parkinsonism) is an X-linked disorder seen only in Filipino Wilson’s disease occurs between childhood and early adult
men, presenting first with dystonia but eventually joined years and, in a minority of cases, it may present with dysto-
by parkinsonism. nia (Starosta-Rubinstein et al. 1987): the dystonia may
In considering the secondary dystonias, each subgroup consist of torticollis, dystonia of the upper or lower
will be treated in turn, beginning with medication-induced extremity, an oculogyric crisis (Lee et al. 1999), or a facial
dystonias. dystonia of the oromandibular type, which may leave the
Of the medications capable of causing dystonia, by far the patient with a fixed, vacuous, wide-mouthed smile. Other
most common are the first-generation antipsychotics, such symptoms and signs, including personality change, gait
as haloperidol and fluphenazine (Keepers et al. 1983; Swett abnormalities and tremor, eventually accrue. Given that
1975). These usually occur within a matter of days of either treatment is available, testing for copper and ceruloplas-
starting the medication or substantially increasing the dose min levels should be performed if there is any suspicion of
(Ayd 1961; Keepers et al. 1983), and are most likely to occur Wilson’s disease. The occurrence of progressive dystonia in
in young males (Boyer et al. 1987). Focal dystonias, includ- early childhood should suggest the Lesch–Nyhan syn-
ing oculogyric crisis, torticollis, and involvement of the drome, especially when accompanied by mutilative lip bit-
upper limb are most common; in some cases, segmental ing. Pantothenate kinase-associated neurodegeneration
spread may occur and, rarely, an acute antipsychotic- presents in childhood or adolescence with progressive dys-
induced dystonia may become generalized. Lingual dystonia tonia, usually of the upper extremity, eventually joined by
may also occur, and patients may become dysarthric and other abnormal movements (such as chorea or tremor)
complain of a ‘thick tongue’; very rarely, laryngeal dystonia and then by a dementia (Dooling et al. 1974). The other
with respiratory embarrassment may occur (Christodoulou neurodegenerative disorders listed in Table 3.7 all have an
and Kalaitzi 2005; Flaherty and Lahmeyer 1978). onset in adult or later years, and, in addition to dystonia,
Interestingly, in patients with schizophrenia, antipsychotic- typically are characterized by other abnormal movements.
induced dystonias may be accompanied by a transient Thus, corticobasal ganglionic degeneration, progressive
increase of psychotic symptoms (Chiu 1989; Thornton and supranuclear palsy, multiple system atrophy, and Fahr’s
McKenna 1994). Although first-generation antipsychotics syndrome are characterized, in addition to dystonia, by
are most commonly at fault, dystonia has been noted, albeit parkinsonism, and dentatorubropallidoluysian atrophy,
rarely, with second-generation agents such as olanzapine neuracanthocytosis and Huntington’s disease are marked
(Alevizos et al. 2003) and aripiprazole (Desarkar et al. 2006); by chorea. In the case of Huntington’s disease, although
there are also case reports of dystonia occurring upon dis- dystonia generally appears only in far-advanced disease,
continuation of clozapine (Ahmed et al. 1998; Mendhekar there are rare cases of Huntington’s disease in which the
p 03.qxd 3/10/08 9:32 AM Page 86
presentation was with dystonia. Finally, there are rare case hemisdystonia or a generalized dystonia, which may be
reports of spinocerebellar ataxia presenting, not with the accompanied by chorea. Although sporadic cases do occur,
expected ataxia, but with dystonia. most are familial, following a pattern consistent with auto-
Of focal lesions capable of causing dystonia, by far the somal dominant inheritance. Further, specific, details for
most common are infarctions of either the basal ganglia each type follow below.
(Krystkowiak et al. 1998; Russo 1983) or thalamus In paroxysmal non-kinesigenic dystonic choreoathetosis
(Lehericy et al. 2001): of note, in these cases, it may take (Bressman et al. 1988; Demirkiran and Jankovic 1995; Fink
weeks, months, or, rarely, years, before the dystonia et al. 1997; Jarman et al. 1997, 2000; Lance 1977; Matsuo
appears (Lehericy et al. 1996). There are also rare reports of et al. 1999; Mount and Reback 1940; Richards and Barnett
cortical infarction causing dystonia, as for example of the 1968; Rosen 1964) attacks are more likely when patients are
parietal cortex (Burguera et al. 2001). Mass lesions may fatigued or have been indulging in alcohol, caffeine, or
also cause dystonia, as has been reported for tumors of the nicotine. A locus has been identified on chromosome 2, and
basal ganglia (Martinez-Cage and Marsden 1984), frontal there appears to be considerable genetic heterogeneity
lobe (Soland et al. 1996b), and cerebellum (Alarcon et al. (Bruno et al. 2007; Chen et al. 2005, Spacey et al. 2006).
2001; Krauss et al. 1997). Paroxysmal kinesigenic dystonic choreoathetosis
Of the miscellaneous secondary causes of dystonia, trau- (Bruno et al. 2004; Demirkiran and Jankovic 1995; Kertesz
matic brain injury is perhaps the most common, and in such 1967; Lance 1977; Stevens 1966) is suggested by the history
cases lesions of the basal ganglia are seen. Dystonia may also of attacks occurring immediately upon some movement,
appear in a post-anoxic encephalopathy, and there are also such as walking, running or, in some cases, simply standing
case reports of dystonia occurring after central pontine up. Another distinguishing feature of this type is the fact
myelinolysis, wherein ‘extrapontine’ myelinolysis, involving that treatment with an anti-epileptic drug (AED) such as
the basal ganglia, also occurred. Other clear-cut precipitat- carbamazepine reliably prevents attacks, often at a low
ing events, rarely associated with dystonia, include intoxica- dose (Wein et al. 1996). In this disorder, a locus has been
tion with cyanide, methanol, or manganese. Encephalitis identified on chromosome 16; however, as for non-
may have dystonia as a sequela, and this has been noted after kinesigenic cases, there is also considerable genetic hetero-
encephalitis lethargica and Japanese encephalitis. AIDS may geneity (Valente et al. 2000).
be characterized by dystonia, and this has been noted in In exercise-induced paroxysmal dystonic choreoatheto-
cases of AIDS that are complicated by progressive multifocal sis (Bhatia et al. 1997a; Munchau et al. 2000) attacks occur
encephalopathy and toxoplasmosis. In one case report only after fairly prolonged exercise, such as walking or
Creutzfeldt–Jakob disease was noted to present with dysto- cycling, and they subside fairly soon with rest. A genetic
nia. Tourette’s syndrome, in addition to tics, may also, albeit locus has not as yet been identified.
rarely, cause dystonia, and cerebral palsy may also be charac- The secondary paroxysmal dystonias include the syn-
terized by dystonia. Remarkably, there are also reports of drome of nocturnal paroxysmal dystonia, ictal dystonia,
dystonia occurring with cervical cord lesions and with and a miscellaneous group.
lesions outside the central nervous system, such as the tho- Nocturnal paroxysmal dystonia is characterized by brief
racic outlet syndrome or with peripheral trauma: in cases of attacks of dystonia that arise from non-REM sleep and are
peripheral trauma, dystonia may also accompany reflex associated with partial awakening. There are probably dis-
sympathetic dystrophy (van Hilten et al. 2001). Finally, dys- tinct subtypes in this syndrome, with some cases represent-
tonia may also occur in association with gastroesophageal ing a parasomnia (Lee et al. 1985) and others representing
reflux disease, in which case one speaks of the ‘Sandifer’s seizures (Lugaresi and Cirignotta 1981; Lugaresi et al.
syndrome’: although this is generally reported only in 1986; Provini et al. 1999; Tinuper et al. 1990): in the latter
children, adult cases have also been noted. subtype the response to an AED, such as carbamazepine, is
The last group in Table 3.7 contains the paroxysmal dys- usually good.
tonias, which may be divided into primary and secondary Ictal dystonia may also be seen during otherwise typical
forms (Demerkiran and Jankovic 1995). The primary forms complex partial seizures, and in such cases the dystonia
are divided into three types, depending on whether the dys- fairly reliably lateralizes the epileptic focus to the contra-
tonia occurs spontaneously or with precipitants: sponta- lateral hemisphere.
neously occurring dystonias are referred to as ‘paroxysmal Finally, the miscellaneous group includes multiple scle-
non-kinesigenic dystonic choreathetosis’; those precipi- rosis (with plaques in the thalamus or posterior limb of the
tated immediately by some movement, as ‘paroxysmal internal capsule), Fahr’s syndrome, and traumatic brain
kinesigenic dystonic choreoathetosis’; and those occurring injury or infarction of the basal ganglia.
only after relatively prolonged exercise, as ‘exercise-induced
paroxysmal dystonic choreoathetosis’. Each of these pri-
mary paroxysmal dystonias has an onset in childhood Differential diagnosis
or adolescence, and in all cases the attacks last generally in
the order of minutes, rarely extending to hours; during Athetosis is somewhat similar to dystonia, in that in both
the attacks most patients will have dystonia, generally a abnormal movements contortion is present; the difference
p 03.qxd 3/10/08 9:32 AM Page 87
3.8 Parkinsonism 87
between the two lies in the degree of mobility seen. In dys- both passive extension and flexion. This rigidity may be
tonia, the contortion gradually assumes a final form, and ‘lead pipe’ in character, in that it is of the same severity
then remains fairly fixed; by contrast, in athetosis, the throughout the full range of motion, or there may be what
contortion constantly changes, in a writhing, almost is known as ‘cogwheel’ rigidity. Cogwheeling is perhaps
serpentine, fashion. most easily appreciated at the elbow by supporting the
elbow in the palm of one’s hand, placing the thumb over
the biceps tendon and then, with the other hand, alter-
Treatment nately slowly extending and flexing the forearm: when cog-
wheeling is present, a peculiar ‘ratcheting’ sensation is
For most of the causes listed in Table 3.7, treatment is dis- appreciated in the thumb over the biceps tendon, as if the
cussed in the respective chapter for the disorder in question. extension of the forearm were proceeding one ‘cog’ at a
In the case of antipsychotic-induced dystonia, emergent time. Postural instability may be suggested by a history of
treatment may be accomplished with diphenydramine, falls, and may be detected using the ‘pull test’: to perform
given intramuscularly or intravenously in a dose of this test, stand several feet behind the patient and, after
25–50 mg, or benztropine, given intramuscularly in a dose warning the patient what is to come, place your hands on
of 2 mg; if needed, oral benztropine, in a similar dose, may the patient’s shoulders and gently, but briskly, pull back.
be given on a preventive basis. For other causes where treat- Normal individuals will quickly make a compensatory step
ment is not well established, consideration may be given to back and catch their balance; those with parkinsonism,
empirical trials of benztropine, clonazepam, baclofen or however, will fail to make compensatory movements and
AEDs, such as carbamazepine; botulinum toxin may be con- begin to tumble backward (in this regard, if the patient is
sidered, and, as a last resort, deep brain stimulation of the large, it is appropriate to position yourself with your back
globus pallidus is an option. to a wall in order to prevent a double fall). Micrographia is
manifest by handwriting that becomes small and scratchy:
in some cases, multiple samples of the patient’s hand-
3.8 PARKINSONISM writing collected over months and years may provide
‘graphic’ evidence of a progression of the syndrome.
Parkinsonism is a syndrome of multiple different etiolo- Other abnormalities that may be seen in classic parkin-
gies: although Parkinson’s disease is the most common sonism include hypomimia, hypophonia, palilalia, and
cause of parkinsonism, it must always be kept in mind that bradyphrenia. Hypomimia (also known as ‘masked facies’)
it is but one of many possible causes, and the physician is an abnormality of facial expression wherein the muscles
must dutifully consider the other causes before deciding of facial expression seem frozen and there is little blinking:
that a patient with parkinsonism has Parkinson’s disease. Kinnier Wilson (Wilson 1955) described it as a ‘starched’
expression. In hypophonia, the voice becomes low, soft,
and monotone; in severe cases it is reduced to an unintelli-
Clinical features gible mumbling. Palilalia is said to be present when the
patient involuntarily repeats the last word of a phrase or
Fully developed, classic parkinsonism is, once recognized, sentence with ever increasing rapidity and ever increasing
almost unforgettable. Patients stand in a flexion posture, indistinctness. Bradyphrenia is the cognitive analog of
bent at the waist and neck, and with the arms held forward bradykinesia and is characterized by a slowness of thought.
in flexion and the knees somewhat bent. A rhythmic pill- Of all of these signs and symptoms, the ‘cardinal’ ones
rolling rest tremor is seen, most notably in the hands. for diagnosis are tremor, bradykinesia, rigidity, and
When patients attempt to do anything, bradykinesia is postural instability.
apparent, with almost all movements initiated and carried
out slowly. The gait is shuffling and patients typically take
small steps; at times the phenomenon of ‘festination’ is Etiology
seen, wherein, with ongoing ambulation, patients begin to
lean forward and take ever smaller, but ever faster steps, The various causes of parkinsonism are listed in Table 3.8,
almost as if they were trying to catch up with their forward- where they are divided into several groups. In the first group
leaning center of gravity. Some patients may also display are neurodegenerative disorders, each of which causes a
another gait abnormality known as ‘freezing’ (Giladi et al. parkinsonism of gradual onset and progression: this group,
1992): here, patients become unable to initiate ambulation, as a whole, is by far the most common cause of parkinson-
as if they were ‘frozen’. This curious phenomenon typically ism, and of the disorders in this group, Parkinson’s disease
occurs at a threshold of some sort, for example a doorway is the most frequent. The next group consists of parkinson-
or the start of a hallway. ism secondary to medications and in almost all of these
Other motor abnormalities are evident on examination, cases the parkinsonism is of relatively acute onset: of all of
and include rigidity, postural instability, and micro- these medications the antipsychotics, by far, are the most
graphia. Rigidity is evident in the limbs, and is present with common offenders. Next considered are cases secondary
p 03.qxd 3/10/08 9:32 AM Page 88
Table 3.8 Causes of parkinsonism

Neurodegenerative disorders Amiodarone (Werner and Olanow 1989)
Parkinson’s disease (Hughes et al., 1993; Martin et al. 1973) Disulfiram (de Mari et al. 1993; Laplane et al. 1992)
Diffuse Lewy body disease (Byrne et al. 1989; Hely et al. 1996) Budesonide (Prodan et al. 2006)
Multiple system atrophy (Watanabe et al. 2002; Wenning Cytosine arabinoside (Luque et al. 1987)
et al. 1995) Kava extract (Meseguer et al. 2002)
Progressive supranuclear palsy (Collins et al. 1995; Litvan et al.
Secondary to toxins and substances of abuse
1996; Maher and Lees 1986; Nath et al. 2003)
Alcohol withdrawal (Carlen et al. 1981)
Corticobasal ganglionic degeneration (Litvan et al. 1997b; Rinne
Methanol (Guggenheim et al. 1971; McLean et al. 1980;
et al. 1994)
Verslegers et al. 1988)
Frontotemporal dementia with parkinsonism linked to chromosome
MPTP (Ballard et al. 1985; Tetrud et al. 1989)
17 (Boeve et al. 2005; Yasuda et al. 2005)
Inhalant abuse (Uitti et al. 1994)
Dentatorubropallidoluysian atrophy (Warner et al. 1995)
Manganese (Abd El Naby and Hassanein 1965; Huang et al.
Neuroacanthocytosis (Hardie et al. 1991)
1989)
Wilson’s disease (Starosta-Rubinstein et al. 1987)
Cyanide poisoning (Uitti et al. 1985)
Fahr’s syndrome (Klawans et al. 1976b; Tambyah et al. 1993)
Diquat (Sechi et al. 1992)
Alzheimer’s disease (Clark et al. 1997; Goodman 1953; Scarmeas
Organophosphates (Bhatt et al. 1999)
et al. 2004)
Hallervorden–Spatz disease (Alberca et al. 1987; Jankovic et al. 1985) Secondary to other precipitating events
Juvenile-onset Huntington’s disease (Bird and Paulson 1971; Dementia pugilistica (Harvey and Davis 1974; Martland
Campbell et al. 1961; Siesling et al. 1997) 1928)
Kufs’ disease (Nijssen et al. 2002) Post-anoxic encephalopathy (Bhatt et al. 1993; Bucher et al.
Lubag (Evidente et al. 2002) 1996; Goto et al. 1997)
Spinocerebellar ataxia (Furtado et al. 2002; Shan et al. 2001) Carbon monoxide poisoning (Choi 1983; Grinker 1926;
Rapid onset dystonia parkinsonism (Brashear et al. 1996, 1997, 2007; Klawans et al. 1982b)
Kabacki et al. 2005; Kramer et al. 1999; Pittock et al. 2000) Encephalitis lethargica (Duvoisin and Yahr 1965; Rail et al.
Hereditary mental depression and parkinsonism (Perry et al. 1975; 1981)
Tsuboi et al. 2002) Arbovirus encephalitis (e.g., western equine [Mulder et al.
Guamian amyotrophic lateral sclerosis–parkinsonism complex 1951; Schultz et al. 1977], Japanese [Pradhan et al. 1999])
(Garruto et al. 1981; Hirano et al. 1967; Malamud et al. 1961)
Secondary to medications Stroke (see text for references)
Antipsychotics (Hardie and Lees 1988) ‘Arteriosclerotic parkinsonism’ (Murrow et al. 1990)
Metoclopramide (Indo et al. 1982; Sethi et al. 1989) Acquired hepatocerebral degeneration (Burkhard et al. 2003)
Prochlorperazine (Edelstein and Knight 1987) Hepatic encephalopathy (Federico and Zochodne 2001)
Neuroleptic malignant syndrome (Rosebush and Stewart 1989; ‘Encephalopathic’ pellagra (Serdaru et al. 1988)
Velamoor et al. 1994) Central pontine myelinolysis (Dickoff et al. 1988; Tomita
Valproic acid (Armon et al. 1996; Easterford et al. 2004; Iijima et al. 1997)
et al. 2002) Multiple sclerosis (Federlein et al. 1997)
Alpha-methyldopa (Strang 1966) Hydrocephalus (Racette et al. 2004)
Lithium (Holroyd and Smith 1995) Systemic lupus erythematosus (Dennis et al. 1992)
Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine [Ernst Sjögren’s syndrome (Walker et al. 1999)
and Steur 1993], paroxetine [Jimenez-Jimenez et al. 1994]) Acquired immune deficiency syndrome (AIDS) (Hersh et al.
Phenelzine (Teusink et al. 1984) 2001)
Calcium channel blockers (e.g., cinnarizine, flunarazine, amlodipine Neurosyphilis (Sandyk 1983)
[Marti-Masso and Poza 1998; Sempere et al. 1995]) Hypoparathyroidism (Stuerenburg et al. 1996)
MPTP, methylphenyltetrahydropyridine.
to toxins and substances of abuse, such as methanol. most likely to cause ‘classic’ parkinsonism as described
Following this, there is a group of cases secondary to other, above. Onset is typically with tremor, with or without
more or less obvious, precipitating events, such as repeated rigidity, or less commonly with rigidity alone; symptoms
head trauma, or anoxia. Finally, there is a group of miscella- generally appear unilaterally, typically in one of the upper
neous causes, prominent among which are stroke and the extremities, and over time spread occurs in a gradual fash-
controversial entity known as ‘vascular parkinsonism’. ion to involve the contralateral extremity and, eventually,
Among the neurodegenerative disorders, Parkinson’s all four extremities. The classic picture may also be more or
disease, in addition to being the most common, is also the less faithfully imitated by diffuse Lewy body disease and
p 03.qxd 3/10/08 9:32 AM Page 89
3.8 Parkinsonism 89
multiple system atrophy; however, certain features may typically also present, such as dystonia in pantothenate
enable a clinical differentiation of these two disorders from kinase-associated neurodegeneration and either dystonia or
Parkinson’s disease. Diffuse Lewy body disease, as noted in chorea in the Huntington’s disease. Kufs’ disease, a very rare
Section 8.6, may present with relatively ‘pure’ parkinson- disorder, may cause parkinsonism, but this is typically
ism; however, in almost all cases, one also sees, within a preceded by myoclonus and seizures. Lubag (also known as
year of such a presentation, the development of a dementia X-linked dystonia parkinsonism) is an X-linked disorder
which is marked by confusion and visual hallucinations: seen only in Filipino men, which typically presents with dys-
although patients with Parkinson’s disease may also become tonia, followed by parkinsonism. Spinocerebellar ataxia type
demented, this usually does not occur until after many years 2 may present with a combination of ataxia and parkinson-
have passed (Biggins et al. 1992; Marder et al. 1995; Mayeux ism or, very rarely, with parkinsonism alone. Rapid-onset
et al. 1992). Multiple system atrophy (of the ‘striatonigral’ dystonia–parkinsonism has a remarkable onset in adult
variant) may likewise cause a fairly pure parkinsonism; years characterized by the appearance, over days or weeks, of
however, here one generally also sees evidence of degenera- a combination of parkinsonism and dystonia that subse-
tion of either the cerebellum or brainstem nuclei (Colosimo quently settles into a stable chronicity. Hereditary mental
et al. 1995; Litvan et al. 1997a; Wenning et al. 1994, 1999), depression and parkinsonism is a rare familial disorder that
with the development of either ataxia and/or autonomic presents in midlife with depression, and which is joined, in a
failure with postural dizziness, syncope, erectile dysfunc- matter of years, by a gradually progressive parkinsonism
tion, or urinary retention/incontinence. and, eventually, hypoventilation. Guamian amyotrophic
The next three neurodegenerative disorders in the list, lateral sclerosis–parkinsonism complex is a rare disorder
namely progressive supranuclear palsy, corticobasal occurring exclusively in residents of Guam, parts of Japan,
ganglionic degeneration and frontotemporal dementia, are and some other Pacific islands.
less likely to cause a classic parkinsonism and are more Turning now to the group of medications capable of
likely to have clearly distinctive characteristics. Progressive causing parkinsonism, the most frequent offenders by far
supranuclear palsy tends to present with frequent, unex- are the antipsychotics. Among the antipsychotics, although
plained falls, and the ensuing parkinsonism is generally first-generation agents (e.g., haloperidol or fluphenazine)
symmetric in onset and marked by rigidity rather than are most likely to cause this side-effect, parkinsonism has
tremor; furthermore, the patient’s posture, rather than one also been caused by second-generation agents, such as
of flexion, is usually quite erect, with the neck often held in risperidone or olanzapine (Carlson et al. 2003). Although in
a rigid dystonic extension (Litvan et al. 1996; Steele 1972); the vast majority of cases the parkinsonism gradually sub-
finally, and most importantly, within several years one typ- sides after the discontinuation of treatment, in a small
ically sees a supranuclear ophthalmoplegia, especially for minority, primarily in the elderly, it may persist indefinitely
downward gaze. Corticobasal ganglionic degeneration typ- (Bocola et al. 1996). Other dopamine blockers, such as
ically presents with bradykinesia and a markedly asymmet- metoclopramide or prochlorperazine may also cause
ric parkinsonism of an upper limb, marked by a dystonic parkinsonism, a fact often not appreciated by many physi-
rigidity; tremor is unusual and, moreover, one typically cians. When parkinsonism occurs in patients treated with
finds cortical sensory loss and apraxia. One of the fron- dopamine blockers, the neuroleptic malignant syndrome,
totemporal dementias (frontotemporal dementia and although rare, must also be considered: this syndrome typ-
parkinsonism linked to chromosome 17) presents not only ically presents with a delirium, followed shortly by parkin-
with parkinsonism, but also with a personality change of sonism and other symptoms such as coarse tremor, fever,
the frontal lobe type, with such symptoms as disinhibition, tachycardia, labile hypertension, and diaphoresis. Although
puerile humor, perseveration, etc. the vast majority of cases of the neuroleptic malignant syn-
The remaining neurodegenerative disorders in the list are drome are caused by treatment with antipsychotics (includ-
far less common than those just discussed, and most also ing clozapine [Miller et al. 1991]), cases have also occurred
have distinctive features. Both dentatorubropallidoluysian secondary to the withdrawal of dopaminergic agents such
atrophy and choreoacanthocytosis cause chorea. Wilson’s as amantadine (Cunningham et al. 1991; Harsch 1987) and
disease may cause a parkinsonian rigidity but this is gener- levodopa (Sechi et al. 1984; Toru et al. 1981). Valproic acid
ally accompanied by dysarthria or dystonia. In Fahr’s syn- may also cause parkinsonism, and, uniquely among med-
drome, although parkinsonism may be seen in an isolated ications capable of causing this side-effect, the parkinson-
fashion, it is typically accompanied by other signs, such as ism here may be of delayed onset, after from 6 months to
ataxia (Nyland and Skre 1977) or intention tremor 4 years (Ristic et al. 2006), thus obscuring the causal role
(Mathews 1957), and neuroimaging will reveal calcification of the drug. The other medications listed in Table 3.8 only
of the basal ganglia. Alzheimer’s disease may be complicated rarely cause parkinsonism.
by a mild parkinsonism, but this occurs only many years The next group to consider are toxins and substances of
after the typical dementia is well established. Adolescent- abuse and the first to consider here is alcohol, wherein
onset parkinsonism may occur with pantothenate kinase- parkinsonism occurs not as a complication of alcohol
associated neurodegeneration or in the Westphal variant intoxication but rather appears during the course of alcohol
of Huntington’s disease, but in both cases other signs are withdrawal in a small minority of cases. In evaluating
p 03.qxd 3/10/08 9:32 AM Page 90
chronic alcoholics who have parkinsonism, one should also and Lees 1987). Arboviral encephalitides associated with
consider the possibility that the patient, unable to obtain parkinsonism include western equine encephalitis,
alcohol, may have used methanol: severe cases of methanol wherein parkinsonism may appear after a latent interval of
intoxication may be complicated by putaminal necrosis from a week to several months, and Japanese encephalitis,
with parkinsonism. The next substance to consider is wherein parkinsonism may appear not only as a delayed
methylphenyltetrahydropyridine (MPTP): this is a contam- sequela but also as part of the acute encephalitic syndrome.
inant of illicitly prepared meperidine (Langston et al. 1983), The final group to consider is the miscellaneous one,
and addicts who injected the contaminated meperidine and of the disorders in this group, stroke may be consid-
developed a parkinsonism of rapid onset. A final example of ered first. Infarctions of the basal ganglia or of the midbrain
substances of abuse capable of causing parkinsonism are (affecting the substantia nigra), rarely, have been noted to
the inhalants, wherein, rarely, intoxication may be compli- cause a contralateral hemiparkinsonism (Boecker et al.
cated by a parkinsonism that then persists. With regard to 1996; Fenelon and Houeto 1997; Kulisevsky et al. 1995).
toxins per se, the classic offender is manganese. Manganese With multiple lacunar infarctions of the basal ganglia, one
exposure may occur in manganese mines, steel mills, bat- may also see vascular parkinsonism. This is a perhaps con-
tery factories, or via drinking contaminated well water and troversial entity, as some authors doubt its existence. There
may be followed, after a variable latent interval, by a gradu- are, however, convincing reports of classic parkinsonism
ally progressive parkinsonism. The parkinsonism itself is occurring in this setting (Bruetsch and Williams 1954;
characterized primarily by rigidity and bradykinesia; Keschner and Sloane 1931; Tolosa and Santamaria 1984;
tremor may be present but is only rarely of the pill-rolling Zijlmans et al. 1995). In most cases, however, rather than a
type. Certain additional features may also be present, classic picture, the parkinsonism here is characterized pri-
including dystonia and what is known as a ‘cock-walk’. marily by rigidity and bradykinesia: tremor is usually
Dystonic rigidity may be found in the neck or in the face, absent, and evidence of damage to the corticospinal tracts
creating a vacuous, rigid grin (Charles 1927). The cock- (e.g., spasticity and hyper-reflexia) and corticobulbar
walk, which may be seen in up to one-third of patients (Abd tracts (pseudobulbar palsy) is generally present.
El Naby and Hassanein 1965) stems from a dystonic rigid- Liver disease may also, albeit rarely, be associated with
ity of the feet, such that patients walk on their metatar- parkinsonism. Acquired hepatocerebral degeneration, seen
sophalangeal joints (as if in high heels [Huang et al. 1997]), in patients with cirrhosis, typically causes a complex move-
at times looking for all the world like they are imitating ment disorder, with postural tremor, athetosis, dystonia,
the walk of a rooster. Interestingly, manganese-induced ataxia, and, in a substantial minority, parkinsonism with
parkinsonism may progress long after exposure has ceased prominent rigidity and bradykinesia. Acute hepatic
(Huang et al. 1993). Another toxin to consider is cyanide, encephalopathy, with elevated ammonia levels, may also
wherein exposure typically occurs after a suicidal overdose cause parkinsonism, but this is relatively rare.
with potassium cyanide: in these cases, parkinsonism Niacin deficiency causes pellagra, and this may occur in
may ensue after a latent interval spanning from weeks two forms. When the deficiency develops slowly, ‘classic’
(Rosenberg et al. 1989) to 1 year (Carella et al. 1988); in pellagra develops, with dementia, diarrhea and a rash on
some cases, dystonia or athetosis may also be present sun-exposed areas; when, however, the deficiency develops
(Rosenow et al. 1995). Finally, parkinsonism has also been suddenly, ‘encephalopathic’ pellagra occurs, with delirium
reported secondary to exposure to the herbicide diquat and and parkinsonism, marked primarily by rigidity. This
to organophosphate pesticides. acute onset ‘encephalopathic’ pellagra is not accompanied
Other, more or less obvious, precipitating events by a rash (Ishii and Nishihara 1981) and, typically, is seen
include repeated head trauma, anoxia, carbon monoxide only in chronic alcoholics in developed countries.
poisoning, and encephalitis. Repeated head trauma, as may Central pontine myelinolysis may be complicated by
occur in boxers, may be followed, after a latent interval of parkinsonism; however, as might be expected, this is not
5–40 years, by the gradual evolution of a condition known secondary to myelinolysis in the pons but to the ‘extrapon-
as ‘dementia pugilistica’, comprising parkinsonism, tine’ myelinolysis that may also occur in this syndrome
dysarthria, ataxia, and dementia. Anoxic coma may, in wherein the striatum is involved. Multiple sclerosis, rarely,
those who survive, be followed weeks to months later by may cause parkinsonism, in one case due to a midbrain
parkinsonism characterized primarily by rigidity and plaque involving the subsantia nigra. The remaining disor-
bradykinesia. Carbon monoxide poisoning may also be ders in Table 3.8 are each very rare causes of parkinsonism.
followed by parkinsonism, generally after a latent interval
of from days to weeks. Of the encephalitides associated
with parkinsonism, the classic example is encephalitis Differential diagnosis
lethargica, wherein parkinsonism occurred after a latent
interval of 1–20 years, and was often accompanied by ocu- A fully developed, classic parkinsonism is distinctive and
logyric crises and blepharospasm: importantly, although very difficult to confuse with other movement disorders.
there have been no further epidemics of encephalitis Difficulty, however, may arise when only fragments of the
lethargica since 1928, sporadic cases still occur (Howard syndrome are present, as may be the case early on in the
p 03.qxd 3/10/08 9:32 AM Page 91
3.9 Akinesia 91
evolution of the syndrome. Thus, care must be taken to dis- Table 3.9 Causes of akinesia
tinguish the rest tremor of parkinsonism from a postural Antipsychotic medications (Rifkin et al. 1975; Van Putten and
tremor, as may be seen, say, in essential tremor. Care must May 1978)
also be taken to distinguish the shuffling gait of parkinson- Stroke (infarction or hemorrhage of the caudate nucleus)
ism from the ‘magnetic’ gait seen in patients with hydro- (Kumral et al. 1999)
cephalus, wherein the feet seem stuck or magnetized to the Post-anoxic (Feve et al. 1993)
floor. Further, in patients who present primarily with rigid- Neurodegenerative disorders
ity a careful distinction must be made with dystonia: Progressive supranuclear palsy (Matsuo et al. 1991)
parkinsonian rigidity, as noted earlier, is typically accompa- Pantothenate kinase-associated neurodegeneration (Molinuevo
nied by the phenomenon of cogwheeling, something not et al. 2003)
seen in dystonia; furthermore, the rigidity of parkinsonism
does not contort the limb, hand or foot, in contrast with
dystonia, for which such contortions are the rule. first-generation antipsychotic, in which case the akinesia
generally develops slowly, over days or weeks, following
Treatment initiation of treatment or a substantial dose increase. Pure
akinesia may also occur with infarction or hemorrhage of
Most of the disorders listed in Table 3.8 are discussed in the caudate nucleus and has been noted as a rare sequela to
their respective chapters, and, as pointed out in those anoxic coma, wherein patients suffered necrosis of the
chapters, symptomatic treatment, if required, is generally globus pallidus. Finally, pure akinesia has rarely occurred
similar to that utilized in Parkinson’s disease, involving use as a ‘forme fruste’ of both progressive supranuclear palsy
of levodopa, direct-acting dopaminergic agents or perhaps and of pantothenate kinase-associated neurodegeneration,
anticholinergics. Of note, levodopa is almost always effec- without any of the symptoms typical of these disorders,
tive in Parkinson’s disease, and thus if a patient with such as parkinsonism or dystonia.
parkinsonism fails to respond to levodopa then it is
unlikely that the parkinsonism in question is occurring on
the basis of Parkinson’s disease. In the case of parkinson-
ism secondary to medications, discontinuation of the
The most important differential consideration is the syn-
offending drug is generally in order; however, in some
drome of parkinsonism, and in evaluating patients with
cases, in particular where antipsychotics are involved, this
akinesia a careful search must be made for symptoms such
may not be possible: here, treatment with the anticholiner-
as a flexion posture, tremor, shuffling gait, rigidity, or pos-
gic benztropine is generally effective.
tural instability: the presence of any of these in an akinetic
patient indicates parkinsonism, and the differential should
3.9 AKINESIA then proceed as outlined in Section 3.8.
Other syndromes to consider include akinetic mutism,
The term ‘akinesia’ is, essentially, synonymous with abulia, depression, and hypothyroidism. In akinetic mutism,
‘bradykinesia’, but is preferentially used when this phe- there is essentially a total failure to initiate any activity,
nomenon is ‘pure’ and unaccompanied by other signs or whereas with akinesia, in contrast, activity does occur,
symptoms, in particular when it appears in the absence of albeit after a delay. In abulia, there is also a failure to initi-
parkinsonism. ate activity; however, here, if patients are closely super-
vised, activity, once initiated, proceeds at a normal rate, in
contrast with akinesia, wherein the execution of activity
Clinical features remains slow. Depression, when marked by psychomotor
retardation, may present a picture quite similar to akinesia;
In motor akinesia, both the initiation and execution of however, here one sees other symptoms, such as depressed
actions are slowed, as if the patient were encased in mood, fatigue, insomnia, etc., symptoms that are absent in
molasses. All activities may be affected, including talking, akinesia. Finally, hypothyroidism, when severe, may cause
walking, or getting dressed. In cognitive (or, as it is some- a slowing of both activity and thought, thus mimicking
times called, ‘psychic’) akinesia, thoughts are likewise slow akinesia; here, however, one sees other typical symptoms
to appear and the ‘stream’ of thought is quite sluggish: and signs, such as cold sensitivity, constipation, hoarse-
some patients may complain of feeling like a ‘zombie’. ness, hair loss, puffiness, and bradycardia.
Etiology Treatment
The causes of akinesia are listed in Table 3.9. Of all of Akinesia secondary to antipsychotics typically responds to
these, by far the most common cause is treatment with a treatment with the anticholinerigc benztropine in doses of
p 03.qxd 3/10/08 9:32 AM Page 92
from 1 to 3 mg daily. The treatment of akinesia occurring Table 3.10 Causes of akathisia
from other causes is not well worked out; consideration Medications:
might be given to a trial of benztropine or, should that fail, Antipsychotics (including both acute akathisia [Van Putten
levodopa. et al. 1984] and tardive akathisia [Dufresene and Wagner
1988; Hershon et al. 1972; Lang 1994])
Droperidol (Foster et al. 1996)
3.10 AKATHISIA Prochlorperazine (Fleishman et al. 1994)
Metoclopramide (Fleishman et al. 1994; Jungmann and
Akathisia, a term coined by Ladislav Haskovec in 1901 Schofflang 1982)
(Hascovec 1901), is derived from the Greek, and means, Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine
literally, ‘an inability to sit still’. This is a very important [Lipinski et al. 1989], paroxetine [Baldassano et al. 1996])
syndrome to recognize, given that it may be disabling and Diltiazam (Jacobs 1983)
that it is, in general, eminently treatable. Interferon-alpha (Horikawa et al. 1999)
Parkinson’s disease (Comella and Goetz 1994; Lang and

Clinical features Johnson 1987)
Basal ganglia lesions (Stuppaeck et al. 1995)

As described by multiple authors (Ayd 1961; Braude et al.
1983; Gibb and Lees 1986; Halstead et al. 1994; Sachdev and
Kruk 1994), akathisia is characterized by a sense of restless-
ness and an inability to keep still; there is a dysphoric feeling and it was only after treatment with propranolol that the
of having to move, and, in most cases, this ‘compulsion’ to patient was able to describe the akathetic ‘chaos of thoughts’
move is translated into action in various ways. If seated, that had besieged her.
patients shift restlessly from one position to another and Akathisia often goes undiagnosed, especially if it is mild
may tap their feet or repeatedly cross and uncross their legs (Fleishman et al. 1994). Consequently, whenever antipsy-
or arms. If standing, patients may rock back and forth, shift- chotics, other dopamine blockers, or selective serotonin
ing their weight alternatively from one foot to another, or reuptake inhibitors (SSRIs) are prescribed it is important
may actually ‘march in place’. Restless pacing may occur as to subsequently enquire after any motoric or cognitive
patients give way to the irresistible impulsion to move restlessness.
about. In almost all cases, this restless urge to pace or move
about is worse when seated, and worst when lying down,
most patients obtaining at least some relief by standing up. Etiology
Coupled with this motoric restlessness, many patients also
experience a ‘cognitive’ or ‘psychic’ akathisia manifest by Of the various causes of akathisia listed in Table 3.10, by far
restless thoughts: thoughts come too fast, are crowded and the most common are medications: among these medica-
may shoot about the mind ‘like ping-pong balls’. In some tions, antipsychotics are the major offenders. Akathisia
cases, this buzzing jumble of thoughts defies expression in secondary to antipsychotics may occur either acutely or, as
speech and patients may become mute. tardive akathisia, after chronic treatment. Acute antipsy-
Although mild akathisia may be tolerable to some chotic-induced akathisia, although most commonly seen
patients, more extreme forms may become unbearable, with first-generation antipsychotics, such as haloperidol,
resulting in suicide attempts (Drake and Ehrlich 1985; has, albeit rarely, also been noted with second-generation
Rothschild and Locke 1991) or assaultive behavior (Siris agents, such as olanzapine (Jauss et al. 1998) and quetiap-
1985). ine (Catalano et al. 2005). Typically, symptoms appear
The appearance of akathisia may also exacerbate symp- some 5–6 days after initiating treatment or substantially
toms of other illnesses. For example, when antipsychotics increasing the dose (Sachdev and Kruk 1994): exceptions
are given to patients with Tourette’s syndrome to amelio- to this rule, however, do occur, with some cases arising in
rate tics, the subsequent appearance of an akathisia may the first day and others being delayed for up to a month
lead to an exacerbation of the tics themselves (Weiden and (Van Putten et al. 1984). Tardive akathisia, a variant of
Bruin 1987). Furthermore, patients with schizophrenia tardive dyskinesia, is symptomatically similar to acute
who develop an akathisia may experience a dramatic exac- akathisia (Burke et al. 1989) and appears gradually, gener-
erbation of their psychotic symptoms (Van Putten 1975; ally only after a year or more of treatment with an antipsy-
Van Putten et al. 1974). Importantly, patients with schizo- chotic; tardive akathisia has also been noted after chronic
phrenia who experience an akathisia-mediated exacerba- treatment with metoclopramide (Shearer et al. 1984).
tion of their illness may neither appear restless nor In all likelihood, akathisia induced by antipsychotics
complain of restlessness if questioned (Weiden and Bruin is secondary to dopamine blockade and, as might be
1987): in one of the author’s patients with schizophrenia, expected, other dopamine blockers may also cause this
an akathisia manifested with muteness and withdrawal, syndrome, including droperidol, prochlorperazine, and
p 03.qxd 3/10/08 9:32 AM Page 93
3.11 Catatonia 93
metoclopramide. The SSRIs have also been associated with increase in psychotic symptoms was secondary to the under-
akathisia, and in this situation the underlying mechanism lying schizophrenia, the physician may increase the dose of
may involve decreased activity of mesencephalic ventral the antipsychotic, thus causing a worsening of the akathisia,
tegmental dopaminergic neurons secondary to serotonin- and a worsening of the psychosis. Whenever there is doubt
ergically mediated inhibition. The other two medications here, a ‘diagnosis by treatment response’, as just described
in Table 3.10, namely diltiazem and alpha-interferon, have above, is probably in order.
only rarely been associated with akathisia. A similar scenario may also occur in patients with
Parkinson’s disease may cause akathisia, and here the depression who are treated with an SSRI. Here, and again
diagnosis may be elusive given that the typical motor rest- days or a week or more after beginning the SSRI, the
lessness may be obscured by bradykinesia. Consequently, patient may complain of an increase in suicidal ideation,
patients must be questioned closely regarding both any or, in some cases, may experience suicidal ideation de novo.
‘inner’ sense of restlessness and any evidence of cognitive In such cases, the concurrent appearance of any restless-
akathisia. ness, whether motoric or cognitive, should prompt an
Finally, akathisia has been reported secondary to bilat- attempt at ‘diagnosis by treatment response’.
eral necrosis of the basal ganglia after carbon monoxide
intoxication.
Treatment
Differential diagnosis With regard to medication-induced akathisia, considera-

tion may be given to either discontinuing the offending
The restless legs syndrome may be confused with akathisia medication or substantially reducing the dose (Braude
as there is in both cases motor restlessness and a tendency et al. 1983). When this is impractical or when the clinical
to pace the floor. Patients with the restless legs syndrome, situation demands immediate relief, any one of a large
however, generally experience parasthesiae in the legs and number of medications may be considered. Propranolol
find some relief in rubbing their feet, characteristics not remains the standard, and is generally effective in total
seen in akathisia; conversely, patients with akathisia often daily doses of 20–80 mg (Adler et al. 1985, 1986, 1993;
‘march in place’, a sign not seen in the restless legs Lipinski et al. 1984); provided that the drug is well
syndrome (Walters et al. 1991). tolerated, and only partial relief has been obtained, higher
Agitation (as may be seen in disorders such as schizo- doses may be utilized. Mirtazapine, in a dose of 15 mg,
phrenia, ‘agitated’ depression, mania, dementia, delirium, appears similar to propranolol (Poyurovsky et al. 2006).
and traumatic brain injury) is typically accompanied by Benztropine, in doses of from 1 to 3 mg may be utilized
restlessness, and in cases when patients with one of these (Adler et al. 1993; DiMascio et al. 1976) but anticholinergic
disorders are treated with an antipsychotic or an SSRI, as is side-effects make this less attractive. Cyproheptadine, in a
very often the case, the differential question can become dose of 8 mg b.i.d. is also effective (Fischel et al. 2001), but
quite acute. A common scenario involves a patient with sedation may prove a limiting factor. Clonazepam, in doses
agitation who is given an antipsychotic, initially improves, of 0.5–2.5 mg/day, is another alternative (Kutcher et al.
then, days later, becomes more agitated, and the question 1989). Vitamin B6 is also effective; however, the doses
here is whether the increasing agitation is due to the under- required are high, ranging from 600 to 1200 mg/day (Lerner
lying disorder or to an antipsychotic-induced akathisia. In et al. 2004) and at these doses toxicity may ensue, with the
some of these cases, the appearance of a tendency to development of a sensory neuropathy (Parry and Bredesen
‘march in place’ or of complaints of a worsening of symp- 1985).
toms upon being seated or lying down, may suggest the The treatment of tardive akathisia is discussed in
correct diagnosis, but when these clues are absent the dif- Section 22.2.
ferential may not be possible on clinical grounds and a The treatment of akathisia secondary to Parkinson’s
‘diagnosis by treatment response’ may be in order. As disease is not well worked out; consideration may be given
noted below, akathisia responds well to treatment with to propranolol (Adler et al. 1991) or one of the other agents
various agents, and a prompt clinical improvement after mentioned above.
initiation of, say, propranolol, would strongly suggest that
the correct diagnosis is akathisia.
As noted above, patients with schizophrenia may expe- 3.11 CATATONIA
rience an exacerbation of their psychotic symptoms due to
akathisia, and when this occurs, as it may at times, without The term catatonia was coined by the German psychiatrist
any motor restlessness, the only clue to the diagnosis may Karl Kahlbaum in 1874, who described it in patients with
be that the exacerbation of the psychotic symptoms schizophrenia. Since then, however, it has become quite
occurred days after the initiation of an antipsychotic or a apparent that schizophrenia, although one of the more
substantial dose increase. Should the diagnosis here be common causes of catatonia, constitutes but one of the
missed, a ‘vicious cycle’ may ensue: believing that the many etiologies of this syndrome.
p 03.qxd 3/10/08 9:32 AM Page 94
Clinical features Posturing is said to occur when patients automatically

and spontaneously assume more or less bizarre postures,
Catatonia, as described by Kraepelin in 1899 (Kraepelin which are then maintained. The arms may be spread in a cru-
1990) and Bleuler (1924), occurs in one of two forms: ciform position, or the head thrown back in full extension;
stuporous (or retarded) catatonia and excited catatonia some may huddle into balls or stand, stork-like, on one leg.
(Morrison 1973). The stuporous form is the most Echo phenomena, as noted, consist of either echolalia,
common, and will be described first. wherein the patient automatically, and without prompting,
repeats back what the examiner said, or echopraxia, wherein,
STUPOROUS CATATONIA again without prompting, the patient automatically mimics
the examiner’s movements, gestures, or posture.
The cardinal signs of stuporous catatonia are immobility, Negativism does not represent mere contrariness, stub-
waxy flexibility (also known as cataplexy or cerea flexibali- bornness or passive aggressiveness, for in each of these phe-
tas) and mutism. Associated symptoms include posturing, nomena, patients have not lost control and may be able to
‘echo’ phenomena (i.e. echolalia and echopraxia), nega- cooperate in situations that, to them, appear to be to their
tivism, and automatic obedience. advantage. In contrast, negativism presents as a mulish,
Immobility in catatonic stupor may persist for hours, almost instinctual tendency to resist, which may be either
days, or longer, with little or no change in the patient’s passive, wherein the patient, in response to a command,
position. Some may simply lie in bed, their legs rigidly simply does nothing, or active, wherein the patient does the
extended and adducted; others may almost curl up into a opposite of what is requested. Negativistic patients may
ball, resting on the floor, a chair or the bed. The eyes may refuse to come to an interview, take a bath, change their
be open or closed; if the eyes are open, patients often stare clothes, take medicines, or even eat food placed in front
fixedly ahead. Patients may not move even to relieve them- of them. In extreme cases, negativism may extend to the
selves and may become foul with urine or feces. Some may patient’s own urges, leading, for example, to extreme con-
not even swallow, allowing saliva or food to dribble from stipation with fecal impaction. Patients with active nega-
their mouths; indeed, if food is placed in the mouth, there tivism may get up from a table when food is placed on it or
is a risk of aspiration, which may be fatal (Bort 1976). may back out of a doorway if asked to walk through it.
Importantly, although patients appear to lack conscious Typically, there is no ‘reasoning’ with negativistic patients,
activity, most remain alert, and some, upon recovery, may as they generally remain mute and inaccessible.
evidence an astonishingly accurate recall of events that Automatic obedience represents, in a sense, the converse
occurred during the stupor. Interestingly, a patient’s of negativism, in that these patients automatically do what
immobility may occasionally undergo a sudden lysis: for is expected of them, without question or hesitation, regard-
example, if a ball is gently thrown to an immobile patient, less of whether the consequences are absurd or harmful.
the patient may suddenly loosen up and catch the ball. This is far from mere agreeableness as patients often seem
Waxy flexibility derives its name from the fact that, to behave in a robotic or automaton-like manner.
upon passive movement of the limbs, the examiner
encounters a rigidity similar to what one would expect
EXCITED CATATONIA
upon bending a waxen object, such as a softened candle. In
most cases, in addition to this waxy flexibility, one also Excited catatonia is characterized by bizarre, frenzied, and
finds that the patient’s limbs tend to stay in whatever posi- purposeless hyperactivity. Uninvolved with others, almost
tion the examiner places them, no matter how uncomfort- sealed off in their own world, patients may gesticulate,
able and regardless of whether or not the examiner march in place or loudly declaim; verbigeration (rapid,
instructs the patient to maintain the position of the limb. bizarre, and senseless speech) may also occur.
Bleuler (1924) recommended a bedside test for waxy flexi- In rare instances, excited catatonia may undergo a pro-
bility that involved taking ‘the patient’s pulse and, as if gression into a condition known as Stauder’s lethal catato-
inadvertently, “holding” his arm high and extended. Then, nia. Here there is an escalation in the hyperactivity, followed
after taking the pulse rate, I release the arm.’ The test was by fever, tachycardia, hypotension, and leukocytosis, and in
considered to be positive when the patient’s arm remained some cases death (Castillo et al. 1989; Mann et al. 1986). The
suspended in essentially the same position. Another bed- recognition of this syndrome is critical, for even when the
side test involves checking for the presence of a ‘psycholog- patient is in extremis (with temperatures as high as 41°C
ical pillow’. Here, when the patient is lying supine in bed [106 °F]), treatment with electroconvulsive therapy may
with the head resting on a pillow, the head is lifted slightly result in recovery (Aronson and Thompson 1950).
and the pillow removed. In a positive test, the patient’s
head remains in essentially the same position, as if the
pillow were still present. Etiology
Mutism in catatonic stupor ranges from partial to com-
plete. Those with only partial mutism may mumble or The various causes of stuporous catatonia and of excited
whisper incomprehensible words or phrases. catatonia are listed in Table 3.11.
p 03.qxd 3/10/08 9:32 AM Page 95
3.11 Catatonia 95
Table 3.11 Causes of catatonia psychosis, in mania, a preceding syndrome of stages I and II
Stuporous catatonia of mania, and in a depressive episode, a preceding typical
Schizophrenia (Johnson 1984; Morrison 1973) depressive syndrome. It must be emphasized that obtaining a
Depressive episode of either major depressive disorder or history from family or others is indispensable in making
bipolar disorder (Barnes et al. 1986) these diagnoses. Periodic catatonia may also be mentioned
Manic episode of bipolar disorder (Abrams and Taylor 1976; here; this is a very rare condition characterized, as the name
Taylor and Abrams 1977) suggests, by recurrent episodes of catatonia; recent research
Periodic catatonia (Gjessing 1974) suggests a genetic basis (Stober et al. 2002).
Of the medications that are capable of causing stu-
Medications porous catatonia, by far the most common offenders are
Antipsychotics (Weinberger and Wyatt 1978) the antipsychotics, especially high-potency first-generation
Disulfiram (Reisberg 1978; Weddington et al. 1980) agents, such as haloperidol, used in high dosage (e.g., over
Ciprofloxacin (Akhtar and Ahmad 1993) 20 mg) (Gelenberg and Mandel 1977). Disulfiram must
Azithromycin (Plana et al. 2006) also be kept in mind, as the diagnosis may be obscured by
Levetiracetam (Chouinard et al. 2006) the fact that disulfiram-induced catatonia may not appear
Benzodiazepine withdrawal (Rosebush and Mazurek 1996) for months after the disulfiram has been administered.
Epileptic conditions Catatonia secondary to ciprofloxacin, azithromycin, and
Complex partial seizures (Engel et al. 1978; Gomez et al. levetiracetam are very rare events. Although benzodi-
1982; Lim et al. 1986; Shah and Kaplan 1980) azepine treatment per se does not cause catatonia, this syn-
Post-ictal psychosis (Logsdail and Toone 1988) drome may occur in a very small minority of patients going
Interictal psychosis (Kristensen and Sindrup 1979; Slater through benzodiazepine withdrawal.
and Beard 1963) Epileptic conditions capable of causing stuporous cata-
Psychosis of forced normalization (Pakainis et al. 1987) tonia include complex partial seizures, post-ictal psychosis,
interictal psychosis, and the rare psychosis of forced
Viral encephalitis normalization.
Herpes simplex encephalitis (Raskin and Frank 1974) Complex partial seizures, in addition to the typical con-
Encephalitis lethargica (Bond 1920; Kirby and Davis 1921) fusion, may manifest with catatonia. The diagnosis is sug-
Miscellaneous conditions gested immediately by the paroxysmal onset of the
Stroke (Saver et al. 1993) disturbance, and, in most cases, by its relatively brief dura-
Vitamin B12 deficiency (Berry et al. 2003) tion. It must be borne in mind, however, that some cases of
Wilson’s disease (Davis and Borde 1993) complex partial status epilepticus with catatonia may
Systemic lupus erythematosus (Lanham et al. 1985; Mac persist for days or even longer.
and Pardo 1983) Post-ictal psychosis is generally seen only after a flurry
Limbic encephalitis (Tandon et al. 1988) of grand mal or complex partial seizures, and may rarely
Hepatic encephalopathy (Jaffe 1967) present with catatonia. Typically, there is a lucid interval,
Lyme disease (Pfister et al. 1993) lasting for days, between the last seizure and the onset of
Subacute sclerosing panencephalitis (Koehler and Jakumeit the psychosis, and the psychosis itself generally persists for
1976) days to months before spontaneously remitting.
Tay–Sachs disease (Rosebush et al. 1995) Interictal psychosis is a chronic condition that evolves
Thrombotic thrombocytopenic purpura (Read 1983) gradually only after many years of uncontrolled epilepsy
and which may, rarely, present with catatonia.
Excited catatonia The psychosis of forced normalization is a very rare dis-
Schizophrenia (Morrison 1973) order occurring in patients with uncontrolled epilepsy,
Viral encephalitis (Penn et al. 1972) which has been brought under control with aggressive
treatment with AEDs, with the clinical improvement being
accompanied by a ‘forced normalization’ of the electro-
encephalogram (EEG). Once again, and rarely, this may
STUPOROUS CATATONIA present with catatonia. The diagnosis is suggested by the
seemingly paradoxical onset of a psychosis after the
The overwhelming majority of cases of stuporous catatonia seizures have been stopped; further support for the diagno-
occur in the course of schizophrenia, a manic episode of sis comes by comparing an EEG that has been carried out
bipolar disorder, or a depressive episode of either major during the psychosis with one performed before aggressive
depressive disorder or bipolar disorder; in the case of depres- anti-epileptic treatment and finding the ‘normalization’.
sion, catatonia is more likely to occur in elderly patients Viral encephalitis may present with stuporous catatonia
(Starkstein et al. 1996). These diagnoses are made primarily (Barnes et al. 1986; Kim and Perlstein 1970; Misra and Hay
on the basis of the clinical context within which the catatonia 1971; Wilson 1976), with the diagnosis being suggested by
occurs. In the case of schizophrenia one finds a preceding fever and headache, and this has been noted with herpes
p 03.qxd 3/10/08 9:32 AM Page 96
simplex viral encephalitis and encephalitis lethargica Rigidity is present, and may be either lead pipe or cogwheel-
(although there have been no further epidemic cases of ing in character: when lead-pipe rigidity is present, the pic-
encephalitis lethargica since 1928, sporadic cases still ture may resemble catatonia; however, the rigidity seen in the
occur; the most recent case with catatonia was reported neuroleptic malignant syndrome is not accompanied by a
in 2000 [Shill and Stacy 2000]). tendency for the limbs to maintain whatever position they
The miscellaneous causes of stuporous catatonia are were placed in. Other symptoms, typical of the neuroleptic
quite heterogeneous. Regarding catatonia occurring in malignant syndrome, but not seen in uncomplicated catato-
stroke, a case of ‘hemicatatonia’ was noted with infarction nia, may also appear and aid in the differential: these include
of the parietal cortex. Furthermore, in about 2 percent of confusion, fever, and autonomic instability.
acute stroke patients waxy flexibility was found ipsilateral
to the infarcted hemisphere, with a hemiparesis contralat- EXCITED CATATONIA
erally (Saposnik et al. 1999): it must be noted that in these
cases, the only catatonic symptom found was waxy flexibil- Excited catatonia must be distinguished from mania and
ity, and that had to be specifically sought after. The other from simple agitation.
causes listed in Table 3.11 only very rarely cause catatonia. Mania, during stages I and II, is marked by hyperactiv-
ity, however here the activity is purposeful and not bizarre.
EXCITED CATATONIA Furthermore, in stages I and II of mania one also finds
symptoms such as heightened mood and pressure of
Excited catatonia is seen virtually exclusively in schizophre- speech, which are absent in excited catatonia. In some
nia; I could find only one convincing case due to another cases of stage III mania, however, the hyperactivity may
cause, namely in a patient with eastern equine encephalitis fragment and lose purpose, and in these cases the differen-
(see Table 3.11). tial may rest on obtaining a history of the preceding, typi-
With regard to schizophrenia, it must be kept in mind cal, stages I and II.
that, over long periods of time, patients may have alternat- Agitation typically is not characterized by bizarreness,
ing episodes of either stuporous or excited catatonia. which is always seen in excited catatonia.
Treatment
The differential diagnosis of the stuporous and excited
In cases of stuporous catatonia in which treatment of the
forms of catatonia are quite different, and thus each is
underlying cause is ineffective or for which emergent treat-
treated separately.
ment is required, consideration may be given to either
lorazepam or electroconvulsive therapy (ECT). Most cases
STUPOROUS CATATONIA of stuporous catatonia will show prompt, albeit temporary,
Stuporous catatonia must be distinguished from stupor of improvement, with parenteral lorazepam (e.g., 2 mg i.v.)
other causes, akinetic mutism, abulia, and the neuroleptic (Bush et al. 1996; Rosebush et al. 1990; Salam et al. 1987);
malignant syndrome. more lasting improvement may follow a course of ECT
Stupor of other cause is generally associated with a (Bush et al. 1996; Malur et al. 2001). Pending improve-
decreased level of consciousness, in contrast with the alert- ment, a careful watch must be maintained for dehydration,
ness seen in catatonia. Furthermore, in stupor eye move- deep venous thrombosis with pulmonary embolism, and
ments may be roving, in contrast with the preservation of aspiration pneumonia.
saccadic eye movements in catatonia. Excited catatonia, as noted above, is seen almost exclu-
Akinetic mutism, being characterized by immobility sively in schizophrenia, and treatment proceeds as outlined
and mutism in an alert patient, is clearly quite similar to in Section 20.1.
catatonia, and the clinical distinction may rest on the
demonstration of waxy flexibility or associated catatonic
3.12 ASTERIXIS
symptoms, such as posturing, echo phenomena or nega-
tivism – symptoms not seen in akinetic mutism.
Asterixis, first described by Adams and Foley in 1953, is a
Abulia, may, at first glance, appear similar to catatonia,
very important diagnostic sign as, in most cases, it indi-
in that abulic patients, lacking any motivation or initiative,
cates a metabolic encephalopathy due to hepatic, renal, or
may be immobile. The diagnosis is readily apparent upon
respiratory failure.
merely urging the patient to act: the abulic patient will
comply, and continue to comply, with instructions (pro-
vided that supervision is ongoing), whereas with the cata- Clinical features
tonic patient there will be no response.
The neuroleptic malignant syndrome may be included in Asterixis represents a precipitous loss of muscle tone
the differential when patients are treated with antipsychotics. (Adams and Foley 1949; Leavitt and Tyler 1964) and is
p 03.qxd 3/10/08 9:32 AM Page 97
3.13 Mirror movements 97
typically tested for by asking patients to hold their arms a stroke syndrome, although occasionally bilateral, is, in the
straight to the front with the hands hyperextended at the vast majority of cases, unilateral. Thus, if a patient has uni-
wrist as far back as possible, and holding that position for lateral asterixis, the presumption must be that it is occurring
at least 30 seconds. When asterixis is present, there will be secondary to infarction or hemorrhage in one of the areas
arrhythmically occurring ‘flaps’ of the hands down, fol- described below.
lowed, after a brief, but distinct, moment, by recovery back Of the metabolic encephalopathies, hepatic encephalopa-
to the hyperextended position; although in most cases both thy is so commonly associated with asterixis that, for a
hands will ‘flap’ down simultaneously, occasionally aster- time, the term ‘liver flap’ was used as a synonym for aster-
ixis will be strictly unilateral, a finding with, as discussed ixis. Uremic encephalopathy is almost always associated
below, considerable diagnostic significance. In cases where with asterixis; in cases of respiratory failure, however, it
patients are unable to hold their arms forward, an alterna- may be less common.
tive approach to eliciting asterixis involves having the Of the medications capable of causing asterixis as a side-
patient rest the arms prone on the bed and then asking him effect, the AEDs and lithium are the most frequent offend-
or her to hyperextend the hands off the bed, again holding ers, with the other agents only uncommonly being
that position for at least 30 seconds. implicated. Metrizamide myelography may be followed by
a delirium accompanied by asterixis.
Infarction or hemorrhage of the cortex (most com-
Etiology monly the frontal cortex), basal ganglia, internal capsule,
thalamus, midbrain, pons, and cerebellum may each cause
As noted in Table 3.12, asterixis may be seen in the course of asterixis, which, as noted above, is generally unilateral, and,
a metabolic encephalopathy, such as hepatic encephalopa- with the exception of cerebellar lesions, is contralateral to
thy, as a side-effect to various medications, and during the the lesion (Degos et al. 1979; Kim et al. 2001b; Rio et al.
course of stroke due either to infarction or hemorrhage. 1995; Stell et al. 1994; Tatu et al. 2000). Notably, of all these
From a diagnostic point of view it is critical to keep in mind areas, it is the thalamus that is most commonly involved.
whether the asterixis is bilateral or unilateral. Asterixis
occurring in the course of a metabolic encephalopathy or as
a side-effect is always bilateral; asterixis occurring as part of Differential diagnosis
Table 3.12 Causes of asterixis Myoclonus is distinguished by the fact that it represents
not an abrupt loss of tone with a ‘flap’ down but rather an
Metabolic encephalopathy abrupt gain of tone with a resultant ‘jerk’. Tremor is distin-
Hepatic encephalopathy (Adams and Foley 1949, 1953; Read guished by the presence of a more or less rhythmic oscilla-
et al. 1961) tory movement secondary to alternating contraction of
Uremic encephalopathy (Mahoney and Arieff 1982; Raskin and agonist and antagonist musculature.
Fishman 1976; Tyler 1965)
Respiratory failure (Austen et al. 1957; Bacchus 1958)
Treatment
Medication side-effect
Phenytoin (Chi et al. 2000; Murphy and Goldstein 1974)
Treatment is directed at the underlying condition; sympto-
Carbamazepine (Rittmannsberger and Lebihuber 1992)
matic treatment is not required.
Gabapentin (Babiy et al. 2005)
Pregabalin (Heckmann et al. 2005)
Valproate (Bodensteiner et al. 1981) 3.13 MIRROR MOVEMENTS
Lithium (Stewart and Williams 2000)
Levodopa (Glantz et al. 1982) Mirror movements are normal in early childhood and may
Clozapine (Rittsmannberger 1996) persist into adult years; they may also be seen in certain
Trimethoprim/sulfamethoxazole (Dib et al. 2004) disorders, for example stroke with hemiparesis.
Ifosfamide (Meyer et al. 2002)
Metrizamide (Bertoni et al. 1981)
Infarction or hemorrhage
Clinical features
Cortex
Mirror movements are typically seen in the hands, and
Basal ganglia
may in some cases involve the arm. They may be elicited by
Internal capsule
asking patients to perform a fine motor task with one
Thalamus
hand, for example sequential finger–thumb apposition. As
Midbrain
the patient performs the maneuver, simply observe the
Pons
other hand for the mirrored movement. With hemiparetic
Cerebellum
patients, a simpler strategy involves telling the patient you
p 03.qxd 3/10/08 9:32 AM Page 98
are going to test grip strength in one hand at a time. Then Table 3.13 Causes of pathologic startle
place the second and third fingers of each of your hands Post-traumatic stress disorder
into the patient’s hands and ask the patient to grip with Generalized anxiety disorder
only one hand. Mirror gripping may then be appreciated in Alcohol or sedative hypnotic withdrawal
the other hand. Interestingly, such mirroring in hemi-
paretic patients is most commonly seen in the unaffected Sympathomimetics
hand (Nelles et al. 1998). Hyperekplexia (Brown et al. 1991; Saenz-Lope et al. 1984;
Tijssen et al. 2002)
Brainstem lesions (see text)
Etiology Post-anoxic encephalopathy (Brown et al. 1991)
Traumatic brain injury (Brown et al. 1991)
Mirror movements, as noted, are normal in young children, Creutzfeldt–Jakob disease (Hansen et al. 1998)
and may persist into adult years; in some cases a familial ‘Jumping Frenchmen of Maine’ (Saint-Hilaire et al. 1986)
tendency is noted (Rasmussen 1993). Mirror movements Latah (Bartholomew 1994)
may also be seen in Kallmann’s syndrome (Krams et al. Myriachit (Stevens 1965)
1999), the Klippel–Feil syndrome, Parkinson’s disease
(Espay et al. 2005b) and, most notably, in stroke patients
with hemiparesis (Nelles et al. 1998). hyperactivity, with anxiety and a greater or lesser degree of
tremulousness, as this persistent state is characteristic of
the most common causes of pathologic startle, namely post-
traumatic stress disorder, generalized anxiety disorder,
alcohol or sedative-hypnotic withdrawal, and various sym-
There is no other sign or symptom that mimics mirror
pathomimetics, such as caffeine (Howard and Ford 1992).
movements.
The other conditions listed in Table 3.13 generally do
not leave the patient with persistent autonomic symptoms.
Treatment Hyperekplexia is an inherited disorder, generally following
an autosomal dominant pattern, which, in the ‘major’
Treatment is rarely required; anecdotally, motor retraining form, has an onset in early infancy, and in the ‘minor’ form,
has been successful (Cincotta et al. 2003). in childhood. Brainstem lesions may also cause pathologic
startle, and this has been noted with pontine lesions, such
as infarction (Kimber and Thompson 1997) or a plaque of
3.14 PATHOLOGIC STARTLE multiple sclerosis (Ruprecht et al. 2002), or with upper
medullary lesions, such as demyelinization (Della Marca
Although a startle response is a normal human reaction, in et al. 2007); compression of either the pons (Gambardella
some cases it may, in one fashion or another, be exagger- et al. 1999) or medulla (Salvi et al. 2000) by an ectatic
ated, in which case it is appropriate to speak of ‘pathologic artery may also be at fault. Post-anoxic encephalopathy,
startle’. traumatic brain injury, and Creutzfeldt–Jakob disease may
all be associated with startle, and the diagnosis is suggested
by the associated cognitive deficits.
Clinical features Finally, there are several ‘culture-bound’ syndromes
wherein individuals who are normally shy, may, in
The startle response is a brief, but sudden and violent, reac- response to an unexpected and ‘startling’ stimulus, engage
tion to an unexpected stimulus, such as a loud noise or a in remarkable behavior characterized not only by patho-
bright light; in severe cases, a mere touch, as a tap on the logic startle, but also by other distinctive behaviors, such as
shoulder, may be sufficient. During the startle response, cursing, swearing and, at times, echolalia. These are gener-
the eyes blink, the face contorts in a grimace, there is flex- ally considered voluntary behaviors and have been noted,
ion of the neck and trunk, and flexion and abduction of the famously, among French–Canadian lumberjacks of the
arms; in severe cases, patients may be thrown off balance nineteenth century (the ‘Jumping Frenchmen of Maine’),
and fall. and in residents of Malaysia (where it is referred to as
‘latah’) and Siberia (where it has been termed ‘myriachit’).
Etiology
The various causes of pathologic startle are listed in
Table 3.13; in pursuing this differential, the first step is A startle reaction is a normal human response, and can be
to ascertain whether or not in between the episodes of elicited in most individuals by a stimulus such as an unex-
pathologic startle there is a persistent state of autonomic pected gunshot; pathologic startle should be considered
p 03.qxd 3/10/08 9:32 AM Page 99
References 99
present only when the startle response is severe, frequent, Alberca RA, Chinchon I, Vadillo J et al. Late onset parkinsonian
and provoked by relatively minor stimuli. syndrome in Hallervorden–Spatz Disease. J Neurol Neurosurg
Startle epilepsy (Aguglia et al 1984; Gimenez-Roldan Psychiatry 1987; 50:1665–8.
and Martin 1980; Manford et al. 1996; Saenz-Lope et al. Alevizos B, Papageorgiou C, Christodoulou GN. Acute dystonia
1984) may be confused with pathologic startle. Startle caused by a low dosage of olanzapine. J Neuropsychiatr Clin
epilepsy represents a form of reflex epilepsy, wherein a Neurosci 2003; 15:241.
startling stimulus is followed first by a startle response and Alpers BJ, Patten CA. Paroxysmal spasm of the eyelids as a
then by a tonic seizure. The differential is fairly easy if the postencephalitic manifestation. Arch Neurol Psychiatry 1927;
patient is observed, and on two counts: first, in the tonic 18:427–32.
seizure, one sees, not flexion, but extension; second, there Altindag A, Yanik M, Asoglu M. The emergence of tics during
is loss of consciousness during the tonic seizure. escitalopram and sertraline treatment. Int Clin
Psychopharmacol 2005; 20:177–8.
Angelini L, Sgro V, Erba A et al. Tourettism as clinical presentation
Treatment of Huntington’s disease with onset in childhood. Ital J Neurol
Sci 1988; 19:383–5.
Treatment is directed at the underlying cause; when this is Antin SP, Prockop LD, Cohen SM. Transient hemiballism.
ineffective, clonazepam may be utilized. Neurology 1967; 17:1068–72.
Armon C, Shin C, Miller P et al. Reversible parkinsonism and
cognitive impairment with chronic valproate use. Neurology
REFERENCES 1996; 47:626–35.
Aronson MJ, Thompson SV. Complications of acute catatonic
Abad V, Ovsiew F. Treatment of persistent myoclonic tardive excitement. Am J Psychiatry 1950; 107:216–20.
dystonia with verapamil. Br J Psychiatry 1993; 162:554–6. Asmus F, Zimprich A, Tezenas du Montcel S et al. Myoclonus-
Abd El Naby S, Hassanein M. Neuropsychiatric manifestations of dystonia syndrome: epsilon-sarcoglycan mutations and
chronic manganism. J Neurol Neurosurg Psychiatry 1965; phenotype. Ann Neurol 2002; 52:489–92.
28:282–5. Atasoy N, Ustundag Y, Konuk N et al. Acute dystonia
Abrams R, Taylor MA. Catatonia. A prospective clinical study. Arch during pegylated interferon alpha therapy in a case with
Gen Psychiatry 1976; 33:579–81. chronic hepatitis B infection. Clin Neuropharmacol 2004;
Adams RD, Foley J. The neurological changes in the more 27:105–7.
common types of liver disease. Trans Am Neurol Assoc 1949; Austen FK, Carmichael MW, Adams RD. Neurologic manifestations
74:217–19. of chronic pulmonary insufficiency. N Engl J Med 1957;
Adams RD, Foley JM. The neurological disorder associated 257:579–90.
with liver disease. Assoc Res Nerv Ment Dis Proc 1953; Ayd FJ. A survey of drug-induced extrapyramidal reactions. J Am
32:198–237. Med Assoc 1961; 175:1054–60.
Adler LA, Angrist B, Peselow E et al. Efficacy of propranolol in Babiy M, Stubblefield MD, Herklotz M et al. Asterixis related to
neuroleptic-induced akathisia. J Clin Psychopharmacol 1985; gabapentin as a cause of falls. Am J Phys Med Rehabil 2005;
5:164–6. 84:136–40.
Adler LA, Angrist B, Peselow E et al. Controlled assessment of Bacchus M. Encephalopathy and pulmonary disease. Arch Int Med
propranolol in the treatment of neuroleptic-induced akathisia. 1958; 102:194–8.
Br J Psychiatry 1986; 149:42–5. Bachman DS. Pemoline-induced Tourette’s disorder: a case report.
Adler LA, Angrist B, Weinreb H et al. Studies on the time course Am J Psychiatry 1981; 138:1116–17.
and efficacy of beta-blockers in neuroleptic-induced akathisia Bain PG, Findley LJ, Britton TC et al. Primary writing tremor. Brain
and the akathisia of idiopathic Parkinson’s disease. 1995; 118:1461–72.
Psychopharmacol Bull 1991; 27:107–11. Bak TH, Bauer M, Schaub RT et al. Myoclonus in patients treated
Adler LA, Peselow E, Rosenthal M et al. A controlled comparison with clozapine: a case series. J Clin Psychiatry 1995;
of the effects of propranolol, benztropine and placebo on 56:418–22.
akathisia: an interim analysis. Psychopharmacol Bull 1993; Baldassano CF, Truman CJ, Nierenberg A et al. Akathisia: a review
29:283–6. and case report following paroxetine treatment. Compr
Aguglia U, Tinuper P, Gastaut H. Startle-induced epileptic Psychiatry 1996; 37:122–4.
seizures. Epilepsia 1984; 25:712–20. Ballard PA Tetrud JW, Langston JW. Permanent human
Ahmed S, Chengappa KN, Naidu VR et al. Clozapine-withdrawal- parkinsonism due to 1-methyl-4-phenyl-
emergent dystonias and dykinesias: a case series. J Clin 1,2,3,6–tetrahydropyridine (MPTP): seven cases. Neurology
Psychiatry 1998; 59:472–7. 1985; 35:949–56.
Akhtar S, Ahmad H. Ciprofloxacin-induced catatonia. J Clin Barak Y, Levine J, Weisz R. Clozapine-induced myoclonus: two
Psychiatry 1993; 54:115–16. case reports. J Clin Psychopharmacol 1996; 16:339–40.
Alarcon F, Tolosa E, Munoz E. Focal limb dystonia in a patient Barclay CL, Lang AE. Dystonia in progressive supranuclear palsy.
with a cerebellar mass. Arch Neurol 2001; 58:1125–7. J Neurol Neurosurg Psychiatry 1997; 62:352–6.
p 03.qxd 3/10/08 9:32 AM Page 100
Barnes MP, Saunders M, Walls TJ et al. The syndrome of Karl Bleuler E. Textbook of psychiatry, 1924, translated by Brill AA.
Ludwig Kahlbaum. J Neurol Neurosurg Psychiatry 1986; New York: Arno Press, 1976.
49:991–6. Blunt SB, Lane RJ, Turjanski N et al. Clinical features and
Bartholomew RE. Disease, disorder or deception? Latah as management of two cases of encephalitis lethargica. Mov
habit in a Malay extended family. J Nerv Ment Dis 1994; Disord 1997; 12:354–9.
182:331–8. Bocola V, Fabbrini G, Sollecito A et al. Neuroleptic induced
Barucha KJ, Sethi DD. Complex movement disorders induced by parkinsonism: MRI findings in relation to clinical course after
fluoxetine. Mov Disord 1996; 11:324–6. withdrawal of neuroleptic drugs. J Neurol Neurosurg
Bataller L, Graus F, Salz A et al. Clinical outcome in adult-onset Psychiatry 1996; 60:213–16.
idiopathic or paraneoplastic opsoclonus-myoclonus. Brain Bodensteiner JB, Morris HH, Golden GS. Asterixis associated with
2001; 124:437–43. sodium valproate. Neurology 1981; 31:194–5.
Becher MW, Rubinsztein DC, Leggo J et al. Dentatorubral and Boecker H, Weindl A, Leenders K et al. Secondary parkinsonism
pallidoluysian atrophy (DRPLA): clinical and neuropathological due to focal substantia nigra lesions: a PET study with
findings in genetically confirmed North American and [18F]FDG and [18F]flourodopa. Acta Neurol Scand 1996;
European pedigrees. Mov Disord 1997; 12:519–30. 93:387–92.
Behan PO, Bone I. Hereditary chorea without dementia. J Neurol Boesch SM, Wenning GK, Ransmayr G et al. Dystonia in multiple
Neurosurg Psychiatry 1977; 40:687–91. system atrophy. J Neurol Neurosurg Psychiatry 2002;
Benesch CG, McDaniel KD, Coc C et al. End-stage Alzheimer’s 73:300–3.
disease: Glasgow coma scale and neurologic examination. Boeve BF, Tremont-Lukats IW, Waclawik AJ et al. Longitudinal
Arch Neurol 1993; 50:1309–15. characteristics of two siblings with frontotemporal dementia
Benito-Leon J, Rodriguez J, Orti-Pareja M et al. Symptomatic and parkinsonism linked to chromosome 17 associated with
orthostatic tremor in pontine lesions. Neurology 1997; the S305N tau mutation. Brain 2005; 128:752–72.
49:1439–41. Bond ED. Epidemic encephalitis and katatonic symptoms. Am J
Berkovic SF, Carpenter S, Andermann F et al. Kufs’ disease: a Insanity 1920; 76:261–4.
critical reappraisal. Brain 1988; 111:27–62. Borgohain R, Singh AK, Thadani R et al. Hemiballismus due to
Berkovic SF, Carpeneter S, Evans A et al. Myoclonus epilepsy and an ipsilateral striatal hemorrhage: an unusual localization.
ragged-red fibers (MERRF). Brain 1989; 112:1231–60. J Neurol Sci 1995; 130:22–4.
Berry N, Sagar R, Tripathi BM. Catatonia and other psychiatric Bort RF. Catatonia, gastric hyperacidity, and fatal aspiration: a
symptoms with vitamin B12 deficiency. Acta Psychiatr Scand preventable syndrome. Am J Psychiatry 1976; 133:446–7.
2003; 108:156–9. Bourgeois M, Bouilh P, Tignol J et al. Brief communication:
Bertoni JM, Schwartzman RJ, Van Horn G et al. Asterixis and spontaneous dyskinesias vs. neuroleptic-induced dyskinesias in
encephalopathy following metrizamide myelography: 270 elderly subjects. J Nerv Ment Dis 1980; 168:177–8.
investigations into possible mechanisms and review of the Boyer WF, Bakalar NH, Lake CR. Anticholinergic prophylaxis of
literature. Ann Neurol 1981; 9:366–70. acute haloperidol-induced dystonic reactions. J Clin
Bharucha KJ, Sethi KD. Tardive Tourettism after exposure to Psychopharmacol 1987; 7:164–6.
neuroleptic therapy. Mov Disord 1995; 10:791–3. Brashear A, Farlow MR, Butler I et al. Variable phenotype of
Bharucha KJ, Sethi KD. Complex movement disorders induced by rapid-onset dystonia–parkinsonism. Mov Disord 1996;
fluoxetine. Mov Disord 1996; 11:324–6. 11:151–6.
Bhatia KP, Soland VL, Bhatt MH. Paroxysmal exercize-induced Brashear A, DeLeon D, Bressman SB et al. Rapid-onset
dystonia: eight new sporadic cases and a review of the dystonia–parkinsonism in a second family. Neurology 1997;
literature. Mov Disord 1997a; 12:1007–12. 48:1066–9.
Bhatia KP, Quinn NP, Marsden CD. Clinical features and natural Brashear A, Dubyns WB, de Carvhalo Aguiar P et al. The
history of axial predominant adult onset primary dystonia. phenotypic spectrum of rapid onset dystonia-parkinsonism
J Neurol Neurosurg Psychiatry 1997b; 63:788–91. (RDP) and mutations in the ATP1A3 gene. Brain 2007;
Bhatt MH, Obeso JA, Marsden CD. Time course of postanoxic 130:828–35.
akinetic–rigid and dystonic syndromes. Neurology 1993; Braude WM, Barnes TRE, Gore SM. Clinical characteristics of
43:314–17. akathisia: a systematic investigation of acute psychiatric
Bhatt MH, Elias MA, Mankodi AK. Acute and reversible in-patient admissions. Br J Psychiatry 1983; 143:139–50.
parkinsonism due to organophosphate pesticide intoxication. Bressman SB, Fahn S, Burke RE. Paroxysmal non-kinesigenic
Five cases. Neurology 1999; 52:1467–71. dystonia. Adv Neurol 1988; 50:403–13.
Biggins CA, Boyd JL, Harrop FM et al. A controlled, longitudinal Brin MF, Blitzer A, Stewart C. Laryngeal dystonia (spasmodic
study of dementia in Parkinson’s disease. J Neurol Neurosurg dysphonia): observations of 901 patients and treatment with
Psychiatry 1992; 55:566–71. botulinum toxin. Adv Neurol 1998; 78:237–52.
Bird MT, Paulson JW. The rigid form of Huntington’s chorea. Brown P, Cathala F, Castaigne P et al. Creutzfeldt–Jakob disease:
Neurology 1971; 21:271–6. clinical analysis of a consecutive series of 230
Bland EF, Jones TD. The natural history of rheumatic fever: a 20 neuropathologically verified cases. Ann Neurol 1986;
year perspective. Ann Int Med 1952; 37:1006–26. 20:597–602.
p 03.qxd 3/10/08 9:32 AM Page 101
References 101
Brown P, Rothwell JC, Thompson PD et al. The hyperekplexias and Cardoso F, Veado CCM, de Oliveira JT. A Brazilian cohort of
their relationship to the normal startle reflex. Brain 1991; patients with Tourette’s syndrome. J Neurol Neurosurg
114:1903–28. Psychiatry 1996; 60:209–12.
Bruetsch WL, Williams CL. Arteriosclerotic muscular rigidity with Cardoso F, Eduardo C, Silva AP et al. Chorea in fifty consecutive
special reference to gait disturbances. Am J Psychiatry 1954; patients with rheumatic fever. Mov Disord 1997; 12:701–3.
111:332–6. Carella F, Grassi MP, Savoiardo M et al. Dystonic-parkinsonian
Bruno MK, Hallett M, Gwinn-Hardy K et al. Clinical evaluation of syndrome after cyanide poisoning: clinical and MRI findings.
idiopathic paroxysmal kinesigenic dyskinesia. New diagnostic J Neurol Neurosurg Psychiatry 1988; 51:1345–8.
criteria. Neurology 2004; 63:2280–7. Carlen PL, Lee MA, Jacob M et al. Parkinsonism provoked by
Bruno MK, Lee H-Y, Auberger GWJ et al. Genotype–phenotype alcoholism. Ann Neurol 1981; 9:84–6.
correlation of paroxysmal non-kinesigenic dyskinesia. Carlson CD, Cavazzoni PA, Berg PH et al. An integrated analysis of
Neurology 2007; 68:1782–9. acute treatment-emergent extrapyramidal syndrome in
Bucher SF, Seelos KC, Dodel RC et al. Pallidal lesions: structural patients with schizophrenia during olanzapine clinical trials:
and functional magnetic resonance imaging. Arch Neurol comparisons with placebo, haloperidol, risperidone or
1996; 53:682–6. clozapine. J Clin Psychiatry 2003; 64:898–906.
Budman C, Sarcevic A. An unusual case of motor and vocal tics Carpenter MB. Ballism associated with partial destruction of the
with obsessive-compulsive symptoms in a young adult with subthalamic nucleus of Luys. Neurology 1955; 5:479–89.
Behcet’s syndrome. CNS Spectr 2002; 7:878–81. Carpenter MR. Athetosis and the basal ganglia. Arch Neurol 1950;
Buetefisch CM, Gutierrez A, Gutmann L. Choreoathetotic 63:895–901.
movements: a possible side-effect of gabapentin. Neurology Casas M, Garcia-Ribera C, Alvarez E et al. Myoclonic movements
1996; 46:851–2. as a side-effect of treatment with therapeutic doses of
Burd L, Kerbeshian J, Fisher W et al. Anticonvulsant medications: clomipramine. Int J Psychopharmacol 1987; 2:333–6.
an iatrogenic cause of tic disorders. Can J Psychiatry 1986; Castillo E, Rubin RT, Holsboer-Trachsler E. Clinical differentiation
31:419–23. between lethal catatonia and neuroleptic malignant
Burguera JA, Bataller L, Valero C. Action hand dystonia after syndrome. Am J Psychiatry 1989; 146:324–8.
cortical parietal infarction. Mov Disord 2001; 16:1183–5. Castillo P, Woodruff B, Caselli R et al. Steroid-responsive
Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patients encephalopathy associated with autoimmune thyroiditis.
with ‘static’ encephalopathy. J Neurol Neurosurg Psychiatry Arch Neurol 2006; 63:197–202.
1980; 43:789. Catalano G, Grace JW, Catalano MC et al. Acute akathisia
Burke RE, Fahn S, Jankovic J et al. Tardive dystonia: late-onset and associated with quetiapine use. Psychosomatics 2005;
persistent dystonia caused by antipsychotic drugs. Neurology 46:291–301.
1982; 32:1335–46. Caviness JN, Evidente VG. Cortical myoclonus during lithium
Burke RE, Kang UJ, Jankovic J et al. Tardive akathisia: an analysis exposure. Arch Neurol 2003; 60:401–4.
of clinical features and response to open therapeutic trials. Cervera R, Asherson RA, Font J et al. Chorea in the
Mov Disord 1989; 4:147–75. antiphospholipid syndrome. Clinical, radiologic, and
Burkhard PR, Delavelle J, Du Pasquier R et al. Chronic immunologic characteristics of 50 patients from our clinics
parkinsonism associated with cirrhosis: a distinct subset of and the recent literature. Medicine 1997; 76:203–12.
acquired hepatocerebral degeneration. Arch Neurol 2003; Chan DB, Lang MF, Fahn S. Idiopathic cervical dystonia. Mov
60:521–8. Disord 1991; 6:119–26.
Bush G, Fink M, Pertrides G et al. Catatonia. II. Treatment with Chandra V, Wharton S, Spunt AL. Amelioration of hemiballismus
lorazepam and electroconvulsive therapy. Arch Psychiatr Scand with sodium valproate. Ann Neurol 1982; 12:407.
1996; 9:137–43. Chang M-H, Li J-Y, Lee S-R et al. Non-ketotic hyperglycaemic
Byrne EJ, Lennox G, Lowe J et al. Diffuse Lewy body disease: chorea: a SPECT study. J Neurol Neurosurg Psychiatry 1996;
clinical features in 15 cases. J Neurol Neurosurg Psychiatry 60:428–30.
1989; 52:709–17. Charles JR. Manganese toxaemia, with special reference to the
Cammarota A, Gershank OS, Garcia S et al. Cervical dystonia due effects of liver feeding. Brain 1927; 50:30–43.
to spinal cord ependymoma: involvement of cervical cord Chen D-H, Matsushita M, Rainier S et al. Presence of alanine-to-
segments in the pathogenesis of dystonia. Mov Disord 1995; valine substitutions in myofibrillogenesis regulator 1 in
10:500–3. paroxysmal nonkinesigenic dyskinesia. Arch Neurol 2005;
Campbell AMG, Corner B, Norman RM et al. The rigid form of 62:597–600.
Huntington’s disease. J Neurol Neurosurg Psychiatry 1961; Chen J-Y, Stern Y, Sano M et al. Cumulative risks of developing
24:71–7. extrapyramidal signs, psychosis, or myoclonus in the course of
Caparros-Lefebvre D, Deleume JF, Bradai N et al. Ballism caused Alzheimer’s disease. Arch Neurol 1991; 48:1141–3.
by bilateral infarction in the substantia nigra. Mov Disord Chi WM, Chua kS, Kong KH. Phenytoin-induced asterixis –
1994; 9:108. uncommon or underdiagnosed? Brain Inj 2000; 14:847–50.
Cardoso F, Jankovic J. Cocaine-related movement disorders. Mov Chiu LPW. Transient recurrence of auditory hallucinations during
Disord 1993; 8:175–8. acute dystonia. Br J Psychiatry 1989; 155:110–13.
p 03.qxd 3/10/08 9:32 AM Page 102
Choi IS. Delayed neurologic sequelae in carbon monoxide Crystal HA. Baclofen therapy may be associated with chorea in
intoxication. Arch Neurol 1983; 40:433–5. Alzheimer’s disease. Ann Neurol 1990; 28:839.
Chokroverty S, Bruetman ME, Berger V et al. Progressive dialytic Crystal HA, Dixon DW, Lizardi JE et al. Antemortem diagnosis of
encephalopathy. J Neurol Neurosurg Psychiatry 1976; diffuse Lewy body disease. Neurology 1990; 40:1523–8.
39:411–19. Cubo E, Gracies JM, Benabou R et al. Early morning off-
Chouinard MJ, Nguyen DK, Clement JF et al. Catatonia induced by medication dyskinesias, dystonia, and choreic subtypes. Arch
levertiracetam. Epilepsy Behav 2006; 8:303–7. Neurol 2001; 58:1379–82.
Chouinard S, Ford B. Adult onset tic disorders. J Neurol Neurosurg Cunningham MA, Darby DG, Donnan GA. Controlled-release
Psychiatry 2000; 68:738–43. delivery of L-dopa associated with nonfatal hyperthermia,
Choy-Kwong M, Lipton RB. Dystonia related to cocaine rigidity and autonomic dysfunction. Neurology 1991;
withdrawal: a case report and pathogenic hypothesis. 41:942–3.
Neurology 1989; 39:996–7. Dale RC, Church AJ, Heyman I. Striatal encephalitis after varicella
Christodoulou C, Kalaitzi C. Antipsychotic drug-induced acute zoster infection complicated by Tourettism. Mov Disord 2003;
laryngeal dystonia: two case reports and a mini review. 18:1554–6.
J Psychopharmacol 2005; 19:307–11. Danek A, Tison F, Rubio J et al. The chorea of McLeod syndrome.
Chu K, Kang DW, Kim DE et al. Diffusion-weighted and gradient Mov Disord 2001; 16:882–9.
echo magnetic resonance findings of hemichorea- Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological
hemiballismus associated with diabetic hyperglycemia: a specturm of Steele–Richardson–Olszewski syndrome
hyperviscosity syndome? Arch Neurol 2002; 59:448–52. (progressive supranuclear palsy): a reappraisal. Brain 1995;
Chudnow RS, Dewey RB, Lawson CR. Choreoathetosis as a 118:759–70.
side-effect of gabapentin therapy in severely neurologically Daras M, Koppel BS, Atos-Radzion E. Cocaine-induced
impaired patients. Arch Neurol 1997; 54:910–12. choreoathetoid movements (‘crack dancing’). Neurology 1994;
Chung SJ, Im JH, Lee MC et al. Hemichorea after stroke: clinical- 44:751–2.
radiological correlation. J Neurol 2004; 251:725–9. Davis EJB, Borde M. Wilson’s disease and catatonia. Br J
Cincotta M, Borgheresi A, Balzini L et al. Separate ipsilateral and Psychiatry 1993; 162:256–9.
contralateral corticospinal projections in congenital mirror Davis JM. Response of hemiballismus to haloperidol. JAMA 1976;
movements: neurophysiological evidence and significance for 235:281–2.
motor rehabilitation. Mov Disord 2003; 18:1294–1300. Davous P, Rondot P, Marion MH et al. Severe chorea after acute
Clark CM, Ewbank D, Lerner A et al. The relationship between carbon monoxide poisoning. J Neurol Neurosurg Psychiatry
extrapyramidal signs and cognitive performance in patients 1986; 49:206–8.
with Alzheimer’s disease enrolled in the CERAD study. Dawson JR. Cellular inclusions in cerebral lesions of epidemic
Neurology 1997; 49:70–5. encephalitis. Arch Neurol Psychiatry 1934; 31:685–700.
Cohen LG, Hallett M. Hand cramps: clinical features and DeCastro RM. Antidepressants and myoclonus: case report. J Clin
electromyographic patterns in a focal dystonia. Neurology Psychiatry 1985; 46:284–7.
1988; 38:1005–12. Defazio G, Berardelli A, Abruzzese G et al. Risk factors for spread
Collins SJ, Ahlskog JE, Parisi JE et al. Progressive supranuclear of blepharospasm: a multicentre investigation of the Italian
palsy: neuropathologically based diagnostic clinical criteria. movement disorders study group. J Neurol Neurosurg
J Neurol Neurosurg Psychiatry 1995; 58:167–73. Psychiatry 1999; 67:613–19.
Colosimo C, Albanese A, Hughes AJ et al. Some specific clinical Defebvre L, Destee A, Cassim F et al. Transient hemiballism and
features differentiate multiple system atrophy (striatonigral striatal infarct. Stroke 1990; 21:967–8.
variety) from Parkinson’s disease. Arch Neurol 1995; 52:294–8. Degos J-D, Verroust J, Bouchareine A et al. Asterixis in focal brain
Comella CL, Goetz CG. Akathisia in Parkinson’s disease. Mov lesion. Arch Neurol 1979; 36:705–7.
Disord 1994; 9:545–9. De La Sayettte V, Schaeffer S, Querel C et al. Lyme
Creak M, Guttmann E. Chorea, tic, compulsive utterances. J Ment neuroborreliosis presenting with propriospinal myoclonus.
Sci 1935; 81:834–9. J Neurol Neurosurg Psychiatry 1996; 64:420.
Crespel A, Genton P, Berrandame M et al. Lamotrigine associated Della Marca G, Retuccia D, Mariotti P et al. Pathologic startle
with exacerbation or de novo myoclonus in idiopathic following brainstem lesion. Neurology 2007; 68:47.
generalized epilepsies. Neurology 2005; 65:762–4. Delwaide PJ, Desseilles M. Spontaneous buccolingualfacial
Critchley EMR, Clark DB, Wikler A. Acanthocytosis and dyskinesia in the elderly. Acta Neurol Scand 1977; 56:256–62.
neurological disorder without abetalipoproteinemia. Arch Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical
Neurol 1968; 18:134–40. features and classification. Ann Neurol 1995; 38:571–9.
Croteau D, Owainati A, Dalmau J et al. Response to cancer therapy Denckla MB, Bemporad JR, MacKay MC. Tics following
in a patient with a paraneoplastic choreiform disorder. methylphenidate administration: a report of 20 cases. JAMA
Neurology 2001; 57:719–22. 1976; 235:1349–51.
Crozier S, Lehericy S, Verstichel P et al. Transient Dennis MS, Byrne EJ, Hopkinson EN et al. Neuropsychiatric
hemiballism/hemichorea due to ipsilateral subthalamic systemic lupus erythematosis in elderly people: a case series.
nucleus infarction. Neurology 1996; 46:267–8. J Neurol Neurosurg Psychiatry 1992; 55:1157–61.
p 03.qxd 3/10/08 9:32 AM Page 103
References 103
Desarkar P, Thakur A, Sinha V. Aripiprazole-induced acute Eisenhauer G, Jermain DM. Fluoxetine and tics in an adolescent.
dystonia. Am J Psychiatry 2006; 163:1112–13. Ann Pharmacother 1993; 27:725–6.
Deshmukh DK, Joshi VS, Agarwal MR. Rabbit syndrome – a rare Engel J, Ludwig BI, Fetell M. Prolonged partial complex status
complication of long-term neuroleptic medication. Br J epilepticus: EEG and behavioral observations. Neurology 1978;
Psychiatry 1990; 157:293. 28:863–9.
Detweiller MB, Harpold GJ. Bupropion-induced acute dystonia. Ernst NH, Steur J. Increase of parkinsonian disability after
Ann Pharmacother 2002; 36:251–4. fluoxetine medication. Neurology 1993; 43:211–13.
Deuschl G, Koester B, Luecking CH et al. Diagnostic and Espay AJ, Hung SW, Sanger TD et al. A writing device improves
pathophysiological aspects of psychogenic tremor. Movement writing in primary writing tremor. Neurology 2005a;
Disord 1998; 13:294–302. 64:1648–50.
Dewey RB, Jankovic J. Hemiballism–hemichorea. Clinical and Espay AJ, Li JY, Johnston L et al. Mirror movements in
pharmacologic findings in 21 patients. Arch Neurol 1989; parkinsonism: evaluation of a new clinical sign. J Neurol
46:862–7. Neurosurg Psychiatry 2005b; 76:1355–8.
Dib E, Bernstein S, Benesch C. Multifocal myoclonus induced by Evidente VG, Gwinn-Hardy K, Caviness JN et al. Risperidone is
trimethoprim-sulfamethoxazole in a patient with nocardia effective in severe hemichorea/hemiballismus. Mov Disord
infection. N Engl J Med 2004; 350:88–9. 1999; 14:377–9.
Dickoff DJ, Raps M, Yahr MD. Striatal syndrome following Evidente VG, Advincula J, Esteban R et al. Phenomenology of
hyponatremia and its rapid correction: a manifestation of ‘Lubag’ or X-linked dystonia-parkinsonism. Mov Disord 2002;
extrapontine myelinolysis confirmed by magnetic resonance 17:1271–7.
imaging. Arch Neurol 1988; 45:112–14. Extein I. Methylphenidate-induced choreoathetosis. Am J
Digre KB. Opsoclonus in adults – report of three cases and review Psychiatry 1978; 135:252–3.
of the literature. Arch Neurol 1986; 43:1165–75. Factor SA, Moltho ES. Adult-onset tics associated with peripheral
DiMascio A, Bernardo DL, Greenblatt DJ et al. A controlled trial of injury. Mov Disord 1997; 12:1052–5.
amantadine in drug-induced extrapyramidal disorders. Arch Factor SA, Troche-Panetto M, Weaver SA. Dystonia in AIDS: report
Gen Psychiatry 1976; 33:599–602. of four cases Mov Disord 2003; 18:1492–8.
Doheny DO, Brin MF, Morrison CE et al. Phenotypic features of Federico P, Zochodne DW. Reversible parkinsonism and
myoclonus-dystonia in three kindreds. Neurology 2002; hyperammonemia associated with portal vein thrombosis.
59:1187–94. Acta Neurol Scand 2001; 103:198–200.
Dominguez-Moran JA, Callejo JM, Fernandex-Ruiz LC et al. Acute Federlein J, Postert Th, Allgeier A et al. Remitting parkinsonism as
paroxysmal dystonia induced by fluoxetine. Mov Disord 2001; a symptom of multiple sclerosis and the associated magnetic
16:767–9. resonance imaging findings. Mov Disorders 1997; 12:1090–1.
Donaldson IM, Espiner EA. Disseminated lupus erythematosus 1994; 241:537–42.
presenting as chorea gravidarum. Arch Neurol 1971; Feighner JP, Boyer WF, Tyler DL et al. Adverse consequences of
25:240–4. fluoxetine–MAOI combination therapy. J Clin Psychiatry 1990;
Dooling EC, Adams RD. Pathologic anatomy or posthemiplegic 51:222–5.
athetosis. Brain 1975; 98:29–48. Feinberg TE, Cianci CD, Morrow JS et al. Diagnostic tests for
Dooling EC, Schoene WC, Richardson EP. Halervorden–Spatz choreoacanthocytosis. Neurology 1991; 41:1000–6.
syndrome. Arch Neurol 1974; 30:70–83. Fenelon G, Houeto J-L. Unilateral parkinsonism following a
Drake RE, Ehrlich J. Suicide attempts associated with akathisia. large infarct in the territory of the lenticulostriate arteries.
Am J Psychiatry 1985; 142:499–501. Mov Disorders 1997; 12:1086–90.
Driesen JJ, Wolters EC. Bilateral ballism induced by oral Fermaglich J, Streib E, Auth T. Chorea associated with systemic
contraceptives J Neurol 1986; 233:379. lupus erythematosus. Arch Neurol 1973; 28:276–7.
Dufresne RL, Wagner RL. Antipsychotic-withdrawal akathisia Fernanadez M, Raskind W, Matsushita M et al. Hereditary benign
versus antipsychotic-induced akathisia: further evidence for chorea: clinical and genetic features of a distinct disease.
the existence of tardive akathisia. J Clin Psychiatry 1988; Neurology 2001; 57:106–10.
49:435–8. Feve AP, Fenelon G, Wallays C et al. Axial motor disturbances
Duvoisin RC, Yahr MD. Encephalitis and parkinsonism. Arch Neurol after hypoxic lesions of the globus pallidus. Mov Disord 1993;
1965; 12:227–39. 8:321–6.
Easterford K, Clugh P, Kellett M et al. Reversible parkinsonism Fidler SM, O’Rourke RA, Buchsbaum HW. Choreoathetosis as a
with normal beta-CIT-SPECT in patients exposed to sodium manifestation of thyrotoxicosis. Neurology 1971; 21:55–7.
valproate. Neurology 2004; 62:1435–7. Fink JK, Hedera P, Mathay JG et al. Paroxysmal dystonic
Edelstein H, Knight RT. Severe parkinsonism in two AIDS patients choreoathetosis linked to chromosome 2q: clinical
taking prochlorperazine. Lancet 1987; 2:341–2. analysis and proposed pathophysiology. Neurology 1997;
Edwards MJ, Dale RC, Church AJ et al. Adult-onset tic disorders, 49:177–83.
motor stereotypies, and behavioral disturbance associated Finlayson MH, Superville B. Distribution of cerebral lesions in
with antibasal ganglia antibodies. Mov Disord 2004; acquired hepatocerebral degeneration. Brain 1981;
19:1190–6. 104:79–95.
p 03.qxd 3/10/08 9:32 AM Page 104
Fischel T, Hermesh H, Aizenberg D et al. Cyproheptadine versus Ghika J, Bogousslavsky J. Spinal pseudoathetosis: a rare, forgotten
propranolol for the treatment of acute neuroleptic-induced syndrome, with a review of old and recent descriptions.
akathisia: a comparative double-blind study. J Clin Neurology 1997; 49:432–7.
Psychopharmacol 2001; 21:612–15. Ghika J, Bogousslavsky J, Henderson J et al. The ‘jerky dystonic
Fishbeck KH, Layzer RB. Paroxysmal choreoathetosis associated unsteady hand’: a delayed motor syndrome in posterior
with thyrotoxicosis. Ann Neurol 1979; 6:453–4. thalamic infarctions. J Neurol 1994; 241:537–42.
Flaherty JA, Lahmeyer HW. Larnyngeal–pharyngeal dystonia as a Ghika-Schmid F, Ghika J, Regli F et al. Hashimoto’s myoclonic
possible cause of asphyxia with haloperidol treatment. Am J encephalopathy: an underdiagnosed treatable condition? Mov
Psychiatry 1978; 135:1414–15. Disord 1996; 11:555–67.
Fleishman SB, Lavin MR, Sattler M et al. Antiemetic-induced Gibb WRG, Lees AJ. The clinical phenomenon of akathisia. J Neurol
akathisia in cancer patients receiving chemotherapy. Am J Neurosurg Psychiatry 1986; 49:861–6.
Psychiatry 1994; 151:763–5. Giladi N, McMahon D, Przedborski S et al. Motor blocks in
Foncke EMJ, Gerrits MLF, van Ruissen F et al. Distal myoclonus Parkinson’s disease. Neurology 1992; 42:333–9.
and later onset in a large Dutch family with myoclonus- Gilbert GJ. Brueghel syndrome: its distinction from Meige
dystonia. Neurology 2006; 67:1677–80. syndrome. Neurology 1996; 46:1767–9.
Foster PN, Stickle BR, Laurence AS. Akathisia following low-dose Gimenez-Roldan S, Martin M. Startle epilepsy complicating
droperidol for antiemesis in day-case patients. Anaesthesia Down syndrome during adulthood. Ann Neurol 1980;
1996; 51:491–4. 7:78–80.
Fox GC, Ebeid S, Vincenti G. Paroxetine-induced chorea. Br J Gjessing LR. A review of periodic catatonia. Biol Psychiatry 1974;
Psychiatry 1997; 170:193–4. 8:23–45.
Francisco GE. Successful treatment of posttraumatic Glantz R, Weiner WJ, Goetz CG et al. Drug-induced asterixis in
hemiballismus with intrathecal baclofen therapy. Am J Phys Parkinson’s disease. Neurology 1982; 32:553–5.
Med Rehabil 2006; 85:779–82. Glass JP, Jankovic J, Borit A. Hemiballism and metastatic brain
Friedman A, Sienkiewicz J. Psychotic complications of long-term tumor. Neurology 1984; 34:204–7.
levodopa treatment of Parkinson’s disease. Acta Neurol Scand Goldings AS, Stewart RM. Organic lead encephalopathy:
1991; 84:111–13. behavioral change and movement disorder following gasoline
Furtado S, Ferrer M, Tsuboi Y et al. SCA-2 presenting as inhalation. J Clin Psychiatry 1982; 43:70–2.
parkinsonism in an Alberta family. Clinical, genetic and PET Gomez EA, Comstock BS, Rosario A. Organic versus functional
findings. Neurology 2002; 59:1625–7. etiology in catatonia: case report. J Clin Psychiatry 1982;
Gallo BV, Shulman LM, Weiner WJ et al. HIV encephalitis 43:200–1.
presenting with severe generalized chorea. Neurol 1996; Gooch JL, Sandell TV. Botulinum toxin for spasticity and athetosis
46:1163–5. in children with cerebral palsy. Arch Phys Med Rehabil 1996;
Gambardella A, Valentino P, Annesi G et al. Hyperekplexia in a 77:508–11.
patient with a brainstem vascular anomaly. Acta Neurol Scand Goodman L. Alzheimer’s disease: a clinico-pathologic analysis of
1999; 99:255–9. twenty-three cases with a theory on pathogenesis. J Nerv
Gamboa ET, Issacs G, Harter DH. Chorea associated with oral Ment Dis 1953; 118:97–130.
contraceptive therapy. Arch Neurol 1971; 25:112–14. Goto S, Kunitoku N, Suyama N et al. Posteroventral pallidotomy in
Garrett PJ, Mulcahey D, Carmody M et al. Aluminium a patient with parkinsonism caused by hypoxic
encephalopathy: clinical and immunologic features. Q J Med encephalopathy. Neurology 1997; 49:707–10.
1988; 69:775–83. de Graaf L, Admiraal R, van Puijenbroeck EP. Ballism associated
Garruto RM, Gajdusek DC, Chen KM. Amyotrophic lateral sclerosis with bupropion use. Ann Pharmacother 2003; 37:302–3.
and parkinsonism-dementia among Filipino immigrants to Graham JM, Grunewald RA, Sagar HJ. Hallucinosis in idiopathic
Guam. Ann Neurol 1981; 10:341–50. Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997;
Garvey MJ, Tollefson GD. Occurrence of myoclonus in patients 63:434–40.
treated with cyclic antidepressants. Arch Gen Psychiatry 1987; Green PM. Chorea induced by oral contraceptives. Neurology
44:269–72. 1980; 30:1131–2.
Gatto EM, Uribe Roca C, Raina G et al. Vascular Grimes DA, Han F, Lang AE et al. A novel focus for inherited
hemichorea/hemiballism and topiramate. Mov Disord 2004; myoclonus-dystonia on 18p11. Neurology 2002;
19:836–8. 59:1183–6.
Gaultieri CT, Patterson DR. Neuroleptic-induced tics in two Grinker RR. Parkinsonism following carbon monoxide poisoning.
hyperactive children. Am J Psychiatry 1986; 143:1176–7. J Nerv Ment Dis 1926; 64:18–28.
Gautier-Smith PC, Prankerd TAJ. Polycythemia vera and chorea. Guggenheim MA, Couch JR, Weinberg W. Motor dysfunction as a
Acta Neurol Scand 1967; 43:357–64. permanent complication of methanol ingestion: presentation
Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry of a case with a beneficial response to levodopa treatment.
1995; 56:283–7. Arch Neurol 1971; 24:550–4.
Gelenberg AJ, Mandel MR. Catatonic reactions to high-potency Gunal DI, Onultan O, Afsar N et al. Tardive dystonia associated
neuroleptic drugs. Arch Gen Psychiatry 1977; 34:947–50. with olanzapine therapy. Neurol Sci 2001; 22:331–2.
p 03.qxd 3/10/08 9:32 AM Page 105
References 105
Gwinn-hardy K, Chen JY, Liu H-C et al. Spinocerebellar ataxia type Hirano A, Arumugasamy N, Zimmerman HM. Amyotrophic lateral
2 with parkinsonism in ethnic Chinese. Neurology 2000; sclerosis: a comparison of Guam and classical cases. Arch
55:800–5. Neurol 1967; 16:357–63.
Halstead SM, Barnes TRE, Speller JC. Akathisia: prevalence and Hoehn MM, Cherington M. Spinal myoclonus. Neurology 1977;
associated dysphoria in an in-patient population with chronic 27:942.
schizophrenia. Br J Psychiatry 1994; 164:177–83. Hofmann A, Tangri N, Lafontaine A-L et al. Myoclonus as an acute
Hammond WA. A treatise on diseases of the nervous system. New complication of low-dose hydromorphone in multiple system
York: Appleton-Century Crofts, 1871. atrophy. J Neurol Neurosurg Psychiatry 2006; 77:994–5.
Hansen HC, Zschocke S, Sturenbur HJ et al. Clinical changes and Holmes G. On certain tremors in organic cerebral lesions. Brain
EEG patterns preceding the onset of periodic sharp wave 1904; 27:327–75.
complexes in Creutzfeldt–Jakob disease. Acta Neurol Scand Holroyd S, Smith D. Disabling parkinsonism due to lithium: a case
1998; 97:99–106. report. J Geriatr Psychiatry Neurol 1995; 8:118–19.
Hansotia P, Cleeland CS, Chun RWM. Juvenile Huntington’s Hori A, Hirose G, Kataoka S et al. Delayed postanoxic
chorea. Neurology 1968; 18:217–24. encephalopathy after strangulation: serial neuroradiological
Hardie RJ, Lees AJ. Neuroleptic-induced Parkinson’s syndrome: and neurochemical studies. Arch Neurol 1991; 48:871–4.
clinical features and results of treatment with levodopa. Horikawa N, Yamazaki T, Sagawa M et al. A case of akathisia
J Neurol Neurosurg Psychiatry 1988; 51:850–4. during interferon-alpha therapy for chronic hepatitis type C.
Hardie RJ, Pullon HWH, Harding AE et al. Neuroacanthocytosis: a Gen Hosp Psychiatry 1999; 21:134–5.
clinical, haematological and pathological study of 19 cases. Howard R, Ford R. From the jumping Frenchmen of Maine to
Brain 1991; 114:13–49. post-traumatic stress disorder: the startle response in
Harsch HH. Neurologyoleptic malignant syndrome: physiological neuropsychiatry. Psychol Med 1992; 22:695–707.
and laboratory findings in a series of nine cases. J Clin Howard RS, Lees AJ. Encephalitis lethargica: a report of four
Psychiatry 1987; 48:328–33. recent cases. Brain 1987; 110:19–33.
Harvey PKP, Davis JN. Traumatic encephalopathy in a young Huang C-C, Chu N-S, Lu C-S et al. Chronic manganese
boxer. Lancet 1974; 2:928–9. intoxication. Arch Neurol 1989; 46:1104–6.
Harwood G, Hierons R, Fletcher NA et al. Lessons from a Huang C-C, Lu C-S, Chu N-S et al. Progression after chronic
remarkable family with dopa-responsive dystonia. J Neurol manganese exposure. Neurology 1993; 43:1479–83.
Neurosurg Psychiatry 1994; 57:460–3. Huang C-C, Chu N-S, Lu C-S et al. Cock gait in manganese
Haskovec L. L’akathisie. Rev Neurol 1901; 9:1107–9. intoxication. Mov Disorders 1997; 12:807–8.
Hayflick SJ, Westaway SK, Levinson B et al. Genetic, clinical, and Hughes AJ, Daniel SE, Blankson S et al. A clinicopathologic study
radiographic delineation of Hallervorden–Spatz syndrome. of 100 cases of Parkinson’s disease. Arch Neurol 1993;
N Engl J Med 2003; 348:33–40. 50:140–8.
Heathfield KWG. Huntington’s chorea. Brain 1967; 90:203–32. Hyman NM, Dennis PD, Sinclair KG. Tremor due to sodium
Heckman JG, Lang CJG, Druschky D et al. Chorea resulting from valproate. Neurology 1979; 29:1172–80.
paraneoplastic encephalitis. Mov Disord 1997; 12:464–6. Iijima M. Valproate-induced parkinsonism in a demented elderly
Heckmann JG, Ulrich H, Dutsch M et al. Pregabalin-associated patient. J Clin Psychiatry 2002; 63:75.
asterixis. Am J Phys Med Rehabil 2005; 84:724. Indo T, Ando K. Metoclopramide-induced parkinsonism. Clinical
Hefter H, Mayer P, Benecke R. Persistent chorea after recurrent characteristics of ten cases. Arch Neurol 1982; 39; 494–6.
hypoglycemia. A case report. Eur Neurol 1993; 33:244–7. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical
Heilman KH. Orthostatic tremor. Arch Neurol 1984; 41:880–1. and pathological study of 20 necropsy cases. J Neurol
Hellman MA, Melamed E. Focal dystonia as the presenting sign in Neurosurg Psychiatry 1981; 44:209–15.
Creutzfeldt–Jakob disease. Mov Disord 2002; 17:1097–8. Jacob PC, Pratap Chand R. Post-traumatic rubral tremor
Hely MA, Reid WGJ, Halliday GM et al. Diffuse Lewy body responsive to clonazepam. Mov Disord 1998; 13:977–8.
disease: clinical features in nine cases without coexistent Jacobs MB. Diltiazem and akathisia. Ann Intern Med 1983;
Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1996; 99:794–5.
60:531–8. Jaffe N. Catatonia and hepatic dysfunction. Dis Nerv Syst 1967;
Hersh BP, Rajendran PR, Battinelli D. Parkinsonism as the 28:606–8.
presenting feature of HIV infection: improvement on HAART. Jain S, Padma MV, Puri A et al. Juvenile myoclonic epilepsy:
Neurology 2001; 56:278–9. disease expression among Indian families. Acta Neurol Scand
Hershon HI, Kennedy PF, McGuire RJ. Persistence of 1998; 97:1–7.
extrapyramidal disorders and psychiatric relapse after Jankovic J, Ashizawa T. Tourettism associated with Huntington’s
withdrawal of long-term phenothiazine therapy. Br J disease. Mov Disord 1995; 10:103–5.
Psychiatry 1972; 120:41–50. Jankovic J, Fahn S. Physiologic and pathologic tremors. Ann Int
Hess CW, Raymond D, de Carbalho Aguiar P et al. Myoclonus- Med 1980; 93:460–5.
dystonia, obsessive-compulsive disorder, and alcohol Jankovic J, Kirkpatrick JB, Blomquist KA et al. Late-onset
dependence in SGCE mutation carriers. Neurology 2007; Hallervorden–Spatz disease presenting as familial
68:522–4. parkinsonism. Neurology 1985; 35:227–34.
p 03.qxd 3/10/08 9:32 AM Page 106
Jankovic J, Caskey TC, Stout T et al. Lesch–Nyhan syndrome: a Kelwala S, Pomara N, Stanley M et al. Lithium-associated
study of motor behavior and cerebrospinal fluid accentuation of extrapyramidal symptoms in individuals
neurotransmitters. Ann Neurol 1988; 23:466–9. with Alzheimer’s disease. J Clin Psychiatry 1984;
Jankovic J, Leder S, Warner D et al. Cervical dystonia: clinical 45:342–4.
findings and associated movement disorders. Neurology 1991; Kerbeshian J, Burd L, Pettit R. A possible post-streptococcal
41:1088–91. movement disorder with chorea and tics. Dev Med Child
Jarman PR, Davis MB, Hodgson SV et al. Paroxysmal dystonic Neurol 1990; 32:642–4.
choreoathetosis: genetic linkage studies in a British family. Kertesz A. Paroxysmal kinesigenic choreoathetosis: an entity
Brain 1997; 120:2125–30. within the paroxysmal choreoathetosis syndrome. Description
Jarman PR, Bhatia KP, Davie C et al. Paroxysmal dystonic of 10 cases, including 1 autopsied. Neurology 1967;
choreoathetosis: clinical features and investigation of 17:680–90.
pathophysiology in a large family. Mov Disord 2000; Keschner M, Sloane P. Encephalitic, idiopathic and arteriosclerotic
15:648–57. parkinsonism: a clinicopathologic study. Arch Neurol
Jauss M, Schroder J, Pantel J et al. Severe akathisia during Psychiatry 1931; 25:1011–41.
olanzapine treatment of acute schizophrenia. Keswani SC, Kossoff EH, Krauss GL et al. Amelioration of spinal
Pharmacopsychiatry 1998; 31:146–8. myoclonus with levetiracetam. J Neurol Neurosurg Psychiatry
Jimenez-Jimenez FJ, Tejeiro J, Martinez-Junquera G et al. 2002; 73:456–9.
Parkinsonism exacerbated by paroxetine. Neurology 1994; Kidron D, Melamed E. Forms of dystonia in patients with
44:2406. Parkinson’s disease. Neurology 1987; 37:1009–11.
Johnson J. Stupor: review of 25 cases. Acta Psychiatr Scand 1984; Kim CH, Perlstein MA. Encephalitis with catatonic schizophrenic
70:370–7. symptoms. Ill Med J 1970; 138:503–7.
Johnson WG, Fahn S. Treatment of vascular hemiballism and Kim JS. Delayed onset mixed involuntary movements after
hemichorea. Neurology 1977; 27:634–6. thalamic stroke. Clinical, radiological and pathophysiological
Johnson WG, Schwartz G, Barbeau A. Studies of dystonia findings. Brain 2001a; 124:299–309.
musculorum deformans. Arch Neurol 1962; 7:301–13. Kim JS. Asterixis after unilateral stroke: Lesion localization of 30
Jung HH, Hergersberg M, Kneifel S et al. McLeod syndrome: a patients. Neurology 2001b; 56:533–6.
novel mutation, predominant psychiatric manifestations, and Kimber TE, Thompson PD. Symptomatic hyperekplexia occurring as
distinct striatal imaging findings. Ann Neurol 2001; a result of pontine infarction. Mov Disord 1997; 12:815–16.
49:384–92. Kinirons P, Fulton A, Keoghan M et al. Paraneoplastic limbic
Jungmann E, Schoffling C. Akathisia and metoclopramide. Lancet encephalitis (PLE) and chorea associated with CRMP-5
1982; 2:221. neuronal antibody. Neurology 2003; 61:1623–4.
Kabacki K, Isbruch K, Schilling K et al. Genetic heterogeneity in Kirby GH, Davis TK. Psychiatric aspects of epidemic encephalitis.
rapid onset dystonia-parkinsonism: description of a new Arch Neurol Psychiatry 1921; 5:491–51.
family. J Neurol Neurosurg Psychiatry 2005; 76:860–2. Kiriakakis V, Bhatia K, Quinn NP et al. The natural history of
Kahlbaum K. Die Katatonie oder das Spanungsirresein. Berlin, tardive dystonia: a long-term follow-up study of 107 cases.
Hirsch, 1874. Brain 1998; 121:2053–66.
Kaiko RF, Foley KM, Grabinski PY et al. Central nervous system Kirubakaren V, Mayfield D, Rengachary S. Dyskinesia and
excitatory effects of meperidine in cancer patients. Ann Neurol psychosis in a patient following baclofen withdrawal. Am J
1983; 13: 180–5. Psychiatry 1984; 141:692–3.
Kalita J, Misra UK. Markedly severe dystonia in Japanese Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse
encephalitis. Mov Disord 2000; 15:1168–72. Lewy body disease: a clinicopathologic study using Alzheimer’s
Kane J, Rifkin A, Quitkin F et al. Extrapyramidal side-effects with disease and Parkinson’s disease comparison groups. Neurology
lithium treatment. Am J Psychiatry 1978; 135:851–3. 1996; 47:1148–52.
Kaplan PW. Nonconvulsive status epilepticus in the emergency Klawans HL, Barr A. Prevalence of spontaneous lingual-
room. Epilepsia 1996; 37:643–50. facial-buccal dyskinesias in the elderly. Neurology 1981;
Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a 31:558–9.
neurologic disorder following rapid correction of Klawans HL, Barr A. Recurrence of childhood multiple tic in late
hyponatremia. Medicine 1993; 72:359–73. adult life. Arch Neurol 1985; 42:1079–80.
Kase CS, Maulsby GO, deJuan E et al. Hemichorea–hemiballism Klawans HL, Goetz CG, Bergen D. Levodopa-induced myoclonus.
and lacunar infarction in the basal ganglia. Neurology 1981; Arch Neurol 1975; 32:331–4.
31:452–5. Klawans HL, Moses H, Nausieda PA et al. Treatment and prognosis
Katayama Y, Yamamoto T, Kobayshi K et al. Deep brain and motor of hemiballism. N Engl J Med 1976a; 295:1348–50.
cortex stimulation for post-stroke movement disorders and Klawans HL, Lipton M, Simon L. Calcification of the basal ganglia
post-stroke pain. Acta Neurochir 2003; 87:121–3. as a cause of levodopa-resistant parkinsonism. Neurology
Keepers GA, Clappison VJ, Casey DE. Initial anticholinergic 1976b; 26:221–5.
prophylaxis for neuroleptic-induced extrapyramidal Klawans HL, Glantz R, Tanner CM et al. Primary writing tremor: a
syndromes. Arch Gen Psychiatry 1983; 40:1113–17. selective action tremor. Neurology 1982a; 32:203–6.
p 03.qxd 3/10/08 9:32 AM Page 107
References 107
Klawans HL, Stein RW, Tanner CM et al. A pure parkinsonian Kuba R, Rektor I, Brazdil M. Ictal limb dystonia in temporal lobe
syndrome following acute carbon monoxide intoxication. Arch epilepsy: an invasive video-EEG finding. Eur J Neurol 2003;
Neurol 1982b; 39:302–4. 10:641–9.
Kleinschmidt-DeMasters BK, Marder BA, Levi ME et al. Naturally Kulisevsky J, Berthier ML, Pujol J. Hemiballismus and secondary
acquired West Nile virus encephalomyelitis in transplant mania following right thalamic infarction. Neurology 1993;
recipients: clinical, laboratory, diagnostic and 43:1422–4.
neuropathological features. Arch Neurol 2004; 61:1210–20. Kulisevsky J, Asuncion A, Berthier ML. Bipolar disorder and
Ko SB, Ahn TB, Kim JR et al. A case of adult-onset tic disorder unilateral parkinsonism after a brainstem infarction. Mov
following carbon monoxide intoxication. Can J Neurol Sci Disord 1995; 10:799–802.
2004; 31:268–70. Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions.
Koehler J, Jakumeit U. Subacute sclerosing panencephalitis Stroke 1999; 30:100–8.
presenting as Leonhard’s speech-prompt catatonia. Br J Kushner MJ. Chorea and cimetidine. Ann Intern Med 1982;
Psychiatry 1976; 129:29–31. 96:126.
Koller WC. Edentulous orodyskinesia. Neurology 1983; 13:97–9. Kutcher SP, Williamson P, MacKenzie S et al. Successful
Koller WC, Cochran JW, Klawans HL. Calcification of the basal clonazepam treatment of neuroleptic-induced akathisia in
ganglia: computerized tomography and clinical correlation. older adolescents and young adults. J Clin Psychopharmacol
Neurology 1979; 29:328–33. 1989; 9:403–6.
Konagaya M, Konagaya Y. MRI in hemiballism due to Sydenham’s Kwak CH, Jankovic J. Tourettism and dystonia after subcortical
chorea. J Neurol Neurosurg Psychiatry 1992; 55:238–9. stroke. Mov Disord 2002; 17:821–5.
Kooiker JC, Sumi SM. Movement disorder as a manifestation of Lai SL, Tseng YL, Hsu MC et al. Magnetic resonance imaging
diphenylhydantoin intoxication. Neurology 1974; 24:68–71. and single-photon emission computed tomography
Koskiniemi M, Donner M, Majuri H et al. Progressive myoclonus changes in hypoglycemia-induced chorea. Mov Disord 2004;
epilepsy: a clinical and histopathological study. Acta Neurol 19:475–8.
Scand 1974; 50:307–32. Lance JW. Familial paroxysmal dystonic choreoathetosis and its
Koukoulis A, Herrerd JS, Gomez-Alonso J. Blepharospasm induced differentiation from related syndromes. Ann Neurol 1977;
by flunarazine. J Neurol Neurosurg Psychiatry 1997; 2:285–93.
63:412–13. Lance JW, Adams RD. The syndrome of intention or action
Krack P. Deuschl G, Kapa M et al. Delayed onset of ‘rubral tremor’ myoclonus as a sequel to hypoxic encephalopathy. Brain 1963;
23 years after brainstem trauma. Mov Disord 1994; 9:240–2. 86:111–36.
Kraepelin E. Psychiatry. A textbook for students and physicians, Lancman ME, Asconape MJ, Penry JK. Choreiform movements
6th edn, 1899, translated by Metoui H, Ayed S. Canton, MA: associated with the use of valproate. Arch Neurol 1994;
Science History Publications, 1990. 51:702–4.
Kramer PL, Mineta M, Klein C et al. Rapid-onset dystonia- Lang AE. Persistent hemiballismus with lesions outside the
parkinsonism: linkage to chromosome 19q13. Ann Neurol subthalamic nucleus. Can J Neurol Sci 1985; 12:125–8.
1999; 46:176–82. Lang AE. Withdrawal akathisia: case reports and a proposed
Krams M, Quinton R, Ashburner J et al. Kallmann’s syndrome: classification of chronic akathisia. Mov Disord 1994;
mirror movements associated with bilateral corticospinal tract 9:188–92.
hypertrophy. Neurology 1999; 52:816–22. Lang AE, Johnson K. Akathisia in idiopathic Parkinson’s disease.
Krauss JK, Jankovic J. Tics secondary to craniocerebral trauma. Neurology 1987; 37:477–81.
Mov Disord 1997; 12:776–82. Langston JW, Ballard P, Tetrud JW et al. Chronic parkinsonism in
Krauss JK, Nobbe F, Wakhloo AK et al. Movement disorders in humans due to a product of meperidine-analog synthesis.
astrocytomas of the basal ganglia and the thalamus. J Neurol Science 1983; 249:979–80.
Neurosurg Psychiatry 1992; 55:1162–7. Lanham JG, Brown MM, Hughes GRV. Cerebral systemic lupus
Krauss JK, Wakhloo AK, Nobbe F et al. MR pathological correlations erythematosus presenting with catatonia. Postgrad Med J
of severe posttraumatic tremor. Neurol Res 1995; 17:409–16. 1985; 61:329–30.
Krauss JK, Seeger W, Jankovic J. Cervical dystonia with tumors of Lapierre YD. Control of lithium tremor with propranolol. Can Med
the posterior fossa. Mov Disord 1997; 12:443–7. Assoc J 1976; 114:619–20.
Kristensen O, Sindrup EH. Psychomotor epilepsy and psychosis. III. Laplane D, Attal N, Sauron B et al. Lesions of basal ganglia due to
Social and psychological correlates. Acta Neurol Scand 1979; disulfiram neurotoxicity. J Neurol Neurosurg Psychiatry 1992;
59:1–9. 55:925–9.
Kronfol Z, Greden JF, Zis AP. Imipramine-induced tremor: effects Lapresle J. Palatal myoclonus. Adv Neurol 1986; 43:265–73.
of a beta-adrenergic blocking agent. J Clin Psychiatry 1983; Leavitt S, Tyler H. Studies in asterixis. Arch Neurol 1964;
44:225–6. 10:360–8.
Krystkowiak P, Martinat P, Defebvre L et al. Dystonia after Ledbetter M. Atomoxetine associated with onset of a motor tic.
striatopallidal and thalamic stroke: clinicoradiological J Child Adolesc Psychopharmacol 2005; 15:331–3.
correlations and pathophysiological mechanism. J Neurol Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann
Neurosurg Pyschiatry 1998; 65:703–8. Neurol 1978; 4:199–204.
p 03.qxd 3/10/08 9:32 AM Page 108
Lee B-C, Hwang S-H, Chang GY. Hemiballismus–hemichorea in Lipinski JF, Mallya A, Zimmerman P et al. Fluoxetine-induced
older diabetic women: a clinical syndrome with MRI akathisia: clinical and theoretical implications. J Clin
correlation. Neurology 1999; 52:646–8. Psychiatry 1989; 50:339–42.
Lee BI, Lesser RP, Pippenger CE et al. Familial paroxysmal Lippmann S, Moskovitz R, O’Tuama L. Tricyclic-induced
hypnogenic dystonia. Neurology 1985; 35:1357–60. myoclonus. Am J Psychiatry 1977; 134:90–1.
Lee MS, Rinne JO, Ceballos-Baumann A et al. Dystonia after head Little JT, Jankovic J. Tardive myoclonus: a case report. Mov Disord
trauma. Neurology 1994; 44:1374–8. 1987; 2:307–11.
Lee MS, Kim YD, Lyoo CH. Oculogyric crises as an initial Litvan I, Mangone CA, McKee A et al. Natural history of
manifestation of Wilson’s disease. Neurology 1999; progressive supranuclear palsy (Steele–Richardson–Olszewski
52:1714–15. syndrome) and clinical predictors of survival: a
Lees AJ, Robertson M, Trimble MR et al. A clinical study of Gilles clinicopathologic study. J Neurol Neurosurg Psychiatry 1996;
de la Tourette syndrome in the United Kingdom. J Neurol 61:615–20.
Neurosurg Psychiatry 1984; 47:1–8. Litvan I, Goetz CG, Jankovic J et al. What is the accuracy of the
Lehericy S, Vidailhet M, Dormont D et al. Striatopallidal clinical diagnosis of multiple system atrophy? A
and thalamic dystonia: a magnetic resonance clinicopathologic study. Arch Neurol 1997a; 54:937–44.
imaging anatamoclinical study. Arch Neurol 1996; Litvan I, Agid Y, Goetz C et al. Accuracy of the clinical diagnosis of
53:241–50. corticobasal degeneration: a clinicopathologic study.
Lehericy S, Grand S, Pollak P et al. Clinical characteristics and Neurology 1997b; 48:119–25.
topography of lesions in movement disorders due to thalamic Logsdail SJ, Toone BK. Postictal psychoses: a clinical and
lesions. Neurology 2001; 57:1055–66. phenomenological description. Br J Psychiatry 1988;
Lenton RJ, Cofti M, Smith RG. Hemiballismus treated with sodium 152:246–52.
valproate. BMJ 1981; 283:17–18. Lombroso CT. Lamotrigene-induced tourettism. Neurology 1999;
Lera G, Scipioni O, Garcia S et al. A combined pattern 52:1191–4.
of movement disorders resulting from posterolateral Louis ED, Lynch T, Kaufmann P et al. Diagnostic guidelines in
thalamic lesions of a vascular nature: a syndrome with central nervous system Whipple’s disease. Ann Neurol 1996;
clinico-radiologic correlation. Mov Disord 2000; 40:561–8.
15:120–6. Louis ED, Klatka LA, Liu Y et al. Comparison of extrapyramidal
Lerner V, Bergman J, Statsensko N et al. Vitamin B6 treatment in features in 31 pathologically confirmed cases of diffuse Lewy
acute neuroleptic-induced akathisia: a randomized, double- body disease and 34 pathologically confirmed cases of
blind, placebo-controlled study. J Clin Psychiatry 2004; Parkinson’s disease. Neurology 1997; 48:376–80.
65:1550–4. Louis ED, Anderson KE, Moskowitz C et al. Dystonia-predominant
Lesch M, Nyhan WL. A familial disorder of uric acid metabolism adult-onset Huntington disease: association between motor
and central nervous system function. Am J Med 1964; phenotype and age of onset in adults. Arch Neurol 2000;
36:561–70. 57:1326–30.
Lewis I, Johnson IM. Chorea: an unusual manifestation of cerebral Lu CS, Huang CC, Chu NS et al. Levodopa failure in chronic
metastases. Neurology 1968; 18:948–52. manganism. Neurology 1994; 44:1600–2.
LeWitt PA, Walters A, Hening W et al. Persistent movement Lugaresi E, Cirignotta F. Hypnogenic paroxysmal dystonia:
disorders induced by buspirone. Mov Disord 1993; 8:331–4. epileptic seizure or a new syndrome? Sleep 1981; 4:129–38.
Lightman SL. Phenobarbital dyskinesia. Postgrad Med J 1978; Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal
54:114–15. dystonia. J Neurol Neurosurg Psychiatry 1986; 49:375–80.
Lim J, Yagnik P, Schrader P et al. Ictal catatonia as a Lundh H, Tunving K. An extrapyramidal choreiform syndrome
manifestation of nonconvulsive status epilepticus. J Neurol caused by amphetamine addiction. J Neurol Neurosurg
Neurosurg Psychiatry 1986; 49:833–6. Psychiatry 1981; 44:728–30.
Lin J-J, Chang M-K. Hemiballism–hemichorea and non-ketotic Luque FA, Selhorst JB, Petruska P. Parkinsonism induced by
hyperglycemia. J Neurol Neurosurg Psychiatry 1994; high-dose cystosine arabinoside. Mov Disord 1987; 2:219–22.
57:748–50. Mac DS, Pardo MP. Systemic lupus erythematosus and catatonia:
Lin J-J, Lin GY, Shih C et al. Presentation of striatal hyperintensity a case report. J Clin Psychiatry 1983; 44:155–6.
on T1-weighted MRI in patients with hemiballism-hemichorea Magaudda A, Ferlazzo E, Nguyen V-H et al. Unverricht–Lundborg
caused by non-ketotic hyperglycemia: report of seven new disease: a condition with self-limited progression: long-term
cases and a review of the literature. J Neurol 2001; follow-up of 20 patients. Epilepsia 2006; 47:860–6.
248:750–5. Maher ER, Lees AJ. The clinical features and natural history of
Lindenmeyer J-P, Da Silva D, Buendia A et al. Tic-like syndrome Steele–Richardson–Olszewski syndrome (progressive
after treatment with clozapine. Am J Psychiatry 1995; supranuclear palsy). Neurology 1986; 36:1005–8.
152:649. Maher J, Choudri S, Halliday W et al. AIDS dementia complex with
Lipinski JF, Zubenko GS, Cohen BM et al. Propranolol in the generalized myoclonus. Mov Disord 1997; 12:593–7.
treatment of neuroleptic induced akathisia. Am J Psychiatry Mahloudji M, Pikielny R. Hereditary essential myoclonus. Brain
1984; 141:412–15. 1967; 90:669–74.
p 03.qxd 3/10/08 9:32 AM Page 109
References 109
Mahoney CA, Arieff AI. Uremic encephalopathies: clinical, McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical
biochemical, and experimental features. Am J Kidney Dis 1982; and pathological study. Ann Neurol 1980; 8:161–7.
2:324–36. McNeill A. Chorea induced by low-dose tranzodone. Eur Neurol
Malamud N, Hirano A, Kurland LT. Pathoanatomic changes in 2006; 55:101–12.
amyotrophic lateral sclerosis on Guam. Neurology 1961; Medlock MD, Cruse RS, Winek SJ et al. A 10-year experience with
5:401–14. postpartum chorea. Ann Neurol 1993; 34:820–6.
Malur C, Pasol E, Francis A. ECT for prolonged catatonia. J ECT Melamed E. Early-morning dystonia, a late effect of long-term
2001; 17:55–9. levodopa therapy in Parkinson’s disease. Arch Neurol 1979;
Manford MR, Fish DR, Shorvon SD. Startle provoked epileptic 36:308–10.
seizures: features in 19 patients. J Neurol Neurosurg Psychiatry Melamed E, Korn-Lubetzk I, Reches A et al. Hemiballismus:
1996; 61: 151–6. detection of focal hemorrhage in subthalamic nucleus by CT
Mann SC, Caroff SN, Bleir HR et al. Lethal catatonia. Am J scan. Ann Neurol 1978; 4:582.
Psychiatry 1986; 143:1374–81. Mendhekar DN, Duggal HS. Isolated oculogyric crisis on clozapine
Manyam BV, Walters AS, Naria KR. Bilateral striatopallidodentate discontinuation. J Neuropsychiatry Clin Neurosci 2006;
calcinosis: clinical characteristics of patients seen in a 18:424–5.
registry. Mov Disord 2001; 16:258–64. Menza MA, Cocchiola J, Golbe LI. Psychiatric symptoms in
Maraganore DM, Folger WN, Swanson JW et al. Movement progressive supranuclear palsy. Psychosomatics 1995;
disorders as sequelae of central pontine myelinolysis: report of 36:550–4.
three cases. Mov Disord 1992; 7:142–8. Mercadante S. Pathophysiology and treatment of opioid-related
Marder K, Ming-Xin T, Cote L et al. The frequency and associated myoclonus in cancer patients. Pain 1998; 74:5–9.
risk factors for dementia in patients with Parkinson’s disease. Meseguer E, Taboada R, Sanchez V et al. Life-threatening
Arch Neurol 1995; 52:695–701. parkinsonism induced by Kava-Kava. Mov Disord 2002;
de Mari M, De Blasi R, Lamberti P et al. Unilateral pallidal lesion 17:195–6.
after acute disulfiram intoxication: a clinical and magnetic Meyer T, Ludolph AC, Munch C. Ifosfamide encephalopathy
resonance imaging study. Mov Disorders 1993; 8:247–9. presenting with asterixis. J Neuol Sci 2002; 15:85–8.
Marsden CD, Harrison MJG. Idiopathic torsion dystonia (dystonia Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for
musculorum deformans): a review of forty-two patients. Brain intrathecal baclofen withdrawal. Arch Phys Med Rehabil 2003;
1974; 97:793–810. 84:638–42.
Marti-Masso JF, Poza JJ. Cinnarizine-induced parkinsonism: ten Miller DD, Sharafuddin MJA, Kathol RG. A case of clozapine-
years later. Mov Disord 1998; 13:453–6. induced neuroleptic malignant syndrome. J Clin Psychiatry
Martin JP, Alcock NS. Hemichorea associated with a lesion of the 1991; 52:99–101.
corpus luysii. Brain 1934; 57:504–16. Misra PC, Hay GG. Encephalitis presenting as acute schizophrenia.
Martin WE, Loewenson RB, Resch JA et al. Parkinson’s disease: Br Med J 1971; 1:532–3.
clinical analysis of 100 patients. Neurology 1973; 23: Mitchell E, Mathews KL. Gilles de la Tourette’s disorder associated
783–90. with pemoline. Am J Psychiatry 1980; 137:1618–19.
Martinez-Cage JM, Marsden CD. Hemi-dystonia secondary to Miwa H, Harori K, Kondo T et al. Thalamic tremor: case reports
localized basal ganglia tumors. J Neurol Neurosurg Psychiatry and implications of the tremor-generating mechanism.
1984; 47:704–9. Neurology 1996; 46:75–9.
Martland HS. Punch drunk. J Am Med Assoc 1928; 91:1103–7. Miyagi Y, Shima F, Ishido K et al. Posteroventral pallidotomy for
Mathews WB. Familial calcification of the basal ganglia with midbrain tremor after a pontine hemorrhage. Case report.
response to parathormone. J Neurol Neurosurg Psychiatry J Neurosurg 1999; 91:885–8.
1957; 20:172–7. Moersch FP, Kernohan JW. Hemiballismus: a clinicopathologic
Matsunaga K, Uozumi T, Qingrui L et al. Amantadine-induced study. Arch Neurol Psychiatry 1939; 41:365–72.
cortical myoclonus. Neurology 2001; 56:279–80. Molinuevo JL, Marti MJ, Blesa R et al. Pure akinesia: an unusual
Matsuo H, Takashima H, Kishikawa M et al. Pure akinesia: an phenotype of Hallervorden–Spatz syndrome. Mov Disord 2003;
atyical manifestation of progressive supranuclear palsy. 18:1351–3.
J Neurol Neurosurg Psychiatry 1991; 54:397–400. Mones RJ, Elizan TS, Siegel GJ. Analysis of L-dopa induced
Matsuo H, Kamakura K, Saito M et al. Familial paroxysmal dyskinesias in 51 patients with parkinsonism. J Neurol
dystonic choreoathetosis. Clinical findings in a large Japanese Neurosurg Psychiatry 1971; 34:668–73.
family and genetic linkage to chromosome 2q. Arch Neurol Morres CA, Dire DJ. Movement disorders as a manifestation of
1999; 56:721–6. nonketotic hyperglycemia. J Emerg Med 1989; 7:359–64.
Mayeux R, Denaro J, Hemenegildo N et al. A population-based Morrison JR. Catatonia. Retarded and excited types. Arch Gen
investigation of Parkinson’s disease with and without Psychiatry 1973; 28:515–16.
dementia: relationship to age and gender. Arch Neurol 1992; Moshe K, Iulian I, Seth K et al. Clomipramine-induced
49:492–7. tourettism in obsessive-compulsive disorder: clinical and
McKee D, Talbot P. Chorea as a presenting feature of variant theoretical implications. Clin Neuropharmacol 1994;
Creutzfeldt–Jakob disease. Mov Disord 2003; 18:837–8. 17:338–43.
p 03.qxd 3/10/08 9:32 AM Page 110
Moulignier A, Allo S, Zittoun R et al. Recombinant interferon- Nyhan WL. Clinical features of the Lesch–Nyhan syndrome. Arch
alpha-induced chorea and frontal subcortical dementia. Int Med 1972; 130:186–92.
Neurology 2002; 58:328–30. Nyland H, Skre H. Cerebral calcinosis with late onset
Mount LA, Reback S. Familial paroxysmal choreoathetosis: encephalopathy: unusual type of pseudo-
preliminary report of an hitherto undescribed clinical pseudohypoparathyroidism. Acta Neurol Scand 1977;
syndrome. Arch Neurol Psychiatry 1940; 44:841–7. 56:309–25.
Mukand JA, Fitzsimmons C, Wennemer HK et al. Olanzapine for Obeso JA, Viteri C, Martinez Lage JM et al. Toxic myoclonus. Adv
the treatment of hemiballismus: a case report. Arch Phys Med Neurol 1986; 43:225–30.
Rehabil 2005; 86:587–90. Oh J, Park KD, Cho HJ et al. Spasmodic dysphonia induced by
Mulder DW, Parrott M, Thaler M. Sequelae of western equine valproic acid. Epilepsia 2004; 45:880–1.
encephalitis. Neurology 1951; 1:318–27. Okun MS, Riestra RA, Nadeau SE. Treatment of ballism and
Munchau A, Mathen D, Cox T et al. Unilateral lesions of the pseudobulbar affect with sertraline. Arch Neurol 2001;
globus pallidus: report of four patients presenting with focal 58:1682–4.
or segmental dystonia. J Neurol Neurosurg Psychiatry 2000; Oppenheim H. Uber eine eigenartige krampfkrankheit des
69:494–8. kindlichen und jugendlichen alters (dysbasia lordotica
Murgod UA, Muthane UB, Ravi V et al. Persistent motor disorders progressiva, dystonia musculorum deformans). Neurol
following Japanese encephalitis. Neurology 2002; Centrabla 1911; 30:1090–107.
57:2313–15. Onofrj M, Thomas A, Paci C et al. Gabapentin in orthostatic
Murphy MJ, Goldsein MN. Diphenylhydantoin-induced asterixis. tremor: results of a double-blind crossover with placebo in
A clinical study. JAMA 1974; 29:538–40. four patients. Neurology 1998; 51:880–2.
Murrow RW, Schweiger GD, Kepes JJ et al. Parkinsonism due to a Opida CL, Korthals JK, Somasunderam M. Bilateral ballismus in
basal ganglia lacunar state: clinicopathologic correlation. phenytoin intoxication. Ann Neurol 1978; 3:186.
Neurology 1990; 40:897–900. Owens DGC, Johnstone EC, Frith CD. Spontaneous involuntary
Nandagopal R, Moorthy SG. Dramatic levodopa responsiveness of disorders of movement: their prevalence, severity, and
dystonia in a sporadic case of spinocerebellar ataxia type 3. distribution in chronic schizophrenics with and without
Postgrad Med J 2004; 80:363–5. treatment with neuroleptics. Arch Gen Psychiatry 1982;
Nath U, Ben-Shlomo Y, Thomson RG et al. Clinical features and 39:452–61.
natural history of progressive supranuclear palsy. Neurology Pacchetti C, Cristina S, Nappi G. Reversible chorea and focal
2003; 60:910–16. dystonia in vitamin B12 deficiency. N Engl J Med 2002;
Nausieda PA, Koller WC, Klawans HL et al. Phenytoin and choreic 347:295.
movements. N Engl J Med 1978; 298:1093–4. Pakainis A, Drake MA, John K et al. Forced normalization: acute
Nausieda PA, Koller WC, Weiner WJ et al. Chorea induced by oral psychosis after seizure control in seven patients. Arch Neurol
contraceptives. Neurology 1979; 29:1605–9. 1987; 44:289–92.
Nausieda PA, Grossman BJ, Koller WC et al. Sydenham chorea: an Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myolonic
update. Neurology 1980a; 30:331–4. epilepsy: a 5-year prospective study. Epilepsia 1994;
Nausieda PA, Weiner WJ, Klawans HL. Dystonic foot response of 35:285–96.
parkinsonism. Arch Neurol 1980b; 37:132–6. Pantano P, Di Cesare S, Ricci M et al. Hemichorea after a striatal
Navin B, Jordan B, Price R. The AIDS–dementia complex. I. Clinical ischemic lesion: evidence of thalamic disinhibition using
features. Ann Neurol 1986; 19:517–24. single-photon emission computed tomography: a case report.
Nelles G, Cramer SC, Schaechter JD et al. Quantitative assessment Mov Disord 1996; 11:445–7.
of mirror movements after stroke. Stoke 1998; 29:1182–7. Papez JW, Hertzman J, Rundles RW. Athetosis and pallidal
Newton MR, Berkovic SF, Austin MC et al. Dystonia, clinical deficiency. Arch Neurol Psychiatry 1938; 40:789–9.
lateralization, and regional blood flow changes in temporal Pardo J, Marcos A, Bhathal H et al. Chorea as a form of
lobe seizures. Neurology 1992; 42:371–7. presentation of human immunodeficiency virus-associated
Nijssen PC, Brusse E, Leyton AC et al. Autosomal dominant adult dementia complex. Neurology 1998; 50:568–9.
neuronal ceroid lipofuscinosis: parkinsonism due to both Parry GJ, Bredesen DE. Sensory neuropathy with low-dose
striatal and nigral dysfunction. Mov Disord 2002; 17:482–7. pyridoxine. Neurology 1985; 35:1466–8.
Nomoto M, Thompson PD, Sheehy MP et al. Anticholinergic- Pascual-Leone A, Dhuna A. Cocaine-associated multifocal tics.
induced chorea in the treatment of focal dystonia. Mov Disord Neurology 1990; 40:999–1000.
1987; 2:53–6. Patel HC, Bruza D, Yerogani V. Myoclonus with trazodone. J Clin
Northam RS, Singer HS. Postencephalitic acquired Tourette-like Psychopharmacol 1988; 8:152.
syndrome in a child. Neurology 1991; 41:592–3. Paus S, Potzach B, Risse JH et al. Chorea and antiphospholipid
Nygaard TG, Duvoisin RC. Hereditary dystonia–parkinsonism antibodies: treatment with methotrexate. Neurology 2001;
syndrome of juvenile onset. Neurology 1986; 36:1424–8. 56:137–8.
Nygaard TG, Trugman JM, de Yebenes JG et al. Dopa-responsive Pedersen SB, Petersen KA. Juvenile myoclonic epilepsy:
dystonia: the spectrum of clinical manifestations in a large clinical and EEG features. Acta Neurol Scand 1998;
North American family. Neurology 1990; 40:66–9. 97:160–3.
p 03.qxd 3/10/08 9:32 AM Page 111
References 111
Penn H, Racy J, Lapham L et al. Catatonic behavior, viral Rasmussen P. Persistent mirror movements: a clinical study of 17
encephalopathy, and death. Arch Gen Psychiatry 1972; children, adolescents and young adults. Dev Med Child Neurol
27:758–61. 1993; 35:699–707.
Perry TL, Bratty PJA, Hansen S et al. Hereditary mental depression Read AE, Laidlaw J, Sherlock S. Neuropsychiatric complications of
and parkinsonism with taurine deficiency. Arch Neurol 1975; portocaval anastamosis. Lancet 1961; 1:961–4.
32:108–13. Read SL. Catatonia in thrombotic thrombocytopenic purpura.
Pfeil ET. Hemiballismus: hemichorea. J Nerv Ment Dis 1952; J Clin Psychiatry 1983; 44:343–4.
116:36–47. Reeves AL, So EL, Sharbrough FW et al. Movement disorders
Pfister H-W, Preac-Mursic V, Wilske B et al. Catatonic syndrome associated with the use of gabapentin. Epilepsia 1996;
in acute severe encephalitis due to Borrelia burgdorferi 37:988–90.
infection. Neurology 1993; 43:433–5. Reisberg B. Catatonia associated with disulfiram therapy. J Nerv
Piccolo I, Causarano R, Sterzi R et al. Chorea in patients with Ment Dis 1978; 166:607–9.
AIDS. Acta Neurol Scand 1999; 100:332–6. Remy P, de Recondo A, Defer G et al. Peduncular ‘rubral’ tremor
Pina MA, Modrego PJ. Dystonia induced by gabapentin. Ann and dopaminergic innervation: a PET study. Neurology 1995;
Pharmacother 2005; 39:380–2. 45:472–7.
Pittock SJ, Joyce C, O’Keane V et al. Rapid-onset dystonia- Richards RN, Barnett HJ. Paroxysmal dystonic choreoathetosis.
parkinsonism. A clinical and genetic analysis of a new kindred. A family study and review of the literature. Neurology 1968;
Neurology 2000; 55:991–5. 18:461–9.
Plana MT, Blanch J, Romero S et al. Toxic catatonia secondary to Rifkin AR, Quitkin F, Klein DF. Akinesia: a poorly recognized drug-
azithromycin. J Clin Psychiatry 2006; 67:492–3. induced extrapyramidal behavioral disorder. Arch Gen
Podskalny GD, Factor SA. Chorea caused by lithium intoxication. Psychiatry 1975; 32:672–4.
A case report and literature review. Mov Disord 1996; 11:733–7. Riley D, Lang AE. Hemiballism in multiple sclerosis. Mov Disord
Poyurovsky M, Pashinian A, Weizman R et al. Low-dose 1988; 3:88–94.
mirtazapine: a new option in the treatment of antipsychotic- Riley DE, Lange AE, Lewis A et al. Cortical-basal ganglionic
induced akathisia. A randomized, double-blind, placebo- and degeneration. Neurology 1990; 40:1203–12.
propranolol-controlled trial. Biol Psychiatry 2006; 59:1071–7. Ringman JM, Jankovic J. Occurrence of tics in Asperger’s
Pradhan S, Pandey N, Shashank S et al. Parkinsonism due to syndrome and autistic disorder. J Child Neurol 2000;
predominant involvement of substantia nigra in Japanese 15:394–400.
encephalitis. Neurology 1999; 53:1781–6. Rinne JO, Lee MS, Thompson PD et al. Corticobasal degeneration:
Prashanth LK, Taly AB, Ravi V et al. Adult subacute sclerosing a clinical study of 36 cases. Brain 1994; 117:1183–96.
panencephalitis: clinical profile of 39 patients from a tertiary Rio J, Montalban J, Pujadas F et al. Asterixis associated with
care center. J Neurol Neurosurg Psychiatry 2006; 77:630–3. anatomic cerebral lesions: a study of 45 cases. Acta Neurol
Priori A, Bertolasi L, Berardelli A et al. Acute dystonic reaction to Scand 1995; 91:377–81.
Ecstasy. Mov Disord 1995; 10:353. Ristic AJ, Svetel M, Dragasevic N et al. Bilateral chorea-ballism
Prodan CI, Monnot M, Ross ED et al. Reversible dementia with associated with hyperthyroidism. Mov Disord 2004;
parkinsonian features associated with budesonide use. 19:982–3.
Neurology 2006; 67:723. Ristic AJ, Vojvodic N, Jankovic S et al. The frequency of reversible
Provini F, Plazzi G, Tinuper P et al. Nocturnal frontal lobe epilepsy. parkinsonism and cognitive decline associated with valproate
A clinical and polygraphic overview of 100 consecutive cases. treatment: a study of 364 patients with different types of
Brain 1999; 122:1017–31. epilepsy. Epilepsia 2006; 47:2183–5.
Quartarone A, Girlanda P, Risitano G et al. Focal hand dystonia in Ritchie EC, Bridenbaugh RH, Jabbari B et al. Acute generalized
a patient with thoracic outlet syndrome. J Neurol Neurosurg myoclonus following buspirone administration. J Clin
Psychiatry 1998; 65: 272–4. Psychiatry 1988; 49:242–3.
Quartarone A, Girlanda P, Vita G et al. Oromandibular dystonia in Rittsmannberger H. Asterixis induced by psychotropic drug
a patient with bilateral putaminal necrosis after methanol treatment. Clin Neuropharmacol 1996; 19:349–55.
poisoning: an electrophysiological study. Eur Neurol 2000; Rittsmannberger H, Lebihuber F. Asterixis induced by
44:127–8. carbamazepine therapy. Biol Psychiatry 1992; 32:364–8.
Racette BA, Esper GJ, Antenor J et al. Pathophysiology of Robertson PL, Garofalo EA, Silverstein FS et al. Carbamazepine-
parkinsonism due to hydrocephalus. J Neurol Neurosurg induced tics. Epilepsia 1993; 34:965–8.
Psychiatry 2004; 75:1617–19. Rodrigues JP, Edwards DJ, Walters SE et al. Blinded placebo
Rail D, Scholtz C, Swash M. Post-encephalitic parkinsonism: crossover study of gabapentin in primary orthostatic tremor.
current experience. J Neurol Neurosurg Psychiatry 1981; Mov Disord 2006; 21:900–5.
44:670–6. Rodriguez ME, Artieda J, Zubieta JL et al. Reflex myoclonus in
Raskin DE, Frank SW. Herpes encephalitis with catatonic stupor. olivopontocerebellar atrophy. J Neurol Neurosurg Psychiatry
Arch Gen Psychiatry 1974; 31:544–6. 1994; 57:316–19.
Raskin NH, Fishman RA. Neurologic disorders in renal failure. Romisher S, Feller R, Dougherty J et al. Tagamet-induced acute
N Engl J Med 1976; 294:143–8, 204–10. dystonia. Ann Emerg Med 1987; 16:1162–4.
p 03.qxd 3/10/08 9:32 AM Page 112
Rosebush PI, Mazurek MF. Catatonia after benzodiazepine Sallee FR, Stiller RL, Perel JM et al. Pemoline-induced abnormal
withdrawal. J Clin Psychopharmacol 1996; 16:315–19. involuntary movements. J Clin Psychopharmacol 1989;
Rosebush P, Stewart T. A prospective analysis of 24 episodes of 9:125–9.
neuroleptic malignant syndrome. Am J Psychiatry 1989; Salt C, Lauter T, Kraus PH et al. Dose-dependent improvement of
146:717–25. myoclonic hyperkinesia due to valproic acid in eight
Rosebush PI, Hildebrand AM, Furlong BG et al. Catatonic Huntington’s disease patients: a case series. BMC Neurol
syndrome in a general hospital psychiatric population: 2006; 6:11.
frequency, clinical presentation, and response to lorazepam. Salvi F, Mascalchi M, Bortolotti C et al. Hypertension,
J Clin Psychiatry 1990; 51:347–53. hyperekplexia, and pyramidal paresis due to vascular
Rosebush PI, MacQueen GM, Clarke JTR et al. Late-onset compression of the medulla. Neurology 2000; 55:1381–4.
Tay–Sachs disease presenting as catatonic schizophrenia: Samie MR, Selhorst JB, Koller WC. Post-traumatic midbrain
diagnostic and treatment issues. J Clin Psychiatry 1995; tremor. Neurology 1990; 40:62–6.
56:347–53. Sandyk R. Parkinsonism secondary to neurosyphilis. A case report.
Rosen JA. Paroxysmal choreoathetosis. Arch Neurol 1964; S Afr Med J 1983; 63:665–6.
11:385–7. Saposnik G, Bueri JA, Rey RC et al. Catalepsy after stroke.
Rosenberg NL, Myers JA, Martin WRW. Cyanide-induced Neurology 1999; 53:1132–5.
parkinsonism: clinical, MRI and 6–flurodopa PET studies. Saunders-Pullman R, Shriberg J, Heiman G et al. Myoclonus
Neurology 1989; 39:142–4. dystonia. Possible association with obsessive-compulsive
Rosenbloom L. Dyskinetic cerebral palsy and birth asphyxia. Dev disorder and alcohol dependence. Neurology 2002;
Med Child Neurol 1994; 36:285–9. 58:242–5.
Rosenow F, Herholz K, Lanfermann H et al. Neurological sequelae Saver JL, Greenstein P, Ronthal M et al. Asymmetric catalepsy
of cyanide intoxication – the patterns of clinical, magnetic after right hemisphere stroke. Mov Disord 1993; 8:69–73.
resonance imaging, and positron emission tomography Sawle GV, Leenders KL, Brooks DJ et al. Dopa-responsive dystonia:
findings. Ann Neurol 1995; 38:825–8. [18F]dopa positron emission tomography. Ann Neurol 1991;
Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious 30:24–30.
suicide attempts by three patients: the role of akathisia. J Clin Scarano V, Pellechia MT, Filia A et al. Hallervorden–Spatz
Psychiatry 1991; 52:491–3. syndrome resembling a typical Tourette syndrome. Mov Disord
Roullet E, Nizou R, Jedynak P et al. Intention and action 2002; 17:618–20.
myoclonus disclosing occupational mercury poisoning. Rev Scarmeas N, Hadjieorgiou GM, Papadimitrou A et al. Motor signs
Neurol 1984; 140:55–8. during the course of Alzheimer’s disease. Neurology 2004;
Rozdilsky B, Cummings JN, Huston AF. Hallervorden–Spatz 63:975–82.
disease: late infantile and adult types, report of two cases. Schmidt A, Jabusch H-C, Altenmuller E et al. Dominantly
Acta Neuropathol 1968; 10:1–16. transmitted focal dystonia in a family of patients with
Ruprecht K, Warmuthmetz M, Waespe W et al. Symptomatic musician’s cramp. Neurology 2006; 67:691–3.
hyperekplexia in a patient with multiple sclerosis. Neurology Schott GD. The relationship of peripheral trauma and pain to
2002; 58:503–4. dystonia. J Neurol Neurosurg Psychiatry 1985; 48:698–701.
Russo LS. Focal dystonia and lacunar infarction of the basal Schule B, Kock N, Svetl M et al. Genetic heterogeneity in ten
ganglia: a case report. Arch Neurol 1983; 40:61–2. families with myoclonus-dystonia. J Neurol Neurosurg
Sachdev P, Kruk J. Clinical characteristics and predisposing factors Psychiatry 2004; 75:1181–5.
in acute drug-induced akathisia. Arch Gen Psychiatry 1994; Schultz DR, Barthal JS, Garrett C. Western equine encephalitis
51:963–74. with rapid onset parkinsonism. Neurology 1977; 27:1095–6.
Sachdev PS. The current status of tardive dyskinesia. Aust N Z J Schwartz A, Hennerici M, Wegener OH. Delayed choreoathetosis
Psychiatry 2000; 34:355–69. following acute carbon monoxide poisoning. Neurology 1985;
Saenz-Lope E, Herranz FJ, Masdeu JC. Startle epilepsy: a clinical 35:98–9.
study. Ann Neurol 1984; 16:78–81. Schwarz GA, Barrows LJ. Hemiballism without involvement of
Sahananthan GL, Geshon S. Imipramine withdrawal: an Luy’s body. Arch Neurol 1960; 2:420–34.
akathisia-like syndrome. Am J Psychiatry 1973; Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal
130:1286–7. of levodopa. Neurology 1984; 34:249–51.
Saint-Hilaire M-H, Saint-Hilaire J-M, Granger L. Jumping Sechi GP, Agnetti V, Piredda M et al. Acute and persistent
Frenchmen of Maine. Neurology 1986; 36:1269–71. parkinsonism after use of diquat. Neurology 1992; 42:261–2.
Saint-Hilaire M-H, Burke RE, Bressman SB et al. Delayed onset Sempere AP, Duarte J, Cabezas C et al. Parkinsonism induced by
dystonia due to perinatal or early childhood asphyxia. amlopidine. Mov Disord 1995; 10:115–16.
Neurology 1991; 41:216–22. Serdaru M, Hausser-Hauw C, Laplane D et al. The clinical
Sakai T, Mawatari S, Hiroshi I et al. Choreoacanthocytosis: clues spectrum of alcoholic pellagra encephalopathy. Brain 1988;
to clinical diagnosis. Arch Neurol 1981; 38:335–8. 111:829–42.
Salam SA, Pillai AK, Beresford TP. Lorazepam for psychogenic Sethi KD, Patel B, Meador KJ. Metoclopramide-induced
catatonia. Am J Psychiatry 1987; 144:1082–3. parkinsonism. South Med J 1989; 82:1581–2.
p 03.qxd 3/10/08 9:32 AM Page 113
References 113
Sethi KD, Patel BP. Inconsistent response to divalproex sodium in Spitz MC, Jankovic J, Killian JM. Familial tic disorder,
hemichorea/hemiballism. Neurology 1990; 40:1630–1. parkinsonism, motor neuron disease and acanthocytosis: a
Shah P, Kaplan SL. Catatonic symptoms in a child with epilepsy. new syndrome. Neurology 1985; 35:366–70.
Am J Psychiatry 1980; 137:738–9. Srinivas K, Rao VM, Subbulakshmi N et al. Hemiballism after
Shahnawaz M, van der Westhuizen LR, Gledhill RF. Episodic striatal hemorrhage. Neurology 1987; 37:1428–9.
cervical dystonia associated with gastro-oesophageal reflux. Stahl SM. Tardive Tourette syndrome in an autistic patient after
A case of adult-onset Sandifer syndrome. Clin Neurol long-term neuroleptic administration. Am J Psychiatry 1980;
Neurosurg 2001; 103:212–15. 137:1267–9.
Shan D-E, Soong B-W, Sun C-M et al. Spinocerebellar ataxia type Starkstein SE, Petracca G, Teson A et al. Catatonia in depression:
2 presenting as familial levodopa-responsive parkinsonism. prevalence, clinical correlates, and validation of a scale.
Ann Neurol 2001; 50:812–15. J Neurol Neurosurg Psychiatry 1996; 60:326–32.
Sharp FR, Rando TA, Greenberg SA et al. Pseudochoreoathetosis: Starosta-Rubinstein S, Young AB, Kluin K et al. Clinical
movements associated with loss of proprioception. Arch assessment of 31 patients with Wilson’s disease: correlations
Neurol 1994; 51:1103–9. with structural changes on magnetic resonance imaging. Arch
Shearer PM, Bownes IT, Curran P. Tardive akathisia and agitated Neurol 1987; 44:365–70.
depression during metoclopramide therapy. Acta Psychiatr Steele JC. Progressive supranuclear palsy. Brain 1972; 95:693–704.
Scand 1984; 70:428–31. Steinberg IN, Sternlieb I. Wilson’s disease. Philadelphia: WB
Sheehy MP, Marsden CD. Writer’s cramp – a focal dystonia. Brain Saunders, 1984.
1982; 105:461–80. Stell R, Davis S, Carroll WM. Unilateral asterixis due to a lesion of
Shepherd GMG, Tauboll E, Bakke SJ et al. Midbrain tremor and the ventrolateral thalamus. J Neurol Neurosurg Psychiatry
hypertrophic olivary degeneration after pontine hemorrhage. 1994; 57:116.
Mov Disord 1997; 12:432–7. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;
Shill HA, Stacy MA. Malignant catatonia secondary to sporadic 148:705–13.
encephalitis lethargica. J Neurol Neurosurg Psychiatry 2000; Stevanin G, Fujigasaki H, Lebre A-S et al. Huntington’s disease-
69:402–3. like phenotype due to trinucleotide repeat expansion in the
Siesling S, Vegter-Van der Vlis M, Roos RAC. Juvenile TBP and JPH3 genes. Brain 2003; 126:1599–603.
Huntington’s disease in the Netherlands. Pediatr Neurol 1997; Stevens H. ‘Jumping Frenchmen of Maine’. Myriachit. Arch Neurol
17:34–43. 1965; 12:311–14.
Singer C, Papapetropoulos S, Spielholz NI. Primary writing tremor: Stevens H. Paroxysmal choreo-athetosis. Arch Neurol 1966;
report of a case successfully treated with botulinum toxin A 14:415–20.
injections and discussion of the underlying mechanism. Mov Stewart JT, Williams LS. A case of lithium-induced asterixis. J Am
Disord 2005; 20:1387–8. Ger Soc 2000; 48:457.
Siris SG. Three cases of akathisia and ‘acting out’. J Clin Psychiatry Stober G, Seelow, D, Ruschendork et al. Periodic catatonia:
1985; 46:395–7. confirmation of linkage to chromosome 15 and further
Slater E, Beard SW. The schizophrenia-like psychoses of epilepsy. evidence for genetic homogeneity. Hum Genet 2002;
I. Psychiatric aspects. Br J Psychiatry 1963; 109:95–112. 111:523–30.
Snyder RD. The involuntary movements of chronic mercury Stojanovic M, Sternic N, Kostic VS. Cloazapine in hemiballismus:
poisoning. Arch Neurol 1972; 26:379–81. report of two cases. Clin Neuropharmacol 1997; 20:171–4.
Soland V, Bhatia KP, Volonte MA et al. Focal task-specific tremors. Stone LA, Jankovic J. The coexistence of tics and dystonia. Arch
Mov Disord 1996a; 11:665–70. Neurol 1991; 48:862–5.
Soland V, Evoy F, Rivest J. Cervical dystonia due to a frontal Strang RR. Parkinsonism occurring during methyldopa therapy.
meningioma. Mov Disord 1996b; 11:336–7. Can Med Assoc J 1966; 95:928–9.
Song X, Hu Z, Zhang H. Acute dystonia induced by lamivudine. Striano P, Elefante A, Coppola A et al. Dramatic response to
Clin Neuropharmacol 2005; 28:193–4. levetiracetam in post-ischemic Holmes’ tremor. J Neurol
Sorensen BF, Hamby WB. Spasmodic torticollis: results Neurosurg Psychiatry 2007; 78:438–9.
in 71 surgically treated patients. Neurology 1966; Stryjer R, Strous RD, Bar F et al. Segmental dystonia as the sole
16:867–78. manifestation of carbamazepine toxicity. Gen Hosp Psychiatry
Sotero de Menezes MA, Rho JM, Murphy P et al. Lamotrigine- 2002; 42:114–15.
induced tic disorder: report of five pediatric cases. Epilepsia Stuerenburg HJ, Hansen HC, Thie A et al. Reversible dementia in
2000; 41:862–7. idiopathic hypoparathyroidism associated with
Spacey SD, Adams PJ, Lam PCP et al. Genetic heterogeneity in normocalcemia. Neurology 1996; 47:474–6.
paroxysmal nonkinesiogenic dyskinesia. Neurology 2006; Stuppaeck CH, Miller CH, Ehrmann H et al. Akathisia induced by
66:1585–90. necrosis of the basal ganglia after carbon monoxide
Speracio RR, Anziska B, Schutta HS. Hypernatremia and chorea. intoxication. Mov Disord 1995; 10:229–31.
A report of two cases. Neurology 1976; 26:46–50. Sunden-Cullberg J, Tedroff J, Aquilonius SM. Reversible chorea in
Spiller WG. Acquired double athetosis (dystonia lenticularis). Arch primary antiphospholipid syndrome. Mov Disord 1998;
Neurol Psychiatry 1920; 4:370–86. 13:147–9.
p 03.qxd 3/10/08 9:32 AM Page 114
Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic Tison F, Arne P, Henry P. Myoclonus and adult coeliac disease.
encephalopathy due to ingestion of bismuth salts: clinical and J Neurol 1989; 236:307–8.
EEG studies of 45 patients. J Neurol Neurosurg Psychiatry Tolosa ES. Clinical features of Meige’s disease (idiopathic
1977; 40:748–52. orofacial dystonia): a report of 17 cases. Arch Neurol 1981;
Sutton GG, Meyere RF. Focal reflex myoclonus. J Neurol Neurosurg 38:147–51.
Psychiatry 1974; 37:207–17. Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts.
Svetel M, Kozic D, Stefanova E et al. Dystonia in Wilson’s disease. Neurology 1984; 34:1516–18.
Mov Disord 2001; 16:719–23. Tombini M Pacifici L, Passarelli F et al. Transient athetosis induced
Swaiman KK. Hallervorden–Spatz syndrome and brain iron by tiagabine. Epilepsia 2006; 47:799–800.
metabolism. Arch Neurol 1991; 48:1285–93. Tomita I, Satoh H, Satoh A et al. Extrapontine myelinolysis
Swedo SE, Leonard HL, Schapiro NB et al. Sydenham’s chorea: presenting with parkinsonism as a sequel of rapid correction
physical and psychological symptoms of St Vitus dance. of hyponatremia. J Neurol Neurosurg Psychiatry 1997;
Pediatrics 1993; 91:706–13. 62:422–3.
Swett C. Drug-induced dystonia. Am J Psychiatry 1975; Toru M, Matsuda O, Makiguchi K et al. Single case study:
132:532–4. neuroleptic malignant syndrome-like state following a
Tabaton M, Mancardi G, Loeb C. Generalized chorea due to withdrawal of antiparkinsonian drugs. J Nerv Ment Dis 1981;
bilateral small, deep cerebral infarcts. Neurology 1985; 169:324–7.
35:588–9. Trautner RJ, Cummings JL, Read SL et al. Idiopathic basal ganglia
Tambyah PA, Ong BKC, Lee KO. Reversible parkinsonism calcification and organic mood disorders. Am J Psychiatry
and asymptomatic hypocalcemia with basal ganglia 1988; 145:350–3.
calcification 26 years after thyroid surgery. Am J Med 1993; Tsuboi Y, Wxzolek ZK, Kusuhara T et al. Japanese family with
94:444–5. parkinsonism, depression, weight loss, and cortical
Tan EK, Lo YL, Chan LL et al. Cervical disc prolapse with cord hypoventilation. Neurology 2002; 58:1025–30.
compression presenting with choreoathetosis and dystonia. Tsubokawa T, Katayama Y, Yamamoto T. Control of persistent
Neurology 2002; 58:661–2. hemiballismus by chronic thalamic stimulation. Report of two
Tan H, Turali G, Ay H et al. Rubral tremor after thalamic infarction cases. J Neurosurg 1995; 82:501–5.
in childhood. Pediatr Neurol 2001; 25:409–12. Tyler HR. Neurological complications of dialysis, transplantation
Tanaka M, Yokode M, Kita T et al. Donepezil and athetosis in an and other forms of treatment in chronic uremia. Neurology
elderly patient with Alzheimer’s disease. J Am Geriatr Soc 1965; 15:1081–8.
2003; 51:889–90. Uitti RJ, Rajput AH, Ashenhurst EM et al. Cyanide-induced
Tandon R, Walden M, Falcon S. Catatonia as a manifestation of parkinsonism: a clinicopathologic report. Neurology 1985;
paraneoplastic encephalopathy. J Clin Psychiatry 1988; 35:921–5.
49:121–2. Uitti RJ, Snow BJ, Shinotoh H et al. Parkinsonism induced by
Tassin J, Durr A, Bonnet A-M et al. Levodopa-responsive dystonia: solvent abuse. Ann Neurol 1994; 35:616–19.
GTP cyclohydrolase I or parkin mutation? Brain 2000; Vakis A, Krasoudakis A, Koutendakis D. Transient post-traumatic
123:1112–21. hemiballism. Report of a case. J Neurosurg Sci 2006;
Tatu L, Moulin T, Martin V et al. Unilateral pure thalamic asterixis: 50:21–3.
clinical, electromyographic, and topographic patterns. Valente EM, Spacey SD, Wali GM et al. A second paroxysmal
Neurology 2000; 54:2339–42. kinesigenic choreoathetosis locus (EKD2) mapping on
Taylor MA, Abrams R. Catatonia: prevalence and importance in 16q13–q22 indicates a family of genes which give rise to
the manic phase of manic-depressive illness. Arch Gen paroxysmal disorders on human chromosome 16. Brain 2000;
Psychiatry 1977; 34:1223–5. 123:2040–5.
Tetrud JW, Langston JW, Garbe PL et al. Mild parkinsonism in Valenzuela R, Court J, Godoy J. Delayed cyanide induced dystonia.
persons exposed to 1-methyl-4-phenyl-1,2,3,6- J Neurol Neurosurg Psychiatry 1992; 55:198–9.
tetrahydropyridine (MPTP). Neurology 1989; 39:1483–7. van Hilten JJ, van de Beek WJ, Vein AA et al. Clinical aspects of
Teusink JP, Alexopoulos GS, Shamoian CA. Parkinsonism side- multifocal or generalized tonic dystonia in reflex sympathetic
effects induced by a monoamine oxidase inhibitor. Am J dystrophy. Neurology 2001; 56:1762–5.
Psychiatry 1984; 141:118–19. Vanek Z, Jankovic J. Dystonia in corticobasal degeneration. Mov
Thornton A, McKenna PJ. Acute dystonic reactions complicated by Disord 2001; 16:252–7.
psychotic phenomena. Br J Psychiatry 1994; 164:115–18. Van Putten T. The many faces of akathisia. Compr Psychiatry
Tijssen MA, Vergouwe MN, van Dijk JG et al. Major and minor 1975; 16:43–7.
forms of hereditary hyperekplexia. Mov Disord 2002; Van Putten T, May PRA. ‘Akinetic depression’ in schizophrenia.
17:826–30. Arch Gen Psychiatry 1978; 35:1101–7.
Tinuper P, Cerullo A, Cirignotta F et al. Nocturnal paroxysmal Van Putten T, Mutalipassi LR, Malkin MD. Phenothiazine-induced
dystonia with short-lasting attacks: three cases with evidence decompensation. Arch Gen Psychiatry 1974; 30:102–5.
for an epileptic frontal lobe origin of seizures. Epilepsia 1990; Van Putten T, May PRA, Marder SR. Akathisia with haloperidol
31:549–56. and thiothixene. Arch Gen Psychiatry 1984; 41:1036–9.
p 03.qxd 3/10/08 9:32 AM Page 115
References 115
Van Uitert RL, Russakoff LM. Hyperthyroid chorea mimicking Waubant E, Alize P, Tourbah A et al. Paroxysmal dystonia (tonic
psychiatric disease. Am J Psychiatry 1979; 136:1208–10. spasm) in multiple sclerosis. Neurology 2001; 57:2320–1.
Van Zandjke M. Treatment of myoclonus. Acta Neurol Belg 2003; Weddington WW, Marks RC, Verghese JP. Disulfiram
103:66–70. encephalopathy as a cause of the catatonic syndrome. Am J
Varga E, Sugerman AA, Varga V et al. Prevalence of spontaneous oral Psychiatry 1980; 137:1217–19.
dyskinesia in the elderly. Am J Psychiatry 1982; 139:329–31. Weiden P, Bruin R. Worsening of Tourette’s disorder due to
Velamoor VR, Norman RMG, Caroff SN et al. Progression of neuroleptic-induced akathisia. Am J Psychiatry 1987;
symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis 144:504–5.
1994; 182:168–73. Wein T, Andermann F, Silver K et al. Exquisite sensitivity of
Velez M, Cosentino C, Torres L. Levodopa-responsive rubral paroxysmal kinesigenic choreoathetosis to carbamazepine.
(Holmes’) tremor. Mov Disorder 2002; 17:741–2. Neurology 1996; 47:1104–5.
Verino S, Tuite P, Adler CH et al. Paraneoplastic chorea associated Weinberger DR, Wyatt RJ. Catatonic stupor and neuroleptic drugs.
with CRMP-5 neuronal antibody and lung carcinoma. Ann JAMA 1978; 239:1846.
Neurol 2002; 51:625–30. Weiner WJ, Nausieda PA, Klawans HL. Methylphenidate-induced
Verslegers W, Van den Kerchove M, Crols R et al. Methanol chorea: case report and pharmacologic implications.
intoxication. Parkinsonism and decreased met-enkephalin Neurology 1978; 28:1041–4.
levels due to putaminal necrosis. Acta Neurol Belg 1988; Wenning GK, Ben-Shlomo Y, Magalhaes M et al. Clinical features
88:163–71. and natural history of multiple system atrophy: an analysis of
Vestergaard P, Poulstrup I, Schou M. Prospective studies on a 100 cases. Brain 1994; 117:835–45.
lithium cohort. 3. Tremor, weight gain, diarrhea, psychological Wenning GK, Ben-Shlomo Y, Magalhaes M et al.
complaints. Acta Psychiatr Scand 1988; 78:434–41. Clinicopathological study of 35 cases of multiple system
Victor M, Adams RD, Cole M. The acquired ‘non-Wilsonian’ type of atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160–6.
chronic hepatocerebral degeneration. Medicine 1965; Wenning GK, Scherfler C, Granata R et al. Time course of
44:345–96. symptomatic orthostatic hypotension in patients with
Vidakovic A, Dragasevic N, Kostic VS. Hemiballism: report of 25 postmortem confirmed parkinsonian syndromes: a
cases. J Neurol Neurosurg Psychiatry 1994; 57:945–9. clinicopathological study. J Neurol Neurosurg Psychiatry 1999;
Volonte MA, Perani D, lanzi R et al. Regression of ventral striatum 67:620–3.
hypometabolism after calcium calcitrol therapy in paroxysmal Werhahan KJ, Brown P, Thompson PD et al. The clinical features
kinesigenic choreoathetosis due to idiopathic primary and prognosis of chronic posthypoxic myoclonus. Mov Disord
hypoparathyroidism. J Neurol Neurosurg Psychiatry 2001; 1997; 12:216–20.
71:691–5. Werner EG, Olanow CW. Parkinsonism and amiodarone therapy.
Walker L. Setrarline-induced akathisia and dystonia misinterpreted Ann Neurol 1989; 25:630–2.
as a panic attack. Psychiatr Serv 2002; 53:1477–8. Whittier JR. Ballism and subthalmic nucleus (nucleus
Walker RH, Spiera H, Brin MF et al. Parkinsonism associated with hypothalamicus; corpus Luysi). Review of the literature and
Sjogren’s syndrome: three cases and a review of the literature. study of thirty cases. Arch Neurol Psychiatry 1947; 58:672–92.
Mov Disord 1999; 14:262–8. Wilson LG. Viral encephalopathy mimicking functional psychosis.
Walsh F. On the symptom complexes of lethargic encephalitis Am J Psychiatry 1976; 133:165–70.
with special reference to the involuntary muscular Wilson P, Preece M. Chorea gravidarum. Arch Int Med 1932a;
contractions. Brain 1920; 43:197–219. 49:471–533.
Walshe JM, Yealland M. Wilson’s disease: the problem of delayed Wilson P, Preece M. Chorea gravidarum. Arch Int Med 1932b;
diagnosis. J Neurol Neurosurg Psychiatry 1992; 55:692–6. 49:671–97.
Walters AS, Hening W, Rubinstein M et al. A clinical and Wilson SAK. Modern problems in neurology. London: Edward
polysomnographic comparison of neuroleptic-induced Arnold, 1928.
akathisia and the idiopathic restless legs syndrome. Sleep Wilson SAK. Neurology, 2nd edn. London: Butterworth, 1955.
1991; 14:339–45. Wojick JD, Falk WE, Fink JS et al. A review of 32 cases of tardive
Warner TT, Lennox GG, Janota I et al. Autosomal-dominant dystonia. Am J Psychiatry 1991; 148:1055–9.
dentatorubropallidoluysian atrophy. Mov Disord 1994; Wolanczyk T, Grabowski-Grzyb A. Transient dystonias in three
9:289–96. patients treated with tiagabine. Epilepsia 2001; 42:944–6.
Warner TT, Williams LD, Walker RWH et al. A clinical and Woods C, Taylor A. Ataxia telangiectasia in the British Isles: the
molecular genetic study of dentatorubropallidoluysian atrophy clinical and laboratory features of 70 affected individuals. Q J
in four European families. Ann Neurol 1995; 37:452–9. Med 1992; 82:169–79.
Watanabe H, Saito Y, Terao S et al. Progression and prognosis in Yadalam KG, Korn ML, Simpson GM. Tardive dystonia: four case
multiple system atrophy. An analysis of 230 Japanese patients. histories. J Clin Psychiatry 1990; 51:17–20.
Brain 2002; 125:1070–83. Yamada K, Haraa M, Goto S. Response of postapoplectic
Waubant E, Simonetta-Moreau M, Clanet M et al. Left arm hemichorea/hemiballism to GPI pallidotomy: progressive
monoballism as a relapse in multiple sclerosis. Mov Disord improvement resulting in complete relief. Mov Disord 2004;
1997; 12:1091–2. 19:1111–14.
p 03.qxd 3/10/08 9:32 AM Page 116
Yassa R, Nair V, Dimitry A. Prevalence of tardive dystonia. Acta Zenzola A, De Mari M, De Blasi R et al. Paroxysmal dystonia with
Psychiatr Scand 1986; 73:629–33. thalamic lesion in multiple sclerosis. Neurol Sci 2001;
Yasuda M, Nakamura Y, Kaamata T et al. Phenotypic 22:391–4.
heterogeneity within a new family with the MAPT P301S Zesiewicz TA, Sullivan KL, Hauser RA. Chorea induced by
mutation. Ann Neurol 2005; 58:920–8. lamotrigine. J Child Neurol 2006; 21:357.
Yazici O, Kantemir E, Tastaban Y et al. Spontaneous improvement Zhang C, Glenn DG, Bell WL et al. Gabapentin-induced myolonus
of tardive dystonia during mania. Br J Psychiatry 1991; in end-stage renal disease. Epilepsia 2005; 46:156–8.
158:847–50. Zijlmans JCM, Thijssen HOM, Vogels OJM et al. MRI in patients
Yokoi S, Austin J, Witmer F et al. Studies in myoclonus epilepsy with suspected vascular parkinsonism. Neurology 1995;
(Lafora body form). Arch Neurol 1968; 19:15–33. 45:2183–8.
Yoshida Y, Akanuma J, Tochikubo S et al. Slowly progressive Zorumski CF, Bakris GL. Choreoathetosis associated with lithium:
dystonia following central pontine and extrapontine case report and literature review. Am J Psychiatry 1983;
myelinolysis. Intern Med 2000; 39:956–60. 140:1621–2.
Zaremba J, Mierzewska H, Lysiak Z et al. Rapid-onset dystonia-
parkinsonism: a fourth family consistent with linkage to
chromosome 19q13. Mov Disord 2004; 19:1506–10.
p 04.qxd 3/10/08 9:33 AM Page 117
4
Other signs and symptoms
4.1 Mutism 117 4.17 Obsessions and compulsions 133

4.2 Akinetic mutism 118 4.18 Reduplicative paramnesia 135
4.3 Stuttering 119 4.19 Confabulation 136
4.4 Palilalia 120 4.20 Amusia 136
4.5 Perseveration 121 4.21 Foreign accent syndrome 137
4.6 Primitive reflexes 121 4.22 Cataplexy 137
4.7 Pseudobulbar palsy 123 4.23 Sympathetic storm 138
4.8 Emotional facial palsy 124 4.24 Catastrophic reaction 139
4.9 Le fou rire prodromique 125 4.25 Flattened affect 139
4.10 Abulia 125 4.26 Inappropriate affect 139
4.11 Environmental dependency syndrome 126 4.27 Mannerisms 140
4.12 Kluver–Bucy syndrome 127 4.28 Stereotypies 140
4.13 Alien hand sign 129 4.29 Echolalia and echopraxia 141
4.14 Balint’s syndrome 131 4.30 Hallucinations and delusions 142
4.15 Phantom and supernumerary limbs 131 4.31 Schneiderian first rank symptoms 146
4.16 Depersonalization 132 References 148
4.1 MUTISM Stroke, when characterized by aphasia or aphemia, may

cause acute mutism. Motor aphasia and transcortical motor
The term mutism is derived from the Latin mutus, meaning aphasia may both, initially, present with mutism: over time,
‘inability to speak’. the mutism resolves, leaving the patient with the typical
aphasic syndrome, as discussed in detail in Section 2.1. Thus,
after resolution of the mutism, the patient with motor
Clinical features aphasia will be left with non-fluent speech but intact com-
prehension, and the patient with transcortical motor aphasia
Mute patients, as noted, do not speak; although in some will be similar but will show improvement of speech with
cases patients may make some noises such as grunts, there repetition.
is no verbalization. Aphemia is an uncommon stroke syndrome characterized
by mutism but, in contrast with the aphasias, there is a pre-
served ability to write; furthermore, as the mutism resolves,
Etiology patients are left, not with an aphasia, but with a hoarse
dysarthria. Aphemia, in most cases, is accompanied by a
As noted in Table 4.1, mutism may appear in several different right hemiparesis and occurs secondary to a small lesion in
clinical settings. Perhaps the most common one in neuropsy- the posterior aspect of the left inferior frontal gyrus or the
chiatric practice is the acute onset of mutism during a stroke. immediately subjacent white matter.
Mutism may also appear gradually in far-advanced neuro- Neurodegenerative disorders capable of causing dementia
degenerative disorders, such as frontotemporal dementia, may also cause a mutism of gradual onset: in this situation,
and is a prominent feature of several other syndromes, however, the mutism generally occurs only at the ‘tail end’ of
including akinetic mutism, catatonia, and severe cases of a long dementing process. Such an evolution has been noted
psychomotorically retarded depression. Finally, there is a in frontotemporal dementia and Alzheimer’s disease.
miscellaneous group of causes including intrinsic laryngeal Some neurodegenerative disorders may also present with
pathology, medications, and, in children, cerebellar surgery. aphasia, in the syndrome known as ‘primary progressive
p 04.qxd 3/10/08 9:33 AM Page 118
118 Other signs and symptoms
Table 4.1 Causes of mutism fact, speak. Although the speech may be effortful, as in
Stroke aphasia, slurred, as in dysarthria, or low and monotone, as
As presentation of certain aphasias in hypophonia, it is still there.
Motor aphasia (David and Bone 1984; Masdeu and O’Hara Selective, or, as it was once called, elective, mutism is a
1983) condition seen in shy and withdrawn children who, although
Transcortical motor aphasia (Alexander and Schmitt 1980; capable of speech with family members, become ‘selectively’
Bogousslavksy and Regli 1990) mute when with strangers or in school (Dummit et al. 1997;
Aphemia (Schiff et al. 1983) Elson et al. 1965; Steinhausen and Juzi 1996; Wergeland
1979).
Neurodegenerative disorders Conversion muteness and malingered muteness typically
Frontotemporal dementia (Neary et al. 1993; Snowden et al. occur as isolated findings, a feature that distinguishes them
1992) from mutism occurring secondary to the causes noted
Alzheimer’s disease (Mayeux et al. 1985) under ‘etiology’, wherein the mutism is accompanied by
Primary progressive aphasia (Gorno-Tempini et al. 2006) distinctive findings on history or examination.
Other syndromes characterized by mutism
Catatonia (Kraepelin 1990)
Depression (Benegal et al. 1992)
Treatment
Akinetic mutism (Cairns et al. 1941)
Treatment is directed at the underlying disorder; speech ther-
Miscellaneous causes of mutism apy may be attempted in cases of mutism secondary to stroke.
Intrinsic laryngeal pathology
Medications
Tacrolimus (Wijdicks et al. 1994) 4.2 AKINETIC MUTISM
Cyclosporine (Valldeoriola et al. 1996)
Cerebellar surgery (Catsman-Berrevoets et al. 1999; Van Dongen The name of this syndrome captures its most distinctive
et al. 1994) features, namely immobility and mutism.
aphasia’, which, over time, may evolve into mutism; this is Clinical features
discussed further in Section 2.1.
Other syndromes characterized by mutism include For the most part, patients are mute and immobile, and,
catatonia, severe depression, and akinetic mutism, and in although at first glance they appear to be in a stupor, closer
all three of these the mutism is accompanied by immobil- observation reveals lively conjugate eye movements as
ity. Several features allow these syndromes to be differenti- patients track objects in the room, such as physicians and
ated one from another. Catatonia is typically accompanied nurses. In some cases, the mutism and akinesia may persist
by the very distinctive finding of waxy flexibility, a sign through all adversities, but in others, patients may respond to
absent in the other two syndromes. Depression of the psy- an especially adversive stimulus with a feeble motion of a
chomotorically retarded type, when severe, may be accom- limb or perhaps by uttering a word. Food may be eaten if
panied by mutism; however, in these cases one finds a placed in the mouth but patients do not seek it, and urine
history of a preceding more typical depressive syndrome, and feces may be passed in the bed. Importantly, there is no
with depressed mood, anergia, anhedonia, and distur- rigidity, especially no waxy flexibility, and no negativism.
bances of appetite and sleep. When a patient with mutism Some examples may serve to flesh out this definition. The
and immobility lacks any of these findings then the diag- first is taken from Cairns’ original description of akinetic
nosis of akinetic mutism should be seriously considered. mutism (Cairns et al. 1941):
Of the miscellaneous causes of mutism, intrinsic laryngeal
pathology (e.g., laryngitis, laryngeal tumors) is the most com- In the fully developed state he makes no sound and
mon, and in these cases the mutism is preceded by hoarseness. lies inert, except that his eyes regard the observer
Medications capable of inducing mutism include tacrolimus steadily or follow the movement of objects, and they
and cyclosporine. Finally, in children who have undergone may be diverted by sound. Despite his steady gaze,
cerebellar surgery a syndrome of mutism may occur, either which seems to give promise of speech, the patient is
immediately postoperatively or within a few days. quite mute, or he answers only in whispered monosyl-
lables. Oft-repeated commands may be carried out in
a feeble, slow, and incomplete manner, but usually
Differential diagnosis there are no movements of a voluntary character: no
restless movements, struggling or evidence of nega-
Aphasia, dysarthria, and hypophonia are all distinguished tivism. Emotional movement is almost in abeyance. A
by the obvious fact that patients with these disorders do, in painful stimulus produces reflex withdrawal of the
p 04.qxd 3/10/08 9:33 AM Page 119
4.3 Stuttering 119
limb and, if the stimulus is maintained, slow, feeble, The persistent vegetative state may also appear similar to
voluntary movements of the limbs may occur in an akinetic mutism; however, in this condition the eye move-
attempt to remove the source of the stimulation, but ments – although at times seeming purposeful – are less con-
usually without tears, noise, or other manifestations of sistently ‘lively’; furthermore, in patients with the persistent
pain or displeasure. The patient swallows readily but vegetative state one always finds a history of coma secondary
has to be fed. Food seen may be recognized as such, to severe traumatic brain injury, global hypoxia, etc.
but there is evidently little appreciation of its taste and The locked-in syndrome, occurring secondary to high
other characteristics: objects normally chewed or brainstem infarction or other lesions, such as central pon-
sucked may be swallowed whole. There is total incon- tine myelinolysis, is characterized by tetraparesis, bilateral
tinence of urine and feces. facial paresis, and mutism, and thus may appear similar to
akinetic mutism. Examination of eye movements, however,
Cairns’ cases, occurring with third-ventricular tumors, will enable the correct diagnosis. In contrast with akinetic
were generally of gradual or subacute onset. Another case mutism, wherein extraocular movements are full, in the
(Nielsen 1951), secondary to infarction of the cingulate locked-in syndrome there is a paralysis of lateral gaze, with
gyri, bears detailed reporting given the remarkable abrupt- only vertical gaze being left intact. Furthermore, and again
ness of its onset. The patient was a 46-year-old woman who: in contrast with akinetic mutism, in the locked-in syndrome
the patient is often desperate for communication and will
was ironing when she suddenly stopped on the spot, attempt to do so by utilizing the remaining vertical eye
complained of a severe headache, but remained stand- movements in a sort of ‘Morse code’.
ing. Her son put her to bed, where she lay motionless, Stupor of various causes may leave patients immobile
without even speaking. She stared at the ceiling and and mute; however, in stupor patients are not alert and eye
did not ask for anything, not even for a drink. After 9 movements, rather than being ‘lively’, are generally roving
days she was hospitalized and on the ward she contin- or dysconjugate.
ued akinetic and mute. Under strong stimulation she Abulia may also be considered on the differential; how-
did say, ‘It hurts,’ and ‘Water,’ but that was all. She was ever, the distinction is readily apparent upon merely
obviously conscious and took note of her environment instructing the patient to do something. When left undis-
but lay day after day motionless, not deigning to call turbed, the abulic patient is mute and immobile like the
for bed pan or food. akinetic mute; however, when the abulic patient is given
directions he or she follows them, in contrast with the aki-
netic mute, who remains immobile.
Etiology
Akinetic mutism has been noted with intraventricular masses Treatment
of the third ventricle, which compressed the surrounding
diencephalon (Cairns et al. 1941), following surgical damage Anecdotally, bromocriptine is effective (Psarros et al. 2003;
to the hypothalamus (Ross and Stewart 1981), in obstruc- Ross and Stewart 1981); treatment may be initiated at
tive hydrocephalus (Messert et al. 1966), and with infarction 2.5 mg/day (given in two divided doses: once in the early
of the anterior cingulate gyri (Barris and Schuman 1953; morning and once in the early afternoon), and increased in
Faris 1969; Freemon 1971; Nielsen 1951). Akinetic mutism similar increments every few days until significant
has also been seen as a side-effect of cyclosporine (Bird et al. improvement or limiting side-effects occur or a maximum
1990) and in a patient treated with total body irradiation dose of 40 mg is reached.
and amphotericin B (Devinsky et al. 1987).
4.3 STUTTERING
Stuttering, a speech dysfluency familiar to most ears,
Akinetic mutism must be distinguished from other condi-
although most commonly seen on a developmental basis,
tions capable of causing immobility and mutism, including
may also, as noted below, occur on an acquired basis.
catatonia, depression, the persistent vegetative state, the
locked-in syndrome, and stupor.
Catatonia is distinguished by the presence of waxy flex- Clinical features
ibility, a sign not seen in akinetic mutism. Depression, when
severe and characterized by psychomotor retardation, may The phenomenology of stuttering differs according to
resemble akinetic mutism; however, in this instance history whether it occurs on a developmental or an acquired basis
will reveal a typical depressive syndrome preceding the (Helm et al. 1978).
evolution of immobility and mutism, with such symptoms In developmental stuttering, patients find themselves
as depressed mood, anergia, anhedonia, and changes in sleep ‘blocked’ as they attempt to speak the first letter or syllable of
and appetite. a word and have particular difficulty getting past the letters
p 04.qxd 3/10/08 9:33 AM Page 120
B, D, K, P, and T. Unable to surmount the sound, patients Of the various causes of acquired stuttering, medications
repeat it again and again, often with progressively increas- are the most common: among these, the tricyclic antidepres-
ing force and volume; with these ever-more vigorous sants and selective serotonin reuptake inhibitors (SSRIs) are
attempts, there may be associated features, such as facial the most frequent offenders, followed by the antipsy-
grimacing, blinking, hissing, and fist-clenching. The block chotics – including both first- and second-generation agents.
is eventually overcome and there is often a cascade of Alprazolam and theophylline only rarely have been reported
words, all clearly and unhesitatingly pronounced, as if the to cause stuttering.
dam had broken. Interestingly, patients with developmen- Stroke may be accompanied by stuttering and this has
tal stuttering may find themselves unblocked if they sing, been noted with infarction of the frontal cortex, the subcor-
read aloud, or are quite angry. tical white matter of the frontal lobe, the parietal cortex, the
Although acquired stuttering may be clinically similar putamen, and the caudate nucleus; there is also a case report
to developmental stuttering, it tends to differ in several ways. of stuttering with infarction of the body of the corpus callo-
First, the block may be as likely to occur on the second or sum. Although most cases of stuttering due to cerebral
subsequent letter as on the first. Second, although patients infarction occur with left-sided infarcts, there are rare cases
may be annoyed at being blocked, and do engage in repeated of ‘crossed’ stuttering wherein stuttering occurred with a
attempts to make the sound, the effort to do so is rarely as right-sided infarction in a right-handed patient (Fleet and
vigorous or as forceful as in developmental stuttering. Heilman 1985).
Finally, when a patient with acquired stuttering does get Parkinsonian conditions, such as Parkinson’s disease
beyond the block, it is unusual to see a subsequent ‘cascade’ and progressive supranuclear palsy may cause de novo stut-
of words. tering, and in the case of Parkinson’s disease, the onset of
parkinsonism may be associated with a relapse of child-
Etiology hood stuttering (Shahed et al. 2001). Stuttering also consti-
tutes the classic presentation of the now vanishingly rare
The various causes of stuttering are listed in Table 4.2, where dialysis dementia.
they are divided into developmental and acquired types.
Developmental stuttering, as noted earlier, is the most Differential diagnosis
common cause of stuttering. Here, as discussed in more
detail in Section 9.20, stuttering usually appears between Palilalia is distinguished by the fact that the last word (or
the ages of 2 and 10 years; although such developmental phrase) of a statement is repeated, in contrast with stutter-
stuttering may persist into adulthood, most cases undergo ing wherein typically it is the first letter or syllable which is
a spontaneous remission by early teenage years. repeated. The effortful speech of patients with motor apha-
sia may suggest stuttering; however, in aphasia one also
Table 4.2 Causes of stuttering finds ‘telegraphic’ speech, with an absence of conjugations,
which stands in contrast with stuttering wherein grammar
Developmental stuttering is preserved.
Acquired stuttering
Medications (Bar et al. 2004; Brady 1998; Christensen et al.
1996; Lee et al. 2001; Nurnberg and Greenwald 1981)
Treatment
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
Treatment of developmental stuttering is discussed in
Antipsychotics
Section 9.20; there are few data regarding treatment of
Alprazolam
stuttering as seen in stroke or parkinsonian conditions.
Theophylline
Stroke
4.4 PALILALIA
Frontal cortex (Freedman et al. 1984) or subcortical
white matter (Ludlow et al. 1987)
Palilalia, first described by Souques in 1908, is characterized,
Parietal cortex (Turgut et al. 2002)
according to Kinnier Wilson, by ‘the repetition of words or
Putamen (Ciabarra et al. 2000)
short phrases perhaps at increasing speed with decreasing
Caudate nucleus (Caplan et al. 1990)
audibility’ (Wilson 1954, p. 138).
Corpus callosum (Hamano et al. 2005)
Parkinsonian conditions
Parkinson’s disease (Koller 1983) Clinical features
Progressive supranuclear palsy (Kluin et al. 1993; Koller
1983) Palilalic patients involuntarily repeat the last phrase or word,
and do so with increasing rapidity, but with diminishing dis-
Dialysis dementia (O’Hare et al. 1983)
tinctness: ‘One patient (Serra-Mestres et al. 1996), when
p 04.qxd 3/10/08 9:33 AM Page 121
4.6 Primitive reflexes 121
asked “How are you today?” replied “I am very well, thank Perseverative behavior may involve drawing, writing, or
you, thank you, thank you, thank you . . .” up to six times other motor activity. After being asked to draw a stick fig-
with increasing speed and decreasing volume.’ ure one patient did so and then drew multiple others until
the page was filled. Another patient who was asked to write
his name wrote out ‘Paul’ and then perseverated with the
Etiology letter ‘l’, until he reached the edge of the page. In another
case, a patient, after being asked to get dressed, went to the
Palilalia occurs in Parkinson’s disease (Benke et al. 2000), closet, took out a pair of pants, then paused and hung them
progressive supranuclear palsy (Kluin et al. 1993), Tourette’s back up, then took them out again, and repeated the
syndrome (Cardoso et al.), and in advanced Alzheimer’s dis- sequence until being asked to stop.
ease (Cummings et al. 1985). There are also rare case reports
of palilalia in multi-infarct dementia (Serra-Mestres et al.
1996), thalamic infarction (Yasuda et al. 1990), and as one Etiology
manifestation of complex partial status epilepticus (Linetsky
et al. 2000). Perseveration is common in dementia (Bayles et al. 1985),
especially frontotemporal dementia (Thompson et al. 2005),
Alzheimer’s disease (Bayles et al. 2004), and diffuse Lewy
Differential diagnosis body disease (Doubleday et al. 2002). It is commonly seen in
delirium, and is also an integral part of the frontal lobe syn-
Verbal perseveration is distinguished by the fact that the drome. Other conditions characterized by perseveration
repeated word or phrase is spoken without the distinctive include aphasia (Albert and Sandson 1986), autism
increasing rapidity and decreasing distinctness. (Rumsey et al. 1986), schizophrenia (Siegel et al. 1976), and
Stuttering is distinguished by the fact that it is the first let- traumatic brain injury (Hotz and Helm-Estabrooks 1995).
ter of a word that is repeated, and echolalia by the fact that in
echolalia what is repeated is not something the patient spoke
but rather what the examiner or another person said. Differential diagnosis
Palilalia is distinguished by the fact that the verbal repeti-

Treatment tion has a distinctive character to it, in that the repeated
word or phrase is said with increasing speed and decreasing
Treatment is directed at the underlying condition. In a case distinctness.
of palilalia occurring as part of a multi-infarct dementia, Stereotypies represent a subset of perseverative motor
trazodone was effective (Serra-Mestres et al. 1996); behavior wherein the repeated behaviors are distinctly pur-
whether this would carry over into other conditions is not poseless and monotonous. In many patients with dementia,
known. schizophrenia or autism, both purposeful and stereotypi-
cal perseveration may appear.
4.5 PERSEVERATION Treatment

Perseverative speech or behavior (Sandson and Albert Perseverative behavior may lessen or remit with treatment
1987) is commonly seen in a variety of conditions, most of the underlying condition. In one unblinded study,
notably dementia. bromocriptine reduced perseverative behavior in dementia
(Imamura et al. 1998).
Clinical features
4.6 PRIMITIVE REFLEXES
Perseverative speech generally occurs in one of two forms.
In one, termed recurrent, patients supply the same response Normal infancy is characterized by numerous reflexes that,
to repeated, but different, questions. For example, one in the usual course of events, tend to fade or disappear with
patient, when asked where she was, replied ‘Louisville;’ development; these may, however, be found in adults, and
when asked next what year it was, she perseverated in her in such cases they are known as ‘primitive’ reflexes. Although
response, and again said ‘Louisville.’ The other form is these reflexes are found in certain pathologic conditions,
termed continuous and here, without being prompted, such as dementia, they may also, as noted below, be found
patients repeat the same word or phrase again and again. in normal individuals, and hence care must be taken in
One of Kinnier Wilson’s (Wilson 1954) patients with Pick’s their interpretation.
disease ‘repeated endlessly, “I want my husband and my Primitive reflexes are also known as developmental
children and I don’t know where they are.” ’ reflexes; ‘frontal release signs’ constitutes another synonym.
p 04.qxd 3/10/08 9:33 AM Page 122
Clinical features had to use his right hand to free himself’ (Seyffarth and
Denny-Brown 1948). In another case (Stewart-Wallace
Four primitive reflexes are considered here, namely the 1939), the patient’s right hand ‘developed a habit of clutch-
palmomental reflex, the snout reflex, the grasp reflex, and ing hold of objects of its own accord, such as the lapel of his
the grope reflex. coat, the edge of his trouser pocket, or the bed-clothes.
The palmomental reflex (Blake and Kunkle 1951; Jacobs This distressed him so much that in order to prevent it, he
and Gossman 1980) is elicited by repeatedly and rapidly used to wear a glove most of the time. At other times he
dragging an object, such as the tip of the reflex hammer, would keep his hand in his pocket, holding a coin or a key’.
across the thenar eminence from the lateral aspect medially Another patient (Walshe and Hunt 1936), questioned
toward the center of the palm: the contact should be defi- about the experience, noted that ‘I can’t leave things alone.
nite, and slightly disagreeable, but not painful. When the If I see anything lying near me, my hand seems to want it.’
reflex is present, one sees a wrinkling of the ipsilateral
mentum, or chin. Etiology
The snout reflex (Jacobs and Gossman 1980) is elicited
by placing one’s index finger just above the patient’s upper Primitive reflexes, as noted earlier, may be found in normal
lip, in the midline, centered upon the philtrum, and then individuals, especially the elderly (Jacobs and Gossman
either gently pressing the finger in or gently tapping it with 1980; Koller et al. 1982); indeed the palmomental reflex has
the reflex hammer: a positive reflex is indicated by a puck- been noted in anywhere from 11 (Jensen et al. 1983) to 37
ering or protruding of the lips. percent (Jacobs and Gossman 1980) of normal people; con-
The grasp reflex is tested for by laying one’s index finger sequently finding one primitive reflex is of uncertain clini-
flat across the palm of the patient’s hand (with the tip of cal significance. Finding more than one primitive reflex,
the finger pointing toward the hypothenar eminence and however, is uncommon and finding three in one patient
the base of the finger resting between the patient’s thumb should raise strong suspicions regarding disease of the
and index finger) and then slowly withdrawing one’s finger frontal lobe (Brown et al. 1998; Di Legge et al. 2001).
between the patient’s thumb and index finger (Adie and As a group, primitive reflexes are commonly found
Critchley 1927; Seyffarth and Denny-Brown 1948). When in parkinsonian conditions, such as Parkinson’s disease
present, the reflex consists of the patient’s fingers involun- (Maartens de Noordhout and Delwaide 1988; Vreeling et al.
tarily closing upon the examiner’s finger, as if grasping it. 1993), diffuse Lewy body disease (Boroni et al. 2006), and
Once the finger has been grasped, attempts by the exam- progressive supranuclear palsy (Brodsky et al. 2004), and in
iner to pull it free often result in a stronger grasp, but if the various dementias (Tweedy et al. 1981; Waite et al. 1996),
examiner ceases all effort to remove the finger the patient’s such as frontotemporal dementia (Sjogren et al. 1997),
hand typically relaxes (Walshe and Robertson 1933). If Alzheimer’s disease (Vreeling et al. 1995), multi-infarct
there is any doubt as to the involuntary nature of the grasp dementia (Vreeling et al. 1995), and AIDS dementia (Marder
the test may be repeated, but only after first instructing the et al. 1995); they have also been noted in patients with schiz-
patient to not grab the examiner’s finger. Interestingly, ophrenia (Barnes et al. 1995; Hyde et al. 2007; Lohr 1985).
such a grasping reflex may be present in a hemiplegic limb, Primitive reflexes are associated with frontal lobe
such that although the patient is unable to flex the fingers pathology, and this is especially the case with the grasp and
voluntarily, grasping occurs with the appropriate stimula- grope reflexes: although they have been noted with infarc-
tion (Stewart-Wallace 1939). tion of the motor and premotor cortex, they appear to be
The grope reflex (also known as ‘instinctive grasping’) is more common with infarction of the medial aspect of the
a truly remarkable clinical phenomenon. Testing is accom- frontal lobe, particularly the cingulate gyrus in its anterior
plished by simply touching the patient’s hand: when the portion, and the supplemental motor area (De Renzi
reflex is present, the patient’s hand will involuntarily reach and Barbieri 1992; Hashimoto and Tanaka 1998; Mori
out in a groping fashion to grasp the examiner’s finger and Yamadori 1985; Stewart-Wallace 1939; Walshe and
(Mori and Yamadori 1985). In some cases, one may also Robertson 1933; Walshe and Hunt 1936).
demonstrate the ‘magnet’ reaction, wherein by successive
touches of the patient’s hand from successively different
positions one may lead the patient’s hand through space, Differential diagnosis
much as if it were being attracted by a magnet (Seyffarth
and Denny-Brown 1948). When fully developed, actual The grope reflex must be distinguished from the alien hand
touch may not be required to elicit the reflex, and the sign, a distinction made possible by attending to the seeming
patient’s hand may automatically begin groping at the ‘intent’ of the moving hand. In groping, the hand reaches for
mere sight of another object (Mori and Yamadori 1985). whatever may be nearby, whether a doorknob or the exam-
The presence of a grope reflex may significantly inter- iner’s hand, and simply grabs hold. In the alien hand sign,
fere with the patient’s day-to-day life. One patient, when- however, the left hand does something with the object,
ever passing through a doorway, found that his ‘left hand something, which, importantly, is at cross-purposes with
clung to [the] door handle . . . with such tenacity that he what the patient is intentionally doing with the right hand.
p 04.qxd 3/10/08 9:33 AM Page 123
4.7 Pseudobulbar palsy 123
Treatment Importantly, these emotional displays are not accompa-

nied by any corresponding feeling of sadness or mirth. In one
Except for the grope reflex, treatment is not required; in case (Davison and Kelman 1939), a patient, although feeling
cases when the grope reflex interferes with activities of no mirth, experienced such ‘gales of laughter’ that he ‘felt
daily living, occupational therapy may assist in developing foolish and ashamed, and had tears in his eyes, because he
strategies to prevent the reflex from happening. could not ‘control the laughter’. The paroxysms of laughter
or crying tend to last on the order of minutes and then resolve
spontaneously; in some cases there may be only laughter, or
4.7 PSEUDOBULBAR PALSY only crying; however, in others one may see laughter suc-
ceeded by crying, or vice versa, in the same episode.
Pseudobulbar palsy is a syndrome that occurs secondary to
interruption of the corticobulbar tracts.
Etiology
Clinical features As noted earlier, pseudobulbar palsy occurs secondary to
interruption of the corticobulbar tract. This tract originates
When fully developed (Langworthy and Hesser 1940; Tilney in the cortex and descends, in concert with corticospinal
1912), the syndrome of pseudobulbar palsy consists of fibers, inferiorly, through the internal capsule, the crus cere-
‘emotional incontinence’, dysarthria, dysphagia, a stiff and bri, the basis pontis, and, finally, the medullary pyramids
shuffling gait, an exaggerated jaw jerk and gag reflex, and a (Besson et al. 1991). Throughout its course in the brainstem,
variable degree of paresis of the tongue; the corticospinal fibers leave the tract to head toward various brainstem
tracts are often also involved, as evidenced by exaggerated nuclei. Most brainstem nuclei are innervated bilaterally and
deep tendon reflexes and bilateral Babinski signs. in most cases bilateral interruption of the corticobulbar
Emotional incontinence (also known as ‘pathologic tracts is required before significant symptomatology occurs.
laughing and crying’ or ‘pseudobulbar affect’) is the most Of the many disorders capable of causing emotional incon-
striking aspect of the syndrome, and is characterized by either tinence, vascular disease is the most common.
laughter or crying, occurring either spontaneously or in Emotional incontinence has been noted after bilateral
response to some otherwise trivial stimulus, such as someone infarction of the posterior frontal cortex (Colman 1894;
approaching the bed (Lieberman and Benson 1977). After Davison and Kelman 1939; Wilson 1924), bilateral lacunar
suffering bilateral strokes, one of Kinnier Wilson’s patients: infarctions affecting the posterior limbs of the internal cap-
sule (Helgason et al. 1988), and bilateral lacunar infarc-
was seen to have a distinctly vacant, apathetic facial tions of the basis pontis (Asfora et al. 1989; Bassetti et al.
expression at rest. She was able to move facial 1996). In many cases of stroke-related emotional inconti-
muscles voluntarily on both sides, although there was nence, one finds a history of a stroke wherein there was
the slightest weakness of the left corner of the mouth. damage to the corticobulbar fibers on one side, with the
On the slightest stimulus, even when the observer current stroke completing the picture by damaging fibers
simply came to her bedside, she at once assumed a on the other side (Wilson 1924). There are, however, rare
most lugubrious expression, her mouth opened widely, cases of emotional incontinence occurring after isolated
and a long, almost noiseless bout of weeping ensued, unilateral infarction of the internal capsule (Ceccaldi et al.
lasting for many seconds, even minutes, at a time. 1994; Derex et al. 1997): the mechanism by which emo-
tional incontinence occurs in such cases is not clear and
(Wilson 1924) may involve congenital abnormalities.
Other disorders capable of causing bilateral interruption
Another of Wilson’s patients, again after bilateral strokes: of the corticobulbar tracts and emotional incontinence
include amyotrophic lateral sclerosis (ALS) (Gallagher 1989;
exhibited characteristic involuntary laughing. Ironside 1956; Ziegler 1930), multiple sclerosis (Feinstein
Whatever the emotional stimulus, and however slight, et al. 1997), central pontine myelinolysis (van Hilten et al.
he at once began to laugh and laugh loudly. Thus, on 1988), progressive supranuclear palsy (Behrman et al. 1969;
reading the war news he at once began to smile, and Menza et al. 1995), and multiple system atrophy (Parvizi et
the more serious and anxious the news, the more he al. 2007). Emotional incontinence may also be seen in disor-
laughed. On examination, there was some voluntary ders characterized by widespread damage to the cortex or
facial paresis on both sides, especially the left, some subcortical areas, including traumatic brain injury (Tateno
dysarthria, and some dysphagia, but during the et al. 2004; Zelig et al. 1996), Binswanger’s disease (Caplan
laughing the facial movements were in no way and Schoene 1978), and, in advanced stages, Alzheimer’s
restricted. A double extensor response was present. disease (Starkstein et al. 1995).
Finally, emotional incontinence has been noted with
(Wilson 1924) intrinsic brainstem tumors (Achari and Colover 1976;
p 04.qxd 3/10/08 9:33 AM Page 124
Cantu and Drew 1966) and also with compression of the are probably second choices, given their side-effect bur-
brainstem, as for example by a meningioma (Motomura dens; citalopram, in contrast, is extraordinarily easy to use.
et al. 1980). In cases when citalopram is ineffective, one might consider
dextromethorphan or one of the other antidepressants;
nortriptyline would probably be the best of these, given its
lower side-effect burden.
‘Emotionalism’ is not at all uncommon after strokes but it
is readily distinguished from the emotional incontinence
of pseudobulbar palsy by the fact that ‘emotional’ patients
4.8 EMOTIONAL FACIAL PALSY
experience an affect congruent with their facial expression,
Most central facial palsies are of the ‘voluntary’ sort, in that
whereas the emotionally incontinent patient feels neither
when patients are asked to voluntarily perform a facial
sadness nor mirth and is often as surprised at the emo-
maneuver, such as showing their teeth, there is a droop evi-
tional display as is the observer.
dent on one side; less commonly one finds an ‘emotional’
Lability of affect, as may be seen in mania, is, like emo-
facial paresis wherein, although voluntary movements are
tionalism, distinguished from emotional incontinence by the
intact, a ‘droop’ becomes evident when the patient smiles
presence of an affect congruent with the facial expression.
in response, say, to a joke. This emotional facial paresis has
Episodes of mirthless laughter may also occur in an iso-
also been termed ‘mimetic’ or ‘involuntary’ facial paresis.
lated fashion as le fou rire prodromique and as a simple par-
tial seizure in gelastic epilepsy. Le fou rire prodromique, as
discussed in Section 4.9, represents a prodrome to stroke Clinical features
and is distinguished from the emotional incontinence of
pseudobulbar palsy in that the mirthless laughter of emo- Facial palsies may be either peripheral or central. In a
tional incontinence occurs after stroke. Gelastic seizures peripheral facial palsy, there is no movement in either the
are suggested by a history of other seizure types, such as forehead or the lower face, whether on voluntary com-
grand mal or complex partial seizures. mand or in response to a joke. Central facial palsies are
immediately distinguished from peripheral palsies in that
this palsy affects only the lower half of the face, with fore-
Treatment
head movements being spared.
The two forms of central facial palsy, namely voluntary
In placebo-controlled, double-blind studies, several med-
and emotional, may be distinguished by first noting facial
ications have been shown to be effective for emotional
movements when patients are instructed to voluntarily
incontinence. For cases occurring secondary to infarction
show their teeth and then, at some point in the examina-
nortriptyline (in doses of from 50 to 100 mg) (Robinson
tion, by closely observing facial movements when the
et al. 1993), imipramine (in doses of 10–20 mg) (Lawson
patient spontaneously smiles, for example in response to a
and McLeod 1969), and citalopram (in doses of 10–20 mg)
joke or recollection of some happy memory (Monrad-
(Andersen et al. 1993) are each effective. For emotional
Krohn 1924).
incontinence in ALS (Brooks et al. 2004) a combination of
In voluntary central facial paresis there is a droop of one
dextromethorphan (30 mg) and quinidine (30 mg), given
side of face when patients are asked to show their teeth;
twice daily, is also effective: in this preparation, quinidine
however, when these patients are observed smiling at a
is used merely in order to inhibit the metabolism of dex-
joke, one sees full facial movements on both sides.
tromethorphan, which is the active agent. In cases of MS,
In emotional facial paresis there is full movement bilat-
both amitriptyline (Schiffer et al. 1985) and the combina-
erally when patients are asked to show their teeth; however,
tion of dextromethorphan and quinidine are effective
when one observes these patients smiling at a joke, there is
(Panitch et al. 2006).
drooping of one side of the face; this produces what might
It must be stressed that although amitriptyline, nortripty-
be called a ‘hemismile’.
line, imipramine, and citalpram are all antidepressants, they
are effective regardless of whether patients are depressed or
not; furthermore, although the response to both amitripty- Etiology
line and nortriptyline may take weeks, the response to
citalopram may be very rapid, with some patients getting Voluntary and emotional facial paresis are dissociated
relief within a day or two. because the corticobulbar fibers subserving these two func-
It is not clear whether the agents that are found to be tions are separate.
effective in stroke cases would be effective in amyotrophic Corticobulbar fibers for voluntary facial movement
lateral sclerosis or multiple sclerosis, and vice versa, and it is arise in the posterior portion of the frontal cortex, descend
not clear whether any of these agents would be effective in through the corona radiata to the posterior limb of the
emotional incontinence of other causes. In choosing among internal capsule and then travel through the ventral mes-
these agents, amitriptyline, nortriptyline and imipramine encephalon in the crus cerebri to the basis pontis. At this
p 04.qxd 3/10/08 9:33 AM Page 125
4.10 Abulia 125
point most of these fibers then cross to travel directly to the In one case (Wali 1993), a 35-year-old woman, ‘after a
contralateral facial nucleus, whereas a minority of them warm shower suddenly began to laugh. The laughter was
descend further into the medulla, cross and ‘loop’ back up inappropriate to the situation and continued for nearly 15
into the pons, and continue to the facial nucleus. minutes at the end of which it became a low grade giggle.
Corticobulbar fibers for emotional facial movements This lasted for another 15 minutes and ended abruptly when
have widespread origins in the cerebrum, including the she collapsed’. On admission she was found to have suffered
supplemental motor area on the medial aspect of the frontal a bilateral pontine infarction, and was left in a ‘locked-in’
lobe and temporal lobe structures (e.g., the amygdala); the state. In another case (Martin 1950), the patient’s first attack
thalamus also plays a role. Fibers descend in the anterior occurred at his mother’s funeral, and, much to his distress,
limb of the internal capsule, pass through the tegmentum of recurred and recurred, without any apparent cause, until he
the mesencephalon and into the dorsal pons. At this point, collapsed and died several days later; autopsy revealed an
most fibers then cross to end in the contralateral facial interpeduncular aneurysm that had ruptured.
nerve; however, a minority of fibers proceed down into the
medulla, crossing in this structure and then looping back
up into the pons to contact the facial nucleus. Etiology
Emotional facial paresis has been reported with con-
tralateral lesions, generally infarctions, of a large number of Such prodromal laughter has been noted with infarction of
structures (Hopf et al. 1992), including the supplemental the following structures: parietotemporal cortex (Lago
motor area (Gelmers 1983), temporal lobe (Remillard et al. 1998), external and extreme capsules (Kumral and Calli
1977), thalamus (Bogousslavsky et al. 1988; Graff-Radford 2006); striatum (Carel et al. 1997), genu (Uzunca et al.
et al. 1984; Ross and Mathiesen 1998), anterior limb of 2005) or posterior limb (Ceccaldi and Milandre 1994) of
the internal capsule (Trosch et al. 1990), mesencephalic the internal capsule, and the basis pontis (Assal et al. 2000;
tegmentum (Wilson 1924), and the dorsal pons (Hopf et al. de AA Gondin et al. 2001; Wali 1993).
2000); a case has also been reported of emotional facial pare-
sis with an ipsilateral medullary lesion (Cerrato et al. 2003).
Emotional facial paresis has also been noted in patients
with chronic complex partial seizures of temporal lobe ori-
Mirthless laughter may be seen in the ‘emotional inconti-
gin, and in these cases the emotional facial paresis is gener-
nence’ of pseudobulbar palsy and during gelastic seizures.
ally contralateral to the side with the seizure focus (Jacob
Pseudobulbar palsy is distinguished by the clinical course,
et al. 2003). The theory here is that repetitive ictal activity
in that in pseudobulbar palsy the episodes of mirthless
leads to damage of the amygdala.
laughter occur after the stroke, whereas in le fou rire pro-
dromique the episodes occur beforehand. Gelastic seizures
Differential diagnosis are suggested by the occurrence, at other times, of other
seizure types, for example grand mal or complex partial.
Some individuals have a congenital ‘lopsided’ grin; the dif-
ferential rests here on determining that the ‘lopsidedness’
has been present since earliest childhood. Treatment
Treatment for the laughter per se is not required as it even-

Treatment tually remits spontaneously; of obviously greater impor-
tance is recognizing mirthless laughter as a possible stroke
Specific treatment is not required.
prodrome and proceeding accordingly.
4.9 LE FOU RIRE PRODROMIQUE

4.10 ABULIA
Very rarely, uncontrollable, mirthless laughter may occur as
the prodrome to an ischemic infarction; this phenomenon The term abulia is derived from the Greek, and means ‘a
was first described by Fere in 1903, who named it le fou rire lack of will or drive’; synonyms include pure psychic akine-
prodromique. sia and athymormia.
Clinical features Clinical features
Le fou rire prodromique manifests as a paroxysmal, uncon- Abulic patients, to a greater or lesser degree, lack ‘will’ in
trollable fit of laughter, lasting for minutes to a half hour, that they fail to experience any initiative or sense of drive:
during which there is full preservation of consciousness there are no impulses of action, no desires, angers, or long-
and, critically, no corresponding sense of mirth. ings; one patient commented that there was ‘a blank in my
p 04.qxd 3/10/08 9:33 AM Page 126
mind’ (Laplane et al. 1984). Importantly, these patients are 2.5 mg in total per day, and increased in similar increments
not depressed or bored; rather they experience a benign every few days until satisfactory improvement or unaccept-
sort of emptiness. able side-effects occur, or a maximum dose of perhaps
Abulic patients, thus volitionally impoverished, may be 40 mg is reached; in all cases, dosage is generally divided
content to sit or lie quietly, doing nothing and saying noth- into two doses: one in the morning and the next in the
ing, and thus present a picture of immobility and mutism. early afternoon.
Importantly, however, if they are asked to do something or
to speak, one finds that they are able to perform and com-
plete tasks in a timely and successful fashion: once left to 4.11 ENVIRONMENTAL DEPENDENCY
themselves, however, they rapidly lapse back into a placid SYNDROME
quietude.
This rare syndrome was initially described in 1983 by
Lhermitte, who named it ‘utilization behavior’; in a subse-
Etiology quent paper, he changed the name to the ‘environmental
dependency syndrome’ (Lhermitte 1986).
Pure abulia may be seen with bilateral or unilateral infarc-
tion or hemorrhage of various subcortical structures includ- Clinical features
ing the caudate nucleus (Bhatia and Marsden 1994; Caplan
et al. 1990; Kumral et al. 1999; Mendez et al. 1989), globus In this syndrome, patients appear to lose their autonomy,
pallidus (Bhatia and Marsden 1994; Giroud et al. 1997; becoming ‘dependent’ on their environment such that they
Laplane et al. 1984), thalamus (Bogousslavsky et al. 1991; feel compelled to pick up and ‘utilize’ whatever may come
Van Der Werf et al. 1999), or genu of the internal capsule to their attention. For example, one patient upon seeing a
(Yamanaka et al. 1996). pair of glasses put them on, even though they were not his;
Abulia has also been noted as a sequela to carbon another patient, upon seeing a toothbrush, picked it up
monoxide intoxication with bilateral necrosis of the globus and began brushing, even though there was no need to do
pallidus (Laplane et al. 1984; Lugaresi et al. 1990). so. At times, the utilization behavior can be more complex.
Finally, abulia occurs commonly in schizophrenia, For example, in describing one of his patients Lhermitte
especially simple schizophrenia. Kraepelin (1921) noted noted that both he and the patient:
that such patients ‘experience no tediousness, have no
need to pass the time . . . but can lie in bed unoccupied for sat down in my office. I put some medical
days and weeks, stand about in corners, “stare into a hole”, instruments on my desk. She immediately picked up
(or) watch the toes of their boots’. the blood pressure gauge and very meticulously took
my blood pressure . . . After this she took the tongue
depressor and placed it in front of my mouth, which I
Differential diagnosis opened, and she examined my throat . . . Last, she
picked up the reflex tester and, to make sure she
Akinetic mutism and catatonia enter the differential as tested the ankle jerks, I knelt down on the chair.
in each of these syndromes the patients, like those with When I asked her what she thought, she said she was
abulia, are immobile and mute. Differentiating them satisfied with my state of health.
from abulia is quite readily done, however, by simply urg-
ing the patient to do something, and providing some ongo- Lhermitte (1983)
ing supervision: akinetic mutes and catatonics will not
respond, whereas the abulic patient does, and will continue Importantly, patients engage in this behavior without
to do so until supervision stops. being invited, asked or told to, and some may even persist
Apathy and depression are both distinguished by the in the behavior despite being asked to stop.
presence of dysphoria. Abulic patients experience nothing
except an untroubled sense of emptiness; depressed or apa-
thetic patients, by contrast, experience a more or less Etiology
oppressive mood.
Abulia may be seen as part of the frontal lobe syndrome, The syndrome has been noted most commonly with bilateral
wherein it may be accompanied by perseveration. or unilateral lesions of the inferior frontal lobe (De Renzi
et al. 1996; Lhermitte 1983, 1986; Lhermitte et al. 1986;
Shallice et al. 1989); cases have also been reported with
Treatment infarction of the white matter subjacent to the superior
frontal gyrus (Ishihara et al. 2002) and with infarction of the
Bromocriptine, anecdotally, has been effective (Barrett thalamus (Eslinger et al. 1991; Hashimoto et al. 1995).
1991); treatment may be commenced at a low dose of Frontotemporal dementia may also exhibit this syndrome.
p 04.qxd 3/10/08 9:33 AM Page 127
4.12 Kluver-Bucy syndrome 127
Differential diagnosis very problematic: patients may display no gender preference

and may proposition males and females alike; there may be
One of the primitive reflexes, namely the grasp reflex, excessive masturbation, sometimes done publicly. The
appears similar to the environmental dependency syn- placidity of these patients is at times remarkable: they seem
drome in that in both cases patients will involuntarily to have no fear, and pointing out the consequences of their
reach and grasp objects. The difference lies in what the behavior to them typically does nothing to disturb them.
patient does with the grasped object: the patient with Some examples from the literature may help to fix this
forced grasping simply holds on, whereas the patient with clinical picture in the reader’s mind. In one case, a 57-year-
the environmental dependency syndrome will utilize the old professor suffered head trauma that led to a maceration
object and do something with it. of the inferior surface of both temporal lobes. After recov-
The alien hand sign also appears similar to utilization ering from the trauma, the patient:
behavior in that the alien hand involuntarily reaches out
and does things with objects: the difference here is that failed to recognize objects placed in front of him or
what the alien hand does is at cross-purposes with what the into his hand. He ate voraciously and, in fact, had a
patient is attempting to do with the ‘good’ hand, whereas tendency to place almost everything that came into
in utilization behavior, the two hands act in concert, with- view in his mouth. For instance, after one meal he
out any conflict. drank a cup of tea and then ate the teabag. He
Echopraxia or ‘imitation behavior’ is said to be present wandered aimlessly and did not know the location of
when patients involuntarily and automatically imitate his room. He made inappropriate sexual advances,
what the examiner is doing. This is fundamentally different rather indiscriminately; both male and female
from environmental dependency, for in the environmental attendants were cautious in his presence. In general,
dependency syndrome the examiner does nothing except however, his affect was flat and unconcerned. He
perhaps place objects in the patient’s view. was readily distracted and there was a constant
Delirious patients may take hold of and use nearby shifting of his attention. If restrained, he became
objects but here one also finds confusion, a sign that is agitated, but when his attention was diverted, he
absent in the environmental dependency syndrome. immediately calmed down.
(Lilly et al. 1983)

Treatment
In another case, a 46-year-old man had a complex par-
Depending on the dangerousness of objects in the patient’s tial seizure wherein:
environment, supervision may or may not be required.
he was awake and alert, but almost mute and lacking
facial expression. He was observed grabbing for objects
4.12 KLUVER–BUCY SYNDROME on his bedside table, and he masturbated in front of the
nursing staff. He also placed objects in his mouth,
In 1939, Kluver and Bucy reported striking behavioral chewed on tissue paper, and attempted to drink from
changes in monkeys subjected to bilateral temporal lobec- his own urine container.
tomy. This Kluver–Bucy syndrome has subsequently been
noted in humans, wherein its most prominent clinical (Nakada et al. 1984)
manifestations are hyperorality and hypersexuality.
Finally, another patient, after recovering from an episode
of complex partial status epilepticus, displayed:
Clinical features
a voracious appetite and indiscriminate eating habits
In the full form of the human Kluver–Bucy syndrome, one which included paper towels, plants, styrofoam cups,
finds a heightened, but indiscriminate, interest in nearby and even faeces. At one point he drank urine from a
objects coupled with hyperorality, hypersexuality, and a cer- catheter bag. The patient was no longer his assertive
tain placidity marked by an absence of fear. Patients appear self and had become quite docile. He tended to wander
to take an almost equal interest in all nearby objects and may about the ward touching objects or people and made
appear restless as they reach out for one object on the bed- inappropriate comments of a sexual nature . . . On the
side table after another, or pace about the room, again, from day of his death, the patient had a respiratory arrest
one thing to another. Hyperorality comes to light in that after stuffing his mouth with surgical gauze. He had
there is a strong tendency on the patients’ part to put any- wandered about the ward picking up whatever he
thing into their mouths, whether it is edible or not: patients could find and putting it into his mouth.
may eat Styrofoam cups, drink urine out of urinals, or stuff
their mouths full of tissue papers. Hypersexuality may be (Mendez and Foti 1997)
p 04.qxd 3/10/08 9:33 AM Page 128
Kluver and Bucy (1939), as noted above, first described Table 4.3 Causes of the Kluver-Bucy syndrome
this syndrome in monkeys and their descriptions are of Bilateral ablation or injury to the temporal lobes
interest. The terminology they utilized is somewhat cum- Temporal lobectomy (Terzian and Dalle Ore 1955)
bersome but is still at times seen in the literature. Traumatic brain injury (Formisano et al. 1995; Lilly et al. 1983)
The heightened interest of the monkeys (which they Late-delayed radiation encephalopathy (Lam and Chiu 1997;
termed ‘hypermetamorphosis’) was manifest by ‘an exces- Thajeb 1995)
sive tendency to take notice of and to attend and react to Post-herpes simplex viral encephalitis (Greenwood et al. 1983;
every visual stimulus . . . the monkey seems to be domi- Marlowe et al. 1975; Shoji et al. 1979)
nated by only one tendency, namely the tendency to con- Infarction (Oliveira et al. 1989)
tact every object as soon as possible [and] . . . when turned
loose in a room, the monkey often behaves as if it were Epileptic conditions
ceaselessly “pulled” from one object to another’. Complex partial seizure (Nakada et al. 1984)
According to Kluver and Bucy’s terminology, the indis- Post-ictal, after either a grand mal seizure (Anson and
criminate nature of this heightened interest represented a Kuhlman 1993) or complex partial status epilepticus (Mendez
kind of ‘psychic blindness’ in that the monkey would and Foti 1997; Varon et al. 2003)
approach and examine objects ‘no matter whether they are Neurodegenerative disorders
very large or very small, dead or alive, edible or inedible, Pick’s disease (Cummings and Duchen 1981; Mendez et al.
moving or stationary . . . The monkey seems to be just as 1993)
eager to examine the tongue of a hissing snake, the mouth Frontotemporal dementia (Gydesen et al. 2002; Heutink et al.
of a cat, feces, a wire cage or a wagon as a piece of bread’. 1997; Mendez and Perryman 2002)
Hyperorality (or, as Kluver and Bucy termed it, ‘oral Alzheimer’s disease (Mendez et al. 1993; Teri et al. 1988)
tendencies’) was manifest by a ‘strong tendency to examine
all objects by mouth’, for example ‘putting the object into Miscellaneous causes
the mouth, biting gently, chewing, licking, touching with Adrenoleukodystrophy (Powers et al. 1980)
the lips and smelling . . . the object’. Heatstroke (Pitt et al. 1995)
Hypersexuality was referred to as ‘changes in sexual
behavior’ and was manifest by a general ‘increase in sexual Epileptic conditions may be characterized by the
behavior’ that could involve other monkeys, regardless of Kluver–Bucy syndrome, either ictally during a complex
their gender, or masturbation. partial seizure or post-ictally after either a grand mal
Placidity was termed ‘emotional changes’ by Kluver and seizure or an episode of complex partial status epilepticus.
Bucy and was marked by ‘absence of all emotional reac- Neurodegenerative disorders may cause a Kluver–Bucy
tions . . . generally associated with anger and fear’. For syndrome of gradual onset and progression, and this is
example, ‘after being attacked and bitten by another ani- most characteristic of those disorders such as Pick’s disease
mal, (the monkey) may approach this animal again and and frontotemporal dementia, which preferentially involve
again in an attempt to examine it’. the temporal lobes early on. Other neurodegenerative dis-
orders, such as Alzheimer’s disease, may, late in their
Etiology course, also cause the syndrome.
Miscellaneous, and very rare, causes of the syndrome
As with monkeys, it appears that in humans the Kluver– include adrenoleukodystrophy and heat stroke.
Bucy syndrome generally appears only with bilateral dam-
age or dysfunction of the temporal lobes – I could find only
one case report of the syndrome occurring with unilateral Differential diagnosis
involvement, namely in a case of unilateral temporal lobec-
tomy (Ghika-Schmid et al. 1995). Table 4.3 lists the various When a patient presents with disinhibition, the frontal
causes reported in the literature. lobe syndrome may come to mind; in this syndrome, as in
Bilateral ablation or injury to the temporal lobes is most the Kluver–Bucy syndrome, one may see inappropriate
obvious after bilateral temporal lobectomy. Traumatic sexual advances. The differential lies in finding features
brain injury, with contusions of the inferior surfaces of such as hyperorality and a heightened and indiscriminate
both temporal lobes, may also cause the syndrome, as may interest in nearby objects, features which are not found in
a late-delayed radiation encephalopathy after irradiation, the frontal lobe syndrome.
say, for a pituitary tumor or nasopharyngeal carcinoma.
Herpes simplex viral encephalitis classically involves both
temporal lobes, and the syndrome may appear as a sequela Treatment
in those who survive. Finally, there are rare cases of infarc-
tion of both temporal lobes (as for example secondary to a There are no controlled studies of the treatment of the
vasculopathy of systemic lupus erythematosus) with a Kluver–Bucy syndrome. Anecdotally, overall improve-
resulting Kluver–Bucy syndrome. ment has been noted with carbamazepine (Stewart 1985),
p 04.qxd 3/10/08 9:33 AM Page 129
4.13 Alien hand sign 129
sertraline (Mendhekar and Duggal 2005), or antipsy- of coffee toward him with the right hand the left hand
chotics (Carrol et al. 2001); should an antipsychotic be would push it away’ (Gottlieb et al. 1992). Similarly, subse-
chosen, a second-generation agent, such as risperidone or quent to a corpus callosotomy, ‘one patient was seen but-
quetiapine, may be considered. Hypersexuality has also toning up his shirt with one hand while the other hand was
been reduced by treatment with leuprolide (Ott 1995). As following along behind it undoing the buttons’ (Bogen
noted in one of the examples above, hyperorality may be 1985b). Akelaitis (1945) noted that one of his patients, also
lethal and appropriate precautions must be taken. after a corpus callosotomy, ‘would be putting on her clothes
with her right hand and pulling them off with her left hand,
opening a door or drawer with the right hand and simulta-
4.13 ALIEN HAND SIGN neously pushing it shut with the left hand’.
More complex behavior is illustrated in the case of a
The alien hand sign represents one of the most remarkable patient who, after suffering an infarction of the corpus cal-
phenomena seen in neuropsychiatric practice, or for that losum, ‘told the story of herself frying a steak, turning it
matter, in the practice of medicine at large. Here, one of over in the frying pan with her right hand and, immedi-
the patient’s hands, almost always the left one, begins to act ately after, finding herself turning it over once again with
as if it had an independent will of its own, often engaging her left hand’ (Barbizet et al. 1974; Degos et al. 1987).
in complex activity that thwarts what the patient is Another patient, after suffering an infarction of the ante-
attempting to do with the right hand. rior portion of the corpus callosum and adjacent medial
This sign was first described by the German physician aspects of both frontal lobes, found, ‘while playing check-
Kurt Goldstein in 1908; Akelaitis, in 1941, described it in ers on one occasion, [that] the left hand made a move that
patients who had been subjected to corpus callosotomy for he did not wish to make, and he corrected the move with
epilepsy, and named it ‘diagonistic dyspraxia’. The current the right hand; however, the left hand, to the patient’s frus-
name, ‘alien hand sign’, is derived from a French paper by tration, repeated the false move’ (Banks et al. 1989).
Brion and Jedynak (1972), who termed it ‘le signe de la Finally, there are examples of a ‘murderous’ alien hand.
main étrangère’: although the authors translated this as the The first reported case of the alien hand sign, described by
‘strange hand’ sign (which is indeed a more faithful trans- Kurt Goldstein (1908), was just such an example: the
lation from the French), English-speaking authors have patient was a 57-year-old female with a callosal infarction
universally favored translating it as ‘alien hand sign’. whose ‘left hand attempted to choke [her] ... and this hand
Another synonym, seen infrequently, is ‘anarchic hand’ had to be pulled away. Furthermore the left hand did other
(Della Sala 1994). unpleasant acts, such as tearing the bedclothes off the bed’
(Geschwind 1981). The patient herself ‘complained, “Es
muss wohl ein boser Geist in der Hand sein” [There must
Clinical features be a devil in my hand]’ (Hanakita and Nishi 1991). In
another case, a patient who had suffered a callosal infarc-
The alien hand sign is said to be present when one of the tion treated her left arm ‘as an alien presence with hostile
patient’s hands (almost, as noted above, always the left one) motivations . . . she complained that the arm moved on its
spontaneously and autonomously acts in a way that is at own and that it struck her and tried to choke her . . . often
definite cross-purposes to what the patient is intending to the hand reached for the neckline of her gown, pinched her
do with the right hand (Bogen 1985a). This ‘intermanual right arm or leg, or knocked her glasses off’ (Levine and
conflict’, as it has been termed, is not merely a matter of a Rinn 1986). Finally, there is the case of a patient who had
clumsy or apraxic left hand ‘getting in the way’, or of reflex- suffered a callosal infarction (Geschwind et al. 1995) who
ive groping or grasping by the left hand, but rather of the ‘awoke several times with her left hand choking her, and
appearance of complex and seemingly purposeful activity while she was awake her left hand would unbutton her
of the left hand, activity that is at definite cross-purposes gown, crush cups on her tray, and fight with the right hand
with the patient’s consciously experienced will and intent. while she was using the phone’.
Patients may be astonished to see the left hand acting inde- Patients’ reactions to the presence of the alien hand
pendently and outside their control, and may comment vary. One patient commented that ‘my hands don’t agree
that it is as if the left hand had ‘a mind of its own’. with each other’ (Degos et al. 1987), and another, that her
Some examples of the alien hand sign will serve to flesh hand ‘disobeyed her’ (Goldenberg et al. 1985), whereas a
out this definition. The complexity of the behavior engaged third felt ‘as if someone “from the moon” were controlling
in by the alien hand ranges from relatively simple activities, her hand’ (Geschwind et al. 1995). Patients also adopt dif-
such as buttoning or unbuttoning, to very complex behav- ferent strategies to control the alien hand: one, ‘to keep her
iors, even to the point of ‘murderous’ behavior. Examples left hand from doing mischief, . . . would subdue it with
of relatively simple alien hand behavior include the case of her right hand’ (Geschwind et al. 1995); another found the
a patient, who, after an infarction of the corpus callosum, behavior ‘so astonishing and uncontrollable that he occa-
found that after he buttoned ‘a shirt with the right hand the sionally hit his left [hand] . . . with the right one’
left hand would proceed to unbutton it and if pulling a cup (Leiguarda et al. 1989). Another patient, ‘encouraged to
p 04.qxd 3/10/08 9:33 AM Page 130
“make friends” with the arm by talking to it, . . . soon came Creutzfeldt–Jakob disease may, very rarely, present with
to treat it as a misbehaving child, fondling and talking to it: a combination of myoclonus and the alien hand sign
‘There, there, behave yourself now . . . Don’t be naughty’’ ’ (MacGowan et al. 1997). In one case, the alien left hand
(Levine and Rinn 1986). ‘would grab [the patient’s] throat or hit her in the face and
As noted earlier, the alien hand sign is almost always she usually limited its activity by holding it in her right
found on the left: indeed, of all the cases of strictly defined hand’s grasp’. In another case presented by the same
alien hand sign that I could find, in only one was the sign authors, the alien hand, again on the left, unbuttoned the
found on the right in a right-handed patient (Della Sala patient’s blouse and removed a hair pin. In both cases, the
et al. 1994). eventual appearance of periodic complexes on the EEG
and dementia suggested the correct diagnosis. There is also
one case report of an alien hand sign occurring due to
Etiology Alzheimer’s disease (Green et al. 1995).
Once one is certain that the clinical phenomenon in ques-

tion is in fact the alien hand sign, one can be reasonably Differential diagnosis
assured that in all likelihood the patient has a lesion in the
corpus callosum. In addition to occurring after section of The alien hand sign must be differentiated from the grasp
the corpus callosum (Akelaitis 1941, 1945; Akelaitis et al. and grope reflexes, asomatagnosia, the ‘levitation’ phe-
1942; Ay et al. 1998; Bogen 1985a,b; Ferguson et al. 1985; nomenon, ‘mirror’ movements and utilization behavior
Gazzaniga et al. 1962; Nishikawa et al. 2001, Rayport et al (as seen in the environmental dependency syndrome).
1983; Smith and Akelaitis 1942; Sperry 1966; Van Waggenen The grasp reflex is easily distinguished from the alien
and Herrin 1940; Wilson et al. 1977), the alien hand sign has hand sign if one attends to what the hand does when it
also been noted in various pathologic lesions of the corpus comes into contact with an object: the grasping hand merely
callosum, including infarction (Banks et al. 1989; Barbizet holds tight and goes no further, whereas the alien hand takes
et al. 1974; Beukelman et al. 1980; Chan and Ross 1988, hold and does something with the object. The grope reflex
1997; Chan et al. 1996; Degos et al. 1987; Geschwind et al. may be a little harder to distinguish, as here the hand
1995; Goldberg and Bloom 1990; Goldenberg et al. 1985; appears to be purposefully ‘groping’ for something. The dis-
Goldstein 1908, 1909; Hanakita and Nishi 1991; Jason tinction is again made possible by attending to what the
and Pajurkova 1992; Nishikawa et al. 2001, Suwanwela and groping hand does once it reaches the object: the groping
Leelacheavasit 2002; Tanaka et al. 1990, 1996; Watson and hand, like the grasping hand, merely holds tight, again in
Heilman 1983; Watson et al. 1985), hemorrhage (Leiguarda contrast with the alien hand, which does something com-
et al. 1989; Starkstein et al. 1988), and tumor or angioma plex with the object. The failure to distinguish these primi-
(Brion and Jedynak 1972). tive reflexes from the ‘intermanual conflict’ seen in the alien
I could find only three cases of strictly defined alien hand hand sign has led to some unfortunate confusion in termi-
sign that appeared to occur secondary to focal lesions that nology, namely a proposal, made by Feinberg et al. (1992)
spared the corpus callosum. Levine and Rinn (1986) (and further elaborated by Chan et al. [1997]) that, rather
described a case secondary to infarction of the basal aspect of than only one alien hand syndrome, there are in fact two:
the temporo-occipital area, but the only imaging performed namely a ‘frontal’ alien hand sign and a ‘callosal’ alien hand
was with computed tomography (CT) scanning and the sign. Close reading of these papers, however, reveals that the
authors admitted that they could not exclude damage to ‘frontal’ alien hand was merely grasping and groping; the
either the splenium or the adjacent white matter. Gottlieb ‘callosal’ type, however, corresponded to the clinical features
et al. (1992) described a case occurring with infarction of the noted above. Given this terminological controversy, it is
medial aspect of the frontoparietal area. Again, only CT incumbent on the reader to examine closely any literature
scanning was performed, but it appeared that the infarction on the subject to see whether the patients described had
was in the watershed area between the distributions of the mere grasping or groping or a true alien hand sign.
anterior and middle cerebral arteries, and thus may truly Asomatagnosia is said to be present when patients deny
have spared the corpus callosum. Perhaps the most convinc- that a limb belongs to them. Although patients with aso-
ing case comes from Dolado et al. (1995), who described a matagnosia and the alien hand sign both experience the
patient with an old infarction in the left parietal lobe who limb as foreign, the phenomena are easily distinguished in
went on to develop the alien hand sign after a fresh infarc- that whereas the ‘foreign’ limb of the patient with aso-
tion in the right parietal lobe. matagnosia does nothing independently, and generally
It is commonly said that the alien hand sign may also be nothing purposeful, the alien hand acts ‘on its own’.
found in corticobasal ganglionic degeneration, but a close The levitation phenomenon, seen in patients with pari-
reading of detailed reports reveals, rather than the alien etal lesions (Denny-Brown et al. 1952), as well as in a small
hand sign, a variety of other signs, such as ‘wandering’ and minority of patients with progressive supranuclear palsy
grasping (Rinne et al. 1994), and levitation (Gibb et al. (Barclay et al. 1999), consists of the upper extremity spon-
1989; Riley et al. 1990). taneously rising up, or ‘levitating’. This differs from the
p 04.qxd 3/10/08 9:33 AM Page 131
4.15 Phantom and supernumerary limbs 131
alien hand sign in that the levitated arm or hand does not examiner’s finger by a wide margin. Interestingly, despite
do anything further, engaging in no complex behavior but this inability, patients are still able to accurately touch parts
simply staying ‘levitated’. of their own body.
Mirror movements are said to be present when patients Optic apraxia, also known as ‘sticky fixation’ or ‘psychic
who are doing something with one limb then find the con- paralysis of visual fixation’, represents a peculiar difficulty
tralateral limb involuntarily engaging in a more or less faith- in eye movement wherein patients are unable to voluntar-
ful imitation. Such mirror movements are more likely when ily look from one fixation point to another. Testing for this
the intended movement is very forceful or sudden; a com- may be performed by first having the patient fix his gaze on
mon example is when one very tightly clenches one fist and an object and then commanding him to look at another
finds that the fingers on the other hand are involuntarily one. When optic apraxia is present there is a peculiar
flexing. Mirror movements are normal in early childhood ‘stickiness’, as if the patient is unable to withdraw his
and, in a minority of individuals, may persist into adult life gaze from the initial object to fix it on the next one.
(Haerer and Currier 1966; Regli et al. 1967). They may be Interestingly, this ‘stickiness’ is present only with voluntary
associated with agenesis of the corpus callosum (Schott and eye movements: should someone walk unexpectedly into
Wyke 1981) and may also occur in patients with hemiplegia, the room, the patient may spontaneously shift his gaze
wherein they are generally found in the paretic limb (Berlin without difficulty to fix it on this new object of interest.
1951; Walshe 1923). Mirror movements may ‘get in the way’
and thus seem to be at cross-purposes; a closer inspection,
however, will reveal that the abnormal movement does in Etiology
fact ‘mirror’ the intended movement in the other limb and
that its ‘interference’ is merely accidental. Most cases of Balint’s syndrome occur secondary to bilateral
Utilization behavior appears similar to the alien hand infarctions in the parieto-occipital areas (Montero et al. 1982;
sign, given that patients with utilization behavior involun- Perez et al. 1996), commonly watershed infarctions seen after
tarily utilize objects. The difference between utilization cardiac arrest. Balint’s syndrome may also constitute part of a
behavior and the alien hand sign lies in the fact that in uti- syndrome known as posterior cortical atrophy. In this syn-
lization behavior there is no intermanual conflict between drome, one may see a gradually progressive, more or less iso-
the hands, which act in concert and with cooperation, lated, Balint’s syndrome; the underlying neuropathology may
whereas in the alien hand sign the left hand acts at definite include corticobasal ganglionic degeneration or Alzheimer’s
cross-purposes with the right. disease (Hof et al. 1993; McMonagle et al. 2006; Mendez
2000; Renner et al. 2004; Tang-Wai et al. 2004). Balint’s syn-
drome has also been noted in Creutzfeldt–Jakob disease
Treatment (Victoroff et al. 1994) and progressive multifocal leukoen-
cephalopathy (Ayuso-Peralta et al. 1994).
A mitt placed on the alien hand may mitigate its effects; in
some cases, the entire extremity must be restrained.
Before deciding that Balint’s syndrome is present, one

4.14 BALINT’S SYNDROME must determine that the visual difficulties are not due to
hemineglect, hemianopia, visual agnosia or, with regard to
This syndrome, first described in 1907 by a Hungarian
optic ataxia, cerebellar dysmetria.
neurologist, Rezso Balint (Husain and Stein 1988), is char-
acterized by the triad of simultanagnosia, optic ataxia, and
optic apraxia. Treatment
Various rehabilitation techniques, anecdotally, have been

Clinical features helpful (Perez et al. 1996; Roselli et al. 2001).
Simultanagnosia, discussed further in Section 2.9, may be

tested for by asking the patient to look at a drawing of a 4.15 PHANTOM AND SUPERNUMERARY LIMBS
complex scene, and asking for a description of each of the
objects in the drawing: typically, patients will fail to men- The phantom limb phenomenon and the supernumerary
tion one or more of the objects. limb phenomenon are similar in that, in both cases, patients
Optic ataxia is characterized by an inability to voluntar- experience the presence of limbs which, in fact, are not pres-
ily reach and touch an object with the hand. Testing may ent. These two phenomena differ, however, in that whereas
be accomplished by holding up your index finger and ask- phantom limb follows amputation and is characterized by a
ing the patient to touch it. When optic ataxia is present, the re-experiencing of the limb that has been lost, supernumer-
patient behaves almost as if he were blind, missing the ary limb occurs with cerebral lesions, such as infarctions,
p 04.qxd 3/10/08 9:33 AM Page 132
and is characterized by the experience of an extra limb, over Supernumerary limbs have been noted with lesions of
and above the normal complement already present. the parietal lobe (Vuilleumier et al. 1997; Weinstein et al.
Phantom limb occurs in the vast majority of patients 1954), the medial aspect of the frontal cortex (McGonigle
after amputation, and typically appears within the first few et al. 2002), the basal ganglia (Halligan et al. 1993), thala-
days post-operatively; in about three-quarters of cases, it is mus (Miyazawa et al. 2004), and pons (Brock and
also accompanied by phantom limb pain. The supernu- Merwarth 1957). Although most supernumerary limbs
merary limb phenomenon, in contrast, is quite rare and is appear on the left side, right-sided occurrence has also
not painful. been noted (Mayeux and Benson 1979). Supernumerary
limbs may also occur as a manifestation of a sensory simple
partial seizure, a diagnosis immediately suggested by the
Clinical features paroxysmal onset and relatively brief duration of the expe-
rience. One patient, for a few seconds, would experience a
Phantom limb (Carlen et al. 1978; Ephraim et al. 2005; Haber
supernumerary arm next to his actual left arm (Riddoch
1956; Henderson and Smythe 1948; Jensen et al. 1984; Shukla
1941); another had such a strong sense that an extra right
et al. 1982) is a tactile experience, rather than a visual one:
arm was over his head that he asked his wife to help him
although patients do not see the limb, they ‘feel’ it and have a
pull it down (Russell and Whitty 1953).
sense of its presence, and in some cases report being able to
move it. Importantly, patients retain insight here and do not,
in fact, believe that a limb is actually present. Phantom limb Differential diagnosis
pain is variously described as burning, electric, throbbing,
cramping, tearing or crushing, and can be quite severe. Over The phantom limb appearing after amputation is not
time, most patients experience what is known as ‘telescop- mimicked by other conditions. It must be kept in mind,
ing’: here, it is as if the phantom were being gradually however, that, albeit rarely, not all pain experienced in the
absorbed back into the remaining limb, the most proximal phantom limb is ‘phantom limb pain’ resulting from corti-
part of the phantom disappearing first and the remaining cal or subcortical reorganization. For example, one patient,
portions telescoping after it, with the most distal portion, who experienced a non-painful phantom after amputation
usually the fingers or toes, disappearing last. In some cases, of a lower extremity, subsequently developed disk disease
the phantom may disappear entirely after months or longer, with typical sciatic pain radiating down into the phantom
whereas in others it may be permanent. (King 1956).
Childhood amputations, before the age of 4 years, are
only rarely followed by phantoms (Simmel 1962). The
congenital absence of a limb may, interestingly, be fol- Treatment
lowed in a small minority by the development of a phan-
tom ‘replacement’ (Weinstein and Sersen 1961), generally The optimum treatment of phantom limb pain is not clear.
around the age of 9 years (Melzak et al. 1997). Opioids are used, and provide some relief (Huse et al. 2001)
The phantom phenomenon, although most common but are certainly not universally effective. Gabapentin in
after amputation of a limb, also occurs after mastectomy in high dosage was effective in one double-blind study (Bone
one-fifth (Ackerly et al. 1955; Jarvis 1967) to two-thirds of et al. 2002) but not in another (Smith et al. 2005). Similarly,
women (Bressler et al. 1956) and may, in a small minority, memantine, in a dose of 30 mg/day, was effective in one
be accompanied by pain. Phantom eye has also been double-blind study (Schley et al. 2006) but ineffective in
reported after enucleation (Soros et al. 2003). two others (Maier et al. 2003; Wiech et al. 2004). Infusions
Supernumerary limb is characterized by the experience of salmon calcitonin were effective in one double-blinded
of having an extra arm or leg. One patient felt the extra arm study (Jaeger and Maier 1992). Anecdotally, patients have
lying across his abdomen (Mayeux and Benson 1979), responded to treatment with a TENS unit (on the contralat-
another experienced it growing out of his forearm (Brock eral extremity) (Carabelli and Kellerman 1985), deep brain
and Merworth 1957), and one patient, after suffering bilat- stimulation (Bittar et al. 2005), clonazepam (Bartusch et al.
eral parietal lobe infarctions, experienced four legs, two on 1996), carbamazepine (Patterson 1988), chlorpromazine
each side (Vuilleumier et al. 1997). Although in some cases (Logan 1983), and, despite an absence of depression, to flu-
patients may retain insight, at times this may be lost and oxetine (Power-Smith and Turkington 1993), and to ECT
patients may insist that, in fact, an extra limb is present (Rasmussen and Rummans 2000).
(Halligan et al. 1993; Weinstein et al. 1954).
Etiology 4.16 DEPERSONALIZATION
The phantom limb phenomenon probably represents Depersonalization is a common experience that is found
persistent activity of those structures, such as the parietal not only in normal individuals, but also in patients with
cortex, which maintain the body schema. epilepsy and various other disorders.
p 04.qxd 3/10/08 9:33 AM Page 133
4.17 Obsessions and compulsions 133
Clinical features Migraine headaches may be preceded by an aura of

depersonalization, and the diagnosis is immediately sug-
In depersonalization, patients feel uncannily detached gested by the succeeding headache. Depersonalization may
from themselves. Although they may continue to engage in also occur as an aura to either a complex partial or grand mal
some activity, whether it be talking, walking, or driving a seizure, and here again the diagnosis is immediately indi-
car, it seems to them as if they are not really doing it but cated by the subsequent seizure. Depersonalization may also
observing it being done, as if it were being carried out by a constitute the sole symptomatology of a simple partial
robot or an automaton. In some cases, visual distortions seizure, and here a high index of suspicion may be required
may occur: arms or legs may appear misshapen or to make the diagnosis. One important clue, of course, would
shrunken. Patients may occasionally have the experience of be a history of other seizure types; however, this may not be
‘floating’ above the scene, watching themselves do things universally present as in some cases epilepsy may be charac-
from a distance. terized only by simple partial seizures, without other seizure
types: in such cases, an exquisitely paroxysmal onset of the
depersonalization may be the only clue.
Traumatic brain injury is very commonly accompanied
Etiology
by depersonalization, especially in those who have suffered
relatively mild trauma.
The various causes of depersonalization are listed in
Panic attacks may have depersonalization as part of
Table 4.4.
their symptomatology, and here the diagnosis is suggested
Depersonalization is most commonly seen as a normal,
by the associated anxiety and other autonomic symptoms
transient reaction to extreme danger, as may occur in com-
such as tremor, tachycardia and diaphoresis.
bat, assaults, traumatic accidents, etc.
Depression may be complicated by depersonalization;
Intoxication with marijuana or MDMA (3,4 methylene-
here the occurrence of depersonalization within the setting of
dioxymethamphetamine, ‘Ecstasy’) is very commonly
chronic depressive symptoms indicates the correct diagnosis.
associated with depersonalization, and in some cases
Finally, when all other causes have been ruled out, one
patients may subsequently re-experience depersonaliza-
is left with a diagnosis, by exclusion, of depersonalization
tion as a ‘flashback’ when not intoxicated. Certain medica-
disorder. This is an idiopathic disorder, with an onset in
tions may also, albeit very rarely, cause depersonalization,
late adolescence or early adult years, characterized by
including quetiapine, fluoxetine, minocycline, and indo-
depersonalization that may either persist in a chronic, wax-
methacin.
ing and waning fashion, or be episodic, with the duration
of the episodes exhibiting an enormous variation that may
last from seconds to days.
Table 4.4 Causes of depersonalization

Normal response to danger (Morgan et al. 2001; Noyes and Kletti
1977; Noyes et al. 1977; Sedman 1966) Autoscopy is a kind of visual hallucination wherein
Intoxicants or medications patients hallucinate a ‘double’ and see themselves as vividly
Marijuana (Mathew et al. 1993, Melges et al. 1970) as if looking in a mirror. Depersonalization differs from
MDMA (Ecstasy) (Vollenweider et al. 1998) this in that there is always an ‘as if’ quality to the experience
Quetiapine (Sarkar et al. 2001) of depersonalization, accompanied by the sense of ‘float-
Fluoxetine (Black and Wojcieszek 1991) ing’ over the scene that one is actually in.
Minocycline (Cohen 2004)
Indomethacin (Schwartz and Moura 1983) Treatment
In association with migraine or seizures
Migraine aura (Lippman 1953) Treatment is directed toward the underlying cause; in the
Aura to complex partial or grand mal seizure (Devinsky case of depersonalization occurring in traumatic brain
et al. 1989; Ionasescu 1960) injury or depersonalization disorder, however, there are no
Simple partial seizure (Williams 1956) established treatments.
Traumatic brain injury (Grigsby and Kaye 1993; Hillbom 1960)
Panic attack (Cassano et al. 1989)

4.17 OBSESSIONS AND COMPULSIONS
Depression (Noyes et al. 1977) True obsessions and compulsions, once considered rare
Depersonalization disorder (Baker et al. 2003; Davison 1964;
oddities, are now known to be quite common, occurring
Shorvon 1946; Simeon et al. 1997, 2003)
not only in idiopathic obsessive–compulsive disorder, but
in a large number of other conditions.
p 04.qxd 3/10/08 9:33 AM Page 134
Clinical features Table 4.5 Causes of obsessions and compulsions

Idiopathic disorders and medication side-effects
Obsessions are involuntary, unwanted, and often distress- Obsessive–compulsive disorder (Rasmussen and Tsuang 1986)
ing thoughts that persistently recur despite attempts on the Major depressive disorder (Kraepelin 1921)
part of patients to stop them. Although the subject matter Schizophrenia (Byerly et al. 2005)
may at times be neutral, it more often than not concerns Second-generation antipsychotic medications (clozapine [Baker
sexual or violent acts, acts in which the patient would never et al. 1992], olanzapine [Mottard and de la Sablonniere 1999],
voluntarily engage. Compulsions represent an overwhelm- risperidone [Alevizos et al. 2002], quetapine [Stamouli and
ing and anxious need to do something, something that Lykouras 2006])
patients realize is more or less nonsensical. The compul-
sion is typically intimately connected with an apprehen- Movement disorders
sion on the part of patients that they have done something Tourette’s syndrome (Frankel et al. 1986, Miguel et al. 1995,
that they ought not to have done, or that they have left Robertson et al. 1988)
undone something that they ought to have done, and the Sydenham’s chorea (Maia et al. 2005, Swedo et al. 1989,
compulsive act serves in some fashion either to undo what 1993)
was done or to make good something that ought to have Huntington’s disease (Cummings and Cunningham 1992)
been done. Parkinson’s disease (Alegret et al. 2001)
An example of an obsession is found in the case of the With precipitating events
mother of a newborn infant, who was horrified to find her- Post-encephalitic (encephalitis lethargica [Jelliffe 1929] and
self recurrently having thoughts of ‘stabbing the child, put- western equine encephalitis [Mulder et al. 1951])
ting the infant in the microwave, or sexually abusing the Post-anoxic (Escalona et al. 1997; Laplane et al. 1984, 1989)
newborn’ (Sichel et al. 1993). In another case, the obses- Traumatic brain injury (Hillbom 1960; McKeon et al. 1984)
sion was, per se, of a neutral character, consisting of ‘silly
poems that kept running through his consciousness’: what Miscellaneous causes
‘appalled’ the patient was the fact that he could not stop Fahr’s syndrome (Lopez-Villegas et al. 1996)
them (Mulder et al. 1951). Infarction of the globus pallidus (Giroud et al. 1997)
Common compulsions include compulsions to wash, to Infarction of the parietal cortex (Simpson and Baldwin 1995)
pray, or to check. Tuke (1894) described a ‘young lady’, Complex partial (Mendez et al. 1996) or simple partial (Kroll
who feared ‘infecting herself’ if she touched anything that and Drummond 1993) seizures
might have germs on it, with the result that ‘the act of Systemic lupus erythematosus (Slatterly et al. 2004)
washing her hands in the morning is repeated, immedi- Velocardiofacial syndrome (Gothelf et al. 2004)
ately, again and again’ such that the hands ‘are quite rough Normal pressure hydrocephalus (Mendhekar et al. 2007)
and discoloured afterward’, and Gordon (1950) described
a patient who felt compelled to repeat his prayers again and
again for fear each time that he had left a word out. Finally, second-generation antipsychotic medications, as used in
Bleuler (1924), in commenting on a patient with a check- the treatment of schizophrenia, may also cause obsessions
ing compulsion, noted that the anxious apprehension that and compulsions as a side-effect: clozapine is most likely to
the door had been left unlocked ‘compels the patient to try do this; however, cases have also been reported secondary
it over and over again’. to olanzapine, risperidone, and quetiapine.
Obsessions and compulsions may also occur secondary
to disorders characterized by abnormal movements, such
Etiology as the tics of Tourette’s syndrome, the chorea of
Sydenham’s chorea or Huntington’s disease, and the
Table 4.5 lists the various causes of obsessions and parkinsonism of Parkinson’s disease. Sydenham’s chorea is
compulsions. of special interest here in that obsessions or compulsions
By far the most common cause is the idiopathic are seen in the majority of patients and, interestingly, tend
disorder known as obsessive-compulsive disorder. This to appear prior to the onset of the chorea.
disorder, characterized primarily by obsessions and com- Of the precipitating events capable of causing obses-
pulsions, has an onset in adolescence or early adult years, sions and compulsions, the classic one is encephalitis
and generally pursues a chronic course. A depressive lethargica, wherein these symptoms occurred as chronic
episode of a major depressive disorder may also cause sequelae, often in association with oculogyric crises. Other
obsessions and compulsions; however, here the occurrence encephalitides, such as western equine encephalitis, have
of these symptoms in the setting of a typical depressive also been implicated. Both anoxic encephalopathy and
episode suggests the correct diagnosis. Schizophrenia, like- traumatic brain injury may also leave obsessions and com-
wise, may be accompanied by obsessions and compulsions; pulsions in their wake.
however, here also it is the setting, in this case a chronic Of the miscellaneous causes, Fahr’s syndrome, with cal-
psychosis, which allows the correct diagnosis. Importantly, cification of the basal ganglia, stands out; infarction of the
p 04.qxd 3/10/08 9:33 AM Page 135
4.18 Reduplicative paramnesia 135
globus pallidus or the right parietal cortex has also rarely behavior for a definite purpose and often attempt to resist
been at fault. Obsessions and compulsions may also consti- the urge. An allied symptom is ‘compulsive’ hoarding or col-
tute part of the symptomatology of a complex partial lecting, as may be seen in various dementias (Hwang et al.
seizure or a simple partial seizure. In the case of a complex 1998) and, rarely, with focal lesions of the frontal lobe
partial seizure the associated defect of consciousness sug- (Anderson et al. 2005).
gests the correct diagnosis; however, with simple partial
seizures there may not be any other symptomatology
besides the obsession or compulsion, and in this case the Treatment
diagnosis may rest on a history of other seizure types.
Finally, there is also an association of obsessions and com- Treatment is directed, if possible, at the underlying cause;
pulsions with systemic lupus erythematosus, the velocar- if this is ineffective, consideration may be given to an
diofacial syndrome, and normal pressure hydrocephalus. empirical trial of one of the medications useful in
In reviewing these various causes of obsessions and obsessive–compulsive disorder, such as an SSRI.
compulsions, it is interesting to note the involvement of
the basal ganglia, especially the globus pallidus. Thus, in
Fahr’s syndrome, one sees calcification of the basal ganglia 4.18 REDUPLICATIVE PARAMNESIA
bilaterally (Lopez-Villegas et al. 1996), and in Sydenham’s
chorea the caudate is heavily involved (Husby et al. 1976). Reduplicative paramnesia, described in 1903 by Pick (Pick
Post-anoxic lesions preferentially involve the globus pal- 1903) is a syndrome in which patients believe that their loca-
lidus bilaterally (Escalona et al. 1997; Laplane et al. 1989), tion has somehow been duplicated, such that, for example,
and unilateral infarction of the globus pallidus has also the house they are in is not actually theirs or, conversely, that
been implicated (Giroud et al. 1997). Given these findings, their house has been relocated at some distance, perhaps to
it may be appropriate to consider obsessions and compul- another city. This syndrome has also been referred to as
sions as having some localizing value to the basal ganglia. ‘double orientation’ or ‘delusional disorientation’.
Clinical features
In some cases, patients may correctly identify the city they
The adjectives ‘obsessive’ and ‘compulsive’ have been used
are in, but may maintain that the building they are in is
not only to refer to true obsessions and compulsions, as
not, in fact, what it appears to be. Some may admit that it
described above, but also to other symptoms, and it is
perhaps looks like their home, but maintain that, in fact, it
important to clearly distinguish ‘true’ obsessions and com-
is not and, in fact, is rather a replica or duplicate of their
pulsions from these other symptoms. Thus, one hears of
actual home (Hudson and Grace 2000).
‘compulsive’ spending, shopping, eating, or sex; however,
In other cases, patients may accurately identify the
one clinical feature clearly distinguishes all these from
building they are in, for example University Hospital, but
‘true’ compulsions, namely the fact that patients with com-
may maintain that the building, in fact, is not in the city,
pulsive spending, shopping, eating, or sex enjoy the behav-
but has been transported or duplicated in another locale
ior they feel ‘compelled’ to partake in, in clear contrast
(Benson et al. 1976), perhaps their home town.
with patients with ‘true’ compulsions who take no pleasure
in their compulsive behavior, whether it be washing, pray-
ing, checking, or whatever. Etiology
Obsessive–compulsive personality traits must also
be distinguished from obsessions and compulsions. Reduplicative paramnesia may occur in the setting of a
Individuals with these personality traits are ‘obsessed’ with dementia, for example Alzheimer’s disease (von Gunten
detail and feel ‘compelled’ to do things perfectly. These et al. 2005), in the setting of a delirium as after a closed head
traits, however, are quite different from ‘true’ obsessions injury (Benson et al. 1976), or in a psychosis, for example
and compulsions in that individuals with these traits typi- delusional disorder or schizophrenia. Occasionally, the
cally see nothing wrong with them (and in fact may even syndrome may occur in a more or less isolated fashion, and
value them), in contrast with patients with ‘true’ obses- in such cases lesions, such as infarctions, have been noted
sions and compulsions who see these experiences as more in the right frontal lobe (Kapur et al. 1988) and in the right
or less senseless and wish to be rid of them. fusiform gyrus (Hudson et al. 2000).
Perseverations, as may be seen in some patients with
frontal lesions, are distinguished from compulsive behaviors
by the patients’ attitude toward the behavior in question. Differential diagnosis
Perseverative patients can often offer no reason for their
repetitive behavior and do not resist engaging in it: by con- Reduplicative paramnesia must be distinguished from dis-
trast, patients with compulsions engage in their compulsive orientation to place. The differential here rests on the
p 04.qxd 3/10/08 9:33 AM Page 136
patient’s reaction when corrected: the disoriented patient dementia, for example frontotemporal dementia (Nedjam
may either accept the correction or simply make no com- et al. 2004).
ment; the patient with ‘delusional disorientation’, how-
ever, will stoutly maintain his or her belief, and may even Differential diagnosis
argue with the physician about it.
Simple lying is distinguished by the presence of a motiva-
Treatment tion for the false statement and by the fact that liars tend to
persist in their lies, in contrast with confabulators who,
Apart from treatment of the underlying cause, no confi- generally, when challenged, renounce their statements
dent recommendations can be made. Should the syndrome without much ado.
persist and be troubling, a case could be made for treat- Delusions about the past, as may be seen in psychosis
ment with an antipsychotic. (e.g., schizophrenia), delirium or advanced dementia, are
generally implausible on their face. For example, a report
by a patient that the night before he had been tortured and
4.19 CONFABULATION that the nurses had ripped his skin off should be consid-
ered a delusion and not a confabulation. In these cases, the
At times, patients with amnesia will report experiences, patient’s speech is often rambling and more or less inco-
which, though plausible-sounding, in fact did not occur. herent, being composed of disconnected statements.
These confabulations seem, as it were, to ‘fill in the blanks’
of those portions of the patient’s past that cannot be Treatment
recalled because of the amnesia.
Treatment is directed at the underlying condition.
Clinical features
4.20 AMUSIA
Confabulations generally appear in response to questions
about the recent past. Patients, although not confused, Amusia, also known as amelodia, is characterized by an
relate experiences which, upon examination, clearly did inability to either recognize or produce a melody, and may
not occur. For example, one patient, hospitalized for 3 occur on either an acquired or a developmental basis.
days, when asked what he had done the evening before,
replied that he’d been out with friends at a restaurant, Clinical features
where everyone had enjoyed a fine meal, etc. Most patients,
when pressed about their confabulated responses, do not Amusia occurs in both receptive and expressive forms.
persist in them, but may offer other confabulated In receptive amusia, patients are, to a greater or lesser
responses. For example, the patient in question, when told degree, ‘tone deaf’. In such a case, if the patient were to lis-
that, according to the nurse, he had been in the hospital on ten to a singer simply humming the tune to a song he
the evening in question, hesitated a moment, then might be unable to recognize it, whereas if the singer actu-
responded that, yes, that was the case, and that he must ally sang the song, the lyrics would immediately allow the
have been mistaken. Asked then what he had, in fact, done patient to recognize the song. As might be expected, if
the night before, he went on to relate how family members patients with receptive amusia listen to instrumental music
had come to visit and had spent the night with him, an they would have difficulty ‘naming the tune’ and might
event that did not, according to the nurse, in fact happen. complain that the music sounded flat.
Further examination reveals that although patients are Patients with expressive amusia have great difficulty in
neither confused nor incoherent, they do, however, have ‘carrying a tune’, and if such patients hum a tune, listeners
short-term memory loss, as manifested by an inability to have great difficulty recognizing it; should these patients
recall all out of three test words after 5 minutes and by sing the lyrics, however, listeners are able to recognize the
some disorientation to date or place. song but may comment that the singing is quite poor.
Patients with expressive amusia also have great difficulty
playing instruments.
Etiology
In some cases, both receptive and expressive compo-
Confabulations are most commonly seen in patients with nents are present, producing a global amusia.
Korsakoff’s syndrome (Benson et al. 1996) and are dis-
cussed further in Section 13.5. They may also occur in the Etiology
amnestic states following rupture of aneurysms of the ante-
rior communicating artery (DeLuca and Cicernone 1991; Most cases of acquired amusia occur secondary to infarc-
Schnider et al. 2005), and may also be seen in patients with tion or hemorrhage. Receptive amusia has been noted with
p 04.qxd 3/10/08 9:33 AM Page 137
4.22 Cataplexy 137
lesions of the temporal lobe (Mazzucchi et al. 1982; Sparr Etiology

2002). Expressive amusia has been noted with lesions of
the superior temporal cortex (McFarland and Fortin 1982) Lesions are found in the left hemisphere, typically in the
and of the frontal cortex (Botez and Werheim 1959). posterior–inferior portion of the frontal cortex (Schiff et al.
Global amusia has been seen with lesions of the superior 1983; Takayama et al. 1993) or subjacent white matter
temporal cortex (Piccirilli et al. 2000) and also of Heschl’s (Blumstein et al. 1987); cases have also been reported sec-
gyrus (Russell and Golfinos 2003). Typically, lesions are ondary to infarction of the left basal ganglia (Fridriksson et
found in the non-dominant hemisphere. al. 2005), and there is one report of the syndrome occur-
Expressive amusia has also been reported as a manifesta- ring with infarction of the mid-portion of the body of the
tion of a simple partial seizure, with the seizure focus being corpus callosum (Hall et al. 2003).
found in the right temporo-occipital region (Bautista and There are also report of the syndrome occurring in the
Ciampetti 2003). course of schizophrenia (Reeves and Norton 2001): in one
Global acquired amusia of gradual onset and slow pro- such case the patient, who had the delusion that he was
gression has also been reported secondary to a neurode- connected with British royalty, spoke with a British accent
generative disorder characterized by bilateral atrophy of (Reeves et al. 2007).
the frontotemporal cortices (Confavreux et al. 1992).
Developmental, or ‘congenital’ amusia, is not uncom-
mon and such ‘tone deaf’ individuals have a variable Differential diagnosis
degree of difficulty in recognizing tunes and singing/play-
ing instruments (Ayotte et al. 2001). Motor aphasia is distinguished by the characteristic effort-
ful speech that stands in contrast with the fluent and effort-
less speech of patients with the foreign accent syndrome; it
Differential diagnosis is distinguished from dysarthria by the fact that in the for-
eign accent syndrome there is simply no slurring of speech.
Aprosodia is distinguished from amusia by the fact that
aprosodia is related to the emotional tone with which one
speaks, whether happy, angry or sad, whereas amusia is Treatment
related to the tune with which one sings.
There is no known treatment.
Treatment
4.22 CATAPLEXY
There are no established treatments.
Cataplexy is a condition characterized by the occurrence of
cataplectic attacks, that is to say episodes of a greater or
4.21 FOREIGN ACCENT SYNDROME lesser degree of muscle atonia.
The foreign accent syndrome, wherein patients speak with

an accent foreign to their native tongue, is a rare syndrome Clinical features
that typically evolves out of either a motor aphasia, or an
aphemia, in stroke patients. Cataplectic attacks (Adie 1926; Dyken et al. 1996;
Guilleminault et al. 1974; Kales et al. 1982; Parkes et al.
1975; Wilson 1928) are generally precipitated by some
Clinical features strong emotion, such as laughter or anger, and are charac-
terized by the paroxysmal onset of more or less generalized
As noted, patients present initially with either a motor weakness lasting on the order of seconds to a minute or so:
aphasia (Christoph et al. 2004) (or its transcortical variant subsequent recovery is rapid and complete. During the
[Graff-Radford et al. 1986]) or an aphemic mutism (Schiff attack, all voluntary muscle power, with the exception of
et al. 1983; Takayama et al. 1993): as the motor aphasia or the diaphragm and, at times, the extraocular muscles, is
the mutism resolve, patients begin to speak intelligibly but lost, and patients may fall to the ground or slump in a
with a foreign accent. One native English speaker spoke chair. In some cases, the muscle weakness, although gener-
with an Irish brogue (Seliger et al. 1992), another with a alized, may be of minor degree, and such patients may
French accent (Hall et al. 2003), and another with a Chinese merely experience their heads lolling forward, their jaws
accent (Schiff et al. 1983). In one most unfortunate case, a slackening, and their knees beginning to buckle. Limited
Norwegian, who developed the syndrome during World attacks, confined perhaps to an arm or leg, have also
War II, spoke in such a convincing German accent that she been reported. Attacks that last much longer than a minute
was suspected of being a traitor (Monrad-Krohn 1947). may be joined by visual or auditory hallucinations
p 04.qxd 3/10/08 9:33 AM Page 138
(Van Den Hoed et al. 1979). Importantly, during the 4.23 SYMPATHETIC STORM
attack, patients remain completely alert and conscious.
Sympathetic storms, also known as acute autonomic crises,
constitute episodes of severe sympathetic hyperactivity,
Etiology and are usually seen after traumatic brain injury.
The overwhelming majority of cases of cataplexy occur
secondary to narcolepsy. As discussed in Section 18.7, this Clinical features
disorder generally presents in late teenage or early adult
years with narcoleptic sleep attacks; cataplectic attacks are The episodes may occur either spontaneously or after some
seen in about three-quarters of patients, and although they trivial precipitant, such as a change in position. During the
typically occur within the first few years after the appear- episode one sees the acute onset of profuse diaphoresis,
ance of sleep attacks, in rare instances they may precede tachycardia, tachypnea, pupillary dilation, and, in some,
them (Parkes et al. 1975). rigid extensor posturing. The diaphoresis is indeed impres-
Isolated cataplectic attacks have also, very rarely, been sive, with beads of sweat dripping from the head. During
reported to occur on an autosomal dominant (Gelardi and the episode, patients may grimace as if in pain, and family
Brown 1967) or idiopathic basis (Van Dijk et al. 1991). members and other observers may become quite alarmed.
Cataplectic attacks, again very rarely, have also been The episodes themselves last from minutes to hours, and
noted with lesions, generally gliomas, of the hypothalamus terminate slowly.
(Anderson and Salmon 1977; Schwartz et al. 1984; Stahl et al.
1980), midbrain tegmentum (Fernandez et al. 1995) or dor-
sal pontomedullary junction (D’Cruz et al. 1994). There are Etiology
also case reports of cataplexy occurring as sequelae to
encephalitis lethargica (Adie 1926; Fournier and Helguera These episodes probably represent disinhibition of the hypo-
1934), in association with paraneoplastic limbic encephalitis thalamus and related structures. Although most commonly
(Rosenfeld et al. 2001) in Niemann–Pick disease (Smit et al. seen after severe traumatic brain injury with prominent dif-
2006), and as a side-effect of clozapine (Desarkar et al. 2007). fuse axonal injury (Baguley et al. 1999), they may also occur
in the setting of acute hydrocephalus (Rossitch and Bullard
1988) and after cardiac arrest (Diamond et al. 2005).
Differential diagnosis Although these episodes were once considered to repre-
sent diencephalic seizures (Penfield and Jasper 1954), there
Cataplectic attacks must be distinguished from verte- is no evidence for epileptic activity during them, and anti-
brobasilar transient ischemic attacks, syncope, and atonic epileptic drugs are not effective (Boeve et al. 1998).
seizures, and one feature helps in distinguishing all of these
from cataplexy, namely, (in contrast with cataplectic
attacks) that none of these is typically provoked by strong Differential diagnosis
emotion.
Attacks of vertebrobasilar insufficiency may be charac- Complex partial seizures are distinguished by their exquis-
terized by ‘drop attacks’ with preservation of conscious- itely paroxysmal onset, over seconds. Furthermore, one
ness. These are usually seen in elderly individuals, and may rarely sees such sympathetic hyperactivity in a complex
be accompanied by other evidence of brainstem ischemia, partial seizure: at most, there may be some modest tachy-
such as transient diplopia, dysarthria, or vertigo. cardia and modestly elevated blood pressure.
Syncopal attacks are immediately distinguished from Malignant hyperthermia, the neuroleptic malignant
cataplexy by loss of consciousness. syndrome and Stauder’s lethal catatonia may all be consid-
Atonic seizures may or may not be accompanied by loss ered (Thorley et al. 2001), however in each of these condi-
of consciousness or by post-ictal confusion. In cases of tions, symptoms, rather than being episodic, are persistent.
atonic seizures with preserved consciousness and no post- The setting, of course, also aids in differentiation, and one
ictal confusion, a history of other seizure types will suggest should look, respectively, for administration of an anes-
the correct diagnosis (Lipinski 1977; Pazzaglia et al. 1985). thetic or an antipsychotic, or pre-existing catatonia.
Treatment Treatment
Treatment of cataplexy occurring in association with nar- The goal of treatment is prevention of future episodes,
colepsy is discussed in Section 18.7; when symptomatic and in this regard chronic treatment with a beta-blocker,
treatment is required for cataplexy occurring secondary to such as propranolol or labetalol (Do et al. 2000), constitutes
other causes, an empirical trial of these same treatments a reasonable first approach. Both morphine sulfate and
would be reasonable. bromocriptine have also been used with success (Bullard
p 04.qxd 3/10/08 9:33 AM Page 139
4.26 Inappropriate affect 139
1987), as has gabapentin, in doses of 600–1800 mg/day differentiated from more ‘free-floating’ agitation, as may
(Baguley et al. 2007). Doses should be titrated to clinical be seen in various deliria or dementias.
effect or tolerance; in some cases a combination of agents,
such as a beta-blocker plus bromocriptine, may be required.
Should pharmacologic treatment fail, consideration may be Treatment
given to intrathecal baclofen (Becker et al. 2000).
Apart from treatment, if possible, of the associated disease,
such as stroke, and a modulation of environmental
4.24 CATASTROPHIC REACTION demands, there is no known treatment.
The catastrophic reaction, originally described by Kurt

Goldstein (1939, 1942), is characterized by an extreme 4.25 FLATTENED AFFECT
emotional reaction when patients are confronted with
tasks that, since falling ill, they are no longer able to accom- Clinical features
plish. This may not be an uncommon phenomenon, being
described in 19 percent of patients with stroke (Starkstein Flattened, or blunted, affect is characterized by a lifeless
et al. 1993) and 16 percent of those with Alzheimer’s and wooden facial expression accompanied by an absence
disease (Tilberti et al. 1998). or diminution of feeling.
Clinical features Etiology
The reaction occurs when patients find themselves unable to Flattened affect is found very commonly in schizophrenia
accomplish a task which, prior to falling ill, would have occa- (Andreasen et al. 1979); it may also occur in other psy-
sioned them little or no difficulty. The task itself might be choses (Cornelius et al. 1991) and, rarely, in dementia sec-
something as simple as making change, or something more ondary to infarction of the mesencephalon or thalamus
formal, as for example answering questions regarding mem- (Katz et al. 1987).
ory or calculations during a mental status examination.
Finding themselves hopelessly unable to proceed, patients
become frustrated, tearful, or angry; some may begin shout-
ing or swearing, and aggressive behavior may occur. Carota
Motor aprosodia is characterized by a monotone voice but,
et al. (2001) noted that when patients with expressive aphasia
in contrast with patients with flattened affect, who feel lit-
were given paper and pencil and asked to write they would
tle, if anything, patients with aprosodia retain lively emo-
‘start crying, showing unwillingness, tearing the paper or
tional feelings. The ‘hypomimia’ seen in parkinsonism is
even throwing the pencil and other objects toward the exam-
distinguished in the same way: although these patients’
iner’. Typically, this catastrophic display of emotion passes
facial movements are more or less frozen and devoid of
soon after patients are relieved of the burdensome task.
expression, they still may have strong feelings.
In depression, the play of emotions on the face is slowed
Etiology and thus depressed affect may appear similar to flattened
affect; however, these patients do experience a sense of sad-
There has been debate as to whether the catastrophic reaction ness in contrast with patients with flattened affect, who,
is merely an expected emotional reaction when patients find again, simply feel nothing.
themselves failing at tasks that would have caused no diffi-
culty in the past or whether it is perhaps related to specific
brain pathologies. Although Goldstein held to the former Treatment
theory, there is some evidence that catastrophic reactions, at
least in patients with stroke, are related to the presence of a Treatment is directed at the underlying cause.
post-stroke depression and to infarctions in the anterior left
hemisphere or the left basal ganglia (Starkstein et al. 1993).
4.26 INAPPROPRIATE AFFECT
There is also some evidence of an association with expressive
aphasia (Carota et al. 2001; Gainotti 1972) but not all studies
The term ‘affect’ refers both to what is felt and to what
support this (Starkstein et al. 1993).
shows in facial expression. Normally, there is a congruence
between these two, as, for example, when sad feelings are
Differential diagnosis accompanied by a sad facial expression. In cases when
there is an involuntary incongruence between these two
Catastrophic reactions, as defined here, are clinical events components of affect – a mismatch as it were between what
that occur in reaction to stressful demands, and thus are is felt and what shows – one speaks of inappropriate affect.
p 04.qxd 3/10/08 9:33 AM Page 140
Clinical features Description

Examples may help fix this sign in the reader’s mind. When Kraepelin (1907) noted that patients with mannerisms
attending his brother’s funeral, one patient, while feeling may ‘. . . walk with a peculiar gait, drag one foot, go in
nothing but grief and sadness, was noted to have a strange straight lines or in circles, hold their spoons at the very end,
grin on his face; another, although reporting pleasure at eat in a definite rhythm, and shake hands with extended
receiving a gift, was noted to grimace as if in pain. fingers’. He felt that mannerisms were ‘. . . especially com-
mon in speech (with) . . . grunts, lisping, peculiar words,
phrases and inflection’.
Etiology Bleuler (1924) commented further regarding the man-
neristic transformation that gestures may undergo, noting
By far the most common condition in which inappropriate that ‘. . . every conceivable stilted gesture occurs. Shaking
affect is seen is schizophrenia (John et al. 2003) and the hands is done very stiffly with the hand turned or only the
closely allied schizotypal personality disorder (Fossati et al. little finger is presented; the hand may be shot forward
2001). Such affect has also been noted during intoxication quickly and withdrawn just as rapidly’.
with hallucinogens, such as ketamine and dimethyltrypta-
mine (Gouzoulis-Mayfrank et al. 2005), and in the very
rare velocardiofacial syndrome (Sachdev 2002). Etiology
Although mannerisms are most commonly seen in schizo-

Differential diagnosis phrenia they may also occur in mental retardation (Leudar
et al. 1984), autism (Sears et al. 1999), ketamine intoxica-
Inappropriate affect, as defined here, must be distin- tion (Krystal et al 2005), and in cases of dementia occur-
guished from the far more common ‘socially’ inappropri- ring in the elderly (Rabinowitz et al. 2004).
ate affect. For example, smiling at a funeral, although
certainly socially inappropriate would not be considered
pathologic if the person smiling felt a sense of triumph at
the death of a hated rival, for here there is no mismatch
between what is felt and what is displayed.
Stereotypies are distinguished by their monotonous
‘Nervous laughter’, for example when someone laughs
repetitiveness.
to cover up a feeling of sadness, although indeed represent-
In patients treated chronically with antipsychotics,
ing a mismatch is distinguished by the fact that the cover-
mannerisms must be distinguished from tardive dyskinesia
ing laughter can be easily dispelled with a few sympathetic
(Granacher 1981). One clue to the differential lies in the
questions, after which the laughter is replaced by an appro-
presence or absence of a motivation for the behavior in
priate look of sadness.
question: mannerisms represent intentional behaviors that
Aprosodia of the sensory type, as discussed in Section
have undergone a bizarre transformation; the abnormal
2.7, is quite similar to inappropriate affect in that in both
movements of tardive dyskinesias, in contrast, are involun-
these signs there is an incongruence, or mismatch, between
tary and occur in the absence of any motivation.
what the patient feels and the tone of voice with which that
feeling is expressed. The difference is that in sensory
aprosodia, patients also have difficulty in comprehending
what others feel by listening to the tone of voice with which Treatment
others speak, whereas in inappropriate affect patients
retain this ability. Treatment is directed at the underlying etiology.
Treatment 4.28 STEREOTYPIES

Treatment is directed at the underlying condition. Stereotypies represent a kind of perseverative motor activity
in which behaviors are repeated again and again in a pur-
poseless, monotonous, and thoroughly stereotyped fashion:
4.27 MANNERISMS they may range from such simple behaviors as hand flap-
ping to complex activities such as repeatedly taking apart
Manneristic transformation of gestures or speech, or of and then putting back together a small machine. Importantly,
activities such as walking or eating, although most common although some of these stereotypies appear, on the surface,
in schizophrenia, may occur in other disorders. The result- to be purposeful, patients are unable to adequately explain
ing mannerisms often strike others as peculiar or bizarre. why they repeatedly engage in the behavior.
p 04.qxd 3/10/08 9:33 AM Page 141
4.29 Echolalia and echopraxia 141
Clinical features is also effective (Lewis et al. 1996). Risperidone (McDougle

et al. 2005) and haloperidol are effective in autism, as is
As noted, stereotypical behaviors can range from simple to clomipramine but this is not as well tolerated as haloperi-
complex. Simple stereotypies might consist of hand- dol (Remington et al. 2001); a recent study also suggested
flapping, shoulder-shrugging or hand-wringing. More com- effectiveness for divalproex (Hollander et al. 2006).
plex stereotypies include folding and unfolding a towel, Various behavioral therapies may also be effective.
repeatedly putting on, then taking off, an article of cloth-
ing, or repeatedly sitting down and standing up.
Stereotypies may persist for anywhere from minutes to 4.29 ECHOLALIA AND ECHOPRAXIA
hours, days, or even longer. Importantly, patients, pro-
vided they are not severely or profoundly retarded, are Echolalia and echopraxia represent, respectively, the repe-
generally able to voluntarily stop the behavior. tition or mirroring of what others say or do (Ford 1989).
Importantly, these echophenomena are not under volun-
tary control and occur regardless of whether patients wish
Etiology them or not.
Among adults, stereotypies are seen in schizophrenia and

in dementia, most particularly front-temporal dementia
Clinical features
and Alzheimer’s disease (Nyatsanza et al. 2003). Both men-
In echolalia, patients automatically repeat, parrot-like,
tal retardation and autism (with or without mental retar-
what others have said: in some cases only single words are
dation) are characterized by frequent stereotypies (Bodfish
repeated, whereas in other whole phrases or sentences may
et al. 2000), and stereotypies may also occur in a small per-
be echoed. In echopraxia, patients, again automatically and
centage of children with attention-deficit disorder or
without being instructed to do so, will mirror what others
learning disabilities (Mahone et al. 2004).
do. For example, if the physician crosses his or her arms,
Stereotypies may be seen during intoxication with
the echopractic patient will do the same thing; likewise, if
amphetamines (where they are classically referred to as
the physician stands, the patient will also stand.
‘punding’) or with cocaine (Brady et al. 1991) and, interest-
ingly, may also occur with treatment with levodopa (Evans
et al. 2000); they may also constitute part of tardive dyski- Etiology
nesia (Stacy et al. 1993). Finally, lesions of the lenticular
nuclei may also cause stereotypies (Laplane et al. 1989). Echophenomena apparently do not occur in isolation but are
seen as part of a larger syndrome, as for example catatonia
(e.g., catatonic schizophrenia [Kraepelin 1971, p. 142]),
autism (Roberts 1989), and Tourette’s syndrome (Comings
and Comings 1987). Echophenomena have also been noted in
As noted above, stereotypies represent a kind of persevera-
post-encephalitic parkinsonism (Wilson 1954), frontotempo-
tion, and, as noted in Section 4.5, are distinguished from
ral dementia (e.g., Pick’s disease [Wilson 1954]), and in the
other perseverations by their purposelessness and monoto-
later stages of Alzheimer’s disease (Cummings et al. 1985).
nous character.
Transcortical aphasia, including transcortical motor aphasia
Tics are generally not repetitious and although they can
(Hadano et al. 1998) and transcortical mixed aphasia
be suppressed this is done only with great effort, and even-
(Mendez 2002), may also be characterized by echolalia.
tual failure. Compulsions are distinguished by the fact that
there is a motivation for the behavior: if you ask a patient
who repeatedly goes to and from the stove, each time Differential diagnosis
touching the gas knob, why he or she is acting so, the
patient with a compulsion might explain that it is because Palilalia is distinguished from echolalia by the fact that the
of an overwhelming anxiety that the stove might not have repetition in palilalia involves not words spoken by others
been turned off, whereas the patient with a stereotypy will but words spoken by the patient. The environmental
not be able to offer a reason. dependency syndrome is distinguished from echopraxia by
the fact that the patient’s automatic behavior represents
not a mirroring of what others do but rather an involun-
Treatment tary utilization of objects at hand.
In patients with schizophrenia, antipsychotics are effec-
tive; the optimal treatment for stereotypies in dementia is Treatment
not clear.
In patients with mental retardation, low-dose antipsy- Treatment is directed at the syndrome of which the
chotics, such as risperidone, are useful and clomipramine echophenomenon is a part.
p 04.qxd 3/10/08 9:33 AM Page 142
4.30 HALLUCINATIONS AND DELUSIONS Table 4.6 Types of hallucinations and delusions
Hallucinations
Hallucinations are said to be present when patients have Visual
the experience of something that is in fact not actually Autoscopy
present. Thus, a patient who hallucinates a dog in the hos- Lilliputian
pital room might report seeing a dog, and even reach down Palinopsia
to pat it, whereas others in the room see nothing. Polyopia
Delusions are false beliefs that cannot be explained on Auditory
the basis of either the patients’ culture or religion and that Tactile
persist despite evidence and reasonable argument to the Olfactory
contrary. Thus, in evaluating patients with false beliefs it is Gustatory
critical to take into account their culture and religion.
Although a belief in zombies would not generally be con- Delusions
sidered to be a delusion in poor and uneducated Haitians, Delusions of persecution
for example, any well-acculturated American who main- Capgras syndrome
tained such a belief would generally be considered delu- Fregoli syndrome
sional. Although some physicians make much of the Delusions of grandeur
‘contextual’ nature of beliefs, most delusions are in prac- Delusions of jealousy
tice so bizarre and unbelievable that there is no question of Erotomanic delusions (De Clerambault syndrome)
their status. Thus, there is but little debate about the status Nihilistic delusions
of such beliefs that bodies of family members are inhabited Cotard’s syndrome
by malevolent aliens or that telepathic listening devices Delusions of sin
have been implanted inside the spleen. Delusions of reference
A group of specific hallucinations and delusions, known
as Schneiderian first rank symptoms, is discussed sepa- ‘Lilliputian’ hallucinations are said to be present when
rately in Section 4.31. As pointed out there, these the hallucinated figures are quite small, much as in the
Schneiderian first rank symptoms, although found in novel Gulliver’s Travels (Alexander 1926; Goldin 1955;
diverse disorders, are highly suggestive of schizophrenia. Leroy 1922).
Palinopsia represents a peculiar kind of visual hallucina-
tion that Critchley (1951) considered to be a type of ‘visual
Clinical features perseveration’. Here, objects originally actually seen by the
patient are subsequently recurrently hallucinated out of
The various types of hallucinations and delusions are place. For example (Michel and Troost 1980), one patient
noted in Table 4.6. As noted there, hallucinations are cate- reported that ‘each person she saw had the face of someone
gorized according to the sensory modality affected, and she had just seen on television. She later peeled a banana
delusions according to their content. Specific descriptions and in a few minutes saw multiple vivid images of bananas
of hallucinations and delusions follow. projected over the wall. She realized they were only images,
and not real. Next, after putting a 20-dollar bill in her purse,
HALLUCINATIONS she saw heaps of 20-dollar bills everywhere’.
Another patient (Meadows and Munro 1977), after see-
Visual hallucinations range from simple to complex in ing someone costumed as Santa Claus at a Christmas party,
form. Simple hallucinations include such phenomena as ‘noticed that a replica of the white beard of . . . Santa Claus
‘zigzag linear patterns’ (Panayiotopoulos 1994) and ‘danc- was superimposed upon the face of everyone she spoke to’.
ing lights, rings and circles’ (Parkinson et al. 1952). Polyopsia refers to a condition in which patients, rather
Complex phenomena may be quite detailed: one patient, than simply seeing ‘double’, see multiple reduplications of
a war veteran, saw ‘stretcher bearers walking past him and the same image (Lopez et al. 1993). Whether or not this
then the figures of nurses whom he would recognize’ should be considered to be a variant of palinopsia is unclear.
(Russell and Whitty 1955); another saw ‘the Queen, with a Hallucinations that occur upon falling asleep or upon
bag over her arm [who] walked from the left to the centre awakening are known, respectively, as hypnagogic and
of the ward, then vanished’ (Lance 1976). hypnopompic (Zarcone 1973).
In some cases, autoscopy may occur, wherein patients Auditory hallucinations may range from such simple
hallucinate an image of themselves (Lukianowicz 1958): phenomena as ‘grinding noises’ or a noise ‘like a freight
one 74-year-old woman ‘suddenly noticed a figure seated train’ (Cascino and Adams 1986) to complex experiences
on [her] left. “It wasn’t hard to realize that it was I myself such as hearing music (Hammeke et al. 1983) or voices.
who was sitting there. I looked younger and fresher than I Voices, the most compelling type of auditory hallucina-
do now. My double smiled at me in a friendly way, as tion, may be soft, mere whisperings, or quite clear and dis-
though she wanted to tell me something” ’ (Kolmel 1985). tinct. They may come from an internal organ or have their
p 04.qxd 3/10/08 9:33 AM Page 143
source outside the patient, in ‘the air’, or perhaps elec- “Glory of Israel”, an inventor, a great singer, can do what
tronic devices or simply the walls. Some patients seem able he will’ (Kraepelin 1921).
to ignore them, whereas others will talk back to them. Delusions of jealousy (Soyka et al. 1991) fuel patients’
There may occasionally be ‘command’ hallucinations, jealousies: the infidelities of spouses or lovers are revealed
which, as noted by Kraepelin (1921), ‘in certain circum- and their ‘playing around’ is no longer hidden. Pro-
stances are very precisely obeyed. They forbid the patient testations of faithfulness have no effect as patients find evi-
to eat and to speak, to work, to go to church . . . “Go on, dence for their suspicions: the spouse is late coming home;
strike him, beat him”.’ the phone rings at odd times; the sheets are rumpled in a
Tactile hallucinations (Berrios 1982) are extraordinarily suggestive way.
varied. Kraepelin (1921), in describing a tactually halluci- Erotomanic delusions are characterized by a belief in an
nated patient, noted that he ‘feels himself laid hold of, ‘amorous communication with a person of much higher
touched over his whole body, he feels tickling in his thigh rank who has been the first to fall in love and the first to
and right up to his neck, pricking in his back and in his make advances’ (Gillett et al. 1990). Also known as De
calves, a curious feeling in his neck, heat in his face’. When Clerambault’s syndrome (Ellis and Mellsop 1985), these
patients hallucinate the feeling of ants or insects crawling delusions often impel patients to attempt contact with
on the skin, one speaks of ‘formication’. these supposed lovers, even to the point of stalking and
Olfactory hallucinations, although at times consisting of kidnapping them.
such pleasant aromas as perfume, are generally unpleasant, Nihilistic delusions entail the belief that animate objects,
even repulsive: Kraepelin (1921) noted ‘a smell of sulphur; such as other people, animals or such living things as trees,
of corpses and chloride of lime, of blood, of fire, of the are in fact dead. In a variant of this, known as Cotard’s
fumes of hell’. syndrome (Joseph and O’Leary 1986), patients come to
Gustatory hallucinations are perhaps the least common believe that they themselves are in fact dead: in one case
of all types: Kraepelin (1921) reported patients who tasted (Cohen et al. 1997), a 13-year-old girl had the ‘absolute
‘petroleum or arsenic’ in the food. conviction that she was already dead, waiting to be buried,
and that she had no teeth and no hair and that her uterus
DELUSIONS was malformed’.
Delusions of sin give form to the patients’ sense that they
Delusions of persecution take the most varied of forms: have committed unpardonable acts: they have cursed God,
patients are spied on and followed; a conspiracy has been engaged in unspeakable practices, betrayed those close to
set up, and the police, FBI, or even the mafia are involved. them and violated all their sacred principles. Such a patient
Neighbors and co-workers, even family members, have ‘is a damned soul, the refuse of humanity’ (Kraepelin 1921).
turned on them: poison gas surrounds them, and their Delusions of reference embody a sense that seemingly
food, indeed even their medicine, has been adulterated. unrelated and chance events in some fashion pertain to or
The Capgras syndrome (Alexander et al. 1979; refer to the patient. ‘Indifferent remarks and chance looks,
Christodoulou 1977; Enoch 1963) represents a particular the whispering of other people, appear suspicious to the
kind of delusion of persecution wherein patients believe patient’ (Kraepelin 1921). In many cases, such delusions of
that malevolent ‘imposters’ have somehow entered and reference serve, as it were, to bolster or reinforce other
taken over the bodies of familiar persons, such as family delusions. Thus, patients with delusions of persecution, on
members or neighbors. In one case (Merrin and Silberfarb seeing police officers talking, might immediately believe
1976), the patient believed that ‘the “substitution” first that the conversation was about them and that it was evi-
occurred on [her] wedding day, when her husband went to dence that the conspiracy had begun in earnest. To take
the men’s room and an imposter took his place’. Although another example, patients with delusions of grandeur
others could not see anything amiss with her husband, the might, upon seeing the sun break radiantly through the
patient felt able to differentiate the husband from the storm clouds, assume that it was a sign of God’s special
imposter given that the imposter ‘had a rotten green toe- grace for them.
nail. Once she even went so far as calling the police and
demanding that her husband remove his shoe to expose
the green toenail to the police’. In some cases of the Etiology
Capgras syndrome, patients may turn on the ‘imposter’, in
the process assaulting innocent parties (Thompson and The causes of delusions or hallucinations are listed in Table
Swan 1993). 4.7. In the vast majority of cases, the delusions or halluci-
In a related kind of delusion of persecution, known as nations occur in the context of a major syndrome, and the
the Fregoli syndrome, patients believe that the body of a first task is to determine whether one of those syndromes is
stranger has somehow been invaded and taken over by a present. Dementia (Section 5.1) is suggested by co-existent
familiar person (O’Sullivan and Dean 1991). cognitive deficits, such as disorientation or short-term
Delusions of grandeur may involve various themes: the memory loss, and delirium (Section 5.3) by similar cogni-
patient ‘is “something better”, born to a higher place, the tive deficits with the all-important addition of confusion.
p 04.qxd 3/10/08 9:33 AM Page 144
Table 4.7 Causes of delusions or hallucinations

Delusions or hallucinations occurring in the context of a Blindness (Charles Bonnet Syndrome) (Schultz and Melzack
major syndrome 1993; Teunisse et al. 1995, 1996)
Dementia Focal intracerebral lesions
Delirium Occipital lobe or occipitotemporal and occipitoparietal
Depression areas (Kolmel 1985; Parkinson et al. 1952)
Mania Thalamus (Noda et al. 1993; Serra Catafau et al. 1992)
Psychosis Mesencephalon (‘peduncular hallucinations’) (Lhermitte
1922, 1932; McKee et al. 1990)
Isolated hallucinations occurring with preserved insight
Pontine tegementum (‘Pick’s visions’) (Bing 1940)
Visual hallucinations
Medications
Narcolepsy (Zarcone 1973)
Dopaminergics (Banerjee et al. 1989; Barnes et al. 2001,
Guillain–Barré syndrome (Cochen et al. 2005)
Fenelon et al. 2000; Goetz et al. 2005, Shaw et al. 1980)
Bereavement (Grimby 1993)
Digoxin (Closson 1983)
Sleep deprivation (Kollar et al. 1968)
Quinidine (Fisher 1981)
Normal (McDonald 1971)
Propranolol (Shopsin et al. 1975)
Acyclovir (Rashiq et al. 1993) Auditory hallucinations
Imipramine (Kane and Keeler 1964; Klein 1964) Medications
Amitriptyline (Hemmingsen and Rafaelsen 1980) Dopaminergics (Goetz et al. 2005)
Maprotiline (Albala et al. 1983) Pentoxyfylline (Gilbert 1993)
Bupropion (Golden et al. 1985) Partial seizures
Trazodone (Hughes and Lessell 1990) Simple partial seizures (Williams 1956)
Selective serotonin reuptake inhibitors (SSRIs) (Marcon Complex partial seizures (Currie et al. 1971)
et al. 2004) Deafness (Griffiths 2000; Hammeke et al. 1983; Miller and
Mirtazapine (Ihde-Scholl and Jefferson 2001) Crosby 1979; Ross et al. 1975)
Risperidone (Lauterbach et al. 2000) Focal intracerebral lesions
Methylphenidate (Gross-Tsur et al. 2004) Temporal lobe (Keschner et al. 1936)
Intoxicants Putamen (Cerrato et al. 2001)
Hallucinogens Mesencephalon (Cascino and Adams 1986)
Mescaline (Mitchell 1896) Pontine tegmentum (Cascino and Adams 1986; Murata
LSD (Bercel et al. 1956; Isbell et al. 1956) et al. 1994; Schielke et al. 2000)
Psilocybin (Hollister et al. 1960) Tactile hallucinations
Phencyclidine (Meyer et al. 1959) Cocaine (Siegel 1978)
Cocaine (Siegel 1978) Amphetamines (Bell 1973)
Solvents (Channer and Stanley 1983; Evans and Olfactory hallucinations
Raistrick 1987) Simple partial seizures (Mauguire and Courjon 1978)
Partial seizures Complex partial seizures (‘uncinate fits’) (Jackson and
Simple partial seizures (Penfield and Perot 1963; Russell Stewart 1899)
and Whitty 1955; Sowa and Pituck 1989; Williams Migraine (Fuller and Guiloff 1987; Wolberg and Ziegler 1982)
1956) Olfactory bulb or tract (Kaufman et al. 1988; Paskind 1935)
Complex partial seizures (Mulder and Daly 1952) Gustatory hallucinations
Aura to complex partial or grand mal seizures (Lee et al. Simple partial seizures (Mulder and Daly 1952)
2005) Complex partial seizures (Daly 1958; Hausser-Hauw and
Migraine (Hachinski et al. 1973; Selby and Lance 1960) Bancaud 1987)
Depression (Section 6.1) is indicated by depressed mood, In this syndrome, despite generally intact orientation and
anergia, anhedonia, and changes in appetite and sleep, and memory, and in the absence of significant depression or
mania (Section 6.3) by heightened mood, hyperactivity, mania, patients exhibit a ‘loss of reality testing’ as evi-
pressured speech, increased energy, and a decreased need denced by the presence of delusions or the presence of hal-
for sleep. Should the delusions or hallucinations be occur- lucinations without insight. Thus, all patients with isolated
ring in the context of any one of these, the differential for delusions are considered to have a psychosis, and in such
that syndrome should be pursued, as described in the cases the differential for that syndrome, as described in
respective chapter. Section 7.1, should be pursued. Isolated hallucinations
In cases where the foregoing syndromes are absent, one may occur either with or without insight, and it is critical
other syndrome must be considered, namely psychosis. to determine which is the case. Happily, this is not terribly
p 04.qxd 3/10/08 9:33 AM Page 145
difficult. ‘Insight’, a much belabored term, refers here not most cases, fairly simple, for example geometric forms,
to some sophisticated level of psychological understand- they may sometimes be complex (e.g. with lysergic diethyl-
ing, but rather simply to whether or not the patient recog- amide [LSD] [Bercel et al. 1956]). Hallucinogen-induced
nizes that the hallucination is ‘not real’. Sometimes simple visual hallucinations may also occur as ‘flashbacks’,
observation will enable one to determine whether the wherein long after hallucinogen intoxication the patient
patient experiences the hallucination as ‘real’: for example, spontaneously re-experiences some of the visual phenom-
should a patient report seeing a dog in the room and then ena that occurred during the intoxication (Abraham 1983;
reach down to pat it, one may reasonably assume that the Horowitz 1969).
patient has no insight into the hallucinatory nature of the Partial seizures may present with visual hallucinations:
experience. In doubtful cases, further inquiry may be in simple partial seizure the visual hallucination may con-
required. Although one might simply ask whether or not stitute the entire symptomatology of the seizure, whereas
the patient thinks the ‘dog’ is ‘really’ there in the room, in complex partial seizures, it will be accompanied by some
such questions may offend some patients, and a more defect of consciousness.
diplomatic approach is often better accepted. Thus, one Migraine headaches are typically preceded by an aura
might say, in an off-handed way, ‘I don’t see it. Could you consisting of a visual hallucination; these tend to be
tell me where it is?’ In cases where insight has been pre- simple, consisting of flashing lights or zigzagging lines
served, the patient might respond, ‘Oh, there’s not a dog (Panayiotopoulos 1994; Russell and Olesen 1996). An aura
here. I must be seeing things.’ Conversely, in cases where may, very rarely, persist long after the headache has
insight has been lost the patient might point emphatically cleared, sometimes for years (Liu et al. 1995).
to a corner of the room and say ‘It’s right over there. Can’t Blindness, whether partial or complete, may be associ-
you see it?’ In cases of hallucinations where insight has ated with either simple or complex visual hallucinations
been lost, the syndromal diagnosis of psychosis is reason- in what is known as the Charles Bonnet syndrome
able, and should be pursued as in Section 7.1. In cases of (Santhouse et al. 2000; White 1980). This syndrome has
isolated hallucinations occurring with preserved insight, been noted with visual loss caused by cataracts (Bartlett
however, the diagnosis should proceed as described below. 1951), macular degeneration (Holroyd et al. 1992), and
In determining the cause of isolated hallucinations lesions of the optic nerve, chiasm, tract and optic radia-
occurring with preserved insight, the differential is differ- tions (Lepore 1990). Although classically the hallucina-
ent for each of the different kinds of hallucinations, and tions of the Charles Bonnet syndrome are said to be
thus each type is discussed in turn, beginning with visual ‘Lilliputian’ in character, it in fact appears that such minia-
hallucinations, and proceeding to auditory, tactile, olfac- turization occurs in only a minority of patients with this
tory, and, finally, gustatory hallucinations. syndrome (Teunisse et al. 1994). The onset of the Charles
Visual hallucinations are by far the most common type, Bonnet syndrome can at times be quite dramatic: in one
and of the various causes of these, medications and intoxi- case (White 1980), a 69-year-old man, while listening to
cants stand out. Of the medications capable of causing music, ‘suddenly saw a brightly coloured circus troupe
hallucinations, by far the most common are dopaminergic burst through the window’.
agents when used in the treatment of Parkinson’s disease. Focal intracerebral lesions, usually infarctions, may
After five or more years of treatment with levodopa, for cause hallucinations, and this has been noted with lesions of
example, visual hallucinations occur in a little over one- the occipital lobe and adjacent temporal and parietal lobes,
fifth of all patients (Friedman and Sienkiewicz 1991; and with lesions of the thalamus, mesencephalon or pons.
Graham et al. 1997). The hallucinations themselves may, at Lesions of the occipital cortex may, of course, also cause
times, be quite elaborate: in one case (Graham et al. 1997) a hemianopia, and in such cases the hallucinations tend to
a patient had ‘hallucinations of miniature people and occur in the hemianopic field (Kolmel 1985; Vaphiades
domestic animals . . . the figures were non-threatening, et al. 1996). The clinical presentation in such cases may be
laughed and talked among themselves, and had a male quite remarkable: one patient (Lance 1976) with a left hemi-
leader who organized them into purposeful activities’. It is anopia saw animals appearing: ‘from the left one at a time.
important to note that although parkinsonian patients At various times he saw dogs, goats, a lion and a horse as well
with levodopa-induced visual hallucinations retain insight as birds and butterflies. The animals would emerge from a
initially, over many years insight tends to be lost and the door on the left side of the room and walk to the mid-line. If
syndrome of psychosis emerges (Goetz et al. 2006). The he looked to the left the animals retreated towards the door
other medications listed in Table 4.7 are far less likely to be but would advance again as he looked to the front’.
at fault. Another patient, a neurologist, after suffering an infarc-
Of the intoxicants capable of causing hallucinations, the tion of the medial left occipital lobe, developed a right
aptly named hallucinogens immediately stand out. Of hemianopia in which he experienced vivid visual halluci-
note, in this group, one of the earliest descriptions was pro- nations: he noted that ‘often there was a pony with his head
vided by the eminent neurologist S. Weir Mitchell, who, in cradled in my right arm’ (Cole 1999).
1896, reported his own experiences with mescaline. Hallucinations occurring secondary to mesencephalic
Although the hallucinogen-induced hallucinations are, in lesions are often referred to as ‘peduncular’ hallucinations,
p 04.qxd 3/10/08 9:33 AM Page 146
given that the lesion typically involves one of the cerebral Partial seizures may manifest with auditory hallucina-
peduncles. These peduncular hallucinations are typically tions. In one case of a simple partial seizure (Williams
complex and vivid: one patient (Geller and Bellor 1987) 1956) the patient heard ‘a buzz’ that was quickly followed
saw ‘cats running about the floor, flowery outdoor scenes by ‘music like a loudspeaker in which he heard clearly a
in bright purple colors, and the faces of neighbors and recognized section of Veni Creator’. One of Penfield and
friends’, whereas another (De La Fuente Fernandez et al. Perot’s (1963) patients, during a complex partial seizure,
1994) saw ‘motorbikes . . . dogs, horses . . . and people . . . ‘heard voices which seemed to come from her right side’ as
entering and driving silently around the room’. Although if she were in the middle of a ‘crowd of people’.
insight is preserved, and patients recognize the unreality of Deafness may be followed by auditory hallucinations,
these peduncular hallucinations, their vivid character can thus constituting, as it were, the ‘auditory’ equivalent of
nonetheless have a profound effect: in one case (Dunn the Charles Bonnet syndrome. Interestingly, the hallucina-
et al. 1983), a patient saw ‘snakes . . . that appeared from tions seen here tend to be musical.
any direction’ and although ‘he knew the snakes were not Focal intracerebral lesions, very rarely, may cause
real (nevertheless) during the examination he frequently isolated auditory hallucinations, and these have been
jumped because he was pulling away from the perceived noted with lesions of the temporal cortex, putamen, mes-
snakes’. The mesencephalic location of the responsible encephalon, and pontine tegmentum.
lesions usually entails ‘neighborhood’ symptoms of localiz- Tactile hallucinations may be seen with intoxication
ing value: thus, a right mesencephalic infarction affecting with either cocaine or amphetamines, and typically consist
both the right cerebral peduncle and the midbrain tegmen- of formication.
tum also caused left hemiplegia and bilateral ptosis (Geller Olfactory hallucinations may represent either the sole
and Bellor 1987); a left mesencephalic infarction that pri- symptomatology of a simple partial seizure or be part of the
marily involved the substantia nigra also caused a parkin- symptomatology of a complex partial seizure. Classically,
sonian syndrome with prominent tremor on the right they indicate a focus in the temporal lobe, particularly the
(De La Fuente Fernandez et al. 1994). uncus, and the resulting seizures are sometime referred to as
Hallucinations occurring secondary to pontine infarc- ‘uncinate fits’. They may also appear as a migraine aura or,
tion have been referred to as ‘Pick’s visions’, and have a very rarely, secondary to lesions of the olfactory bulb or tract.
distinctive character in that they often consist of halluci- Gustatory hallucinations with preserved insight have
nating people walking through walls (Bing 1940). been reported during simple or complex partial seizures.
Of the miscellaneous causes of visual hallucinations,
narcolepsy is the most common and in this disorder they Differential diagnosis
occur on either a hypnogogic or hypnopompic basis.
Guillain–Barré syndrome, at its height, may cause visual As noted earlier, delusions must be distinguished from cultur-
hallucinations, possibly due to direct central nervous sys- ally or religiously sanctioned beliefs. Hallucinations, in turn,
tem involvement. Normal individuals may experience must be distinguished from illusions. Illusions are distorted
hallucinations during bereavement, with sleep deprivation, experiences of actual objects, as for example the experience of
or, occasionally, on a hypnogogic basis. Hallucinations a shimmering pool of water floating above a distant hot pave-
seen in bereavement are often of the deceased and the ment, a pool that ‘disappears’ as one approaches closer.
grieving person often finds them comforting; they tend to
clear spontaneously within a few months.
Before leaving this section on visual hallucinations, a few
Treatment
extra words are in order regarding palinopsia as its differen-
Treatment is directed, wherever possible, at the underlying
tial is quite limited. Palinopsia has been noted with treat-
cause. In the case of the Charles Bonnet syndrome, although
ment with trazodone (Hughes and Lessell 1990),
there are no controlled studies, anecdotal reports attest to the
mirtazapine (Ihde-Scholl and Jefferson 2001) and risperi-
efficacy of generally low-dose treatment with various med-
done (Lauterbach et al. 2000), as a manifestation of a simple
ications including valproate (Hori et al. 2000), gabapentin
partial seizure (Muller et al. 1995), and with lesions of the
(Paulig et al. 2001), carbamazepine (Batra et al. 1997),
occipital lobe (Michel and Troost 1980), occipitotemporal
donepezil (Ukai et al. 2004), venlafaxine (Lang et al. 2007),
region (Meadows and Munro 1977), occipitoparietal region
risperidone (Maeda et al. 2003), and olanzapine (Coletti
(Bender et al. 1968), and the parietal lobe (Critchley 1951).
Moja et al. 2005). In the case of hallucinations occurring with
Auditory hallucinations occurring with preserved
focal intracerebral lesions, an empirical trial of a low-dose
insight are relatively uncommon, and may be seen as side-
antipsychotic may be justified.
effects to medications, manifestations of partial seizures,
with deafness, or with focal intracerebral lesions.
Levodopa, used in the treatment of parkinsonism, may 4.31 SCHNEIDERIAN FIRST RANK SYMPTOMS
cause auditory hallucinations, but these are less common
than the visual hallucinations discussed earlier. There is also Kurt Schneider (1887–1967) was a very influential German
a case report of hallucination secondary to pentoxyfylline. psychiatrist whose classic text Clinical Psychopathology
p 04.qxd 3/10/08 9:33 AM Page 147
4.31 Schneiderian first rank symptoms 147
went through multiple revisions from its first edition in Thought withdrawal represents a delusion wherein
1939 up to the fifth, and last, edition, published in 1959. In patients experience their thoughts being directly removed
this text, Schneider described a number of hallucinations and withdrawn from their minds. One of Kraepelin’s
and delusions that he believed were of ‘first rank’ impor- (1921) patients spoke of his thoughts being ‘drawn off’.
tance in the diagnosis of schizophrenia. Although these This is quite different from simply losing track of what one
Schneiderian first rank symptoms are, indeed, most com- was thinking: those who lose track have a sense of having
monly seen in schizophrenia, they may also, as pointed out forgotten or lost something, whereas those with thought
by Schneider himself, occur in ‘diverse’ other conditions, withdrawal have, as emphasized by Schneider (1959), a
as described below. definite sense that some other agency or person has directly
removed the thought.
Thought insertion represents the delusional belief of
Clinical features patients that the thoughts occurring in their minds are not
their own but rather originate from, as Schneider (1959)
The various Schneiderian first rank symptoms, as noted in put it, ‘other people, who intrude their thoughts upon the
Table 4.8, may be divided into those which are auditory patient’. Such inserted thoughts are quite different from
hallucinations and those which represent delusions. obsessions: obsessions are recognized by patients as their
Audible thoughts are said to occur when patients hear own thoughts and as originating within them, whereas
their own thoughts as if they were spoken out loud and inserted thoughts are experienced as a kind of cognitive
indeed as if others might be able to hear them also. One of ‘foreign body’.
Schneider’s (1959) patients said, ‘I hear my own thoughts. Thought broadcasting represents the delusion that oth-
I can hear them when everything is quiet.’ ers can know what a patient is thinking without the patient
Voices commenting on what the patient does, keep up, in any way relating those thoughts. This ‘thought diffusion’
as it were, a running commentary on the patient’s behav- led one of Schneider’s (1959) patients to complain that, ‘if
ior. One of Schneider’s (1959) patients ‘heard a voice say, I think of anything, at once those opposite me know it and
whenever she wanted to eat, “Now she is eating, here she is it is embarrassing.’ As she believed that ‘the doctor too
munching again,” ’ and one of Kraepelin’s (1921) patients knew exactly what she was thinking, . . . she suggested that
heard a voice telling her, ‘Mary, you’re talking nonsense, she would stop talking and (the physician) could just lis-
the policeman has seen you already.’ ten’. In some cases, patients will elaborate on this delusion,
Voices arguing with each other, or, as Schneider (1959) developing further beliefs about how such thought transfer
elaborated, merely ‘conversing with one another’, may is possible: Kraepelin (1921) noted that some patients
engage patients’ attention, as if the voices were carrying on believe that ‘their thoughts are conveyed by a machine,
a debate about them. there is a “mechanical arrangement”, “a sort of little con-
Delusions of passivity or influence are said to be present veyance”, telepathy’.
when ‘feelings, impulses (drives) and volitional acts . . . are
experienced by the patient as the work or influence of
others’ (Schneider 1959). Such patients believe that their Etiology
thoughts, feelings or behavior are under the direct and
unmediated control of some outside force or agency. Thus It has, at times, been felt that Schneiderian first rank symp-
passively played upon by these forces, patients feel as if toms were virtually pathognomonic of schizophrenia,
they were robots or automatons. Patients will typically occurring in virtually no other condition. The source of
elaborate on this delusion of influence and express a belief this belief is not clear: it certainly does not come from
as to the source of the influence, for example an ‘electrical Schneider, who clearly stated that these first rank symp-
device’, ‘distant computers’, or ‘powerful magnets’. toms could occur secondary to a ‘number of diverse mor-
bid cerebral processes’ (Schneider 1959).
The various causes of the first rank symptoms are listed
in Table 4.9. Of all of these, schizophrenia is, by far, the
Table 4.8 Schneiderian first rank symptoms
most common cause, with first rank symptoms being
Auditory hallucinations found in anywhere from one-third (Radhakrishnan et al.
Audible thoughts 1983) to over one-half (Tandon and Greden 1987) of such
Voices commenting on what the patient does patients. Among patients with schizophrenia, it appears
Voices arguing with each other that thought broadcasting and thought insertion are prob-
Delusions
ably most common out of all the first rank symptoms
Delusions of passivity or influence
(Mellor 1970). Schizoaffective disorder is probably the
Thought withdrawal
next most common cause, with symptoms noted in about
Thought insertion
one-quarter of these patients (Tandon and Greden 1987).
Mania, as seen in bipolar disorder, during stage II or III,
Thought broadcasting
may also cause first rank symptoms, and the diagnosis here
p 04.qxd 3/10/08 9:33 AM Page 148
Table 4.9 Causes of Schneiderian first rank symptoms Treatment

Schizophrenia (Tandon and Greden 1987)
Schizoaffective disorder (Koehler and Seminario 1979) Treatment is directed at the underlying condition.
Mania (Gonzales-Pinto et al. 2003; Jampala et al. 1989)
Depression (Tandon and Greden 1987)
Substance or medication-related REFERENCES
Intoxications
Amphetamines (Angrist and Gershon 1970; Bell 1973; Abraham HD. Visual phenomenology of the LSD flashback. Arch
Janowsky and Risch 197) Gen Psychiatry 1983; 40:884–9.
Cocaine (Harris and Batki 2000; Rosse et al. 1994) Achari AN, Colover J. Posterior fossa tumors with pathological
Phencyclidine (Rosse et al. 1994) laughter. JAMA 1976; 235:1469–71.
Alcohol hallucinosis (Marneros 1988) Ackerly W, Lhamom W, Fitts WT. Phantom breast. J Nerv Ment Dis
Benzodiazepine withdrawal (Roberts and Vass 1986) 1955; 121:177–8.
Fluvoxamine (Ueda et al. 2003) Adie WJ. Idiopathic narcolepsy: a disease sui generis, with
Epileptic conditions remarks on the mechanism of sleep. Brain 1926; 49:257–306.
Simple partial seizures (Mesulam 1981) Adie WJ, Critchley M. Forced grasping and groping. Brain 1927;
Chronic interictal psychosis (Kido and Yamaguchi 1989; 50:142–70.
Slater and Beard 1963) Akelaitis AJ. Psychobiological studies following section of the
Miscellaneous causes corpus callosum. Am J Psychiatry 1941; 97:1147–57.
Cushing’s syndrome (Trethowan and Cobb 1952) Akelaitis AJ. Studies on the corpus callosum. IV. Diagonistic
New-variant Creutzfeldt–Jakob disease (Zeidler et al. 1997) dyspraxia in epileptics following partial and complete section
Subacute sclerosing panencephalitis (Duncalf et al. 1989) of the corpus callosum. Am J Psychiatry 1945; 101:594–9.
Fahr’s syndrome (Cummings et al. 1983) Akelaitis AJ, Risteen WA, Herren RY et al. Studies on the corpus
Metrizamide myelography (Davis et al. 1986) callosum. III. A contribution to the study of dyspraxia and
apraxia following partial and complete section of the corpus
callosum. Arch Neurol Psychiatry 1942; 47:971–1008.
Albala AA, Weinberg N, Allen SM. Maprotilene induced
is suggested by typical manic symptoms seen in stage I, hyonopompic hallucinations. J Clin Psychiatry 1983; 44:149–50.
such as pressured speech, hyperactivity, increased energy, Albert ML, Sandson J. Perseveration in aphasia. Cortex 1986;
decreased need for sleep, etc. Depression, as seen in major 22:103–15.
depressive disorder, is only rarely associated with first rank Alevizos B, Lykouras L, Zervas IM et al. Risperidone-induced
symptoms, and hence the appearance of such a symptom obsessive-compulsive symptoms. A review of six cases. J Clin
in a depressed patient should make one pause before giving Psychopharmacol 2002; 22:461–7.
a diagnosis of major depression; in such cases a diagnosis Alexander MC. Lilliputian hallucinations. J Ment Sci 1926;
of schizoaffective disorder may be more likely. 72:187–91.
The other causes noted in Table 4.9, although rare, must Alexander MP, Schmitt MA. The aphasia syndrome of stroke in the
be kept in mind. Of these, intoxications with ampheta- left anterior cerebral artery territory. Arch Neurol 1980;
mines, cocaine, or phencyclidine are perhaps most com- 37:97–100.
mon. Chronic, severe, alcoholism may be associated with Alexander MP, Stuss DT, Benson DF. Capgras syndrome: a
alcohol hallucinosis, which may be characterized by first reduplicative phenomenon. Neurology 1979; 29:334–9.
rank symptoms, and there are case reports of these symp- Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke
toms occurring during benzodiazepine withdrawal and as pathological crying. Lancet 1993; 342:837–9.
a side-effect to fluvoxamine. Anderson M, Salmon MV. Symptomatic cataplexy. J Neurol
Epileptic conditions associated with first-rank symp- Neurosurg Psychiatry 1977; 40:186–91.
toms include simple partial seizures and the chronic inter- Anderson SW, Damasio H, Damasio AR. A neural basis for
ictal psychosis. In one case of a simple partial seizure, the collecting behavior in humans. Brain 2005; 128:201–18.
patient, during the ictus, had ‘blurry vision, abdominal Andreasen NC. Affective flattening and criteria for schizophrenia.
discomfort, sensation of imminent death, intense fear, and Am J Psychiatry 1979; 136: 944–7.
the conviction that his body (was) controlled by external Angrist B, Gershon S. The phenomenology of experimentally induced
forces’ (Mesulam 1981). The chronic interictal psychosis, amphetamine psychosis. Biol Psychiatry 1970; 2:95–107.
discussed further in Section 7.1, is seen only in patients Anson JA, Kuhlman DT. Post-ictal Kluver–Bucy syndrome after
with chronic, severe, uncontrolled epilepsy: one of Slater temporal lobectomy. J Neurol Neurosurg Psychiatry 1993;
and Beard’s (1963) patients believed that there was a ‘pick- 56:311–13.
up’ device in his body ‘which transmitted thoughts from Asfora WT, DeSalles AAF, Masamitsu ABE et al. Is the syndrome of
the brain, and also made the brain receive’. pathological laughing and crying a manifestation of
The remaining miscellaneous causes listed in Table 4.9 pseudobulbar palsy? J Neurol Neurosurg Psychiatry 1989;
only very rarely cause first rank symptoms. 52:523–5.
p 04.qxd 3/10/08 9:33 AM Page 149
References 149
Assal F, Valenza N, Landis T. Clinicoanatomic correlates of a Fou Batra A, Bartels M, Wormstall H. Therapeutic options in Charles
rire prodromique in a pontine infarction. J Neurol Neurosurg Bonnet Syndrome. Acta Psychiatr Scand 1997; 96:129–33.
Psychiatry 2000; 69:697–8. Bautista RE, Ciampetti MZ. Expressive aprosody and amusia as a
Ay H, Buoanno S, Price BH et al. Sensory alien hand syndrome: manifestation of right hemisphere seizures. Epilepsia 2003;
case report and review of the literature. J Neurol Neurosurg 44:466–7.
Psychiatry 1998; 65:366–9. Bayles KA, Tomoeda CK, Kaszniak AW et al. Verbal perseveration
Ayotte J, Peretz I, Hyde K. Congenital amusia. A group study of of dementia patients. Brain Lang 1985; 25:102–16.
adults afflicted with a music-specific disorder. Brain 2001; Bayles KA, Tomoeda CK, McKnight PE et al. Verbal perseveration
125:238–51. in individuals with Alzheimer’s disease. Semin Speech Lang
Ayuso-Peralta L, Jimenez-Jimenez FJ, Tejeiro J et al. Progressive 2004; 25:335–47.
multifocal leukoencephalopathy in HIV infection presenting as Becker R, Benes L, Sure U et al. Intrathecal baclofen alleviates
Balint’s syndrome. Neurology 1994; 44:1339–40. autonomic dysfunction in severe brain injury. J Clin Neurosci
Baguley IJ, Nicholls JL, Felmingham KL et al. Dysautonomia after 2000; 7:316–19.
traumatic brain injury: a forgotten syndrome? J Neurol Behrman S, Carroll JD, Janota I et al. Progressive supranuclear
Neurosurg Psychiatry 1999; 67:39–43. palsy. Brain 1969; 92:663–78.
Baguley IJ, Heriseanu RE, Gurka JA et al. Gabapentin in the Bell DS. The experimental reproduction of amphetamine
management of dysautonomia following severe traumatic psychosis. Arch Gen Psychiatry 1973; 29:35–40.
brain injury: a case series. J Neurol Neurosurg Psychiatry 2007; Benke T, Hohenstein C, Poewe W et al. Repetitive speech
78:539–41. phenomena in Parkinson’s disease. J Neurol Neurosurg
Baker D, Hunter E, Lawrence E et al. Depersonalization disorder: Psychiatry 2000; 69:319–24.
clinical features of 204 cases. Br J Psychiatry 2003; Bender MB, Feldman M, Sobin AJ. Palinopsia. Brain 1968;
182:428–33. 91:321–38.
Baker RW, Chengappa R, Baird JW et al. Emergence of obsessive Benegal V, Hingorani S, Khanna S et al. Is stupor by itself a
compulsive symptoms during treatment with clozapine. J Clin catatonic symptom? Psychopathology 1992; 25:229–31.
Psychiatry 1992; 53:439–42. Benson DF, Gardner H, Meadows JC. Reduplicative paramnesia.
Banerjee AJ, Falkai PG, Savidge M. Visual hallucinations in the Neurology 1976; 26:147–51.
elderly associated with the use of levodopa. Postgrad Med J Benson DF, Djenderedjian A, Miller A et al. Neural basis of
1989; 65:358–61. confabulation. Neurology 1996; 46:1239–43.
Banks G, Short P, Martinez AJ et al. The alien hand syndrome: Bercell NA, Travis LE, Olinger LB et al. Model psychoses induced by
clinical and postmortem findings. Arch Neurol 1989; 46:456–9. LSD-25 in normals. I. Psychophysiological investigations, with
Bar KJ, Hager F, Sauer H. Olanzapine- and clozapine-induced special reference to the mechanism of the paranoid reaction.
stuttering. A case series. Pharmacopsychiatry 2004; 37:131–4. Arch Neurol Psychiatry 1956; 75:588–611.
Barbizet J, Degos JD, Duizabo Ph et al. Syndrome de deconnexion Berlin I. Mirror movements. Report of two cases. Arch Neurol
interhemispherique d’origine ischemique. Rev Neurol 1974; Psychiatry 1951; 66:394.
130:127–42. Berrios GE. Tactile hallucinations: conceptual and historical
Barclay CL, Bergeron C, Lang AE. Arm levitation in progressive aspects. J Neurol Neurosurg Psychiatry 1982; 45:285–93.
supranuclear palsy. Neurology 1999; 52:879–82. Besson G, Bogousslavsky J, Regli F et al. Acute pseudobulbar or
Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a suprabulbar palsy. Arch Neurol 1991; 48:501–7.
review and phenomenological survey. J Neurol Neurosurg Beukelman DR, Flowers CR, Swanson PD. Cerebral disconnection
Psychiatry 2001; 70:72–3. associated with anterior communicating aneurysm:
Barnes TR, Crichton P, Nelson HE et al. Primitive (developmental) implications for evaluation of symptoms. Arch Phys Med
reflexes, tardive dyskinesia and intellectual impairment in Rehabil 1980; 61:18–23.
schizophrenia. Schizophr Res 1995; 16:47–52. Bhatia K, Marsden CD. The behavioral and motor consequences of
Barrett K. Treating organic abulia with bromocriptine and lisuride: focal lesions of the basal ganglia in man. Brain 1994;
four case studies. J Neurol Neurosurg Psychiatry 1991; 117:859–76.
54:718–21. Bing R. Compendium of regional diagnosis in lesions of the brain
Barris RW, Schuman HR. Bilateral anterior cingulate gyrus lesions: and spinal cord, 11th edn, translated by Haymaker W. St Louis:
syndrome of the anterior cingulate gyri. Neurology 1953; CV Mosby, 1940.
3:44–52. Bird GLA, Meadows J, Goka J et al. Cyclosporin-associated akinetic
Bartlett JEA. A case of organized visual hallucinations in an old mutism and extrapyramidal syndrome after liver transplantation.
man with cataract, and their relationship to the J Neurol Neurosurg Psychiatry 1990; 53:1068–71.
phenomenology of the phantom limb. Brain 1951; 79:363–73. Bittar RG, Otero S, Carter H et al. Deep brain stimulation for
Bartusch SL, Sander BJ, D’Alessio JG et al. Clonazepam for the phantom limb pain. J Clin Neurosci 2005; 12:399–404.
treatment of lancinating phantom limb pain. Clin J Pain 1996; Black DW, Wojcieszek J. Depersonalizaton syndrome induced by
12:59–62. fluoxetine. Psychosomatics 1991; 32:468–9.
Bassetti C, Bogousslavsky J, Barth A et al. Isolated infarcts of the Blake JR, Kunkle EC. The palmomental reflex. A physiological and
pons. Neurology 1996; 46:165–75. clinical analysis. Arch Neurol Psychiatry 1951; 65:337–45.
p 04.qxd 3/10/08 9:33 AM Page 150
Bleuler E. Textbook of psychiatry, 1924, translated by Brill AA. Cairns H, Oldfield RC, Pennybacker JB et al. Akinetic mutism with
New York: Arno Press, 1976. an epidermoid cyst of the 3rd ventricle. Brain 1941;
Blumstein SE, Alexander MP, Ryalls JH et al. On the nature of the 64:273–90.
foreign accent syndrome; a case study. Brain Lang 1987; Cantu RC, Drew JH. Pathological laughing and crying associated
31:215–44. with a tumor ventral to the pons. J Neurosurg 1966;
Bodfish JW, Symons FJ, Parker DE et al. Varieties of repetitive 24:1024–6.
behavior in autism: comparisons to mental retardation. J Caplan LR, Schoene WC. Clinical features of subcortical
Autism Dev Disorder 2000; 30:237–43. arteriosclerotic encephalopathy (Binswanger’s disease).
Boeve BF, Wijdicks EF, Benarroch EE et al. Paroxysmal Neurology 1978; 28:1206–15.
sympathetic storms (‘diencephalic seizures’) after severe Caplan LR, Schmahmann JD, Kase CS et al. Caudate infarcts. Arch
diffuse axonal head injury. Mayo Clin Proc 1998; 73:148–52. Neurol 1990; 47:133–43.
Bogen JE. The callosal syndrome. In: Heilmann KM, Valenstein E Carabelli RA, Kellerman WC. Phantom limb pain: relief by
eds. Clinical neuropsychology, 2nd edn. New York: Oxford application of TENS to contralateral extremity. Arch Phys Med
University Press, 1985a. Rehabil 1985; 66:466–7.
Bogen JE. Split-brain syndromes. In: Vinken PJ, Bruyn GW, Cardoso F, Veado CC, de Oliveira JT. A Brazilian cohort of patients
Klawans HL eds. Handbook of clinical neurology, 2nd edn. with Tourette’s syndrome. J Neurol Neurosurg Psychiatry 1996;
Amsterdam: Elsevier, 1985b. 60:209–12.
Bogousslavsky J, Regli F. Anterior cerebral artery territory Carel C, Albucher JF, Manelfe C et al. Fou rire prodromique
infarction in the Lausanne stroke registry: clinical and heralding a left internal carotid artery occlusion. Stroke 1997;
etiologic patterns. Arch Neurol 1990; 47:144–50. 28:2081–3.
Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical Carlen PL, Wall PD, Nadvorna H et al. Phantom limbs and related
syndromes, etiology, and prognosis. Neurology 1988; 38:837–48. phenomena in recent traumatic amputations. Neurology 1978;
Bogousslavsky J, Delayoe-Bischof A, Assal G. Loss of psychic self- 28:211–17.
activation with bithalamic infarction: neurobehavioral, CT, MRI Carota A, Rossetti AO, Karapanayiotides T et al. Catastrophic
and SPECT correlates. Acta Neurol Scand 1991; 83:309–26. reaction in acute stroke: a reflex behavior in aphasic patients.
Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation Neurology 2001; 57:1902–5.
phantom limb pain: a randomized, double-blind, placebo- Carroll BT, Goforth HW, Raimonde LA. Partial Kluver-Bucy
controlled, cross-over study. Reg Anesth Pain Med 2002; syndrome: two cases. CNS Spectr 2001; 6:329–32.
27:481–6. Cascino GD, Adams RD. Brainstem auditory hallucinosis.
Borroni B, Broli M, Costanzi C et al. Primitive reflex evaluation in Neurology 1986; 36:1042–7.
the clinical assessment of extrapyramidal syndromes. Eur J Cassano GB, Petracca A, Perugi G et al. Derealization and panic
Neurol 2006; 13:1026–8. attacks: a clinical evaluation on 150 patients with panic
Botez MI, Werheim N. Expressive aphasia and amusia following right disorder/agoraphobia. Compr Psychiatry 1989; 30:5–12.
frontal lesion in a right-handed man. Brain 1959; 82:187–202. Catsman-Berrevoets CE, Van Dongen HR, Mulder PG et al. Tumor
Brady JP. Drug-induced stuttering: a review of the literature. type and size are high risk factors for the syndrome of
J Clin Psychopharmacol 1998; 18:50–4. ‘cerebellar’ mutism and subsequent dysarthria. J Neurol
Brady TK, Lydiard RB, Malcom R et al. Cocaine-induced psychosis. Neurosurg Psychiatry 1999; 67:755–7.
J Clin Psychiatry 1991; 52:509–12. Ceccaldi M, Milandre L. A transient fit of laughter as the
Bressler B, Cohen SI, Magnussen F. The problem of phantom inaugural symptom of capsular-thalamic infarction. Neurology
breast and phantom pain. J Nerv Ment Dis 1956; 123:181–7. 1994; 44:1762.
Brion S, Jedynak CP. Troubles de transport interhemispherique: Ceccaldi M, Poncet M, Milandre L et al. Temporary forced laughter
a propos de trois observations de tumeurs du corps calleux. after unilateral strokes. Eur Neurol 1994; 34:36–9.
Rev Neurol 1972; 126:257–66. Cerrato P, Imperiale D, Giraudo M et al. Complex musical
Brock S, Merwarth HR. The illusory awareness of body parts in hallucinosis in a professional musician with a left subcortical
cerebral disease. Arch Neurol Psychiatry 1957; 77:366–75. hemorrhage. J Neurol Neurosurg Psychiatry 2001; 71:280–1.
Brodsky H, Vuong KD, Thomas M et al. Glabellar and palmomental Cerrato P, Imperilae D, Bergoni M et al. Emotional facial paresis in
reflexes in parkinsonian disorders. Neurology 2004; 63:1096–8. a patient with a lateral medullary infarction. Neurology 2003;
Brooks BR, Thisted RA, Appel SH et al. Treatment of pseudobulbar 60:723–4.
affect in ALS with destromethorphan/quidine. A randomized Chan JL, Ross ED. Left-handed mirror writing following right
trial. Neurology 2004; 63:1364–70. anterior cerebral artery infarction: evidence for non-mirror
Brown DL, Smith TL, Knepper LE. Evaluation of five primitive transformations of motor programs by right supplementary
reflexes in 240 young patients. Neurology 1998; 51:322. motor area. Neurology 1988; 38:59–63.
Bullard DE. Diencephalic seizures: responsiveness to Chan J-L, Ross ED. Alien hand syndrome: influence of neglect on
bromocriptine and morphine. Ann Neurol 1987; 21:609–11. the clinical presentation of frontal and callosal variants.
Byerly M, Goodman W, Acholonu W et al. Obsessive compulsive Cortex 1997; 33:287–99.
symptoms in schizophrenia: frequency and clinical features. Chan JL, Chen RS, Ng KK. Leg manifestations in alien hand
Schizophr Res 2005; 76:309–16. syndrome. J Formosan Med Assoc 1996; 45:342–6.
p 04.qxd 3/10/08 9:33 AM Page 151
References 151
Channer KS, Stanley S. Persistent visual hallucinations secondary Davis RE, Cummings JL, Malin BD et al. Prolonged psychosis with
to chronic solvent encephalopathy: case report and review of first-rank symptoms following metrizamide myelography.
the literature. J Nerv Ment Dis 1983; 46:83–6. Psychosomatics 1986; 27:373–5.
Christensen RC, Byerly MJ, McElroy RA. A case of sertraline- Davison C, Kelman H. Pathologic laughing and crying. Arch Neurol
induced stuttering. J Clin Psychopharmacol 1996; 16:92–3. Psychiatry 1939; 42:595–643.
Christodoulou GN. The syndrome of Capgras. Br J Psychiatry 1977; Davison K. Episodic depersonalization: observations on 7 patients.
130:556–64. Br J Psychiatry 1964; 110:505–13.
Christoph DH, de la Freias GR, Dos Santos DP et al. Different D’Cruz OF, Vaughn BV, Gold SH et al. Symptomatic cataplexy in
perceived foreign accents in one patient after prerolandic ponto-medullary lesions. Neurology 1994; 44:2189–91.
hematoma. Eur Neurol 2004; 52:198–201. Degos JD, Gray F, Louarn F et al. Posterior callosal infarction:
Ciabarra A, Elkino MS, Roberts JK et al. Subcortical infarction clinicopathological correlations. Brain 1987; 110:1155–71.
resulting in acquired stuttering. J Neurol Neurosurg Psychiatry De La Fuente Fernandez R, Lopez JM, Del Corral PR et al.
2000; 69:546–9. Peduncular hallucinosis and right hemiparkinsonism caused by
Closson RG. Visual hallucinations as the earliest symptom of left mesencephalic parkinsonism. J Neurol Neurosurg
digoxin intoxication. Arch Neurol 1983; 40:386. Psychiatry 1994; 57:870.
Cochen V, Arnulf I, Demeret S et al. Vivid dreams, hallucinations, Della Sala S, Mrachetti C, Spinnler H. The anarchic hand: a
psychosis and REM sleep in Guillian-Barre syndrome. Brain fronto-mesial sign. In: Boller F, Grafman J eds. Handbook of
2005; 128:2535–45. neuropsychology, vol. 9. Amsterdam: Elsevier Science, 1994.
Cohen D, Cottias C, Basquin M. Cotard’s syndrome in a 15-year- DeLuca J, Cicerone KD. Confabulation following aneurysm of the
old girl. Acta Psychiatr Scand 1997; 95:164–5. anterior communicating artery. Cortex 1991; 27:417–23.
Cohen PR. Medication-associated depersonalization symptoms: Denny-Brown D, Meyer JS, Horenstein S. The significance of
report of transient depersonalization symptoms induced by perceptual rivalry resulting from parietal lesions. Brain 1952;
monocycline. South Med J 2004; 97:70–3. 75:433–71.
Cole M. When the left brain is not right the right brain may be De Renzi E, Barbieri C. The incidence of the grasp reflex following
left: report of personal experience of occipital hemianopia. hemispheric lesion, and its relation to frontal damage. Brain
J Neurol Neurosurg Psychiatry 1999; 67:169–73. 1992; 115:293–313.
Coletti Moja M, Milano E, Gasverde S et al. Olanzapine therapy in De Renzi E, Cavalleri F, Facchini S. Imitation and utilization
hallucinatory visions related to Bonnet syndrome. Neurol Sci behavior. J Neurol Neurosurg Psychiatry 1996; 61:396–400.
2005; 26:168–70. Derex L, Ostrowsky K, Nighoghossian N et al. Severe pathological
Colman WS. A case of pseudo-bulbar paralysis, due to lesions in crying after left anterior choroidal artery infarct. Reversibility
each internal capsule; degeneration of direct and crossed with paroxetine treatment. Stroke 1997; 28:1464–6.
pyramidal tracts. Brain 1894; 17:88–9. Desarkar P, Goyan N, Khess CRJ. Clozapine-induced cataplexy.
Comings DE, Comings BG. A controlled study of Tourette J Neuropsychiatry Clin Neurosci 2007; 19:87–8.
syndrome, IV: obsession, compulsion, and schizoid behavior. Devinsky O, Lemann W, Evans AC et al. Akinetic mutism in a bone
Am J Med Genet 1987; 41:782–803. marrow transplant recipient following total-body irradiation
Confavreux C, Croisile B, Garassus P et al. Progressive amusia and and amphotericin-B chemoprophylaxis. Arch Neurol 1987;
aprosody. Arch Neurol 1992; 49:971–6. 44:414–17.
Cornelius JR, Day NL, Fabrega H et al. Characterizing organic Devinsky O, Felmann E, Burrowes K et al. Autoscopic phenomenon
delusional syndrome. Arch Gen Psychiatry 1991; 48:997–9. with siezures. Arch Neurol 1989; 46:1080–8.
Critchley M. Types of visual perseveration: ‘paliopsia’ and ‘illusory Diamond AL, Callison RC, Shokri J et al. Paroxysmal sympathetic
visual spread’. Brain 1951; 74:267–99. storm. Neurocrit Care 2005; 2:288–91.
Cummings JL, Cuningham K. Obsessive-compulsive disorder in DiLegge S, Di Piero V, Altieri M et al. Usefulness of primitive
Huntington’s disease. Biol Psychiatry 1992; 31:263–70. reflexes in demented and non-demented cerebrovascular
Cummings JL, Duchen LW. Kluver–Bucy syndrome in Pick disease: patients in daily clinical practice. Eur Neurol 2005; 41;104–10.
clinical and pathologic correlations. Neurology 1981; Do D, Sheen VL, Bromfield E. Treatment of paroxysmal
31:1415–22. sympathetic storm with labetalol. J Neurol Neurosurg
Cummings JL, Gosenfeld LF, Houlihan JP et al. Neuropsychiatric Psychiatry 2000; 69:832–3.
disturbnces associated with idiopathic calcification of the Dolado AM, Castrillo C, Urra DG et al. Alien hand sign or alien
basal ganglia. Biol Psychiatry 1983; 18:591–601. hand syndrome? J Neurol Neurosurg Psychiatry 1995;
Cummings JL, Benson F, Hill MA et al. Aphasia in dementia of 59:100–1.
Alzheimer’s type. Neurology 1985; 35:394–7. Doubleday EK, Snowden JS, Varma AR et al. Qualitative
Currie S, Heathfield KW, Henson RA et al. Cinical course and performance characteristics differentiate dementia with Lewy
prognosis of temporal lobe epilepsy. A survey of 666 patients. bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry
Brain 1971; 94:173–90. 2002; 72:602–7.
Daly D. Ictal affect. Am J Psychiatry 1958; 115:97–108. Dummit ES, Klein RG, Tancer NK et al. Systematic assessment of
David AS, Bone I. Mutism following left hemisphere infarction. 50 children with selective mutism. J Am Acad Child Adolesc
J Neurol Neurosurg Psychiatry 1984; 47:1342–4. Psychiatry 1997; 36:653–60.
p 04.qxd 3/10/08 9:33 AM Page 152
Duncalf CM, Kent JNG, Harbord M et al. Subacute sclerosing Fournier JCM, Helguera RAL. Postencephalitic narcolepsy and
panencephalitis presenting as schizophreniform psychosis. Br J cataplexy: muscle and motor nerves electrical inexcitability
Psychiatry 1989; 155:557–9. during the attack of cataplexy. J Nerv Ment Dis 1934;
Dunn DW, Weisberg LA, Nadell J. Peduncular hallucinations 80:159–62.
caused by brainstem compression. Neurology 1983; Frankel M, Cummings JL, Robertson MM et al. Obsessions and
33:1360–1. compulsions in Gilles de la Tourette’s syndrome. Neurology
Dyken ME, Yamada T, Lin-Dyken DC et al. Diagnosing narcolepsy 1986; 36:378–82.
through the simultaneous clinical and electrophysiologic Freedman M, Alexander MP, Naeser MA. Anatomic basis of
analysis of cataplexy. Arch Neurol 1996; 53:456–60. transcortical motor aphasia. Neurology 1984; 34:409–17.
Ellis P, Mellsop G. De Clerambault’s syndrome – a nosological Freemon FR. Akinetic mutism and bilateral anterior cerebral artery
entity? Br J Psychiatry 1985; 146:90–5. occlusion. J Neurol Neurosurg Psychiatry 1971; 34:693–8.
Elson A, Pearson C, Jones CD et al. Follow-up study of childhood Fridriksson J, Ryalls J, Rorden C et al. Brain damage and cortical
elective mutism. Arch Gen Psychiatry 1965; 13:182–7. compensation in foreign accent syndrome. Neurocase 2005;
Enoch MD. The Capgras syndrome. Acta Psychiatr Scand 1963; 11:319–24.
39:437–62. Friedman A, Sienkiewicz J. Psychotic complications of long-term
Ephraim PL, Wegener ST, MacKenzie EJ et al. Phantom pain, levodopa treatment of Parkinson’s disease. Acta Neurol Scand
residual limb pain, and back pain in amputees: results of a 1991; 84:111–13.
national survey. Arch Phys Med Rehabil 2005; 86:1910–19. Fuller GN, Guiloff RJ. Migrainous olfactory hallucinations. J
Escalona PR, Adair JC, Roberts BB et al. Obsessive-compulsive Neurol Neurosurg Psychiatry 1987; 50:1688–90.
disorder following bilateral globus pallidus infarction. Biol Gainotti G. Emotional behavior and hemispheric side of lesion.
Psychiatry 1997; 42:410–12. Cortex 1972; 8:41–55.
Eslinger PJ, Warner GC, Grattan LM et al. ‘Frontal lobe’ utilization Gallagher JP. Pathologic laughter and crying in ALS: a search for
behavior associated with paramedian thalamic infarction. their origin. Acta Neurol Scand 1989; 80:114–17.
Neurology 1991; 41:450–2. Gazzaniga MS, Bogen JE, Sperry RW. Some functional effects of
Evans AC, Raistrick D. Phenomenology of intoxication with sectioning the cerebral commissures in man. Proc Nat Acad Sci
toluene-based adhesives and butane gas. Br J Psychiatry 1987; 1962; 48:1765–9.
150:769–73. Gelardi J-A M, Brown JW. Hereditary cataplexy. J Neurol
Faris AA. Limbic system infarction: a report of two cases. Neurosurg Psychiatry 1967; 30:455–7.
Neurology 1969; 19:91–6. Geller TJ, Bellor SN. Peduncular hallucinosis: magnetic resonance
Feinberg TE, Schindler RJ, Flanagan NG et al. Two alien hand imaging confirmation of mesencephalic infarction during life.
syndromes. Neurology 1992; 42:19–24. Ann Neurol 1987; 21:602–4.
Feinstein A, Feinstein K, Gray T et al. Prevalence and Gelmers HJ. Non-paralytic motor disturbance and speech
neurobehavioral correlates of pathological laughing and crying disorders: the role of the supplementary motor area. J Neurol
in multiple sclerosis. Arch Neurol 1997; 54:1116–21. Neurosurg Psychiatry 1983; 46:1052.
Fenelon G, Mahieux F, Huon R et al. Hallucinations in Parkinson’s Geschwind DH, Iacoboni M, Mega MS et al. Alien hand syndrome:
disease: prevalence, phenomenonology and risk factors. Brain interhemispheric motor disconnection due to a lesion in
2000; 123:733–45. the midbody of the corpus callosum. Neurology 1995;
Fere C. Le fou rire prodromique. Rev Neurol 1903; 11:353–8. 45:802–8.
Ferguson SM, Rayport M, Corrie WS. Neuropsychiatric Geschwind N. The perverseness of the right hemisphere. Behav
observations of corpus callosum section for seizure control. In: Brain Sci 1981; 4:106–7.
Reeves AJ ed. Epilepsy and the corpus callosum. New York: Ghika-Schmid F, Assal G, De Tribolet N et al. Kluver-Bucy
Plenum Press, 1985. syndrome after left anterior temporal resection.
Fernandez JM, Sadaba F, Villaverde FJ et al. Cataplexy associated Neuropsychologia 1995; 33:101–13.
with midbrain lesion. Neurology 1995; 45:393–4. Gibb WRC, Luthert PJ, Marsden CD. Corticobasal degneration.
Fisher CM. Visual disturbances associated with quinidine and Brain 1989; 112:1171–92.
quinine. Neurology 1981; 31:1569–71. Gilbert GJ. Pentoxifylline-induced musical hallucinations.
Fleet WS, Heilman KM. Acquired stuttering from a right hemisphere Neurology 1993; 43:1621–2.
lesion in a right-hander. Neurology 1985; 35:1343–6. Gillett T, Eminson SR, Hassanyeh F. Primary and secondary
Ford RA. The psychopathology of echophenomena. Psychol Med erotomania. Clinical characteristics and follow-up. Acta
1989; 19:627–35. Psychiatr Scand 1990; 82:65–9.
Formisano R, Saltuari L, Gerstendbrand F. Prevalence of Kluver- Giroud M, Lemesle M, Madinier G et al. Unilateral lenticular
Bucy syndrome as a positive prognostic feature for the infarcts: radiological and clinical syndromes, etiology,
remission of traumatic prolonged disturbances of and prognosis. J Neurol Neurosurg Psychiatry 1997;
consciousness. Acta Neurol Scand 1995; 91:54–7. 63:611–15.
Fossati A, Maffei C, Battaglia M et al. Latent class analysis of Goetz CG, Wuu J, Curgian LM et al. Hallucinations and sleep
DSM-IV schizotypal personality disorder criteria in psychiatric disorders in PD. Six-year prospective longitudinal study.
patients. Schizophr Bull 2001; 27:59–71. Neurology 2005; 64:81–6.
p 04.qxd 3/10/08 9:33 AM Page 153
References 153
Goetz CG, Fan W, Leurgans S et al. The malignant course of Greenwood R, Bhalla A, Gordon A et al. Behavior disturbances
‘benign hallucinations’ in Parkinson disease. Arch Neurol 2006; during recovery from herpes simplex encephalitis. J Neurol
63:713–16. Neurosurg Psychiatry 1983; 46:809–17.
Goldberg G, Bloom KK. The alien hand syndrome: localization, Griffiths TD. Musical hallucinosis in acquired deafness.
lateralization, and recovery. J Phys Med Rehab 1990; 69:228–38. Phenomenology and brain substrate. Brain 2000;
Golden RN, James SP, Sherer MA et al. Psychoses associated with 123:2065–76.
bupropion treatment. Am J Psychiatry 1985; 42:1459–62. Grigsby J, Kaye K. Incidence and correlates of depersonalization
Goldenberg G, Wimmer A, Holzner F et al. Apraxia of the left limb following head trauma. Brain Inj 1993; 7:507–13.
in a case of callosal disconnection: the contribution of medial Grimby A. Bereavement among elderly people: grief reactions,
frontal lobe damage. Cortex 1985; 21:135–48. post-bereavement hallucinations and quality of life. Acta
Goldin S. Lilliputian hallucinations. J Ment Sci 1955; 101:569–76. Psychiatr Scand 1993; 87:72–80.
Goldstein K. Sur Lehre der motorischen Apraxia. J fur Psychologie Gross-Tsu V, Joseph A, Shlev RS. Hallucinations during
und Neurologie 1908; 11:169–87. methylphenidate therapy. Neurology 2004; 63:753–4.
Goldstein K. Der makroskopische Hirnbefund in meinem Falle von Guilleminault C, Wilson RA, Dement WC. A study on cataplexy.
linksseitiger motorischer Apraxie. Neurol Centralbl 1909; Arch Neurol 1974; 31:255–61.
28:898–906. von Gunten A, Miklossy J, Suva ML et al. Environmental
Goldstein K. The organism: a holistic approach to biology derived reduplicative paramnesia in a case of atypical Alzheimer’s
from pathological data in man. New York: American Books, disease. Neurocase 2005; 11:216–26.
1939. Gydesen S, Brown JN, Brun A et al. Chromosome 3 linked
Goldstein K. After effects of brain injuries in war. New York: Grune frontotemporal dementia (FTD-3). Neurology 2002;
and Stratton, 1942. 59:1585–94.
de AA Gondin F, Parks BJ, Cruz-Flores S. ‘Fou rire prodromique’ as Haber WB. Observations on phantom-limb phenomena. Arch
the presentation of pontine ischemia secondary to Neurol Psychiatry 1956; 75:624–36.
vertebrobasilar stenosis. J Neurol Neurosurg Psychiatry 2001; Hachinski VC, Porchawka J, Steele JC. Visual symptoms in the
71:802–4. migraine syndrome. Neurology 1973; 23:570–9.
Gonzales-Pinto A, van Os J, Perez de Heredia JL et al. Age- Hadano K, Nakamura H, Hamanaka T. Effortful echolalia. Cortex
dependence of Schneiderian psychotic symptoms in bipolar 1998; 34:67–82.
patients. Schizophren Res 2003; 61:157–62. Haerer AE, Currier RD. Mirror movements. Neurology 1966;
Gordon A. Transition of obsessions into delusions. Am J Psychiatry 16:757–60.
1950; 107:455–8. Hall DA, Anderson CA, Filley CM et al. A French accent after
Gorno-Tempini ML, Ogar JM, Brambati SM et al. Anatomical corpus callosum infarct. Neurology 2003; 60:1551–2.
correlates of early mutism in progressive nonfluent speech. Halligan PW, Marshall JC, Wade DT. Three-arms: a case study of
Neurology 2006; 67:1849–51. supernumerary phantom limbs after right hemisphere stroke. J
Granacher RP. Differential diagnosis of tardive dyskinesias: an Neurol Neurosurg Psychiatry 1993; 56:159–66.
overview. Am J Psychiatry 1981; 38:1288–97. Hamano T, Hiraki S, Kawamur Y et al. Acquired stuttering
Gothelf D, Presburger G, Zohar AH et al. Obsessive-compulsive secondary to callosal infarction. Neurology 2005; 64:1092–3.
disorder in patients with velocardiofacial (22q11 deletion) Hammeke TA, McQuillen MP, Cohen BA. Musical hallucinations
syndrome. Am J Med Genet Neuropsychiatr Genet associated with acquired deafness. J Neurol Neurosurg
2004;126:99–105. Psychiatry 1983; 46:570–2.
Gottlieb D, Robb K, Day B. Mirror movements in the alien hand Hanakita J, Nishi S. Left alien hand sign and mirror writing after
syndrome. Am J Phys Med Rehabil 1992; 71:297–300. left anterior cerebral artery infarction. Surg Neurol 1991;
Gouzoulis-Mayfrank E, Heekeren K, Neukirch A et al. 35:290–3.
Psychological effects of (S)-ketamine and N,N- Harris DL, Batki SL. Stimulant psychosis: symptom profile and
dimethyltryptamine (DMT): a double-blind, cross-over study in acute clinical course. Am J Addict 2000; 9:28–37.
healthy volunteers. Pharmacopsychiatry 2005; 38:301–11. Hashimoto R, Tanaka Y. Contribution of the supplmentary motor
Graff-Radford NR, Eslinger PJ, Damasio AR et al. Nonhemorrhagic area and anterior cingulate gyrus to pathological grasping
infarction of the thalamus: behavioral, anatomic, and phenomena. Eur Neurol 1998; 40:151–8.
physiologic correlates. Neurology 1984; 34:14–23. Hashimoto R, Yoshida M, Tanaka Y. Utilization behavior after
Graff-Radford NR, Cooper WE, Colsher PL et al. An unlearned right thalamic infarction. Eur Neurol 1995; 35:58–62.
foreign ‘accent’ in a patient with aphasia. Brain Lang 1986; Hause-Hauw C, Bancaud J. Gustatory hallucinations in epileptic
28:86–94. seizures. Electrophysiological, clinical and anatomical
Graham JM, Gruenwald RA, Sagar HJ. Hallucinosis in idiopathic correlates. Brain 1987; 110:39–59.
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; Helgason C, Wilbur A, Weiss A et al. Acute pseudobulbar mutism
63:434–40. due to discrete bilateral capsular infarction in the territory of
Green RC, Goldstein FC, Mirra SS et al. Slowly progressive apraxia the anterior choroidal artery. Brain 1988; 111:507–24.
in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1995; Helm NA, Butler RB, Benson DF. Acquired stuttering. Neurology
59:312–15. 1978; 28:1159–65.
p 04.qxd 3/10/08 9:33 AM Page 154
Hemmingsen R, Rafaelsen OJ. Hypnagogic and hypnopompic Ionasescu V. Paroxysmal disorders of the body image in temporal
hallucinations during amitriptyline treatment. Acta Neurol lobe epilepsy. Acta Psychiatr Neurol Scand 1960; 35:171.
Scand 1980; 62:364–8. Ironside R. Disorders of laughter due to brain lesions. Brain 1956;
Henderson WR, Smythe GE. Phantom limbs. J Neurol Neurosurg 79:589–609.
Psychiatry 1948; 11:89–112. Isbell H, Belleville RE, Fraser HF et al. Studies on lysergic acid
Heutink P, Stevens M, Rizzu P et al. Hereditary frontotemporal diethylamide (LSD-25). Arch Neurol Psychiatry 1956;
dementia is linked to chromosome 17q21–q22: a genetic and 76:468–78.
clinicopathological study of three Dutch families. Ann Neurol Ishihara K, Nishino H, Maki T et al. Utilization behavior as a
1997; 41:150–9. white matter disconnection syndrome. Cortex 2002;
Hillbom E. After-effects of brain-injuries. Acta Psychiatr Neurol 38:379–87.
Scand 1960; 142(suppl.):1–195. Jackson JH, Stewart P. Epileptic attacks with a warning of a crude
Hof PR, Archin N, Osmand AP et al. Posterior cortical atrophy in sensation of smell and with the intellectual aura (dreamy
Alzheimer’s disease: analysis of a new case and re-evaluation state) in a patient who had symptoms pointing to gross
of a historical report. Acta Neuropathol 1993; 86:215–23. organic disease of the right temporo-sphenoidal lobe. Brain
Hollander E, Soorya L, Wasserman S et al. Divalproex sodium vs. 1899; 32:209.
placebo in the treatment of repetitive behaviors in autism Jacobs L, Gossman MD. Three primitive reflexes in normal adults.
spectrum disorder. Int J Neuropsychopharmacol 2006; Neurology 1980; 30:184–8.
9:209–13. Jaeger H, Maier C. Calcitonin in phantom limb pain: a double-
Hollister LE, Prusmack JJ, Paulsen JA et al. Comparison of three blind study. Pain 1992; 48:21–7.
psychotropic drugs (psilocybin, JB-329, IT-290) in volunteer Jampala VC, Taylor MA, Abrams R. The diagnostic implication of
subjects. J Nerv Ment Dis 1960; 131:428–34. formal thought disorder in mania and schizophrenia: a
Holroyd S, Rabins PV, Finkelstein D et al. Visual hallucinations in reassessment. Am J Psychiatry 1989; 146:459–63.
patients with macular degeneration. Am J Psychiatry 1992; Janowsky DS, Risch C. Amphetamine psychosis and psychotic
149:1701–6. symptoms. Psychopharmacology 1979; 65:73–7.
Hopf HC, Muller-Forell W, Hopf NJ. Localization of emotional and Jaob A, Cherian PJ, Radhakrishnan K et al. Emotional facial paresis
volitional facial paresis. Neurology 1992; 42:1918–23. in temporal lobe epilepsy: its prevalence and lateralizing value.
Hopf HC, Fitzek C, Mark J et al. Emotional facial paresis of Seizure 2003; 12:60–4.
pontine origin. Neurology 2000; 54:1217. Jarvis JH. Post-mastectomy breast phantoms. J Nerv Ment Dis
Hori H, Terao T, Shiraishi Y et al. Treatment of Charles Bonnet 1967; 144:266–72.
syndrome with valproate. Int Clin Psychopharmacol 2000; Jason GW, Pajurkova EM. Failure of metacontrol: breakdown of
15:117–19. behavioral unity after lesions of the corpus callosum and
Horowitz MJ. Flashbacks: recurrent intrusive images after the use inferomedial frontal lobes. Cortex 1992; 28:241–60.
of LSD. Am J Psychiatry 1969; 126:565–9. Jelliffe SE. Oculogyric crises as compulsion phenomena in
Hotz G, Helm-Estabrooks N. Perseveration. Part II: A study of postencephalitis: their occurrence, phenomenology and
perseveration in closed-head injury. Brain Inj 1995; 9:161–72. meaning. J Nerv Ment Dis 1929; 69:59–68, 165–84, 278–97,
Hudson AJ, Grace GM. Misidentification syndromes related to 415–26, 531–51, 666–79.
face specific area in the fusiform gyrus. J Neurol Neurosurg Jensen JPA, Gron U, Pakkenberg H. Comparison of three primitive
Psychiatry 2000; 69:645–8. reflexes in neurological patients and in normal volunteers. J
Hughes MS, Lessell S. Trazodone-induced palinopsia. Arch Neurol Neurosurg Psychiatry 1983; 46:162–7.
Ophthalmol 1990; 108:359. Jensen TS, Krebs B, Nielsen J et al. Non-painful phantom limb
Husain M, Stein J. Rezso Balint and his most celebrated case. Arch phenomena in amputees: incidence, clinical characteristics
Neurol 1988; 45:89–93. and temporal course. Acta Neurol Scand 1984; 70:407–14.
Huse E, Larbig W, Flor H et al. The effect of opioids on phantom John JP, Khanna S, Thennarasau K et al. Exploration of dimensions
limb pain and cortical reorganization. Pain 2001; 90:47–55. of psychopathology in neuroleptic-naive patients with recent-
Husby G, van de Rijn I, Zabriskie JB et al. Antibodies reacting with onset schizophrenia/schizophreniform disorder. Psychiatry Res
cytoplasm of subthalamic and caudate neurons in chorea and 2003; 121:11–20.
acute rheumatic fever. J Exp Med 1976; 144:1094–110. Joseph AB, O’Leary DH. Brain atrophy and interhemispheric fissure
Hwang JP, Tsai SJ, Yang CH et al. Hoarding behavior in dementia. enlargement in Cotard’s syndrome. J Clin Psychiatry 1986;
A preliminary report. Am J Geriatr Psychiatry 1998; 6:285–9. 47:518–20.
Hyde TM, Goldberg TE, Egan MF et al. Frontal release signs and Kales A, Cadieux RJ, Soldatos CR et al. Narcolepsy–cataplexy. I.
cognition in people with schizophrenia, their siblings and Clinical and electrophysiologic characteristics. Arch Neurol
healthy controls. Br J Psychiatry 2007; 191:120–5. 1982; 39:164–8.
Ihde-Scholl T, Jefferson JW. Mirtazapine-associated palinopsia. Kane FT, Keeler MH. Visual hallucinations while receiving
J Clin Psychiatry 2001; 62:373. imipramine. Am J Psychiatry 1964; 121:611–12.
Imamura T, Takanashi M, Hattori N et al. Bromocriptine treatment Kapur N, Turner A, King C. Reduplicative paramnesia: possible
for perseveration in demented patients. Alzheimer Dis Assoc anatomical and neuropsychological mechanisms. J Neurol
Disord 1998; 12:109–13. Neurosurg Psychiatry 1988; 51:579–81.
p 04.qxd 3/10/08 9:33 AM Page 155
References 155
Katz DI, Alexander MP, Mandell AM. Dementia following strokes Lang UE, Stogowski D, Schulze D et al. Charles Bonnet syndrome:
in the mesencephalon and diencephalons. Arch Neurol 1987; successful treatment of visual hallucinations due to vision loss
44:1127–33. with selective serotonin reuptake inhibitors. J Psycho-
Kaufman MD, Lassiter KR, Shenoy BV. Paroxysmal unilateral pharmacol 2007; 21:553–5.
dysosmia: a cured patient. Ann Neurol 1988; 24:450–1. Langsworthy OR, Hesser FH. Syndrome of pseudobulbar palsy.
Keschner M, Bender MB, Strauss I. Mental symptoms in cases of Arch Int Med 1940; 65:106–21.
tumor of the temporal lobe. Arch Neurol Psychiatry 1936; Laplane D, Baulac M, Widocher D et al. Pure psychic akinesia with
35:572–96. bilateral lesion of basal ganglia. J Neurol Neurosurg Psychiatry
Kido H, Yamaguchi N. Clinical studies of schizophrenia-like state 1984; 47:377–85.
in epileptic patients. Jpn J Psychiatry Neurol 1989; 43:433–8. Laplane D, Levasseur M, Pillon B et al. Obsessive-compulsive and
King AB. ‘Phantom’ sciatica. Arch Neurol Psychiatry 1956; 76:72–4. other behavioral changes with bilateral basal ganglia lesions.
Klein DF. Visual hallucinations with imipramine. Am J Psychiatry A neuropsychological, magnetic resonance imaging and
1964; 121:911–14. positron tomography study. Brain 1989; 112:699–725.
Kluin KJ, Norman LF, Berent S et al. Perceptual analysis of speech Lauterbach EC, Abdlhamid A, Annandale JB. Posthallucinogen-like
disorders in progressive supranuclear palsy. Neurology 1993; visual illusions (palinopsia) with risperidone in a patient without
43:563–6. previous hallucinogen exposure: possible relation to serotonin
Kluver H, Bucy PC. Preliminary analysis of functions of the temporal 5-HT2A blockade. Pharmacopsychiatry 2000; 33:38–41.
lobes in monkeys. Arch Neurol Psychiatry 1939; 42:979–1000. Lawson IR, McLeod RD. The use of imipramine (‘Tofranil’) and
Koehler K, Seminario I. Research diagnosable ‘schizo-affective’ other psychotropic drugs in organic emotionalism. Br J
disorder in Schneiderian ‘first rank’ schizophrenia. Acta Psychiatry 1969; 115:281–5.
Psychiatr Scand 179; 60:347–54. Lee HJ, Lee HS, Kim L et al. A case of risperidone-induced
Kollar EJ, Namerow N, Pasnau RO et al. Neurological findings during stuttering. J Clin Psychopharmacol 2001; 21:115–16.
prolonged sleep deprivation. Neurology 1968; 18:836–40. Lee SK, Lee SL, Kim D-W et al. Occipital lobe epilepsy: clinical
Koller WC. Dysfluency (stuttering) in extrapyramidal disease. Arch characteristics, surgical outcome, and role of diagnostic
Neurol 1983; 40:175–7. modalities. Epilepsia 2005; 46:688–95.
Koller WC, Glatt S, Wilson RS et al. Primitive reflexes and Leiguarda R, Starkstein S, Berthier M. Anterior callosal
cognitive function in the elderly. Ann Neurol 1982; 12:302–4. hemorrhage. A partial interhemispheric disconnection
Kolmel HW. Complex visual hallucinations in the hemianopic syndrome. Brain 1989; 112:1019–37.
field. J Neurol Neurosurg Psychiatry 1985; 48:29–38. Lepore FE. Spontaneous visual phenomena with visual loss: 104
Kraepelin E. Clinical psychiatry. Translated by Diefendorff, R. New patients with lesions of retinal and visual afferent pathways.
York: MacMillan Company, 1907, p. 86. Neurology 1990; 40:444–7.
Kraepelin E. Dementia praecox and paraphrenia. Translated by Leroy R. The syndrome of Lilliputian hallucinations. J Nerv Ment
Barclay RM, Robert E. Huntington, NY: Krieger Publishing, 1971. Dis 1922; 56:325–33.
Kraepelin E. Manic-depressive insanity and paranoia, 1921. New Leudar I, Fraser WI, Jeeves MA. Behavior disturbances and mental
York: Arno Press, 1976. handicap: typology and longitudinal trends. Psychol Med
Kraepelin E. Psychiatry. A textbook for students and physicians, 1984; 14:923–35.
6th edn, 1899. Translated by Metoui H, Ayed S. Canton, MA: Levine DN, Rinn WE. Opticosensory ataxia and alien hand
Science History Publications, 1990. syndrome after posterior cerebral artery territory infarction.
Kroll L, Drummond LM. Temporal lobe epilepsy and obsessive- Neurology 1986; 36:1094–7.
compulsive symptoms. J Nerv Ment Dis 1993; 181:457–8. Lewis MH, Bodfish JW, Powell SB et al. Clomipramine treatment
Krystal JH, Perry EB, Gueorguieva R et al. Comparative and for self-injurious behavior of individuals with mental
interactive human psychopharmacologic effects of ketamine retardation: a double-blind comparison with placebo. Am J
and amphetamine: implications for gluatamatergic and Ment Retard 1996; 100:654–65.
dopaminergic model psychoses and cognitive function. Arch Lhermitte F. ‘Utilization behavior’ and its relation to lesions of the
Gen Psychiatry 2005; 62:985–94. frontal lobes. Brain 1983; 106:237–55.
Kumral E, Calli C. External and extreme capsular stroke: clinical, Lhermitte F. Human anatomy and the frontal lobes. II. Patient
topographical and etiologic patterns. Cerebrovasc Dis 2006; behavior in complex and social situations: the ‘environmental
21:217–22. dependency syndrome’. Ann Neurol 1986; 19:335–43.
Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Lhermitte F, Pillon B, Serdaru M. Human anatomy and the frontal
Stroke 1999; 30:100–8. lobes. I. Imitation and utilization behavior: a neuropsychological
Lago A. Fou Rire Prodromique and ischemic stroke. Stroke 1998; study of 75 patients. Ann Neurol 1986; 19:326–44.
29:1067–8. Lhermitte J. Syndrome de la calotte du pedoncule cerebral. Les
Lam LC, Chiu HF. Kluver-Bucy syndrome in a patient with troubles psycho-sensoriels dans les lesions du mesocephale.
nasopharyngeal carcinoma: a late complication of radiation Rev Neurol 1922; 38:1359–65.
brain injury. J Geriatr Psychiatry Neurol 1997; 10:111–13. Lhermitte J. L’hallucinose pedonculaire. Encephale 1932; 27:422–35.
Lance JW. Simple formed hallucinations confined to the area of a Lieberman A, Benson DF. Control of emotional expression in
specific visual field defect. Brain 1976; 99:719–34. pseudobulbar palsy. Arch Neurol 1977; 34:717–19.
p 04.qxd 3/10/08 9:33 AM Page 156
Lilly R, Cummings JL, Benson DF et al. The human Kluver–Bucy Martin JP. Fits of laughter (sham-mirth) in organic cerebral
syndrome. Neurology 1983; 33:1141–5. disease. Brain 1950; 73:453–64.
Linetsky E, Planer D, Ben-Hur T. Echolalia-palilalia as the sole Masdeu JC, O’Hara RJ. Motor aphasia unaccompanied by
manifestation of nonconvulsive status epilepticus. Neurology faciobrachial weakness. Neurology 1983; 33:519–21.
2000; 55:733–4. Mathew RJ. Wilson WH, Humphreys D et al. Depersonalization
Lipinski CG. Epilepsies with astatic seizures of late onset. Epilepsia after marijuana smoking. Biol Psychiatry 1993; 33:431–41.
1977; 18:13–20. Mauguire F, Courjon J. Somatosensory epilepsy: a review of 127
Lippman CO. Hallucinations of physical disability in migraine. J cases. Brain 1978; 101:307–32.
Nerv Ment Dis 1953; 117:345–50. Mayeux R, Benson DF. Phantom limb and multiple sclerosis.
Liu GT, Scatz NJ, Galetta SL et al. Persistent positive visual Neurology 1979; 29:724–6.
phenomena in migraine. Neurology 1995; 45:664–8. Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the
Logan TP. Persistent phantom limb pain: dramatic response to Alzheimer type: evidence of subgroups. Neurology 1985;
chlorpromazine. South Med J 1983;76:1585. 35:453–61.
Lohr JB. Transient grasp reflexes in schizophrenia. Biol Psychiatry Mazzucchi A, Marchini C, Budai R et al. A case of receptive
1985; 20:172–5. amusia with prominent timbre perception defect. J Neurol
Lopez JR, Adornato BT, Hoyt WF. ‘Entomopia’: a remarkable case Neurosurg Psychiatry 1982; 45:644–7.
of cerebral polyopia. Neurology 1993; 43:2145–6. McDonald C. A clinical study of hypnagogic hallucinations. Br J
Lopez-Villegas D, Kulisevsky J, Deus J et al. Neuropsychological Psychiatry 1971; 118:543–7.
alterations in patients with computed tomography-detected McDougle CJ, Scahill L, Aman MG et al. Risperidone for the core
basal ganglia calcification. Arch Neurol 1996; 53:251–6. symptom domains of autism: results from the study by the
Ludlow CL, Rosenberg J, Salazar A et al. Site of penetrating brain autism network of the research units on pediatric
lesion causing chronic acquired stuttering. Ann Neurol 1987; psychopharmacology. Am J Psychiatry 2005; 162:1142–8.
22:60–6. McFarland HR, Fortin D. Amusia due to right temporoparietal
Lugaresi A, Montagna P, Morreale A et al. ‘Psychic akinesia’ following infarct. Arch Neurol 1982; 39:725–7.
carbon monoxide poisoning. Eur Neurol 1990; 30:167–9. McGonigle DJ, Hanninen R, Salenius S et al. Whose arm is it
Lukianowicz N. Autoscopic phenomena. Arch Neurol Psychiatry anyway? An fMRI study of supernumerary phantom limb.
1958; 80:199–220. Brain 2002; 125:1265–74.
MacGowan DJL, Delanty N, Petito F et al. Isolated myoclonic alien McKee AC, Levine DN, Kowall NW et al. Peduncular hallucinosis
hand as the sole presentation of pathologically established associated with isolated infarction of the substantia nigra pars
Creutzfeldt–Jakob disease: a report of two patients. J Neurol reticulata. Ann Neurol 1990; 27:500–4.
Neurosurg Psychiatry 1997; 63:404–7. McKeon J, McGuffin P, Robinson P. Obsessive-compulsive neurosis
Maeda K, Shirayama Y, Nukima S et al. Charles Bonnet syndrome following head injury. A report of four cases. Br J Psychiatry
with visual hallucinations of childhood experience: successful 1984; 144:190–2.
treatment of 1 patient with risperidone. J Clin Psychiatry McMonagle P, Deering F, Berliner Y et al. The cognitive profile of
2003; 64:1131–2. posterior cortical atrophy. Neurology 2005; 66:331–8.
Maertens de Noordhout AM, Delwaide PJ. The palmomental reflex Meadows JL, Munro SSF. Palinopsia. J Neurol Neurosurg
in Parkinson’s disease: comparisons with normal subjects and Psychiatry 1977; 40:5–8.
clinical relevance. Arch Neurol 1988; 45:425–7. Melges FT, Tinklenberg JR, Hollister LE et al. Temporal
Mahone EM, Bridges D, Prahme C et al. Repetitive arm and hand disintegration and depersonalization during marijuana
movements (complex motor stereotypies) in children. J Pediatr intoxication. Arch Gen Psychiatry 1970; 23:204–10.
2004; 145:391–5. Mellor CS. First rank symptoms of schizophrenia. I. The frequency
Maia DP, Teixeira AL, Cunningham MCQ et al. Obsessive- in schizophrenics on admission to hospital. II. Differences
compulsive behavior, hyperactivity, and attention deficit between individual first rank symptoms. Br J Psychiatry 1970;
disorder in Sydnham chorea. Neurology 2005; 64:1799–801. 117:15–23.
Maier C, Derwinkel R, Mansourian N et al. Efficacy of NMDA- Melzak R, Israel R, Lacroix R et al. Phantom limbs in people with
receptor antagonist memantine in patients with chronic congenital limb deficiency or amputation in early childhood.
phantom limb pain: results of a randomized double-blinded, Brain 1997; 120:1603–20.
placebo-controlled trial. Pain 2003; 103:277–83. Mendez MF. Corticobasal ganglionic degeneration with Balint’s
Marcon G, Cancelli I, Zamarian L et al. Visual hallucinations with syndrome. J Neuropsychiatry Clin Neurosci 2000; 12:273–5.
sertraline. J Clin Psychiatry 2004; 65:446–7. Mendez MF. Prominent echolalia from isolation of the speech
Marder K, Liu X, Stern Y et al. Neurologic signs and symptoms in a area. J Neuropsychiatry Clin Neurosci 2002; 14:56–7.
cohort of homosexual men followed for 4.5 years. Neurology Mendez MF, Foti DJ. Lethal hyperoral behavior from the
1995; 45:261–7. Kluver–Bucy syndrome. J Neurol Neurosurg Psychiatry 1997;
Marlowe WB, Mancall EL, Thomas TJ. Complete Kluver–Bucy 62:293–4.
syndrome in man. Cortex 1975; 11:53–9. Mendez MF, Perryman KM. Neuropsychiatric features of
Marneros A. Schizophrenia first-rank symptoms in organic mental frontotemporal dementia: evaluation of consensus criteria and
disorders. Br J Psychiatry 1988; 152:625–8. review. J Neuropsychiatry Clin Neurosci 2002; 14:424–9.
p 04.qxd 3/10/08 9:33 AM Page 157
References 157
Mendez MF, Adams NL, Lewandowski KS. Neurobehavioral changes Mulder DW, Parrott M, Thaler M. Sequelae of western equine
associated with caudate lesions. Neurology 1989; 39:349–54. encephalitis. Neurology 1951; 1:318–27.
Mendez MF, Selwood A, Mastri AR et al. Pick’s disease versus Muller T, Buttner TH, Kuhn W et al. Palinopsia as sensory epileptic
Alzheimer’s disease: a comparison of clinical characteristics. phenomenon. Acta Neurol Scand 1995; 91:433–6.
Neurology 1993; 43:289–92. Murata S, Naritomi H, Sawada T. Musical auditory hallucinations
Mendez MF, Cherrier MM, Perryman KM. Epileptic forced thinking caused by a brainstem lesion. Neurology 1994; 44:156–8.
from left frontal lesions. Neurology 1996; 47:79–83. Nakada T, Lee H, Kwee IL et al. Epileptic Kluver–Bucy syndrome:
Mendhekar DN, Duggal HS. Sertraline for Kluver-Bucy syndrome case report. J Clin Psychiatry 1984; 45:87–8.
in an adolescent. Eur Psychiatry 2005; 20:355–6. Neary D, Snowden JS, Mann DMA. Familial progressive atrophy:
Mendhekar DN, Sharma A, Inamdar A. Obsessive-compulsive its relationship to other forms of lobar atrophy. J Neurol
disorder with hydrocephalus: effect of ventricular shunting. Neurosurg Psychiatry 1993; 56:1122–5.
J Neuropsychiatry Clin Neurosci 2007; 19:84. Nedjam Z, Devouche E, Della Barabara G. Confabulation, but not
Menza MA, Cocchiola J, Golbe LI. Psychiatric symptoms in executive dysfunction discriminate AD from frontotemporal
progressive supranuclear palsy. Psychosomatics 1995; 36:550–4. dementia. Eur J Neurol 2004; 11:728–33.
Merrin EL, Silberfarb PM. The Capgras phenomenon. Arch Gen Nielsen JM. The cortical components of akinetic mutism. J Nerv
Psychiatry 1976; 33:965–8. Ment Dis 1951; 114:459–61.
Messert B, Henke TK, Langheim W. Syndrome of akinetic mutism Nishkawa T, Okuda J, Mizuta I et al. Conflict of intentions due to
associated with obstructive hydrocephalus. Neurology 1966; callosal disconnection. J Neurol Neurosurg Psychiatry 2001;
16:635–49. 63:462–71.
Mesulam M-M. Dissociative states with abnormal temporal lobe Noda S, Mizoguchi M, Yamamoto A. Thalamic experiential
EEG. Arch Neurol 1981; 38:176–81. hallucinosis. J Neurol Neurosurg Psychiatry 1993; 56:1224–6.
Meyer JS, Greifenstein F, Devault M. A new drug causing symptoms Nordgren RE, Markesbery WR, Fukada K et al. Seven cases of
of sensory deprivation. J Nerv Ment Dis 1959; 129:54–61. cerebromedullospinal disconnection: the ‘locked-in’ syndrome.
Michel EM, Troost BT. Palinopsia: cerebral localization with Neurology 1971; 21:1140–8.
computed tomography. Neurology 1980; 30:887–9. Noyes R, Kletti R. Depersonalization in accident victims and
Miguel EC, Coffey BJ, Baer L et al. Phenomenology of intentional psychiatric patients. Compr Psychiatry 1977; 18:375–84.
repetitive behavior in obsessive-compulsive disorder and Noyes R, Hoenk P, Kuperman S et al. Depersonalization in
Tourette’s disorder. J Clin Psychiatry 1995; 56:246–55. accident victims and psychiatric patients. J Nerv Ment Dis
Miller TC, Crosby TW. Musical hallucinations in a deaf elderly 1977; 164:401–7.
patient. Ann Neurol 1979; 5:301. Nurnberg HG, Greenwald B. Stuttering: an unusual side-effect of
Mitchell SW. The effects of Anhelonium lewinii (the mescal phenothiazines. Am J Psychiatry 1981; 138:386–7.
button). BMJ 1896; 2:1625–9. Nyatsanza S, Shetty T, Gregory C et al. A study of stereotypic
Miyazawa N, Hayashi M, Komiya K et al. Supernumerary phantom behaviors in Alzheimer’s disease and frontal and temporal
limbs associated with left hemispheric stroke: case report and variant frontotemporal dementia. J Neurol Neurosurg
review of the literature. Neurosurgery 2004; 54:228–31. Psychiatry 2003; 74:1398–402.
Monrad-Krohn GH. On the dissociation of voluntary and O’Hare JA, Callaghan NM, Murnaghan DJ. Dialysis
emotional innervation in facial paresis of central origin. Brain encephalopathy. Clinical, electroencephalographic, and
1924; 47:22–35. interventional aspects. Medicine 1983; 62:129–41.
Monrad-Krohn GH. Dysprosody or altered ‘melody of language’. Oliveira V, Ferro JM, Foreid JP et al. Kluver-Bucy syndrome in
Brain 1947; 70:405–15. systemic lupus erythematosus. J Neurol 1989; 236:55–6.
Montero J, Pena J, Genis D et al. Balint’s syndrome. Report of four O’Sullivan D, Dean C. The Fregoli syndrome and puerperal
cases with watershed parieto-occipital lesions from psychosis. Br J Psychiatry 1991; 159:274–7.
vertebrobasilar ischemia or systemic hypotension. Acta Neurol Ott BR. Leuprolide treatment of sexual aggression in a patient
Belg 1982; 82:270–80. with dementia and the Kluver-Bucy syndrome. Clin
Morgan CA, Hazlett G, Wang S et al. Symptoms of dissociation in Neuropharmacol 1995; 18:443–7.
humans experiencing acute uncontrollable stress: a prospective Panayiotopoulos CP. Elementary visual hallucinations in migraine
investigation. Am J Psychiatry 2001;158: 1239–47. and epilepsy. J Neurol Neurosurg Psychiatry 1994;
Mori E, Yamadori A. Unilateral hemispheric injury and ipsilateral 57:1371–4.
instinctive grasp reaction. Arch Neurol 1985; 42:485–8. Panitch HS, Thisted RA, Smith RA et al. Randomized controlled
Motomura S, Tabira T, Kuroiwa Y. A clinical comparative study of trial of dextromethorphan/quinidine for pseudobulbar affect in
multiple sclerosis and neuro-Behçet’s syndrome. J Neurol multiple sclerosis. Ann Neurol 2006; 59:780–7.
Neurosurg Psychiatry 1980; 43:210–13. Parkes JD, Baraitser M, Marsden CD et al. Natural history,
Mottard J-P, de la Sablonniere J-F. Olanzapine-induced symptoms and treatment of the narcoleptic syndrome. Acta
obsessive-compulsive disorder. Am J Psychiatry 1999; Neurol Scand 1975; 52:337–53.
156:799–800. Parkinson D, Rucker CW, McK Craig W. Visual hallucinations
Mulder DW, Daly D. Psychiatric symptoms associated with lesions associated with tumors of the occipital lobe. Arch Neurol
of temporal lobe. J Am Med Assoc 1952; 150:173–6. Psychiatry 1952; 68:60–8.
p 04.qxd 3/10/08 9:33 AM Page 158
Parvizi J, Joseph J, Press DZ et al. Pathological laughter and crying Reeves RR, Norton JW. Foreign accent-like syndrome during
in patients with multiple system atrophy-cerebellar type. Mov psychotic exacerbations. Neurpsychiatry Neuropsychol Behav
Disord 2007; 22:798–803. Neurol 2001; 14:135–8.
Paskind HA. Parosmia in tumorous involvement of olfactory bulbs Reeves RR, Burke RS, Parker JD. Characterization of psychotic
and nerves. Arch Neurol Psychiatry 1935; 33:835–8. patients with foreign accent syndrome. J Neuropsychiatry Clin
Patterson JF. Carbamazepine in the treatment of phantom limb Neurosci 2007; 19:70–6.
pain. South Med J 1988;81:1100–2. Regli F, Filippa G, Wiesendanger M. Hereditary mirror movements.
Paulig M, Mentrup H. Charles Bonnet’s syndrome: complete Arch Neurol 1967; 16:620.
remission of complex visual hallucinations treated by Remillard GM, Andermann F, Rhi-Sausa A et al. Facial asymmetry
gabapentin. J Neurol Neurosurg Psychiatry 2001; in patients with temporal lobe epilepsy. Neurology 1977;
70:813–14. 27:109–14.
Pazzaglia P, D’Alessandro R, Ambrosetto G et al. Drop attacks: an Remington G, Sloman L, Konstantareas M et al. Clomipramine
ominous change in the evolution of partial epilepsy. Neurology versus haloperidol in the treatment of autistic disorder: a
1985; 35:1725–30. double-blind, placebo-controlled, crossover study. J Clin
Penfield W, Jasper H. Epilepsy and the functional anatomy of the Psychopharmacol 2001; 21:440–4.
human brain. Boston: Little, Brown and Company, 1954, pp. Renner JA, Burns JM, Hou CE et al. Progressive posterior cortical
383–4. dysfunction. A clinicopathologic series. Neurology 2004;
Penfield W, Perot P. The brain’s record of auditory and visual 63:1175–80.
experience. Brain 1963; 86:595. Riddoch G. Phantom limbs and body shape. Brain 1941;
Perez FM, Tunkel RS, Lachmann EA et al. Balint’s syndrome arising 64:197–222.
from bilateral posterior cortical atrophy or infarction: Riley DE, Lang AE, Resch L et al. Cortico-basal ganglionic
rehabilitation strategies and their limitation. Disabil Rehabil degeneration. Neurology 1990; 40:1203–12.
1996; 18:300–4. Rinne JO, Lee MS, Thompson PD et al. Cortico-basal degeneration.
Piccirilli M, Sciarma T, Luzzi S. Modularity of music: evidence Brain 1994; 117:1183–96.
from a case of pure amusia. J Neurol Neurosurg Psychiatry Roberts JM. Echolalia and comprehension in autistic children. J
2000; 69:541–5. Autism Dev Disord 1989; 19:271–81.
Pick A. On reduplicative paramnesia. Brain 1903; 26:260–7. Roberts K, Vass N. Schneiderian first-rank symtoms caused by
Pitt DC, Kriel RL, Wagner NC et al. Kluver–Bucy syndrome benzodiazepine withdrawal. Br J Psychiatry 1986; 148:593–4.
following heat stroke in a 12-year-old girl. Pediatr Neurology Robertson MM, Trimble MR, Lees AJ. The psychopathology of
1995; 13:73–6. Gilles de la Tourette’s syndrome: a phenomenological analysis.
Powers JM, Schaumburg HH, Gaffney CL. Kluver–Bucy syndrome Br J Psychiatry 1988; 182:388–90.
caused by adrenoleukodystrophy. Neurology 1980; Robinson RG, Parikh RM, Lipsey JR et al. Pathological laughing
30:1131–2. and crying following stroke; validation of a measurement scale
Power-Smith P, Turkington D. Fluoxetine in phantom limb pain. Br and a double-blind treatment study. Am J Psychiatry 1993;
J Psychiatry 1993; 163:105–6. 150:286–93.
Psarros T, Zours A, Coimbra C. Bromocriptine-responsive akinetic Rosenfeld MR, Eichen JG, Wade DF et al. Molecular and clinical
mutism following endoscopy for ventricular diversity in paraneoplastic immunity to Ma proteins. Ann
neurocysticercosis. Case report and review of the literature. J Neurol 2001; 50:339–48.
Neurosurg 2003; 99:397–401. Ross ED, Stewart RM. Akinetic mutism from hypothalamic
Rabinowitz J, Katz JR, De Deyn PP et al. Behavioral and damage: successful treatment with dopamine agonists.
psychological symptoms in patients with dementia as a target Neurology 1981; 31:1435–9.
for pharmacotherapy with risperidone. J Clin Psychiatry 2004; Ross ED, Jossman PB, Bell B et al. Musical hallucinations in
65:1329–34. deafness. JAMA 1975; 231:620–1.
Radhakrishnan J, Mathew K, Richard J et al. Schneider’s first rank Ross RT, Mathiesen R. Images in clinical medicine: volitional and
symptoms – prevalence, diagnostic use and prognostic emotional supranuclear facial weakness. N Engl J Med 1998;
implications. Br J Psychiatry 1983; 142:557–9. 338:1515.
Rashiq S, Briewa L, Moooney M et al. Distinguishing aclovir Rosse RB, Collins JP, Fay-McCarthy M et al. Phenomenologic
neurotoxicity from encephalomyelitis. J Int Med 1993; comparison of the idiopathic psychosis of schizophrenia and
234:507–11. drug-induced cocaine and phencyclidine psychoses: a
Rasmussen KG, Rummans TA. Electroconvulsive therapy for retrospective study. Clin Neuropharmacol 1994; 17:359–69.
phantom limb pain. Pain 2000; 85:297–9. Rosselli M, Ardila A, Beltran C. Rehabilitation of Balint’s syndrome:
Rasmussen SA, Tsuang MT. Clinical characteristics and family a single case report. Appl Neuropsychol 2001; 8:242–7.
history in DSM-III obsessive-compulsive disorder. Am J Rossitch E, Bullard DE. The autonomic dysfunction syndrome:
Psychiatry 1986; 143:317–22. aetiology and treatment. Br J Neurosurg 1988; 2:471–8.
Rayport M, Ferguson SM, Corrie WS. Outcomes and indications of Rumsey JM, Andreasen NC, Rapoport JL. Thought, language,
corpus callosum section for intractable seizure control. Appl communication and affective flattening in autistic adults.
Neurophysiol 1983; 46:47–51. Arch Gen Psychiatry 1986; 43:771–7.
p 04.qxd 3/10/08 9:33 AM Page 159
References 159
Russell MB, Olesen J. A nosographic analysis of the migraine aura Serra-Mestres J, Shapleske J, Tym E. Treatment of palilalia with
in a general population. Brain 1996; 119:355–61. trazodone. Am J Psychiatry 1996; 153:580–1.
Russell SM, Golfinos JG. Amusia following resection of Heschl Seyffarth H, Denny-Brown D. The grasp reflex and the instinctive
gyrus glioma. Case report. J Neurosurg 2003; 98:1109–12. grasp reflex. Brain 1948; 71:109–83.
Russell WR, Whitty CWM. Studies in traumatic epilepsy. 2. Focal Shahed J, Jankovic J. Re-emergence of childhood stuttering in
motor and somatic sensory fits: a study of 85 cases. J Neurol Parkinson’s disease: an hypothesis. Mov Disord 2001; 16:114–18.
Neurosurg Psychiatry 1953; 16:73–97. Shallice T, Burgess PW, Schon F et al. The origins of utilization
Russell WR, Whitty CWM. Studies in traumatic epilepsy. 3. Visual behavior. Brain 1989; 112:1587–98.
fits. J Neurol Neurosurg Psychiatry 1955; 18:79–96. Shaw KM, Lees AJ, Stern GM. The impact of treatment with
Sachdev P. Schizophrenia-like illness in velo-cardio-facial levodopa on Parkinson’s disease. Q J Med 1980; 49:283–93.
syndrome: a genetic subsyndrome of schizophrenia? J Shoji H, Teramoto H, Satowa S et al. Partial Kluver–Bucy
Psychosom Res 2002; 53:721–7. syndrome following probable herpes simplex encephalitis. J
Sandson J, Albert ML. Perseveration in behavioral neurology. Neurol 1979; 221:163–7.
Neurology 1987; 37: 1736–41. Shopsin B, Hirsch J, Gershon S. Visual hallucinations and
Santhouse AM, Howard RJ, ffytche DH. Visual hallucinatory propranolol. Biol Psychiatry 1975; 10:105–7.
syndrome and the anatomy of the visual brain. Brain Shorvon H. The depersonalization syndrome. Proc R Soc Med
2000;123:2055–64. 1946; 39:779–92.
Sarkar J, Jones N, Sulivan G. A case of depersonalization- Shukla GD, Sahu SC, Tripathi RP et al. Phantom limb: a
derealization syndrome during treatment with quetiapine. J phenomenological study. Br J Psychiatry 1982; 141:54–8.
Psychopharmacol 2001; 15:209–11. Sichel DA, Cohen LS, Dimmock JA et al. Postpartum obsessive
Schielke E, Reuter U, Hoffmnn O et al. Musical hallucinations with compulsive disorder: a case series. J Clin Psychiatry 1993;
dorsal pontine lesions. Neurology 2000; 55:454–5. 54:156–9.
Schiff HB, Alexander MP, Naeser MA et al. Aphemia: clinical- Siegel A, Harrow M, Reilly FE et al. Loose associations and
anatomic correlations. Arch Neurol 1983; 40:720–7. disordered speech patterns in chronic schizophrenia. J Nerv
Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic Ment Dis 1976; 162:105–12.
laughing and weeping with amitriptyline. N Engl J Med 1985; Siegel RK. Cocaine hallucinations. Am J Psychiatry 1978;
312:1480–2. 135:309–14.
Schley M, Topfner S, Wiech K et al. Continuous brachial plexus Simeon D, Gross C, Guralnik O et al. Feeling unreal: 30 cases of
blockade in combination with the NMDA receptor antagonist DSM-III-R depersonalization disorder. Am J Psychiatry 1997;
memantine prevents phantom limb pain in acute traumatic 154:1107–13.
upper limb amputees. Eur J Pain 2007; 11:299–308. Simeon D, Knutelska M, Nelson O et al. Feeling unreal: a
Schneider K. Clinical psychopathology. London: Grune & Stratton, depersonalization disorder update of 117 cases. J Clin
1959. Psychiatry 2003; 64:990–7.
Schnider A, Bonvallat J, Emond H et al. Reality confusion in Simmel ML. Phantom experiences following amputation in
spontaneous confabulation. Neurology 2005; 65:1117–19. childhood. J Neurol Neurosurg Psychiatry 1962; 25:69–78.
Schott GD, Wyke MA. Congenital mirror movements. J Neurol Simpson S, Baldwin B. Neuropsychiatry and SPECT of an acute
Neurosurg Psychiatry 1981; 44:586–99. obsessive-compulsive syndrome patient. Br J Psychiatry 1995;
Schultz G, Melzack R. Visual hallucinations and mental state: a 166:390–7.
study of 14 Charles Bonnet syndrome hallucinations. J Nerv Sjogren M, Wallin A, Edman A. Symptomatological differences
Ment Dis 1993; 181:639–43. distinguish between frontotemporal dementia and vascular
Schwartz JI, Moura RJ. Severe depersonalization and anxiety dementia with a dominant frontal lobe syndrome. Int J Geriatr
associated with indomethacin. South Med J 1983; 76:679–80. Psychiatry 1997; 12:656–61.
Schwartz W, Stakes JW, Jobson JA. Transient cataplexy after Slater E, Beard AW. The schizophrenia-like psychoses of epilepsy.
removal of a craniopharyngioma. Neurology 1984; 34:1372–5. i. Psychiatric aspects. Br J Psychiatry 1963; 109:95–112.
Sears LL, Vest C, Mohamed S et al. An MRI study of the basal Slatterly MJ, Dubbert BK, Allen AJ et al. Prevalence of obsessive-
ganglia in autism. Prog Neuropsychopharmacol Biol Psychiatry compulsive disorder in patients with systemic lupus
1999; 23:613–24. erythematosus. J Clin Psychiatry 2004; 65:301–6.
Sedman G. Depersonalization in a group of normal subjects. Br J Smit LS, Lammers GJ, Catsman-Berrevoets CE. Cataplexy leading
Psychiatry 1966; 112:907–12. to the diagnosis of Niemann-Pick disease type C. Pediatr
Selby G, Lance JW. Observations on 500 cases of migraine and Neurol 2006; 35:82–4.
allied vascular headache. J Neurol Neurosurg Psychiatry 1960; Smith DG, Ehds DM, Hanley MA et al. Efficacy of gabapentin in
23:23–32. treating chronic phantom limb and residual limb pain. J
Seliger GM, Abrams GM, Horton A. Irish brogue after stroke. Rehabil Res Dev 2005; 42:645–54.
Stroke 1992; 23:1655–6. Smith KU, Akelaitis AJ. Studies on the corpus callosum. I.
Serra Catafau J, Rubio R, Peres Serra J. Peduncular halucinosis Laterality in behavior and bilateral motor organization in man
associated with posterior thalamic infarction. J Neurol 1992; before and after section of the corpus callosum. Arch Neurol
239:89–90. Psychiatry 1942; 47:519–43.
p 04.qxd 3/10/08 9:33 AM Page 160
Snowden JS, Neary D, Mann DMA et al. Progressive language Tanaka Y, Yoshida A, Kawahata N et al. Diagnostic dyspraxia:
disorder due to lobar atrophy. Ann Neurol 1992; 31:174–83. clinical characteristics, responsible lesions and possible
Soros P, Vo G, Husstedt I-W et al. Phantom eye syndrome. Its underlying mechanism. Brain 1996; 119:859–74.
prevalence, phenomenology and putative mechanisms. Tandon R, Greden JF. Schneiderian first rank symptoms:
Neurology 2003; 60:1542–3. reconfirmation of high specificity for schizophrenia. Acta
Souques A. Palilalia. Rev Neurol 1908; 16:340–3. Psychiatr Scand 1987; 75:392–6.
Sowa MV, Pituck S. Prolonged spontaneous complex visual Tang-Wai DF, Graff-Radford NR, Boeve BF et al. Clinical, genetic,
hallucinations and illusions as ictal phenomena. Epilepsia and neuropathologic characteristics of posterior cortical
1989; 30:524–6. atrophy. Neurology 2004; 63:1168–74.
Soyka M, Naber G, Volcker A. Prevalence of delusional jealousy in Tateno A, Jorge RE, Robinson RG. Pathological laughing and
different psychiatrc disorders. Br J Psychiatry 1991; crying following traumatic brain injury. J Neuropsychiatry Clin
158:549–53. Neurosci 2004; 16:426–34.
Sparr SA. Receptive amelodia in a trained musician. Neurology Teri L, Larson EB, Reifler BV. Behavioral disturbance in dementia
2002; 59:1659–60. of the Alzheimer’s type. J Am Ger Soc 1988; 36:1–6.
Sperry RW. Brain bisection and mechanisms of consciousness. In: Terzian H, Dalle Ore G. Syndrome of Kluver and Bucy: reproduced
Eccles JC ed. Brain and conscious experience. New York: in man by bilateral removal of the temporal lobes. Neurology
Springer-Verlag, 1966. 1955; 5:373–80.
Stacy M, Cardoso F, Jankovic J. Tardive stereotypy and other Teunisse RJ, Zitman FG, Raes DCM. Clinical evaluation of 14
movement disorders in tardive dyskinesias. Neurology 1993; patients with the Charles Bonnet syndrome (isolated visual
43:937–41. hallucinations). Compr Psychiatry 1994; 35:70–5.
Stahl SM, Layzer RB, Aminoff MJ et al. Continuous cataplexy in a Teunisse RJ, Cruysberg JRM, Verbeek A et al. The Charles Bonnet
patient with a midbrain tumor: the limp man syndrome. syndrome: a large prospective study in the Netherlands. Br J
Neurology 1980; 30:1115–18. Psychiatry 1995; 166:234–57.
Stamouli S, Lykouras L. Quetiapine-induced obsessive-compulsive Teunisse RJ, Cruysberg JR, Hoefnagels WH et al. Visual
symptoms: a series of five cases. J Clin Psychopharmacol 2006; hallucinations in psychologically normal people: Charles
26:396–400. Bonnet’s syndrome. Lancet 1996; 347:794–7.
Starkstein SE, Berthier M, Leiguarda R. Disconnection syndrome in Thajeb P. Progressive late delayed postirradiation encephalopathy
a right-handed patient with right hemispheric speech with Kluver-Bucy syndrome. Serial MRI and clinico-
dominance. Eur Neurol 1988; 28:187–90. pathological studies. Clin Neurol Neurosurg 1995; 97:264–8.
Starkstein SE, Federoff JP, Price TR et al. Catastrophic reaction after Thompson AE, Swan M. Capgras syndrome presenting with violence
cerebrovascular lesions: frequency, correlates, and validation of following heavy drinking. Br J Psychiatry 1993; 162:692–4.
a scale. J Neuropsychiatry Clin Neurosci 1993; 5:189–94. Thompson JC, Stopford CL, Snowden JS et al. Qualitative
Starkstein SE, Migliorelli R, Teson A et al. Prevalence and clinical neuropsychological performance characteristics in
correlates of pathological affective display in Alzheimer’s frontotemporal dementia and Alzheimer’s disease. J Neurol
disease. J Neurol Neurosurg Psychiatry 1995; 59:55–60. Neurosurg Psychiatry 2005; 76:920–7.
Steinhausen H-C, Juzi C. Elective mutism: an analysis of 100 Thorley RR, Wertsch JJ, Kingbell GE. Acute hypothalamic
cases. J Am Acad Child Adolesc Psychiatry 1996; 35:606–14. instability in traumatic brain injury: a case report. Arch Phys
Stewart JT. Carbamazepine treatment of a patient with Kluver- Med Rehabil 2001; 82:246–9.
Bucy syndrome. J Clin Psychiatry 1985; 46:496–7. Tilberti C, Sabe L, Kuzis G et al. Prevalence and correlates of the
Stewart-Wallace AM. An unusual case of the grasp reflex, with catastrophic reaction in Alzheimer’s disease. Neurology 1998;
some observations on the volitional and reflex components. 50:546–8.
J Neurol Neurosurg Psychiatry 1939; 2:149–53. Tilney F. Pseudobulbar palsy clinically and pathologically
Suwanwela NC, Leelacheavasit N. Isolated corpus callosal infarction considered with the clinical report of five cases. J Nerv Ment
secondary to pericallosal artery disease presenting as alien hand Dis 1912; 39:505–35.
syndrome. J Neurol Neurosurg Psychiatry 2002; 72:533–6. Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing’s
Swedo SE, Rapoport JL, Cheslow DL et al. High prevalence of syndrome. Arch Neurol Psychiatry 1952; 67:283–309.
obsessive-compulsive symptoms in patients with Sydenham’s Trosch RM, Sze G, Brass LM et al. Emotional facial paresis with
chorea. Am J Psychiatry 1989; 146:246–9. striatocapsular infarction. J Neurol Sci 1990;98:195–201.
Swedo SE, Leonard HL, Schapiro MB et al. Sydenham’s chorea: Tuke DH. Imperative ideas. Brain 1894; 17:179–97.
physical and psychological symptoms of St. Vitus dance. Turgut N, Utku U, Balci K. A case of acquired stuttering resulting
Pediatrics 1993; 91:706–13. from left parietal infarction. Acta Neurol Scand 2002;
Takayama Y, Sugishita M, Kido T et al. A case of foreign accent 105:408–10.
syndrome without aphasia caused by a lesion of the left Tweedy J, Reding M, Garcia C et al. Significance of cortical
precentral gyrus. Neurology 1993; 43:1361–3. disinhibition signs. Neurology 1981; 31:169–73.
Tanaka Y, Iwasa H, Yoshuida M. Diagonistic dyspraxia: case report Ueda N, Tarao T, Ohmori O et al. Schneiderian first-rank
and movement-related potentials. Neurology 1990; symptoms associated with fluvoxamine treatment: a case
40:657–61. report. Hum Psychopharmacol 2003;18:477–8.
p 04.qxd 3/10/08 9:33 AM Page 161
References 161
Ukai S, Yamamoto M, Tanaka M et al. Treatment of typical Charles Walshe FMR, Robertson EG. Observations upon the form and
Bonnet syndrome with donepezil. Int Clin Psychopharmacol nature of the ‘grasping’ movements and ‘tonic innervation’
2004; 19:355–7. seen in certain cases of lesions of the frontal lobe. Brain 1933;
Uzunca I, Utku U, Asil T et al. ‘Fou rire prodromique’ associated 56:40–70.
with simultaneous bilateral capsular genu infarction. J Clin Watson RT, Heilman KM. Callosal apraxia. Brain 1983;
Neurosci 2005; 12:174–5. 106:391–403.
Valldeoriola F, Graus F, Rimola A et al. Cyclosporine-induced Watson RT, Heilman KM, Bowers D. Magnetic resonance imaging
mutism in liver transplant patients. Neurology 1996; (MRI, NMR) scan in a case of callosal apraxia and
46:252–4. pseudoneglect. Brain 1985; 108:535–6.
Van den Hoed J, Lucas EA, Dement WC. Hallucinatory experiences Weinstein EA, Kahn RL, Malitz S et al. Delusional reduplication of
during cataplexy in patients with narcolepsy. Am J Psychiatry parts of the body. Brain 1954; 77:45–60.
1979; 136:1210–11. Weinstein S, Sersen EA. Phantoms in cases of congenital absence
Van Der Werf YD, Weerts JGE, Jolles J et al. Neuropsychological of limbs. Neurology 1961; 11:905–11.
correlates of a right unilateral lacunar thalamic infarction. J Wergeland H. Elective mutism. Acta Psychiatr Scand 1979;
Neurol Neurosurg Psychiatry 1999; 66:36–42. 59:218–28.
Van Dijk JG, Lammers GJ, Blansjaar BA. Isolated cataplexy of more White NJ. Complex visual hallucinations in partial blindness due
than 40 years duration. Br J Psychiatry 1991; 154:719–21. to eye disease. Br J Psychiatry 1980; 136:284–6.
Van Dongen HR, Catsman-Berrevoets CE, van Mourik M. The Wiech K, Kiefer RT, Topfner S et al. A placebo-controlled
syndrome of ‘cerebellar’ mutism and subsequent dysarthria. randomized crossover trial of the N-methyl-D-aspartate acid
Neurology 1994; 44:2040–6. receptor antagonist, memantine, in patients with chronic
Van Hilten JJ, Buruma OJ, Kessing P et al. Pathologic crying as a phantom limb pain. Anesth Analg 2004; 98:408–13.
prominent behavioral manifestation of central pontine Wijdicks EF, Wiesner RH, Dahlke LJ et al. FK506-induced
myelinolysis. Arch Neurol 1988; 45:936. neurotoxicity in liver transplantation. Ann Neurol 1994;
Van Waggenen WP, Herren RY. Surgical division of commisural 35:498–501.
pathways in the corpus callosum: relation to spread of an Williams D. The structure of emotions reflected in epileptic
epileptic attack. Arch Neurol Psychiatry 1940; 44:740–57. experiences. Brain 1956; 79:29–67.
Vaphiades MS, Celesia GG, Brigell MG. Positive spontaneous Wilson DH, Reeves A, Gazzaniga M. Cerebral commisurotomy for
visual phenomena limited to the hemianopic field in lesions of control of intractable seizures. Neurology 1977; 27:708–15.
central visual pathways. Neurology 1996; 47:408–17. Wilson SAK. Some problems in neurology. II. Pathological
Varon D, Pritchard PB, Wagner MT et al. Transient Kluver-Bucy laughing and crying. J Neurol Psychopathology 1924;
syndrome following complex partial status epilepticus. 4:299–333.
Epilepsy Behav 2003; 4:348–51. Wilson SAK. The narcolepsies. Brain 1928; 51:63–109.
Victoroff J, Ross GW, Benson DF et al. Posterior cortical atrophy. Wilson SAK. Neurology, 2nd edn. London: Butterworth & Co,
Neuropathologic correlations. Arch Neurol 1994; 51:269–74. 1954.
Vollenweider FX, Gamma A, Liechti M et al. Psychological and Wolberg FL, Ziegler DK. Olfactory hallucinations in migraine. Arch
cardiovascular effects and short-term sequelae of MDMA Neurol 1982; 39:382.
(‘ecstasy’) in MDMA-naive healthy volunteers. Yamamaka K, Fukuyama H, Kimura J. Abulia from unilateral
Neuropsychopharmacology 1998; 19:241–51. capsular genu infarction: report of two cases. J Neurol Sci
Vreeling FW, Verhey FR, Houx PJ et al. Primitive reflexes in 1996; 143:181–4.
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1993; Yasuda Y, Akiguchi I, Ino M et al. Paramedian thalamic and
56:1323–6. midbrain infarcts associated with palilalia. J Neurol Neurosurg
Vreeling FW, Houx PJ, Jolles J et al. Primitive reflexes in Psychiatry 1990; 53:797–9.
Alzheimer’s disease and vascular dementia. J Geriatr Psychiatr Zarcone V. Narcolepsy. N Engl J Med 1973; 288:1154–66.
Neurol 1995; 8:111–17. Zeidler M, Johnstone EC, Bamber RWK et al. New variant
Vuilleumier P, Reverdin A, Landis T. Four legs: illusory Creutzfeldt–Jakob disease: psychiatric features. Lancet 1997;
reduplication of the lower limbs after bilateral parietal lobe 350:908–10.
damage. Arch Neurol 1997; 54:1543–7. Zelig G, Drubach DA, Katz-Zelig M et al. Pathological laughter and
Waite LM, Broe GA, Creasey H et al. Neurological signs, aging, and crying in patients with closed traumatic brain injury. Brain Inj
the neurodegenerative syndromes. Arch Neurol 1996; 1996; 10:591–7.
53:498–502. Ziegler LH. Psychotic and emotional phenomena associated with
Wali GM. ‘Fou rire prodromique’ heralding a brainstem stroke. J amyotrophic lateral sclerosis. Arch Neurol Psychiatry 1930;
Walshe FMR. On certain tonic or postural reflexes in hemiplegia
with special reference to the so-called ‘associated
movements’. Brain 1923; 46:1–37.
Walshe FMR, Hunt JH. Further observations upon grasping
movements and reflex tonic grasping. Brain 1936; 59:315–23.
p 05.qxd 3/10/08 9:34 AM Page 162
5
Syndromes of cognitive impairment
5.1 Dementia 162 5.4 Amnesia 183

5.2 Mild cognitive impairment 173 5.5 Mental retardation 187
5.3 Delirium 174 References 190
5.1 DEMENTIA occasioned by the patient’s day-to-day life. For example,

an accountant may find it no longer possible to understand
The dementias constitute one of the most common syn- complex accounting formulae or a chess player may find it
dromes seen in neuropsychiatric practice. Accurate diag- impossible to think out moves.
nosis is critical not only for prognostic purposes, but also Calculating ability is tested for by asking patients to do
because a not insignificant number of the diseases capable simple arithmetic, such as subtracting 8 from 12, and, if
of causing dementia are treatable. they perform well at this task, asking them to perform
‘serial 7’s’ by first subtracting 7 from 100, then 7 from that
answer, etc. Any deficits here must be judged in light of the
Clinical features patients’ educational experience and their premorbid abil-
ities. Difficulties with calculations may be evident in day-
Dementia is a syndrome of multiple different etiologies to-day life as patients have trouble making change or
characterized by a global decrement in cognitive function- balancing a checkbook.
ing occurring in a clear sensorium, without significant A loss of good judgment is often what first calls patients
confusion (Cummings 1987). When the condition is fully to medical attention. Patients may make ruinous financial
developed, patients display deficits in memory, abstracting agreements or allow themselves to be misled in a variety
abilities, calculations, and judgment. of ways.
Memory impairment is manifest most prominently Some patients, impaired by these cognitive deficits, may
with short-term memory loss, as manifest during examina- experience a ‘catastrophic reaction’. As discussed in more
tion by an inability to recall all out of three words after detail in Section 4.24, these patients become acutely agi-
5 minutes; this memory loss may be apparent as one obtains tated when they find themselves unable to accomplish a
a history and finds that patients have forgotten where they cognitive task that, premorbidly, would have caused no
put their keys or wallets, or tend to forget what family difficulty.
members have told them earlier. Long-term memory also In addition to these symptoms one often sees a person-
suffers, although not as severely as does the short-term ality change. This may be of a specific type, such as the
type: patients may be unable to recall public facts, such as frontal lobe syndrome, but is more often non-specific. In
the names of the last four presidents, or biographical facts, some cases, previously maladaptive traits may become
such as where they last worked, or where they went to accentuated, as when an overly thrifty person becomes
school. Whenever memory impairment is present, one also miserly. In other cases, new traits may appear: a previously
typically finds partial or complete disorientation to time shy person may become overly familiar or a well-mannered
and, albeit less commonly, to place. person may become sloppy and crude.
Abstracting ability is tested formally by asking patients Other deficits, such as aphasia, apraxia, or agnosia, may
to interpret familiar proverbs, such as ‘don’t count your or may not be present, depending on the underlying cause
chickens before they hatch’ and watching for a ‘concrete’ of the dementia.
response, such as ‘well, they might not all hatch’, rather Dementia may also be accompanied by agitation and
than an ‘abstract’ one, such as ‘don’t count on things’. delusions or hallucinations. The delusions tend to be perse-
Difficulty with abstract thinking may also be evident in the cutory and patients may accuse others of stealing from them.
patient’s daily life, depending on the cognitive demands Delusions of infidelity may also occur and patients may
p 05.qxd 3/10/08 9:34 AM Page 163
5.1 Dementia 163
accuse spouses of having affairs. One may also encounter the If, after a thorough history and examination, the cause of
‘phantom boarder’ delusion wherein patients believe that the dementia is still not clear, one may consider choosing
someone is hiding in the house, perhaps in the basement or from among the following ‘screening’ tests: complete blood
attic. Hallucinations tend to be visual and may be quite com- count (CBC) chemistry survey, magnetic resonance (MR)
plex: patients may see animals or people. Auditory hallucina- scanning, thyroid profile, vitamin B12 and folate levels,
tions, although less common, may also occur, and patients fluorescent treponemal antibody (FTA), anti-nuclear anti-
may hear music, voices, or bells. body (ANA), and erythrocyte sedimentation rate (ESR).
Depression is common, and insomnia, with or without
depression, may also occur. OF GRADUAL OR SUBACUTE ONSET, OFTEN LACKING IN
DISTINCTIVE FEATURES
Etiology Of all the disorders capable of causing a dementia of more or

less gradual onset without distinctive features, Alzheimer’s
The causes of dementia are numerous, as indicated by the disease is the most common, followed by diffuse Lewy body
lengthy list provided in Table 5.1. In an attempt to bring disease and two vascular disorders, namely Binswanger’s dis-
some order to the differential task, the various causes are ease and lacunar dementia. Other disorders to keep in mind,
divided into several groups. The first group to consider in large part because they are eminently treatable, include
contains those disorders which may cause a dementia of hypothyroidism, hyperthyroidism, vitamin B12 deficiency,
gradual or subacute onset, often lacking in distinctive features, folate deficiency, depression, and, in some cases, tumors and
such as Alzheimer’s disease. Next is a group of vascular dis- hydrocephalus. Infectious disorders that may or may not
orders, all of which may cause a dementia in the setting of a yield to treatment include AIDS dementia, Lyme disease and
history of strokes, for example multi-infarct dementia. neurosyphilis. The other disorders listed in this section are all
Following this is a group of disorders that tend to present relatively rare causes of dementia presenting in this fashion.
with a dementia characterized by a frontal lobe syndrome, as Alzheimer’s disease is typically of gradual or insidious
may be seen in frontotemporal dementia. The next group onset, often presenting with a gradually worsening amne-
contains those disorders that may present with a progressive sia (Goodman 1953; Linn et al. 1995), which is eventually
aphasia, which, subsequently, and gradually, evolves into a joined by various ‘cortical’ signs such as aphasia, apraxia,
dementia, as may be seen in a variety of neurodegenerative and primitive reflexes (Huff et al. 1987; Price et al. 1993).
disorders. Diffuse Lewy body disease may present with a gradually
The next groups are each marked by dementia occur- progressive dementia that, early on, may be difficult to dis-
ring in concert with a movement disorder. Such abnormal tinguish from that seen in Alzheimer’s disease. Helpful dif-
movements must be carefully sought for in the examina- ferential clues include visual hallucinations, spontaneously
tion as they provide very valuable diagnostic clues: these appearing episodes of confusion, and the eventual appear-
groups include dementia occurring with parkinsonism ance of parkinsonism. Visual hallucinations are prominent
(e.g., Parkinson’s disease), chorea (e.g., Huntington’s dis- early on, and may be quite vivid (Byrne et al. 1989; McKeith
ease), dystonia (e.g., corticobasal ganglionic degeneration), et al. 1994a; Tiraboschi et al. 2006). Episodes of confusion
myoclonus (e.g., Creutzfeldt–Jakob disease), and ataxia last on the order of hours and, in contrast with the confu-
(e.g., multiple system atrophy). sional episodes that may occur in patients with other
The next group in the list is a heterogeneous one, contain- dementias when patients are confronted with cognitively
ing a number of disorders, each with distinctive features, for demanding tasks, the episodes seen in diffuse Lewy body
example the tendon enlargement seen in cerebrotendinous disease appear spontaneously, without any obvious precip-
xanthomatosis. Following this is a group characterized by itating factors (Ballard et al. 2001; Bradshaw et al. 2004).
dementias occurring with obvious precipitating events, such as Parkinsonism eventually appears in almost all patients,
traumatic brain injury with subdural hematoma or diffuse and generally within a year of the onset of the dementia.
axonal injury. Even before the onset of parkinsonism, patients may dis-
Next is a group of disorders, each causing dementia in play a pronounced ‘neuroleptic sensitivity’, when treated
the setting of mental retardation, as may be seen in Down’s with an antipsychotic, developing severe antipsychotic-
syndrome. Finally, there is a group of miscellaneous causes, induced parkinsonism (McKeith et al. 1992).
for example systemic lupus erythematosus. Binswanger’s disease, occurring on the basis of a vascular
In working up a patient with dementia, it is reasonable microangiopathy with diffuse white matter disease, as noted
to keep in mind the most common causes: Alzheimer’s dis- by Binswanger (Blass et al. 1991) himself, may present with
ease, diffuse Lewy body disease, multi-infarct dementia, a slowly progressive dementia, which, although often
Parkinson’s disease and traumatic brain injury. Furthermore, accompanied by strokes (Caplan and Schoene 1978), may
given the frequency with which these occur, it is not at all lack them entirely (Kinkel et al. 1985; Yoshitake et al. 1995).
uncommon to find patients with a ‘mixed’ dementia, for Lacunar dementia, like Binswanger’s disease, may also
example a combination of Alzheimer’s disease and multi- present with a gradually progressive dementia and although
infarct dementia (Molsa et al. 1985). this is more likely to be accompanied by stroke (of the
p 05.qxd 3/10/08 9:34 AM Page 164
164 Syndromes of cognitive impairment
Table 5.1 The causes of dementia

Of gradual or subacute onset, often lacking in Dementia pugilistica
distinctive features Fahr’s syndrome
Alzheimer’s disease Carbon monoxide intoxication
Diffuse Lewy body disease Manganese intoxication
Binswanger’s disease Methanol intoxication
Lacunar dementia Valproic acid
Hypothyroidism Hypoparathyroidism
Hyperthyroidism Pantothenate kinase-associated neurodegeneration
Vitamin B12 deficiency Huntington’s disease of juvenile onset
Folate deficiency Systemic lupus erythematosus
Depression
With chorea
Tumors
Huntington’s disease
Hydrocephalus
Choreoacanthocytosis
Acquired autoimmune deficiency syndrome (AIDS)
Dentatorubropallidoluysian atrophy
Lyme disease
Acquired hepatocerebral degeneration
Neurosyphilis
Pick’s disease With dystonia
Cerebral amyloid angiopathy Corticobasal ganglionic degeneration
Creutzfeldt–Jakob disease Wilson’s disease
Multiple sclerosis Pantothenate kinase-associated neurodegeneration
With myoclonus
Amyotrophic lateral sclerosis
Creutzfeldt–Jakob disease
Systemic lupus erythematosus
Post-anoxic dementia
Granulomatous angiitis
Dialysis dementia
In the setting of a history of strokes AIDS dementia
Multi-infarct dementia Diffuse Lewy body disease
Lacunar dementia Multiple system atrophy
Binswanger’s disease Corticobasal ganglionic degeneration
Cranial arteritis Dentatorubropallidoluysian atrophy
Cerebral amyloid angiopathy Alzheimer’s disease
Cerebral autosomal dominant arteriopathy with subcortical Subacute sclerosing panencephalitis
infarcts and leukoencephalopathy (CADASIL) Juvenile-onset Huntington’s disease
Mitochondrial myopathy, encephalopathy, lactic acidosis, and Whipple’s disease
stroke (MELAS) Idiopathic hemochromatosis
Characterized by a frontal lobe syndrome Thalamic degeneration
Frontotemporal dementia With ataxia
Pick’s disease Multiple system atrophy
Amyotrophic lateral sclerosis Spinocerebellar ataxia
Tumors Fragile X-associated tremor/ataxia syndrome (FXTAS)
With a progressive aphasia Dentatorubropallidoluysian atrophy
Alzheimer’s disease Creutzfeldt–Jakob disease
Pick’s disease Gerstmann–Sträussler–Scheinker disease
Frontotemporal dementia Lithium intoxication
Corticobasal ganglionic degeneration Mercury intoxication
Progressive supranuclear palsy Tin intoxication
Tumors Inhalant abuse
Dementia pugilistica
With parkinsonism
Acquired hepatocerebral degeneration
Parkinson’s disease
Metachromatic leukodystrophy
Diffuse Lewy body disease
Progressive rubella panencephalitis
Multiple system atrophy
Progressive supranuclear palsy With distinctive features
Corticobasal ganglionic degeneration Cerebrotendinous xanthomatosis (tendon enlargement)
Frontotemporal dementia with parkinsonism Myotonic dystrophy (myotonia)
Vascular parkinsonism Thallium intoxication (painful polyneuropathy and alopecia)
(continued)
p 05.qxd 3/10/08 9:34 AM Page 165
5.1 Dementia 165
Table 5.1 (Continued)

Arsenic intoxication (painful polyneuropathy and alopecia) In the setting of mental retardation
Pellagra (diarrhea and dermatitis) Down’s syndrome
Behçet’s syndrome (aphthous oral and genital ulcers) Sturge–Weber syndrome
Sjögren’s syndrome (dry eyes and mouth) Congenital rubella syndrome
Polymyalgia rheumatica (polymyalgia)
Sneddon’s syndrome (livedo reticularis)
With obvious precipitating events Polyarteritis nodosa
Subdural hematoma Anti-phospholipid syndrome
Diffuse axonal injury Sarcoidosis
Dementia pugilistica Progressive multifocal
Post-anoxic encephalopathy leukoencephalopathy
Delayed post-anoxic encephalopathy Kufs’ disease
Radiation encephalopathy Metachromatic leukodystrophy
Post-encephalitic Adrenoleukodystrophy
Status epilepticus Pantothenate kinase-associated
Dialysis dementia neurodegeneration
Hypoglycemia Hypoparathyroidism
Prednisone Whipple’s disease
Valproic acid Lead intoxication
Disulfiram Thalamic degeneration
Lithium Sleep apnea
Methanol Bilateral carotid occlusion
Heroin vapor Hyperviscosity syndrome
Alcoholic dementia Hypereosinophilia
Inhalant dementia Hypertriglyceridemia
‘lacunar’ variety), its presentation may be confined to a other dementia and may indeed be very severe. Clues to the
dementia (Ishii et al. 1986; Yoshitake et al. 1995). correct diagnosis include the presence of significant
Hypothyroidism may cause a dementia (Asher 1949) depressive symptoms, such as disturbances in sleep and
marked by sluggishness (de Fine Olivarious and Roder 1970). appetite, and, above all, a history of past depressive
In most cases, one will also see other, typical symptoms of episodes (Rabins et al. 1984). Furthermore, the appearance
hypothyroidism, such as myxedema, cold sensitivity, consti- of depression in a patient with a pre-existing dementia may
pation, and hair loss. worsen the patient’s cognitive deficits (Greenwald et al.
Hyperthyroidism may cause dementia: although this is 1989). It must be borne in mind that these elderly patients
only rarely reported in typical cases, wherein it is accompa- are still liable to other dementing disorders and may
nied by autonomic signs such as tremor and tachycardia indeed develop a dementia of another cause in the future
(Bulens 1981), it is not uncommon in elderly patients with (Alexopoulus et al. 1993).
the ‘apathetic’ variant, wherein the only clue may be atrial Tumors of the frontal lobe (Sachs 1950), corpus callo-
fibrillation (Martin and Deam 1996). sum (Alpers and Grant 1931; Ironside and Guttmacher
Vitamin B12 deficiency may cause dementia (Lurie 1919) 1929), thalamus (Smyth and Stern 1938), and hypothala-
and although this is usually accompanied by a macrocytic mus (Alpers 1937; Liss 1958; Lobosky et al. 1984; Strauss
anemia, cases have occurred that lacked both anemia and and Globus 1931) may all cause a gradually progressive
macrocytosis (Chatterjee et al. 1996; Lindenbaum et al. dementia without striking distinctive features: tumors in
1988). other locations may of course cause dementia, but these
Folate deficiency can clearly cause dementia. Cases have are often accompanied by focal deficits, such as hemiple-
been reported of folate deficiency dementia occurring with gia, which are also gradually progressive and strongly sug-
subacute combined degeneration (Pincus et al. 1972) or gest a space-occupying lesion. Some hypothalamic tumors
spasticity (Reynolds et al. 1973), or in the absence of any capable of causing dementia may also be accompanied by
other symptoms (Strachan and Henderson 1967). other symptoms (Lobosky et al. 1984) such as hyper-
Depression, as may be seen in major depression, is a not somnolence (Strauss and Globus 1931), massive weight
uncommon cause of dementia (Reding et al. 1985). The gain (Liss 1958), or diabetes insipidus (Alpers 1937).
dementia of depression used to be called a ‘pseudo- Chronic hydrocephalus (Gustafson and Hagberg 1978;
dementia’ (Caine 1981; Wells 1979), but this is inappropriate Harrison et al. 1974; McHugh 1964; Messert and Baker
as the dementia of depression is no more ‘pseudo’ than any 1966), including normal pressure hydrocephalus (Adams
p 05.qxd 3/10/08 9:34 AM Page 166
et al. 1965; Hill et al. 1967), may present primarily with a disease (Hansotia et al. 1968) and in a 60-year-old patient
dementia, but this may be accompanied by other symp- (Case records 1992): in both cases, chorea eventually
toms and signs, such as urinary incontinence, and a broad- appeared after a number of years.
based shuffling gait often marked by a ‘magnetic’ aspect Amyotrophic lateral sclerosis may present with a
wherein the feet seem to be magnetically ‘stuck’ to the combination of dementia and typical upper and lower
floor. motor neuron signs (i.e., fasciculations, hyper-reflexia, and
AIDS dementia, although generally occurring with other pseudobulbar palsy) (Horoupian et al. 1984; Robertson
symptoms suggestive of AIDS (e.g. Pneumocystis pneumonia, 1953; Wechsler and Davison 1932) or may rarely present
Kaposi’s sarcoma, and thrush) may, in a small minority, be with dementia alone (Ferrer et al. 1991).
the presenting symptom of AIDS (Navia and Price 1987; Systemic lupus erythematosus may, very rarely, present
Navia et al. 1986a,b). with a gradually progressive dementia: in one patient, who
Lyme disease, during its third stage, may cause a mild recovered with steroid treatment, the diagnosis was
dementia (Halperin et al. 1989; Logigian et al. 1990). The delayed until the development of a fever and pleural effusion
history may or may not reveal the original tick bite and ery- suggested the correct diagnosis (MacNeill et al. 1976).
thema chronica migrans of stage I or the polyarthralgia of Granulomatous angiitis may present with a dementia
stage II, and patients may or may not have the oligoarthritis (Case records 1989) and, although headache is often promi-
that typifies stage III. nent, it is not invariable.
Neurosyphilis, presenting as general paresis of the insane,
although much less common than early in the twentieth IN THE SETTING OF A HISTORY OF STROKES
century, when it filled hospital wards, is still with us and
making something of a comeback, especially in connection In the evaluation of a patient with dementia, a history of
with AIDS. The dementia may be non-specific or may be repeated stroke is of great diagnostic import. Large ‘territo-
accompanied by dysarthria and pupillary changes, including rial’ infarctions may be associated with multi-infarct demen-
the classic Argyll Robertson pupil (Gomez and Aviles 1984; tia, and small subcortical lacunar infarctions with lacunar
Storm-Mathisen 1969). dementia. Binswanger’s disease, as noted earlier, is character-
Pick’s disease, although typically presenting with a per- ized by a vascular microangiopathy and hence generally does
sonality change, often of the frontal lobe type (Munoz et al. not cause clinically discernible stroke; Binswanger’s disease,
1993), may occasionally present in a fashion quite similar however, is often associated with other vascular pathology,
to that of Alzheimer’s disease (Wisniewski et al. 1972). such as small vessel disease that can cause stroke (of the lacu-
Cerebral amyloid angiopathy, although classically marked nar variety) and hence is also considered in this section.
by a gradually progressive dementia punctuated by lobar Cranial arteritis should be considered in any patient with
intracerebral hemorrhages, may cause a progressive demen- stroke, especially when there is a history of temporal
tia alone without any strokes (Bornebroek et al. 1996; headache or visual loss. Cerebral amyloid angiopathy is sug-
Cosgrove et al. 1985; Haan et al. 1990; Nobuyoshi et al. 1984). gested by a history of lobar intracerebral hemorrhages.
In some cases, however, there may be transient events similar Finally, consideration may be given to two rare disorders,
to transient ischemic attacks (Greenberg et al. 1993). CADASIL (cerebral autosomal dominant arteriopathy with
Creutzfeldt–Jakob disease may present with a dementia subcortical infarcts and leukoencephalopathy) and MELAS
with few distinguishing features (Brown et al. 1984; Will (mitochondrial encephalopathy with lactic acidosis and
and Mathews 1984), although in approximately 80 percent stroke-like episodes), both of which are associated with
of cases, myoclonus eventually appears (Brown et al. 1986; migrainous headaches.
Roos et al. 1973), thus suggesting the correct diagnosis. It Multi-infarct dementia is typically characterized by a
must be borne in mind, however, that not all cases will dementia that progresses in a ‘stepwise’ fashion, each step
develop myoclonus (Zochodne et al. 1988); the relative corresponding to a fresh, large, cortical, or subcortical
rapidity of the progression, measured in months, may sug- infarction. Critically, in between the ‘steps’, the patient
gest the diagnosis. experiences a clinical plateau without any between-step
Multiple sclerosis may cause dementia, which is in most deterioration (Erkinjunti et al. 1988; Tomlinson et al. 1970;
cases seen to occur in the context of a history of signs and Yoshitake et al. 1995). An examination of such patients
symptoms indicating white matter lesions ‘disseminated in typically reveals various focal findings, such as hemiplegia,
time and space’. In a minority the dementia may be the pri- aphasia, and apraxia, corresponding to the location of the
mary expression of multiple sclerosis, being accompanied prior infarctions. Rarely, a dementia will result from one
by few other symptoms (Jennekens-Schinkel and Sanders large or strategically placed infarction: clearly, subsuming
1986; Mendez and Frey 1992) and, very rarely, it may con- these cases under the rubric of ‘multi-infarct’ constitutes
stitute the presentation of the disease without any other something of a semantic trespass but a term equivalent to
symptoms or signs (Fontaine et al. 1994; Hotopf et al. 1994). ‘single-infarct dementia’ has simply not found its way into
Huntington’s disease, although typically presenting current usage. Examples of such ‘single’ infarctions include
with either a personality change or chorea, may rarely present large cortical infarctions or strategically placed subcortical
with a dementia, as has been noted in juvenile Huntington’s infarctions (Yoshitake et al. 1995).
p 05.qxd 3/10/08 9:34 AM Page 167
5.1 Dementia 167
Lacunar dementia may also pursue a classic ‘stepwise’ Pick’s disease classically presents with the frontal lobe
course; however, several features serve to distinguish it syndrome (Bouton 1940; Ferraro and Jervis 1936), and it is
from multi-infarct dementia. First, one typically finds a indeed this presentation that most strongly distinguishes it
history of ‘lacunar syndromes’, such as pure motor stroke, from Alzheimer’s disease (Litvan et al. 1997a; Mendez et al.
pure sensory stroke, etc. Second, as noted earlier, in lacu- 1993).
nar dementia, one may also find a progressive downhill Amyotrophic lateral sclerosis, once thought to spare the
course in between the obvious strokes (Ishii et al. 1986; cortex outside the precentral gyrus, is now known to involve
Yoshitake et al. 1995). Third, and finally, lacunar dementia the frontal lobes. In a minority, the disease may present with
is often marked clinically by a frontal lobe syndrome (Ishii a frontal lobe syndrome followed by a dementia and typical
et al. 1986; Wolfe et al. 1990). Eventually, however, the diag- upper and lower motor neuron signs (Cavalleri and De
nosis is often made on MR scanning, which reveals multiple Renzi 1994; Neary et al. 1990; Peavy et al. 1992).
subcortical lacunes. Tumors of the frontal lobe may present with a dementia
Binswanger’s disease classically presents with a dementia marked by a frontal lobe syndrome (Avery 1971; Frazier
that pursues a gradual downhill course; this disease, however, 1936; Williamson 1896), which is true not only of tumors
often is accompanied by small vessel disease and lacunar confined to the frontal lobe, but also of those tumors of the
strokes (Caplan and Schoene 1978; Kinkel et al. 1985; corpus callosum that extend laterally into the adjacent
Revesz et al. 1989) and is difficult to distinguish from lacu- frontal lobes (Moersch 1925).
nar dementia on a clinical basis. MR scanning will reveal,
however, the leukoencephalopathy typical of Binswanger’s WITH A PROGRESSIVE APHASIA
disease, thus making the diagnosis.
Cranial arteritis may rarely cause a dementia, of either A number of different neurodegenerative diseases may
the multi-infarct or lacunar type (Caselli 1990, Nightingale present with an isolated aphasia in a syndrome known as
et al. 1982). Diagnostic clues include unilateral headache ‘primary progressive aphasia’. In such cases, the aphasia
(generally temporal in location), amaurosis fugax, and progressively worsens and is eventually joined by a demen-
polymyalgia rheumatica. tia. Such a scenario has been noted in Alzheimer’s disease
Cerebral amyloid angiopathy classically presents with (Green et al. 1990, 1996; Karbe et al. 1993), Pick’s disease
a gradually progressive dementia punctuated by lobar (Kertesz et al. 1994), and frontotemporal dementia (Neary
intracerebral hemorrhages (Cosgrove et al. 1985; Gilles et al. et al. 1993; Snowden et al. 1992; Turner et al. 1996); other,
1984), demonstrable on computed tomography (CT) or mag- much less common, causes include corticobasal ganglionic
netic resonance imaging (MRI) and suggested clinically by the degeneration (Ikeda et al. 1996), progressive supranuclear
prominent headache associated with the lobar hemorrhage. palsy (Knibb et al. 2000), and Creutzfeldt–Jakob disease
CADASIL presents in a fashion similar to that of (Mandell et al. 1989). It must be borne in mind that a sim-
Binswanger’s disease. Distinguishing features include ilar picture may occur with slowly growing appropriately
migrainous headaches and a family history consistent with situated tumors.
an autosomal dominant inheritance (Dichgans et al. 1998;
Jung et al. 1995; Malandrini et al. 1996). WITH PARKINSONISM
MELAS syndrome is a rare maternally inherited disorder
that, although generally presenting in the childhood years, The combination of dementia and parkinsonism may
may present in adulthood with stroke-like episodes, pro- occur secondary to a large number of disorders, of which
gressive dementia, migraine-like headaches, and hearing loss certain neurodegenerative disorders are the most common.
(Clark et al. 1996). Of these neurodegenerative disorders, the most frequent
causes are Parkinson’s disease, diffuse Lewy body disease,
CHARACTERIZED BY A FRONTAL LOBE SYNDROME and multiple system atrophy, each one of which, in addi-
tion to dementia, may cause a fairly ‘classic’ parkinsonism;
The frontal lobe syndrome, as discussed further in Section other neurodegenerative disorders to consider include
7.2, is marked by varying degrees of affective changes progressive supranuclear palsy, corticobasal ganglionic
(euphoria or irritability), disinhibition and perseveration, degeneration, and frontotemporal dementia; however, as
and its appearance early on in a dementing disorder is detailed below, the parkinsonism seen in these disorders
strongly suggestive of frontal pathology, as may be seen tends to have some distinctive atypical features. Some
with various tumors and in certain neurodegenerative dis- other disorders that present in a fashion similar to these
orders, such as Pick’s disease, frontotemporal dementia, neurodegenerative ones include vascular parkinsonism,
and amyotrophic lateral sclerosis. dementia pugilistica, and Fahr’s syndrome.
Frontotemporal dementia, like Pick’s disease, typically Less common disorders to consider include those with
presents with a frontal lobe syndrome. A distinguishing more or less obvious precipitating factors, such as intoxica-
feature in some cases is the early appearance of an aphasic tions (carbon monoxide, manganese, methanol) and treat-
disturbance of the motor or anomic type (Heutink et al. ment with valproic acid. Miscellaneous, and rare, causes
1997; Mann et al. 1993; Neary et al. 1993). include hypoparathyroidism, pantothenate kinase-associated
p 05.qxd 3/10/08 9:34 AM Page 168
neurodegeneration, juvenile-onset Huntington’s disease, and Vascular parkinsonism is characterized by a gradually pro-
systemic lupus erythematosus. gressive rigidity, bradykinesia, and gait abnormality, all
Parkinson’s disease may cause dementia but this is a late notably in the absence of tremor. This parkinsonism is typi-
development, generally not appearing until five or more cally accompanied by signs of damage to the corticospinal and
years after the parkinsonism has been well established. The corticobulbar tracts, such as spasticity, hyper-reflexia, and
prevalence of dementia in patients with Parkinson’s disease pseudobulbar palsy. In some cases, a dementia may appear
increases with age (Biggins et al. 1992; Marder et al. 1995) (Bruetsch and Williams 1954; Keschner and Sloane 1931).
and overall, in population-based studies, the prevalence of Dementia pugilistica has a gradual onset anywhere from
dementia ranges from 18 percent (Tison et al. 1995) to 41 5 to 40 years after repeated head trauma (e.g., as in boxing),
percent (Mayeux et al. 1992). with a combination of parkinsonism, dysarthria, ataxia,
Diffuse Lewy body disease may present with parkinson- and dementia (Harvey and Davis 1974; Martland 1928).
ism; however, within a year of the onset of the parkinson- Fahr’s syndrome (Margolin et al 1980; Mathews 1957;
ism, patients develop a dementia, and it is this ‘one year Nyland and Skre 1977) may present with parkinsonism
rule’ that most reliably distinguishes diffuse Lewy body and dementia. Cerebellar signs such as dysarthria, intention
disease from Parkinson’s disease. Other, helpful differen- tremor, and ataxia may also be present, but the distinctive
tial features include the presence of hallucinations and finding is calcification of the basal ganglia, which is best
spontaneous episodes of confusion in the dementia of dif- demonstrated on CT scanning.
fuse Lewy body disease, features that are generally not as Carbon monoxide intoxication may, after a lucid interval
prominent in Parkinson’s disease (Burkhardt et al. 1988; of from days to weeks, be followed in a minority of cases by
Klatka et al. 1996; McKeith et al. 1994). the subacute onset of dementia and parkinsonism (Choi
Multiple system atrophy of the striatonigral degeneration 1983; Min 1986).
type presents with a typical parkinsonism but it is generally Manganese intoxication, as may occur in those working
accompanied by evidence of either autonomic failure or in manganese mines, steel mills, or battery factories, may
cerebellar involvement (Colosimo et al. 1995; Litvan et al. cause a gradually progressive parkinsonism that may be
1997b; Wenning et al. 1994, 1995). The autonomic failure joined by a dementia (Cook et al. 1974). The parkinsonism
may include postural hypotension and dizziness, urinary in these cases is often marked by dystonic rigidity of the
incontinence or retention, fecal incontinence, and erectile neck and face and by ankle dystonia, which results in the
dysfunction; cerebellar signs include ataxia and intention classic ‘cock-walk’ gait.
tremor. A minority of these patient will eventually develop Methanol intoxication, as may occur in desperate
a dementia (Robbins et al. 1992). alcoholics, may, as a sequela, leave patients with dementia,
Progressive supranuclear palsy typically presents with parkinsonism, and blindness (McLean et al. 1980).
postural instability and frequent unexplained falls; over time, Valproic acid, with chronic use, as for epilepsy or bipo-
parkinsonism develops, marked by rigidity, bradykinesia, lar disorder, may cause a combination of dementia and
and, notably, a dystonic axial extension, which may also be parkinsonism, which is potentially reversible on discontin-
evident in the neck (Collins et al. 1995; Daniel et al. 1995; uation of the drug (Armon et al. 1996; Shill and Fife 2000);
Litvan et al. 1996a,b,c, 1997c). Most, but not all, patients importantly, this side-effect of valproic acid may take from
eventually demonstrate the hallmark of this disease, namely 6 months to 4 years to appear (Ristic et al. 2006).
supranuclear ophthalmoplegia for vertical gaze. Most Hypoparathyroidism may cause parkinsonism and
patients also eventually become demented and many will dementia but this is usually in the context of Fahr’s syn-
also develop a pseudobulbar palsy with emotional inconti- drome, which, as noted above, includes calcification of the
nence (Menza et al. 1995). basal ganglia. In one rare case, however, dementia and
Corticobasal ganglionic degeneration typically presents parkinsonism occurred with hypoparathyroidism in the
with a strikingly asymmetric rigid–akinetic parkinsonism, absence of calcification and with a normal serum calcium
generally in an arm, which may be accompanied by a dys- level. The only clue to the diagnosis was cataracts; the
tonic rigidity. Apraxia is a common accompaniment, and parathyroid hormone level was low and the patient recovered
some patients may also develop myoclonus (Litvan et al. with dihydroxycholecalciferol (Stuerenburg et al. 1996).
1997d; Riley et al. 1990; Rinne et al. 1994). A minority may Pantothenate kinase-associated neurodegeneration of
eventually become demented. Uncommonly, the disease the late-onset type may present with a slowly progressive
may present with dementia (Grimes et al. 1999), and in parkinsonism that is eventually joined by dementia and
such cases, parkinsonism may appear later (Schneider et al. dystonia (Jankovic et al. 1985, Murphy et al. 1989).
1997). Huntington’s disease of juvenile onset, seen in late
Frontotemporal dementia, specifically frontotemporal childhood or adolescence, may present with parkinsonism
dementia with parkinsonism linked to chromosome 17 and dementia (Bird and Paulson 1971; Campbell et al.
(FTDP-17) (Pickering-Brown et al. 2002) typically presents 1961; Siesling et al. 1997).
with a dementia marked by a personality change with frontal Systemic lupus erythematosus very rarely presents with
lobe features that may, over years, be joined by parkinson- a combination of dementia and parkinsonism (Dennis
ism in a minority of cases. et al. 1992).
p 05.qxd 3/10/08 9:34 AM Page 169
5.1 Dementia 169
WITH CHOREA Finally, myoclonus may also be seen in certain rare dis-
orders such as Whipple’s disease, idiopathic hemochro-
The prototypical cause of dementia occurring in the setting matosis, and thalamic degeneration.
of chorea is Huntington’s disease; two other neurodegener- Creutzfeldt–Jakob disease is the classic example of a dis-
ative conditions that present in a somewhat similar fashion ease causing dementia with myoclonus: approximately 80
are choreoacanthocytosis and dentatorubropallidoluysian percent of patients eventually display this sign (Brown et al.
atrophy. Other disorders to consider are acquired hepat- 1986, 1994; Roos et al. 1973). New-variant Creutzfeldt–Jakob
ocerebral degeneration and Wilson’s disease. disease, contracted by eating beef from cows with ‘mad
Huntington’s disease, as noted by George Huntington cow’ disease (bovine spongiform encephalopathy), like
himself (Brody and Wilkins 1967), typically presents with Creutzfeldt–Jakob disease also eventually causes myoclonus
chorea which, over years, is joined by a dementia (Pflanz in most patients (Zeidler et al. 1997).
et al. 1991). Post-anoxic dementia, appearing after an anoxic coma,
Choreoacanthocytosis may also present with chorea may be accompanied by myoclonus, which is often of the
and dementia. A diagnostic clue is involuntary lip biting or intention type (Werheran et al. 1997).
other self-injurious behavior (Critchley et al. 1968; Hardie Dialysis dementia is immediately suggested by the
et al. 1991), although this is not seen in all patients. appearance of dementia after several years of hemodialysis.
Dentatorubropallidoluysian atrophy may likewise present Myoclonus is common and helps to confirm the diagnosis
with chorea and dementia; diagnostic clues include ele- (Burks et al. 1976; Lederman and Henry 1978).
ments of ataxia and dystonia (Becher et al. 1997; Warner AIDS dementia, once well established, may, in a minor-
et al. 1994, 1995). ity, be accompanied by myoclonus (Navia et al. 1986b), and
Acquired hepatocerebral degeneration, occurring after myoclonus may also play a minor role in the dementia seen
repeated bouts of hepatic encephalopathy, is seen most in diffuse Lewy body disease (Louis et al. 1997), multiple sys-
often in chronic alcoholics and may present with a demen- tem atrophy (Rodriguez et al. 1994), corticobasal ganglionic
tia accompanied by a complex movement disorder, with degeneration (Litvan et al. 1997d), dentatorubropalli-
chorea and tremor (Finlayson and Superville 1981; Victor doluysian atrophy (of childhood onset) (Becher et al. 1997),
et al. 1965). and in end-stage Alzheimer’s disease (Benesch et al. 1993;
Chen et al. 1991).
WITH DYSTONIA Subacute sclerosing panencephalitis, typically with an
Corticobasal ganglionic degeneration, as noted earlier, typ- onset in childhood or adolescence, presents with dementia
ically presents with parkinsonism and dementia; however, that is eventually joined by myoclonus (Dawson 1934).
in some cases the dominant movement disorder may be a Juvenile-onset Huntington’s disease is distinguished by
unilateral dystonia. parkinsonism and dementia, as noted above. In a minority
Wilson’s disease may present with dystonia, later to be of cases myoclonus may also appear (Siesling et al. 1997).
joined by a dementia (Walshe and Yealland 1992). The fact Whipple’s disease may cause a dementia and, although a
that this disease is treatable mandates testing in any young history of abdominal complaints (especially diarrhea) and
person who presents with a compatible clinical picture. arthopathy is generally most helpful diagnostically, about
Pantothenate kinase-associated neurodegeneration typ- one-quarter of these patients will also have myoclonus
ically presents in childhood or adolescence with a progressive (Louis et al. 1996).
dystonia and dementia (Dooling et al. 1974, 1980; Hayflick Idiopathic hemochromatosis may present, very rarely,
et al. 2003). with dementia and myoclonus (Jones and Hedley-Whyte
1983). Other, suggestive clinical features include hepatic
WITH MYOCLONUS failure, diabetes mellitus, and cardiomyopathy.
Thalamic degeneration is a very rare syndrome that may
Myoclonus, when prominent in the overall clinical picture, present with dementia and myoclonus (Little et al. 1986).
is a very important diagnostic sign and, although more com-
monly associated with delirium (as described in Section 6.3), WITH ATAXIA
it may also be a significant clue in the diagnosis of dementia
in adults. Of the dementing disorders associated with Dementia occurring in the setting of ataxia may be seen in
myoclonus, the most important is Creutzfeldt–Jakob disease neurodegenerative disorders such as multiple system atrophy,
(including the ‘new-variant’ type) and two other disorders: spinocerebellar atrophy, fragile X-associated tremor/ataxia
post-anoxic dementia and dialysis dementia. Myoclonus syndrome (FXTAS) and dentatorubropallidoluysian atrophy,
may also appear in AIDS dementia and in various neurode- and in prion diseases such as Creutzfeldt–Jakob disease and
generative disorders; however, here it plays only a minor Gerstmann–Sträussler–Scheinker disease. A similar constella-
role and is overshadowed by other clinical features. tion may occur with more or less obvious precipitating fac-
Among children or adolescents, myoclonus is an impor- tors such as intoxications with lithium, mercury, or tin,
tant sign in subacute sclerosing panencephalitis and may long-term inhalant use, repeated head trauma, and cirrhosis.
also be seen in the juvenile form of Huntington’s disease. Finally, when this clinical picture occurs in childhood or
p 05.qxd 3/10/08 9:34 AM Page 170
adolescence, one must consider metachromatic leukodystro- 1972; Rauschka et al. 2006; Reider-Grosswasser and
phy and the very rare progressive rubella panencephalitis. Bornstein 1987).
Multiple system atrophy of the olivopontocerebellar Progressive rubella panencephalitis, although usually
type may present with ataxia (Wenning et al. 1994) and may occurring in the setting of the congenital rubella syndrome
also cause dementia (Robbins et al. 1992). The presence of with mental retardation, may occasionally present in the
evidence of autonomic failure (e.g., postural hypotension late teenage years in patients of normal premorbid intelli-
and dizziness, urinary incontinence or retention, fecal gence. One patient had cataracts and microphthalmos due
incontinence, or erectile dysfunction) or mild parkinson- to congenital rubella (Townsend et al. 1976), whereas
ism is an important diagnostic clue. another had contracted rubella in childhood but had no
Spinocerebellar ataxia presents with a progressive sequelae at the time (Wolinsky et al. 1976); in both cases,
ataxia, which, in a minority, is eventually joined by dementia the dementia was accompanied by ataxia.
(Carter and Sukavajuna 1956; Chandler and Bebin 1956;
Goldfarb et al. 1989; Lasek et al. 2006; Modi et al. 2000; WITH DISTINCTIVE FEATURES
Sasaki et al. 1996; Zhou et al. 1998).
FXTAS is characterized by the gradual onset of a pro- The following disorders are all relatively rare causes of
gressive ataxia and tremor in middle or later years, with, in dementia which, in each case, have certain distinctive fea-
a minority, the eventual development of a dementia tures, as described below.
(Hagerman et al. 2001). Cerebrotendinous xanthomatosis, when fully developed,
Dentatorubropallidoluysian atrophy may rarely present manifests with dementia, tendon enlargement, cataracts,
with a combination of ataxia and dementia (Potter et al. and ataxia. Tendon enlargement is the most distinctive fea-
1995). ture, and although it may appear in a variety of areas, it is
Creutzfeldt–Jakob disease may present with ataxia, fol- most commonly, and classically, found in the Achilles ten-
lowed within weeks or months by a dementia (Brown et al. don. The disease evolves very slowly and may present with
1986, 1994; de Villemeur et al. 1996). any one of these features anywhere from childhood or ado-
Gerstmann–Sträussler–Scheinker disease, an inherited lescence to the adult years (Berginer et al. 1988; Farpour
prion disease, typically presents with ataxia and dementia and Mahloudji 1975; Watts et al. 1996).
(Barbanti et al. 1996; Brown et al. 1991). Myotonic dystrophy typically presents with myotonia
Lithium intoxication, if severe, may leave patients per- in late adolescence or early adult years. Over time, a ‘myo-
manently ataxic and demented (Schou 1984). pathic facies’, with frontal baldness, ptosis, and temporal
Mercury, in large amounts, may cause dementia and wasting appears, as does weakness and atrophy, most
ataxia: this has been noted with mercury salts (as found in prominent distally. In a small minority, a dementia may
a laxative [Davis et al. 1974]), methyl mercury (as used in a also occur (Huber et al. 1989; Perini et al. 1989).
fungicide for wheat [Rustam and Hamri 1974]), and ethyl Thallium intoxication may be followed by dementia
mercury (as occurred with industrial exposure [Hay et al. with a painful polyneuropathy and prominent alopecia
1963]). (Thompson et al. 1988; Reed et al. 1963).
Tin intoxication, in one case, caused a coma from which Arsenic intoxication with organic arsenicals may cause a
the patient emerged with dementia and ataxia (Wu et al. picture similar to that of thallium intoxication but with less
1990). prominent hair loss.
Inhalant abuse may, if chronic, cause a dementia accom- Pellagra of the chronic, gradual onset type classically
panied by ataxia and other cerebellar signs such as intention presents with the ‘three Ds’: diarrhea, dermatitis, and
tremor, nystagmus, and titubation (Escobar and Aruffo dementia (Langworthy 1931; Pierce 1924).
1980; Fornazzari et al. 1983; Holmes et al. 1986; Lazar et al. Behçet’s syndrome causes dementia in only a small
1983; Rosenberg et al. 1988). minority of patients, virtually all of whom have both oral
Dementia pugilistica, occurring 5–40 years after and genital aphthous ulcers (Serdaroglu et al. 1989). The
repeated head trauma, as, for example, in boxers, may dementia may follow upon numerous prior attacks
present with dementia and prominent ataxia, a sign that (Rubinstein and Urich 1963) or may be slowly progressive
accounts for the colloquial name for this disorder: ‘punch- (Borson 1982).
drunk’ (Harvey and Davis 1974; Martland 1928). Sjörgen’s syndrome is an autoimmune disorder that
Acquired hepatocerebral degeneration, generally occur- typically involves the exocrine glands, producing the ‘sicca
ring in the setting of alcoholic cirrhosis after repeated bouts syndrome’ with dry eyes and a dry mouth. Rarely, a
of hepatic encephalopathy, may present with a dementia and dementia (Kawashima et al. 1993) may occur, probably
a complex movement disorder: although chorea and tremor secondary to a cerebral vasculitis (Caselli et al. 1991).
are most common, in some cases ataxia may dominate the Polymyalgia rheumatica, distinguished by severe
clinical picture (Raskin et al. 1984; Victor et al. 1965). pain and stiffness of the proximal muscle groups, is rarely
Metachromatic leukodystrophy typically causes a demen- associated with a dementia, both the dementia and the
tia that may be accompanied by ataxia in both juvenile- polymyalgia responding to treatment with steroids
(Haltia et al. 1980) and adult-onset cases (Hirose and Bass (Nightingale et al. 1982).
p 05.qxd 3/10/08 9:34 AM Page 171
5.1 Dementia 171
Sneddon’s syndrome is a rare disorder characterized in Dialysis dementia may appear gradually after approxi-
adults by livedo reticularis, strokes, transient ischemic mately 3 years of hemodialysis, often presenting with a
attacks, and, in some, dementia (Adair et al. 2001; Tourbah stuttering type of aphasia (Garrett et al. 1988; O’Hare et al.
et al. 1997). 1983).
Hypoglycemia, if severe (e.g., a glucose level of less than
WITH OBVIOUS PRECIPITATING EVENTS 1.11–1.37 mmol/L [20–25 mg/dL]) and prolonged, may
cause neuronal death, leaving the patient demented
Dementia may appear as a sequela to obvious precipitating (Kalimo and Olsson 1980).
events such as traumatic brain injury, anoxia, radiation, Prednisone, in doses of 60 mg or more, has been reported
encephalitis, status epilepticus, chronic dialysis, and hypo- to cause a dementia that cleared on discontinuation of the
glycemia. Various medications, even when taken at normal drug (Varney et al. 1984).
doses, may also cause dementia, and these include pred- Valproic acid may, with chronic use, cause a dementia,
nisone, valproic acid, and disulfiram. Intoxications with which, as noted earlier, may be accompanied by parkin-
lithium, methanol, or heroin vapor may have dementia as sonism (Armon et al. 1996) or may occur without any dis-
a sequela, and chronic alcoholics or chronic inhalant tinguishing features (Guerrini et al. 1998; Papazian et al.
abusers may also eventually become demented. 1995).
Subdural hematoma of the chronic type may cause a Disulfiram, taken over decades at a therapeutic dosage, in
dementia (Arieff and Wetzel 1964; Black 1984), but there one case caused a dementia and polyneuropathy (Borrett
may be an interval lasting anywhere from months to years et al. 1985).
between the initial trauma and the onset of the dementia. Lithium intoxication, if severe, may leave patients with a
In some cases, the trauma itself may have been forgotten. dementia, which, as noted above, may be accompanied by
Diffuse axonal injury, occurring secondary to violent ataxia (Schou 1984).
acceleration–deceleration during a ‘closed head’ injury Methanol intoxication, when severe, may leave patients
may, depending on its severity, leave patients in a coma, a demented with, as previously noted, parkinsonism (McLean
persistent vegetative state, or a dementia of varying severity et al. 1980).
(Strich 1956). Heroin vapor, produced by heating heroin on aluminum
Dementia pugilistica (Harvey and Davis 1974; Martland foil, may cause dementia accompanied by a varying degree
1928) is one of the sequelae of repeated head trauma, as of bradykinesia and ataxia (Kriegstein et al. 1999)
may occur in boxers, and appears after a latent interval Alcoholic dementia appears in the setting of chronic,
of anywhere from 5 to 40 years. As noted above, it is often severe and ongoing alcoholism, and is distinguished by
accompanied by a combination of parkinsonism and apathy and an overall coarsening of the personality (Lee
ataxia. et al. 1979; Lishman 1981).
Post-anoxic encephalopathy (Richardson et al. 1959) Inhalant-induced dementia makes a gradual appearance
occurs after global hypoxic–ischemic injury. Those who in the setting of chronic, ongoing inhalant use and, as noted
survive and emerge from coma are initially delirious; as the earlier, is often accompanied by ataxia and other cerebellar
delirium gradually resolves, a dementia is left in its wake. signs (Escobar and Aruffo 1980; Fornazzari et al. 1983;
Delayed post-anoxic leukoencephalopathy presents with Holmes et al. 1986; Lazar et al. 1983; Rosenberg et al. 1988).
a delirium generally within weeks of recovery from an
anoxic insult. Although most patients eventually recover, IN THE SETTING OF MENTAL RETARDATION
some, after the confusion clears, are left with a dementia
(Plum et al. 1962). Certain forms of mental retardation may, in the natural
Radiation encephalopathy of the late-delayed type may course of events, be complicated years or decades later by
present with a gradually progressive dementia anytime from dementia, including Down’s syndrome, Sturge–Weber
months to decades after brain irradiation. Interestingly, this syndrome, and the congenital rubella syndrome.
sequela may occur after either whole-brain (Correa et al. Down’s syndrome, in those who survive past the age of
2004; DeAngelis et al. 1989; Duffy et al. 1996) or focal irradi- 40, is eventually complicated by the development of
ation; note that in the case of focal irradiation it is essential Alzheimer’s disease in over one-half of all patients (Lai and
that critical structures such as the temporal lobes have been Williams 1989). In those with pre-existing mild mental
exposed (Crompton and Layton 1961; Shewmon and retardation, the dementia presents with a typical loss of cog-
Masdeu 1980). nitive function; in those with a moderate or more severe
Post-encephalitic dementia has been noted after both degree of retardation, a loss of cognitive ability may be diffi-
herpes simplex encephalitis and arbovirus encephalitis cult to appreciate, and the dementia may instead come to
(Przelomski et al. 1988; Richter and Shimojyo 1961). attention because of apathy and decreased social interaction.
Status epilepticus, whether grand mal or complex partial, Sturge–Weber syndrome is characterized by a unilateral
has been reported to leave patients demented (Krumholz facial port-wine stain, seizures, hemiplegia, and mental
et al. 1995); however, this is not at all inevitable with most retardation. In those with frequent seizures, a dementia
patients surviving without cognitive sequelae. may supervene with a drop in cognitive ability below the
p 05.qxd 3/10/08 9:34 AM Page 172
baseline that characterized the pre-existing mental retarda- Adrenoleukodystrophy may present in childhood, adoles-
tion (Lichtenstein 1954; Petermann et al. 1958; Sujanksy cence, or adulthood. Childhood- or adolescent-onset often
and Conradi 1995). occurs with a personality change and dementia accompanied
Congenital rubella syndrome is characterized by by hemianopia or cortical blindness and spasticity of the
cataracts, deafness, and mental retardation; in a minority, a lower extremities (Moser et al. 1984; Schaumberg et al.
dementia may appear in childhood or adolescence secondary 1975). Adult-onset adrenoleukodystrophy may likewise be
to progressive rubella panencephalitis (Townsend et al. accompanied by visual symptoms such as blindness (Powers
1975; Weil et al. 1975). et al. 1980) or Balint’s syndrome (Uyama et al. 1993) but, in
some cases, visual symptoms are lacking: in one patient, the
MISCELLANEOUS CAUSES clue to the correct diagnosis was generalized hyper-reflexia
(Coria et al. 1993), whereas in another it was bronzing of the
Systemic lupus erythematosus may cause a dementia (Brey skin (Weller et al. 1992).
et al. 2002; Johnson and Richardson 1968; Kirk et al. 1991) via Pantothenate kinase-associated neurodegeneration, as
a number of different mechanisms (Devinsky et al. 1988a), noted above, typically presents with dementia in the setting
including infarctions and an autoimmune cerebritis. In most of dystonia or, less commonly, parkinsonism. There are,
cases, the dementia is accompanied by such systemic symp- however, adult-onset cases that are marked by other signs,
toms as arthralgia, rash, pleural effusion, and constitutional such as a fine tremor (Dooling et al. 1974) or dysarthria
symptoms such as fever, fatigue, and weight loss. and clumsiness (Rozdilsky et al. 1968).
Polyarteritis nodosa may cause a dementia (MacKay Hypoparathyroidism, without basal ganglia calcification,
et al. 1950), but, as with lupus, this is usually in the setting may present with a dementia accompanied by seizures and
of systemic symptoms such as renal or gastrointestinal dis- cataracts (Mateo and Gimenez-Roldan 1982).
ease or constitutional symptoms. Whipple’s disease, although typically presenting with
Anti-phospholipid antibody syndrome is characterized diarrhea and arthropathy, very rarely may affect the central
by recurrent arterial and venous thrombosis and, in women, nervous system in isolation, and in such cases these typical
by a history of recurrent miscarriage. Strokes may occur, symptoms may be absent. One case was marked by hypo-
producing a multi-infarct dementia (Coull et al. 1987). In thalamic involvement with hypersomnia (Adams et al.
some cases, however, the dementia may occur without spe- 1987) and another by seizures (Romanul et al. 1977).
cific MRI findings, suggesting a direct antineuronal effect Lead intoxication may initially cause a delirium and
(Van Horn et al. 1996). upon recovery patients may be left demented (Jenkins and
Sarcoidosis may cause dementia (Camp and Frierson Mellins 1957).
1962; Sanson et al. 1996) but only in a very small minority Thalamic degeneration, a rare syndrome, may present
(fewer than 1 percent) of patients (Oksanen 1986); in such with dementia alone (Moosy et al. 1987) or dementia
cases, granulomata have been found in the cerebrum accompanied by somnolence (Stern 1939).
(Cordingly et al. 1981; Miller et al. 1988). A clue to Sleep apnea, in one extraordinary case, presented with a
the diagnosis is a chest radiograph finding of either bilat- dementia: the only clue to the diagnosis was the presence of
eral hilar lymphadenopathy or bilateral reticulonodular daytime sleepiness and a history of prominent snoring
infiltrates. (Scheltens et al. 1991).
Progressive multifocal leukoencephalopathy, as may be Bilateral carotid occlusion, the brain being perfused pri-
seen in AIDS or other immunocompromised states, typi- marily by only one vertebral artery, has been shown to cause
cally presents with a focal sign such as hemiplegia or aphasia, a dementia that was reversed by intracranial–extracranial
which is eventually joined by a gradually progressive demen- bypass surgery (Tatemichi et al. 1995).
tia (Krupp et al. 1985; Richardson 1961); rarely, the presen- Very rare causes include the hyperviscosity syndrome
tation may be with dementia alone (Sellal et al. 1996; Zunt (as occurred in one case secondary to multiple myeloma
et al. 1997). [Mueller et al. 1983]), hypereosinophilia (92 percent
Kufs’ disease, or the adult form of neuronal ceroid lipo- eosinophils) (Kaplan et al. 1990), and extreme hyper-
fuscinosis may present with a dementia which may or may triglyceridemia (with values of at least 10 times the normal
not be accompanied by myoclonus and ataxia (Burneo value) (Heilman and Fisher 1974; Mas et al. 1985).
et al. 2003)
Metachromatic leukodystrophy may, in addition to
ataxia (as noted above), also cause dementia associated Differential diagnosis
with seizures, spasticity, or chorea (Alves et al. 1986; Haltia
et al. 1980; Wulff and Trojaborg 1985); polyneuropathy Dementia must be distinguished from mild cognitive
may also be obvious (Bosch and Hart 1978). Personality impairment, delirium, mental retardation, and amnesia.
change is also prominent, especially in adults, with aggres- Mild cognitive impairment is a syndrome characterized,
siveness and irritability (Hageman et al. 1995) and ‘frontal as the name clearly suggests, by cognitive impairments
lobe’ symptoms such as disinhibition, poor judgment, and that, although similar to those seen in dementia, are so mild
socially inappropriate behavior (Shapiro et al. 1994). that they cause little in the way of impairment. As noted in
p 05.qxd 3/10/08 9:34 AM Page 173
5.2 Mild cognitive impairment 173
Section 5.2, this may or may not be a syndrome sui genereis – feel ‘at home’, for example by bringing in familiar photo-
it might just as well be thought of as a prodrome to a graphs and, where possible, furniture, and by subscribing
dementia. to the patient’s home-town paper. If patients are admitted
Delirium is distinguished from dementia by the pres- to hospital, the same measures should be undertaken; fur-
ence of prominent confusion; here, however, one must thermore, the room should have a large calendar and clock
keep in mind that some diseases may be characterized by and, whenever possible, a window with a view.
both dementia and intermittent delirium. In multi-infarct The need for prosthetic devices (e.g., glasses, hearing aids,
dementia, for example, each fresh stroke may be heralded dentures, and ‘quad canes’) should be assessed, and medical
by an episode of delirium that, once having cleared sponta- regimens should be kept as simple as possible. Although
neously, leaves the patient not confused but more many patients eventually require a wheelchair, ambulation
demented. Furthermore, some diseases, albeit characterized should be encouraged and maintained for as long as possible.
primarily by dementia, may also cause intermittent, brief, Rigorous internal medical follow-up is essential, and it
episodes of confusion, as may occur in diffuse Lewy body must be kept in mind that, in patients with dementia, even
disease. trivial intercurrent illnesses, such as an uncomplicated
Mental retardation is distinguished primarily by its urinary tract infection, may cause dramatic cognitive
course: in mental retardation, the intellectual development decrements.
of patients proceeds only to a certain point, at which it In addition to implementing treatment, where possible,
‘stalls’, leaving patients on an intellectual ‘plateau’ beyond of the underlying cause of the dementia, consideration
which they do not progress. Importantly, there is no decre- may also be given to symptomatic treatment of various
ment in intellectual ability but merely a plateauing. In con- clinical features such as agitation, delusions or hallucina-
trast, there is in dementia a definite decrement from a tions, depression, and insomnia.
previously acquired level of intellectual ability. Importantly, Agitation in dementia, as discussed in detail in Section
as noted above, some disorders may cause both mental 6.4, may respond to either risperidone or olanzapine, in low
retardation and a dementia: for example, in the setting of doses, for example 0.25–1 mg of risperidone or 2.5–7.5 mg
mental retardation secondary to Down’s syndrome, a of olanzapine; the same medications may also be effective in
dementia eventually develops in most patients who survive the treatment of delusions or hallucinations. It must be
past the age of 40. borne in mind, however, that, although safer than the first-
Amnesia is distinguished from dementia by the restricted generation antipsychotics (e.g., haloperidol) (Wang et al.
nature of the cognitive deficit: in amnestic disorders, one 2005), these second-generation agents still carry with them
finds only a deficit in memory, whereas in dementia, in an increased risk of death or stroke, especially in those
addition to a defective memory, one also finds other cogni- patients who are 80 years or older, or those treated concur-
tive deficits, for example in abstracting or calculating abili- rently with benzodiazepines (Kryzhanovskaya et al. 2006),
ties. It must be borne in mind, however, that some and, consequently, they must be used cautiously and con-
dementing conditions, such as Alzheimer’s disorder, may tinued only if the benefits are substantial.
present with a pure amnesia that persists for a prolonged Depression may be treated with an antidepressant, and
period before being joined by other cognitive deficits. consideration may be given to either citalopram or esc-
italopram, as these tend to be the best tolerated of the avail-
able agents.
Treatment Insomnia may be treated with melatonin or ramelteon;
if these are ineffective, consideration may be given to
Treatment, if possible, is directed at the underlying condi- agents such as zolpidem, with careful monitoring for any
tion, as discussed in the respective chapters. What follows daytime sedation.
here are general measures, applicable in most cases.
Patients’ liberty should be circumscribed proportionate
to their reduced abilities; thus, financial affairs should usu- 5.2 MILD COGNITIVE IMPAIRMENT
ally be managed by others and guardianship may be
required. Driving privileges are often retained by patients Mild cognitive impairment (MCI) (Gautier et al. 2006;
with great tenacity, but these too must eventually be with- Portet et al. 2006; Winblad et al. 2004) is a recently
drawn. Visiting nurses, ‘meals on wheels’ and adult day- described syndrome seen in elderly patients, characterized,
care centers should each be considered, as they help patients as the name suggests, by an impairment in cognitive ability
maintain functional abilities and enable them to stay at that, although clearly representing a departure from the
home longer. Cognitively stimulating activities should also patient’s premorbid baseline, is not severe enough to cause
be encouraged (Olazaran et al. 2004) and patients should be significant impairment in day-to-day activities; among
encouraged to do crossword puzzles, play card games, etc., those patients of 65 years or older, the prevalence of such
as these all help to preserve cognitive abilities. impairment ranges anywhere from 3 to 19 percent.
If patients have to move, for example to a retirement/ As noted below, neuropathologic studies indicate that
nursing home, efforts should be made to make the patient most of these patients suffer from an early stage of one or
p 05.qxd 3/10/08 9:34 AM Page 174
more of the common causes of dementia, most notably Treatment

Alzheimer’s disease. Given this, it may be just as accurate
to refer to these patients as being in the prodromal stage of The overall treatment of patients with MCI should begin
a dementia. with a thorough diagnostic evaluation, as discussed in the
chapters on dementia and amnesia, with every attempt
being made to determine the underlying cause; treatment
Clinical features should then proceed as for that cause. In cases of amnestic
MCI, most of which represent ‘incipient’ Alzheimer’s dis-
Cognitive impairments seen in MCI include deficits in
ease, donepezil may be given (Petersen et al. 2005); in cases
short-term memory, calculating ability, abstracting ability,
preceded by depression wherein depressive symptoms per-
visuospatial ability, etc. Of all these deficits, short-term
sist, a case may be made for treatment with an antidepres-
memory loss is the most common and, when this is seen in
sant; and when toxic factors are present, for example
isolation, one speaks of the ‘amnestic’ type of MCI. When
anticholinergic medications, these, obviously, should be
two or more deficits are present (which may or may not
discontinued.
include difficulty with short-term memory), the term
‘mixed domain’ MCI is used; when memory is intact but
some other deficit is present, one speaks of ‘single-domain
5.3 DELIRIUM
non-memory’ MCI.
Cognitive impairment typically occurs gradually, and
Delirium is one of the most common neuropsychiatric dis-
should be present for roughly a year before the diagnosis is
orders seen in general hospital practice and is especially
made. In all three types, although patients or others report
common among the hospitalized elderly (Francis 1992).
the cognitive impairment, which in turn is demonstrable
Prompt diagnosis is critical as, in many cases, the underly-
on clinical evaluation, there is nevertheless no significant
ing cause of the syndrome, untreated, carries a grave prog-
disruption to the patients’ routine daily functioning.
nosis (Cameron et al. 1987; Pompeii et al. 1994; Rabins and
Although most cases of MCI demonstrate a gradual
Folstein 1982).
progression over the years, in a minority the impairment
remains stable or undergoes improvement.
Clinical features
Etiology
Delirium, as reviewed by Lipowski (1983, 1987, 1989), is
In autopsy studies (Bennett et al. 2005; Guillozet et al. 2003; characterized by confusion, disorientation, memory loss,
Jicha et al. 2006; Petersen et al. 2006; Storandt et al. 2006), the and often other symptoms such as hallucinations and delu-
most common findings are changes typical of Alzheimer’s sions. The syndrome is typically of acute or subacute onset,
disease in medial temporal structures; other pathologies and most patients develop the full syndrome within a day
found include infarcts and diffuse Lewy body disease. or two (Levkoff et al. 1992).
There is also an association with pre-existing depression Confusion, or, as it is also known, ‘clouding of the sen-
(Barnes et al. 2006; Geda et al. 2006) and with chronic use sorium’, is the cardinal symptom of delirium and is present
of medications with anticholinergic properties (Ancelin in all cases. Patients may appear dazed, their attention
et al. 2006). wanders, and they often seem to drift off. In most cases, a
varying degree of incoherence will also be seen (Johnson
et al. 1992; Sirois 1988). Disorientation, found in almost all
Differential diagnosis cases (Morse and Litin 1971) may be for both place and
time together, or merely in one of these spheres. Memory
MCI must be distinguished from dementia and amnesia. loss is typically of the short-term or anterograde type:
One differential feature that distinguishes MCI from both patients are unable to remember all of three words after
of these is the severity of the cognitive deficits and their 5 minutes and consequently have grave difficulty in keeping
effect on activities of daily living. As noted earlier, in MCI track of what happens around them. Retrograde amnesia
the deficits are mild and tend to have little or no effect on may also be present but is generally less prominent:
day to day functioning; in contrast, in dementia and amne- patients may have trouble recalling clearly what happened
sia the deficits are of sufficient severity to cause obvious in the days or weeks prior to the onset of the delirium.
difficulties in patients’ abilities to function. Importantly, in Hallucinations are seen in about one-half of all cases
many, if not most, cases, long-term follow-up reveals a (Morse and Litin 1971) and may be either visual or, less
progression of both the severity and number of cognitive commonly, auditory (Cutting 1987; Sirois 1988). Patients
deficits to the point when a diagnosis of dementia is justi- may see family members in the hospital room, and bugs or
fied (Tschanz et al. 2006). small animals may hide in the sheets. Auditory hallucina-
Delirium is immediately distinguished from MCI by the tions range from such simple phenomena as bells or sirens
presence of confusion, which, by definition, is absent in MCI. to hearing voices.
p 05.qxd 3/10/08 9:34 AM Page 175
5.3 Delirium 175
Delusions are generally fragmentary and unsystem- of certain etiologies. Postural tremor may be seen in toxic
atized. One typically finds evidence of delusions of persecu- deliria (e.g., the serotonin and neuroleptic malignant syn-
tion (Morse and Litin 1971; Sirois 1988), and patients may dromes), metabolic deliria (e.g., uremic and hepatic
report that family members are trying to get rid of them or encephalopathy, hypoglycemia), and all of the substance
that the medicine given by the nurse is actually poison. withdrawal deliria. Myoclonus, likewise, may be seen in
The overall behavior of patients with delirium may be toxic deliria (e.g., the serotonin syndrome), metabolic
characterized by either agitation or quietude. Although, in a deliria (e.g., uremic encephalopathy, hyperglycemia), and
minority of cases, patients are either consistently hyper- certain others (e.g., Hashimoto’s encephalopathy). Asterixis
active or consistently hypoactive, one sees in most a mix – is highly suggestive of one of three metabolic deliria, namely
patients now agitated, now quiet (Johnson et al. 1992; uremic encephalopathy, hepatic encephalopathy, and respi-
Liptzin and Levkoff 1992). In some cases, one may see an ratory failure.
‘occupational delirium’ wherein patients act as if they were When, after a through history and examination, the cause
at work (Wolff and Curran 1935): one patient, a former of the delirium is not clear, one may consider a laboratory
truck driver, was found with his hands held out in front of ‘screen’. To begin with, this should include a complete blood
him as if gripping a steering wheel, busily ‘driving’ his bed count, a urinalysis, a chemistry survey (including sodium,
around the ward. Sleep reversal is common (Johnson et al. blood urea nitrogen (BUN), creatinine, glucose, calcium,
1992), and many patients display the phenomenon of ‘sun- magnesium, liver enzymes, and bilirubin) and an ammonia
downing’, wherein their confusion markedly worsens with level; an ANA and ESR may be ordered if an autoimmune
the coming of darkness. In some mild cases of delirium, disorder is suspected, and a drug screen may be considered if
patients may be relatively lucid in the morning, with obvi- intoxication seems likely. If there is any suspicion of pneu-
ous symptoms only appearing later in the day and as night monia a chest radiograph is ordered and, if respiratory failure
falls: this is an important fact to keep in mind, for such is suspected, oximetry or arterial blood gases should be con-
‘lucid intervals’ may deceive the physician making morning sidered. Neuroimaging, preferably with MR scanning, is in
rounds into thinking that the patient is cognitively intact. order if an intracranial disorder is suspected. An electroen-
cephalogram (EEG) is often ordered but, with the exception
of delirium secondary to status epilepticus, often does not
Etiology add much; as discussed in Section 1.5, generalized slowing or
FIRDA (frontal intermittent delta activity) is common in
For practical diagnostic purposes, it is useful, as laid out in toxic and metabolic deliria and in various of the intracranial
Table 5.2, to subdivide delirium into various types. First, disorders; periodic complexes are somewhat more specific,
there is toxic delirium, occurring secondary to medications indicating such disorders as hepatic encephalopathy, uremic
(e.g., opioids) or actual intoxicants (e.g., cocaine). After encephalopathy, or herpes simplex viral encephalitis. Lumbar
this, there is metabolic delirium, due to specific metabolic puncture is reserved for suspected encephalitis.
derangements (e.g., uremia), systemic effects of infections These various etiologic types of delirium are now con-
(e.g., pneumonia), or vitamin deficiencies (e.g., Wernicke’s sidered in turn, beginning with toxic delirium.
encephalopathy). Following this is substance withdrawal
delirium (e.g., delirium tremens during alcohol with- TOXIC DELIRIUM
drawal). Next one considers delirium secondary to
intracranial disorders (e.g., stroke). At this point attention is Toxic delirium, as noted above, may occur due to the
shifted to a syndrome known as post-operative delirium: toxicity of certain medications, most notably opioids, or to
this is a very common disorder, and, in most cases, repre- the effects of intoxicants per se, such as cocaine. Medications
sents, etiologically, a combination of toxic, metabolic, or are considered first.
intracranial pathologies. Finally, there is a group of other
causes, each of them relatively uncommon, including, for Medications
example, autoimmune disorders, endocrinologic disorders, In evaluating the role medications may play in a delirium it
and epileptic disorders. is essential to have an accurate listing of all of the patient’s
In general hospital practice, the vast majority of deliria medications, including both those taken on a regular basis
are toxic or metabolic in character; withdrawal delirium and those administered as needed; furthermore, one must
and delirium due to intracranial disorders are somewhat note when each medication was started, and, importantly,
less common. In working up a case, it must be kept in whether there have been any recent changes in dosage. In
mind, however, that very often the etiology is multifactorial, this regard, when evaluating hospitalized patients, it is also
and that the various factors involved may be simultaneous essential to obtain a list of home medications from a reli-
or sequential. able historian, such as a close family member. Although, as
In the physical examination it is very important to take noted further on, certain medications are more likely to
note of the presence of certain abnormal movements, cause delirium than others, virtually any medicine can be
namely, postural tremor (Section 3.1), myoclonus (Section at fault: this is particularly the case in elderly patients or
3.2), and asterixis (Section 3.12), as they are very suggestive those with pre-existing brain disease, who may be exquisitely
p 05.qxd 3/10/08 9:34 AM Page 176
sensitive to medications which, when taken by a younger with levodopa or with amantadine. Clinically, within a day
person with an intact brain, are generally innocuous. or two of the abrupt diminution of dopaminergic tone,
Confirmation of a medicine’s etiologic role rests on patients develop varying combinations of delirium, fever,
demonstrating a temporal relationship between the onset rigidity, and autonomic instability (Pope et al. 1986;
of the delirium and the initiation (or substantial dosage Rosebush and Stewart 1989; Velamoor et al. 1994).
increase) of a medicine, and the resolution of the delirium The remaining medications in the list are grouped under
subsequent to a discontinuation (or substantial dose customary headings (dopaminergic medications, cardiac
decrease) of the selfsame medicine. In assessing this tem- medications, antimetabolites, antimicrobials, anti-epileptics,
poral relationship one must keep in mind that although antidepressants and mood stabilizers, and a miscellaneous
the delirium may appear fairly promptly, often within a group); for the most part these medications have only
day or so, the resolution of the delirium may be gradual, rarely been implicated in delirium and hence a fairly strong
corresponding not only to the gradual ‘washout’ of the case would have to be made before ascribing a delirium to
offending medication, but also to the diminution of the any one of them, not only by demonstrating a clear tempo-
medication’s pharmacodynamic effects, which may persist ral relationship, but also by ruling out other, more likely
for some time longer. causes. With regard to delirium secondary to valproate, it
Of the medications listed in Table 5.2, by far the most must be kept in mind that in some cases this is associated
common offenders are the opioid analgesics (Lawlor with elevated ammonia levels (Eyer et al. 2005), and that in
et al. 2000; Tuma and DeAngelis 2000); although both these cases carnitine may be an effective treatment.
propoxyphene and tramadol can also cause delirium they It must be kept in mind that this list is not presented as
are very much less likely to do so. Medications with anti- being comprehensive; new case reports continue to appear
cholinergic effects, most notably diphenhydramine and and both new and old medicines (even those long considered
scopolamine, run a close second to the opioid analgesics: to be innocuous) continue to be implicated.
although in some cases, they may produce a full anti-
cholinergic syndrome, with, as described in Section 22.6, Intoxicants
mydriasis and dry skin, these additional features may not Delirium secondary to intoxication with illicit substances
be present. Following this is a group of medicines, such as is not uncommonly seen in the emergency room. Delirium
baclofen, which, although not carrying a high risk are so secondary to cocaine or amphetamine is suggested by agi-
commonly prescribed in some settings that they must be tation, hypertension, and mydriasis. Delirium secondary
kept clearly in mind. With regard to baclofen it must be to phencyclidine, cannabis, inhalants, and methanol is typ-
remembered that delirium may occur not only during ically accompanied by cerebellar signs, such as dysarthria
treatment with baclofen, but also after long-term use, with and ataxia.
its discontinuation.
Next are two specific syndromes, namely the serotonin METABOLIC DELIRIUM
syndrome and the neuroleptic malignant syndrome,
which, although not common, must, given their lethality, Metabolic deliria, as indicated earlier, may be due not only
be considered. The serotonin syndrome occurs secondary to to specific metabolic derangements, such as uremia, but
pharmacologically enhanced serotoninergic tone, which, also to the systemic effects of infection and to vitamin defi-
in turn, generally requires the administration of a combi- ciencies. Each of these types is considered in turn.
nation of serotoninergic agents. Of the various combina-
tions of medications reported to cause this syndrome Specific metabolic derangements
(discussed in detail in Section 22.5), the most toxic is the The specific metabolic deliria are so common that in the
combination of a selective serotonin reuptake inhibitor evaluation of delirious patients it is almost customary to
(SSRI) and a monoamine oxidase inhibitor. Clinically, the order a screening chemistry survey. In general, acute
serotonin syndrome presents with a combination of delir- derangements are more likely to cause symptoms; gradual
ium, myoclonus, dysarthria or ataxia, and hyper-reflexia changes are much better tolerated.
(Feighner et al. 1990; Sternbach 1991). The neuroleptic Uremic encephalopathy, as discussed in Section 13.18, is
malignant syndrome occurs secondary to any pharmaco- generally accompanied by both asterixis and myoclonus.
logic manipulation that leads to an abrupt diminution in In renal failure of acute onset, a BUN of over 100 is gener-
dopaminergic tone. Most commonly, such a diminution ally sufficient to cause delirium; however, in those cases
occurs secondary to the use of a dopamine blocker, such as where the renal failure is gradually progressive, much higher
one of the first-generation antipsychotics. Second-genera- levels may be tolerated before a delirium supervenes.
tion antipsychotics, such as risperidone and clozapine, Hepatic encephalopathy, discussed further in Section
may also be at fault. The neuroleptic malignant syndrome 13.19, may likewise be accompanied by asterixis and
will occasionally be seen secondary not to dopamine block- myoclonus, and one may, clinically, appreciate a character-
ade but to an abrupt discontinuation of a dopaminergic istic bad breath or fetor hepaticus. Importantly, although
agent. Thus, the neuroleptic malignant syndrome has been the ammonia level is generally elevated, cases have been
seen after an abrupt discontinuation of long-term treatment reported with normal levels.
p 05.qxd 3/10/08 9:34 AM Page 177
5.3 Delirium 177
Table 5.2 Causes of delirium

Toxic delirium Anti-epileptics
Medications Valproic acid (Beversdorf et al. 1996)
Analgesics Carbamazepine (Horvath et al. 2005)
Opioids (Crawford and Baskoff 1980; Eisendrath et al. 1987; Gabapentin (Zhang et al. 2005)
Morisy and Platt 1986; Steinberg et al. 1992) Antidepressants and mood stabilizers
Propoxyphene (Nomdedeu et al. 2001) Amitriptyline (Preskorn and Simpson 1982)
Tramadol (Kunig et al. 2006) Imipramine (Goodwin 1983)
Anticholinergics Bupropion (Ames et al. 1992)
Diphenhydramine (Agostini et al. 2001) Lithium (DePaulo et al. 1982; Kaplan et al. 2006; Simard
Scopolamine (Minagar et al. 1999; Ziskind 1988) et al. 1989)
Benztropine (De Smet et al. 1982) Valproic acid (Beversdorf et al. 1996)
Commonly prescribed Miscellaneous
Baclofen (Lee et al. 1992) Propranolol (Topliss and Bond 1977)
Baclofen withdrawal (Leo and Bar 2005) Verapamil (Jacobsen et al. 1987)
Metoclopramide (Fishbain and Rogers 1987) Interleukin 2 (Illowsky et al. 1996)
Cyclobenzaprine (Engel and Chapron 1993) Disulfiram (Hotson and Langston 1976; Kirubakaran et al.
Amantadine (Postma and Van Tilburg 1975) 1983; Knee and Razani 1974; Laplane et al. 1992)
Benzodiazepines (Marcantano et al. 1994) Gold (McCauley et al. 1977)
Dextromethorphan (Lotrich et al. 2005) Aspirin (in overdose [Steele and Morton 1986])
Specific syndromes Bismuth (Gordon et al. 1995; Jungreis and Shaumberg
Serotonin syndrome 1993; Molina et al. 1989; Supino-Viterbo et al. 1977)
Combination of serotoninergic medications (Bodner Bromide (Curran 1938; Palatucci 1978)
et al. 1995) Metrizamide (Elliot et al. 1984)
Neuroleptic malignant syndrome Intoxicants
First-generation (Keck et al. 1987; Pope et al. 1986; Cocaine (Fischman et al. 1976)
Rosebush and Stewart 1989) and second-generation Amphetamine (Hollister and Gillespie 1970)
(Meterissian 1996, Miller et al. 1991; Sachdev et al. 1995) Phencyclidine (Allen and Young 1978; Pearlson 1981)
antipsychotics Cannabis (Chopra and Smith 1974; Palsson et al. 1982)
Discontinuation of dopaminergic agents (e.g., levodopa Inhalants (Evans and Raistrick 1987)
[Sechi et al. 1984; Toru et al. 1981], amantadine Methanol (Bennett et al. 1953; Erlanson et al. 1965;
[Cunningham et al. 1991; Harsch 1987]) Wood and Buller 1904)
Dopaminergic medications
Metabolic delirium
Levodopa (Friedman and Sienkiewicz 1991)
Specific metabolic derangements
Bromocriptine (Serby et al. 1978)
Uremic encephalopathy (Raskin and Fishman 1976;
Lergotrile (Serby et al. 1978)
Stenback and Haapanen 1967; Tyler 1968)
Cardiac medications
Hepatic encephalopathy (Fraser and Arieff 1985; Read
Amiodarone (Anastasiou-Nana et al. 1986; Athwal
et al. 1961; Summerskill et al. 1956)
et al. 2003; Barry and Franklin 1999)
Respiratory failure (Austen et al. 1957; Bacchus 1958; Dulfano
Digoxin (Eisendrath and Sweeney 1987; Shear and
and Ishikawa 1965; Westlake et al. 1955)
Sacks 1978)
Obstructive sleep apnea (Lee 1998; Munoz et al. 1998; Whitney
Quinidine (Qunitanilla 1957)
and Gannon 1996)
Antimetabolites
Hyponatremia (Karp and Laureno 1993; Swanson and Iseri
Tacrolimus (Buis et al. 2002)
1958; Welti 1956)
Cyclosporine (Buis et al. 2002)
Hypernatremia (Jana and Romano-Jana 1973)
Antimicrobials
Hypoglycemia (Case records 1988a; Hart and Frier 1998;
Acyclovir (Rashiq et al. 1993; Tomson et al. 1985)
Malouf and Brust 1985; Moersch and Kernohan 1938)
Gancyclovir (Davis et al. 1990)
Hyperglycemia (Gomez Diaz et al. 1996; Khardori and
Vidarabine (Cullis and Cushing 1984)
Soler 1984)
Trimethoprim (Antonen et al. 1999)
Hypocalcemia (Denko and Kaelbling 1962, Hossain 1970)
Cefipime (Capparelli et al. 2005)
Hypercalcemia (Karpati and Frame 1964; Weizman et al.
Ciprofloxacin (Altes et al. 1989)
1979)
Oflaxacin (Fennig and Mauas 1992)
Hypomagnesemia (Fishman 1965; Hall and Joffe 1973)
Clarithromycin (Mermelstein 1997)
Hypermagnesemia (Clark and Bowen 1992)
Metronidazole (Kusumi et al. 1980)
Systemic effects of infection
Ketoconazole (Fisch and Lahad 1989)
Sepsis (Eidelman et al. 1996)
(continued)
p 05.qxd 3/10/08 9:34 AM Page 178

Pneumonia (Johnson et al. 2000) Autoimmune disorders
Urinary tract infection (Manepalli et al. 1990) Systemic lupus erythematosus (Ainiala et al. 2001; Johnson and
Vitamin deficiencies Richardson 1968; O’Connor and Musher 1966)
Wernicke’s encephalopathy (Harper 1983) Polyarteritis nodosa (Ford and Siekert 1965)
Encephalopathic pellagra (Ishii and Nishihara 1981; Hashimoto’s encephalopathy (Bohnen et al. 1997;
Serdaru et al. 1988) Ghika-Schmid et al. 1996; Henchey et al. 1995; Shaw
Substance withdrawal delirium et al. 1991; Thrush and Boddie 1974)
Delirium tremens (Isbell et al. 1955; Lundquist 1961; Limbic encephalitis (Alamowitch et al. 1997; Antoine et al.
Nielsen 1965; Rosenbaum et al. 1941) 1995; Brennan and Craddock 1983; Case records 1988b;
Benzodiazepine withdrawal (Heritch et al. 1987. Levy 1984, Glaser and Pincus 1969)
Zipursky et al. 1985) Endocrinologic disorders
Barbiturate withdrawal (Fraser et al. 1958; Isbell et al. 1950) Adrenocortical insufficiency (Engel and Margolin 1941;
Gamma-hydroxybutyric acid (Snead et al. 2005) Fang and Jaspan 1989)
1-4 butanediol and gamma butyrolactone withdrawal Cushing’s syndrome (Kelly 1996; Kawashima et al. 2004)
(Catalano et al. 2001) Thyroid storm (Friedman and Kanzer 1937)
Gabapentin withdrawal (Pittenger and Desan 2007) Epileptic disorders
Complex partial status epilepticus (Mayeux and Lueders
Intracranial disorders 1978; Narayanan et al. 2007; Rennick et al. 1969; Sheth
Stroke (see text for references) et al. 2006; Tomson et al. 1992)
Microembolism syndromes Petit mal status epilepticus (Narayanan et al. 2007; Tucker
Cardiac catheterization (Karalis et al. 1996) or coronary and Forster 1958, Zappoli 1955)
artery bypass grafting (McKhann et al. 2002; Wityk Post-ictal state (after grand mal or complex partial
et al. 2001) seizure)
Multiple cholesterol emboli syndrome (Ezzeddine Miscellaneous causes
et al. 2000) Migraine (Gardner et al. 1997)
Fat embolism syndrome (Jacobson et al. 1986) Heat stroke (Yaqub and Al Deeb 1998)
Infectious and related disorders Malaria (Blocker et al. 1968)
Acute encephalitis (Chaudhuri and Kennedy 2002) Hepatic porphyria (Cross 1956; Goldberg 1959; Hierons
Abscess (e.g., bacterial [Jefferson and Keogh 1977]) 1957; Maramattom et al. 2005)
Acute disseminated encephalomyelitis (Dolgopol et al. Pancreatitis (Estrada et al. 1979; Menza and Murray 1989)
1955; Giffin et al. 1948; Miller et al. 1956; Tenenbaum Heavy metal intoxication
et al. 2002) Lead (Akelaitis 1941; Morris et al. 1964; Whitfield et al.
Progressive multifocal leukoencephalopathy (Astrom et al. 1958; 1972)
Davies et al. 1973; Richardson 1961; Sponzilli et al. 1975) Thallium (Bank et al. 1972; Reed et al. 1963)
Global hypoxic-ischemic disorders Arsenic (Freeman and Couch 1978; Jenkins 1966)
Cardiac arrest, severe hypotension (Barcroft 1920) Tin (Feldman et al. 1993; Wu et al. 1990)
Carbon monoxide intoxication (Finck 1966) Inherited disorders of urea cycle metabolism with
Delayed post-anoxic encephalopathy (Choi 1983; hyperammonemia (ornithine transcarbamylase deficiency
Gottfried et al. 1997; Norris et al. 1982; Plum et al. 1962) [Hu et al. 2007] and citrullinemia [Wong et al. 2007])
Traumatic brain injury (Rao and Lyketsos 2000) Celiac disease (Hadjivassiliou et al. 2001; Hu et al.
Miscellaneous disorders 2006)
Tumors Marchiafava–Bignami disease (Bohrod 1942; Ironside
Temporal lobe (Keschner et al. 1936) et al. 1961; Kamaki et al. 1993; Koeppen and Barron 1978;
Hypothalamus (Alpers 1940) Rosa et al. 1991)
Brainstem (Wallack et al. 1977) Behçet’s syndrome (Akman-Demir et al. 1993; Serdaroglu
Hypertensive encephalopathy (Chester et al. 1978; Healton et al. 1989)
et al. 1982; Oppenheimer and Fishberg 1928) Wegener’s granulomatosus (Nishino et al. 1993; Weinberger
Reversible posterior leukoencephalopathy (Hinchey et al. 1996) et al. 1993)
Thrombotic thrombocytopenic purpura (Bakshi et al. 1999; Granulomatous angiitis (Hughes and Brownell 1966; Koo
Druscky et al. 1998; Silverstein 1968) and Massey 1988; Vollmer et al. 1993)
Central pontine myelinolysis (Adams et al. 1959; Sarcoidosis (Douglas and Maloney 1973; Silverstein and
Brunner et al. 1990; Karp and Laureno 1993) Siltzbach 1965; Wiederholdt and Siekert 1965)
Post-operative delirium (see text for references) Rheumatoid arthritis with pachymeningitis (Starosta and
Other causes Brandwein 2007)
p 05.qxd 3/10/08 9:34 AM Page 179
5.3 Delirium 179
Respiratory failure, as may be seen in pneumonia or acutely, whereas levels as high as 18 mg/dL may be toler-
decompensated chronic obstructive pulmonary disease ated if reached very gradually.
(COPD), generally produces a delirium when the PaO2 falls
below 50 mmHg; CO2 levels are not as reliable a guide in Systemic effects of infection
this regard: although acute rises to 70 mmHg may be asso- Although an association between sepsis and delirium is
ciated with delirium, levels of 90 mmHg or more may be well known, it is perhaps not as well appreciated that less
tolerated if reached gradually. In cases where the delirium is severe infections can also cause delirium. This is especially
secondary to elevated CO2 levels, patients may appear the case in the elderly, as for example in the case of pneu-
intoxicated, a phenomenon that accounts for the old term monia or even uncomplicated urinary tract infections.
for this condition, namely ‘CO2 narcosis’. Indeed, in the author’s experience, several cases of urinary
Obstructive sleep apnea may be accompanied by delir- tract infection have presented with delirium. In all likeli-
ium, not only during nocturnal awakenings, but also while hood, the delirium is mediated by cytokines (Reichenberg
the patient is awake during the day, and this appears to be et al. 2001).
particularly common in stroke patients early in their
recovery (Sandberg et al. 2001). Although the mechanism Vitamin deficiencies
underlying the daytime delirium is not clear, it is probably Of the vitamin deficiencies seen in malnourished patients,
related to nocturnal hypoxemia and hypercarbia. two are typified by delirium: namely Wernicke’s
Hyponatremia, most commonly seen, in hospital set- encephalopathy and encephalopathic pellagra.
tings at least, as part of the syndrome of inappropriate Wernicke’s encephalopathy, occurring secondary to thi-
antidiuretic hormone (ADH) secretion, generally is not amine deficiency, although most commonly seen in alco-
associated with delirium until the sodium level falls to holics, may occur secondary to thiamine deficiency of any
120 mEq/L; although gradually developing falls to this level cause, including fasting (Frantzen 1966), prolonged vomit-
may be tolerated, falls below 110 mEq/L are generally ing (as in post-gastric restriction surgery [Abarbanel et al.
symptomatic. 1987; Paulson et al. 1985]), or prolonged intravenous feeding
Hypernatremia, typically seen in the setting of dehydra- without adequate thiamine supplementation (Vortmeyer
tion, may, if of acute onset, cause a delirium when the et al. 1992). Although most of us were taught to look for the
sodium level reaches 160 mEq/L; gradual rises are better classic ‘triad’ of delirium, ataxia, and nystagmus, this combi-
tolerated, and some patients may not experience delirium nation is, in fact, the exception (Cravioto et al. 1961), and
even with levels of 170 mEq/L. most patients with Wernicke’s encephalopathy present with
Hypoglycemia may cause autonomic symptoms, such delirium alone (Harper et al. 1986). The recognition of this
as anxiety, tremor, and diaphoresis, but these may or may syndrome is critical: treated promptly, patients may survive
not be present in cases of hypoglycemia-associated delir- without sequelae; untreated, or with delayed treatment,
ium; in any case, cognitive dysfunction generally does not patients may recover but be left with a permanent
appear until the blood glucose level falls below 50 mg/dL, Korsakoff’s syndrome (Malamud and Skillicorn 1956).
or lower, if the fall is gradual. Pellagra, due to niacin deficiency, occurs in two forms.
Hyperglycemia of sufficient degree to cause delirium is The chronic form is characterized by the classic ‘three Ds’
generally only found in either diabetic ketoacidosis or the of dementia, dermatitis, and diarrhea. By contrast, the
hyperglycemic, hyperosmolar, non-ketotic syndrome. In acute, ‘encephalopathic’ form is marked by delirium, mild
diabetic ketoacidosis delirium may appear with blood glu- parkinsonism, and dysarthria.
cose levels in the range of 300 to 700 mg/dL, whereas in the
hyperglycemic, hyperosmolar, non-ketotic syndrome the SUBSTANCE WITHDRAWAL DELIRIUM
range associated with cognitive dysfunction is higher, from
600 mg/dL up to an astounding 2000 mg/dL. Withdrawal from alcohol, benzodiazepines, or barbitu-
Hypocalcemia of sufficient degree to cause delirium is rates may produce a syndrome of delirium accompanied
generally associated with muscle cramping and tetany. by autonomic signs such as postural tremor, diaphoresis,
Acute falls to 8 mg/dL may cause symptoms, whereas grad- and tachycardia. This diagnosis, sadly, is often missed.
ual falls to 6 mg/dL may be well tolerated. Alcoholics in delirium tremens may deny using alcohol to
Hypercalcemia is typically associated with nausea, vom- excess, and their relatives are often complicit in this denial,
iting, constipation, and abdominal pain; delirium may and the same holds true for those abusing benzodiazepines
supervene when the level rises above 16 mg/dL. or barbiturates. Both benzodiazepines and barbiturates
Hypomagnesemia typically does not cause symptoms may also be taken in high doses for therapeutic reasons,
until the level falls below 1.2 mg/dL; given that magnesium and when writing admission orders it is not uncommon
is required for the release of parathyroid hormone, there is for physicians not to order these home medications, even
often an associated hypocalcemia. although aware of them, on the belief that they are ‘not
Hypermagnesemia, generally occurring only with needed’.
increased magnesium intake in the presence of renal fail- Gamma hydroxybutyrate is now available on prescrip-
ure, may cause delirium at a level of 6 mg/dL if reached tion for treatment of cataplexy, but it is not appreciated by
p 05.qxd 3/10/08 9:34 AM Page 180
many physicians that a withdrawal delirium, similar to delir- Cardiac catheterization or coronary artery bypass graft
ium tremens, may occur upon its abrupt discontinuation. surgery may be followed by an encephalopathy. In these
Two related compounds, namely 1-4 butanediol and cases, the ascending aorta is generally severely arterioscle-
gamma butyrolactone, taken illicitly, carry the same liability. rotic, and multiple minute emboli are released either as a
Gabapentin, used chronically and in high dosage, may catheter scrapes by or during cross-clamping of the aorta.
also, if abruptly discontinued, cause delirium. Typically, patients are found to be delirious upon recovery
from anesthesia, and diffusion-weighted MRI will reveal
INTRACRANIAL DISORDERS multiple small infarcts.
The multiple cholesterol emboli syndrome may occur
Various intracranial disorders may present with delirium, after cardiac catheterization, coronary artery bypass graft-
including stroke, various microembolic syndromes (e.g., ing, or carotid catheterization. In this syndrome, multiple
after coronary artery bypass grafting), infectious and related cholesterol crystals embolize from atherosclerotic plaques
disorders, global hypoxic-ischemic disorders, traumatic brain and eventually lodge in the brain. This syndrome, clini-
injury, and a group of miscellaneous disorders, such as cally, differs from that seen with embolization of athero-
tumors. Stroke will be considered first. sclerotic debris in that the onset of the encephalopathy is
typically delayed for a day or so, corresponding to the time
Stroke required for the development of an inflammatory response
In cases of delirium of acute onset wherein there is no obvious to these crystals; furthermore, one typically also finds evi-
cause, consideration should be given to stroke. Delirium dence of embolization to the kidneys, with renal failure,
has been noted with territorial infarction in the area of dis- and to the lower extremities, with livedo reticularis.
tribution of the following arteries: right middle cerebral The fat embolism syndrome represents an uncommon
artery (primarily the inferior division with infarction of the complication of fractures of the long bones or trauma to
temporal cortex [Caplan et al. 1986], but also the superior fatty tissues; in both instances, globules of fat pass via the
division with infarction of the frontal cortex [Mori and venous circulation first to the lungs, causing dyspnea, and
Yamdori 1987]), the left posterior cerebral artery (with thence to the brain, causing multiple microinfarcts and an
infarction of the inferomedial aspect of the left temporal encenphalopathy.
lobe [Medina et al. 1974]), and the right posterior cerebral
artery (with infarction of the inferomedial aspect of the Infectious and related disorders
right temporal lobe) (Devinsky et al. 1988b; Medina et al. The acute appearance of a delirium in the context of
1974). Delirium has also been noted with lacunar infarction headache and fever, especially if accompanied by seizures
of the thalamus (Fromm et al. 1985; Kumral et al. 2001; or focal signs, should immediately suggest the diagnosis of
Perren et al. 2005), either unilaterally (on the left [Graff- acute encephalitis, cerebral abscess, or post-infectious
Radford et al. 1984] or the right [Friedman 1985]) or bilat- encephalomyelitis.
erally (Bogousslavsky et al. 1988; Giannopoulos et al. 2006). Acute encephalitis, as discussed further in Section 7.6., is
The diagnosis of delirium due to infarction is typically generally due a viral infection, such as herpes simplex or one
suspected when there are associated deficits, such as hemi- of the arboviruses; rarely one may see a bacterial encephali-
plegia. Unfortunately for the diagnostician, in many cases, tis, as for example with Rocky Mountain spotted fever.
especially when it is the temporal lobe that is infarcted, Abscesses, whether bacterial or mycotic, may also cause
there may be no obvious signs, such as hemiplegia, and, delirium, and this is more likely in cases of multiple abscesses.
although patients may indeed have other signs (such as Acute disseminated encephalomyelitis is probably an
hemianopia or various agnosias) their confusion may be so autoimmune disorder, triggered by a preceding, usually
great as to preclude examination. It cannot be stressed viral, infection. Within days to weeks after the infection,
enough that delirium, in itself, may at times be a ‘focal’ patients develop an illness very similar to that seen with
sign, indicating acute damage to the temporal lobe. acute encephalitis.
Another disorder to consider here is progressive multi-
Microembolism syndromes focal leukoencephalopathy. This is an uncommon disor-
A ‘shower’ of microemboli to the cerebrum may cause der, generally seen only in immunosuppressed patients,
multiple microinfarcts and present as a delirium, with or occurring secondary to infection by the JC virus; the onset,
without obvious focal signs, such as hemiplegia. The in contrast with the disorders just discussed, is generally
emboli themselves may be composed of various materials: subacute or gradual, and is characterized, initially, by pro-
atherosclerotic debris may be released from plaques of the gressively worsening focal signs; delirium supervenes only
ascending aorta during cardiac catheterization or coronary in a small minority of cases.
bypass graft surgery; cholesterol emboli may be released
during coronary or carotid catheterization to produce the Global hypoxic-ischemic disorders
multiple cholesterol emboli syndrome; and fat emboli may Global hypoxia or ischemia, if sustained for more than a few
be released into the venous circulation with fractures of the minutes, will cause a variable degree of cortical necrosis. In
long bones to produce the fat embolism syndrome. those who survive and emerge from coma, a delirium is
p 05.qxd 3/10/08 9:34 AM Page 181
5.3 Delirium 181
seen; over time the confusion gradually resolves either leav- although in common usage, may be a little misleading as it
ing patients completely recovered or with a dementia known appears to designate a specific entity, whereas in fact delir-
as post-anoxic encephalopathy. In general hospital practice ium seen post-operatively, rather than being an entity sui
the most common causes of such global hypoxia or ischemia generis, merely results, as noted earlier, from one or more
are cardiac arrest or severe and sustained hypotension, as toxic, metabolic, or intracranial disorders occurring intra-
may be seen intraoperatively or during sepsis. or post-operatively.
Carbon monoxide, by binding with hemoglobin and Although post-operative delirium can occur in any
displacing oxygen, also leads to tissue hypoxia, causing patient, regardless of age or premorbid status, it is most
delirium and headache. commonly seen in the elderly and in those with pre-existing
Those who recover from a global hypoxic insult are at cognitive impairment (Litaker et al. 2001).
risk for the development of a delayed post-anoxic leuko- It is imperative to determine the etiology of the delir-
encephalopathy. This is an autoimmune disorder, triggered ium, and in this regard it must be kept in mind that most
by cellular damage during the preceding hypoxic insult; cases are multifactorial. Toxicity secondary to medications
clinically, within days to months after the initial hypoxic is very common, being seen especially with opioids and
delirium, patients redevelop a delirium, often accompanied benzodiazepines (Marcantoni et al. 1994) and with any
by incontinence, extensor plantar responses, and a move- medications with anticholinergic properties (Mach et al.
ment disorder – either parkinsonism or, less commonly, 1995; Tune et al. 1981). Metabolic factors (Yildizeli et al.
chorea or dystonia. 2005) commonly seen include uremia, hepatic failure, res-
piratory failure, and significant elevations or depressions
Traumatic brain injury of sodium or glucose. Pneumonia, line infections, or uri-
Traumatic brain injury, as discussed in Section 7.5, is char- nary tract infections may contribute to the delirium via
acterized pathologically by various intracranial injuries, their systemic effects. Unrecognized alcoholism or benzo-
including diffuse axonal injury, cerebral contusions, sub- diazepine dependence is not uncommon, and patients may
dural hematomas, etc. Clinically, patients who do recover develop withdrawal delirium; furthermore, malnourished
consciousness will be delirious for a variable period of time alcoholics are at risk for Wernicke’s encephalopathy.
and may, eventually, be left with a dementia. Intracranial disorders, seen particularly after cardiac sur-
gery, such as valve replacement or coronary artery bypass
Miscellaneous disorders grafting, include stroke and microembolism of atherosclerotic
Tumors, if appropriately situated, for example in the tem- debris or cholesterol crystals. Hypoxic–ischemic injury is not
poral lobe, hypothalamus or brainstem, may cause a delir- uncommon and the operative report should be inspected for
ium, which, in contrast with most other deliria, will be of any episodes of significant hypotension or blood loss.
subacute or gradual onset, in keeping with the relatively
slow growth of the responsible tumor. Focal signs may or
may not be present. Other causes
Hypertensive encephalopathy may occur in the setting
of an acute elevation of diastolic pressure, generally to The other causes of delirium may be heuristically grouped
130 mmHg or more; patients present over a day or so with into autoimmune disorders, endocrinologic disorders,
headache, nausea and vomiting, delirium, blindness (or epileptic disorders, and, finally, a large, heterogeneous
mere visual blurring) and, in many cases, seizures. group of miscellaneous causes.
The reversible posterior leukoencephalopathy syndrome Of the autoimmune disorders, the most important to keep
presents in a fashion similar to hypertensive encephalopathy, in mind is systemic lupus erythematosus. In this disease,
and is strongly associated with use of various antimetabolites, delirium may occur secondary to infarction or to a lupus
such as tacrolimus, cyclosporine, vincristine, and others. cerebritis, and this diagnosis should be considered whenever
Thrombotic thrombocytopenic purpura (TTP), gener- a delirium occurs in the setting of constitutional symptoms,
ally seen in young or middle-aged adults, is characterized by arthralgia, rashes, pleurisy, pericarditis, and various cyto-
delirium, transient focal signs and thrombocytopenia, with penias. Polyarteritis nodosa may cause delirium secondary to
a platelet count below 30 000; other features include fever, multiple cerebral infarctions and, as in lupus, the delirium
renal failure, and purpura. The delirium itself typically generally occurs in the context of constitutional symptoms.
shows a marked fluctuation in severity throughout the day. Hashimoto’s encephalopathy is a very important cause of
Central pontine myelinolyis, occurring days after the delirium, given its treatability, and should be suspected
overly rapid correction of chronic hyponatremia, typically when delirium occurs concurrent with myoclonus, ataxia,
presents with delirium and a flaccid quadriparesis; uncom- or stroke-like episodes. Limbic encephalitis, a paraneopla-
monly, the presentation may be with delirium alone. stic syndrome, may present with delirium alone, and, impor-
tantly, may constitute the presentation of the underlying
Post-operative delirium malignancy; the diagnosis is often entertained in cases of
Delirium is seen in a significant minority of patients after delirium of unknown cause in middle-aged or elderly
major operations. The term ‘post-operative delirium’, patients, especially those at risk for cancer.
p 05.qxd 3/10/08 9:34 AM Page 182
Endocrinologic disorders only rarely directly cause delir- A differential point is confusion: aphasic patients, despite
ium. Adrenocortical insufficiency is suggested by postural their incoherence, are generally focused and appear
dizziness and nausea and vomiting, Cushing’s syndrome attuned to events in their environment; in contrast, deliri-
by moon facies, truncal obesity, and violaceous abdominal ous patients, with their confusion, appear dazed and have
striae, and thyroid storm by proptosis, postural tremor, great difficulty attending to events around them.
tachycardia, and restlessness. Amnesia, like dementia and sensory aphasia, is distin-
Epileptic disorders characterized by delirium include sta- guished by an absence of confusion. In some cases, how-
tus epilepticus of the complex partial or petit mal types, ever, a single underlying pathology may initially present
and the post-ictal state. Status epilepticus is suggested by with a delirium, which, upon resolution, leaves the patient
the exquisitely paroxysmal onset of the delirium, over sec- with an amnesia. A familiar example is thiamine defi-
onds, and a history of epilepsy, and is confirmed by an ictal ciency, which, acutely, causes the delirium of Wernicke’s
EEG. It is important to keep in mind that these episodes of encephalopathy, and which, upon resolution, leaves the
status can last for hours, days, or even longer. The post- patient with the amnestic Korsakoff’s syndrome.
ictal state, after either a grand mal or a complex partial Psychosis, although primarily characterized by delu-
seizure, is immediately suggested by the preceding seizure. sions and hallucinations, may, when severe, also be charac-
The miscellaneous causes listed in Table 5.2 constitute terized by confusion. A common example is the psychosis
rare causes of delirium but should be considered when the of schizophrenia: here, during periods of exacerbation,
diagnostic work-up has been unrevealing. confusion may be quite severe. It is not clear whether or
not one should consider this development of confusion,
DIFFERENTIAL DIAGNOSIS nosologically, as merely part of the psychosis, or whether
one should make a diagnosis of psychosis with superim-
Delirium must be distinguished from dementia, sensory posed delirium. Certainly, if the confusion persists after
aphasia, amnesia, and psychosis. treatment of the psychosis when the delusions and halluci-
Dementia is distinguished by an absence of significant nations have cleared then it would be appropriate to con-
confusion. As noted earlier, confusion is the cardinal sider a ‘dual’ diagnosis and proceed with a work-up as
symptom of delirium: both delirium and dementia are described above.
characterized by memory deficits, disorientation, etc., but
only in delirium does one find prominent and persistent
confusion. At times, however, one may find dementia and Treatment
delirium in the same patient. Pre-existing brain damage of
any sort makes patients more sensitive to various toxic and Concurrent with symptomatic treatment, as described
metabolic insults (Koponen and Riekkinen 1993; Koponen below, it is imperative to pursue a vigorous diagnostic
et al. 1989; Layne and Yudofsky 1971; O’Keefe and Lavan investigation and, if possible, treat the underlying cause.
1997), and it is not uncommon to find a patient with Symptomatic treatment, in all cases, involves environ-
dementia, for example due to Alzheimer’s disease or multi- mental measures; symptomatic pharmacologic treatment
infarct dementia, promptly becoming delirious upon com- may also be required in ‘noisy’ deliria when agitation is
ing being given an opioid analgesic or coming down with prominent, and in cases where delusions or hallucinations
pneumonia. Furthermore, some disorders capable of caus- impel patients to dangerous behaviors.
ing dementia may also, at times, of themselves, cause con- Environmental measures are aimed at enabling
fusion. This is perhaps most problematic, from a diagnostic patients, as much as possible, to stay ‘in touch’ with the
point of view, in cases of diffuse Lewy body disease, environment and the current situation. Large calendars
wherein patients, once demented, are prone to develop and digital clocks should be kept in full view, and the
transient episodes of confusion, lasting perhaps hours, importance of having a window in the room cannot be
which then resolve spontaneously. Another common overstated (Wilson 1972). At night, the room should be as
example is multi-infarct dementia, wherein the dementia quiet as possible, and nursing procedures that can be
is, as it were, punctuated by an episode of confusion occur- delayed to the daylight hours should be. A night-light
ring with each fresh infarction: as the peri-infarct edema should be left on, and a nurse’s call button should be
resolves, the delirium clears, leaving the patient one cogni- within easy reach. In some cases, for example when con-
tive ‘step’ further down. Finally, in the end-stage of most fused patients are apt to get out of bed and either wander
neurodegenerative disorders, most patients gradually off, or perhaps slip and fall, sitters may be required.
develop a persistent confusion: whether, nosologically, this Pharmacologic treatment, as discussed further in Section
should be considered merely an extension of the dementing 6.4, may involve use of either risperidone or haloperidol. In
process or the transition of a dementia into a delirium, emergent situation, one may begin with either risperidone
may be a moot point. (as the concentrate) in a dose of from 0.25 to 1 mg, or
Sensory aphasia is characterized by incoherence and haloperidol, 1–5 mg (either as the concentrate or parenter-
hence these patients with this condition appear similar to ally, using roughly half the oral dose), with repeat doses
those delirious patients who also demonstrate incoherence. every 1–2 hours until the patient is out of danger, limiting
p 05.qxd 3/10/08 9:34 AM Page 183
5.4 Amnesia 183
side-effects occur, or one reaches a maximum dose (approx- are formed, and, as it were ‘stored’, they may, with a greater
imately 5 mg of risperidone or 20 mg or haloperidol). The or lesser degree of difficulty, be recalled. Amnesia may
patient should then be started on a regular daily dose, affect either one of these aspects of memory: when there is
roughly equivalent to the total amount required in p.r.n. difficulty in forming new memories, one speaks of ‘antero-
doses, with an order for repeat doses on as needed basis; on grade’ amnesia, and when there is difficulty in summoning
subsequent days, the total daily dose should be adjusted up memories one speaks of ‘retrograde’ amnesia.
based on the clinical situation and on the amount required in Anterograde amnesia is often also referred to as ‘short-
p.r.n. doses over the preceding 24 hours. In non-emergent term’ memory loss, and is tested for, formally, by giving
situations, one may begin with risperidone in a dose of patients three words to remember, having them repeat
0.5–1 mg or haloperidol in doses of from 2 to 5 mg, with them once, and then, after 5 minutes spent on other items,
subsequent dosage adjustments made on a daily basis. Other coming back and asking patients to recall the three words,
antipsychotics, for example, quetiapine, although not as yet noting how many are accurately recalled: normally, all
proven effective in blinded studies, are, in fact, used with three are remembered. Informally, one may find during
success, and may be considered. Quetiapine may be given in the interview that patients with short-term memory loss
emergent situations in doses of 25 mg orally every 2–3 hours repeat the same question they asked minutes earlier, as
until one of the end-points just described, with the maxi- they have no recall of the answer that had been provided.
mum total dose being roughly 200 mg; in non-emergent sit- Retrograde amnesia is also referred to as ‘long-term’
uations one may begin with quetiapine in a dose of from memory loss, and is tested for during the interview by a
25 to 75 mg, with subsequent daily adjustments. Lorazepam series of questions, focusing on memories of autobio-
is often used in general hospital practice; however, as pointed graphic events successively more distant in the past. Thus,
out in Section 6.4, blinded work suggests that the side-effects one may ask patients what they had for breakfast, what
of lorazepam may outweigh any benefits. brought them to the hospital, how they had spent the past
In some cases, restraints may be required: one should few weeks, where they lived, went to school, etc.; long-term
not be shy about ordering these, as they may be life-saving. memory for public events may similarly be tested by asking
about current newsworthy events or by asking patients to
name the last four presidents.
5.4 AMNESIA There are three different types of amnestic syndromes.
The first is constituted by transient episodes characterized
Memory is technically divided into two broad types: mem- by anterograde amnesia with a variable retrograde compo-
ory for how things are done (known as procedural mem- nent. The second type is chronic and characterized not
ory) and memory for things that have happened in the past only by an anterograde component but also by a promi-
(known as declarative memory). An example of procedural nent retrograde one. The third is quite rare, and is charac-
memory would be one’s ability to remember how to ride a terized primarily by a deficit in retrograde memory. Each
bicycle or play a piano, and examples of declarative mem- of these is now considered in turn.
ory include one’s ability to remember what happened
5 minutes earlier, a day earlier, or years ago. These two types EPISODIC ANTEROGRADE AMNESIA
of memory are quite distinct, and procedural memory may
Episodes of anterograde amnesia typically begin abruptly
remain intact in cases of profound deficits in declarative
and generally resolve in less than a day. During the episode,
memory (Cavaco et al. 2004). From a clinical point of view,
patients are unable to keep track of what is happening, and
disorders of declarative memory are most important, and
are unable to recall three out of three words after 5 minutes.
this section focuses on these.
There may also be a retrograde component, in that patients
Defective memory may or may not be accompanied by
may have difficulty recalling what happened in the minutes
other cognitive deficits, such as confusion or deficits in
or hours (and sometimes months or years) just prior to the
abstracting or calculating abilities; when other deficits are
onset of the episode. Once the episode terminates, patients
present, consideration, as discussed below under
are once again able to keep track of ongoing events, and are
‘Differential diagnosis’, should be given to a diagnosis of
able to recall three out of three words after 5 minutes; fur-
syndromes such as delirium or dementia. This section
thermore, they are able to recall events that happened up
focuses on amnesia as a specific syndrome, characterized
until, or just before, the episode began. Notably, however,
by a more or less isolated and ‘pure’ memory deficit.
they are unable to recall what happened while they were in
the episode: looking back, it is as if there is an ‘island’ of
amnesia, a period of time for which they have no recall.
Clinical features
CHRONIC ANTEROGRADE AMNESIA WITH A
New memories are formed on an ongoing basis and this RETROGRADE COMPONENT
process may occur either automatically or as a matter of
effort, for example when one ‘pays attention’ to something Depending on the underlying cause, as discussed further
in an attempt to ‘commit’ it to memory. Once memories on, this type of amnesia may have either a relatively acute
p 05.qxd 3/10/08 9:34 AM Page 184
onset (e.g., after infarction of the temporal lobes) or a Table 5.3 Causes of amnesia
gradual one (e.g., when due to a neurodegenerative disor- Episodic anterograde amnesia
der such as Alzheimer’s disease). Upon examination one Transient global amnesia
finds that patients are unable to keep track of ongoing Pure epileptic amnesia
events and unable to recall three out of three words after 5 Blackouts
minutes. Furthermore, they will have difficulty recalling Concussion
events of the more distant past, events which, before falling Transient ischemic attacks
ill, they were able to recall without difficulty. This retro- ‘Transient tumor attacks’
grade component often exhibits a ‘temporal gradient’ in
that the patients’ recall, although perhaps quite poor for Chronic anterograde amnesia with a retrograde
component
relatively recent events, becomes progressively better for
Korsakoff’s syndrome
events progressively more distant in the past (Albert et al.
Stroke
1979; Seltzer and Benson 1974).
Temporal lobe
Thalamus
RETROGRADE AMNESIA Tumors
Limbic encephalitis
This is a very rare, and quite unusual, type of amnesia.
Neurodegenerative disorders
Premorbidly, patients have no difficulty in remembering
Alzheimer’s disease
events of their past; once having fallen ill, however, they are
Pick’s disease
unable to summon up memories of past events: one
Frontotemporal dementia
patient commented that it was as if his memories had been
Traumatic brain injury
‘destroyed’. Remarkably, in the face of this severe retro-
Global hypoxic injury
grade memory deficit, patients retain anterograde capabil-
Encephalitis
ities, and are able to keep track of ongoing events and to
Status epilepticus
recall all three out of three words after 5 minutes.
Certain neurosurgical procedures
Retrograde amnesia
Etiology Epileptic
The various causes of amnesia are listed in Table 5.3, and Herpes simplex encephalitis
discussed in detail below, beginning with the episodic
anterograde amnesias.
EPISODIC ANTEROGRADE AMNESIA (Butler et al. 2007; Lee et al. 1992; Palmini et al. 1992;
Stracciari et al. 1990). These amnestic episodes differ from
Transient global amnesia (discussed further in Section those of transient global amnesia in that they are of hyper-
10.18) is the prototype of episodic anterograde amnesia. acute, or paroxysmal, onset, relatively brief, and may not
This condition usually has an onset in the seventh decade be accompanied by anxious questioning on the patient’s
of life and is characterized by the appearance of one or part. Furthermore one typically finds evidence of either
more episodes, lasting anywhere from 4 to 18 hours, and complex partial or grand mal seizures in the history.
sometimes longer, during which there is a dense antero- Blackouts (Goodwin 1971; Goodwin et al. 1969a,b) may
grade amnesia coupled with a retrograde amnesia of vari- complicate moderate or severe alcohol intoxication, and
able duration, from hours to decades (Hodges and Ward although characteristic of chronic alcoholism, they may at
1989; Kritchevsky and Squire 1989; Kushner and Hauser times be seen in normal subjects. The patients themselves
1985; Miller et al. 1987; Quinette et al. 2006; Shuttleworth are generally not aware anything is amiss, and apart from
and Morris 1966). Characteristically during the episode, other evidence of intoxication (e.g., dysarthria), others
patients, although not confused, may repeatedly ask what may not be able to discern any problem either. The next
is happening. Recovery is typically complete except for an day, however, patients may find that they have no memory
‘island’ of amnesia extending backwards in time from of the night before, and may anxiously (and often circum-
when the episode resolved to perhaps an hour or two spectly) ask others what happened. Importantly, although
before the episode began. In some cases, it appears that the alcohol is the usual culprit, blackouts may also occur with
episode is precipitated by some emotionally laden event, benzodiazepines, especially those of high potency, such as
such as sexual intercourse or an argument (Fisher 1982; triazolam (Greenblatt et al. 1991).
Kushner and Hauser 1985). Concussion, as may occur after minor head injury (Fisher
Pure epileptic amnesia (discussed further in Section 7.3) 1966) or whiplash (Miller 1982), may be accompanied by a
represents a partial seizure characterized solely by a combi- dense anterograde and variable retrograde amnesia, and
nation of anterograde and variable retrograde amnesia upon recovery, the patient is left with the typical ‘island’ of
p 05.qxd 3/10/08 9:34 AM Page 185
5.4 Amnesia 185
amnesia, extending back from the time of recovery to, gener- 1990; Malamut et al. 1992; von Cramon et al. 1985), the
ally, either the injury itself or a short time before that. In one anterior thalamic nuclei (Pepin and Auray-Pepin 1993),
famous example (as reported in the New York Daily News of and perhaps the mediodorsal nucleus (Clarke et al. 1994;
3 August 1928), Gene Tunney, a heavyweight contender, Gorelick et al. 1988). Turning next to the temporal lobes,
recalled nothing of a boxing match even though he won the temporal lobectomy may cause amnesia (Penfield and
fight. He later decided to quit boxing before a blow would, as Mathieson 1974), and lesions confined to the hippocam-
he put it, ‘permanently hurt my brain’. pus (Duyckaerts et al. 1985), specifically fields CA1 and
Transient ischemic attacks may be characterized in CA2 of the hippocampus (Kartsounis et al. 1995) or CA1
whole or in part by an episode of amnesia. This has been alone (Zola-Morgan et al. 1986), have also been responsi-
noted with ischemia of the left thalamus (Gorelick et al. ble. Lesions of the fornix have been implicated (D’Esposito
1988) and in the area of distribution of the posterior cere- et al. 1995; Gaffan et al. 1991; Sweet et al. 1958), including
bral arteries; in the latter case, the presence of visual prob- those located beneath the splenium (Heilman and Sypert
lems, such as hemianopia or cortical blindness, served to 1977) and those involving the columns (Calabrese et al.
indicate the cortical areas involved (Benson et al. 1974). In 1995; Hodges and Carpenter 1991).
another case, an episode occurred during cardiac angiogra- Although these lesions have in most cases been bilateral,
phy, presumably on an embolic basis (Shuttleworth and it appears that a properly situated unilateral lesion may
Wise 1973). Distinguishing between amnesia resulting also be to blame. Thus, amnesia has occurred with unilat-
from a transient ischemic attack and that caused by tran- eral lesions of the thalamus, either on the left (Choi et al.
sient global amnesia may be difficult unless there are asso- 1983; Clarke et al. 1994; Gorelick et al. 1988; Landi et al.
ciated symptoms such as hemianopia. 1982) or on the right (Pepin and Auray-Pepin 1993), and
‘Transient tumor attacks’ occur in association with with unilateral lesions of the temporal lobes, with either
cerebral tumors and may happen either because of tran- temporal lobectomy (Scoville and Milner 1957; Walker
sient compression of a nearby artery or because of a 1957) or infarction (Gaffan et al. 1991).
tumor-related seizure. In one case of a left-sided tem- Specific disorders capable of producing such lesions of
poroparietal mass, the attack was characterized by an the circuit of Papez are now discussed, beginning with the
episode of amnesia (Lisak and Zimmerman 1977). prototype, namely, Korsakoff’s syndrome.
Korsakoff’s syndrome occurs as a sequela to Wernicke’s
CHRONIC ANTEROGRADE AMNESIA WITH A encephalopathy (Malamud and Skillicorn 1956; Victor and
RETROGRADE COMPONENT Yakovlev 1955). Wernicke’s encephalopathy occurs second-
ary to thiamine deficiency and is characterized, pathologi-
As this type of amnesia localizes reasonably well to the cir- cally, by hemorrhage in the mammillary bodies and
cuit of Papez, a review of the relevant neuroanatomy may dorsomedial nuclei of the thalamus. Clinically, patients with
be helpful. The circuit of Papez involves the mamillary Wernicke’s encephalopathy present with delirium (with or
body, thalamus, hippocampus, and fornix. Fibers from the without nystagmus and ataxia); as the delirium clears,
mamillary body project to the anterior thalamic nuclei via patients are left with an amnesia. Of note, from a nosologic
the mamillothalamic tract. The anterior thalamic nuclei, in point of view, the term ‘Korsakoff’s syndrome’ is often used
turn, project to the cingulate cortex and its cingulum, to refer to all cases of chronic anterograde amnesia with a
which in turn projects to the entorhinal and subicular cor- retrograde component; in this text, however, it refers only to
tices on the medial aspect of the temporal lobe. Fibers from the form occurring secondary to thiamine deficiency.
the entorhinal cortex extend, via the perforant pathway, to Stroke may be characterized by amnesia, this having
terminate in the dentate gyrus, from where fibers arise that been noted with infarction of the medial aspect of the tem-
project to the pyramidal cells of the hippocampus proper. poral lobe or the medial portion of the thalamus.
In turn, hippocampal fibers become incorporated into the Infarction of the medial aspect of the temporal lobe, in the
fornix, which also receives fibers directly from the subic- area of distribution of the posterior cerebral artery,
ular cortex. The fornix then proceeds posteriorly and supe- involves, among other structures, the hippocampus, and it
riorly, arching up under the splenium to course anteriorly is from this lesion that the amnesia arises (DeJong et al.
under the corpus callosum, eventually turning inferiorly, 1969; Victor et al. 1961). The involvement of other ‘down-
as the columns of the fornix, to dive down into and stream’ structures may lead to symptoms that suggest the
through the hypothalamus, finally coming to rest in the correct diagnosis, including hemianopia, cortical blind-
mamillary body and thus completing the circuit. ness, or alexia without agraphia (Benson et al. 1974). In the
This type of amnesia has been noted with lesions in case of thalamic infarction, the stroke may be initially char-
most portions of the circuit of Papez, beginning with the acterized by coma (Hodges and McCarthy 1993; Malamut
mamillary bodies (Kahn and Crosby 1971; Tanaka et al. et al. 1992) or delirium (Clarke et al. 1994); as alertness
1997). Amnesia has also occurred with thalamic lesions but returns and confusion clears, the patient is left with an
it has been difficult to pinpoint exactly which tracts or amnesia. In two remarkable cases, however, amnesia was
nuclei in the thalamus are involved. Lesion studies strongly the dominant and initial manifestation of the infarction
implicate the mamillothalamic tract (Graff-Radford et al. (Pepin and Auray-Pepin 1993; Warren et al. 2000).
p 05.qxd 3/10/08 9:34 AM Page 186
Thalamic hemorrhage may also be at fault with, in one Certain neurosurgical procedures may have amnesia as
such case, an amnesia emerging after the clearing of a delir- a complication. Unilateral temporal lobectomy may be at
ium (Choi et al. 1983). Amnesia has also been noted as a fault (Walker 1957), but in some cases at least, this appears
sequela of infarction of the fornices (Fukatsu et al. 1998; to be because the remaining temporal lobe had already
Park et al. 2000). been damaged in some fashion (Penfield and Mathieson
Tumors, if properly situated, may cause a progressive 1974). Surgery for an anterior communicating artery
amnesia, which has been noted with the following: cranio- aneurysm may be followed by an amnesia (Abe et al. 1998;
pharyngiomas (which compress the overlying mamillary Phillips et al. 1987; Talland et al. 1967), and this appears to
bodies) (Kahn and Crosby 1971; Palmai et al. 1967; Tanaka be not uncommon when preceded by actual rupture of the
et al. 1997; Williams and Pennybacker 1954), thalamic aneurysm (Lindquist and Norlen 1966). Neurosurgical
tumors (Ziegler et al. 1977), large tumors affecting struc- intervention directed toward the third ventricle, as in an
tures such as the corpus callosum, fornices, and thalami attempt to remove a colloid cyst, may cause injury to the
(Sprofkin and Sciarra 1952), and a subsplenial tumor, fornices, with a resulting amnesia (Hodges and Carpenter
which damaged both fornices (Heilman and Sypert 1977). 1991).
Limbic encephalitis results from an autoimmune
assault on the limbic system, including the hippocampus. RETROGRADE AMNESIA
Although most patients present with delirium, the delir-
ium will, in a small minority, be preceded by an amnestic Pure retrograde amnesia, without any anterograde compo-
syndrome (Alamowitch et al. 1997; Bak et al. 2001; Nokura nent, may occur on either an episodic or a chronic basis.
et al. 1997, Scheid et al. 2004). Episodic retrograde amnesia occurred, in one case, as a
Neurodegenerative disorders may present with an manifestation of a seizure: the patient experienced the sud-
amnesia that evolves very slowly into a dementia; in a sense, den onset of an inability to recall any events of his life, but
the amnesia represents a ‘prodrome’ to the dementia. This was able, even during the seizure, to keep track of ongoing
is most commonly seen with Alzheimer’s disease (Crystal events; once the seizure terminated, he was again able to
et al. 1989; Didic et al. 1998; Linn et al. 1995; Sim et al. 1966), recall his past (Venneri and Caffarra 1998).
but has also been noted with Pick’s disease (Wisniewski et al. Chronic retrograde amnesia appears to localize to the
1972) or frontotemporal dementia (Graham et al. 2005). anterior portions of the temporal lobes, as may be seen in
Traumatic brain injury characteristically causes coma, traumatic brain injury (Kroll et al. 1997; Markowitsch et al.
and upon recovery from the coma, the patient may be left 1993) or after herpes simplex encephalitis (Calabrese et al.
with various cognitive deficits, prominent among which 1996). In one traumatic brain injury case, a young woman,
may be an amnesia. The amnesia has both anterograde and despite being eventually able to recall most of the events
retrograde components, and the duration of the antero- that had occurred after the head trauma, was unable to
grade amnesia generally (but not always) correlates well remember anything that happened before the trauma, all
with the severity of the injury itself (Russell and Smith the way back to early childhood (Kapur et al. 1992).
1961; Wilson et al. 1994). The retrograde amnesia exhibits Further, after resolution of a herpes simplex encephalitis, a
a temporal gradient (Levin et al. 1988), and as the patient patient, although able to recall events that occurred subse-
experiences some recovery, the period of time covered by quent to her recovery from the encephalitis, could not
the retrograde amnesia gradually shrinks (Russell and recall autobiographical events that occurred before the
Nathan 1946). Importantly, neither missile nor crush encephalitis, such as her own wedding (Tanaka et al. 1999).
injuries are associated with much in the way of amnesia, Before leaving this discussion of retrograde amnesia,
and indeed, in some cases, there may be none at all (Russell note must be made of a condition known as dissociative
1951; Russell and Schiller 1949). amnesia. Here, patients report a chronic inability to recall
Global hypoxic injury, as may occur with attempted some, or all, of their past. However, in this condition, in
hanging (Berlyne and Strachan 1968; Medalia et al. 1991), contrast with cases of chronic retrograde amnesia occur-
carbon monoxide intoxication (Alison 1961), cardiorespi- ring with, for example, traumatic brain injury, patients
ratory arrest (Broman et al. 1997; Cummings et al. 1984), with psychotherapy are generally able to recover these
or after inhalation anesthesia (Muramoto et al. 1979), may, memories (Abeles and Schilder 1935; Kanzer 1939). This is
upon the recovery of consciousness, be followed by an a controversial condition and there is some doubt regarding
amnesia. whether it actually exists.
Encephalitis may have an amnesia as one of its sequelae
(Rose and Symonds 1960); this is particularly true of her-
pes simplex encephalitis, which often affects medial tem- Differential diagnosis
poral structures (Hokkanen et al. 1996; Kapur et al. 1994;
McGrath et al. 1997; Young et al. 1992). Amnesia must be distinguished from delirium and demen-
Status epilepticus may leave an amnesia in its wake, as tia. Although both of these syndromes include difficulty
occurred in one case after grand mal status (Meierkord with memory, they are distinguished by the presence of
et al. 1997). additional features, not seen in amnesia, such as confusion
p 05.qxd 3/10/08 9:34 AM Page 187
in delirium, and in dementia deficits in abstracting and cal- ‘developmental’ age at which the patient’s intellectual and
culating ability. social progress generally stalls. Mild mental retardation is
MCI may manifest with a chronic deficit in anterograde most common, seen in about 80–85 percent of cases; 10–12
memory and the differential here is based on severity: in percent are moderate, 3–7 percent are severe, and roughly
MCI, the memory deficit is not severe enough to interfere 1 percent are profoundly retarded. Among the mildly
with activities of daily living, whereas in amnesia it is. It retarded, males outnumber females; however, as the grade
must be kept in mind, as discussed earlier in Section 5.2, of retardation increases, the sex ratio approaches unity.
that in most instances MCI constitutes merely a prodrome Each of these grades is described below in more detail.
to a full syndrome of either amnesia or dementia. Mild mental retardation may not become apparent until
Depression may mimic an amnestic condition, espe- the child is in elementary school. These children have diffi-
cially when the task of recall is effortful (Cohen et al. 1982; culty in learning to read, write, and do arithmetic, and at
Roy-Byrne et al. 1986): such depressed patients essentially best they may progress academically to a fourth-, fifth-, or
‘give up’ on the task. The presence of other depressive perhaps sixth-grade level. Thinking is more or less concrete,
symptoms, such as depressed mood, fatigue, and insomnia, and seeing things from another’s point of view or appreci-
suggests the correct diagnosis. ating the importance of anything that lies outside of their
immediate concerns is difficult. These patients fail to grasp
social nuances and may appear ‘immature’. Affects tend to
Treatment
be exaggerated, with little or no shading: a patient may slip
from joyful exuberance to profound, seemingly incon-
Where available, treatment is directed at the underlying
solable, despair within moments. Judgment tends to be
condition. Supervision of a variable degree is often required
poor and a certain degree of gullibility is often displayed.
during the amnesia, and this may suffice for the transient
Sudden changes or new situations often catch these patients
forms. In the case of persistent amnesias, various tech-
helpless and render them in need of direct, one-on-one
niques, such as the use of mnemonics and lists, may enable
supervision if they are to make it successfully through the
the patient to better navigate the temporal landscape.
transition. In tranquil circumstances, however, many of
these patients are able to work at simple jobs and to live
5.5 MENTAL RETARDATION independently or with only minimal supervision.
Moderate mental retardation is generally apparent dur-
Mental retardation is characterized by a failure to progress, ing pre-school years. These children are often able to talk
despite adequate educational opportunity, beyond a cer- but have great difficulty in learning to read, write, or do
tain developmental point, in both an intellectual and a arithmetic and at best may progress academically to a sec-
social sense. This is a very common disorder, seen in about ond-grade level. Thinking is sparse, very concrete, and lim-
1 percent of the general population. ited to immediate needs. These patients fail to understand
ordinary social conventions and have great difficulty in
getting along with others. With close supervision they may
Clinical features be able to perform simple work and live outside of an insti-
tution, perhaps in a group home.
Mental retardation is divided, according to its severity, into
Severe mental retardation is generally apparent during
four grades, namely mild, moderate, severe, and profound.
the first several years of life. Malformations may be appar-
Thus, those with mild mental retardation generally
ent at birth and seizures are not uncommon. These infants
progress no further than an elementary school level, those
are slow to laugh, have difficulty in imitating others, and at
with moderate mental retardation a second-grade level,
best acquire only limited speech. They do not learn to read
those with severe mental retardation a pre-school level,
or write, and at best may be able to count on their fingers.
and those with profound mental retardation the level seen
Some may be able to live with family or in closely super-
in infants or very small children. By convention, these var-
vised group homes; however, many are unable to survive
ious grades of mental retardation are also demarcated by
outside of an institution.
IQ level and these are presented in Table 5.4, along with the
Profound mental retardation is usually apparent during
the first year of life. Malformations are common, as are
Table 5.4 Grades of mental retardation seizures. These infants are generally unable to walk, and
Developmental some may be unable to stand or even sit. Speech is gener-
Grade age (years) IQ ally not acquired, and vocalizations are generally limited to
grunts, cries, or some expression of pleasure. Constant
close supervision is required to maintain adequate nutri-
Mild 7–11 50–55 to 65–75
tion and hygiene, and institutional care is generally
Moderate 3–7 35–40 to 50–55
required.
Severe 1–3 20–25 to 35–40
In addition to these specific aspects, patients with mental
Profound ⬍1 ⬍20–25
retardation often display a number of associated features.
p 05.qxd 3/10/08 9:34 AM Page 188
Aggression, impulsivity, a low frustration tolerance, and an supervene in adults with Down’s syndrome. Although typ-
insistence on routine may be seen in all grades. Among ically in such cases autopsy reveals pathology characteristic
those with moderate and higher grades, feeding difficulties, of Alzheimer’s disease (Evenhuius 1990), these patients are
stereotypies and self-injurious behaviors may be seen, and also prone to hypothyroidism, which, of itself, may also
among the severely and profoundly retarded, rectal digging cause dementia (Lai and Williams 1989).
and coprophagia may occur. Fragile X syndrome may cause mental retardation in
Feeding difficulties include pica, rumination, and food affected males, and is suggested by facial dysmorphism
refusal. Food refusal at times may be related to conditions with a long, narrow face, prognathism, and, in those who
such as pharyngeal or esophageal dysmotility, or to reflux, have passed puberty, macro-orchidism (Finelli et al. 1985;
but at times appears to have no other cause than the men- Wisniewski et al. 1985).
tal retardation. Klinefelter’s syndrome may also cause mental retarda-
Common stereotypies include rocking, head-rolling, tion and is suggested by a tall stature, small testicular size,
waving or hand-flapping, finger-sucking, or repeated, and, in some, gynecomastia (Ratcliffe et al. 1982).
meaningless utterances. Tuberous sclerosis commonly causes mental retardation
Self-injurious behaviors may include slapping, scratch- and is suggested by the presence of adenoma sebaceum and
ing, head-banging, hair-pulling, biting, and eye-gouging. seizures (Lagos and Gomez 1967; Pampiglione and
Rectal digging, as noted, is generally seen only in the Moynahan 1976; Ross and Dickerson 1943).
severely and profoundly retarded, and generally only in Sturge–Weber syndrome is suggested by a facial port-
those who are institutionalized. Although it may be related wine stain, a contralateral hemiplegia, and in some, mental
to conditions such as hemorrhoids or pinworms, at times it retardation; in those with seizures, a dementia, as noted in
seems simply to stem from the mental retardation. In addi- Section 5.1, may supervene (Lichtenstein 1954; Pascual-
tion to coprophagia, fecal smearing may also occur. Castroviejo et al. 1993; Petermann et al. 1958).
Other neuropsychiatric disorders are seen in one-half or Von Recklinghausen’s disease, suggested by café au lait
more of patients with mental retardation (Gillberg et al. spots and neurofibromas (Huson et al. 1988) may, in a
1986; Gostason 1985) and may include attention-deficit/ minority, also cause mental retardation (Rosman and
hyperactivity, major depressive disorder, bipolar disorder, Pearce 1967).
or schizophrenia. In instances where another disorder does Both the Prader–Willi syndrome and the Bardet–Biedl
occur the mental retardation itself modifies the presenta- syndrome may cause mental retardation, both being char-
tion of the new disorder, occasionally making it almost acterized by massive obesity and hypogonadism. Distin-
unrecognizable. Thus, depression may present merely with guishing characteristics for the Prader–Willi syndrome
insomnia, weight loss, and psychomotor change, and mania
may present as irritability, agitation, and sleeplessness.
Schizophrenia may manifest only with bizarre behavior. Table 5.5 Common causes of mental retardation
Genetic and chromosomal abnormalities

Polygenic inheritance
Etiology
Down’s syndrome
Fragile X syndrome
Although there are over a thousand different causes of
Klinefelter’s syndrome
mental retardation, only several dozen account for the vast
Tuberous sclerosis
majority of cases. Common causes are noted in Table 5.5,
Sturge–Weber syndrome
where they are divided into three groups: genetic and chro-
Von Recklinghausen’s syndrome
mosomal abnormalities, intrauterine insults, and peri-
Prader–Willi syndrome
natal or post-natal factors. In the United States, by far the
Bardet–Biedl syndrome
most common causes of mental retardation are Down’s
Lesch–Nyhan syndrome
syndrome, fragile X syndrome, and fetal alcohol syndrome.
Rett’s syndrome
These common causes are discussed below; in working
Phenylketonuria
up a case, if the clinical and laboratory results fail to sup-
port one of these then referral to a specialist is in order. Intrauterine insults
Fetal alcohol syndrome
GENETIC AND CHROMOSOMAL ABNORMALITIES Anti-epileptic drugs
Rubella
Polygenic inheritance is of particular importance, especially Toxoplasmosis
in cases of mild mental retardation (Thapar et al. 1994).
Peri-natal or post-natal factors
Down’s syndrome is suggested by a characteristic
Cerebral palsy
appearance with narrowed palpebral fissures, epicanthal
Prematurity
folds, a broad nasal root, and an often-protruding tongue.
Malnutrition
Importantly, as noted in the Section 5.1, a dementia may
p 05.qxd 3/10/08 9:34 AM Page 189
(Bray et al. 1983; Hall and Smith 1972; Robinson et al. school years, consideration must first be given to whether
1992) include a characteristic dysmorphism, with almond- the environment was such that, given normal intelligence,
shaped eyes, and for the Bardet–Biedl syndrome (Rathmell these skills could be acquired. Thus, in cases of severe dep-
and Burns 1938; Roth 1947), retinitis pigmentosa and rivation or inadequate educational opportunity, the failure
either polydactyly or syndactyly. to acquire these skills may not reflect mental retardation at
The Lesch–Nyhan syndrome often causes mental retar- all. Observing an individual’s social behavior may offer a
dation and is suggested by choreoathetosis and self- clue here: those of normal intelligence who failed to
mutilating lip- or finger-biting (Jankovic et al. 1988; Lesch progress academically due to a lack of educational oppor-
and Nyhan 1964; Nyhan 1972). tunity may yet display a keen and subtle grasp of social
Rett’s syndrome is seen virtually only in females and is nuances: here, this demonstration of ‘native’ intelligence is
suggested by a characteristic history (Hagberg 1993; a more accurate reflection of intellectual capacity than is
Hagberg et al. 1983): at around the age of 1.5 years, mental performance on tests of academic ability.
retardation becomes apparent, along with a characteristic Various other conditions may, even in the presence of
stereotyped hand movement, much like hand-washing. adequate educational resources, prevent the acquisition of
Microcephaly also gradually becomes apparent. At around academic skills, including significant deafness or reduced
the age of 3 years, there may be some partial recovery of visual acuity, developmental disabilities (such as develop-
communicative ability, and seizures often appear. Patients mental dyslexia or developmental dysphasia), attention-
may then remain stable until the adult years, when scolio- deficit/hyperactivity, schizophrenia, and significant
sis and dystonia gradually ensue. depression.
Phenylketonuria as a cause of mental retardation Dementia is clearly distinguished from mental retarda-
is uncommon today, thanks to newborn screening. tion by its course. In mental retardation, there is no falling
Importantly, however, adherence to the low-phenylalanine off or decrement in intellectual ability from a previously
diet should be lifelong in order to prevent deterioration. It acquired level: rather, there is, as noted above, a ‘stalling’ of
is especially critical that mothers with phenylketonuria development wherein patients reach a plateau, signifi-
adhere strictly to the diet during pregnancy in order to cantly below that expected for their age, beyond which
prevent neurologic damage to the fetus. Mothers who are there is no further progress. By contrast, there is in demen-
heterozygous for the gene should also adopt the diet dur- tia a definite falling off from a previously acquired level,
ing pregnancy in order to prevent fetal damage (Lenke and this decrement being more or less profound.
Levy 1980).
INTRAUTERINE INSULTS Treatment

The fetal alcohol syndrome, a very common cause of men- In addition to any treatment specific for the condition
tal retardation (Abel and Sokol 1986; Spohr et al. 1993), is responsible, several measures are generally applicable for
characterized by short stature, microcephaly, and a charac- mental retardation, regardless of the cause.
teristic facies, with shortened palpebral fissures, epicanthal Educational and training measures are especially
folds, a thin upper lip with a smooth philtrum, maxillary important for those with mild and moderate mental retar-
hypoplasia, and a degree of micrognathia. dation, and family members generally will benefit from
Anti-epileptic drugs, notably phenytoin (Hanson and counseling; in genetic or chromosomal cases, genetic
Smith 1975) and valproate, taken during pregnancy may counseling should be offered.
cause retardation. Aggressiveness and impulsivity may respond to low-
Maternal infection with either rubella (Miller et al. 1982) dose risperidone (Aman et al. 2002, Vanden Borre et al.
or toxoplasmosis (Desmonts and Couvrer 1974) may cause 1993); lithium may also be effective (Craft et al. 1987;
severe mental retardation. Spreat et al. 1989); troublesome stereotypies may respond
to behavioral programs and in some cases risperidone may
PERI-NATAL OR POST-NATAL FACTORS also be effective. Self-injurious behaviors may also respond
to behavioral programs; antipsychotics appear less respon-
Of all the disorders of peri-natal origin that may cause men-
sive here, but clomipramine may be effective (Lewis et al.
tal retardation, cerebral palsy (Nicholson and Alberman
1996).
1992) is the most important. Both prematurity (Collin et al.
Attention-deficit/hyperactivity may be treated with
1991; Volpe 1991) and malnutrition (Chase and Martin
stimulants in the usual fashion (Gadow 1985; Handen et al.
1970) may also cause the syndrome.
1990; Payton et al. 1989); however, careful attention must
be paid to any worsening of stereotypies with stimulant
Differential diagnosis treatment; should this occur, alternatives, as discussed in
Section 9.15, should be considered.
In evaluating an individual who never progressed, in an Mood disorders and schizophrenia may also be treated
academic sense, beyond levels expected in elementary in the usual way.
p 05.qxd 3/10/08 9:34 AM Page 190
REFERENCES Alpers BJ, Grant FC. The clinical syndrome of the corpus calosum.
Arch Neurol Psychiatry 1931; 25:67–86.
Abarbanel JM, Berginer VM, Osimani A et al. Neurologic Altes J, Gasco J, de Antonio J et al. Ciprofloxacin and delirium.
complications after gastric restriction surgery for morbid Ann Int Med 1989; 110:170–1.
obesity. Neurology 1987; 37:196–200. Alves D, Pires MM, Guimaraes A et al. Four cases of late onset
Abe K Inokawa A, Yanagihara T. Amnesia after a discrete basal metachromatic leukodystrophy in a family: clinical,
forebrain lesion. J Neurol Neurosurg Psychiatry 1998; biochemical and neuropathological studies. J Neurol
Abel EL, Sokol RJ. Fetal alcohol syndrome is now leading cause of Aman MG, De Smedt G, Derivan A et al. Double-blind, placebo-
mental retardation. Lancet 1986; 2:1222. controlled study of risperidone for the treatment of disruptive
Abeles M, Schilder P. Psychogenic loss of personal identity. Arch behaviors in children with subaverage intelligence. Am J
Neurol Psychiatry 1935; 34:587–604. Psychiatry 2002; 159:1337–46.
Adair JC, Digre KB, Swanda RM et al. Sneddon’s syndrome: a Ames D, Wirshing WC, Szuba MP. Organic mental disorders
cause of cognitive decline in young adults. Neuropsychiatry associated with bupropion in three patients. J Clin Psychiatry
Neuropsychol Behav Neurol 2001; 14:197–204. 1992; 53:53–5.
Adams M, Rhyner PA, Day J et al. Whipple’s disease confined to Anastasiou-Nana MI, Anderson JL, Nanas JS et al. High incidence
the central nervous system. Ann Neurol 1987; 21:104–8. of clinical and subclinical toxicity associated with amiodarone
Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a treatment of refractory tachyarrhythmias. Can J Cardiol 1986;
hitherto undescribed disease occurring in the alcoholic and 2:138–45.
malnourished patient. Arch Neurol Psychiatry 1959; Ancelin ML, Artero S, Portet F et al. Non-degenerative mild
81:154–72. cognitive impairment in elderly people and use of
Adams RD, Fisher CM, Hakim S et al. Symptomatic occult anticholinergic drugs: longitudinal cohort study. BMJ 2006;
hydrocephalus with ‘normal’ cerebrospinal fluid pressure. N 332:455–9.
Engl J Med 1965; 273:117–26. Antoine JC, Honnorat J, Anterion CT et al. Limbic encephalitis and
Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and other immunological perturbations in two patients with thymoma. J
adverse effects of diphenhydramine in hospitalized older Neurol Neurosurg Psychiatry 1995; 58:706–10.
adults. Arch Int Med 2001; 161:2091–7. Antonen JA, Markula KP, Pertovaara MI et al. Adverse drug
Ainiala H, Loukkola J, Peltola J et al. The prevalence of reactions in Sjogren’s syndrome. Frequent allergic drug
neuropsychiatric syndromes in systemic lupus erythematosus. reactions and a specific trimethoprim-associated systemic
Neurology 2001; 57:496–500. reaction. Scand J Rheumatol 1999; 38:157–9.
Akelaitis AJ. Lead encephalopathy in children and adults. J Nerv Arieff AJ, Wetzel N. Subdural hematoma following epileptic
Ment Dis 1941; 93:313–32. convulsion. Neurology 1964; 14:731–2.
Akman-Demir G, Baykan-Kurt B, Serdaroglu P et al. Seven-year Armon C, Shin C, Miller P et al. Reversible parkinsonism and
follow-up of neurologic involvement in Behçet’s syndrome. cognitive impairment with chronic valproate use. Neurology
Arch Neurol 1993; 53:691–4. 1996; 47:626–35.
Alamowitch S, Graus F, Uchuya M et al. Limbic encephalitis and Asher R. Myxoedematous madness. BMJ 1949; 2:555–62.
small cell lung cancer: clinical and immunological features. Astrom K-E, Mancall EL, Richardson EP. Progressive multi-focal
Brain 1997; 120:923–8. leuko-encephalopathy: a hitherto unrecognized complication
Albert MS, Butters N, Levin J. Temporal gradients in the of chronic lymphocytic leukaemia and Hodgkin’s disease. Brain
retrograde amnesia of patients with alcoholic Korsakoff’s 1958; 81:93–111.
disease. Arch Neurol 1979; 36:211–16. Athwal H, Murphy G, Chun S. Amiodarone-induced delirium. Am J
Alexopoulus GS, Meyers BS, Young RC et al. The course of Geriatr Psychiatry 2003; 11:696–7.
geriatric depression with ‘reversible dementia’: a controlled Austen FK, Carmichael MW, Adams RD. Neurologic manifestations
study. Am J Psychiatry 1993; 150:1693–9. of chronic pulmonary insufficiency. N Engl J Med 1957;
Allen RM, Young SJ. Phencyclidine induced psychosis. Am J 257:579–90.
Psychiatry 1978; 135:1081–4. Avery TL. Seven cases of frontal tumor with psychiatric
Alison RS, Chronic amnesic syndromes in the elderly, Proc R Soc presentation. Br J Psychiatry 1971; 111:19–23.
Med 1961; 54:961–5. Bacchus M. Encephalopathy and pulmonary disease. Arch Int Med
Alpers BJ. Relation of the hypothalamus to disorders of 1958; 102:194–8.
personality: report of a case. Arch Neurol Psychiatry 1937; Bak TH, Antoun N, Balan KK et al. Memory lost, memory
38:291–303. regained: neuropsychological findings and neuroimaging in
Alpers BJ. Personality and emotional disorders associated with two cases of paraneoplastic limbic encephalitis with radically
hypothalamic lesions. In: Fulton JF, Ranson SW, Frantz AM different outcomes. J Neurol Neurosurg Psychiatry 2001;
eds. Research publications. Association for Research in Nervous 71:40–7.
and Mental Disease. Volume XX. The hypothalmus and central Bakshi R, Shaikh ZA, Bates VE et al. Thrombotic thrombocytopenic
levels of autonomic function. Baltimore, MD: Williams & purpura: brain CT and MRI findings in 12 patients. Neurology
Wilkins, 1940. 1999; 52:1285–8.
p 05.qxd 3/10/08 9:34 AM Page 191
References 191
Ballard C, O’Brien J, Gray A et al. Attention and Bogousslavsky J, Ferrazzini M, Regli F et al. Manic delirium and
fluctuating attention in patients with dementia wih Lewy frontal-like syndrome with paramedian infarction of the right
bodies and Alzheimer’s disease. Arch Neurol 2001; thalamus. J Neurol Neurosurg Psychiatry 1988; 51:116–19.
58:977–82. Bohnen NILJ, Parnell KJ, Harper CM. Reversible MRI findings in a
Bank WJ, Pleasure DE, Suzuki K et al. Thallium poisoning. Arch patient with Hashimoto’s encephalopathy. Neurology 1997;
Neurol 1972; 26:456–64. 49:246–7.
Barbanti P, Fabrini G, Salvatore M et al. Polymorphism at codon Bohrod MG. Primary degeneration of the corpus callosum
129 or codon 219 of PRNP and clinical heterogeneity in a (Marchiafava’s disease): report of the second American case.
previously unreported family with Arch Neurol Psychiatry 1942; 47:465–73.
Gerstmann–Sträussler–Scheinker disease (PrP-P102L Bornebroek M, Haan J, van Buchem MA et al. White matter
mutation). Neurology 1996; 47:734–41. lesions and cognitive deterioration in presymptomatic carriers
Barcroft J. Anoxemia. Lancet 1920; 2:485–9. of the amyloid precursor protein gene codon 693 mutation.
Barnes DE, Alexopoulos GS, Lopez EL et al. Depressive symptoms, Arch Neurol 1996; 53:43–8.
vascular disease, and mild cognitive impairment: findings from Borrett D, Ashby P, Bilbao J et al. Reversible, late-onset
the Cardiovascular Health Study. Arch Gen Psychiatry 2006; disulfiram-induced neuropathy and encephalopathy. Ann
63: 273–9. Neurol 1985; 17:396–9.
Barry JJ, Franklin K. Amiodarone-induced delirium. Am J Borson S. Behçet’s disease as a psychiatric disorder: a case report.
Psychiatry 1999; 156:1119. Am J Psychiatry 1982; 139:1348–9.
Becher MW, Rubinsztein DC, Leggo J et al. Dentatorubral and Bosch EP, Hart MN. Late adult-onset metachromatic
pallidoluysian atrophy (DRPLA): clinical and neuropathological leukodystrophy: dementia and polyneuropathy in a 63-year-
findings in genetically confirmed North American and old man. Arch Neurol 1978; 35:475–7.
European pedigrees. Mov Disord 1997; 12:519–30. Bouton SM. Pick’s disease. J Nerv Ment Dis 1940; 91:9–30.
Benesch CG, McDaniel KD, Cox C et al. End-stage Alzheimer’s Bradshaw J, Saling M, Hopwood M et al. Fluctuating cognition in
disease: Glasgow coma scale and neurologic examination. dementia with Lewy bodies and Alzheimer’s disease is
Arch Neurol 1993; 50:1309–15. qualitatively distinct. J Neurol Neurosurg Psychiatry 2004;
Bennett DA, Schneider JA, Bienias JL et al. Mild 75:382–7.
cognitive impairment is related to Alzheimer disease Bray GA, Dahms WT, Swerdloff RS et al. The Prader–Willi
pathology and cerebral infarctions. Neurology 2005; 64: syndrome: a study of 40 patients and a review of the
834–41. literature. Medicine 1983; 62:59–88.
Bennett IL, Cary FM, Mitchell GL et al. Acute methyl alcohol Brennan LV, Craddock PR. Limbic encephalopathy as a non-
poisoning: a review based on experience in an outbreak of 323 metastatic complication of oat cell cancer: its reversal after
cases. Medicine 1953; 32:431–63. treatment of the primary lung lesion. Am J Med 1983;
Benson DF, Marsden CD, Meadows JC. The amnesia syndrome of 75:518–20.
posterior cerebral artery occlusion. Acta Neurol Scand 1974; Brey RL, Holliday SL, Saklad AR et al. Neuropsychiatric syndromes
50:133–45. in lupus. Prevalence using standardized definitions. Neurology
Berginer VM, Foster NL, Sadowsky M et al. Psychiatric disorders in 2002; 58:1214–20.
patients with cerebrotendinous xanthomatosis. Am J Brody IA, Wilkins RH. Huntington’s chorea. Arch Neurol 1967;
Psychiatry 1988; 145:354–7. 17:331–3.
Berlyne N, Strachan M. Neuropsychiatric sequelae of attempted Broman M, Rose AL, Hotson G et al. Severe anterograde amnesia
hanging. Br J Psychiatry 1968; 114:411–22. with onset in childhood as a result of anoxic encephalopathy.
Beversdorf D, Allen C, Nordgren R. Valproate induced Brain 1997; 120:417–33.
encephalopathy treated with carnitine in an adult. J Neurol Brown P, Rodgers-Johnson P, Cathala F et al. Creutzfeldt–Jacob
Neurosurg Psychiatry 1996; 61:211. disease of long duration: clinicopathological characteristics,
Biggins CA, Boyd JL, Harrop FM et al. A controlled, longitudinal biotransmissibility, and differential diagnosis. Arch Neurol
study of dementia in Parkinson’s disease. J Neurol Neurosurg 1984; 16:295–304.
Psychiatry 1992; 55:566–71. Brown P, Cathala F, Castaigne P et al. Creutzfeldt–Jakob disease:
Bird MT, Paulson GW. The rigid form of Huntington’s chorea. clinical analysis of a consecutive series of 230
Neurology 1971; 21:271–6. neuropathologically verified cases. Ann Neurol 1986;
Black DW. Mental changes resulting from subdural hematoma. Br 20:597–602.
J Psychiatry 1984; 145:200–3. Brown P, Goldfarb LG, Brown WT et al. Clinical and molecular
Blass JP, Hoyer S, Nitsch R. A translation of Otto Binswanger’s genetic study of a large German kindred with
article ‘ The deliniation of the generalized progressive Gerstmann–Sträussler–Scheinker syndrome. Neurology 1991;
paralyses’. Arch Neurol 1991; 48:961–72. 41:375–9.
Blocker WW, Kastl AJ, Daroff RB. The psychiatric manifestations Brown P, Gibbs CJ, Rodgers-Johnson P et al. Human spongiform
of cerebral malaria. Am J Psychiatry 1968; 125:192–6. encephalopathy: the National Institutes of Health series of
Bodner RA, Lynch T, Lewis L et al. Serotonin syndrome. Neurology 300 cases of experimentally transmitted disease. Ann Neurol
1995; 45:219–23. 1994; 35:513–29.
p 05.qxd 3/10/08 9:34 AM Page 192
Bruetsch WL, Williams CL. Arteriosclerotic rigidity with special Caselli RJ, Scheithauer BW, Bowles CA et al. The treatable
reference to gait disturbances. Am J Psychiatry 1954; dementia of Sjorgen’s syndrome. Ann Neurol 1991;
111:332–6. 30:98–101.
Brunner JE, Redmond JM, Haggar AM et al. Central pontine Case records of the Massachusetts General Hospital. Case
myelinolysis and pontine lesion after rapid correction of 23–1988. N Engl J Med 1988; 318:1523–7.
hyponatremia: a prospective magnetic resonance imaging Case records of the Massachusetts General Hospital. Case
study. Ann Neurol 1990; 27:61–6. 39–1988. N Engl J Med 1988; 319:849–60.
Buis CI, Wiesner RH, Ruud AF et al. Acute confusional state Case records of the Massachusetts General Hospital. Case
following liver transplantation for alcoholic liver disease. 8–1989. N Engl J Med 1989; 320:514–24.
Neurology 2002; 59:601–5. Case records of the Massachusetts General Hospital. Case
Bulens C. Neurologic complications of hyperthyroidism: remission 2–1992. N Engl J Med 1992; 326:117–25.
of spastic paraplegia, dementia and optic neuropathy. Arch Catalano MC, Glass JM, Catalano G et al. Gamma butyrolactone
Neurol 1981; 38:669–70. withdrawal syndromes. Psychosomatics 2001; 42:83–8.
Burkhardt CR, Filley CM, Kleineschmidt-DeMasters BK et al. Cavaco S, Anderson SW, Allen JS et al. The scope of preserved
Diffuse Lewy body disease and progressive dementia. procedural memory in amnesia. Brain 2004; 127:1853–67.
Neurology 1988; 38:1520–8. Cavalleri F, De Renzi E. Amyotrophic lateral sclerosis with
Burks JS, Alfrey AC, Huddlestone J et al. A fatal encephalopathy in dementia. Acta Neurol Scand 1994; 89:391–4.
chronic hemodialysis patients. Lancet 1976; 1:764–8. Chandler JH, Bebin J. Hereditary cerebellar ataxia:
Burneo JG, Arnold T, Palemr CA et al. Adult-onset neuronal ceroid olivopontocerebellar type. Neurology 1956; 6:187–95.
lipofuscinosis (Kufs’ disease) with autosomal dominant Chase HP, Martin HP. Undernutrition and child development. N
inheritance in Alabama. Epilepsia 2003; 44:841–6. Engl J Med 1970; 282:933–9.
Butler CR, Graham KS, Hodges JR et al. The syndrome of transient Chatterjee A, Yapundich R, Palmer CA et al. Leukoencephalopathy
epileptic amnesia. Ann Neurol 2007; 61:587–98. associated with cobalmin deficiency. Neurology 1996;
Byrne EJ, Lennox G, Lowe J et al. Diffuse Lewy body disease: 46:832–4.
clinical features in 15 cases. J Neurol Neurosurg Psychiatry Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral
1989; 52:709–17. encephalitis. Postgrad Med J 2002; 78:575–83.
Caine ED. Pseudodementia: current concepts and future Chen J-Y, Stern Y, Sano M et al. Cumulative risks of developing
directions. Arch Gen Psychiatry 1981; 38:1359–64. extrapyramidal signs, psychosis, or myoclonus in the course of
Calabrese P, Markowitsch HJ, Harders AG et al. Fornix damage Alzheimer’s disease. Arch Neurol 1991; 48:1141–3.
and memory: a case report. Cortex 1995; 31:555–64. Chester EM, Agamanolis DP, Banker BP et al. Hypertensive
Calabrese P, Markowitsch HJ, Widlitzek H et al. Right encephalopathy: a clinicopathologic study of 20 cases.
temporofrontal cortex as a critical locus for the ecphory of old Neurology 1978; 28:928–39.
episodeic memories. J Neurol Neurosurg Psychiatry 1996; Choi D, Sudarsky L, Schacter S et al. Medial thalamic hemorrhage
61:304–12. with amnesia. Arch Neurol 1983; 40:611–13.
Cameron DJ, Thomas RI, Mulvihill M et al. Delirium: a test of Choi IS. Delayed neurologic sequelae in carbon monoxide
DSM-III criteria on medical inpatients. J Am Geriatr Soc 1987; intoxication. Arch Neurol 1983; 40:433–5.
35:1007–10. Chopra GS, Smith JW. Psychotic reactions following cannabis use
Camp WA, Frierson JG. Sarcoidosis of the central nervous system. in East Indians. Arch Gen Psychiatry 1974; 30:24–7.
Arch Neurol 1962; 7:432–41. Clark BA, Bowen RS. Unsuspected morbid hypermagnesemia in
Campbell AMG, Corner B, Norman RM et al. The rigid form of elderly patients. Am J Nephrol 1992; 12:336–43.
Huntington’s disease. J Neurol Neurosurg Psychiatry 1961; Clark JM, Marks MP, Adalsteinsson E et al. MELAS: clinical and
24:71–7. pathologic correlation with MRI, xenon/CT, and MR
Caplan LR, Schoene WC. Clinical features of subcortical spectroscopy. Neurology 1996; 46:223–7.
arteriosclerotic encephalopathy (Binswanger disease). Clarke S, Assal G, Bogousslavsky J et al. Pure amnesia after
Neurology 1978; 28:11206–15. unilateral left polar thalmic infarct: topographic and
Caplan LR, Kelly M, Kase CS et al. Infarcts of the inferior division sequential neurophysiological and metabolic (PET)
of the right middle cerebral artery: mirror image of Wernicke’s correlations. J Neurol Neurosurg Psychiatry 1994; 57:27–34.
aphasia. Neurology 1986; 36:1015–20. Cohen RM, Weingartner H, Smallberg SA et al. Effort and
Capparelli FJ, Diaz MF, Hlavnika A et al. Cefipine- and cefixime- cognition in depression. Arch Gen Psychiatry 1982; 39:593–7.
induced encephalopathy in a patient with normal renal Collin MF, Halsey CL, Anderson CL. Emerging developmental
function. Neurology 2005; 65:1840. sequelae in the ‘normal’ extremely low birthweight infant.
Carter HR, Sukavajuna C. Familial cerebello-olivary degeneration Pediatrics 1991; 88:115–20.
with the late development of rigidity and dementia. Neurology Collins SJ, Ahlskog JE, Parisi JE et al. Progressive supranuclear
1956; 6:876–84. palsy: neuropathologically based diagnostic clinical criteria. J
Caselli RJ. Giant cell (temporal) arteritis: a treatable Neurol Neurosurg Psychiatry 1995; 58:167–73.
cause of multi-infarct dementia. Neurology 1990; Colosimo C, Albanese A, Hughes AJ et al. Some specific clinical
40:753–5. features differentiate multiple system atrophy (striatonigral
p 05.qxd 3/10/08 9:34 AM Page 193
References 193
variety) from Parkinson’s disease. Arch Neurol 1995; Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological
52:294–8. spectrum of Steele–Richardson–Olszewski syndrome
Cook DG, Fahn S, Brait KA. Chronic manganese intoxication. Arch (progressive supranuclear palsy): a reappraisal. Brain 1995;
Neurol 1974; 30:59–64. 118:759–70.
Cordingly G, Navarro C, Brust JCM et al. Sarcoidosis presenting as Davies JA, Hughes JT, Oppenheimer DR. Richardson’s disease
senile dementia. Neurology 1981; 31:1148–51. (progressive multifocal leukoencephalopathy). Q J Med 1973;
Coria F, Garcia-Viejo MA, Delgado JA et al. Diagnosis of 42:481–93.
X-adrenoleukodystrophy phenotypic variants. Acta Neurol Davis CL, Springmeyer S, Gmerek BJ. Central nervous system side-
Scand 1993; 87:499–502. effects of ganciclovir. N Engl J Med 1990; 322:933–4.
Correa DD, DeAngelis LM, Shi W et al. Cognitive functions in Davis LE, Wands JR, Weiss SA et al. Central nervous system
survivors of primary central nervous system lymphoma. intoxication from mercurous chloride laxatives. Arch Neurol
Neurology 2004; 62:548–55. 1974; 30:428–31.
Cosgrove CR, Leblanc R, Meagher-Villemure K et al. Dawson JR. Cellular inclusions in cerebral lesions of epidemic
Cerebral amyloid angiopathy. Neurology 1985; encephalitis. Arch Neurol Psychiatry 1934; 31:685–700.
35:625–31. DeAngelis LM, Delattre J-Y, Posner JB. Radiation-induced
Coull BM, Bourdette DN, Goodnight SH et al. Multiple cerebral dementia in patients cured of brain metastases. Neurology
infarctions and dementia associated with anticardiolipin 1989; 39:172–7.
antibodies. Stroke 1987; 18:1107–12. DeJong RN, Itabashi HH, Olson JR. Memory loss due to
Craft M, Ismail IA, Krishnamurti D et al. Lithium in the treatment hippocampal lesions. Arch Neurol 1969; 20:339–48.
of aggression in mentally handicapped patients: a double- Denko J, Kaelbling R. The psychiatric aspects of
blind trial. Br J Psychiatry 1987; 150:685–9. hypoparathyroidism. Acta Psychiatr Scand 1962; (suppl.
von Cramon DY, Hebel N, Schuri U. A contribution to the 164):1–70.
anatomical basis of thalamic amnesia. Brain 1985; Dennis MS, Byrne EJ, Hopkinson N et al. Neuropsychiatric
108:993–1008. systemic lupus erythematosus in elderly people. J Neurol
Cravioto H, Korein J, Silberman J. Wernicke’s encephalopathy: a Neurosurg Psychiatry 1992; 55:1157–61.
clinical and pathological study of 28 autopsied cases. Arch DePaulo JR, Folstein MF, Correa EI. The course of delirium due to
Neurol 1961; 4:510–19. lithium intoxication. J Clin Psychiatry 1982; 43:447–9.
Crawford RD, Baskoff JD. Fentanyl-associated delirium in man. De Smet Y, Ruberg M, Serdaru M et al. Confusion, dementia and
Anesthesiology 1980; 53:168–9. anticholinergics in Parkinson’s disease. J Neurol Neurosurg
Critchley EMR, Clark DB, Wikler A. Acanthocytosis and Psychiatry 1982;45:1161–4.
neurological disorder without abetalipoproteinemia. Arch Desmonts G, Couvrer J. Congenital toxoplasmosis. N Engl J Med
Neurol 1968; 18:134–40. 1974; 290:1110–16.
Crompton MR, Layton DD. Delayed radionecrosis of the brain D’Esposito M, Verfaellie M, Alexander MP et al. Amnesia following
following therapeutic X-irradiation of the pituitary. Brain traumatic bilateral fornix transection. Neurology 1995;
1961; 84:85–101. 45:1546–50.
Cross TN. Porphyria – a deceptive syndrome. Am J Psychiatry Devinsky O, Petito CK, Alonso DR. Clinical and neuropathological
1956; 112:1010–14. findings in systemic lupus erythematosus: the role of
Crystal HA, Grober E, Masur D. Preservation of visual memory in vasculitis, heart emboli and thrombotic thrombocytopenic
Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1989; purpura. Ann Neurol 1988a; 23:380–4.
52:1415–16. Devinsky O, Bear D, Volpe BT. Confusional states following
Cullis PA, Cushing R. Vidarabine encephalopathy. J Neurol posterior cerebral artery infarction. Arch Neurol 1988b;
Cummings JL. Dementia syndrome: neurobehavioral and Dichgans M, Mayer M, Uttner I et al. The phenotypic spectrum of
neuropsychiatric features. J Clin Psychiatry 1987; 48(suppl. CADASIL: clinical findings in 102 cases. Ann Neurol 1998;
5):3–8. 44:731–9.
Cummings JL, Tomiyasu U, Read S et al. Amnesia with Didic M, Cherif AA, Gambarelli D et al. A permanent pure
hippocampal lesions after cardiopulmonary arrest. Neurology amnestic syndrome of insidious onset related to Alzheimer’s
1984; 34:679–81. disease. Ann Neurol 1998; 43:526–30.
Cunningham MA, Darby DG, Donnan GA. Controlled-release Dolgopol VB, Greenberg M, Aronoff R. Encephalitis following
delivery of L-dopa associated with nonfatal hyperthermia, smallpox vaccination. Arch Neurol Psychiatry 1955;
rigidity and autonomic dysfunction. Neurology 1991; 73:216–23.
41:942–3. Dooling EC, Schoene WC, Richardson EP. Hallervorden–Spatz
Curran FJ. A study of fifty cases of bromide psychosis. J Nerv Ment syndrome. Arch Neurol 1974; 30:70–83.
Dis 1938; 88:163–92. Dooling EC, Richardson EP, Davis KR. Computed tomography in
Cutting J. The phenomenology of acute organic psychosis: Hallervorden–Spatz disease. Neurology 1980; 30:1128–30.
comparison with acute schizophrenia. Br J Psychiatry 1987; Douglas AC, Maloney AFJ. Sarcoidosis of the central nervous
151:324–32. system. J Neurol Neurosurg Psychiatry 1973; 36:1024–33.
p 05.qxd 3/10/08 9:34 AM Page 194
Druscky A, Erbguth F, Strauss R et al. Central nervous system Feldman RG, White RF, Eriator II. Trimethyltin encephalopathy.
involvement in thrombotic thrombocytopenic purpura. Eur Arch Neurol 1993; 50:132–4.
Neurol 1998; 40:220–4. Fennig S, Mauas L. Oflaxacin-induced delirium. J Clin Psychiatry
Duffy P, Chari G, Cartlidge NEF et al. Progressive deterioration of 1992; 53:137–8.
intellect and motor function occurring several decades after Ferraro A, Jervis GA. Pick’s disease: clinicopathologic study with
cranial irradiation. Arch Neurol 1996; 53:814–18. report of two cases. Arch Neurol Psychiatry 1936; 36:738–67.
Dulfano MJ, Ishikawa S. Hypercapnia: mental changes and Ferrer I, Roig C, Espino A et al. Dementia of the frontal lobe type
extrapulmonary complications. Ann Int Med 1965; 63:829–41. and motor neuron disease: a Golgi study of the frontal cortex.
Duyckaerts C, Derouesne C, Signoret JL et al. Bilateral and limited J Neurol Neurosurg Psychiatry 1991; 54:932–4.
amygdalohippocampal lesions causing a pure amnestic Finck MA. Exposure to carbon monoxide: review of the literature
syndrome. Ann Neurol 1985; 18:314–19. and 567 autopsies. Mil Med 1966; 131:1513–19.
Eidelman LA, Putterman D, Putterman C et al. The spectrum of de Fine Olivarius B, Roder E. Reversible psychosis and dementia in
septic encephalopathy: definitions, etiologies and mortalities. myxedema. Acta Psychiatr Scand 1970; 46:1–13.
JAMA 1996; 275:470–3. Finelli PF, Pueschel SM, Padre-Mendoza T et al. Neurological
Eisendrath SJ, Sweeney MA. Toxic neuropsychiatric effects of findings in patients with the fragile-X syndrome. J Neurol
digoxin at therapeutic serum concentrations. Am J Psychiatry Neurosurg Psychiatry 1985; 48:150–3.
1987; 144:506–7. Finlayson MH, Superville B. Distribution of cerebral lesions in
Eisendrath SJ, Goldman B, Douglas J et al. Meperidine-induced acquired hepatocerebral degeneration. Brain 1981;
delirium. Am J Psychiatry 1987; 144:1062–5. 104:79–95.
Elliott RL, Wild JH, Snow WT. Prolonged delirium after Fisch RZ, Lahad A. Adverse psychiatric reaction to ketoconazole.
metrizamide myelography. JAMA 1984; 252:2057–8. Am J Psychiatry 1989; 146:939–40.
Engel GL, Margolin SG. Neuropsychiatric disturbances in Addison’s Fischman MW, Schuster CR, Resnekov L et al. Cardiovascular and
disease and the role of impaired carbohydrate metabolism in subjective effects of intravenous cocaine administration in
production of abnormal cerebral function. Arch Neurol humans. Arch Gen Psychiatry 1976; 33:983–9.
Psychiatry 1941; 45:881–4. Fishbain DA, Rogers A. Delirium secondary to metoclopramide
Engel PA, Chapron D. Cyclobenzaprine-induced delirium in two hydrochloride. J Clin Psychopharmacol 1987; 7:281–2.
octogenarians. J Clin Psychiatry 1993; 54:39. Fisher CM. Concussion amnesia. Neurology 1966; 16:826–30.
Erkinjunti T, Haltia M, Palo J et al. Accuracy of the clinical diagnosis Fisher CM. Transient global amnesia: precipitating activities and
of vascular dementia: a prospective clinical and post-mortem other observations. Arch Neurol 1982; 39:605–8.
study. J Neurol Neurosurg Psychiatry 1988; 51:1037–44. Fishman RA. Neurological aspects of magnesium metabolism.
Erlanson P, Fritz H, Hagstam KE et al. Severe methanol Arch Neurol 1965; 12:562–9.
intoxication. Acta Med Scand 1965; 177:393–408. Fontaine B, Seilhean D, Tourbah A et al. Dementia in two
Escobar A, Aruffo C. Chronic thinner intoxicaton: clinico- histologically confirmed cases of multiple sclerosis: one case
pathologic report of a human case. J Neurol Neurosurg with isolated dementia and one case associated with psychiatric
Psychiatry 1980; 43:986–94. symptoms. J Neurol Neurosurg Psychiatry 1994; 57:353–9.
Estrada RV, Moreno J, Martinez E et al. Pancreatic Ford RG, Siekert RG. Central nervous system manifestations of
encephalopathy. Acta Neurol Scand 1979; 59:135–9. periarteritis nodosa. Neurology 1965; 15:114–22.
Evans AC, Raistrick D. Phenomenology of intoxication with Fornazzari L, Wilkinson DA, Kapur BM et al. Cerebellar, cortical
toluene-based adhesives and butane gas. Br J Psychiatry 1987; and functional impairment in toluene abusers. Acta Neurol
150:769–73. Scand 1983; 67:319–29.
Evenhuius HM. The natural history of dementia in Down’s Francis J. Delirium in older patients. J Am Geriatr Soc 1992;
syndrome. Arch Neurol 1990; 47:263–7. 40:829–38.
Eyer F, Felgenhauer N, Gempel K et al. Acute valproate poisoning. Francis J, Martin D, Kapoor W. A prospective study of delirium in
J Clin Psychopharmacol 2005; 25:376–80. hospitalized elderly. JAMA 1990; 263:1097–101.
Ezzeddine MA, Primavera JM, Rosand J et al. Clinical Frantzen E. Wernicke’s encephalopathy: 3 cases occurring in
characteristics of pathologically proved cholesterol emboli to connection with severe malnutrition. Acta Neurol Scand 1966;
the brain. Neurology 2000; 54:1681–3. 42:426–41.
Fang VBS, Jaspan JB. Delirium and neuromuscular symptoms in an Fraser CL, Arieff AI. Hepatic encephalopathy. N Engl J Med 1985;
elderly man with isolated corticotroph deficiency syndrome 313:865–73.
completely reversed with glucocorticoid replacement. J Clin Fraser HF, Wiler A, Essig CF et al. Degree of physical dependence
Endocrinol Metab 1989; 69:1073–7. induced by secobarbital or pentobarbital. J Am Med Assoc
Farpour H, Mahloudji M. Familial cerebrotendinous 1958; 166:126–9.
xanthomatosis: report of a new family and review of the Frazier CH. Tumor involving the frontal lobe alone: a symptomatic
literature. Arch Neurol 1975; 32:223–5. survey of one hundred and five verified cases. Arch Neurol
Feighner JP, Boyer WF, Tyler DL et al. Adverse consequences of Psychiatry 1936; 35:525–71.
fluoxetine–MAOI combination therapy. J Clin Psychiatry 1990; Freeman JW, Couch JR. Prolonged encephalopathy with arsenic
51:222–5. poisoning. Neurology 1978; 28:853–5.
p 05.qxd 3/10/08 9:34 AM Page 195
References 195
Friedman A, Sienkiewicz J. Psychotic complications of long-term Goodman L. Alzheimer’s disease: a clinico-pathologic analysis of
levodopa treatment of Parkinson’s disease. Acta Neurol Scand twenty-three cases with a theory on pathogenesis. J Nerv
1991; 84:111–13. Ment Dis 1953; 118:97–130.
Friedman JH. Syndrome of diffuse encephalopathy due to non- Goodwin CD. Case report of tricyclic-induced delirium at a
dominant thalamic infarction. Neurology 1985; 35:1524–6. therapeutic drug concentration. Am J Psychiatry 1983;
Friedman JH, Kanzer M. Thyrotoxicosis with psychosis: clinico- 140:1517–18.
neuropathologic observations in a case. J Nerv Ment Dis 1937; Goodwin DW. True species of alcoholic ‘blackout’. Am J Psychiatry
85:30–5. 1971; 127:1665–70.
Fromm D, Holland AL, Swindell CS et al. Various complications of Goodwin DW, Crane JB, Guze SB. Alcoholic ‘blackout’: a review
subcortical stroke: prospective study of 16 consecutive cases. and clinical study of 100 alcoholics. Am J Psychiatry 1969a;
Arch Neurol 1985; 42:943–50. 126:191–8.
Fukatsu R, Yamadori A, Fujii T. Impaired recall and preserved Goodwin DW, Crane JB, Guze SB. Phenomenological aspects of
encoding in prominent amnesic syndrome: a case of basal the alcoholic ‘blackout’. Br J Psychiatry 1969b; 115:1033–8.
forebrain amnesia. Neurology 1998; 50:539–41. Gordon MF, Abrams RI, Rubin DB et al. Bismuth subsalicylate
Gadow KD. Prevalence and efficacy of stimulant drug use with toxicity as a cause of prolonged encephalopathy with
mentally retarded children and youth. Psychopharmacol Bull myoclonus. Mov Disord 1995; 10:220–2.
1985; 21:291–303. Gorelick PB, Amico LL, Ganellen R et al. Transient global amnesia
Gaffan EA, Gaffan D, Hodges JR. Amnesia following damage to and thalamic infarction. Neurology 1988; 38:496–9.
the left fornix and to other sites. Brain 1991; 114:1297–13. Gostason R. Psychiatric illness among mentally retarded: a
Gardner K, Barmada M, Ptacek LJ et al. A new locus for Swedish population study. Acta Psychiatr Scand 1985; (suppl.
hemiplegic migraine maps to chromsome /q3/. Neurology 318):1–117.
1997; 49:1231–8. Gottfried JA, Mayer SA, Shungu DC et al. Delayed posthypoxic
Garrett PJ, Mulcahy D, Carmody M et al. Aluminium demyelination: association with arylsulfatase A deficiency and
encephalopathy: clinical and immunologic features. Q J Med lactic acidosis and proton MR spectroscopy. Neurology 1997;
1988; 69:775–83. 49:140–4.
Gautier S, Reisberg B, Zaudig M et al. Mild cognitive impairment. Graff-Radford NR, Eslinger PJ, Damasio AR et al. Nonhemorrhagic
Lancet 2006; 367: 1262–70. infarction of the thalamus: behavioral, anatomic, and
Geda YA, Knopman DS, Mrazek DA et al. Depression, physiologic correlates. Neurology 1984; 34:14–23.
apolipoprotein E genotype, and the incidence of mild cognitive Graff-Radford NR, Tranel D, Van GW et al. Diencephalic amnesia.
impairment: a prospective cohort study. Arch Neurol 2006; Brain 1990; 113:1–25.
63:435–40. Graham A, Davies R, Xuereb J et al. Pathologically proven
Ghika-Schmid F, Ghika J, Regli F. Hashimoto’s myoclonic frontotemporal dementia presenting with severe amnesia.
encephalopathy: an underdiagnosed treatable condition? Brain 2005; 128:597–605.
Mov Disord 1996; 11:555–62. Green J, Morris JC, Sandson J et al. Progressive aphasia: a
Giannopoulos S, Kostadima V, Selvi A et al. Bilateral paramedian precursor of global dementia? Neurology 1990; 40:423–9.
thalamic infarcts. Arch Neurol 2006; 63:1625. Greenberg SM, Vonsattel JPG, Stakes JW et al. The clinical
Giffin ME, Rogers HM, Kernohan JW. Postvaccinial (typhoid) spectrum of cerebral amyloid angiopathy: presentations
encephalitis. Arch Neurol Psychiatry 1948; 59:233–40. without lobar hemorrhage. Neurology 1993; 43:2073–9.
Gillberg C, Persson E, Grufman M et al. Psychiatric disorders in Greenblatt DJ, Harmatz JS, Shapiro L et al. Sensitivity to triazolam
mildly and severely mentally retarded urban children and in the elderly. N Engl J Med 1991; 324:1691–8.
adolescents. Epidemiological aspects. Br J Psychiatry 1986; Greene JBW, Patterson K, Xuereb J et al. Alzheimer disease and
149:68–74. nonfluent progressive aphasia. Arch Neurol 1996; 53:1072–8.
Gilles C, Brucher JM, Khoubesserian P et al. Cerebral amyloid Greenwald BS, Kramer-Ginsberg E, Marin DB et al. Dementia with
angiopathy as a cause of multiple intracerebral hemorrhages. coexistent major depression. Am J Psychiatry 1989; 146:1472–8.
Neurology 1984; 34:730–5. Grimes DA, Lang AE, Bergeron CB. Dementia as the most common
Glaser G, Pincus JH. Limbic encephalitis. J Nerv Ment Dis 1969; presentation of cortical-basal ganglionic degeneration.
149:59–67. Neurology 1999; 53:1969–74.
Goldberg A. Acute intermittent porphyria. Q J Med 1959; Guerrini R, Belmonte A, Canapicchi R et al. Reversible
28:183–209. pseudoatrophy of the brain and mental deterioration
Goldfarb LG, Chumakov MP, Petrov PA et al. Olivopontocerebellar associated with valproate treatment. Epilepsia 1998;
atrophy in a large Iakut kinship in eastern Siberia. Neurology 39:27–32.
1989; 39:1527–30. Guillozet AL, Weintraub S, Mash DC et al. Neurofibrillary tangles,
Gomez EA, Avilens M. Neurosyphilis in community mental health amyloid, and memory in aging and mild cognitive impairment.
clinics: a case series. J Clin Psychiatry 1984; 45:127–9. Arch Neurol 2003; 60:729–36.
Gomez Diaz RA, Rivera Moscosco R, Ramos Rodriguez R et al. Gustafson L, Hagberg B. Recovery in hydrocephalic dementia after
Diabetic ketoacidosis in adults: clinical and laboratory shunt operation. J Neurol Neurosurg Psychiatry 1978;
features. Arch Med Res 1996; 27:177–81. 41:940–7.
p 05.qxd 3/10/08 9:34 AM Page 196
Haan J, Lanser JBK, Zijderveld I et al. Dementia in hereditary Hay WJ, Rickards AG, McMenemy WH et al. Organic mercurial
cerebral hemorrhage with amyloidosis – Dutch type. Arch encephalopathy. J Neurol Neurosurg Psychiatry 1963;
Neurol 1990; 47:965–7. 26:199–202.
Hadjivassiliou M, Grunewald RA, Lawden M et al. Headache and Hayflick SJ, Westaway SK, Levinson B et al. Genetic, clinical, and
CNS white matter abnormalities associated with luten radiographic delineation of Hallervorden–Sptaz syndrome. N
sensitivity. Neurology 2001; 56:385–8. Engl J Med 2003; 348:33–40.
Hagberg B (ed.). Rett syndrome: clinical and biological aspects. Healton EB, Brust JC, Feinfeld DA et al. Hypertensive
London: MacKeith Press, 1993. encephalopathy and the neurologic manifestations of
Hagberg B, Aicardi J, Dias K et al. A progressive syndrome of malignant hypertension. Neurology 1982; 32:127–30.
autism, dementia, ataxia, and loss of purposeful hand Heilman KM, Fisher WR. Hyperlipidemic dementia. Arch Neurol
movements: Rett’s syndrome: report of 35 cases. Ann Neurol 1974; 31:67–8.
1983; 14:471–9. Heilman KM, Sypert GW. Korakoff’s syndrome
Hageman ATM, Gabreels FJM, de Jong JGN et al. Clinical resulting from bilateral fornix lesion. Neurology 1977;
symptoms of adult metachromatic leukodystrophy and 27:490–3.
arylsulfatase A pseudodeficiency. Arch Neurol 1995; Henchey R, Cibula J, Helveston W et al. Electroencephalographic
52:408–13. findings in Hashimoto’s encephalopathy. Neurology 1995;
Hagerman RJ, Leehey M, Heinrichs W et al. Intention tremor, 45:977–81.
parkinsonism, and generalized brain atrophy in male carriers Heritch AJ, Capwell R, Roy-Byrne PR. A case of psychosis and
of fragile X. Neurology 2001; 57:127–30. delirium following withdrawal from triazolam. J Clin
Hall BD, Smith DW. Prader–Willi syndrome. A resume of 32 cases Psychiatry 1987; 48:168–9.
including an instance of affected first cousins, one of whom is Heutink P, Stevens M, Rizzu P et al. Hereditary frontotemporal
of normal stature and intelligence. J Pediatrics 1972; dementia is linked to chromosome 17q21–q22: a genetic and
81:286–93. clinicopathological study of three Dutch families. Ann Neurol
Hall RCW, Joffe JR. Hypomagnesemia: physical and psychiatric 1997; 41:150–9.
symptoms. J Am Med Assoc 1973; 224:1749–51. Hierons R. Changes in the nervous system in acute porphyria.
Halperin JJ, Luft BJ, Anand AK et al. Lyme neuroborreliosis: central Brain 1957; 80:176–92.
nervous system manifestations. Neurology 1989; 39:753–9. Hill ME, Lougheed WM, Barnett HJM. A treatable form of
Haltia T, Palo J, Haltia M et al. Juvenile metachromatic dementia due to normal pressure, communicating
leukodystrophy: clinical, biochemical, and neuropathologic hydrocephalus. Can Med Assoc J 1967; 97:1309.
studies in nine new cases. Arch Neurol 1980; 37:42–6. Hinchey J, Chaves C, Appignani B et al. A reversible posterior
Handen BL, Beaux AM, Gosling A et al. Efficacy of methylphenidate leukoencephalopathy syndrome. N Engl J Med 1996;
among mentally retarded children with attention deficit 334:494–500.
hyperactivity disorder. Pediatrics 1990; 86:922–30. Hirose G, Bass NH. Metachromatic leukodystrophy in the adult: a
Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatrics biochemical study. Neurology 1972; 22:312–20.
1975; 87:285–90. Hodges JR, Carpenter K. Anterograde amnesia with fornix damage
Hansotia P, Cleeland CS, Chun RWM. Juvenile Huntington’s following removal of IIIrd ventricle colloid cyst. J Neurol
chorea. Neurology 1968; 18:217–24. Neurosurg Psychiatry 1991; 54:633–8.
Hardie RJ, Pullon HWH, Harding AE et al. Neuroacanthocytosis: a Hodges JR, McCarthy RA. Autobiographical amnesia resulting
clinical, haemotological and pathological study of 19 cases. from bilateral paramedian thalamic infarction: A case study in
Brain 1991; 114:13–49. cognitive neurobiology. Brain 1993; 116:921–40.
Harper C. The incidence of Wernicke’s encephalopathy in Australia Hodges JR, Ward CD. Observations during transient global
– a neuropathologial study of 131 cases. J Neurol Neurosurg amnesia: a behavioral and neuropsychological study of five
Psychiatry 1983; 46:593–8. cases. Brain 1989; 112:595–620.
Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Hokkanen L, Salonen O, Launes J. Amnesia in acute
Wernicke–Korsakoff complex: a retrospective analysis of 131 herpetic and nonherpetic encephalitis. Arch Neurol 1996;
cases diagnosed at necropsy. J Neurol Neurosrug Psychiatry 53:972–8.
1986; 49:341–5. Hollister LE, Gillespie HK. Marijuana, ethanol, and
Harrison MJG, Robert CM, Uttley D. Benign aqueductal stenosis in dextroamphetamine: mood and mental function alterations.
adults. J Neurol Neurosurg Psychiatry 1974; 37:1322–8. Arch Gen Psychiatry 1970; 23:199–203.
Harsch HH. Neuroleptic malignant syndrome: physiological and Holmes JT, Filley CM, Rosenberg NL. Neurologic sequelae of
laboratory findings in a series of nine cases. J Clin Psychiatry chronic solvent vapor abuse. Neurology 1986; 36:698–702.
1987; 48:328–33. Horoupian DS, Thal L, Katzman R et al. Dementia and motor
Hart SP, Frier BM. Causes, management and morbidity of acute neuron disease: morphometric, biochemical, and golgi studies.
hypoglycemia in adults requiring hospital admission. Q J Med Ann Neurol 1984; 16:305–13.
1998; 91:505–10. Horvath J, Coeytax A, Jallow P et al. Carbamazepine
Harvey PKP, Davis JN. Traumatic encephalopathy in a young encephalopathy masquerading as Creutzfeldt–Jakob disease.
boxer. Lancet 1974; 2:928–9. Neurology 2005; 65:650–1.
p 05.qxd 3/10/08 9:34 AM Page 197
References 197
Hossain M. Neurological and psychiatric manifestations in Jankovic J, Caskey TC, Stout T et al. Lesch–Nyhan syndrome: a
idiopathic hypoparathyroidism: response to treatment. study of motor behavior and cerebrospinal fluid
J Neurol Neurosurg Psychiatry 1970; 33:153–6. neurotransmitters. Ann Neurol 1988; 23:466–9.
Hotopf MH, Pollock S, Lishman WA. An unusual presentation of Jefferson AA, Keogh AJ. Intracranial abscesses: a review of treated
multiple sclerosis. Psychol Med 1994; 24:525–8. patients over 20 years. Q J Med 1977; 46:389–400.
Hotson JR, Langston JW. Disulfiram-induced encephalopathy. Jenkins CD, Mellins RB. Lead poisoning in children: a study of
Arch Neurol 1976; 33:141–2. forty-six cases. Arch Neurol Psychiatry 1957; 77:70–8.
Hu WT, Murray JA, Greenaway MC et al. Cognitive impairment Jenkins RB. Inorganic arsenic and the nervous system. Brain 1966;
and celiac disease. Arch Neurol 2006; 63:1440–6. 89:479–98.
Hu WT, Kantarc OH, Meritt JL et al. Ornithine transcarbamylase Jennekens-Schinkel A, Sanders EACM. Decline of cognition in
deficiency presenting as encephalopathy during adulthood multiple sclerosis: dissociable deficits. J Neurol Neurosurg
following bariatric surgery. Arch Neurol 2007; 64:126–8. Psychiatry 1986; 49:1354–60.
Huber SJ, Kissel JT, Shuttleworth EC et al. Magnetic resonance Jicha GA, Parisi JE, Dickson DW et al. Neuropathologic outcome of
imaging and clinical correlates of intellectual impairment in mild cognitive impairment following progression to clinical
myotonic dystrophy. Arch Neurol 1989; 46:536–40. dementia. Arch Neurol 2006; 63:674–81.
Huff FJ, Boller F, Lucchelli F et al. The neurologic examination in Johnson JC, Kerse NM, Gottleib G et al. Prospective versus
patients with probable Alzheimer’s disease. Arch Neurol 1987; retrospective methods of identifying patients with delirium. J
44:929–32. Am Geriatr Soc 1992; 40:316–19.
Hughes JT, Brownell B. Granulomatous giant-celled angiitis of the Johnson JC, Jayadevappa R, Baccash PD et al. Nonspecific
central nervous system. Neurology 1966; 16:293–8. presentation of pneumonia in hospitalized people: age effect
Huson SM, Harper PS, Compston DAS et al. Von Recklinghausen or dementia? J Am Geriatr Soc 2000; 48:1316–20.
neurofibromatosis: A clinical and population study in south- Johnson RI, Richardson EP. The neurological manifestations of
east Wales. Brain 1988; 111:1355–81. systemic lupus erythematosus. Medicine 1968; 47:337–69.
Ikeda K, Akiyama H, Iritani S et al. Corticobasal degeneration with Jones HR, Hedley-Whyte T. Idiopathic hemochromatosis (IHC):
primary progressive aphasia and accentuated cortical lesion in dementia and ataxia as presenting signs. Neurology 1983;
superior temporal gyrus: case report and review. Acta 33:1479–83.
Neuropathol 1996; 92:534–9. Jung HH, Bassetti C, Tournier-Lasserve E et al. Cerebral autosomal
Illowsky B, Yang JC, Khorsand M et al. Multiple cerebral lesions dominant arteriopathy with subcortical infarcts and
complicating therapy with interleukin–2. Neurology 196; leukoencephalopathy: a clinicopathological and genetic study
47:417–24. of a Swiss family. J Neurol Neurosurg Psychiatry 1995;
Ironside R, Guttmacher M. The corpus callosum and its tumors. 59:138–43.
Brain 1929; 52:442–83. Jungreis AC, Shaumberg HH. Encephalopathy from abuse of
Ironside R, Bosanquet FD, McMenemy WH. Central demyelination bismuth subsalicylate (Pepto-Bismol). Neurology 1993;
of the corpus callosum (Marchaifava-Bignami disease): with 43:1265.
report of a second case in Great Britian. Brain 1961; Kahn EA, Crosby EC. Korsakoff’s syndrome associated with
84:212–30. surgical lesions involving the mammillary bodies. Neurology
Isbell H, Alstschul S, Kornetsky CH et al. Chronic barbiturate 1971; 21:117–25.
intoxication. Arch Neurol Psychiatry 1950; 64:1–28. Kalimo H, Olsson Y. Effect of severe hypoglycemia on the human
Isbell H, Fraser HF, Wickler A et al. An experimental study of brain. Acta Neurol Scand 1980; 62:345–56.
etiology of ‘rum fits’ and delirium tremens. Q J Stud Alcohol Kamaki M, Kawamura M, Moriya H et al. ‘Crossed homonymous
1955; 16:1–33. hemianopia’ and ‘crossed left hemispatial neglect’ in a case of
Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical Marchiafava–Bignami disease. J Neurol Neurosurg Psychiatry
and pathological study of 20 necropsy cases. J Neurol 1993; 56:1027–32.
Neurosurg Psychiatry 1981; 44:209–15. Kanzer M. Amnesia: a statistical study. Am J Psychiatry 1939;
Ishii N, Nishihara Y, Imamura T. Why do frontal lobe symptoms 96:711–16.
predominate in vascular dementia with lacunes? Neurology Kaplan PW, Birbeck G. Lithium-induced confusional states:
1986; 36:340–5. nonconvulsive status epilepticus or triphasic encephalopathy?
Jacobsen FM, Sack DA, James SP. Delirium induced by verapamil. Epilepsia 2006; 47:2071–7.
Am J Psychiatry 1987; 144:248. Kaplan PW, Waterbury L, Kawas C et al. Reversible dementia with
Jacobson DM, Terrance CF, Reinmuth OM. The neurologic idiopathic hypereosinophilia. Neurology 1990; 40:1388–91.
manifestations of fat embolism. Neurology 1986; Kapur N, Ellison D, Smith MP et al. Focal retrograde amnesia
36:847–51. following isolated bilateral temporal lobe pathology. Brain
Jana DK, Romano-Jana L. Hypernatremic psychosis in the elderly: 1992; 115:73–85.
case reports. J Am Ger Soc 1973; 21:473–7. Kapur N, Barker S, Burrows EH et al. Herpes simplex encephalitis:
Jankovic J, Kirkpatrick JB, Blomquist KA et al. Late-onset long-term magnetic resonance imaging and
Hallervorden–Spatz disease presenting as familial neuropsychological profile. J Neurol Neurosurg Psychiatry
parkinsonism. Neurology 1985; 35:227–34. 1994; 57:1334–42.
p 05.qxd 3/10/08 9:34 AM Page 198
Karalis DG, Quinn V, Victor MF et al. Risk of catheter-related Koeppen AH, Barron KD. Marchaifava–Bignami disease. Neurology
emboli in patients wth atherosclerotic debris in the thoracic 1978; 28:290–4.
aorta. Am Heart J 1996; 131:1149–55. Koo EH, Massey EW. Granulomatous angiitis of the central
Karbe H, Kertesz A, Polk M. Profiles of language impairment in nervous system: protean manifestations and response to
primary progressive aphasia. Arch Neurol 1993; 50:192–201. treatment. J Neurol Neurosurg Psychiatry 1988; 51:1126–33.
Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a Koponen HJ, Riekkinen PJ. A prospective study of delirium in
neurologic disorder following rapid correction of elderly patients admitted to a psychiatric hospital. Psychol
hyponatremia. Medicine 1993; 72:359–73. Med 1993; 23:103–9.
Karpati G, Frame B. Neuropsychiatric disorders in primary Koponen H, Stenback U, Mattila E et al. Delirium among elderly
hyperparathyroidism: clinical analysis with review of the persons admitted to a psychiatric hospital: clinical course
literature. Arch Neurol 1964; 10:387–97. during the acute stage and one-year follow-up. Acta Psychiatr
Kartsounis LD, Rudge P, Stevens JM. Bilateral lesions of CA1 and Scand 1989; 79:579–85.
CA2 fields of the hippocampus are sufficient to cause a severe Kriegstein AR, Shungu DC, Millar WS et al. Leukoencephalopathy
amnesia syndrome in humans. J Neurol Neurosurg Psychiatry and raised brain lactate from heroin vapor inhalation (‘chasing
1995; 59:95–8. the dragon’). Neurology 1999; 53:1765–73.
Kawashima N, Shindo R, Kohno M. Primary Sjorgen’s syndrome Kritchevsky M, Squire LR. Transient global amnesia: evidence for
with subcortical dementia. Intern Med 1993; 32:561–4. extensive, temporally graded retrograde amnesia. Neurology
Kawashima T, Oda M, Kund T et al. Metyrapone for delirium due 1989; 39:213–18.
to Cushing’s syndrome induced by occult ectopic Kroll NEA, Markowitsch HJ, Knight RT et al. Retrieval of old
adrenocorticotrophic hormone secretion. J Clin Psychiatry memories: the temporofrontal hypothesis. Brain 1997;
2004; 65:1019–20. 120:1377–99.
Keck PE, Pope HG, McElroy SL. Frequency and presentation of Krupp LB, Lipton RB, Swerdlow ML et al. Progressive multifocal
neuroleptic malignant syndrome: a prospective study. Am J leukoencephalopathy: clinical and radiographic features. Ann
Psychiatry 1987; 144:1344–6. Neurol 1985; 17:344–9.
Kelly WF, Psychiatric aspects of Cushing’s syndrome. Q J Med Kryzhanovskaya LA, Jeste PV, Young CA et al. A review of
1996; 89:543–51. treatment-emergent adverse events during olanzapine clinical
Kertesz A, Hudson L, MacKenzie IRA et al. The pathology and trials in elderly patients with dementia. J Clin Psychiatry 2006;
nosology of primary progressive aphasia. Neurology 1994; 67:933–45.
44:2065–72. Kumral E, Evyapan D, Balkir K et al. Bilateral thalamic infarction:
Keschner M, Sloane P. Encephalitis, idiopathic and arteriosclerotic clinical, etiological and MRI correlates. Acta Neurol Scand
parkinsonism: a clinicopathologic study. Arch Neurol 2001; 103:35–42.
Psychiatry 1931; 25:1011–45. Kunig G, Datwyler S, Eschen A et al. Unrecognized long-lasting
Keschner M, Bender MB, Strauss I. Mental symptoms in cases of tramadol-induced delirium in two elderly patients. A case
tumor of the temporal lobe. Arch Neurol Psychiatry 1936; report. Pharmacopsychiatry 2006; 39:194–9.
35:572–96. Kushner MJ, Hauser WA. Transient global amnesia: a case-control
Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic study. Ann Neurol 1985; 18:684–91.
syndrome. Report of 22 cases and brief review. Am J Med Kusumi RK, Plouffe JF, Wyatt RH et al. Central nervous system
1984; 77:899–904. toxicity associated with metronidazole therapy. Ann Int Med
Kinkel WR, Jacobs L, Polachino I et al. Subcortical arteriosclerotic 1980; 93:59–60.
encephalopathy (Binswanger’s disease): computed Lagos JC, Gomez MR. Tuberose sclerosis: reappraisal of a clinical
tomographic, nuclear magnetic resonance, and clinical entity. Mayo Clin Proc 1967; 42:26–49.
correlations. Arch Neurol 1985; 42:951–9. Lai F, Williams RS. A prospective study of Alzheimer’s disease in
Kirk A, Kertesz A, Polk MJ. Dementia with leukoencephalopathy in Down syndrome. Arch Neurol 1989; 46:849–53.
systemic lupus erythematosus. Can J Neurol Sci 1991; Landi G, Giusti MC, Guidotti M. Transient global amnesia due to
18:344–8. left temporal hemorrhage. J Neurol Neurosurg Psychiatry
Kirubakaran V, Liskow B, Mayfield D et al. Case report 1982; 45:1062–3.
of acute disulfiram overdose. Am J Psychiatry 1983; Langworthy OR. Lesions of the central nervous system
140:1513–14. characteristic of pellagra. Brain 1931; 54:291–302.
Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Laplane D, Attal N, Sauron B et al. Lesions of basal ganglia
Lewy body disease: a clinicopathologic study using Alzheimer’s due to disulfiram. J Neurol Neurosurg Psychiatry 1992;
disease and Parkinson’s disease comparison groups. Neurology 55:925–9.
1996; 47:1148–52. Lasek K, Lencer R, Gaser C et al. Morphological basis for the
Knee ST, Razani J. Acute organic brain syndrome: a complication spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA
of disulfiram therapy. Am J Psychiatry 1974; 131:1281–2. 17). Brain 2006; 129:2341–52.
Knibb J, Xuereb JH, Patterson K et al. Clinical and pathological Lawlor PG, Gagnon B, Mancini IL et al. Occurrence, causes, and
characterization of progressive aphasia. Ann Neurol 2006; outcome of delirium in patients with advanced cancer: a
59:156–65. prospective study. Arch Int Med 2000; 160:786–94.
p 05.qxd 3/10/08 9:34 AM Page 199
References 199
Layne OL, Yudofsky SC. Postoperative psychosis in cardiotomy Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J
patients: the role of organic and psychiatric features. N Engl J Psychiatry 1992; 161:843–5.
Med 1971; 284:518–20. Lisak RP, Zimmerman RA. Transient global amnesia due to a
Lazar RB, Ho SU, Melen O et al. Multifocal central nervous system dominant hemisphere tumor. Arch Neurol 1977; 34:317–18.
damage caused by toluene abuse. Neurology 1983; Lishman WA. Cerebral disorder in alcoholism: syndromes of
33:1337–40. impairment. Brain 1981; 104:373–410.
Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann Liss L. Pituicytoma, a tumor of the hypothalamus. Arch Neurol
Neurol 1978; 4:199–204. Psychiatry 1958; 80:567–76.
Lee BI, Lee BC, Hwang YM et al. Prolonged ictal amnesia with Litaker D, Locala J, Franco K et al. Preoperative risk factors for
transient focal abnormalities on magnetic resonance imaging. postoperative delirium. Gen Hosp Psychiatry 2001; 23:84–9.
Epilepsia 1992; 33:1042–6. Little BW, Brown PW, Rodgers-Johnson P et al. Familial myoclonic
Lee JW. Recurrent delirium associated with obstructive sleep dementia masquerading as Creutzfeldt–Jakob disease. Ann
apnea. Gen Hosp Psychiatry 1998; 30:120–2. Neurol 1986; 20:231.
Lee K, Moller L, Hardt F et al. Alcohol induced brain damage and Litvan I, Mangone CA, McKee A et al. Natural history of
liver damage in young males. Lancet 1979; 2:759–61. progressive supranuclear palsy (Steele–Richardson–Olszewski
Lee TH, Chen SS, Su SL et al. Baclofen intoxication: report of four syndrome) and clinical predictors of survival: a
cases and review of the literature. Clin Neuropharmacol clinicopathologic study. J Neurol Neurosurg Psychiatry 1996a;
1992;15:56–62. 61:615–20.
Lenke RR, Levy HL. Maternal phenylketonuria and Litvan I, Agid Y, Jankovic J et al. Accuracy of clinical criteria for
hyperphenylalanemia: an international survey of the outcome the diagnosis of progressive supranuclear palsy
of treated and untreated pregnancies. N Engl J Med 1980; (Steele–Richardson–Olszewski syndrome). Neurology 1996b;
303:1202–8. 46:922–30.
Leo RJ, Baer D. Delirium associated with baclofen withdrawal: a Litvan I, Mega MS, Cumings JL et al. Neuropsychiatric aspects of
review of common presentations and management strategies. progressive supranuclear palsy. Neurology 1996c; 47:1184–9.
Psychosomatics 2005; 46:503–7. Litvan I, Agid Y, Sastrj N et al. What are the obstacles for an
Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and accurate clinical diagnosis of Pick’s disease? Neurology 1997a;
central nervous system dysfunction. Am J Med 1964; 36:561–70. 49:62–9.
Levkoff SE, Evans DA, Liptzin B et al. Delirium: the occurrence and Litvan I, Goetz G, Jankovic J et al. What is the accuracy of the
persistence of symptoms among elderly hospitalized patients. clinical diagnosis of multiple system atrophy? A
Arch Intern Med 1992; 152:334–40. clinicopathologic study. Arch Neurol 1997b; 54:937–44.
Levin HS, High WM, Eisenberg HM. Learning and forgetting during Litvan I, Campbell G, Mangone CA et al. Which clinical features
post-traumatic amnesia in head injured patients. J Neurol differentiate progressive supranuclear palsy
Neurosurg Psychiatry 1988; 51:14–20. (Steele–Richardson–Olszewski syndrome) from related
Levy AB. Delirium and seizures due to abrupt alprazolam disorders? A clinicopathologic study. Brain 1997c; 120:65–74.
withdrawal: case report. J Clin Psychiatry 1984; 45:38–9. Litvan I, Agid Y, Goetz C et al. Accuracy of the clinical diagnosis
Lewis MH, Bodfish JW, Powell SB et al. Clomipramine treatment of corticobasal degeneration: a clinicopathologic study.
for self-injurious behavior of individuals with mental Neurology 1997d; 48:119–25.
retardation: a double-blind comparison with placebo. Am J Lobosky JM, Vangilder JC, Damasio AR. Behavioral manifestations
Ment Retard 1996; 100:654–65. of third ventricular colloid cysts. J Neurol Neurosurg Psychiatry
Lichtenstein BW. Sturge–Weber–Dimitri syndrome: cephalic form 1984; 47:1075–80.
of neurocutaneous hemangiomatosus. Arch Neurol Psychiatry Logigian EL, Kaplan RF, Steere AC. Chronic neurologic
1954; 71:291–301. manifestations of Lyme disease. N Engl J Med 1990;
Lindenbaum J, Healton EB, Savage DG et al. Neuropsychiatric 323:1438–44.
disorders caused by cobalamin deficiency in the absence of Lotrich FE, Rosen J, Pollock BG. Dextromethorphan-induced
anemia or macrocytosis. N Engl J Med 1988; 318:1720–8. delirium and possible methadone interaction. Am J Geriatr
Lindquist G, Norlen G. Korsakoff’s syndrome after operation on Pharmacother 2005; 3:17–20.
ruptured aneurysm of the anterior communicating artery. Acta Louis ED, Lynch T, Kaufmann P et al. Diagnostic guidelines in central
Psychiatr Scand 1966; 42:24–34. nervous system Whipple’s disease. Ann Neurol 1996; 40:561–8.
Linn RT, Wolf PA, Bachman DL et al. The ‘preclinical phase’ of Louis ED, Klatka LA, Liu Y et al. Comparison of extrapyramidal
probable Alzheimer’s disease. Arch Neurol 1995; 52:485–90. features in 31 pathologically confirmed cases of diffuse Lewy
Lipowski ZJ. Transient cognitive disorders (delirium, acute body disease and 34 pathologically confirmed cases of
confusional states) in the elderly. Am J Psychiatry 1983; Parkinson’s disease. Neurology 1997; 48:376–80.
140:1426–36. Lundquist G. Delirium tremens: a comparative study of
Lipowski ZJ. Delirium (acute confusional state). JAMA 1987; pathogenesis, course and prognosis with delirium tremens.
258:1789–92. Acta Psychiatr Neurol Scand 1961; 36:443–66.
Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989; Lurie LA. Pernicious anemia with mental symptoms: observations
320:578–82. on the variable extent and probable duration of central
p 05.qxd 3/10/08 9:34 AM Page 200
nervous system lesions in four necropsied cases. Arch Neurol Margolin D, Hammerstad J, Orwoll E et al. Intracranial
Psychiatry 1919; 2:67–109. calcification in hyperparathyroidism associated with gait
Mach J, Dysken M, Richards H et al. Serum anticholinergic activity apraxia and parkinsonism. Neurology 1980; 30:1005–7.
in hospitalized older persons with delirium: a preliminary Markowitsch HJ, Calabrese P, Liess J et al. Retrograde amnesia
study. J Am Geriatr Soc 1995; 43:491–5. after traumatic injury of the fronto-temporal cortex. J Neurol
MacKay ME, McLardy T, Harris C. A case of periarteritis nodosa of Neurosurg Psychiatry 1993; 56:988–92.
the central nervous system. J Ment Sci 1950; 96:470–5. Martin FI, Deam DR. Hyperthyroidism in elderly hospitalized
MacNeill A, Grennan DM, Ward D et al. Psychiatric problems in patients. Clinical features and treatment outcomes. Med J Aust
systemic lupus erythematosus. Br J Psychiatry 1976; 1996; 164:200–3.
128:442–5. Martland HS. Punch drunk. J Am Med Assoc 1928; 91:1103–7.
McCauley DLF, Lecky BRF, Earl CJ. Gold encephalopathy. J Neurol Mas J-L, Bousser M-G, Lacombe C et al. Hyperlipidemic dementia.
Neurosurg Psychiatry 1977; 40:1021–2. Neurology 1985; 35:1385–7.
McHugh PR. Occult hydrocephalus. Q J Med 1964; 33:297–308. Mateo D, Gimenez-Roldan S. Dementia in idiopathic
McKeith IG, Fairbairn A, Perry RH. Neuroleptic sensitivity with hypoparathyroidism: rapid efficacy of alfacalcidol. Arch Neurol
senile dementia of the Lewy body type. BMJ 1992; 1982; 39:424–5.
305:673–8. Mathews WB. Familial calcification of the basal ganglia with
McKeith IG, Fairbairn AF, Bothwell RA et al. An evaluation of the response to parathormone. J Neurol Neurosurg Psychiatry
predictive ability and inter-rater reliability of clinical 1957; 20:172–7.
diagnostic criteria for senile dementia of the Lewy body type. Mayeux R, Lueders H. Complex partial status epilepticus: case
Neurology 1994a; 44:872–7. report and proposal for diagnostic criteria. Neurology 1978;
McKeith IG, Fairbairn AF, Perry RH et al. The clinical diagnosis and 28:957–61.
misdiagnosis of senile dementia of Lewy body type (SDLT). Br J Mayeux R, Denaro J, Hemenegildo N et al. A population-based
Psychiatry 1994b; 165:324–32. investigation of Parkinson’s disease with and without
McKhann GM, Grega MA, Borowicz LM et al. Encephalopathy and dementia: relationship to age and gender. Arch Neurol 1992;
stroke after coronary artery bypass grafting: incidence, 49:492–7.
consequences, and prediction. Arch Neurol 2002; 59:1422–8. Medalia AA, Merriam AE, Ehrenreich JH. The neuropsychological
McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical sequelae of attempted hanging. J Neurol Neurosurg Psychiatry
and pathological study. Ann Neurol 1980; 8:161–7. 1991; 54:546–8.
Malamud N, Skillicorn SA. Relationship between the Wernicke Medina, JL, Rubino FA, Ross E. Agitated delirium caused by
and the Korsakoff syndrome. Arch Neurol Psychiatry 1956; infarctions of the hippocampal formation and fusiform and
76:585–91. lingual gyri. Neurology 1974; 24:1181–4.
Malamut BL, Graff-Radford N, Chawluk J et al. Memory in a case Medina JL, Sudhansu C, Rubino FA. Syndrome of agitated delirium
of bilateral thalamic infarction. Neurology 1992; 42:163–9. and visual impairment: a manifestation of medial temporo-
Malandrini A, Carrera P, Palmeri ST et al. Clinicopathological and occipital infarction. J Neurol Neurosurg Psychiatry 1977;
genetic studies of two further Italian families with cerebral 40:861–4.
autosomal dominant arteriopathy. Acta Neuropathol 1996; Meierkord H, Wieshman U, Niehaus L et al. Structural
92:115–22. consequences of status epilepticus with serial magnetic
Malouf R, Brust JCM. Hypoglycemia: causes, neurological resonance imaging. Acta Neurol Scand 1997; 96:127–32.
manifestations, and outcome. Ann Neurol 1985; 17:421–30. Mendez MF, Frey WH. Multiple sclerosis dementia. Neurology
Mandell AM, Alexander MP, Carpenter S. Creutzfeldt–Jakob 1992; 42:696.
disease presenting as isolated aphasia. Neurology 1989; Mendez MF, Selwood A, Mastri AR et al. Pick’s disease versus
39:55–8. Alzheimer’s disease: a comparison of clinical characteristics.
Manepalli J, Grossberg GT, Mueller C. Prevalence of delirium and Neurology 1993; 43:289–92.
urinary tract infection in a psychogeriatric unit. J Geriatr Menza M, Murray GB. Pancreatic encephalopathy. Biol Psychiatry
Psychiatry Neurol 1990; 3:198–202. 1989; 25:781–4.
Mann DMA, South PW, Snowden JS et al. Dementia of the frontal Menza MA, Cocchiola J, Golbe LI. Psychiatric symptoms in
lobe type: neuropathology and immunohistochemistry. J progressive supranuclear palsy. Psychosomatics 1995;
Maramattom BV, Zaldivar RA, Glynn SM et al. Acute intermittent Mermelstein HT. Clarithromycin-induced delirium in a general
porphyria presenting as a diffuse encephalopathy. Ann Neurol hospital. Psychosomatics 1997; 39:540–2.
2005; 57:51–4. Messert B, Baker NH. Syndrome of progressive spastic ataxia and
Marcantino ER, Juarez G, Goldman L et al. The relationship of apraxia associated with occult hydrocephalus. Neurology
postoperative delirium with psychoactive medications. JAMA 1966; 16:440–52.
1994; 272:1518–22. Meterissian GB. Risperidone-induced neuroleptic malignant
Marder K, Ming-Xin T, Cote L et al. The frequency and associated syndrome: a case report and review. Can J Psychiatry 1996;
risk factors for dementia in patients with Parkinson’s disease. 41:52–4.
Arch Neurol 1995; 52:695–701. Miller CM. Whiplash amnesia. Neurology 1982; 32:667–8.
p 05.qxd 3/10/08 9:34 AM Page 201
References 201
Miller DD, Sharafuddin MJA, Kathol RG. A case of clozapine- Muramoto O, Kuru Y, Sugishita M et al. Pure memory loss with
induced neuroleptic malignant syndrome. J Clin Psychiatry hippocampal lesions: a pneumoencephalographic study. Arch
1991; 52:99–101. Neurol 1979; 36:54–6.
Miller DH, Kendall BE, Barter S et al. Magnetic resonance imaging Murphy MA, Feldman JA, Kilburn G. Hallervorden–Spatz disease in
in central nervous system sarcoidosis. Neurology 1988; a psychiatric setting. J Clin Psychiatry 1989; 50:66–8.
38:378–83. Narayanan ST, Murthy JMK. Nonconvulsive status epilepticus in a
Miller E, Craddock-Watson JE, Pollock TM. Consequences of neurological intensive care unit: profile in a developing
confirmed maternal rubella at successive stages of pregnancy. country. Epilepsia 2007; 48:900–6.
Lancet 1982; 2:781–4. Navia BA, Price RW. The acquired immunodeficiency syndrome
Miller HG, Stanton JB, Gibbons JL. Para-infectious dementia complex as the presenting or sole manifestation of
encephalomyelitis and related syndromes. Q J Med 1956; human immunodeficiency infection. Arch Neurol 1987;
25:427–505. 44:65–9.
Miller JW, Petersen RC, Metter EJ. Transient global amnesia: Navia BA, Petito CK, Gold JWM et al. Cerebral toxoplasmosis
clinical characteristics and prognosis. Neurology 1987; complicating the acquired immune deficiency syndrome:
37:733–7. clinical and neuropathological findings in 27 patients. Ann
Min SK. A brain syndrome associated with delayed Neurol 1986a; 19:224–38.
neuropsychiatric sequelae following acute carbon monoxide Navia BA, Jordan BD, Price RW. The AIDS–dementia complex: I.
intoxication. Acta Psychiatr Scand 1986; 73:80–6. Clinical features. Ann Neurol 1986b; 19:517–24.
Minagar A, Shulman LM, Weiner WJ. Transderm-induced Neary D, Snowden JS, Mann DMA et al. Frontal lobe dementia and
psychosis in Parkinson’s disease. Neurology 1999; 53:433–4. motor neuron disease. J Neurol Neurosurg Psychiatry 1990;
Modi G, Modi M, Martinus R et al. The clinical and genetic 53:23–32.
characteristics of spinocerebellar ataxia type 7 (SCA7) in three Neary D, Snowden JS, Mann DMA. Familial progressive atrophy:
black South African families. Acta Neurol Scand 2000; its relationship to other forms of lobar atrophy. J Neurol
Moersch FP. Psychic manifestations in cases of brain tumors. Am J Nichelli P, Bahmanian-Behbahani G, Gentilini M et al. Preserved
Psychiatry 1925; 81:707–24. memory abilities in thalamic amnesia. Brain 1988;
Moersch FP, Kernohan JW. Hypoglycemia: neurologic and 111:1337–53.
neuropathologic studies. Arch Neurol Psychiatry 1938; Nicholson A, Alberman E. Cerebral palsy – an increasing
39:242–57. contributor to severe mental retardation. Arch Dis Child 1992;
Molina JA, Calandre L, Bermejo F. Myoclonic encephalopathy due 67:1050–5.
to bismuth salts: treatment with dimercaprol and analysis of Nielsen J. Delirium tremens in Copenhagen. Acta Psychiatr Scand
CSF transmitters. Acta Neurol Scand 1989; 79:200–3. 1965; 41(suppl. 187):1–92.
Molsa PK, Paljarvi L, Rinne JO et al. Validity of clinical diagnosis in Nightingale S, Venables GS, Bates D. Polymyalgia rheumatica with
dementia: a prospective clinico-pathological study. J Neurol diffuse cerebral disease responding rapidly to steroid therapy.
Neurosurg Psychiatry 1985; 48:1085–90. J Neurol Neurosurg Psychiatry 1982; 45:841–3.
Moosy J, Martinez AJ, Hanin I et al. Thalamic and subcortical Nishino H, Rubino FA, Parisi JE. The spectrum of neurologic
gliosis with dementia. Arch Neurol 1987; 44:510–13. involvement in Wegener’s granulomatosis. Neurology 1993;
Mori E, Yamadori A. Acute confusional state and acute agitated 43:1334–7.
delirium: occurrence after infarction in the right middle Nobuyoshi I, Nishihara Y, Horie A. Amyloid angiopathy and lobar
cerebral artery territory. Arch Neurol 1987; 44:1139–43. cerebral hemorrhage. J Neurol Neurosurg Psychiatry 1984;
Morisy L, Platt D. Hazards of high-dose meperidine. JAMA 1986; 47:1203–10.
255:467–8. Nokura K, Yamamoto H, Okawara Y et al. Reversible limbic
Morris LE, Heyman A, Pozersky T. Lead encephalopathy caused by encephalitis caused by ovarian teratoma. Acta Neurol Scand
ingestion of illicitly distilled whiskey. Neurology 1964; 14:493–9. 1997; 95:367–73.
Morse RM, Litin EM. The anatomy of delirium. Am J Psychiatry Nomdedeu M, Miro O, Nogue S et al. Hallucinatory
1971; 128:111–16. delirium and psychomotor agitation as a paradoxical
Moser HU, Moser AE, Singh I et al. Adrenoleukodystrophy: survey manifestation of acute propoxyphene poisoning. Med Clin
of 303 cases: biochemistry, diagnosis and therapy. Ann Neurol 2001; 116:318.
1984; 16:628–41. Norris CR, Trench JM, Hook R. Delayed carbon monoxide
Mueller J, Hotson JR, Langston JW. Hyperviscosity-induced encephalopathy: clinical and research implications. J Clin
dementia. Neurology 1983; 33:101–3. Psychiatry 1982; 43:294–5.
Munoz MF, Selwood A, Mastri AR et al. Pick’s disease versus Nyhan WL. Clinical features of the Lesch–Nyhan syndrome. Arch
Alzheimer’s disease: a comparison of clinical abnormalities. Int Med 1972; 130:186–92.
Neurology 1993; 43:289–92. Nyland H, Skre H. Cerebral calcinosis with late onset
Munoz X, Marti S, Sumalla J et al. Acute delirium as a encephalopathy – unusual type of pseudo-
manifestation of obstructive sleep apnea syndrome. Am J pseudohypoparathyroidism. Acta Neurol Scand 1977;
Respir Crit Care Med 1998; 158:1306–7. 56:309–25.
p 05.qxd 3/10/08 9:34 AM Page 202
O’Connor JF, Musher DM. Central nervous system involvement in Perren F, Clarke S, Bogousslavsky J. The syndrome of combined
systemic lupus erythematosus. Arch Neurol 1966; 14:157–64. polar and paramedian thalamic infarction. Arch Neurol 2005;
O’Hare JA, Callaghan NM, Murnaghan DJ. Dialysis 62:1212–16.
encephalopathy. Clinical, electroencephalographic, and Perry JR, Warner E. Transient encephalopathy after paclitaxel
interventional aspects. Medicine 1983; 62:129–41. (Taxol) infusion. Neurology 1996; 46:1596–9.
O’Keefe S, Lavan J. The prognostic significance of delirium in older Petermann AF, Hayles AB, Dockerty MB et al. Encephalotrigeminal
hospital patients. J Am Geriatr Soc 1997; 45:174–8. angiomatosis (Sturge–Weber disease). Clinical study of thirty-
Oksanen V. Neurosarcoidosis: clinical presentations and course in five cases. J Am Med Assoc 1958; 167:2169–76.
50 patients. Acta Neurol Scand 1986; 73:283–90. Petersen RC, Thomas RG, Grundman M et al. Vitamin E and
Olazaran J, Muniz R, Reisberg B et al. Benefits of cognitive-motor donepezil for the treatment of mild cognitive impairment. N
intervention in mild to moderate Alzheimer’s disease. Engl J Med 2005; 352:2379–88.
Neurology 2004; 63:2348–53. Petersen RC, Parisi JE, Dickson DW et al. Neuropathologic features
Oppenheimer BS, Fishberg AM. Hypertensive encephalopathy. of amnestic mild cognitive impairment. Arch Neurol 2006;
Arch Int Med 1928; 41:264–78. 63:665–72.
Palatucci DM. Paradoxical halide levels in bromide intoxication. Pflanz S, Besson JAO, Ebmeier KP et al. The clinical manifestations
Neurology 1978; 28:1189–92. of mental disorders in Huntington’s disease: a retrospective
Palmai G, Taylor DC, Falconer MA. A case of craniopharyngioma case record study of disease progression. Acta Psychiatr Scand
presenting as Korsakoff’s psychosis. Br J Psychiatry 1967; 1991; 83:53–60.
113:619–23. Phillips S, Sangalang V, Sterns G. Basal forebrain infarction: a
Palmini AL, Gloor P, Jones-Gotman M. Pure amnestic seizures in clinicopathologic corelation. Arch Neurol 1987; 44:1134–8.
temporal lobe epilepsy. Brain 1992; 115:749–69. Pickering-Brown SM, Richardson AMT, Snowden JS et al. Inherited
Palsson A, Thulin SO, Tunving K. Cannabis psychosis in south frontotemporal dementia in nine British families associated
Sweden. Acta Psychiatr Scand 1982; 66:311–21. with intronic mutations in the tau gene. Brain 2002;
Pampiglione G, Moynahan EJ. The tuberous sclerosis syndrome: 125:732–51.
clinical and EEG studies in 100 children. J Neurol Neurosurg Pierce LB. Pellagra: report of a case. Am J Psychiatry 1924;
Psychiatry 1976; 39:666–73. 81:237–43.
Papazian O, Canizales E, Alfonso I et al. Reversible dementia and Pincus JH, Reynolds EH, Glaser GH. Subacute combined system
apparent brain atrophy during valproate therapy. Ann Neurol degeneration with folate deficiency. J Am Med Assoc 1972;
1995; 38:687–91. 221:496–7.
Park SA, Hahn JH, Kim JI et al. Memory deficits after bilateral Pittinger C, Desan PH. Gabapentin abuse, and delirium tremens
anterior fornix infarction. Neurology 2000; 54:1379–82. upon gabapentin withdrawal. J Clin Psychiatry 2007;
Pascual-Castroviejo I, Diaz-Gonzalez C, Garcia-Melian RM et al. 68:483–4.
Sturge–Weber syndrome: study of 40 patients. Pediatr Neurol Plum F, Posner JB, Hain RF. Delayed neurological deterioration
1993; 9:283–8. after anoxia. Arch Int Med 1962; 110:56–63.
Paulson GW, Martin EW, Mojzisik C et al. Neurologic Pompeii P, Foreman M, Rudberg MA et al. Delirium in hospitalized
complications of gastric partitioning. Arch Neurol 1985; older persons: outcomes and predictors. J Am Geriatr Soc
42:675–7. 1994; 42:809–15.
Payton JB, Burkhart JE, Hersen M et al. Treatment of ADDH in Pope HG, Keck PE, McElroy SL. Frequency and presentation of
mentally retarded children: a preliminary study. J Am Acad neuroleptic malignant syndrome in a large psychiatric
Child Adolesc Psychiatry 1989; 28:761–7. hospital. Am J Psychiatry 1986; 143:1227–33.
Pearlson GD. Psychiatric and medical symptoms associated with Portet F, Ousset PJ, Visser PJ et al. Mild cognitive impairment in
phencyclidine (PCP) abuse. Johns Hopkins Med J 1981; medical practice: critical review of the concept and new
148:25–33. diagnostic procedure. Report of the MCI working group of the
Peavy GM, Herzog AG, Rubin NP et al. Neuropsychological aspects European Consortium on Alzheimer’s disease (EADC). J Neurol
of motor neuron disease: a report of two cases. Neurology Neurosurg Psychiatry 2006; 77:714–18.
1992; 42:1004–8. Postma JU, Van Tilburg W. Visual hallucinations and delirium
Penfield W, Mathieson G. Memory: autopsy findings and during treatment with amantadine (Symmetrel). J Am Geriatr
comments on the role of hippocampus in experiential recall. Soc 1975; 23:212–15.
Arch Neurol 1974; 31:145–54. Potter NT, Meyer MA, Zimmerman AW et al. Molecular and
Penfield W, Milner B. Memory deficit produced by bilateral lesions in clinical findings in a family with dentatorubral-pallidoluysian
the hippocampal zone. Arch Neurol Psychiatry 1958; 79:475–97. atrophy. Ann Neurol 1995; 37:273–7.
Pepin EP, Auray-Pepin L. Selective dorsolateral frontal lobe Powers JM, Schaumburg HH, Gafney CL. Kluver–Bucy syndrome
dysfunction associated with diencephalic amnesia. Neurology caused by adrenoleukodystrophy. Neurology 1980;
1993; 43:733–41. 30:1131–2.
Perini GI, Colombi G, Armani M et al. Intellectual impairment and Preskorn SH, Simpson S. Tricyclic-antidepressant-induced delirium
cognitive evoked potentials in myotonic dystrophy. J Nerv and plasma drug concentration. Am J Psychiatry 1982;
Ment Dis 1989; 177:750–4. 139:822–3.
p 05.qxd 3/10/08 9:34 AM Page 203
References 203
Price BH, Gurvit H, Weintraud S et al. Neuropsychological patterns Richardson JC, Chambers RA, Heywood PM. Encephalopathies of
and language deficits in 20 consecutive cases of autopsy- anoxia and hypoxemia. Arch Neurol 1959; 1:178–90.
confirmed Alzheimer’s disease. Arch Neurol 1993; 50:931–7. Richter RW, Shimojyo S. Neurologic sequelae of Japanese B
Przelomski MM, O’Rourke E, Grady GF et al. Eastern equine encephalitis. Neurology 1961; 1:553–9.
encephalitis in Massachusetts. Neurology 1988; 38:736–9. Riley DE, Lang AE, Lewis A et al. Cortical-basal ganglionic
Quinette P, Guillery-Giraud B, Dayan J et al. What does transient degeneration. Neurology 1990; 40:1203–12.
global amnesia really mean? Review of the literature and Rinne JO, Lee MS, Thompson PD et al. Corticobasal degeneration:
thorough study of 142 cases. Brain 2006; 129:1640–58. a clinical study of 36 cases. Brain 1994; 117:1183–96.
Qunitanilla J. Psychosis due to quinidine intoxication. Am J Ristic AJ, Vojvodic N, Jankovic S et al. The frequency of reversible
Psychiatry 1957; 113:1031–2. parkinsonism and cognitive decline associated with valproate
Rabins PV, Folstein MF. Delirium and dementia: diagnostic criteria treatment: a study of 364 patients with different types of
and fatality rates. Br J Psychiatry 1982; 140:149–53. epilepsy. Epilepsia 2006; 47:2183–5.
Rabins PV, Merchant A, Nestadt G. Criteria for diagnosing Robbins TW, James M, Lance TW et al. Cognitive performance in
reversible dementia caused by depression: validation by 2-year multiple system atrophy. Brain 1992; 115:271–91.
follow-up. Br J Psychiatry 1984; 144:488–92. Robertson EE. Progressive bulbar paralysis showing heredofamilial
Rao V, Lyketsos C. Neuropsychiatric sequelae of traumatic brain incidence and intellectual impairment. Arch Neurol Psychiatry
injury. Psychosomatics 2000; 41:95–103. 1953; 69:197–207.
Rashiq S, Briewa L, Mooney M et al. Distinguishing acyclovir Robinson WP, Bottani A, Yagang X. Molecular, cytogenetic, and
neurotoxicity from encephalomyelitis. J Intern Med 1993; clinical investigations of Prader–Willi syndrome patients. Am J
234:507–11. Hum Genet 1992; 49:1219–34.
Raskin NH, Fishman RA. Neurologic disorders in renal failure. N Rodriguez ME, Artieda J, Zubieta JL et al. Reflex myoclonus in
Engl J Med 1976; 294:143–8. olivopontocerebellar atrophy. J Neurol Neurosurg Psychiatry
Raskin NH, Bredesen D, Ehrenfeld WK et al. Periodic confusion 1994; 57:316–19.
caused by congenital extrahepatic portocaval shunt. Romanul FCA, Radvany J, Rosales RK. Whipple’s disease confined
Neurology 1984; 34:666–9. to the brain: a case confirmed clinically and pathologically. J
Ratcliffe SG, Bancroft J, Axworthy D et al. Klinefelter’s syndrome Neurol Neurosurg Psychiatry 1977; 40:901–9.
in adolescents. Arch Dis Child 1982; 57:6–12. Roos R, Cajdusek DC, Gibbs CJ. The clinical characteristics of
Rathmell TK, Burns MA. The Laurence–Moon–Biedl syndrome transmissible Creutzfeldt–Jakob disease. Brain 1973; 96:1–20.
occurring in a brother and a sister. Arch Neurol Psychiatry Rosa A, Demiati M, Cartz L et al. Marchiafava–Bignami disease,
1938; 39:1033–42. syndrome of interhemispheric disconnection, and right handed
Rauschka H, Colsch B, Baumann N et al. Late-onset agraphia in a left-hander. Arch Neurol 1991; 48:986–8.
metachromatic leukodystrophy. Genotype strongly influences Rose FC, Symonds CP. Persistent memory defect following
phenotype. Neurology 2006; 67:859–63. encephalitis. Brain 1960; 83:195–212.
Read AE, Laidlaw J, Sherlock S. Neuropsychiatric complications of Rosebush P, Stewart T. A prognostic analysis of 24 episodes of
portocaval anastamosis. Lancet 1961; 1:961–4. neuroleptic malignant syndrome. Am J Psychiatry 1989;
Reding M, Haycox J, Blass J. Depression in patients referred to a 146:717–25.
dementia clinic: a three-year prospective study. Arch Neurol Rosenbaum M, Lewis M, Piker P et al. Convulsive seizures in
1985; 42:894–6. delirium tremens. Arch Neurol Psychiatry 1941; 45:486–93.
Reed D, Crawley J, Faro SN et al. Thallotoxicosis. J Am Med Assoc Rosenberg NL, Kleineschmidt-DeMasters BK, Davis KA et al.
1963; 183:516–22. Toluene abuse causes diffuse central nervous system white
Reichenberg A, Yirmiya R, Schuld A et al. Cytokine-associated matter changes. Ann Neurol 1988; 23:611–14.
emotional and cognitive disturbances in humans. Arch Gen Rosman NP, Pearce J. The brain in multiple neurofibromatosis
Psychiatry 2001; 58:445–52. (Von Recklinghausen’s disease): a suggested neuropathological
Reider-Grosswasser I, Bornstein N. CT and MRI in late-onset basis for the associated mental defect. Brain 1967;
metachromatic leukodystrophy. Acta Neurol Scand 1987; 90:829–37.
75:64–9. Ross AT, Dickerson WW. Tuberous sclerosis. Arch Neurol Psychiatry
Rennick PM, Perez-Borja C, Rodin EA. Transient mental deficits 1943; 50:233–57.
associated with recurrent prolonged epileptic clouded state. Roth A. Familial eunuchoidism: the Laurence–Moon–Biedl
Epilepsia 1969; 10:397–405. syndrome. J Urol 1947; 57:427–42.
Revesz T, Hawkins CP, du Boulay EPGH et al. Pathological findings Roy-Byrne PR, Weingartner H, Bierer LM et al. Effortful and
correlated with magnetic resonance imaging in subcortical automatic cognitive processes in depression. Arch Gen
arteriosclerotic encephalopathy (Binswanger’s disease). J Psychiatry 1986; 43:265–7.
Neurol Neurosurg Psychiatry 1989; 52:1337–44. Rozdilsky B, Cummings JN, Huston AF. Hallervorden–Spatz
Reynolds EH, Rothfeld P, Pincus JH. Neurological disease disease: late infantile and adult types, report of two cases.
associated with folate deficiency. BMJ 1973; 2:398–400. Acta Neuropathol 1968; 10:1–16.
Richardson EP. Progressive multifocal leukencephalopathy. N Engl Rubinstein LJ, Urich H. Meningo-encephalitis of Behçet’s disease:
J Med 1961; 265:815–23. case report with pathological findings. Brain 1963; 86:151–60.
p 05.qxd 3/10/08 9:34 AM Page 204
Russell WR. Disability caused by brain wounds. J Neurol Shapiro EG, Lockman LA, Knopman D et al. Characteristics of the
Neurosurg Psychiatry 1951; 14:35–9. dementia in late-onset metachromatic leukodystrophy.
Russell WR, Nathan PW. Traumatic amnesia. Brain 1946; Neurology 1994; 44:662–5.
68:280–300. Shaw PJ, Walls TJ, Newman PK et al. Hashimoto’s
Russell WR, Schiller F. Crushing injuries to the skull. J Neurol encephalopathy: a steroid-responsive disorder associated with
Neurosurg Psychiatry 1949; 12:52–60. high anti-thyroid antibody titers: report of 5 cases. Neurology
Russell WR, Smith A. Post-traumatic amnesia in closed head 1991; 41:228–33.
injury. Arch Neurol 1961; 5:4–17. Shear MK, Sacks MH. Digitalis delirium: report of two cases. Am J
Rustam H, Hamri T. Methyl mercury poisoning in Iraq. Brain 1974; Psychiatry 1978; 135:109–10.
97:499–510. Sheth RD, Drazkowski JF, Sirven JI. Protracted ectal confusion in
Sachdev P, Kruk J, Kneebone M et al. Clozapine-induced elderly patients. Arch Neurol 2006; 63:529–32.
neuroleptic malignant syndrome: review and report of new Shewmon DA, Masdeu JC. Delayed radiation necrosis of the brain
cases. J Clin Psychopharmacol 1995; 15:365–71. contralateral to original tumor. Arch Neurol 1980; 37:592–4.
Sachs E. Meningiomas with dementia as the first and presenting Shill HA, Fife TD. Valproic acid toxicity mimicking multiple system
feature. J Ment Sci 1950; 96:998–1007. atrophy. Neurology 2000; 55:1936–7.
Sandberg O, Franklin KA, Bucht G et al. Sleep apnea, delirium, Shuttleworth EC, Morris CE. The transient global amnesia
depressed mood, cognition and ADL ability after stroke. J Am syndrome. Arch Neurol 1966; 15:515–20.
Geriatr Soc 2001; 49;391–7. Shuttleworth EC, Wise GR. Transient global amnesia due to
Sanson M, Duyckaerts C, Thibault J-L et al. Sarcoidosis presenting arterial embolism. Arch Neurol 1973; 29:340–2.
as late-onset dementia. J Neurol 1996; 243:484–7. Siesling S, Vester-van der Vlis M, Roos RAC. Juvenile Huntington’s
Sasaki H, Fukazawa T, Yanagihara T et al. Clinical features and disease in the Netherlands. Pediatr Neurology 1997;
natural history of spinocerebellar ataxia type 1. Acta Neurol 17:34–43.
Scand 1996; 93:64–71. Silverstein A. Thrombotic thrombocytopenic purpura: the initial
Schaumberg HH, Powers JM, Raine CS et al. neurologic manifestations. Arch Neurol 1968; 18:358–62.
Adrenoleukodystrophy: a clinical and pathological study of 17 Silverstein A, Siltzbach LE. Neurologic sarcoidosis: study of 18
cases. Arch Neurol 1975; 32:577–91. cases. Arch Neurol 1965; 12:1–11.
Scheid R, Honnarat J, Delmont E et al. A new anti-neuronal Sim M, Turner E, Smith WR. Cerebral biopsy in the investigation
antibody in a case of paraneoplastic limbic encephalitis of presenile dementia. I. Clinical aspects. Br J Psychiatry 1966;
associated with breast cancer. J Neurol Neurosurg Psychiatry 112:119–25.
2004; 75:338–40. Simard M, Gumbiner B, Lee A et al. Lithium carbonate
Scheltens P, Visscher F, Van Keimpema ARJ et al. Sleep apnea intoxication: a case report and review of the literature. Arch
syndrome presenting with cognitive impairment. Neurology Int Med 1989; 149:36–46.
1991; 41:155. Sirois F. Delirium: 100 cases. Can J Psychiatry 1988; 33:375–8.
Schneider JA, Watts RL, Gearing M et al. Corticobasal Smyth GE, Stern K. Tumours of the thalamus – a
degeneration neuropathologic and clinical heterogenity. clinicopathological study. Brain 1938; 61:339–74.
Neurology 1997; 48:959–69. Snead OC, Gibson KM. Gamma-hydroxybutyric acid. N Engl J Med
Schou M. Long-lasting neurological sequelae after lithium 2005; 352:2721–32.
intoxication. Acta Neurol Scand 1984; 70:594–602. Snowden JS, Neary D, Mann DMA et al. Progressive language
Scoville WB, Milner B. Loss of recent memory after bilateral disorder due to lobar atrophy. Ann Neurol 1992; 31:174–83.
hippocampal lesion. J Neurol Neurosurg Psychiatry 1957; Spohr HL, Willms J, Steinhausen HC. Prenatal alcohol exposure
20:11–21. and long-term developmental consequences. Lancet 1993;
Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal 341:907–10.
of levodopa. Neurology 1984; 34:249–51. Sponzilli EE, Smith JK, Malamud N et al. Progressive multifocal
Sellal F, Mohr M, Collard M. Dementia in a 58-year-old woman. leukoencephalopathy: a complication of immunosuppressive
Lancet 1996; 347:236. treatment. Neurology 1975; 25:664–8.
Seltzer B, Benson DF. The temporal pattern of retrograde Spreat S, Behar D, Reneski B et al. Lithium carbonate for
amnesia in Korsakoff’s disease. Neurology 1974; aggression in mentally retarded persons. Compr Psychiatry
24:527–30. 1989; 30:505–11.
Serby M, Angrist B, Lieberman A. Mental disturbance during Sprofkin BE, Sciarra D. Korsakoff’s psychosis associated with
bromocriptine and lergotrile treatment of Parkinson’s disease. cerebral tumor. Neurology 1952; 2:427–34.
Am J Psychiatry 1978; 135:1227–9. Starosta MA, Brandwein SR. Clinical manifestation and treatment
Serdaroglu P, Yazici H, Ozdemir C et al. Neurologic involvement in of rheumatoid pachymeningitis. Neurology 2007; 68:1079–80.
Behçet’s syndrome: a prospective study. Arch Neurol 1989; Steele TE, Morton WA. Salicyclate-induced delirium.
46:265–9. Psychosomatics 1986; 27:455–6.
Serdaru M, Hausser-Hauw C, Laplane D et al. The clinical Steinberg RB, Gilman DE, Johnson F. Acute toxic delirium in a
spectrum of alcoholic pellagra encephalopathy. Brain 1988; patient using transdermal fentanyl. Anesth Analg 1992;
111:829–42. 75:1014–16.
p 05.qxd 3/10/08 9:34 AM Page 205
References 205
Stenback A, Haapanen E. Azotemia and psychosis. Acta Psychiatr Thompson C, Dent J, Saxby P. Effects of thallium poisoning on
Scand 1967; (suppl. 197):1–65. intellectual function. Br J Psychiatry 1988; 153:396–9.
Stern K. Severe dementia associated with bilateral symmetric Thrush DC, Boddie HG. Episodic encephalopathy associated with
degeneration of the thalamus. Brain 1939; 62:157–71. thyroid disorders. J Neurol Neurosurg Psychiatry 1974;
Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 37:696–700.
148:705–13. Tiraboschi P, Salmon DP, Hansen LA et al. What best differentiates
Storandt M, Grant EA, Miller P et al. Longitudinal course and Lewy body from Alzheimer’s disease in early-stage dementia?
neuropathologic outcome in original versus revised MCI and in Brain 2006; 129:729–35.
pre-MCI. Neurology 2006; 67:467–73. Tison F, Dartigues JF, Auriacombe S et al. Dementia in Parkinson’s
Storm-Mathisen A. General paresis: a follow-up study of 203 disease: a population-based study in ambulatory and
patients. Acta Psychiatr Scand 1969; 45:118–32. institutionalized individuals. Neurology 1995; 45:705–8.
Stracciari A, Ciucci G, Bianchedi G et al. Epileptic transient Tomlinson BE, Blessed GE, Roth M. Observations on the brains of
amnesia. Eur Neurol 1990; 30:176–90. demented old people. J Neurol Sci 1970; 11:205–42.
Strachan RW, Henderson JG. Dementia and folate deficiency. Q J Tomson CR, Goodship TH, Rodger RS. Psychiatric side-effects of
Med 1967; 36:189–204. acyclovir in patients with chronic renal failure. Lancet 1985;
Strauss I, Globus JH. Tumor of the brain with disturbance in 2:385–6.
temperature regulation. Arch Neurol Psychiatry 1931; Tomson T, Lindbom U, Nilsson BY. Nonconvulsive status
25:506–22. epilepticus in adults: thirty-two consecutive patients from a
Strich SJ. Diffuse degeneration of the cerebral white matter in general hospital population. Epilepsia 1992; 33:829–35.
severe dementia following head injury. J Neurol Neurosurg Topliss D, Bond R. Acute brain syndrome after propranolol
Psychiatry 1956; 19:163–85. treatment. Lancet 1977; 2:1133–4.
Stuerenburg HJ, Hansen HC, Thie A et al. Reversible dementia in Toru M, Matsuda O, Makiguchi K et al. Single case study:
idiopathic hypoparathyroidism associated with neuroleptic malignant-like state following a withdrawal of
normocalcemia. Neurology 1996; 47:474–6. antiparkinsonian drugs. J Nerv Ment Dis 1981; 169:324–7.
Sujanski E, Conradi S. Sturge-Weber syndrome: age of onset of Tourbah A, Piette JC, Iba-Zizen MT et al. The natural course of
seizures and glaucoma and the prognosis for affected children. cerebral lesions in Sneddon’s syndrome. Arch Neurol 1997;
J Child Neurol 1995; 10:49–58. 54:53–60.
Summerskill WHJ, Davidson EA, Sherlock S et al. The Townsend JJ, Baringer JR, Wolinsky JS et al. Progressive rubella
neuropsychiatric syndrome associated with hepatic cirrhosis panencephalitis: late onset after congenital rubella. N Engl J
and extensive portal collateral circulation. Q J Med 1956; Med 1975; 292:990–3.
25:245–52. Townsend JJ, Wolinsky JS, Baringer JR. The neuropathology of
Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic progressive rubella panencephalitis of late onset. Brain 1976;
encephalopathy due to ingestion of bismuth salts: clinical and 99:81–90.
EEG studies of 45 patients. J Neurol Neurosurg Psychiatry Trzepacz PT, Teague GB, Lipowski ZJ. Delirium and other organic
1977; 40:748–52. mental disorders in a general hospital. Gen Hosp Psychiatry
Swanson AG, Iseri OA. Acute encephalopathy due to water 1985; 7:101–6.
intoxication. N Engl J Med 1958; 258:831–4. Tschanz JT, Welsh-Bohmer KA, Lyketsos CG et al. Conversion to
Sweet WH, Talland GA, Erwin FR. Loss of recent memory following dementia from mild cognitive disorder. The Cache County
section of the fornix. Trans Am Neurol Assn 1958; 84:76–82. study. Neurology 2006; 67:229–34.
Talland GH, Sweet WH, Ballantine HT. Amnesic syndrome with Tucker WM, Forster FM. Petit mal epilepsy occurring in status.
anterior communicating artery aneurysm. J Nerv Ment Dis Arch Neurol Psychiatry 1958; 64:823–7.
1967; 145:179–92. Tuma R, DeAngelis LM. Altered mental status in patients with
Tanaka Y, Miyazawa Y, Akaoka F et al. Amnesia following damage cancer. Arch Neurol 2000; 57:1727–31.
to the mammillary bodies. Neurology 1977; 48:160–5. Tune L, Damlouji NF, Holland A et al. Association of postoperative
Tanaka Y, Miyazawa Y, Hashimoto R et al. Postencephalitic focal delirium with raised serum levels of anticholinergic drugs.
retrograde amnesia after bilateral anterior temporal lobe Lancet 1981; 2:651–3.
damage. Neurology 1999; 53:344–50. Tune L, Carr S, Cooper T et al. Association of anticholinergic
Tatemichi TK, Desmond DW, Prohovnik I et al. Dementia activity of prescribed medications with postoperative delirium.
associated with bilateral carotid occlusions: J Neuropsychiatry Clin Neurosci 1993; 5:208–10.
neuropsychological and haemodynamic course after Turner RS, Kenyon LC, Trojanowski JQ et al. Clinical,
extracranial to intracranial bypass surgery. J Neurol Neurosurg neuroimaging, and pathologic features of progressive
Psychiatry 1995; 38:633–6. nonfluent aphasia. Ann Neurol 1996; 39:166–73.
Tenenbaum S, Chamoles N, Fejerman N. Acute disseminated Tyler RH. Neurologic disorders in renal failure. Am J Med 1968;
encephalomyelitis. A long-term follow-up of 84 pediatric 44:734–8.
patients. Neurology 2002; 59:1224–31. Uyama E, Iwagoe H, Maeda J et al. Presenile-onset cerebral
Thapar A, Gottesman II, Owen MJ et al. The genetic mental adrenoleukodystrophy presenting as Balint’s syndrome and
retardations. Br J Psychiatry 1994; 164:747–58. dementia. Neurology 1993; 43:1249–51.
p 05.qxd 3/10/08 9:34 AM Page 206
Vandenn Borre R, Vermote R, Buttiens M et al. Risperidone as Watts GF, Mitchell WD, Bending JJ et al. Cerebrotendinous
add-on therapy in behavioral disturbances in mental xanthomatosis: a family study of sterol 27–hydroxylase
retardation: a double-blind placebo-controlled cross-over mutations and pharmacotherapy. Q J Med 1996; 89:55–63.
study. Acta Psychiatr Scand 1993; 87:167–71. Wechsler IS, Davison C. Amyotrophic lateral sclerosis with mental
Van Horn G, Arnett FC, Dimachkie MM. Reversible dementia and symptoms: a clinicopathologic study. Arch Neurol Psychiatry
chorea in a young woman with the lupus anticoagulant. 1932; 327:859–80.
Neurology 1996; 46:1599–603. Weil ML, Itabashi H, Cramer NE et al. Chronic progressive
Varney NR, Alexander B, MacIndoe JH. Reversible steroid panencephalitis due to rubella virus simulating subacute
dementia in patients without steroid psychosis. Am J sclerosing panencephalitis. N Engl J Med 1975; 292:994–8.
Psychiatry 1984; 141:369–73. Weinberger LM, Cohen ML, Remler BF et al. Intracranial
Velamoor VR, Norman RMG, Caroff SN et al. Progression of Wegener’s granulomatosis. Neurology 1993; 43:1831–4.
symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis Weizman A, Eldar M, Shoenfeld Y et al. Hypercalcemia-induced
1994; 182:168–73. psychopathology in malignant diseases. Br J Psychiatry 1979;
Venneri A, Caffarra P. Transient autobiographic amnesia: EEG and 135:363–6.
single-photon emission CT evidence of an organic etiology. Weller M, Liedtke W, Petersen D et al. Very-late-onset
Neurology 1998; 50:186–91. adrenoleukodystrophy: possible precipitation of demyelination
Victor M, Yakovlev PI. S.S. Korsakoff’s psychic disorder in by cerebral contusion. Neurology 1992; 42:367–70.
conjunction with peripheral neuritis: a translation of Wells CE. Pseudodementia. Am J Psychiatry 1979; 136:895–900.
Korsakoff’s original article with brief comments on the author Welti W. Delirium with low serum sodium. Arch Neurol Psychiatry
and his contribution to clinical medicine. Neurology 1955; 1956; 76:559–64.
5:394–406. Wenning GK, Shlomo YB, Magalhaes M et al. Clinical features and
Victor M, Angevine JB, Mancall EL et al. Memory loss with lesions natural history of multiple system atrophy: an analysis of 100
of the hippocampal formation. Arch Neurol 1961; 5:244–63. cases. Brain 1994; 117:835–45.
Victor M, Adams RD, Cole M. The acquired ‘non-Wilsonian’ type of Wenning GK, Ben-Shlomo Y, Magalhaes M et al.
chronic hepatocerebral degeneration. Medicine 1965; Clinicopathological study of 35 cases of multiple system
44:345–96. atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160–6.
de Villemeur TB, Deslys J-P, Pradel A et al. Creutzfeldt–Jacob Werheran KJ, Brown P, Thompson PD et al. The clinical features
disease from contaminated growth hormone extracts in and prognosis of chronic posthypoxic myoclonus. Mov Disord
France. Neurology 1996; 47:690–5. 1997; 12:216–20.
Vollmer TL, Guarnaccia J, Harrington W et al. Idiopathic Westlake EK, Simpson T, Kaye M. Carbon dioxide narcosis in
granulomatous angiitis of the central nervous system: emphysema. Q J Med 1955; 24:155–73.
diagnostic challenges. Arch Neurol 1993; 50:925–30. Whitfield CL, Ch’ien LT, Whitehead LD. Lead encephalopathy in
Volpe JJ. Cognitive deficits in premature infants. N Engl J Med adults. Am J Med 1972; 52:289–98.
1991; 325:276–8. Whitney JF, Gannon DE. Obstructive sleep apnea presenting as
Vortmeyer AO, Hagel C, Laas R. Haemorrhagic thiamine deficient acute delirum. Am J Emerg Med 1996; 14:370–1.
encephalopathy following prolonged parenteral nutrition. J Wiederholdt WL, Siekert RG. Neurological manifestations of
Neurol Neurosurg Psychiatry 1992; 55:826–9. sarcoidosis. Neurology 1965; 15:1147–54.
Walker AE. Recent memory impairment in unilateral temporal Wilkins RH, Brody IA. Encephalitis lethargica. Arch Neurol 1968;
lesions. Arch Neurol Psychiatry 1957; 78:543–57. 18:324–8.
Wallack EM, Reavis WM, Hall CD. Primary brain stem reticulum Will RG, Mathews WB. A retrospective study of Creutzfeldt–Jakob
sarcoma causing dementia. Dis Nerv Syst 1977; 38:744–7. disease in England and Wales 1970–1979. I. Clinical features.
Walshe JM, Yealland M. Wilson’s disease: the problem of delayed J Neurol Neurosurg Psychiatry 1984; 47:134–40.
diagnosis. J Neurol Neurosurg Psychiatry 1992; 55:692–6. Williams M, Pennybacker J. Memory disturbances in third
Wamboldt FS, Jefferson JW, Wamboldt MZ. Digitalis intoxication ventricle tumours. J Neurol Neurosurg Psychiatry 1954;
misdiagnosed as depression by primary care physician. Am J 17:115–23.
Psychiatry 1986; 143:219–21. Williamson RT. On the symptomatology of gross lesions (tumours
Wang PS, Schneeweiss S, Avorn J et al. Risk of death in elderly and abscesses) involving the pre-frontal regions of the brain.
users of conventional vs. atypical antipsychotic medications. N Brain 1896; 19:346–65.
Engl J Med 2005; 353:2335–41. Wilson JTL, Teasdale GM, Hadley DM et al. Post-traumatic
Warner TT, Lennox GG, Janota I et al. Autosomal-dominant amnesia: still a valuable yardstick. J Neurol Neurosurg
dentatorubropallidoluysian atrophy. Mov Disord 1994; 9:289–96. Psychiatry 1994; 57:198–201.
Warner TT, Williams LD, Walker RWH et al. A clinical and Wilson LM. Intensive care delirium: the effect of outside deprivation
molecular genetic study of dentatorubropallidoluysian atrophy in a windowless unit. Arch Intern Med 1972; 130:225–6.
in four European families. Ann Neurol 1995; 37:452–9. Winblad B, Palmer K, Kivipelto M et al. Mild cognitive
Warren JD, Thompson PD, Thompson PD. Diencephalic amnesia impairment: beyond controversies, towards a consensus:
and apraxia after left thalamic infarction. J Neurol Neurosurg report of the International Working Group on Mild Cognitive
Psychiatry 2000; 68:248. Impairment. J Intern Med 2004; 256: 240–6.
p 05.qxd 3/10/08 9:34 AM Page 207
References 207
Wisniewski HM, Coblentz JM, Terry RD. Pick’s disease: a clinical Japanese population: the Hisayama study. Neurology 1995;
and ultrastructural study. Arch Neurol 1972; 26:97–108. 45:1161–8.
Wisniewski KE, Frency JH, Fernando S et al. Fragile X syndrome: Young CA, Humphrey DM, Ghadiali EJ et al. Short-term memory
associated neurological abnormalities and developmental impairment in an alert patient as a presentation of herpes
disabilities. Ann Neurol 1985; 18:665–9. simplex encephalitis. Neurology 1992; 42:260–1.
Wityk RJ, Goldsborough MA, Hillis A et al. Diffusion- and Zappoli R. Two cases of prolonged twilight state with almost
perfusion-weighted brain magnetic resonance imaging in continuous ‘wave-spikes’. Electroencephalogr Clin
patients with neurologic complications after cardiac surgery. Neurophysiol 1955; 7:421–3.
Arch Neurol 2001; 58:571–6. Zeidler M, Stewart GE, Barraclough CR et al. New variant
Wolfe HG, Curran D. Nature of delirium and allied states. Arch Creutzfeldt–Jakob disease: neurological features and
Neurol Psychiatry 1935; 33:1175–215. diagnostic tests. Lancet 1997; 350:903–7.
Wolfe N, Linn R, Babikian VL et al. Frontal system impairment Ziegler DK, Kaufman A, Marshall HE. Abrupt memory loss
following multiple lacunar infarcts. Arch Neurol 1990; associated with thalamic tumor. Arch Neurol 1977; 34:545–8.
47:129–32. Zhang C, Glenn DG, Bell WL et al. Gabapentin-induced myoclonus
Wolinsky JS, Berg BO, Maitland CJ. Progressive rubella in end stage renal disease. Epilepsia 2005; 46:156–8.
panencephalitis. Arch Neurol 1976; 33:722–3. Zhou Y-X, Wang G-X, Tang B-S et al. Spinocerebellar ataxia type
Wong Y-C, Au WL, Xu M et al. Magnetic resonance spectroscopy 2 in China: molecular analysis and genotype–phenotype
in adult-onset citrullinemia. Elevated glutaime levels in correlation in nine families. Neurology 1998; 51:595–8.
comatose patients. Arch Neurol 2007; 64:1034–7. Zipursky RB, Baker RW, Zimmer B. Alprazolam withdrawal
Wood CA, Buller F. Poisoning by wood alcohol. Cases of death and delirium unresponsive to diazepam: case report. J Clin
blindness from Columbian spirits and other methylated Psychiatry 1985; 46:344–5.
preparations. J Am Med Assoc 1904; 43:972–7, 1058–62, Ziskind AA. Transdermal scopolamine-induced psychosis. Postgrad
1117–23, 1213–21. Med 1988; 84:73–6.
Wu R-M, Chang Y-L, Chiu H-C. Acute triphenyltin intoxication: a Zochodne DW, Young GB, McLachlan RS et al. Creutzfeldt–Jakob
case report. J Neurol Neurosurg Psychiatry 1990; 53:356–7. disease without periodic sharp wave complexes: a clinical,
Wulff CH, Trojaborg W. Adult metachromatic leukodystrophy: electroencephalographic, and pathologic study. Neurology
neuropsychologic findings. Neurology 1985; 35:1776–8. 1988; 38:1056–60.
Yaqub B, Al Deeb S. Heat stroke; aetiopathogenesis, neurological Zola-Morgan S, Squire LR, Amaral DG. Human amnesia and the
characteristics, treatment and outcome. J Neurol Sci 1998; medial temporal region: enduring memory impairment
156:144–51. following a bilateral lesion limited to field CA1 of the
Yildizeli B, Ozyurtkan MO, Batirel HF et al. Factors associated with hippocampus. J Neurosci 1986; 6:2950–67.
postoperative delirium after thoracic surgery. Ann Thorac Surg Zunt JR, Tu RK, Anderson DM et al. Progressive multifocal
2005; 79: 1004–9. leukoencephalopathy presenting as human immunodeficiency
Yoshitake T, Kiyohara Y, Kato I et al. Incidence and risk factors of virus type 1 (HIV)-associated dementia. Neurology 1997;
vascular dementia and Alzheimer’s disease in a defined elderly 49:263–5.
p 06.qxd 3/10/08 9:34 AM Page 208
6
Syndromes of disturbances of mood and affect
6.1 Depression 208 6.4 Agitation 222

6.2 Apathy 214 6.5 Anxiety 225
6.3 Mania 215 References 227
6.1 DEPRESSION Others may actively seek death, perhaps by hanging, shoot-
ing, jumping from bridges, or taking overdoses.
Depression, as conceived of here, is a syndrome that may Difficulty with concentration may be profound. Patients
result from any one of a large number of underlying may complain that it is as if a ‘fog’ had settled in, and that
causes. Although the most common cause of depression is they feel dull and heavy headed. Memory seems to fail, and
major depressive disorder, it is critical to subject each patients may be unable to recall where they put things or
depressed patient to a thorough diagnostic evaluation what was said. Attempts at cognitive activities often end in
before concluding that major depressive disorder, or per- failure: patients, in trying to read a book, may read the same
haps one of the other idiopathic disorders discussed below, paragraph again and again, and find themselves unable to
is the cause. absorb or understand what they have read. Things seem too
complex and making decisions may be impossible.
The remaining symptoms, namely anhedonia, anergia,
Clinical features sleep disturbance, appetite change, and psychomotor change,
are often referred to, collectively, as the ‘vegetative’ symp-
The syndrome of depression, in its fully developed form, toms of depression, in that they represent disturbances in
includes not only a depressed or irritable mood, but also the basic vegetative functions critical for survival.
other symptoms, as listed in Table 6.1; each one of these is Anhedonia represents an inability to take pleasure in
considered in turn. things, and patients may complain that nothing arouses or
Mood is depressed or sometimes irritable; some, in addi- attracts them. Thus unable to experience pleasure, patients
tion to these symptoms, may also complain of anxiety. At lose interest in formerly pleasurable activities and must
times patients may deny a depressed mood, but rather com- force themselves to get through their days, which, to them,
plain of a sense of discouragement, or perhaps lassitude and seem desolate and lifeless. Libido is especially lost, and
a sense of being weighted down. The patient’s affect gener- patients may withdraw entirely from any sexual activities.
ally mirrors the mood, and there may be copious tears. Anergia, or a dearth of energy, may leave patients com-
At times, and especially in those with anxiety, there may plaining of fatigue, tiredness, and exhaustion, or of being
be a ‘pained’ facial expression. Occasionally, patients may ‘drained’. The anergia may be so extreme that patients are
attempt to hide their depressed mood by feigning a ‘happy’ unable to complete routine tasks; some may even be
affect, thus creating a ‘smiling depression’. unable to find the energy to get dressed.
Self-esteem typically sinks during depression, and the Sleep disturbance may manifest with either insomnia or
workings of conscience may become so prominent as to hypersomnia. Insomnia is more common, and may be a
create an almost insupportable burden of guilt: patients particular torment to the patient. Although some complain
may see their sins multiply in front of them, and in review- of what is technically known as ‘initial’ insomnia, that is to
ing their past may be blind to their accomplishments and say trouble initiating or falling asleep, a more characteristic
see only their misdeeds. Pessimism settles in and patients complaint is ‘middle’ insomnia, wherein patients awaken in
see no hope for themselves, either now or in the future. the middle of the night, and have great difficulty in falling
Suicidal ideation is typically present, and may be either back asleep; some complain that their ‘mind’ simply won’t
passive or active. Patients may say that they would not mind ‘shut off’. Some may also experience ‘terminal’ insomnia, or,
if they were in a fatal accident or died of some disease. as it is also known, ‘early morning awakening’, wherein they
p 06.qxd 3/10/08 9:34 AM Page 209
6.1 Depression 209
Table 6.1 Symptoms of depression withhold the diagnosis until symptoms have persisted for
Depressed or irritable mood about 2 weeks, some judgment is required here as there are
Low self-esteem, guilt, pessimism clearly cases wherein patients have severe and numerous
Suicidal ideation depressive symptoms, which, however, are relatively brief in
Difficulty with concentration or forgetfulness duration. Examples include the premenstrual dysphoric dis-
Anhedonia (lack of interest in formerly pleasurable activities) order, some medication-induced depressions, and ictal
Anergia (lack of energy) depressions. In practice, most clinicians will relax the time
Sleep disturbance (insomnia or hypersomnia) duration in proportion to the increasing severity and num-
Appetite disturbance (anorexia or increased appetite) ber of symptoms.
Psychomotor change (agitation or retardation)
Etiology
awaken well before the desired time of arousal and then are The various causes of depression are listed in Table 6.2, in
unable to fall back asleep. When morning finally does come, which they are divided into several groups. The first group
patients arise unrefreshed and exhausted, sometimes feeling includes the primary or idiopathic disorders, such as major
as if they had not slept at all. Hypersomnia is relatively depressive disorder: the disorders in this group account,
uncommon: here, patients may sleep 12, 16, or even 18 hours by far, for the most cases of depression. The next group
a day. Remarkably, despite such extremes of sleep, patients includes toxic depressions, which may be either medication
do not feel refreshed during their waking hours. induced, for example the depression seen with high-dose
Appetite is typically lost and this anorexia may be accom- prednisone, or due to substances of abuse or toxins, as may
panied by an altered taste. Patients may complain that their be seen in chronic alcoholism. Metabolic depressions are
food has no taste or has perhaps become unpalatable; some considered next, including such disorders as obstructive
may say their food tastes like cardboard. Although some sleep apnea. Medication or substance withdrawal depressions
patients may force themselves to eat, most cannot and follow, and include depressions occurring upon discontin-
weight loss is typical, possibly extreme. Increased appetite is uation of long-term treatment with anticholinergic medica-
relatively uncommon but when it does occur the accompa- tions or as may be seen during withdrawal from stimulants.
nying weight gain may be impressive. Endocrinologic disorders constitute a very important cause
Psychomotor change tends more to agitation than to of depression, and include such familiar conditions as
retardation. Agitation, when slight, may be confined to a hypothyroidism and Cushing’s syndrome. Various neu-
certain sense of inner restlessness. When more severe, rodegenerative and dementing disorders may cause depres-
there may be hand-wringing and restless pacing: patients sion, and indeed approximately one-third of patients with
may complain of being unable to keep still; they may Parkinson’s disease will be so affected. Depression may also
loudly lament their fate, and some may give way to wailing be seen in a large number of other intracranial disorders, for
and miserable pleas for help. The tension experienced by example in the syndrome of post-stroke depression. Each of
these patients may be almost palpable to the observer and these groups is considered in more detail below, beginning
yet, despite their pleas, these patients cannot be comforted with the primary or idiopathic disorders.
no matter what is done for them. Psychomotor retardation
is less common. Patients may speak slowly and haltingly, PRIMARY OR IDIOPATHIC DISORDERS
and some may become mute, as if the effort to speak were
simply too great; if asked, they may report that their As noted earlier, the disorders in this group constitute, by
thoughts are sluggish and come very slowly. These patients far, the most common causes of depression. As a group,
may move very little, and some may become almost com- however, they constitute ‘rule-out’ diagnoses, and a diagno-
pletely immobile: efforts to get them up may be met with sis of one of these disorders should generally not be made
reluctance, even irritation, and some patients, if left to until one is reasonably certain that the depressive syndrome
themselves, may neither bathe nor change their clothes. in question is not caused by one of the other disorders in
There is debate as to how many of these symptoms must Table 6.2. It must also be kept in mind that it is not at
be present before a syndromal diagnosis of depression is all uncommon that in any given patient more than one dis-
warranted. Some authorities insist on a large number and order may be present. For example, a patient with well-
although such an approach yields a relatively ‘pure’ group it established major depressive disorder, with a long history of
runs the risk of ignoring patients whose symptoms, recurrent depressions, may come down with a depression
although few in number, are severe, even disabling. I recom- during a course of prednisone treatment, which remits shortly
mend, as a preliminary approach, reserving the diagnosis for after treatment is discontinued. Furthermore, some depres-
those who, in addition to a depressed mood, also have at sions may be multifactorial: consider a patient, again with
least three of the remaining symptoms noted in Table 6.1. well-established major depressive disorder, who, shortly
There is also debate as to the duration of symptoms after treatment with metoclopramide, develops a depression
before the diagnosis is given. Although it is customary to that persists for weeks, or longer, rather than remitting after
p 06.qxd 3/10/08 9:34 AM Page 210
210 Syndromes of disturbances of mood and affect
Table 6.2 Causes of depression

Primary or idiopathic disorders Pellagra
Major depressive disorder Pancreatic cancer
Bipolar disorder
Medication or substance withdrawal
Dysthymia
Cholinergic rebound
Premenstrual dysphoric disorder
Stimulants
Post-partum blues
Anabolic steroids
Post-partum depression
Schizoaffective disorder Endocrinologic disorders
Post-psychotic depression in schizophrenia Hypothyroidism
Hyperthyroidism
Toxic depressions
Cushing’s syndrome
Medication-induced
Adrenocortical insufficiency
Prednisone (Wolkowitz et al. 1990)
Hyperaldosteronism
Alpha-interferon (Fried et al. 2002; Krauss et al. 2003;
Hyperprolactinemia
Raison et al. 2005; Torriani et al. 2004)
Beta 1b-interferon (Neilley et al. 1996) Neurodegenerative and dementing disorders
Metoclopramide (Friend and Young 1997) Parkinson’s disease
Pimozide (Bloch et al. 1997b) Diffuse Lewy body disease
Propranolol (Petrie et al. 1982; Pollack et al. 1985) Hereditary mental depression with parkinsonism
Nifedipine (Hullett et al. 1988) Huntington’s disease
Cimetidine (Billings et al. 1981) Alzheimer’s disease
Ranitidine (Billings and Stein 1986) Multi-infarct dementia
Subdermal estrogen–progestin (Wagner 1996; Wagner and
Berenson 1994) Other intracranial disorders
Alpha-methyl dopa (DeMuth and Ackerman 1983) Stroke
Reserpine (Jensen 1959; Quetsch et al. 1959) Traumatic brain injury
Levetiracetam (Mula et al. 2003; Wier et al. 2006) Multiple sclerosis
Isotretinoin (Wysowski et al. 2001) Epilepsy-associated depression
Bismuth (Supino-Viterbo et al. 1977) Ictal depression
Substances of abuse or toxins Interictal depression
Chronic alcoholism Tumors
Lead intoxication Hydrocephalus
Fahr’s syndrome
Metabolic depressions Systemic lupus erythematosus
Obstructive sleep apnea Limbic encephalitis
Chronic hypercalcemia Tertiary neurosyphilis
Vitamin deficiencies New-variant Creutzfeldt–Jakob disease
Vitamin B12 deficiency Down’s syndrome
the metoclopramide is discontinued. In this instance, it is will, in over 90 percent of cases, occur within 10 years of the
reasonable to assume that the medication triggered a new first depressive episode or by the time five or more episodes
depressive episode of the major depressive disorder, which of depression have occurred, whichever comes first (Dunner
then persisted. et al. 1976).
Major depressive disorder and bipolar disorder are both Although not as reliable, certain clinical characteristics of
characterized by recurrent episodes of depression, the two the depressive episode may also suggest whether that depres-
disorders being distinguished by the fact that in bipolar dis- sive episode is occurring on a basis of bipolar disorder or
order one also sees, at some point in the patient’s history, a major depression. Specifically, depressive episodes of bipo-
manic episode, whereas in major depressive disorder, manic lar disorder are, in contrast with those of major depression,
episodes never occur. Given that bipolar disorder may com- more likely to have an acute onset (over weeks rather than
mence with one, or several, episodes of depression before months) (Winokur et al. 1993) and are also more likely to be
the first episode of mania occurs, one must, in evaluating a accompanied by delusions or hallucinations (Guze et al.
patient who has had only depressive episodes, allow a 1975).
lengthy period of observation to pass before making a firm Dysthymia is characterized by chronic, low-level, and
diagnosis of major depression. Statistically speaking, in generally fluctuating depressive symptoms. This condition
patients with bipolar disorder, the first episode of mania is of uncertain nosologic status. In many cases, there will be
p 06.qxd 3/10/08 9:34 AM Page 211
6.1 Depression 211
an exacerbation of symptoms to the degree found in a emerges as a frequent cause. The other medications listed
depressive episode (Devanand et al. 1994), and, from my in Table 6.2 only rarely cause depression, and before one
point of view, it may be appropriate to think of dysthymia ascribes any given depression to them it is necessary to
simply as a chronic, low-level depressive episode that could demonstrate a close temporal relationship between the ini-
be part of either major depression or bipolar disorder. tiation of treatment and the onset of the depression and,
Premenstrual dysphoric disorder is characterized by rela- ideally, a similarly close relationship between discontinua-
tively brief depressions that occur with each menstrual cycle, tion and remission of the depression. This list of medicines
beginning anywhere from hours to one and a half weeks should not be considered comprehensive, and the clinician
before the onset of menses and remitting spontaneously 2–3 should maintain a high index of suspicion for a medica-
days after menstrual flow begins. The depression is typically tion-induced depression whenever such temporal relation-
characterized by prominent lability of mood (Bloch et al. ships can be established, and other, more common, causes
1997a). of depression appear absent.
Post-partum blues is immediately suggested by its onset Chronic alcoholism is commonly associated with
within the first few days post-partum and by its characteris- depression, indeed a majority of newly admitted alcoholics
tic lability of affect (Pitt 1973; Rohde et al. 1997; Yalom et al. will be so affected (Davidson 1995). Importantly, the symp-
1968). toms typically resolve spontaneously during the first 4
Post-partum depression is distinguished from the weeks of abstinence (Brown et al. 1995).
post-partum blues by its later onset, with a latency of at Lead intoxication may be characterized by depression
least several weeks between delivery and the onset of the (Schottenfeld and Cullen 1984), and the diagnosis should
depression. be considered in cases wherein the depression is accompa-
Schizoaffective disorder is characterized by chronic, nied by a motor peripheral neuropathy with wrist or, less
persistent psychotic symptoms with the ‘superimposition’ commonly, foot drop.
of episodes of either depression or of mania, during either
of which the pre-existing psychotic symptoms undergo a
significant exacerbation. Differentiating schizoaffective METABOLIC DEPRESSIONS
disorder from bipolar disorder may be difficult (Pope et al.
Obstructive sleep apnea may cause a depression marked by
1980), and the reader is directed to Section 20.2 for a dis-
tiredness, indecisiveness, irritability, and complaints of
cussion of this.
insomnia (Millman et al. 1989). The diagnosis is suggested
Post-psychotic depression in schizophrenia is seen in
by a history of prominent snoring, and by a relief of symp-
about one-third of patients with schizophrenia. In these
toms upon successful treatment of the sleep apnea, as for
patients, after a more or less complete remission of psy-
example with continuous positive airway pressure.
chotic symptoms (whether occurring spontaneously or by
Chronic hypercalcemia, as seen in hyperparathyroidism,
virtue of antipsychotic treatment), a depressive episode
may be accompanied by depression (Linder et al. 1988;
occurs, typically within a matter of months (Mandel et al.
Petersen 1968; Reinfrank 1961) and may in some cases pres-
1982). In contrast with schizoaffective disorder, however,
ent with depression (Gatewood et al. 1975; Karpati and
there is during this post-psychotic depression no exacerba-
Frame 1964).
tion of psychotic symptoms.
Both vitamin B12 deficiency and niacin deficiency may,
rarely, cause depression. In one case of B12 deficiency-
TOXIC DEPRESSIONS induced depression, the only clue was a concurrent macro-
cytic anemia (Fraser 1960). Chronic niacin deficiency
Toxic depressions may be either medication induced or sec-
causes pellagra, which, in one case, presented with a com-
ondary to substances of abuse or actual toxins. Medications
bination of depression and the familiar rash/diarrhea
are considered first.
(Hardwick 1943).
Of the various medications listed in Table 6.2, the most
Pancreatic cancer is associated with depression (Holland
common offender is prednisone, given in relatively high
et al. 1986; McDaniel et al. 1995) and may indeed present
doses of 40–60 mg/day or more; similar effects may be
with depression (Fras et al. 1967; Rickles 1945). The even-
expected with other corticosteroids. Alpha-interferon, as
tual appearance of abdominal pain suggests the correct
used in the treatment of hepatitis C and melanoma, is
diagnosis.
another major offender, inducing depression within a few
weeks in approximately one-third of all patients: the effect
here is so profound that prophylactic treatment is recom- MEDICATION OR SUBSTANCE WITHDRAWAL
mended, with one study demonstrating effectiveness for
paroxetine (Musselman et al. 2001). Depression has also Cholinergic rebound may occur after abrupt discontinua-
been associated with beta-1b-interferon, but this is com- tion of long-term treatment with anticholinergic agents,
paratively rare. Metoclopramide, although producing such as tricyclic antidepressants: shortly thereafter,
depression in only a very small percentage of patients who patients fairly abruptly develop a depression accompanied
take it, is, however, so commonly prescribed that it too by nausea (Dilsaver et al. 1983).
p 06.qxd 3/10/08 9:34 AM Page 212
Stimulant withdrawal, for example after extended use of Hyperprolactinemia, as may be seen with prolactino-
either amphetamines (Watson et al. 1972) or cocaine mas, may cause depression, which, in turn, remits with
(Weddington et al. 1990), is typically characterized by a treatment with bromocriptine (Cohen 1995; Mattox et al.
depression that tends to resolve in a few weeks. 1986). The diagnosis may be suggested by galactorrhea or
Anabolic steroids may be taken chronically by athletes; erectile dysfunction.
abrupt discontinuation may be followed by a depression
(Pope and Katz 1988) that tends to remit spontaneously NEURODEGENERATIVE AND DEMENTING DISORDERS
within weeks or months.
Depression may occur in the context of various neurode-
generative and dementing disorders.
ENDOCRINOLOGIC DISORDERS Parkinsonian disorders capable of causing depression
include Parkinson’s disease, diffuse Lewy body disease, and
The endocrinologic disorders constitute a particularly
a very rare disorder known as hereditary mental depression
important group not only because they are a relatively com-
with parkinsonism. Parkinson’s disease, in most (but not
mon cause of depression, but also because they are emi-
all [Hantz et al. 1994]) studies, is associated with depres-
nently treatable. Of them, hypothyroidism is perhaps the
sion of varying degrees of severity in up to 40 percent of
most important.
cases (Mayeux et al. 1986; Starkstein et al. 1990a). Diffuse
Hypothyroidism may cause severe depression (Tonks
Lewy body disease (distinguished from Parkinson’s disease
1964; Whybrow et al. 1969). In addition to such features as
by the occurrence, within a year of the onset of parkinson-
weight gain, hair loss, dry skin, and voice change, the con-
ism, of dementia) is characterized by depression in about
dition is also suggested by prominent fatigue, sluggishness,
one-half of patients (Klatka et al. 1996). Hereditary mental
and drowsiness (Nickel and Frame 1958).
depression with parkinsonism is a very rare familial disor-
Hyperthyroidism, although generally associated with
der that presents with depression, followed, years later, by
anxiety and agitation, appears just as likely to cause depres-
parkinsonism (Perry et al. 1975).
sion (Kathol and Delahunt 1986; Trzepacz et al. 1988) and
Huntington’s disease not uncommonly causes depres-
the correct diagnosis may be suggested by the presence
sion (Caine and Shoulson 1983) and the suicide rate in this
of weight loss in the face of increased appetite (Trzepacz
disorder is particularly elevated.
et al. 1988) or autonomic signs such as tremor and tachy-
Alzheimer’s disease, suggested by the gradual onset of a
cardia (Taylor 1975). Apathetic hyperthyroidism is a con-
dementia with prominent amnestic features, is accompa-
dition seen in elderly patients with hyperthyroidism, and is
nied by prominent depressive symptoms in about one-fifth
distinguished from the more common presentation of
of all cases (Burns et al. 1990a; Starkstein et al. 1997, 2005a).
hyperthyroidism seen in younger patients by marked apathy
Multi-infarct dementia, suggested by its stepwise course
and the relative absence of tremor (Lahey 1931; Thomas
and prominent focal findings, produces depression in over
et al. 1970). In some cases, rather than apathy, however,
one-half of all sufferers (Cummings et al. 1987).
one may see depression (Thomas et al. 1970). Important
clues to the correct diagnosis include atrial fibrillation OTHER INTRACRANIAL DISORDERS
or congestive heart failure (Arnold et al. 1974; Thomas
et al. 1970). Of the other intracranial disorders capable of causing
Cushing’s syndrome, as seen with pituitary or adrenal depression, the most common are stroke and traumatic
tumors (Haskett 1985), may be characterized by depres- brain injury. Other somewhat less common causes are
sion, as noted by Cushing himself (Cushing 1932), and this multiple sclerosis and epilepsy. Finally, there is a miscella-
has been noted in over one-half of all cases (Cohen 1980; neous group, including tumors, hydrocephalus, etc.
Haskett 1985; Kelly 1996; Starkman 1981). Suggestive fea- Post-stroke depression, which can be quite severe (Lipsey
tures include weight gain, moon facies, hirsutism, acne, a et al. 1986), may develop in the weeks or months after stroke
buffalo hump, violaceous abdominal striae, hypertension, in up to one-half of all patients. Most (Hermann et al. 1993;
and diabetes mellitus (Haskett 1985; Spillane 1951). Robinson et al. 1983, 1984, 1985), but not all (House et al.
Cushing’s syndrome may also occur on a paraneoplastic 1990; MacHale et al. 1998; Stern and Bachman 1991), stud-
basis, and, in one case secondary to Hodgkin’s disease, the ies note that such depression is more likely with infarctions
patient presented with depression and slight facial puffi- in the left frontal lobe than elsewhere. Such patients typically
ness (Anderson and McHugh 1971). recover within a year (Astrom et al. 1993; Robinson et al.
Adrenocortical insufficiency, when chronic, may cause 1987). Post-stroke depression has also been associated with
depression (Engel and Margolin 1941; Varadaraj and infarction of the left basal ganglia (Morris et al. 1996;
Cooper 1986) and is suggested by associated features such as Starkstein et al. 1987a, 1988a).
nausea, vomiting, abdominal pain, and postural dizziness. Traumatic brain injury may be associated with depres-
Hyperaldosteronism, as may occur with adrenal tumors, sion in up to one-half of all patients (Federoff et al. 1992).
very rarely, may cause depression: in one case the diagnosis Multiple sclerosis is more likely to cause depression
was suggested by hypokalemia and weakness and cramping than are other comparably debilitating disorders such as
of the legs (Malinow and Lion 1979). amyotrophic lateral sclerosis (Schiffer and Babigian 1984;
p 06.qxd 3/10/08 9:34 AM Page 213
6.1 Depression 213
Whitlock and Siskind 1980). Although this depression is New-variant Creutzfeldt–Jakob disease may present
correlated with overall disability early in the course of the with depression (Zeidler et al. 1997a) but eventually, over
disease (Millefiorini et al. 1992), this correlation vanishes weeks or months this will be joined by other symptoms,
as the disease progresses (Fassbender et al. 1998; Moller et such as ataxia, delirium, or dementia (Zeidler 1997b).
al. 1994); in more chronic cases, by contrast, one finds that Down’s syndrome, immediately suggested by mental
depression correlates with the extent of cerebral (rather retardation and a characteristic facies, may, in adults, cause
than cord) involvement (Rabins et al. 1986; Schiffer et al. depression (Collacott et al. 1992), which may be very
1983), specifically with involvement of the left arcuate fas- severe (Warren et al. 1989).
ciculus (Pujol et al. 1997). As with other signs of multiple
sclerosis, the depression may also have a relapsing and
remitting course (Dalos et al. 1983). Differential diagnosis
Epilepsy may be associated with depression, not only in
that certain partial seizures may manifest with depression, Depression is a normal reaction to the adverse events of life,
but also, and, from a numeric point of view, more impor- especially losses, and this normal depression must be distin-
tantly, in that patients with epilepsy may develop a chronic, guished from depression caused by one of the disorders
interictal depression. Partial seizures (Weil 1956, 1959; described above. Several features of normal depression are
Williams 1956) may manifest with the paroxysmal onset of helpful in this differential. First, the severity of normal
depression, which may be severe, with psychomotor retar- depression is generally proportionate to the severity of the
dation or agitation, and which may last for from minutes to, preceding adverse event, whether it be the loss of a loved one,
in cases of complex partial status epilepticus, weeks. In addi- serious illness, or financial reversals; thus, although severe
tion to the paroxysmal onset, important clues to the diagno- symptoms are to be expected after the death of a child, they
sis are the presence of olfactory hallucinations and a history would not be normal after, say, getting a parking ticket.
of more typical seizures at other times. Interictal depression Second, normal depressions generally remit spontaneously
of epilepsy occurs in a large proportion of patients with and do so, in most cases, within 6 months or so, rarely, if
recurrent seizures (Mendez et al. 1986), especially those with ever, lasting more than a year (Harlow et al. 1991); thus,
recurrent complex partial seizures (Indaco et al. 1992; Perini depression lasting longer, surely, than a year, should not be
et al. 1996). considered a ‘normal’ reaction, unless, of course, the adverse
Intracerebral tumors may cause depression, as has been event were ongoing. Third, and finally, normal depressions
noted with tumors of the anterior portion of the corpus generally lack severe vegetative symptoms and never are
callosum (Ironside and Guttmacher 1929). characterized by delusions; thus, the presence of severe mid-
Hydrocephalus may present with depression (Jones dle or terminal insomnia, anorexia or psychomotor change,
1993) and in a minority of cases of normal-pressure hydro- or any delusions, argues strongly against a normal depres-
cephalus, it may play a prominent part in the overall clinical sion. Clearly, the exercise of good clinical judgment is
picture (Pujol et al. 1989). The presence of an ataxic/apraxic required in making this differential. Many patients (and their
or ‘magnetic’ gait may suggest the correct diagnosis. family members) seem offended at the suggestion that they
Fahr’s syndrome may, rarely, present with depression, might be depressed, and wounded pride may prompt such
which is eventually joined by more typical signs such as comments as ‘well, wouldn’t you be depressed if you’d gone
dementia (Slyter 1979) and parkinsonism (Trautner et al. through what I did?’ Whether or not the physician would is
1988); calcification of the basal ganglia, apparent on com- immaterial; what is important is for the physician to deter-
puted tomography, strongly suggests this diagnosis. mine whether the patient’s depression is normal or not.
Systemic lupus erythematosus can definitely cause Akinesia must also be considered in the differential of
depression (Dennis et al. 1992). What is disputed, how- depression. Akinesia is perhaps most commonly seen in
ever, is how frequently it does so: some have found depres- patients treated with antipsychotics, especially first-genera-
sion to be common in lupus (Ainiala et al. 2001; Brey et al. tion agents, and is characterized by a sluggishness of thought
2002; Ganz et al. 1972; Lim et al. 1988; Miguel et al. 1994), and an overall dulling of emotion: some patients complain of
whereas older studies have not (Guze 1967; Hugo et al. feeling like a ‘zombie’ (Rifkin et al. 1975; Van Putten and May
1996). The diagnosis should be suspected in patients with 1978). Two points serve to differentiate this from depression:
arthralgia, rashes, and constitutional symptoms. first, there is little in the way of changes in sleep or appetite,
Limbic encephalitis may present with a depression, and actually little depressed mood, either; second, akinesia
which is later joined by other, more typical evidence of the responds promptly to treatment with anticholinergics, such
encephalitis, such as delirium (Glaser and Pincus 1969) or as benztropine, which have no effect on depression.
dementia (Corsellis et al. 1968).
Tertiary neurosyphilis may cause a dementia (general
paresis of the insane, GPI) characterized not only by cogni- Treatment
tive deficits, but also by depression (Dewhust 1969; Gomez
and Aviles 1984) in almost one-fifth of all cases (Storm- Treatment, wherever possible, is directed at the underlying
Mathisen 1969). cause. Where this is not possible, or is perhaps ineffective,
p 06.qxd 3/10/08 9:34 AM Page 214
consideration may be given to symptomatic treatment with Dementia may be accompanied by apathy and this has
an antidepressant. In general, given their overall effective- been noted in various neurodegenerative disorders (Levy
ness, and, most importantly, their safety, selective serotonin et al. 1998), most notably Alzheimer’s disease (Starkstein et al.
reuptake inhibitors (SSRIs) constitute a first choice. Some 2001, 2005b, 2006), frontotemporal dementia (Levy et al.
studies back this up. With regard to post-stroke depression, 1996), Parkinson’s disease (Isella et al. 2002, Pluck and
citalopram was found to be superior to placebo (Anderson Brown 2002), progressive supranuclear palsy (Litvan et al.
et al. 1994), and depression occurring after traumatic brain 1996), and Huntington’s disease (Burns et al. 1990b).
injury may respond to sertaline (Fann et al. 2000). If an SSRI Although in many of these demented patients apathy appears
is used for depression in parkinsonian conditions, a careful in association with a depressive syndrome, there is a definite,
watch should be kept for any aggravation of the parkinson- although minority, group, wherein apathy appears without
ism as has been seen with both fluoxetine (Ernst and Steur any associated depressed mood, lack of energy, or other
1993) and paroxetine (Jimenez-Jimenez et al. 1994); fur- symptoms typical of a depressive syndrome. Apathy is seen
thermore, if a monamine oxidase inhibitor (MAOI) is being commonly after traumatic brain injury, and, in these cases, is
used for the treatment of parkinsonism, SSRIs should not be more common when the right hemisphere is involved, espe-
prescribed, given the risk of a serotonin syndrome. cially its subcortical portions (Andersson et al. 1999).
The frontal lobe syndrome, as discussed in Section 7.2,
may, along with disinhibition and perseveration, also
include apathy.
6.2 APATHY
Depressive syndromes often include apathy as a symp-
tom along with depressed mood, fatigue, insomnia, etc.
Apathy, or indifference, is very common in geriatric
Such syndromes may, as noted above, be seen in various
patients, and, as noted below, may occur secondary to a
dementing disorders, or more commonly, may appear as a
variety of causes.
manifestation of major depressive disorder (Feil et al. 2003;
Starkstein et al. 2001).
Psychosis, as for example schizophrenia (Roth et al.
Clinical features 2004), may also include apathy as a symptom, along with
delusions, hallucinations, etc.
Normally, thoughts of doing something, whether thinking a
problem through, getting dressed, going to a movie, or
whatever, when they appear, are invested with a greater or Differential diagnosis
lesser degree of motivation to carry out the plan. In apathetic
patients, however, such thoughts come, as it were, stillborn, Abulia, superficially, appears almost identical to apathy, in
and without sufficient associated motivation to impel the that in both cases, afflicted patients are inactive. There are,
thinker to carry them into action. In apathetic patients, there however, significant differences. In abulia, there simply are
is such a pervasive sense of not ‘caring’ enough that many no thoughts, plans or inclinations: the ‘mental horizon’ is
lapse into inactivity, and appear detached and indifferent. empty and undisturbed. By contrast, thoughts, etc., do
occur with apathy but without sufficient associated motiva-
tion to carry the patient into action. Furthermore, when
Etiology abulic patients are subject to supervision they do carry out
tasks, and typically do so at a normal rate, provided that the
Apathy may appear in a more or less isolated fashion or supervision is ongoing; by contrast, apathetic patients may
may occur as part of another syndrome, such as dementia, shirk or withdraw when told to do something, and comply
the frontal lobe syndrome, or depression. only half-heartedly, if that, with ongoing supervision.
Apathy in a more or less isolated form may be seen in Bradyphrenia and bradykinesia, as seen in parkinsonian
stroke, acquired autoimmune deficiency syndrome (AIDS) conditions, may also appear similar to apathy in that, to a
(Paul et al. 2005), myotonic muscular dystrophy (Rubinsztein brief inspection, there is little activity. The differential,
et al. 1998), and hyperthyroidism in the elderly (‘apathetic’ however, is relatively easy if one only observes the patient
hyperthyroidism [Brenner 1978]). In the case of stroke, apa- for a while: given enough time, the bradykinetic patient
thy has been associated with ischemic infarction involv- will get the job done, as here it is not a lack of motivation
ing the posterior limb of the internal capsule (Starkstein but rather a slowing down of all activities, whereas, by con-
et al. 1993), both thalami (Catsman-Berrevoets and von trast, the apathetic patient will remain inactive.
Harskamp 1988), and the right frontosubcortical circuitry Depressed mood, when accompanied by anhedonia,
(Brodaty et al. 2005). Apathy has also been noted as a side- may appear very similar to apathy. Depressed mood, how-
effect of treatment with antipsychotics, and, with chronic ever, is a definite mood: patients feel sad, ‘blue’, or inter-
use, SSRIs (Hoehn-Saric et al. 1990). Finally, isolated apa- nally oppressed. By contrast, apathetic patients typically
thy may occur in geriatric nursing home patients in whom experience an absence of any particular mood, except, of
it appears to result from chronic understimulation. course, for a sense of indifference. Furthermore, depressed
p 06.qxd 3/10/08 9:34 AM Page 215
6.3 Mania 215
patients who have lost their hedonic capacity may never- Clinical features
theless at times feel some motivation to act but then fail to
carry through as they realize that there will be no pleasure The syndrome of mania, following the elegant descriptive
in finishing the task. By contrast, apathetic patients, lack- study of Carlson and Goodwin in 1973, may be divided
ing any motivation to act at all, simple fail to get started. into three stages. Stage I mania, also known as hypomania,
is present in all cases, and, in its fully developed form
Treatment includes all the symptoms listed in Table 6.3. Most
patients, over time, will enter into stage II mania, known
In cases where apathy appears as part of another syndrome, as acute mania, with this transition being marked by an
the first approach is to treat the larger syndrome, as suc- exacerbation of the symptoms seen in hypomania and by
cessful treatment in this regard may, in some cases, be fol- the appearance of delusions. A minority of patients will
lowed by substantial improvement of the apathy. Examples progress further, into stage III mania, known also as deliri-
include: cholinesterase inhibitors for Alzheimer’s disease ous mania, and here one finds confusion, hallucinations,
and Parkinson’s disease dementia; levodopa or direct- worsening delusions, and an overall disintegration of
acting dopamine agonists for Parkinson’s disease and pro- behavior. As the manic syndrome gradually resolves,
gressive supranuclear palsy; antidepressants for depressive patients tend, as it were, to retrace the symptomatic steps
syndromes; and antipsychotics for psychoses. When SSRIs that marked the evolution of the syndrome: thus, a patient
or antipsychotics (especially first-generation agents) are who reached stage III would gradually settle back into stage
used, one must be alert to their potential, as noted earlier, II, then stage I, only finally to experience a remission of
to cause apathy. symptoms. The onset of a manic syndrome tends to be
In cases when treatment of a larger syndrome leaves fairly acute, over perhaps days to a week; the range here is
associated apathy untouched, or in cases where apathy is wide, from gradual onsets spanning months to hyperacute
occurring in an isolated fashion, consideration may be ones lasting hours or less. The overall duration of a manic
given to symptomatic treatment aimed at apathy itself. In episode depends on the underlying cause: in bipolar disor-
this regard, the most commonly used medication is der, the most common cause, episodes typically last from
methylphenidate, which appears effective for apathy associ- weeks to months.
ated with dementia (e.g., due to Alzheimer’s disease or mul- Additional studies have largely backed up this division by
tiple strokes [Galynker et al. 1997]), apathy occurring in an Carlson and Goodwin into stage I (Abrams and Taylor 1976;
isolated fashion after subcortical infarction (Watanabe et al. Carlson and Strober 1978; Clayton et al. 1965; Taylor and
1995), and apathy occurring in institutionalized geriatric Abrams 1973, 1977; Winokur and Tsuang 1975; Winokur
patients (Kaplitz 1975). Methylphenidate should be started et al. 1969), stage II (Loudon et al. 1977; Rosenthal et al.
at a low dose, for example 2.5 mg in the morning and 1979, 1980; Taylor and Abrams 1973, 1977), and stage III
2.5 mg in the early afternoon, and increased gradually every (Black and Nasrallah 1989; Bowman and Raymond 1931;
2 or 3 days, in similar increments until a response is seen, Brockington et al. 1980; Carlson and Strober 1978; Rosenthal
limiting side-effects occur, or a maximum dose of et al. 1979, 1980; Taylor and Abrams 1973, 1977; Winokur
60 mg/day is reached: in many elderly patients, a total daily 1984).
dose of from 10 to 20 mg generally suffices. Each one of the three stages of mania is described fur-
Apathy occurring after traumatic brain injury may also ther below; in several instances quotations are provided
respond to bromocriptine (Powell et al. 1996), amantadine from Emil Kraepelin’s (1921) masterful Manic-Depressive
(Van Reekum et al. 1995), or selegeline (Newburn and Insanity and Paranoia.
Newburn 2005).
When attempting pharmacologic treatment of apathy, it STAGE I MANIA: HYPOMANIA
should be borne in mind that of the studies noted above all
were open except that by Kaplitz et al. (for methylphenidate Of the symptoms of hypomania listed in Table 6.3, a
in institutionalized geriatric patients), which utilized a heightened mood is present in all cases and although most
double-blind protocol with 44 patients, and that by Van patients will have all of the others, some may play only a
Reekum et al. (for amantadine in traumatic brain injury relatively minor part in the clinical picture.
patients), which was an ‘N of 1’ study that also utilized a
Table 6.3 The symptoms of hypomania
double-blind protocol. Clearly, more work is needed.
Heightened mood (either euphoric or irritable)
Increased energy
6.3 MANIA Decreased need for sleep
Pressure of speech
Mania is one of the most distinctive syndromes in neuropsy-
Flight of ideas
chiatric practice: once seen, never forgotten. Although most
Distractibility
commonly caused by bipolar disorder, mania may occur
Hyperactivity
secondary to a host of other causes, as described below.
p 06.qxd 3/10/08 9:34 AM Page 216
Heightened mood Increased energy

Heightened mood may be either predominantly euphoric Energy is greatly, even immensely increased: patients are
or irritable. on the go, busy, and involved throughout the day. They
Euphoric patients are full of jollity and cheerfulness. wish to be a part of life and to be more involved in the lives
Although at times selfish and pompous, their mood is never- of those around them. They are strangers to fatigue and
theless quite ‘infectious’. They joke, make wisecracks and still quite active when their companions, exhausted, plead
delightful insinuations, and those around them often get for sleep.
quite caught up in the spirit, always laughing with these
patients and not at them. Indeed, when physicians find them- Decreased need for sleep
selves unable to suppress their laughter when interviewing a Decreased need for sleep typically accompanies this increased
patient, the diagnosis of mania should be seriously consid- energy. The patient, as described by Kraepelin, ‘cannot stay
ered. Self-esteem and self-confidence are greatly increased. long in bed; early in the morning, even at four o’clock he gets
Inflated with their own grandiosity, patients may boast of up, he clears out lumber rooms, discharges business that was
fabulous achievements and lay out plans for even grander in arrears, undertakes morning walks, excursions’.
accomplishments in the future. Such patients rarely recognize
that anything is wrong with them, and although their judg- Pressure of speech
ment is obviously impaired they have little or no insight into Patients with pressured speech, as noted by Kraepelin,
their condition. Kraepelin noted that the manic patient: ‘talk a great deal, hastily, in loud tones, with great verbosity
is in imperturbable good temper, sure of success, and prolixity’. Speech becomes imperious, incredibly rapid
‘courageous’, feels happy and merry, not rarely and almost unstoppable, and listeners may feel veritably
overflowingly so, wakes up every morning ‘in excellent deluged by the torrent of words. Occasionally, patients
humor’. He sees himself surrounded by pleasant and may succumb to others’ protests to stop and may be able to
aristocratic people, finds complete satisfaction in the keep silent and withhold their speech, but such respites
enjoyment of friendship, of art, of humanity; he will typically do not hold long and soon the dam bursts once
make everyone happy, abolish social wretchedness, again.
convert all in his surroundings. For the most part an Pressured speech is often accompanied by pressure
exuberant unrestrained mood inclined to practical jokes of thought, and patients may complain of racing thoughts.
of all kinds is developed. Occasionally there is developed Kraepelin noted that ‘thoughts come of themselves,
a markedly humorous trait, the tendency to look at obtrude themselves, impose upon the patients. “I can’t
everything and every occurrence from the jocular side, grasp all the thoughts which obtrude themselves,” said a
to invent nicknames, to make fun of himself and others. patient. “It is so stormy in my head,” declared another,
A patient called himself a ‘thoroughbred professional “everything goes pell-mell.” “My thoughts are all tattered.”
fool’; another declared that the hospital was a ‘nerve- “I am not master over my thoughts.”.’
ruining institution’; a third stated that he was a ‘poet,
cattle-driver, author, tinker, teacher, popular reformer, Flight of ideas
chief anarchist and detective’. In flight of ideas the patients’ train of thought is character-
ized by abrupt leaps from one topic to another. When mild,
Kraepelin (1921) the connections between these various topics, although per-
haps tenuous, may nevertheless by ‘understandable’ to the
Irritable patients are loud, insistent, demanding, and listener. In higher grades, however, the connections may
intolerant, and the threat of violence hangs about them as seem to lack any logic, and may come to depend more and
a malignant fog. Kraepelin noted that such a patient is: more on puns or word-plays.
dissatisfied, intolerant, fault-finding, especially in
intercourse with his immediate surroundings, where he Distractibility
lets himself go; he becomes pretentious, positive, For distractible patients, other conversations or events, are
regardless, impertinent and even rough, when he like glittering jewels that they must attend to, take as their
comes up against opposition to his wishes and own, or furiously admire, although peripheral to their
inclinations; trifling external occasions may bring present purposes. In listening to patients one may find that
about extremely violent outbursts of rage. In his fury a fragment of another conversation has suddenly been
he thrashes his wife and children, threatens to smash interpolated into their flight of ideas or there may be an
everything to smithereens, to run amuck, to set the absolutely abrupt change of topic triggered by a seemingly
house on fire, abuses the ‘tribe’ of his relatives in the irrelevant event: one patient, in the midst of an exultant
most violent language, especially when under the tirade, suddenly stopped and declared his unbounded
influence of alcohol. admiration for the physician’s tie, paused for a matter of
seconds in great satisfaction, then proceeded with his
Kraepelin (1921) previous rush of speech.
p 06.qxd 3/10/08 9:34 AM Page 217
6.3 Mania 217
Hyperactivity With the intensification of hypomanic symptoms and

Hyperactivity, which might just as well be termed pressure the appearance of delusions, the overall behavior of these
of activity, follows from the patients’ grandiosity and patients may become quite extravagant. Kraepelin noted
increased energy. Patients may enter into business arrange- that patients may:
ments with unbounded and completely uncritical enthusi- run out of the house in a shirt, go to church in a
asm. Ventures are begun, stocks are bought on a hunch, petticoat, spend the night in a field of corn, give away
money is loaned out without collateral, and when the fam- their property, disturb the service in church by
ily fortune is spent, manic patients, undaunted, may seek screaming and singing, kneel and pray on the street,
to borrow more money for yet another prospect. Spending fire a pistol in the waiting-room, put soap and soda in
sprees are also quite typical. Clothes, furniture, and cars the food, try to force their way into the palace, throw
may be bought; the credit card is pushed to the limit, and objects out at the window. A female patient jumped
another one is obtained; checks, without any foundation in into the carriage of a prince for a joke . . . A male
the bank account, are written with alacrity. Kraepelin patient appropriated the property of others in taverns.
noted that such a patient is swelled by a ‘need to get out of Another appeared in the court of justice in order to
himself, to be on more intimate terms with his surround- catch a murderer.
ings, to play a part’. It causes him:
Kraepelin (1921)
to change about his furniture, to visit distant
acquaintances, to take himself up with all possible STAGE III MANIA: DELIRIOUS MANIA
things and circumstances, which formerly he never
thought about. Politics, the universal language, The transition to delirious mania is marked by the appear-
aeronautics, the women’s question, public affairs of ance of confusion, more hallucinations, and an intense
all kinds and their need of improvement, give him exacerbation of all the symptoms seen in stage II. There
employment. A physician advertised about ‘original may be a dream-like clouding of consciousness and
sin, Genesis, natural selection and breeding’. Another patients may become unaware of where they are; incoher-
patient drove about in a cab and distributed pictures ence may appear and, as described by Kraepelin, ‘Their lin-
of the saints. The patient enters into numerous guistic utterances alternate between inarticulate sounds,
engagements, suddenly pays all his business debts praying, abusing, entreating, stammering, disconnected
without it being necessary, makes magnificent talk, in which clang-associations, senseless rhyming, diver-
presents, builds all kinds of castles in the air, and sion by external impressions, persistence of individual
with swift enthusiasm precipitates himself in daring phrases, are recognized’. Hallucinations become promi-
undertakings much beyond his powers. He has 16,000 nent, and as further described by Kraepelin, ‘The patient
picture post-cards of his little village printed. . . . sees heaven open, full of camels and elephants, the King,
his guardian-angel, the Holy Ghost; the devil has assumed
Kraepelin (1921) the form of the Virgin Mary. The ringing of bells is heard,
shooting, the rushing of water, a confused noise; Lucifer is
STAGE II MANIA: ACUTE MANIA speaking; the voice of God announces to him the day of
judgment, redemption from all sins’.
The transition from hypomania to acute mania is marked by With this evolution into stage III, overall behavior
a severe exacerbation of the symptoms seen in hypomania becomes very fragmented, and patients may ‘become stu-
and by the appearance of delusions, typically delusions of pefied, confused, bewildered’, they may:
grandeur. Kraepelin noted, ‘The patient asserts that he is
descended from a noble family, that he is a gentleman; he dance about, perform peculiar movements, shake
calls himself a genius, the Emperor William, the Emperor of their head, throw the bedclothes pell-mell, are
Russia, Christ; he can drive out the devil. A patient suddenly destructive, pass their movements under them, smear
cried out on the street that he was the Lord God . . . ’. everything, make impulsive attempts at suicide, take
Delusions of persecution may also occur, especially in off their clothes. A patient was found completely
patients with irritability. Patients may assert that their fail- naked in a public park. Another ran half-clothed into
ures are not their own but the result of treacheries and the corridor and then into the street, in one hand a
betrayals by family members or business colleagues. They revolver in the other a crucifix.
are persecuted by those jealous of their grandeur; they are
pilloried and crucified by their enemies. Terrorists have set a Kraepelin (1921)
watch on their houses and seek to destroy them before they
can ascend their thrones. Occasionally, in addition to these Etiology
delusions, there may be transitory hallucinations. Grandiose
patients may hear a chorus of angels; persecuted patients The various causes of mania are listed in Table 6.4, in which
may hear the resentful muttering of the envious crowd. they are organized into several groups. The first group is
p 06.qxd 3/10/08 9:34 AM Page 218
Table 6.4 Causes of mania

Primary, idiopathic disorders Endocrinologic
Bipolar disorder Cushing’s syndrome
Cyclothymia Hyperthyroidism
Schizoaffective disorder
Post-partum psychosis Intracranial disorders
Infarctions
Toxic
Midbrain
Prednisone (Lyons et al. 1988, Minden et al. 1988, Wolkowitz
Thalamus
et al. 1990)
Caudate
Anabolic steroids (Pope and Katz 1988, 1994)
Frontal lobe
Oral contraceptives (Sale and Kalucy 1981)
Temporal lobe
Levodopa (Ryback and Schwab 1971; Van Woert et al. 1971)
Tumors
Pramipexole (Singh et al. 2005)
Midbrain
Ropinirole (Singh et al. 2005)
Hypothalamus
Antidepressants (Shulman et al. 2001; Stoll et al. 1994)
Thalamus
Buspirone (Liegghid and Yeragani 1988; Price and Bielfeld 1989)
Frontal lobe
Alpha-interferon (Constant et al. 2005)
Multiple sclerosis
Zidovudine (Maxwell et al. 1988; O’Dowd and McKegney
1988; Wright et al. 1989)
As part of certain dementing disorders
Abacavir (Brouilette and Routy 2007)
Alzheimer’s disease
Clarithromycin (Abouesh and Hobbs 1998)
Ciprofloxacin (Bhalerao et al. 2006)
Neurosyphilis
Isoniazid (Chaturvedi and Upadhyaya 1988; Jackson 1957)
Topiramate (Jochum et al. 2002)
Metachromatic leukodystrophy
Phenytoin (Patten et al. 1989)
Adrenoleukodystrophy
Zonisamide (Sullivan et al. 2006)
Procyclidine (in high dosage) (Coid and Strang 1982)
Miscellaneous
Propafenone (Jack 1985)
Procarbazine (Mann and Hutchinson 1967)
Epileptic disorders
Disulfiram (Ceylan et al. 2007)
Ictal mania
Aspartame (in high dosage) (Walton 1986)
Post-ictal mania
Bromide (Sayed 1976)
Mannitol (Navarro et al. 2001)
Vitamin B12 deficiency
Metrizamide (Kwentus et al. 1984)
Sydenham’s chorea
Baclofen withdrawal (Kirubakaren et al. 1984)
Chorea gravidarum
Tiagabine withdrawal (Pushpal and Shamshul 2006)
Encephalitis lethargica
Reserpine withdrawal (Kent and Wilber 1982)
Acute disseminated encephalomyelitis
Alpha-methyldopa withdrawal (Labbatte and Holzgang 1989)
Fahr’s syndrome
Metabolic Dialysis dementia
Hepatic encephalopathy Tuberous sclerosis
Uremia Velocardiofacial syndrome
composed of primary, idiopathic disorders, such as bipolar PRIMARY, IDIOPATHIC DISORDERS

disorder, which by far constitute the most common causes
of mania. The next group, the toxic causes, includes medica- Bipolar disorder is by far the most common cause of mania
tions, for example prednisone, capable of inducing mania and is characterized, in most cases, by recurrent episodes of
as a side-effect. Metabolic causes come next, and include mania and recurrent episodes of depression throughout the
both hepatic encephalopathy and uremia. Endocrinologic lifetime of the patient. Critically, in the intervals between
causes include Cushing’s syndrome and hyperthyroidism. these episodes, patients are either asymptomatic or experi-
Intracranial disorders capable of causing mania are consid- ence only mild residual symptoms, tending toward either
ered next, including infarctions and tumors. Mania may also euphoria or depression. The first episode of illness may be
occur as part of certain dementing disorders, for example either manic or depressive in character. In cases where the
Alzheimer’s disease. Finally, there is a miscellaneous group of first episode is depressive, a manic episode generally occurs
causes, including lupus and others. within either 10 years or, if there are recurrent depressive
p 06.qxd 3/10/08 9:34 AM Page 219
6.3 Mania 219
episodes, five depressive episodes, whichever comes first remain manic (Giovannoni et al. 2000). Mania may also
(Dunner et al. 1976). Importantly, however, although in the occur secondary to direct-acting dopaminergics, such as
intervals between episodes, there may be mild disturbances pramipxole and ropinirole but this is much less common.
of mood, as noted above, there are never any psychotic Antidepressants are notorious for inducing mania, but this
symptoms. Some variations on the typical course of bipolar generally only occurs in patients with pre-existing bipolar
disorder described earlier are worthy of note. First, it rarely disorder, and in these cases it is appropriate to consider that
appears that some patients (often referred to as ‘unipolar the antidepressant ‘triggered’ a manic episode. Anabolic
manic’) have only manic episodes during their lifetime steroid abuse, as seen in athletes such as weight-lifters and
(Pfohl et al. 1982; Shulman and Tohen 1994) and never American football players, may cause mania, which may be
experience a depressive one. Second, a minority of cases marked by extreme irritability and violence: manic symp-
may also be characterized by ‘rapid cycling’, wherein four toms occurring in a ‘bulked-up’ athlete should always sug-
or more episodes of illness occur during a year (Dunner gest anabolic steroid use and prompt a search for
et al. 1977). corroborating clinical evidence, such as gynecomastia and
Cyclothymia is best thought of as a very mild form of testicular atrophy. The other medications listed in Table 6.4
bipolar disorder (Akiskal et al. 1977). Like bipolar disor- only rarely cause mania, and before attributing any given
der, it is characterized by episodes of mood disturbance case to one of them, one would want to be able to demon-
but these are much milder in intensity and indeed may not strate not only a fairly close temporal relationship between
bring the patient to clinical attention. starting the medication (or substantially increasing the
Schizoaffective disorder, bipolar type (Grossman et al. dose) and the onset of the mania, but also an absence of
1984; Pope et al. 1980; Rosenthal et al. 1980), possesses a other, more common causes.
distinctive overall course: patients with this illness are not Before ending consideration of these toxic causes of
only chronically psychotic, but also, in the context of this mania, further comments are in order regarding the last
ongoing psychosis, experience episodes of mania and four entries, namely baclofen, tiagabine, reserpine, and
episodes of depression. The chronic psychosis, which leaves alpha-methyldopa. For each of these medications, mania
them with psychotic symptoms (such as delusions and hal- occurs, not during treatment, but rather within days to a
lucinations) in the intervals between mood disturbances, week after discontinuation of long-term treatment; here
clearly distinguishes this illness from bipolar disorder, which the mania occurs as a withdrawal phenomenon.
is free of psychotic symptoms in the intervening periods.
Post-partum psychosis has an abrupt onset between METABOLIC
3 days and several weeks after delivery (Munoz 1985) and
is, in many cases, characterized by manic symptoms Hepatic encephalopathy is often characterized by manic
(Brockington et al. 1981). Importantly, these patients are symptomatology, with euphoria and gregariousness (Murphy
well at other times, and although they may have recurrent et al. 1948). Uremia may rarely present with mania: in one
post-partum psychoses after subsequent deliveries (Hadley case (El-Mallakh et al. 1987) the only sign of uremia,
1941; Kumar et al. 1983), they do not have manic symp- despite a blood urea nitrogen level of 100 mg/dL and a cre-
toms outside the puerperium. This is the critical difference atinine concentration of 5.0 mg/dL, was mania.
between post-partum psychosis and bipolar disorder, for
although female patients with bipolar disorder may indeed ENDOCRINOLOGIC
have manic episodes in the puerperium, they also have
them at other times in their lives (Bratfos and Haug 1966). Cushing’s syndrome may produce manic symptoms, which
have been noted in from 11 percent (Starkman et al. 1981)
TOXIC to 30 percent (Haskett 1985) of cases. Other symptoms of
Cushing’s syndrome, such as weight gain, hypertension,
Of all the medications listed in Table 6.4, by far the most diabetes mellitus, acne, hirsutism, and easy bruising, typi-
common causes are prednisone and levodopa. Prednisone, cally accompany these manic changes (Haskett 1985) and
in doses of 80 mg or more per day, may produce mania in serve to suggest the correct diagnosis.
approximately three-quarters of patients. Levodopa, as Thyrotoxicosis may be accompanied by mania (Lee et al.
used in Parkinson’s disease, in turn may cause mania in 1991; Trzepacz et al. 1988), and the correct diagnosis is usu-
about one-tenth of patients (Celesia and Barr 1970; O’Brien ally suggested by such signs as proptosis, tremor, and tachy-
et al. 1971). Celesia and Barr (1970) noted that their cardia. In one case, however, the only clue as to the correct
patients became euphoric with ‘excessive self-confidence, diagnosis was a tachycardia of 130 beats per minute
over optimism, buoyancy, lack of inhibition, exaggerated (Ingham and Nielsen 1931).
motor activity and drive. They made inappropriate jokes,
were garrulous, and were often impudent’. In some cases, INTRACRANIAL DISORDERS
levodopa-induced mania may be accompanied by halluci-
nations (Lin and Ziegler 1976). In some cases, the mania is Appropriately situated infarctions, tumors, or plaques of
so appealing that patients may abuse levodopa in order to multiple sclerosis may all cause mania and, as noted below,
p 06.qxd 3/10/08 9:34 AM Page 220
it appears that mania, although not of much localizing an underlying craniopharyngioma [Malamud 1967] or pitu-
value, may have some lateralizing value. itary adenoma [Alpers 1940]), the right thalamus (Stern and
Infarctions of the midbrain, thalamus, anterior limb of Dancey 1942), the right cingulate gyrus (Angelini et al.
the internal capsule and adjacent head of the caudate 1980), the inferior right frontal lobe (Gross and Herridge
nucleus, or the frontal or temporal lobes may all cause 1988), or both frontal lobes (Starkstein et al. 1988b) have
mania. In the case of midbrain infarction not only has mania all been associated with mania. As an aside, it is worth not-
been seen, but also, remarkably, in these cases there were ing the remarkable ability of hypothalamic disturbances to
recurrent episodes of mania and of depression: this has been cause mania. In one case (Alpers 1940), the patient was
noted after an infarction secondary to a subarachnoid hem- undergoing surgery for the removal of a craniopharyn-
orrhage (Blackwell 1991) and after an ischemic lesion of the gioma; when the surgeon produced traction on the hypo-
right mesencephalopontine area (Kulisevsky et al. 1995). In thalamus, ‘the patient burst forth in a push of speech,
this latter case, the patient, a 59-year-old woman, suddenly quoting passages in Latin, Greek and Hebrew . . . and with
lost consciousness and fell to the ground. After coming to, every word of the [surgeon] broke into a flight of ideas’.
she experienced transient dizziness and right ptosis, and Multiple sclerosis has long been associated with manic
then did well for about 2 weeks. She subsequently developed symptomatology; indeed, Cottrell and Wilson (1926), noted
a severe depression accompanied by left hemiparkinsonism, euphoria in 63 percent of their 100 patients. Subsequent case
both of which persisted, only to spontaneously remit after 19 series have reported a lower rate, varying from 42 percent
months. She progressed well for the next 5 months and then (Rabins et al. 1986) to 26 percent (Surridge 1969), and a
developed mania characterized by elation, heightened activ- nationwide survey in Israel found euphoria in only 5 percent
ity and sexual interest, logorrhea, intrusiveness, and of cases (Kahana et al. 1971). Of all reasons underlying the
decreased sleep. Eventually she was successfully treated with admission of patients with multiple sclerosis to a psychiatric
lithium. Thalamic infarctions capable of causing mania hospital, mania is, however, one of the most common: in
may be either unilateral – on the right side – or bilateral. one study, of over 2000 psychiatric admissions, 10 had mul-
Regarding unilateral lesions, Cummings and Mendez (1984) tiple sclerosis, and seven of these patients were admitted
reported a case of mania accompanied by left-sided hemi- because of mania (Pine et al. 1995). Importantly, in patients
anesthesia and slight hemiparesis, and Bogousslavsky et al. with multiple sclerosis, the presence of mania correlates with
(1988) described a sudden onset of delirium that cleared in a brain, rather than spinal cord, involvement (Rabins et al.
few days, leaving behind mania as the sole indication of a 1986).
right paramedian thalamic infarction. Kulisevsky et al. A review of the cases of mania secondary to infarctions
(1993) reported a case of mania accompanied by chorea and and tumors allows for some speculation regarding both the
ballismus occurring secondary to an infarction of the ventral localizing and the lateralizing value of this syndrome. The
tier nuclei on the right. Bilateral thalamic infarction caused localizing value of mania does not appear to be high, as it has
mania in two cases. In the first case (McGilchrist et al. 1993), been noted with lesions of the mesencephalon (Blackwell
there was an acute onset of drowsiness, followed by a cycling 1991; Greenberg and Brown 1985; Kulisevsky et al. 1995),
of mania and depression. The depression lasted for weeks thalamus (Bogousslavsky et al. 1988; Cummings and Mendez
and was characterized by apathy and increased eating and 1984; Gentilini et al. 1987; Kulisevsky et al. 1993; Liebson
sleeping. The manias were brief, lasting only 1–2 days and 2000; McGilchrist et al. 1993; Starkstein et al. 1988a; Stern
were characterized by elation, pressured speech, and flight of and Dancey 1942), hypothalamus (Alpers 1940; Malamud
ideas. The second case (Gentilini et al. 1987) presented, like 1967), anterior limb of the internal capsule and adjacent
the first, with somnolence, which was accompanied by head of the caudate (Starkstein et al. 1990b), cingulate gyrus
amnesia and a vertical gaze paresis. As the patient, a 66-year- (Angelini et al. 1980), and frontal (Benjamin et al. 2000;
old man, became more alert, he displayed hypersexuality Gross and Herridge 1988; Starkstein et al. 1988b, 1990b), and
and grandiosity, asserting that he had a Swiss bank account temporal lobes (Starkstein et al. 1990b). The lateralizing
and was a General in the Air Force. After 7 months, the value of mania, however, may be higher. In all but one of the
amnesia had cleared but not the mania: he was ‘cheerful . . . instances cited above, the lesion responsible for mania was
garrulous . . . [and] looking for a young girl who, enticed by either on the right side or bilateral: in only one case, namely
his wealth, would be willing to marry him’. Capsular infarc- after the excision of an arteriovenous malformation from the
tion involving the anterior limb of the internal capsule and left frontal lobe (Benjamin et al. 2000), did mania occur sec-
the adjacent head of the caudate nucleus has been noted to ondary to a left-sided lesion. This impression is bolstered by
cause either depression followed within a month by mania, some controlled studies: although not all agree (House et al.
or mania alone (Starkstein et al. 1990b). Cortical or subcor- 1990), it appears that when the frontal, temporal, or limbic
tical white matter infarction of the right frontoparietal areas of the cerebrum are involved mania is more likely with
region (Jampala and Abrams 1983; Starkstein et al. 1988), right-sided lesions (Robinson et al. 1988; Starkstein et al.
bilateral orbitofrontal areas, or the right basotemporal area 1987b). This impression is further reinforced by a study of 19
(Starkstein et al. 1990b) has been associated with mania. patients who underwent hemispherectomy: of the 14 who
Tumors affecting the mesencephalon (Greenberg and had a right hemispherectomy, 12 became euphoric and none
Brown 1985), the hypothalamus (via compression from was depressed; of the five who had a left hemispherectomy,
p 06.qxd 3/10/08 9:34 AM Page 221
6.3 Mania 221
one was euphoric, one was depressed, and the other three episodes of depression (Parker 1957). The manic syn-
showed no mood change (Sackeim et al. 1982). drome following traumatic brain injury may be quite clas-
sic in character (Bakchine et al. 1989): one patient
AS PART OF DEMENTING DISORDERS (Bracken 1987) with euphoria, pressured speech, and flight
of ideas had the grandiose delusion that he was writing a
Alzheimer’s disease may, in a small minority, be character- ‘best seller’.
ized by mild manic symptoms such as an elevated mood Epileptic disorders characterized by mania include both
(Burns et al. 1990), but this is seen only long after the ictal and post-ictal mania. Ictal mania may occur as an aura
dementia has become well established. or as part of a complex partial seizure. Dostoyevsky
Huntington’s disease, in addition to chronic chorea described his ecstatic aura as follows: ‘the air was filled with
and dementia, may also, in a small minority of patients, cause a big noise . . . I felt that Heaven was going down upon the
manic symptoms, which range from simple ‘excitement’ Earth and that it had engulfed me. I have really touched
(Oliver 1970) or ‘euphoria’ (Tamir et al. 1969) to a fuller God . . . healthy people . . . can’t imagine the happiness
syndrome with delusions of grandeur (Bolt 1970; Heathfield which we epileptics feel during the second before our fit . . .
1967). for all the joys that life may bring, I would not exchange this
Neurosyphilis, when manifesting as parenchymatous one’ (Alajouanine 1963). Complex partial seizures may
general paresis of the insane, presents with a dementia that themselves occasionally be characterized by manic symp-
may be marked by mania (Merritt and Springlova 1932): toms: one patient (Mulder and Daly 1952), during her
indeed, in one large study of 203 patients, approximately attack, ‘was euphoric, talkative and pleasant. When asked
one-half were euphoric and excited (Storm-Mathisen how she felt, she replied “wonderful” ’.
1969). Rarely, neurosyphilis may present with mania Post-ictal mania may be seen 1–2 days after a ‘flurry’ of
(Binder and Dickman 1980). Whenever a diagnosis of neu- complex partial seizures, and this may be characterized by
rosyphilis is entertained, it is critical to carry out a serum either stage I or stage II mania (Barczak et al. 1988; Nishida
fluorescent treponemal antibody absorption test and, if et al. 2006).
that is positive, to proceed to lumbar puncture regardless of Systemic lupus erythematosus may be marked by manic
whether the serum Venereal Disease Research Laboratory symptoms, and in such cases other typical symptoms, such
(VDRL) test is positive or not. as rash, arthralgia, pleurisy, pericarditis, nephritis, or
Creutzfeldt–Jakob disease is rarely characterized by cytopenia, suggest the diagnosis (Brey et al. 2002, Johnson
mania but in one very rare case the disease presented with and Richardson 1968).
mania (Lendvai et al. 1999). Vitamin B12 deficiency may, very rarely, present with
Metachromatic leukodystrophy may, very rarely, pres- mania, as was reported in one 81-year-old man (Goggans
ent with mania. One patient, a 22-year-old woman (Besson 1984).
1980), was grandiose, ‘spent money irresponsibly . . . and Sydenham’s chorea may, in addition to the acute onset
called out the fire brigade’; she eventually became of chorea, be characterized by mania (often with promi-
demented after several years. nent lability [Adams 1975; Gatti and Rosenheim 1969]),
Adrenoleukodystrophy, when occurring in the adult which may in turn be characterized by prominent halluci-
years, often presents with a dementia, with the dementia in nations and delusions, typically of persecution (Powell
one case (Weller et al. 1992) being accompanied by mania. 1889; Reaser 1940; Shaskan 1938; Van Der Horst 1947).
Chorea gravidarum, which essentially represents a
MISCELLANEOUS recurrence of Sydenham’s chorea during pregnancy, may
also, in addition to chorea, be characterized by mania
Of these miscellaneous disorders capable of causing mania, (Wilson and Preece 1932).
perhaps the most important is traumatic brain injury. Velocardiofacial syndrome, a rare disorder suggested by
Mania was found in 9 percent of 66 patients recovering a characteristic facial dysmorphism with hypertelorism, a
from a traumatic injury over a 1-year follow-up, and there large nose and micrognathia, may be characterized by
was a correlation between this sequela and damage to the mania in over one-half of all cases (Papalos et al. 1996).
inferior and polar regions of the temporal lobes, either on Encephalitis lethargica, currently a very rare disorder,
the left or on the right (Jorge et al. 1993a). In some cases, typically presents with headache, fever, sleep reversal, delir-
the mania may appear almost immediately after the patient ium, and oculomotor paralyses. In some cases, patients dis-
recovers from the post-coma delirium (Bakchine et al. played euphoria, sometimes accompanied by lability and
1989; Bracken 1987), whereas in others there may be a pressured speech (Hohman 1921).
latent interval, lasting up to several months, before the Acute disseminated encephalomyelitis results from an
mania appears (Clark and Davison 1987; Nizamie et al. autoimmune assault on the brain that is triggered by a pre-
1988). Although, in most cases the mania is either persist- ceding, usually viral, infection and generally has an acute
ent or eventually remits without recurrence, there may onset within 2–21 days of the initial infection. Although the
rarely be an episodic course closely resembling that seen in typical presentation is with delirium, a mania may occasion-
bipolar disorder, with alternating episodes of mania and ally appear. In one case (Moscovich et al. 1995), 2 weeks
p 06.qxd 3/10/08 9:34 AM Page 222
after an influenza infection, a 32-year-old woman developed requires urgent symptomatic treatment, one may consider
mania, which remained the only indication of the underly- use of one of the mood-stabilizing agents, with or without
ing encephalitis for almost 2 weeks, after which she became an antipsychotic (discussed further in Section 6.4).
delirious and incontinent. In another case (Paskavitz et al. Of the three mood-stabilizing agents (namely dival-
1995), a post-mononucleosis acute disseminated encep- proex, carbamazepine, and lithium), divalproex is proba-
halitis presented with a combination of mania and a grand bly easiest to use and treatment may begin with a loading
mal seizure. dose of from 20 to 25 mg/kg/day, with subsequent doses
Fahr’s syndrome, suggested by calcification of the basal determined on the basis of clinical response, side-effects,
ganglia, may, very rarely present with mania (Trautner and blood levels. Generally, at least a few days are required
et al. 1988). to see a salutary effect, and in the meantime one may use
Dialysis dementia, also very rarely, may be character- adjunctive haloperidol, risperidone, or olanzapine. Initially,
ized by mania (Jack et al. 1983). haloperidol may be given in a dose of 5 mg (either as the
Tuberous sclerosis, in a very rare case, presented with concentrate or intramuscularly), risperidone in a dose of
classic mania in a 5-year-old child (Khanna and Borde 1989). 2 mg (as the concentrate) or olanzapine 10 mg (as a tablet
or intramuscularly), with repeat doses every 1–2 hours
until the patient is calm, limiting side-effects occur or a
Differential diagnosis maximum of approximately 20 mg of haloperidol, 6 mg of
risperidone or 40 mg of olanzapine. In truly emergent cases,
Hypomania is a distinctive syndrome, and very difficult to some authorities recommend combining lorazepam – 2 mg
confuse with anything else; thus if the physician either sees intramuscularly with either haloperidol or risperidone. If
the patient during stage I, or has a compatible history from a effective, the adjunctive regimen should be continued until
reliable historian, the diagnosis is generally straightforward. the mood-stabilizer has controlled the situation, after which
Difficulty can arise in cases where patients have progressed it may be tapered and discontinued, leaving the patient on
to stage II or stage III; but even here if one has a clear history a mood-stabilizer alone.
of a preceding stage I, again the diagnosis remains relatively Mood-stabilizers have also been used prophylactically
easy. However, if patients come to medical attention during in situations wherein mania is expected: thus, both lithium
stages II or III and there is no history available then one (Falk et al. 1979; Siegal 1978) and valproic acid (Abbas and
must consider other syndromes that may cause significant Styra 1994) have been used preventively in patients who
agitation, namely psychosis, catatonia, and delirium. have experienced mania during prior courses of steroid
Psychosis, that is to say a syndrome marked by delu- treatment.
sions and hallucinations, naturally enters into the differen-
tial for patients in stages II or III. Here, the differential rests
on identifying the persisting hypomanic symptoms. 6.4 AGITATION
Catatonia of the excited subtype is characterized by
bizarre and purposeless hyperactivity, and hence may, to a Agitation is extraordinarily common in general hospital
degree, resemble the behavior of patients in stage III mania. and nursing home work. It is, as noted below, a non-
In stage III mania, however, one may still see distinctive specific symptom, being seen in a variety of conditions.
stage I symptoms; moreover, although the behavior of
patients in stage III is fragmented, individual fragments may
still retain some purpose. Furthermore, whereas the hyper- Clinical features
active catatonic tends to remain withdrawn, the hyperactive
stage III manic still retains an interest in others. Agitated patients are tense and restless. If confined to bed,
Delirium is marked by confusion and incoherence, they may thrash about; intravenous lines and tubes may be
symptoms also seen in stage III mania. Here again, one pulled out. Ambulatory patients may pace their rooms or
must rely on identifying fragments of stage I mania, symp- up and down the hall, perhaps shouting or cursing. Some
toms typically not seen in delirium. may become violent, slamming doors or throwing furni-
It cannot be stressed enough that the easiest way to make ture, and some, especially if attempts are made to restrain
these differentials is to obtain a ‘longitudinal’ view of the them, may become assaultive.
patient’s illness by repeatedly questioning family, acquain-
tances, nurses, and aides until one can reliably say that the
typical symptoms of hypomania were, or were not, present. Etiology
Agitation, of sufficient degree to merit clinical attention, gen-

Treatment erally occurs as part of a large number of conditions, includ-
ing dementia, delirium, psychosis, traumatic brain injury,
Treatment is directed at the underlying cause. In cases alcohol withdrawal, mania, depression, and during various
when this is not possible, or where the clinical situation intoxications, for example with stimulants. Agitation may
p 06.qxd 3/10/08 9:34 AM Page 223
6.4 Agitation 223
also occur as a side-effect to various medications, for exam- noted, are based on double-blind studies. Importantly, as
ple bupropion. Pain may also cause patients to become agi- noted under the concluding remarks, these recommenda-
tated and this is particularly the case in elderly patients with tions are offered as guidelines only: clinical reality often dic-
dementia. tates alternative approaches and good clinical judgment is
absolutely required.
Dementia
Anxious patients may appear quite tense but generally are For non-emergent care, effectiveness has been demon-
not given to restless pacing, and certainly not to violent or strated for risperidone (Brodaty et al. 2003; De Deyn et al.
destructive behavior. 2005), quetiapine (Zhong et al. 2007), haloperidol (Allain
Akathisia, seen primarily as a side-effect to antipsy- et al. 2000), and olanzapine, with haloperidol being of equal
chotics, may appear very similar to agitation. Clues to the effectiveness to olanzapine (Verhey et al. 2006) and risperi-
correct diagnosis include a worsening of symptoms when done of equal effectiveness to olanzapine (Fontaine et al.
sitting or lying down and a tendency to ‘march in place’. 2003). In a partially blinded study (Porsteinsson et al. 2001)
divalproex was effective, but a double-blinded study found
it to be no more effective than placebo (Sival et al. 2002). In
Treatment addition, one study found trazodone to be of similar effi-
cacy to haloperidol (Sultzer et al. 1997).
Environmental measures can sometimes be remarkably In looking at more specific kinds of dementia, the effec-
effective in calming an agitated patient (Alessi et al. 1999). tiveness of haloperidol in Alzheimer’s disease is uncertain:
Overall stimulation should be kept to a minimum, and one study (Devanand et al. 1998) supported its use, whereas
patients should be provided with constructive and quietly another (Teri et al. 2001) did not. Olanzapine (Street et al.
engaging activities. Interactions with the patient should 2000) appeared effective in a comparison with placebo, and
preferably be on a one-to-one basis and, if it is necessary to in a large study olanzapine and risperidone were more effec-
have two people with the patient, it is important to ensure tive than either quetiapine or placebo (Schneider et al.
that only one person does all the talking. When patients 2006). Carbamazepine (Olin et al. 2001; Tariot et al. 1998)
tend to roam, they should generally be allowed to do so, appears effective but valproic acid is not (Hermann et al.
provided that their behavior endangers neither themselves 2007; Tariot et al. 2005). Trazodone does not appear to be
nor others. A private room should be provided, and if that effective (Teri et al. 2001). There is an intriguing study sug-
is not possible then a calm patient should be selected as a gesting that citalopram may be effective (Pollock et al. 2002).
roommate; in all cases, the room should have a large clock In Parkinson’s disease and diffuse Lewy body disease, queti-
and calendar, and a window. Visitors should be screened, as apine was not effective (Kurlan et al. 2007).
in some cases certain visitors will agitate patients further; in Overall, for the non-emergent treatment of agitation in
general, there should be only one visitor at a time. Sitters are dementia, it may be best to begin with a low dose of risperi-
often utilized, and may obviate the need for restraints but, done, perhaps 0.25 or 0.5 mg/day, with a gradual titration up
like visitors, sitters should be carefully screened: although to a maximum of perhaps 2 mg. Should this be ineffective or
some have a good ‘way’ with agitated patients, others may not tolerated then consideration may be given to quetiapine,
simply worsen the situation. Seclusion or restraints may at beginning at 25 mg and increasing the dose gradually, if nec-
times be required and one must not be shy about ordering essary, to 200 mg, or to olanzapine, beginning with a low
them, as they may at times be life-saving. dose of perhaps 2.5 mg and titrating gradually, if necessary,
In all instances of agitation, it is also necessary to dove- to a maximum of 10 mg. Consideration may also be given to
tail the symptomatic treatment of agitation with other carbamazepine and, perhaps, divalproex: in either case, the
aspects of treatment of the parent syndrome, and the initial dose should be low, with very gradual titration to
reader is directed to the appropriate chapter on dementia, effectiveness, limiting side-effects, or a blood level within the
delirium, etc. therapeutic range, whichever comes first.
Pharmacologic treatment is typically required: agents In emergent cases, consideration may be given to
utilized include antipsychotics (e.g., risperidone, haloperi- intramuscular olanzapine in a dose of 5 mg (Meehan et al.
dol, quetiapine, or olanzapine), anti-epileptic drugs (e.g., 2002), with repeat doses if needed.
divalproex and carbamazepine), and benzodiazepines (e.g., Before leaving this section, some words are in order
lorazepam). As noted above, agitation usually occurs as regarding the risk of death or stroke in elderly demented
part of a larger syndrome and the choice of pharmacologic patients treated with antipsychotics. Although these
agent is often dictated by the syndrome within which the risks are indeed increased for second-generation agents
agitation is occurring. In the following, each of the more (Kryzhanovskaya et al. 2006), and even more so for first-
common syndromes is considered in turn, with recom- generation agents (Wang et al. 2005), this increased risk, as
mendations for both non-emergent and emergent treat- with any medical treatment, must be weighed against the
ment; all of the recommendations, except where otherwise benefits obtained with treatment.
p 06.qxd 3/10/08 9:34 AM Page 224
Delirium i.m.), risperidone (2 mg, as the concentrate), aripiprazole

I could not find any double-blind studies regarding the (9.75 mg, intramuscularly), or olanzapine (10 mg, i.m.),
non-emergent pharmacologic treatment of delirium. In with repeat doses every 1–2 hours until the patient is calm,
practice, patients are treated with low doses of antipsy- limiting side-effects occur, or maximum doses of approxi-
chotics (e.g., risperidone, 0.5–1 mg or haloperidol, 2–5 mg), mately 20 mg haloperidol, 6 mg of risperidone, 39 mg of
with dosage adjustments made every day or so as needed. aripiprazole, or 40 mg of olanzapine are reached. Although
In emergent cases, risperidone and haloperidol (Breitbart monotherapy is generally preferred, in cases when very
et al. 1996) are both effective and probably equally so (Han rapid control is essential, intramuscular lorazepam (2 mg),
and Kim 2004); chlorpromazine may also be considered may be safely given along with doses of either haloperidol
(Breitbart et al. 1996); open studies also support use of olan- or risperidone; note that it is probably also safe to give
zapine (Skrobik et al. 2004) and quetiapine (Sasaki et al. lorazepam with olanzapine but this has not been demon-
2003). Valproic acid, in open studies, used as ‘add-on’ ther- strated as yet.
apy with antipsychotics, reportedly decreased agitation
(Bourgeois et al. 2005). Lorazepam, in one study (Breitbart
et al. 1996), was ineffective and associated with severe In non-emergent situations, propranolol is effective (Brooke
side-effects (sedation, disinhibition, ataxia, and increased et al. 1992); open studies also suggest effectiveness for
confusion). quetiapine (Kim and Bijlani 2006), valproic acid
In emergent situations, one may begin with either (Chatham-Showalter and Kimmel 2000; Wroblewski et al.
risperidone (as the concentrate) 0.25–1 mg, or haloperidol 1997), carbamazepine (Azouvi et al. 1999) and lithium
(either as the concentrate or intramuscularly or intra- (Glenn et al. 1989), amantadine (Chandler et al. 1988),
venously) 1–5 mg, with repeat doses every hour until the amitriptyline (Mysiw et al. 1988), and sertraline (Kant et al.
patient is calm, limiting side-effects occur, or a maximum 1998)
dose is reached of either 5 mg of risperidone or 20 mg of Given the dearth of studies in this area, it is difficult to
haloperidol. Should the patient respond satisfactorily, a make firm recommendations for non-emergent treatment;
regular daily dose is started the next day, roughly equiva- in my experience use of one of the antidepressants (espe-
lent to the total required for success on the first day, with cially mirtazapine) or carbamazepine has worked out well.
provisions for repeat doses if required, and further adjust- Regarding emergent treatment, there are no double-
ments being made to the regular daily dose until no further blind studies. In practice, patients are generally treated in a
p.r.n. doses are required. This maintenance dose is then manner similar to that for the emergent treatment of delir-
continued until the cause of the delirium has been effec- ium, as described above.
tively treated, at which point the dose may be tapered to
discontinuation over a few days. Alcohol withdrawal
In non-emergent cases, alcohol withdrawal may be treated
Psychosis with either divalproex (Reoux et al. 2001) or carba-
Studies regarding the treatment of agitated patients with mazepine (Stuppacek et al. 1992). Loading doses may be
psychosis for the most part involve patients with schizo- utilized (20 mg/kg/day of divalproex, 600–800 mg/day of
phrenia. carbamazepine), with the total daily loading dose divided
In non-emergent cases, one may simply begin with the into two or three doses: subsequent adjustments are made
antipsychotic judged most appropriate for the patient’s case. based on effectiveness, side-effects, and blood levels.
In emergent cases, rapid control of agitation has been In emergent cases, one may give lorazepam (Miller and
achieved with a combination of haloperidol and lorazepam, McCurdy 1984): a typical protocol calls for lorazepam,
with the combination being more effective than use of either 2 mg, orally or parenterally, every 2 hours until symptoms
agent alone (Bieniek et al. 1998); a combination of risperi- are controlled, limiting side-effects occur, or a maximum
done and lorazepam was also shown to be as effective as dose of approximately 20 mg is reached (it must be borne
combined treatment with haloperidol and lorazepam in mind, however, that some patients require much higher,
(Currier et al. 2004). Aripiprazole is of similar effectiveness even heroic, doses). The next day, the patient is treated
to haloperidol and better tolerated (Tran-Johnson et al. with a regular daily dose of oral lorazepam in a total daily
2007). Olanzapine is also of similar effectiveness to haloperi- dose approximately equivalent to that required for control
dol (Breier et al. 2002; Wright et al. 2001); a combination of the first day, with the total daily dose divided into three or
olanzapine at a dose of 10 mg plus lorazepam as needed was four doses. Provision is also made for p.r.n. doses of
less effective than simply using olanzapine alone at a higher 1–2 mg lorazepam every 2 hours for breakthrough agita-
dose of 25–30 mg (Baker et al. 2003). Blinded work compar- tion, with the total daily dose being appropriately adjusted
ing ziprasidone in doses of 20 mg (Daniel et al. 2001) or on a daily basis until no further p.r.n. doses are required.
10 mg (Lesem et al. 2001) with ziprasidone in a dose of 2 mg Early on in this process one should generally load the
indicates effectiveness for the higher doses. patient with either divalproex or carbamazepine. As soon
Overall, for emergent treatment, it seems reasonable to thereafter as the agitation is controlled and the blood level
begin with either haloperidol (5 mg, as the concentrate or is therapeutic, it is generally possible to rapidly taper the
p 06.qxd 3/10/08 9:34 AM Page 225
6.5 Anxiety 225
lorazepam without any loss of control. The anti-epileptic and the tremor itself is fine and postural. Tachycardic patients
drug is then continued for a week or more until the with- may complain that the heart is ‘racing’ and there may be pal-
drawal has run its course, at which time it may be tapered pitations. Diaphoresis may be evident when one shakes the
and discontinued over a few days. patient’s hand. The duration of this persistent form of anxiety
depends on the underlying cause and may, for example, range
Mania from years or decades in the case of generalized anxiety disor-
In cases of mania wherein significant agitation has der to weeks or less in alcohol withdrawal.
appeared, emergent care is almost always required, and Anxiety attacks typically arise acutely, over minutes,
treatment may be undertaken with either divalproex and symptoms crescendo rapidly. In addition to the anxi-
(McElroy et al. 1996) or an antipsychotic (e.g., haloperidol ety, which may be quite extreme, patients also typically
[McElroy et al. 1996], aripiprazole [Zimbroff et al. 2007], experience a variety of other symptoms, including tremor,
or olanzapine [Tohen et al. 2002]), or, often, with a combi- tachycardia, palpitations, diaphoresis, dyspnea, light-
nation of divalproex and an antipsychotic. Divalproex may headedness, nausea, and parasthesiae. The duration of the
be given in a loading dose of 20 mg/kg/day in two or three attack, although determined by the underlying cause, is
divided doses, with subsequent adjustments based on clin- generally brief, lasting from minutes to an hour or more.
ical response, side-effects, and blood levels. Haloperidol,
aripiprazole, or olanzapine may be given as described
above, under psychosis. Once the mania is controlled, it is Etiology
often possible to taper and discontinue the antipsychotic.
Depression The various causes of anxiety are listed in Table 6.5, where
they are divided into those causing persistent anxiety and
In most cases of agitated depression, reassurance coupled those causing anxiety attacks.
with ongoing treatment with an antidepressant, will suffice.
Emergent treatment, occasionally, may be required
when agitation is extreme. In such cases, case reports sug- PERSISTENT ANXIETY
gest an effectiveness for benzodiazepines such as alprazo-
The most common cause of persistent anxiety is an idio-
lam (Gilbert and Hendrie 1987), and case series, for
pathic disorder, namely generalized anxiety disorder
low-dose divalproex (Debattista et al. 2005).
(Anderson et al. 1984; Nisita et al. 1990). This disorder
Concluding remarks generally has an onset in adolescence or early adult years,
and the characteristic anxiety tends to persist, in a waxing
Good clinical judgment often dictates a course of treat-
and waning fashion, for from years to decades.
ment that differs from those recommended above. Doses
Toxic causes include caffeine (Greden 1974; Hughes
must often be reduced in elderly or frail patients, and in
et al. 1991a) and sympathomimetics such as ephedrine
those with significant hepatic dysfunction. Antipsychotics
and phenylpropanolamine (Sawyer et al. 1982) and ephedra
other than risperidone, haloperidol, and olanzapine are
alkaloids, found in many ‘herbal supplements’ (Haller and
often used successfully, and haloperidol, given its tendency
Benowitz 2000). Others include theophylline (Trembath
to cause extrapyramidal side-effects, is falling into disfavor.
and Boobis 1979) and levodopa (Celesia and Barr 1970).
Lorazepam is used quite routinely, and its sedative effect is
Although, in general, anxiety only occurs with high doses,
often quite welcome. In some cases, certain medications
some patients may be quite sensitive to these medications
are relatively contraindicated: for example, in cases of
and experience considerable anxiety at ‘therapeutic’ doses.
dementia secondary to diffuse Lewy body disease haloperi-
Metabolic causes include hypocalcemia, as may be seen
dol should probably not be used, given the risk of severe,
in hypoparathyroidism (Carlson 1986; Denko and
even fatal, parkinsonism (McKeith et al. 1992).
Kaelbling 1962; Lawlor 1988), and the hypoxia and hyper-
carbia associated with respiratory failure, as in advanced
6.5 ANXIETY chronic obstructive pulmonary disease (Brenes 2003) and
severe congestive heart failure.
Pathologic anxiety occurs in two forms. In one, anxiety is Substance or medication withdrawals are considered
more or less persistent, whereas in the other it occurs in next. Of the substance withdrawals, alcohol withdrawal
discrete attacks. (Isbell et al. 1955) probably constitutes one of the most
common causes of persistent anxiety seen in general hospi-
tal practice, and the diagnosis is often missed, given that
Clinical features patients in withdrawal typically either minimize their alco-
hol use or deny it altogether. A similar scenario may occur
Persistent anxiety tends to come on gradually, and waxes in patients withdrawing from sedative/hypnotics, such as
and wanes over time. The anxiety itself is typically accom- benzodiazepines (Rickels et al. 1990). Nicotine withdrawal
panied by autonomic signs such as tremor, tachycardia, and is typified by anxiety, irritability, and a craving for a ‘smoke’
diaphoresis. Patients complain of a sense of tremulousness, (Hughes and Hatsukami 1986; Hughes et al. 1991b), and
p 06.qxd 3/10/08 9:34 AM Page 226
Table 6.5 Causes of anxiety

Persistent anxiety Anxiety attacks
Primary, idiopathic anxiety Idiopathic disorders
Generalized anxiety disorder Panic disorder
Toxic Phobias
Caffeine Post-traumatic stress disorder
Sympathomimetics Obsessive–compulsive disorder
Theophylline Toxic
Levodopa Cocaine
Metabolic Cannabis
Hypocalcemia Hallucinogens
Chronic obstructive pulmonary disease Clozapine
Congestive heart failure Metabolic
Substance or medication withdrawal Hypoglycemia
Alcohol Hyperventilation
Sedative/hypnotic Endocrinologic
Nicotine Pheochromocytoma
Anticholinergic Miscellaneous
Endocrinologic Simple partial seizures
Hyperthyroidism Right temporal lobe tumor
Cushing’s syndrome Paroxysmal atrial tachycardia
Intracranial disorders Angina or myocardial infarction
Post-stroke Pulmonary embolus
Traumatic brain injury Parkinson’s disease
likewise may go undiagnosed, given the shame associated post-traumatic stress disorder and obsessive–compulsive
with smoking and patients’ reluctance to admit it. Anti- disorder. Panic disorder is the prototypical cause of anxiety
cholinergic withdrawal, occurring after an abrupt discon- attacks, which, when occurring in this disorder, are often
tinuation of drugs with strong anticholinergic properties referred to as ‘panic attacks’. In this disorder, anxiety
such as benztropine or tricyclic antidepressants, may be fol- attacks typically occur first in adolescence or early adult
lowed by a cholinergic rebound, with anxiety, jitteriness, years, and then recur, with variable frequency, over years
insomnia, and nausea (Dilsaver et al. 1983). or decades. Interestingly, the anxiety attacks seen in panic
Endocrinologic causes include hyperthyroidism and disorder may awaken patients from sleep (Mellman and
Cushing’s syndrome. Hyperthyroidism classically causes Uhde 1989) and may, in a minority, be accompanied by
chronic anxiety and may be suggested by such signs and such ‘temporal lobe phenomena’ as micropsia and macrop-
symptoms as heat intolerance, diaphoresis, and lid retrac- sia (Coyle and Sterman 1986). Phobias, including specific
tion (Dietch 1981; Greer et al. 1973; Kathol and Delahunt phobia, social phobia, and agoraphobia, may all be charac-
1986; MacCrimmon et al. 1979; Trzepacz et al. 1988). terized by anxiety attacks when patients are brought into
Cushing’s syndrome, although classically associated with close proximity to the phobic object, such as a snake for a
depression, may at times be characterized by severe anxiety specific phobic, speaking to an audience for the social pho-
(Kelly 1996). The diagnosis is suggested by such features as bic with a fear of public speaking, and venturing away from
a ‘moon’ facies, buffalo hump, acne, hirsutism, violaceous home for the agoraphobic. Post-traumatic stress disorder
abdominal striae, hypertension, and diabetes mellitus. may also be characterized by anxiety attacks when patients
Intracranial disorders associated with persistent anxiety are exposed to events or objects that remind them of the
include stroke and traumatic brain injury. Post-stroke anxi- original trauma; thus, a combat veteran might be seized
ety occurs chronically in a minority of patients and appears with anxiety if a combat scene appeared on a television
to be more likely with a right hemisphere infarction (Castillo program. Obsessive–compulsive disorder may likewise be
et al. 1993, 1995; Starkstein et al. 1990c). Traumatic brain characterized by anxiety attacks when patients attempt to
injury may be associated with anxiety in a small minority of resist their compulsions. Thus, patients with a hand-washing
cases (Fann et al. 1995; Jorge et al. 1993b). compulsion may experience unbearable anxiety if they
attempt to resist the urge to wash.
ANXIETY ATTACKS Toxic causes of anxiety attacks are relatively rare, and
include intoxication with cocaine (Louie et al. 1996),
By far the most common causes of anxiety attacks are cer- cannabis (Bromberg 1934), and hallucinogens, such as LSD
tain idiopathic disorders, namely panic disorder, phobias, (Isbell et al. 1956; Kuramochi and Takahashi 1964); anxiety
p 06.qxd 3/10/08 9:34 AM Page 227
References 227
attacks have also been reported secondary to treatment with threatening events, the clinician should suspect pathology
clozapine (Bressan et al. 2000). in cases when either the severity of the anxiety, or its dura-
Metabolic causes include the classic examples of hypo- tion, seem out of proportion to the inciting event.
glycemia and hyperventilation. Hypoglycemic-induced anx- Consideration should also be given to the possibility
iety attacks are typically seen in diabetics on insulin who that the anxiety in question is existing as part of a larger
miss a meal, and are suggested by the associated hunger. The syndrome, such as depression or delirium. Depression is
hyperventilation syndrome is suggested by prominent dysp- commonly accompanied by anxiety, and hence in evaluat-
nea and by a resolution of symptoms with rebreathing ing any patient with anxiety one should enquire after
through a paper bag. depressive symptoms, such as insomnia (especially middle
Endocrinologically caused anxiety attacks may occur in or terminal insomnia), anergia, anhedonia, anorexia, etc.,
pheochromocytoma, and in such cases the anxiety attack is and, if they are present then the differential for depression
typically accompanied not only by an elevated blood pres- should be pursued, as discussed earlier under Depression.
sure, but also by headache (Doust 1958; Modlin et al. 1979; Delirious patients are often quite anxious, and hence the
Starkman et al. 1985; Thomas et al. 1966). diagnostician should be alert to such symptoms as confu-
Of the miscellaneous causes of anxiety attacks, perhaps sion, disorientation, short-term memory loss, etc., and if
the most important are simple partial seizures, which, rarely, these are present the differential outlined in Section 5.3
may manifest solely with anxiety attacks (Sazgar et al. 2003). should be pursued.
Although such ictal anxiety often lasts only seconds or min-
utes (Williams 1956), the seizure may in rare cases be very
prolonged: one patient for 12 hours endured ictal fear of Treatment
such a degree that she ‘continually looked back over her
shoulder’ (McLachlan and Blume 1980). There are two clues Treatment is directed at the underlying cause; in cases of
to the correct diagnosis of these simple partial seizures: first, persistent anxiety when this is not possible or ineffective,
the exquisitely paroxysmal nature of the onset, and second, consideration may be given to symptomatic treatment with
the occurrence, at other times in the patient’s life, of more a benzodiazepine, such as lorazepam or clonazepam, or,
obvious ictal phenomena such as complex partial or grand when these are relatively contraindicated, an antidepressant
mal seizures. or an antipsychotic, such as quetiapine. With regard to anx-
Anxiety attacks have also, very rarely, been associated iety attacks, symptomatic treatment is generally not indi-
with mass lesions in the right temporal lobe (Ghadarian cated: most attacks are of such brevity that they resolve
et al. 1986). spontaneously before any pharmacologic effects could be
Cardiopulmonary conditions associated with anxiety obtained.
attacks include paroxysmal atrial tachycardia, angina or
myocardial infarction, and pulmonary embolus. Paroxysmal
atrial tachycardia is suggested by the almost instantaneous REFERENCES
onset of severe tachycardia, followed immediately by severe
anxiety as the patient becomes aware of the fluttering in his Abbas A, Styra R. Valproate prophylaxis against steroid-induced
or her chest. The onset with tachycardia is suggestive, and the psychosis. Can J Psychiatry 1994; 39:188–9.
ability of the patient to terminate the attack with a Valsalva Abouesh A, Hobbs WR. Clarithromycin-induced mania. Am J
maneuver is also suggestive of the diagnosis. Angina or Psychiatry 1998; 155:1626.
myocardial infarction may, in a minority, present primarily Abrams R, Taylor MA. Mania and schizoaffective disorder, manic
with anxiety, with chest pain or dyspnea being relatively type: a comparison. Am J Psychiatry 1976; 133:1445–7.
minor symptoms. A pulmonary embolus, at the moment of Adams J. Psychological correlates of the course of Sydenham’s
its lodging in a large artery, can produce severe anxiety and chorea. Repeat evaluation of a case. J Abnormal Child Psychol
dyspnea. The diagnosis is suggested by the dyspnea and by 1975; 3:33–40.
such clinical settings as prolonged immobilization or deep Ainiala H, Loukkola J, Peltola J et al. The prevalence of
venous thrombophlebitis. neuropsychiatric syndromes in systemic lupus erythematosus.
Finally, Parkinson’s disease will, in a significant minor- Neurology 2001; 57:496–500.
ity of levodopa-treated patients, be characterized by anxi- Akiskal HS, Djenderedjian AH, Rosenthal RH et al. Cyclothymic
ety attacks during the ‘off’ interval as the effectiveness of disorder: validating criteria for inclusion in the bipolar
the previous dose of levodopa wanes (Vazquez et al. 1993). affective group. Am J Psychiatry 1977; 134:1227–33.
Alajouanine T. Dostoiewski’s epilepsy. Brain 1963; 86:209.
Alessi CA, Yoon EJ, Schnelle JF et al. A randomized trial of a
Differential diagnosis combined physical activity and environmental intervention in
nursing home residents: do sleep and agitation improve? J Am
The first task in differential diagnosis is to decide whether Geriatr Soc 1999; 37:784–91.
or not the anxiety in question is normal or pathologic. Allain H, Dautzenberg PH, Maurere K et al. Double blind study of
Although the experience of anxiety is a normal reaction to tiapride versus haloperidol and placebo in agitation and
p 06.qxd 3/10/08 9:34 AM Page 228
aggressiveness in elderly patients with cognitive impairment. Black DW, Nasrallah H. Hallucinations and delusions in 1,715
Psychopharmacology 2000; 148:361–6. patients with unipolar and bipolar affective disorders.
Alpers BJ. Personality and emotional disorders associated with Psychopathology 1989; 22:28–34.
hypothalamic lesions. In: Fulton JF, Ranson SW, Frantz AM Blackwell MJ. Rapid-cycling manic-depressive illness following
eds. Research publications. Association for Research in Nervous subarachnoid haemorrhage. Br J Psychiatry 1991; 159:279–80.
and Mental Disease. Vol. XX. The hypothalamus and central Bloch M, Schmidt PJ, Rubinow DR. Premenstrual syndrome:
levels of autonomic function. Baltimore, MD: Williams & evidence for symptom stability across cycles. Am J Psychiatry
Wilkins, 1940. 1997a; 154:1741–6.
Anderson AE, McHugh PR. Oat cell carcinoma with hyper- Bloch M, Stager S, Braun A et al. Pimozide-induced depression in
cortisolemia presenting to a psychiatric hospital as a suicide men who stutter. J Clin Psychiatry 1997b; 58:433–6.
attempt. J Nerv Ment Dis 1971; 152:427–31. Bogousslavsky J, Ferrazzini M, Regli F et al. Manic delirium and
Anderson G, Vestergaard K, Lauritzen L. Effective treatment of frontal-like syndrome with paramedian infarction of the right
poststroke depression with the selective serotonin reuptake thalamus. J Neurol Neurosurg Psychiatry 1988; 51:116–19.
inhibitor citalopram. Stroke 1994; 25:1099–104. Bolt JMW. Huntington’s chorea in the West of Scotland. Br J
Anderson JD, Noyes R, Crowe RR. A comparison of panic disorder Psychiatry 1970; 116:259–70.
and generalized anxiety disorder. Am J Psychiatry 1984; Bourgeois JA, Koike AK, Simmons JE et al. Adjunctive valproic acid
141:572–5. for delirium and/or agitation on a consultation-liaison service:
Andersson S, Krogstad JM, Finset A. Apathy and depressed mood a report of six cases. J Neuropsychiatry Clin Neurosci 2005;
in acquired brain damage: relationship to lesion localization 17:232–8.
and psychophysiological reactivity. Psychol Med 1999; Bowman KM, Raymond AF. A statistical study of hallucinations in the
29:447–56. manic-depressive psychoses. Am J Psychiatry 1931; 88:299–309.
Angelini L, Mazzuchi A, Picciotto F et al. Focal lesion of the right Bracken P. Mania following head injury. Br J Psychiatry 1987;
cingulum: a case report in a child. J Neurol Neurosurg 150:690–2.
Psychiatry 1980; 43:355–7. Bratfos O, Haug JO. Puerperal mental disorders in manic-
Arnold BM, Casal G, Higgins HP. Apathetic thyrotoxicosis. Can depressive females. Acta Psychiatr Scand 1966; 42:285–94.
Med Assoc J 1974; 111:957–8. Breier A, Meehan K, Birkett M et al. A double-blind, placebo-
Astrom M, Adolfsson R, Asplund K. Major depression in stroke controlled dose-response comparison of intramuscular
patients: a 3-year longitudinal study. Stroke 1993; 24:976–82. olanzapine and haloperidol in the treatment of acute agitation
Azouvi P, Jokic C, Attal N et al. Carbamazepine in agitation and in schizophrenia. Arch Gen Psychiatry 2002; 59:441–8.
aggressive behavior following severe closed-head injury: Breitbart W, Marotta R, Platt MM et al. A double-blind trial of
results of an open trial. Brain Inj 1999; 13:797–804. haloperidol, chlorpromazine, and lorazepam in the treatment
Baker RW, Kinon BJ, Maguire GA et al. Effectiveness of rapid of delirium in hospitalized AIDS patients. Am J Psychiatry
initial dose escalation of up to 40 mg per day of oral 1996; 153:231–7.
olanzapine in acute agitation. J Clin Psychopharmacol 2003; Brenes GA. Anxiety and chronic obstructive pulmonary disease:
23:342–8. prevalence, impact, and treatment. Psychosom Med 2003;
Bakchine S, Lacomblez L, Benoit N et al. Manic-like state after 65:963–70.
bilateral orbitofrontal and right temperoparietal injury: Brenner I. Apathetic hyperthyroidism. J Clin Psychiatry 1978;
efficacy of clonidine. Neurology 1989; 39:777–81. 39:479–80.
Barczak P, Edmunds E, Betis T et al. Hypomania following complex Bressan RA, Monteiro VBM, Dias CC. Panic disorder associated
partial seizures: a report of three cases. Br J Psychiatry 1988; with clozapine. Am J Psychiatry 2000; 157:2056.
152:137–9. Brey RL, Holliday SL, Saklad AR et al. Neuropsychiatric syndromes
Benjamin S, Kirsch D, Visscher T et al. Hypomania from left frontal in lupus. Prevalence using standardized definitions. Neurology
AVM resection. Neurology 2000; 54:1389–90. 2002; 58:1214–20.
Besson JAO. A diagnostic pointer to adult metachromatic Brockington IF, Wainwright S, Kendell RE. Manic patients with
leukodystrophy. Br J Psychiatry 1980; 137:186–7. schizophrenic or paranoid symptoms. Psychol Med 1980;
Bieniek SA, Ownby RL, Penalver A et al. A double-blind study of 10:73–83.
lorazepam versus the combination of haloperidol and lorazepam Brockington IF, Cernik KF, Schofield EM et al. Puerperal psychosis:
in managing agitation. Pharmacotherapy 1998; 18:57–62. phenomenon and diagnosis. Arch Gen Psychiatry 1981;
Bhalerao S, Talsky A, Hansen K et al. Ciprofloxacin-induced manic 38:829–33.
episode. Psychosomatics 2006; 47:539–40. Brodaty H, Ames D, Snowdon J et al. A randomized placebo-
Billings RF, Stein MB. Depression associated with ranitidine. Am J controlled trial of risperidone for the treatment of aggression,
Psychiatry 1986; 143:915–16. agitation, and psychosis of dementia. J Clin Psychiatry 2003;
Billings RG, Tang SW, Rakoff VM. Depression associated with 64:134–43.
cimetidine. Can J Psychiatry 1981; 26:260–1. Brodaty H, Sachdev PS, Withall A et al. Frequency and clinical,
Binder RL, Dickman WA. Psychiatric manifestations of neuropsychological and neuroimaging correlates of apathy
neurosyphilis in middle-aged patients. Am J Psychiatry 1980; following stroke: the Sydney Stroke Study. Psychol Med 2005;
137:741–2. 35:1707–16.
p 06.qxd 3/10/08 9:34 AM Page 229
References 229
Bromberg W. Marijuana intoxication. Am J Psychiatry 1934; Coid J, Strang J. Mania secondary to procyclidine (‘Kemadrin’)
91:303–30. abuse. Br J Psychiatry 1982; 141:81–4.
Brooke MM, Patterson DR, Questad KA et al. The treatment of Collacott RA, Cooper S-A, McGrother C. Differential rates of
agitation during initial hospitalization after traumatic brain psychiatric disorder in adults with Down’s syndrome compared
injury. Arch Phys Med Rehabil 1992; 73:917–21. with other mentally handicapped adults. Br J Psychiatry 1992;
Brouilette M-J, Routy J-P. Abacavir sulfate and mania in HIV. Am 161:671–4.
J Psychiatry 2007; 164:979–80. Constant A, Castera L, Dantzer R et al. Mood alterations during
Brown SA, Inaba RK, Gillin JC et al. Alcoholism and affective interferon-alfa therapy in patients with chronic hepatitis C:
disorder: clinical course of depressive symptoms. Am J evidence for an overlap between manic/hypomanic and
Psychiatry 1995; 152:45–52. depressive symptoms. J Clin Psychiatry 2005; 66:1050–7.
Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s Corsellis JAN, Goldberg GJ, Norton AR. ‘Limbic encephalitis’ and
disease. III. Disorders of mood. Br J Psychiatry 1990a; its association with carcinoma. Brain 1968; 91:481–96.
157:81–6. Cottrell SS, Wilson SAK. The affective symptomatology of
Burns A, Folstein S, Brandt J et al. Clinical assessment of disseminated sclerosis: a study of 100 cases. J Neurol
irritability, aggression, and apathy in Huntington and Psychopathology 1926; 7:1–30.
Alzheimer disease. J Nerv Ment Dis 1990b; 178:30–6. Coyle PK, Sterman AB. Focal neurologic symptoms in panic
Caine ED, Shoulson I. Psychiatric syndromes in Huntington’s attacks. Am J Psychiatry 1986; 143:648–9.
disease. Am J Psychiatry 1983; 140:728–33. Cummings JL, Mendez MF. Secondary mania with focal
Carlson GA, Goodwin FK. The stages of mania: a longitudinal cerebrovascular lesions. Am J Psychiatry 1984; 141:1084–7.
analysis of the manic episode. Arch Gen Psychiatry 1973; Cummings JL, Miller B, Hill MA et al. Neuropsychiatric aspects of
28:221–8. multi-infarct dementia and dementia of the Alzheimer type.
Carlson GA, Strober M. Affective disorders in adolescence: issues Arch Neurol 1987; 44:389–93.
in misdiagnosis. J Clin Psychiatry 1978; 39:59–66. Currier GW, Chou JC, Feifel D et al. Acute treatment of psychotic
Carlson RJ. Longitudinal observations of two cases of organic agitation: a randomized comparison of oral treatment with
anxiety syndrome. Psychosomatics 1986; 27:529–31. risperidone and lorazepam versus intramuscular treatment
Castillo CS, Starkstein SE, Federoff JP et al. Generalized anxiety with haloperidol and lorazepam. J Clin Psychiatry 2004;
disorder following stroke. J Nerv Ment Dis 1993; 181:100–6. 65:386–94.
Castillo CS, Schultz SK, Robinson RG. Clinical correlates of early- Cushing H. The basophil adenomas of the pituitary body and their
onset and late-onset poststroke generalized anxiety. Am J clinical manifestations (pituitary basophilism). Bull Johns
Psychiatry 1995; 152:1174–9. Hopkins Hosp 1932; 50:137–95.
Catsman-Berrevoets CE, von Harskamp F. Compulsive pre-sleep Dalos NP, Rabins PV, Brooks BR et al. Disease activity and
behavior and apathy due to bilateral thalamic stroke: response emotional state in multiple sclerosis. Ann Neurol 1983;
to bromocriptine. Neurology 1988; 38:647–9. 13:573–7.
Celesia GG, Barr AN. Psychosis and other psychiatric Daniel DG, Potkin SG, Reeves KR et al. Intramuscular (IM)
manifestations of levodopa therapy. Arch Neurol 1970; ziprasidone 20 mg is effective in reducing acute agitation
23:193–200. associated with psychosis: a double-blind, randomized trial.
Ceylan ME, Turkcan A, Mutlu E et al. Manic episode with Psychopharmacology 2001; 155:128–34.
psychotic symptoms associated with high dose disulfiram: Davidson KM. Diagnosis of depression in alcohol dependence:
a case report. J Clin Psychopharmacol 2007; 27:224–5. changes in prevalence with drinking status. Br J Psychiatry
Chandler MC, Barnhill JL, Gualtieri CT. Amantadine for the 1995; 166:199–204.
agitated head-injury patient. Brain Inj 1988; 2:309–11. DeBattista C, Solomon A, Arnow B et al. The efficacy of divalproex
Chatham-Showalter PE, Kimmel DN. Agitated symptom response sodium in the treatment of agitation associated with major
to divalproex following acute brain injury. J Neuropsychiatry depression. J Clin Psychopharmacol 2005; 25:476–9.
Clin Neurosci 2000; 12:395–7. De Deyn PP, Katz IR, Brodaty H et al. Management of agitation,
Chaturvedi SK, Upadhyaya M. Secondary mania in a patient aggression, and psychosis associated with dementia: a pooled
receiving isonicotinic acid hydrazide and pyroxidine: case analysis including three randomized, placebo-controlled
report. Can J Psychiatry 1988; 33:675–6. double-blind trials in nursing home residents treated with
Clark AF, Davison K. Mania following head injury: a report of two risperidone. Clin Neurol Neurosurg 2005; 107:497–508.
cases and a review of the literature. Br J Psychiatry 1987; DeMuth GW, Ackerman SH. Alpha-methyldopa and depression: a
150:841–4. clinical study and review of the literature. Am J Psychiatry
Clayton P, Pitts FN, Winokur G. Affective disorder. IV. Mania. 1983; 140:534–8.
Compr Psychiatry 1965; 3:313–22. Denko J, Kaelbling R. The psychiatric aspects of
Cohen AJ. Bromocriptine for prolactinoma-related dissociative hypoparathyroidism. Acta Psychiatr Scand 1962; (suppl.
disorder and depression. J Clin Psychopharmacol 1995; 164):1–70.
15:144–5. Dennis MS, Byrne EJ, Hopkinson N et al. Neuropsychiatric
Cohen SI. Cushing’s syndrome: a psychiatric study of 29 patients. systemic lupus erythematosus in elderly people: a case series. J
Br J Psychiatry 1980; 136:120–4. Neurol Neurosurg Psychiatry 1992; 55:1157–61.
p 06.qxd 3/10/08 9:34 AM Page 230
Devanand DP, Nobler MS, Singer T et al. Is dysthymia a different Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa–2a
disorder in the elderly? Am J Psychiatry 1994; 151:1591–9. plus ribaverin for chronic hepatitis C infection. N Engl J Med
Devanand DP, Marder K, Michaels KS et al. A randomized, 2002; 347:975–82.
placebo-controlled dose-comparison trial of haloperidol for Friend KD, Young RC. Late-onset major depression with delusions
psychosis and disruptive behaviors in Alzheimer’s disease. Am J after metoclopramide treatment. Am J Geriatr Psychiatry 1997;
Psychiatry 1998; 155:1512–20. 5:79–82.
Dewhurst K. The neurosyphilitic psychoses today: a survey of 91 Galynker I, Ieronimo C, Miner C et al. Methylphenidate treatment
cases. Br J Psychiatry 1969; 115:31–8. of negative symptoms in patients with dementia. J Neuro-
Dietch JT. Diagnosis of organic anxiety disorders. Psychosomatics psychiatry Clin Neurosci 1997; 9:231–9.
1981; 22:661–9. Ganz VH, Gurland BJ, Deming WE et al. The study of psychiatric
Dilsaver SC, Feinberg M, Greden JF. Antidepressant withdrawal symptoms of systemic lupus erythematosus: a biometric study.
symptoms treated with anticholinergic agents. Am J Psychiatry Psychosom Med 1972; 34:207–20.
1983; 140:249–51. Gatewood JW, Organ CH, Mead BT. Mental changes associated
Doust BC. Anxiety as a manifestation of pheochromocytoma. Arch with hyperparathyroidism. Am J Psychiatry 1975; 132:129–32.
Int Med 1958; 102:811–55. Gatti FM, Rosenheim E. Sydenham’s chorea associated with
Dunner DL, Fleiss JL, Fieve R. The course of development of mania transient intellectual impairment. Am J Dis Child 1969;
in patients with recurrent depression. Am J Psychiatry 1976; 118:915–18.
133:905–8. Gentilini M, De Renzi E, Crisi G. Bilateral paramedian thalamic
Dunner DL, Patrick V, Fieve RR. Rapid cycling manic depressive artery infarcts: report of eight cases. J Neurol Neurosurg
patients. Compr Psychiatry 1977; 18:561–6. Psychiatry 1987; 50:900–9.
El-Mallakh RS, Shrader SA, Widger E. Single case study: mania as Ghadarian AM, Gauthier S, Bertrand S. Anxiety attacks in a
a manifestation of end-stage renal disease. J Nerv Ment Dis patient with a right temporal lobe meningioma. J Clin
1987; 175:243–5. Psychiatry 1986; 47:270–1.
Engel GL, Margolin SG. Neuropsychiatric disturbances in Addison’s Gilbert A, Hendrie HC. Treatment of agitated depression with
disease and the role of impaired carbohydrate metabolism in alprazolam. Am J Psychiatry 1987; 144:688.
the production of abnormal cerebral function. Arch Neurol Giovannoni G, O’Sullivan JD, Turner K et al. Hedonistic
Psychiatry 1941; 45:881–4. homeostatic dysregulation in patients with Parkinson’s disease
Ernst NH, Steur J. Increase of parkinsonian disability after on dopamine replacement therapies. J Neurol Neurosurg
fluoxetine medication. Neurology 1993; 43:211–13. Psychiatry 2000; 68:423–8.
Falk WE, Mahnke MD, Poskanzer MD. Lithium prophylaxis Glaser G, Pincus JH. Limbic encephalitis. J Nerv Ment Dis 1969;
of corticotropin-induced psychosis. JAMA 1979; 149:59–67.
241:1011–12. Glenn MB, Wroblewski B, Parziale J et al. Lithium carbonate for
Fann JR, Uomoto JM, Katon WJ. Sertaline in the treatment of aggressive behavior of affective instability in ten brain-injured
major depression following mild traumatic brain injury. patients. Am J Phys Med Rehabil 1989; 68:221–6.
J Neuropsychiatry Clin Neurosci 2000; 12:226–32. Goggans FC. A case of mania secondary to vitamin B12
Fann KR, Katon WJ, Uomoto JM et al. Psychiatric disorders and deficiency. Am J Psychiatry 1984; 141:300–1.
functional disability in outpatients with traumatic brain Gomez EA, Aviles M. Neurosyphilis in community mental health
injuries. Am J Psychiatry 1995; 152:1493–9. clinics: a case series. J Clin Psychiatry 1984; 45:127–9.
Fassbender K, Schmidt R, Mofsner R et al. Mood disorders and Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J
dysfunction of the hypothalmic-pituitary-adrenal axis in Psychiatry 1974; 131:1089–92.
multiple sclerosis. Arch Neurol 1998; 55:66–72. Greenberg DB, Brown GL. Single case study: mania resulting from
Federoff PJ, Starkstein SE, Forrester AW et al. Depression in brain stem tumor. J Nerv Ment Dis 1985; 173:434–6.
patients with acute traumatic brain injury. Am J Psychiatry Greer S, Ramsey I, Bagley C. Neurotoxic and thyrotoxic anxiety:
1992; 149:918–23. clinical, psychological and physiological measurements. Br J
Feil D, Razani J, Boone K et al. Apathy and cognitive performance Psychiatry 1973; 122:549–54.
in older adults with depression. Int J Geriatr Psychiatry 2003; Gross RA, Herridge P. A maniclike illness associated with a right
18:479–85. frontal arteriovenous malformation. J Clin Psychiatry 1988;
Fontaine CS, Hynn LS, Koch K et al. A double-blind comparison of 49:119–20.
olanzapine versus risperidone in the acute treatment of Grossman LS, Harrow M, Fudala JL et al. The longitudinal course
dementia-related behavioral disturbances in extended care of schizoaffective disorders: a prospective follow-up study. J
facilities. J Clin Psychiatry 2003; 64:726–30. Nerv Ment Dis 1984; 172:140–9.
Fras I, Litin EM, Pearson JS. Comparison of psychiatric symptoms Guze SB. The occurrence of psychiatric illness in systemic lupus
in carcinoma of the pancreas with those in some other erythematosus. Am J Psychiatry 1967; 123:1562–70.
intra-abdominal neoplasms. Am J Psychiatry 1967; Guze SB, Woodrugg RA, Clayton PJ. The significance of psychotic
123:1553–62. affective disorders. Arch Gen Psychiatry 1975; 32:1147–50.
Fraser TN. Cerebral manifestations of addisonian pernicious Hadley HG. A case of puerperal psychosis recovering from four
anemia. Lancet 1960; 2:458–9. attacks. J Nerv Ment Dis 1941; 94:540–1.
p 06.qxd 3/10/08 9:34 AM Page 231
References 231
Haller CA, Benowitz NL. Adverse cardiovascular and central nervous Isbell H, Belleville RE, Fraser HF et al. Studies on lysergic acid
system events associated with dietary supplements containing diethylamide (LSD–25). Arch Neurol Psychiatry 1956;
ephedra alakaloids. N Engl J Med 2000; 343:1833–8. 76:468–78.
Han CS, Kim YK. A double-blind trial of risperidone and Isella V, Melzi P, Grimaldi M et al. Clinical, neuropsychological,
haloperidol for the treatment of delirium. Psychosomatics and morphometric correlates of apathy in Parkinson’s disease.
2004; 45:297–301. Mov Disord 2002; 17:366–71.
Hantz P, Caradoc-Davies G, Caradoc-Davies T et al. Depression in Jack RA. A case of mania secondary to propafenone. J Clin
Parkinson’s disease. Am J Psychiatry 1994; 151:1010–14. Psychiatry 1985; 46:104–5.
Hardwick SW. Pellagra in psychiatric patients: twelve recent Jack RA, Rivers-Bulkeley NT, Rabin PL. Single case study:
cases. Lancet 1943; 2:43–5. secondary mania as a presentation of progressive dialysis
Harlow SD, Goldberg EL, Constock GW. A longitudinal study of the encephalopathy. J Nerv Ment Dis 1983; 171:193–5.
prevalence of depressive symptomatology in elderly widowed Jackson SL. Psychosis due to isoniazid. Br Med J 1957; 2:743–6.
and married women. Arch Gen Psychiatry 1991; 48:1065–8. Jampala VC, Taylor MA, Abrams R. The diagnostic implications of
Haskett RF. Diagnostic categorization of psychiatric disturbance formal thought disorder in mania and schizophrenia: a
in Cushing’s syndrome. Am J Psychiatry 1985; 142:911–16. reassessment. Am J Psychiatry 1989; 146:459–63.
Heathfield KW. Huntington’s chorea. Investigation into the Jensen K. Depression in patients treated with reserpine for arterial
prevalence of the disease in the area covered by the North hypertension. Acta Psychiatr Neurol Scand 1959; 34:195–204.
East Metropolitan Regional Hospital Board. Brain 1967; Jimenez-Jimenez FJ, Tejeiro J, Martinez-Junquera G et al.
90:203–32. Parkinsonism exacerbated by paroxetine. Neurology 1994;
Hermann M, Bartels C, Wallesch C-W. Depression in acute and 44:2406.
chronic aphasia: symptoms, pathoanatomical–clinical Jochum T, Bar KJ, Sauer H. Topiramate-induced manic episode. J
correlations and functional implications. J Neurol Neurosurg Neurol Neurosurg Psychiatry 2002; 73:208–10.
Psychiatry 1993; 56:672–8. Johnson RJ, Richardson EP. The neurological manifestations of
Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in systemic lupus erythematosus. Medicine 1968; 47:337–69.
patients on fluvoxamine and fluoxetine. J Clin Jones AM. Psychiatric presentation of a third ventricular colloid
Psychopharmacol 1990; 10:343–5. cyst in a mentally handicapped woman. Br J Psychiatry 1993;
Hohman LB. Epidemic encephalitis (lethargic encephalitis): its 163:677–8.
psychotic manifestations with a report of twenty-three cases. Jorge RE, Robinson RG, Starkstein SE et al. Secondary mania
Arch Gen Psychiatry 1921; 6:295–333. following traumatic brain injury. Am J Psychiatry 1993a;
Holland JC, Korzun AH, Tross S et al. Comparative psychological 150:916–21.
disturbance in patients with pancreatic and gastric cancer. Am Jorge RE, Robinson RG, Starkstein SE et al. Depression and anxiety
J Psychiatry 1986; 143:982–6. following traumatic brain injury. J Neuropsychiatry Clin
House A, Dennis M, Warlow C et al. Mood disorders after stroke Neurosci 1993b; 5:369–74.
and their relation to lesion location. Brain 1990; 1113–29. Kahana E, Liebowitz U, Alter M. Cerebral multiple sclerosis.
Hughes JR, Hatsukami D. Signs and symptoms of tobacco Neurology 1971; 21:1179–85.
withdrawal. Arch Gen Psychiatry 1986; 43:289–94. Kant R, Smith-Seemiller L, Zeiler D. Treatment of aggression and
Hughes JR, Higgins ST, Bickel WK et al. Caffeine self-administration, irritability after head injury. Brain Inj 1998; 12:661–6.
withdrawal, and adverse effects among coffee drinkers. Arch Kaplitz SE. Withdrawn, apathetic geriatric patients responsive to
Gen Psychiatry 1991a; 48:611–17. methylphenidate. J Am Geriatr Soc 1975; 23:271–6.
Hughes JR, Gust SW, Skoog K et al. Symptoms of tobacco Karpati G, Frame B. Neuropsychiatric disorders in primary
withdrawal: a replication and extension. Arch Gen Psychiatry hyperparathyroidism. Arch Neurol 1964; 10:387–97.
1991b; 48:52–9. Kathol RG, Delahunt JW. The relationship of anxiety and
Hugo FJ, Halland AM, Spangenberg JJ et al. DSM-III-R depression to symptoms of hyperthyroidism using operational
classification of psychiatric symptoms in systemic lupus criteria. Gen Hosp Psychiatry 1986; 8:23–8.
erythematosus. Psychosomatics 1996; 37:262–9. Kelly WF. Psychiatric aspects of Cushing’s syndrome. Q J Med
Hullett FJ, Potkin SG, Levy AB et al. Depression associated with 1996; 89:543–51.
nifedipine-induced calcium channel blockade. Am J Psychiatry Kent TA, Wilber RD. Single case study: reserpine withdrawal
1988; 145:1277–9. psychosis: the possible role of denervation supersensitivity of
Indaco A, Carrieri PB, Nappi C et al. Interictal depression in receptors. J Nerv Ment Dis 1982; 170:502–4.
epilepsy. Epilepsy Res 1992; 12:45–50. Khanna R, Borde M. Mania in a five-year-old child with tuberous
Ingham SD, Nielsen JM. Thyroid psychosis: difficulties in sclerosis. Br J Psychiatry 1989; 155:117–19.
diagnosis. J Nerv Ment Dis 1931; 74:271–7. Kim E, Bijlani M. A pilot study of quetiapine treatment of
Ironside R, Guttmacher M. The corpus callosum and its tumors. aggression due to traumatic brain injury. J Neuropsychiatry
Brain 1929; 52:442–83. Clin Neurosci 2006; 18:547–9.
Isbell H, Fraser HF, Wickler A et al. An experimental study of Kirubakaren V, Mayfield D, Rengachary S. Dyskinesia and
etiology of ‘rum fits’ and delirium tremens. Q J Stud Alcohol psychosis in a patient following baclofen withdrawal. Am J
1955; 16:1–33. Psychiatry 1984; 141:692–3.
p 06.qxd 3/10/08 9:34 AM Page 232
Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lin J T-Y, Ziegler DK. Psychiatric symptoms with initiation of
Lewy body disease: a clinicopathologic study using Alzheimer’s carbidopa-levodopa treatment. Neurology 1976; 26:699–700.
disease and Parkinson’s disease comparison groups. Neurology Linder J, Brismar K, Granberg P-O et al. Characteristic changes in
1996; 47:1148–52. psychiatric symptoms, cortisol and melatonin but not prolactin
Krauss MR, Schafer A, Faller H et al. Psychiatric symptoms in in primary hyperparathyroidism. Acta Psychiatr Scand 1988;
patients with chronic hepatitis C receiving inteferon alfa–2b 78:32–40.
therapy. J Clin Psychiatry 2003; 64:708–14. Lipsey JR, Spencer WC, Rabins PV et al. Phenomenological
Kraepelin E. Manic depressive insanity and paranoia, 1921, trans- comparison of functional and post-stroke depression. Am J
lated by Barclay RM. New York: Arno Press, 1976. Psychiatry 1986; 143:527–9.
Kryzhanovskaya LA, Jeste DV, Young CA et al. A review of treat- Litvan I, Mega MS, Cummings JL et al. Neuropsychiatric aspects of
ment emergent adverse events during olanzapine clinical trials progressive supranuclear palsy. Neurology 1996; 47:1184–9.
in elderly patients with dementia. J Clin Psychiatry 2006; Loudon JB, Blackburn IM, Ashworth CM. A study of the
67:933–45. symptomatology and course of manic illness using a new
Kulisevsky J, Berthier ML, Pujol J. Hemiballismus and secondary scale. Psychol Med 1977; 7:723–9.
mania following right thalamic infarction. Neurology 1993; Louie AK, Lannon RA, Rutzick EA et al. Clinical feaures of cocaine-
43:1422–4. induced panic. Biol Psychiatry 1996; 40:938–40.
Kulisevsky J, Asuncion A, Berthier ML. Bipolar affective disorder Lyons PR, Newman PK, Saunders M. Methylprednisolone therapy
and unilateral parkinsonism after a brainstem infarction. in multiple sclerosis: a profile of adverse effects. J Neurol
Movement Disord 1995; 10:799–802. Neurosurg Psychiatry 1988; 51:285–7.
Kumar R, Issacs S, Meltzer E. Recurrent post-partum psychosis: a MacCrimmon DJ, Wallace JE, Goldberg WM et al. Emotional
model for prospective clinical investigation. Br J Psychiatry disturbances and cognitive deficits in hyperthyroidism.
1983; 142:618–20. Psychosom Med 1979; 41:331–40.
Kuramochi H, Takahashi R. Psychopathology of LSD intoxication: MacHale SM, O’Rourke SJ, Wardlaw JM et al. Depression and its
study of experimental psychosis induced by LSD–25: relation to lesion location after stroke. J Neurol Neurosurg
description of LSD symptoms in normal oriental subjects. Arch Psychiatry 1998; 64:371–4.
Gen Psychiatry 1964; 11:151–61. McDaniel JS, Musselman DL, Proter MR. Depression in patients
Kurlan R, Cummings J, Raman R et al. Quetiapine for agitation or with cancer. Arch Gen Psychiatry 1995; 52:89–99.
psychosis in patients with dementia and parkinsonism. McElroy SL, Keck PE, Stanton SP et al. A randomized comparison
Neurology 2007; 68:1356–63. of divalproex oral loading versus haloperidol in the initial
Kwentus JA, Silverman JJ, Sprague M. Manic syndrome after treatment of acute psychotic mania. J Clin Psychiatry 1996;
metrizamide myelography. Am J Psychiatry 1984; 141:700–2. 57:142–6.
Labbatte LA, Holzgang AJ. Manic syndrome after discontinuation McGilchrist I, Goldstein LH, Jadresic D et al. Thalamo-frontal
of methyldopa. Am J Psychiatry 1989; 146:1075–6. psychosis: a case report. Br J Psychiatry 1993; 163:113–15.
Lahey FH. Non-activated (apathetic) type of hyperthyroidism. N McKeith I, Fairbarin A, Perry R et al. Neuroleptic sensitivity in
Engl J Med 1931; 204:747–8. patients with senile dementia of Lewy body type. BMJ 1992;
Lawlor BA. Hypocalcemia, hypoparathyroidism, and organic 305:1158–9.
anxiety syndrome. J Clin Psychiatry 1988; 49:317–18. McLachlan RS, Blume WT. Isolated fear in complex partial status
Lee S, Chow CC, Wing Yk et al. Mania secondary to thyrotoxicosis. epilepticus. Ann Neurol 1980; 8:639–41.
Br J Psychiatry 1991; 159:712–13. Malamud N. Psychiatric disorder with intracranial tumors of the
Lendvai I, Saravay SM, Steinberg MD. Creutzfeldt–Jakob disease limbic system. Arch Neurol 1967; 17:113–23.
presenting as secondary mania. Psychosomatics 1999; Malinow KC, Lion JR. Hyperaldosteronism (Conn’s disease)
40:524–5. presenting as depression. J Clin Psychiatry 1979; 40:358–9.
Lesem MD, Zajecka JM, Swift RH et al. Intramuscular ziprasidone, Mandel MR, Severe JB, Schooler NR et al. Development and
2 mg versus 10 mg, in the short-term management of agitated prediction of postpsychotic depression in neuroleptic-treated
psychotic patients. J Clin Psychiatry 2001; 62:12–18. schizophrenia. Arch Gen Psychiatry 1982; 39:197–203.
Levy ML, Miller BL, Cummings JL et al. Alzheimer disease and Mann AM, Hutchinson JL. Manic reaction associated with
frontotemporal dementias. Behavioral distinctions. Arch procarabazine hydrochloride therapy of Hodgkin’s disease. CM
Neurol 1996; 53:687–90. AJ 1967; 97:1350–3.
Levy ML, Cummings JL, Fairbanks LA et al. Apathy is not Mattox JH, Buckman MT, Bernstein J et al. Dopamine agonists for
depression. J Neuropsychiatry Clin Neurosci 1998; 10:314–19. reducing depression associated with hyperprolactinemia. J
Liebson E. Anosognosia and mania associated with right thalamic Reproduct Med 1986; 31:694–8.
hemorrhage. J Neurol Neurosurg Psychiatry 2000; 68:107–8. Maxwell S, Scheftner WA, Kessler HA et al. Manic syndrome
Liegghid NE, Yeragani VK. Buspirone-induced hypomania. J Clin associated with zidovudine treatment. JAMA 1988;
Psychopharmacol 1988; 8:226–7. 259:3406–7.
Lim L, Ron MA, Ormerod IEC et al. Psychiatric and neurological Mayeux R, Stern Y, Williams JBW et al. Clinical and biochemical
manifestations in systemic lupus erythematosus. Q J Med features of depression in Parkinson’s disease. Am J Psychiatry
1988; 66:27–38. 1986; 143:756–9.
p 06.qxd 3/10/08 9:34 AM Page 233
References 233
Mehan KM, Wang H, David SR et al. Comparison of rapidly acting Mysiw WJ, Jackson RD, Corrigan JD. Amitryptiline for post-
intramuscular olanzapine, lorazepam, and placebo: a double- traumatic agitation. Am J Phys Med Rehabil 1988; 67:29–33.
blind, randomized study in acutely agitated patients with Navarro V, Vieta E, Gasto C. Mannitol-induced acute manic state.
dementia. Neuropsychopharmacology 2002; 26:494–504. J Clin Psychiatry 2001; 62:126.
Mellman TA, Uhde TW. Sleep panic attacks: new clinical findings and Neilley LK, Goodin DS, Goodkin DE et al. Side effect profile of
theoretical implications. Am J Psychiatry 1989; 146:1204–7. interferon beta–1b in MS: results of an open-label trial.
Mendez MF, Cummings JL, Benson DF. Depression in epilepsy. Neurology 1996; 46:552–4.
Significance and phenomenology. Arch Neurol 1986; Newburn G, Newburn D. Selegiline in the management of
43:766–70. apathy following traumatic brain injury. Brain Inj 2005;
Merritt H, Springlova M. Lissauer’s dementia paralytica: a clinical 19:149–54.
and pathologic study. Arch Neurol Psychiatry 1932; Nickel SN, Frame B. Neurologic manifestations of myxedema.
27:987–1030. Neurology 1958; 8:511–17.
Miguel EC, Rodriguez Pereira RM, de Braganca Pereira CA et al. Nishida T, Kudo T, Inoue Y et al. Postictal mania versus postictal
Psychiatric manifestations of systemic lupus erythematosus: psychosis: differences in clinical features, epileptogenic zone,
clinical features, symptoms, and signs of central nervous and brain functional changes during postictal period. Epilepsia
system activity in 43 patients. Medicine 1994; 73:224–32. 2006; 47:2104–14.
Millefiorini E, Padovani A, Pozzilli C et al. Depression in the early Nisita C, Petracca A, Akiskal HS et al. Delimitation of generalized
phase of MS: influence of functional disability, cognitive anxiety disorder: clinical comparisons with panic and major
impairment and brain abnormalities. Acta Neurol Scand 1992; depressive disorder. Compr Psychiatry 1990; 31:409–15.
86:354–8. Nizamie SH, Mizamie A, Borde M et al. Mania following head
Miller WC, McCurdy L. A double-blind comparison of the efficacy injury: case reports and neuropsychological findings. Acta
and safety of lorazepam and diazepam in the treatment of the Psychiatr Scand 1988; 77:637–9.
acute alcohol withdrawal syndrome. Clin Ther 1984; 6:364–71. O’Brien CP, DiGiacomo JN, Fahn J et al. Mental effects of high-
Millman RP, Fogel BS, McNamara ME et al. Depression as a dose levodopa. Arch Gen Psychiatry 1971; 24:61–4.
manifestation of obstructive sleep apnea: reversal with nasal O’Dowd MA, McKegney FP. Manic syndrome associated with
continuous positive airway pressure. J Clin Psychiatry 1989; zidovudine. JAMA 1988; 260:3587–8.
50:348–51. Oliver JE. Huntington’s chorea in Northamptonshire. Br J
Minden SL, Orav J, Schildkraut JJ. Hypomanic reactions to ACTH Psychiatry 1970; 116:241–53.
and prednisone treatment for multiple sclerosis. Neurology Olin JT, Fox LS, Pawluczyk S et al. A pilot randomized trial of
1988; 38:1631–4. carbamazepine for behavioral symptoms in treatment-
Modlin IM, Farndon JR, Shepherd A et al. Pheochromocytomas in resistant outpatients with Alzheimer disease. Am J Geriatr
72 patients: clinical and diagnostic features, treatment and Psychiatry 2001; 9:400–5.
long-term results. Br J Surg 1979; 66:456–65. Papolos DF, Faedda GL, Veit S et al. Bipolar spectrum disorders in
Moller A, Wiedemann G, Rohde U et al. Correlates of cognitive patients diagnosed with velo-cardio-facial syndrome: does a
impairment and depressive mood disorder in multiple sclerosis. hemizygous deletion of chromosome 22q11 result in bipolar
Acta Psychiatr Scand 1994; 89:117–21. affective disorder? Am J Psychiatry 1996; 153:1541–7.
Morris RLP, Robinson RG, Raphael B et al. Lesion location and Parker N. Manic-depressive psychosis following head injury. Med J
poststroke depression. J Neuropsychiatr Clin Neurosci 1996; Aust 1957; 2:20–2.
8:399–403. Paskavitz JF, Anderson CA, Filley CM et al. Acute arcuate fiber
Moscovich DG, Singh MB, Efa FJ et al. Acute disseminated demyelinating encephalopathy following Epstein–Barr virus
encephalomyelitis presenting as an acute psychotic state. infection. Ann Neurol 1995; 38:127–31.
J Nerv Ment Dis 1995; 183:116–17. Patten SB, Klein GM, Lussier C et al. Organic mania induced by
Mula M, Trimble MR, Yuen A et al. Psychiatric adverse events phenytoin: a case report. Can J Psychiatry 1989; 34:457.
during levetriracetam therapy. Neurology 2005; 61:704–6. Paul R, Flanigan TP, Tashima K et al. Apathy correlates with
Mula PL, Robinson RG, Raphael B et al. Lesion location and cognitive function but not CD4 status in patients with human
poststroke depression. J Neuropsychiatry Clin Neurosci 1996; immunodeficiency virus. J Neuropsychiatry Clin Neurosci 2005;
8:399–403. 17:114–18.
Mulder DW, Daly D. Psychiatric symptoms associated with lesions Perini GI, Tosin C, Carraro C et al. Interictal mood and personality
of temporal lobe. JAMA 1952; 150:173–6. disorders in temporal lobe epilepsy and juvenile myoclonic
Munoz RA. Postpartum psychosis as a discrete entity. J Clin epilepsy. J Neurol Neurosurg Psychiatry 1996; 61:601–5.
Psychiatry 1985; 46:182–4. Perry TL, Bratty PJA, Hansen S et al. Hereditary mental depression
Murphy TL, Chalmers TC, Eckhardt RD et al. Hepatic coma: clinical and parkinsonism with taurine deficiency. Arch Neurol 1975;
and laboratory observations on 40 patients. N Engl J Med 32:108–13.
1948; 239:605–12. Petersen P. Psychiatric disorders in primary hyperparathyroidism. J
Musselman DL, Lawson DH, Gumnick JF et al. Paroxetine for the Clin Endo Metab 1968; 28:1491–5.
prevention of depression induced by high-dose interferon-alfa. Petrie WM, Maffucci RJ, Woosley RL. Propranolol and depression.
N Engl J Med 2001; 344:961–6. Am J Psychiatry 1982; 139:93–4.
p 06.qxd 3/10/08 9:34 AM Page 234
Pfohl B, Vasquez N, Nasrallah H. Unipolar vs. bipolar mania: a Reinfrank RF. Primary hyperparathyroidism with depression. Arch
review of 247 patients. Br J Psychiatry 1982; 141:453–8. Int Med 1961; 108:162–6.
Pine DS, Douglas CJ, Charles E et al. Patients with multiple Reoux JP, Saxon AJ, Malte CA et al. Divalproex sodium in alcohol
sclerosis presenting to psychiatric hospitals. J Clin Psychiatry withdrawal: a randomized double-blind placebo-controlled
1995; 56:297–306. trial. Alcohol Clin Exp Res 2001; 25:1324–9.
Pitt B. Maternity blues. Br J Psychiatry 1973; 122:431–3. Rickels K, Schweizer E, Case W et al. Long-term therapeutic use of
Pluck GC, Brown RG. Apathy in Parkinson’s disease. J Neurol benzodiazepines. I: Effects of abrupt discontinuation. Arch Gen
Pollack MH, Rosenbaum JF, Cassem NH. Brief communication: Rickles NK. Functional symptoms as first evidence of pancreatic
propranolol and depression revisited: three cases and a review. disease. J Nerv Ment Dis 1945; 101:566–71.
J Nerv Ment Dis 1985; 173:118–19. Rifkin AR, Quitkin F, Klein DF. Akinesia: a poorly recognized drug-
Pollock BG, Mulsant BH, Rosen J et al. Comparison of citalopram, induced extrapyramidal behavioral disorder. Arch Gen
perphenazine, and placebo for the acute treatment of Psychiatry 1975; 32:672–4.
psychosis and behavioral disturbances in hospitalized, Robinson RG, Kubos KL, Starr LB et al. Mood changes in stroke
demented patients. Am J Psychiatry 2002; 159:460–5. patients: relationship to lesion location. Compr Psychiatry
Pope HG, Katz DL. Affective and psychotic symptoms associated 1983; 24:555–66.
with anabolic steroid use. Am J Psychiatry 1988; 145:487–90. Robinson RG, Kubos KL, Starr LB et al. Mood disorders in stroke
Pope HG, Katz DL. Homicide and near-homicide by anabolic patients. Brain 1984; 107:81–93.
steroid users. J Clin Psychiatry 1990; 51:28–31. Robinson RG, Lipsey JR, Bolla-Wilson K et al. Mood disorders in
Pope HG, Katz DL. Psychiatric and medical effects of anabolic- left-handed stroke patients. Am J Psychiatry 1985;
androgenic steroid use: a controlled study of 160 athletes. 142:1424–9.
Arch Gen Psychiatry 1994; 51:375–82. Robinson RG, Bolduc P, Price TR. A two year longitudinal study of
Pope HG, Lipinski JF, Cohen BM et al. ‘Schizoaffective disorder’: post-stroke depression: diagnosis and outcome at one and two
an invalid diagnosis? A comparison of schizoaffective disorder, year follow-up. Stroke 1987; 18:837–43.
schizophrenia and affective disorder. Am J Psychiatry 1980; Robinson RG, Boston JD, Starkstein SE et al. Comparison of mania
137:921–7. and depression after brain injury: causal factors. Am J
Powell E. Two fatal cases of acute chorea with insanity. Brain Psychiatry 1988; 145:172–8.
1889; 12:157–60. Rohde LA, Busnello E, Wolf A et al. Maternity blues in Brazilian
Powell JH, al-Adawi S, Morgan J et al. Motivational deficits after women. Acta Psychiatr Scand 1997; 95:231–5.
brain injury: effects of bromocriptine in 11 patients. J Neurol Rosenthal NE, Rosenthal LN, Stallone F et al. Psychosis as a
Neurosurg Psychiatry 1996; 60:416–21. predictor of response to lithium maintenance treatment in
Porsteinsson AP, Tariot PN, Erb R et al. Placebo-controlled study bipolar affective disorder. J Affect Disord 1979; 1:237–45.
of divalproex for agitation in dementia. Am J Geriatr Rosenthal NE, Rosenthal LN, Stallone F et al. Toward the
Psychiatry 2001; 9:58–66. validation of RDC schizoaffective disorder. Arch Gen Psychiatry
Price WA, Bielfeld M. Buspirone-induced mania. J Clin 1980; 37:804–10.
Psychopharmacol 1989; 9:150–1. Roth RM, Flashman LA, Saykin AJ et al. Apathy in schizophrenia:
Pujol J, Leal S, Fluvia X et al. Psychiatric aspects of normal reduced frontal lobe volume and neuropsychological deficits.
pressure hydrocephalus. Br J Psychiatry 1989; 154 (suppl. Am J Psychiatry 2004; 161:157–9.
4):77–80. Rubinsztein JS, Rubinsztein DC, Goodburn S et al. Apathy and
Pujol J, Bello J, Deus J et al. Lesions in the left arcuate fasciculus hypersomnia are common features of myotonic dystrophy. J
region and depressive symptoms in multiple sclerosis. Neurol Neurosurg Psychiatry 1998; 64:510–15.
Neurology 1997; 49:1105–10. Ryback RS, Schwab RS. Manic response to levodopa therapy:
Pushpal D, Shamhul HN. Tiagabine withdrawal-emergent mania. report of a case. N Engl J Med 1971; 285:788–9.
Aust N Z J Psychiatry 2006; 40:719. Sackeim HA, Greenberg MS, Weman Al et al. Hemispheric
Quetsch RM, Achor RWP, Litin EM et al. Depressive reactions in asymmetry in the expression of positive and negative
hypertensive patients. Circulation 1959; 19:366–75. emotions: neurologic evidence. Arch Neurol 1982; 39:210–18.
Rabins PV, Brooks BR, O’Donnell P et al. Structural brain Sale I, Kalucy P. Psychosis associated with oral contraceptive-
correlates of emotional disorder in multiple sclerosis. Brain induced chorea. Med J Aust 1981; 1:79–80.
1986; 109:585–97. Sasaki Y, Matsuyama T, Inoue S et al. A prospective, open-label,
Raison CL, Borisov AS, Broadwell SD et al. Depression during flexible-dose study of quetiapine in the treatment of delirium.
pegylated interferon-alpha plus ribaverin therapy: prevalence J Clin Psychiatry 2003; 64:1316–21.
and presentation. J Clin Psychiatry 2005; 66:41–8. Sawyer DR, Connor CS, Rumack BH. Managing acute toxicity from
Reaser EF. Chorea of infectious origin. South Med J 1940; nonprescription stimulants. Clin Pharm 1982; 1:529–33.
33:1324–8. Sayed AJ. Mania and bromism: a case report and a look to the
van Reekum R, Bayley M, Garner S et al. N of 1 study: amantadine future. Am J Psychiatry 1976; 133:228–9.
for the amotivational syndrome in a patient with traumatic Sazgar M, Carlen PL, Wennberg R. Panic attack semiology in right
brain injury. Brain Inj 1995; 9:49–53. temporal lobe epilepsy. Epileptic Disord 2003; 5:93–100.
p 06.qxd 3/10/08 9:34 AM Page 235
References 235
Schiffer RB, Babigian H. Behavioral disorders in multiple sclerosis, Starkstein SE, Cohen BS, Federoff P et al. Relationship between
temporal lobe epilepsy, and amyotrophic lateral sclerosis: an anxiety disorders and depressive disorders in patients with
epidemiologic study. Arch Neurol 1984; 41:1067–9. cerebrovascular injury. Arch Gen Psychiatry 1990c; 47:785–9.
Schiffer RB, Caine ED, Bamford KA et al. Depressive episodes in Starkstein SE, Federoff JP, Price TR et al. Apathy following
patients with multiple sclerosis. Am J Psychiatry 1983; cerebrovascular lesions. Stroke 1993; 24:1625–30.
140:1498–500. Starkstein SE, Chemerinski E, Sabe L et al. Prognostic longitudinal
Schneider LS, Tariot PN, Dagerman KS et al. Effectiveness of study of depression and anosognosia in Alzheimer’s disease. Br
atypical antipsychotic drugs in patients with Alzheimer’s J Psychiatry 1997; 171:47–52.
disease. N Engl J Med 2006; 355:1525–38. Starkstein SE, Petracca G, Chemerinski E et al. Syndromic validity of
Schottenfeld RS, Cullen MR. Organic affective illness associated apathy in Alzheimer’s disease. Am J Psychiatry 2001; 158:872–7.
with lead intoxication. Am J Psychiatry 1984; 141:1425–6. Starkstein SE, Jorge R, Mizrahi R et al. The construct of minor and
Shaskan D. Mental changes in chorea minor. Am J Psychiatry major depression in Alzheimer’s disease. Am J Psychiatry
1938; 95:193–202. 2005a; 162:2086–93.
Shulman KI, Tohen M. Unipolar mania revisited: evidence from an Starkstein SE, Ingram L, Garau ML et al. On the overlap between
elderly cohort. Br J Psychiatry 1994; 164:547–9. apathy and depression in dementia. J Neurol Neurosurg
Shulman RB, Scheftner WA, Mayudu S. Velafaxine-induced mania. Psychiatry 2005b; 76:1070–4.
J Clin Psychopharmacol 2001; 21:239–41. Starkstein WE, Jorge R, Mizrahi R et al. A propsective longitudinal
Siegal FP. Lithium for steroid-induced psychosis. N Engl J Med study of apathy in Alzheimer’s disease. J Neurol Neurosurg
1978; 299:155–6. Psychiatry 2006; 77:8–11.
Singh A, Althoff R, Martineau RJ et al. Pramipexole, ropinirole, Stern K, Dancey TE. Glioma of the diencephalon in a manic
and mania in Parkinson’s disease. Am J Psychiatry 2005; patient. Am J Psychiatry 1942; 98:716–19.
162:814–15. Stern RA, Bachman DL. Depressive symptoms following stroke. Am
Sival RC, Haffmans PM, Jansen PA et al. Sodium valproate in the J Psychiatry 1991; 148:351–6.
treatment of aggressive behavior in patients with dementia: Stoll Al, Mayer PV, Kolbrener M et al. Antidepressant-associated
a randomized placebo controlled clinical trial. Int J Geriar mania: a controlled comparison with spontaneous mania. Am J
Psychiatry 2002; 17:579–85. Psychiatry 1994; 151:1642–5.
Skrobik YK, Bergeron N, Dumont M et al. Olanzapine vs Storm-Mathisen A. General paresis: a follow-up study of 203
haloperidol: treating delirium in a critical care setting. patients. Acta Psychiatr Scand 1969; 45:118–32.
Intensive Care Med 2004; 30:444–9. Street JS, Clark WS, Gannnon KS et al. Olanzapine treatment of
Slyter H. Idiopathic hypoparathyroidism presenting as dementia. psychotic and behavioral symptoms in patients with Alzheimer
Neurology 1979; 29:393–4. disease in nursing care facilities: a double-blind, randomized,
Spillane JD. Nervous and mental disorders in Cushing’s syndrome. placebo-controlled trial. The HGEU Study Group. Arch Gen
Brain 1951; 74:72–94. Psychiatry 2000; 57:968–76.
Starkman MN, Schteingart DE, Schork MA. Depressed mood and Stuppacek CH, Pycha R, Miller C et al. Carbamazepine versus
other psychiatric manifestations of Cushing’s syndrome: oxazepam in the treatment of alcohol withdrawal: a double-
relationship to hormone levels. Psychosom Med 1981; blind study. Alcohol Alcoholism 1992; 27:153–8.
43:3–18. Sullivan KL, Ward CL, Zesiewicz TA. Zonisamide-induced mania in
Starkman MN, Zelnick TC, Nesse RM et al. Anxiety in patients essential tremor patient. J Clin Psychopharmacol 2006;
with pheochromocytomas. Arch Int Med 1985; 26:439–40.
145:248–52. Sultzer DL, Gray KF, Gunay I et al. A double-blind comparison of
Starkstein SE, Robinson RG, Price TR. Comparison of cortical and trazodone and haloperidol for treatment of agitation in
subcortical lesions in the production of poststroke mood patients with dementia. Am J Geriatr Psychiatry 1997;
disorders. Brain 1987a; 110:1045–59. 5:60–9.
Starkstein SE, Pearlson GD, Boston J et al. Mania after brain Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic
injury: a controlled study of causative factors. Arch Neurol encephalopathy due to ingestion of bismuth salts: clinical and
1987b; 44:1069–73. EEG studies of 45 patients. J Neurol Neurosurg Psychiatry
Starkstein SE, Robinson RG, Berthier ML et al. Differential mood 1977; 40:748–52.
changes following basal ganglia versus thalamic lesions. Arch Surridge D. An investigation into some psychiatric aspects of
Neurol 1988a; 45:725–30. multiple sclerosis. Br J Psychiatry 1969; 115:749–64.
Starkstein SE, Boston JD, Robinson RG. Mechanism of mania after Tamir A, Whittier J, Korenys C. Huntington’s chorea: a sex
brain injury: 12 case reports and review of the literature. J difference in psychopathological symptoms. Dis Nerv Syst
Nerv Ment Dis 1988b; 176:87–100. 1969; 30:103.
Starkstein SE, Preziosis TJ, Bolduc PL et al. Depression in Tariot PN, Erb R, Podgorski CA et al. Efficacy and tolerability of
Parkinson’s disease. J Nerv Ment Dis 1990a; 178:27–31. carbamazepine for agitation and aggression in dementia. Am J
Starkstein SE, Mayberg HS, Berthier ML et al. Mania after brain Psychiatry 1998; 155:54–61.
injury: neuroradiological and metabolic findings. Ann Neurol Tariot PN, Raman R, Jakimovich L et al. Divalproex sodium in
1990b; 27:652–9. nursing home residents with possible or probably Alzheimer
p 06.qxd 3/10/08 9:34 AM Page 236
disease complicated by agitation: a randomized, controlled Wagner KD, Berenson AB. Norplant-associated major depression
trial. Am J Geriatr Psychiatry 2005; 13:942–9. and panic disorder. J Clin Psychiatry 1994; 55:478–80.
Taylor JW. Depression in thyrotoxicosis. Am J Psychiatry 1975; Walton RG. Seizure and mania after high intake of aspartame.
132:552–3. Psychosomatics 1986; 27:218–20.
Taylor MA, Abrams R. The phenomenology of mania: a new Wang PS, Schneeweiss S, Avorn J et al. Risk of death in elderly
look at some old patients. Arch Gen Psychiatry 1973; users of conventional vs atypical antipsychotic medicines. N
29:520–2. Engl J Med 2005; 353:2335–41.
Taylor MA, Abrams R. Catatonia: prevalence and importance in Warren AC, Holyroyd S, Folstein MF. Major depression in Down’s
the manic phase of manic-depressive illness. Arch Gen syndrome. Br J Psychiatry 1989; 155:202–5.
Psychiatry 1977; 34:1223–5. Watanabe MD, Martin EM, DeLeon OA et al. Successful
Teri L, Logsdon RG, Peskind E et al. Treatment of agitation in AD: a methylphenidate treatment of apathy after subcortical
randomized, placebo-controlled trial. Neurology 2000; infarcts. J Neuropsychiatry Clin Neurosci 1995; 7:502–4.
55:1271–8. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal:
Thomas FB, Mazzaferri EL, Skillman TG. Apathetic thyrotoxicosis: affective state, sleep patterns, and MHPG excretion. Am J
a distinctive clinical and laboratory entity. Ann Intern Med Psychiatry 1972; 129:263–9.
1970; 72:679–85. Weddington WW, Brown BS, Haertzen CA et al. Changes in mood,
Thomas JE, Rooke ED, Kuale WF. The neurologist’s experience with craving, and sleep during short-term abstinence reported by
pheochromocytoma: a review of 100 cases. J Am Med Assoc male cocaine addicts. Arch Gen Psychiatry 1990; 47:861–8.
1966; 197:754–8. Weil AA. Ictal depression and anxiety in temporal lobe disorders.
Tohen M, Ketter TA, Zarate CA et al. Olanzapine versus divalproex Am J Psychiatry 1956; 113:149–57.
sodium in the treatment of acute mania. Am J Psychiatry Weller M, Liedtke W, Petersen D et al. Very-late-onset
2002; 159:1011–17. adrenoleukodystrophy: possible precipitation of demyelination
Tonks CM. Mental illness in hypothyroid patients. Br J Psychiatry by cerebral contusion. Neurology 1992; 42:367–70.
1964; 110:706–10. Whitlock FA, Siskind MM. Depression as a major symptom of
Torriani FJ, Rodriguez-Turres M, Rockstroh JK et al. Peginterferon multiple sclerosis. J Neurol Neurosurg Psychiatry 1980;
alfa–2a plus ribaverinfor chronic hepatitis C in HIV-infected 43:861–5.
patients. N Engl J Med 2004; 351:438–50. Whybrow PC, Prange AJ, Treadway CR. Mental changes
Tran-Johnson TK, Sack DA, Marcus RN et al. Efficacy and safety of accompanying thyroid gland dysfunction. Arch Gen Psychiatry
intramuscular aripiprazole in patients with acute agitation: a 1969; 20:48–63.
randomized, double-blind, placebo-controlled trial. J Clin Wier LM, Tavares SB, Tyrka AR et al. Levetiracetam-induced
Psychiatry 2007; 68:111–19. depression in a healthy adult. J Clin Psychiatry 2006;
Trautner RJ, Cummings JL, Read SL et al. Idiopathic basal ganglia 67:1159–60.
calcification and organic mood disorder. Am J Psychiatry 1988; Williams D. The structure of emotions reflected in epileptic
145:350–3. experiences. Brain 1956; 79:29–67.
Trembath PW, Boobis SW. Plasma theophylline levels after Wilson P, Preece AA. Chorea gravidarum. Arch Int Med 1932;
sustained-release aminophylline. Clin Pharmacol Ther 1979; 49:671–97.
26:654–9. Winokur G. Psychosis in bipolar and unipolar affective illness with
Trzepacz P, McCue M, Klein I et al. A psychiatric and special reference to schizo-affective disorder. Br J Psychiatry
neuropsychological study of patients with untreated Graves’ 1984; 145:236–42.
disease. Gen Hosp Psychiatry 1988; 10:49–55. Winokur G, Tsuang MT. Elation versus irritability in mania. Compr
Van Der Hurst L. Rheumatism and psychosis. Digest Neurol Psychiatry 1975; 16:435–6.
Psychiatry 1947; 15:399–416. Winokur G, Clayton PJ, Reich T. Manic-depressive illness. St Louis,
Van Putten T, May PRA. ‘Akinetic depression’ in schizophrenia. MA: CV Mosby, 1969.
Arch Gen Psychiatry 1978; 35:1101–7. Winokur G, Coryell W, Endicott J et al. Further distinctions
Van Woert MH, Ambani LM, Weintraub MI. Manic behavior and between manic-depressive illness (bipolar disorder) and
levodopa. N Engl J Med 1971; 285:1326. primary depressive disorder (unipolar depression). Am J
Varadaraj R, Cooper AJ. Addison’s disease presenting with Psychiatry 1993; 150:1176–81.
psychiatric features. Am J Psychiatry 1986; 143:553–4. Wolkowitz OM, Rubinow D, Doran AR et al. Prednisone effects on
Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P et al. ‘Panic neurochemistry and behavior. Arch Gen Psychiatry 1990;
attacks’ in Parkinson’s disease. Acta Neurol Scand 1993; 47:963–8.
87:14–18. Wright JM, Sachdev PS, Perkins RJ et al. Zidovudine related
Verhey FR, Verkaaik M, Lousberg R. Olanzapine versus haloperidol mania. Med J Aust 1989; 150:339–41.
in the treatment of agitation in elderly patients with Wright P, Birkett M, David SR et al. Double-blind, placebo-
dementia: results of a randomized controlled double-blind controlled comparison of intramuscular olanzapine and
trial. Dement Geriatr Cogn Disord 2006; 21:1–8. intramuscular haloperidol in the treatment of acute
Wagner KD. Major depression and anxiety disorders associated agitation in schizophrenia. Am J Psychiatry 2001;
with Norplant. J Clin Psychiatry 1996; 57:152–7. 158:1149–51.
p 06.qxd 3/10/08 9:34 AM Page 237
References 237
Wroblewski BA, Joseph AB, Kupfer J et al. Effectiveness of valproic Zeidler M, Stewart GE, Barraclough CR et al. New variant
acid on destructive and aggressive behaviors in patients with Creutzfeldt–Jakob disease: neurological features and
acquired brain injury. Brain Inj 1997; 11:37–47. diagnostic tests. Lancet 1997b; 350:903–7.
Wysowski DK, Pitts M, Beiz J. Depression and suicide in patients Zhong KX, Tariot PN, Mintzer J et al. Quetiapine to treat agitation
treated with isotretinoin. N Engl J Med 2001; 344:460. in dementia: a randomized, double-blind, placebo-controlled
Yalom ID, Lunde DT, Moos RH et al. ‘Postpartum blues’ syndrome: study. Curr Alzheimer Res 2007; 4:81–93.
a description and related variables. Arch Gen Psychiatry 1968; Zimbroff DL, Marcus RN, Manos G et al. Management of acute
18:16–27. agitation in patients with bipolar disorder: efficacy and safety
Zeidler M, Johnstone EC, Bamber RWK et al. New variant of intramuscular aripiprazole. J Clin Psychopharmacol 2007;
Creutzfeldt–Jakob disease: psychiatric features. Lancet 1997a; 27:171–6.
350:908–10.
p 07.qxd 3/10/08 9:35 AM Page 238
7
Other major syndromes
7.1 Psychosis 238 7.6 Acute encephalitis 294

7.2 Personality change 244 7.7 Somatoform disorders 296
7.3 Seizures and epilepsy 249 7.8 Malingering and factitious illness 302
7.4 Stroke 275 References 303
7.1 PSYCHOSIS the most frequent. Next are the toxic psychoses, for example
those seen with stimulants such as amphetamine or
The term psychosis has been used differently by different cocaine. Endocrinologic psychoses, such as the ‘myxedema
authors, and this has led to some confusion in the litera- madness’ of hypothyroidism, are considered next, fol-
ture. In this text, psychosis refers to a condition character- lowed by various intracranial disorders capable of causing
ized by hallucinations (without insight) and/or delusions, psychosis, such as stroke or tumors. Consideration is then
in the absence of either significant cognitive deficits or pro- given to the various epileptic psychoses and then to
nounced disturbances of mood. encephalitic and post-encephalitic psychoses. Finally, there is
a miscellaneous group, including the ‘megaloblastic mad-
ness’ that may be seen with vitamin B12 deficiency.
Clinical features
Delusions and hallucinations are discussed at length in IDIOPATHIC DISORDERS

Section 4.30, and readers unfamiliar with these are encour-
aged to consult that chapter. Although in most cases of psy- Schizophrenia is by far the most common cause of chronic
chosis both delusions and hallucinations are present, psychosis. The onset typically occurs in the late teens or early
exceptions do occur; thus in some disorders, for example twenties with the subacute or gradual elaboration of a psy-
delusional disorder, one may find only delusions, whereas in chosis characterized by varying combinations of hallucina-
the psychosis caused by levodopa in patients with parkinso- tions, delusions, incoherence, and bizarre behavior. In many
nian conditions one may find only hallucinations. Critically, cases, the symptomatology will crystallize into an enduring
as discussed in Section 4.30, in cases characterized by only and recognizable subtype: paranoid, hebephrenic, catatonic,
hallucinations the diagnosis of psychosis should be reserved or simple (Fenton and McGlashen 1991; Kendler et al.
for situations wherein insight is absent and patients react to 1994). Although the symptoms gradually wax and wane
their hallucinations as if they were real. over time, the illness is generally chronic and lifelong, prob-
Depending on the cause of the psychosis, other symp- ably never going into a spontaneous and full remission.
toms may also be present; however, the part they play in the Schizoaffective disorder is, like schizophrenia, charac-
overall clinical picture is relatively minor compared with the terized by a chronic psychosis: the difference is that in
delusions and hallucinations. Thus there may be some inco- schizoaffective disorder one also finds recurrent episodes
herence, minor mood changes, anxiety, or even agitation. of either depression or mania, during either of which the
chronically present psychotic symptoms undergo a signifi-
cant exacerbation.
Etiology Delusional disorder, also like schizophrenia, is charac-
terized by a chronic psychosis: here, however, hallucina-
The various causes of psychosis are listed in Table 7.1, in tions, incoherence, and bizarre behavior are negligible or
which they are divided into several groups. The first group, absent, with the primary or sole symptom of the illness
composed of idiopathic disorders, constitutes by far the most being one or more delusions. Importantly, these delusions
common causes of psychosis and of these schizophrenia is are not bizarre but indeed have a certain plausibility to
p 07.qxd 3/10/08 9:35 AM Page 239
7.1 Psychosis 239
Table 7.1 Causes of psychosis
Idiopathic disorders Tumors

Schizophrenia Frontal lobe
Schizoaffective disorder Corpus callosum
Delusional disorder Temporal lobe
Post-partum psychosis Multiple sclerosis
Obsessive–compulsive disorder Traumatic brain injury
Body dysmorphic disorder Heredodegenerative disorders:
Borderline personality disorder Huntington’s disease
Dentatorubropallidoluysian atrophy
Toxic psychoses
Spinocerebellar ataxia
Amphetamine
Wilson’s disease
Cocaine
Miscellaneous
Hallucinogens
Phencyclidine
Fatal familial insomnia
Cannabis
Fahr’s syndrome
Anabolic steroids
Aqueductal stenosis
Chronic alcoholism (alcoholic paranoia, alcoholic
hallucinosis) Epileptic psychoses
Neuroleptic-induced supersensitivity psychosis (‘tardive Ictal psychosis
psychosis’) Post-ictal psychosis
Dopaminergics (levodopa, bromocriptine, lergotrile, Chronic interictal psychosis
pramipexole) Psychosis of forced normalization
Levetiracetam
Topiramate Encephalitic and post-encephalitic psychoses
Vigabatrin Encephalitic
Phenylpropanolamine Herpes simplex encephalitis
Phenylephrine Infectious mononucleosis
Bupropion Encephalitis lethargica
Fluoxetine Post encephalitic
Disulfiram Herpes simplex encephalitis
Methysergide Encephalitis lethargica
Manganese intoxication
Miscellaneous
Baclofen withdrawal
Vitamin B12 deficiency
Endocrinologic psychoses Neurosyphilis
Hypothyroidism AIDS
Hyperthyroidism Systemic lupus erythematosus
Cushing’s syndrome Sydenham’s chorea
Adrenocortical insufficiency Chorea gravidarum
Hepatic porphyria
Intracranial disorders Metachromatic leukodystrophy
Stroke Velocardiofacial syndrome
Temporal lobe Vanishing white matter leukoencephalopathy
Frontal lobe Subacute sclerosing panencephalitis
Thalamus Prader–Willi syndrome
them (Kendler 1980; Opjordsmoen and Rettersol 1991; by prominent agitation (Bagedahl-Strindlund 1986).
Winokur 1977). Certain variants of this disorder deserve Importantly, it is not uncommon for certain disorders,
special mention: parasittosis is characterized by a persist- such as schizophrenia, to undergo an exacerbation post-
ent belief that one is infested by some parasitic bug or other partum, and such patients should not receive an additional
(Andrews et al. 1986; Mitchell 1989) and the olfactory ref- diagnosis of post-partum psychosis.
erence syndrome by a delusion that one is emitting a foul The following disorders, namely obsessive–compulsive
odor (e.g., as in halitosis or flatus) that others detect and disorder, body dysmorphic disorder, and borderline per-
comment on (Videbech 1966). sonality disorder, although generally not associated with
Post-partum psychosis may appear between several days delusions and hallucinations, may at times cause these
and several months post-partum and is often characterized symptoms and hence are included here.
p 07.qxd 3/10/08 9:35 AM Page 240
240 Other major syndromes
Both obsessive–compulsive disorder (Eisen and The appearance of a psychosis in a ‘bulked-up’ young per-
Rasmussen 1993; Gordon 1950; Insel and Akiskal 1986) son should suggest this diagnosis.
and body dysmorphic disorder (McElroy et al. 1993) may Chronic alcoholism may be complicated by two differ-
have psychotic subtypes wherein patients ‘lose insight’ and ent psychoses: alcoholic paranoia and alcohol hallucinosis.
come to accept their troubling ideas as true. Thus, a patient Alcoholic paranoia (Albert et al. 1996; Soyka et al. 1991) is
with obsessive–compulsive disorder might come to believe characterized by the gradual development of delusions,
that his troubling need to pray recurrently was, in fact, often of either jealousy or persecution. By contrast, alcohol
ordained by God (Gordon 1950) or a patient with body hallucinosis typically appears as a sequela to an alcohol
dysmorphic disorder may come to believe that his or her withdrawal delirium: whereas the other symptoms of the
face was, in fact, deformed. delirium tremens (DTs), such as tremor, clear, the audi-
Patients with a borderline personality disorder may, tory hallucinations, often accompanied by delusions of
when under great stress, develop transient auditory hallu- persecution, persist (Soyka 1990; Victor and Hope 1958).
cinations or delusions of persecution (Chopra and Beatson Antipsychotic-induced supersensitivity psychosis appears
1986): such patients are distinguished by the chronic char- in a very small minority of patients treated with antipsy-
acteristic traits of intolerance of being alone, anger, impul- chotics for a year or more and is characterized by delusions
sivity, and disturbed relationships (Gunderson and Kolb and hallucinations, which may appear either while the
1978). patient is still taking the neuroleptic or shortly after discon-
tinuation or a significant dose reduction (Chouinard and
TOXIC PSYCHOSES Jones 1980; Steiner et al. 1990). This psychosis probably has
an etiology similar to that of tardive dyskinesia and hence is
Amphetamines, if taken in a sufficiently high dose, may often referred to as ‘tardive psychosis’; like tardive dyskinesia,
cause a psychosis (Bell 1973; Griffith et al. 1972) that is typ- it exists as a strong reminder not to use antipsychotics chron-
ically characterized by delusions of persecution and often ically unless they are absolutely necessary.
of reference. Hallucinations may also occur, being much Dopaminergic drugs, such as levodopa or direct-acting
more commonly auditory than visual. The psychosis typi- agents, for example bromocriptine, ropinirole, or pram-
cally clears within a week, but in some cases longer dura- ipexole, as used in the treatment of parkinsonism, may cause
tions of up to 3 months have been reported (Iwanami et al. a psychosis. In the case of levodopa (Celesia and Barr 1970;
1994). Fenelon et al. 2000; Moskovitz et al. 1978), the psychosis
Cocaine may cause a psychosis characterized by halluci- may occur either upon the initiation of treatment (Lin and
nations, more often auditory than visual, and delusions of Ziegler 1976) or, much more commonly, after 3–4 years
persecution and reference (Brady et al. 1991; Satel et al. (Friedman and Sienkiewicz 1991). This levodopa-induced
1991; Sherer et al. 1988). Although such a psychosis may psychosis may be characterized by hallucinations, often
occur in ‘recreational’ users (Siegel 1978), it is more char- visual but also auditory (Fenelon et al. 2000; Inzelberg et al.
acteristic of addicts, who often note that a progressively 1998), and, in a minority, delusions of persecution (Graham
lower ‘dose’ becomes capable of inducing the psychosis et al. 1997). In the overwhelming majority of cases, patients
(Brady et al. 1991). Although, in most cases, the psychosis first experience hallucinations with preserved insight: how-
clears either with the intoxication itself or shortly there- ever, over many months insight is gradually lost, thus pro-
after, it may persist in some until after the withdrawal ducing the syndrome of psychosis (Barnes and David 2001;
‘crash’ resolves (Satel et al. 1991). Goetz et al. 2006). Direct-acting dopaminergic drugs may
Hallucinogens, such as LSD, typically cause visual hallu- also cause psychosis but this is much less common than with
cinations, but most patients remain aware of their unreality. levodopa: bromocriptine, lergotrile (Serby et al. 1978), and
In a minority, however, the intoxication will be complicated pramipexole (Almeida and Ranjith 2006) have all been
by delusions of persecution (Bercel et al. 1956; Kuramochi implicated.
and Takahashi 1964). The remaining drugs in the list only rarely cause psy-
Phencyclidine intoxication may render patients agitated chosis. These include the anti-epileptic drugs levetiracetam
and psychotic (Allen and Young 1978), with delusions of (Mula et al. 2003), topiramate (Kober and Gabbard 2005),
grandeur or persecution and auditory hallucinations. The vigabatrin (Sander et al. 1991) (in the case of levetiracetam
finding of nystagmus is a very important diagnostic clue. the onset may, as with the others, occur soon after starting
Cannabis intoxication, if a sufficiently high dose is the drug, or may be delayed for up to 3–9 months [Kossoff
taken, may be characterized by fearfulness and delusions of et al. 2001; Motamedi et al. 2003]), the sympathomimetics
persecution and reference (Kroll 1975; Thacore and Shukla phenylpropanolamine and ephedrine (Lambert 1987), the
1976) that may outlast the intoxication itself by a matter antidepressants bupropion (Golden et al. 1985) and fluox-
of days. etine (Mandalos and Szarek 1990), and disulfiram
Anabolic steroids, as may be abused by athletes, may, in (Bicknell and Moore 1960) and methysergide (Cittandi
a small minority, cause a psychosis variously characterized and Goadsby 2005).
by delusions of persecution or grandeur, delusions of refer- A toxic psychosis may also occur with chronic man-
ence, and auditory hallucinations (Pope and Katz 1988). ganese exposure. This ‘manganese madness’ may present
p 07.qxd 3/10/08 9:35 AM Page 241
7.1 Psychosis 241
with a combination of parkinsonism, excitation, delusions, Stroke

and hallucinations (Abd El Naby and Hassanein 1965). Stroke may be characterized by the fairly sudden onset of
Finally, note should also be made of a psychosis associ- psychosis: this has been noted with infarction of the tempo-
ated with baclofen. Here, the psychosis occurs not during ral lobe (Peroutka et al. 1982); in one case (Thompson and
use of the drug but rather as a withdrawal phenomenon Nielsen 1949), the patient, a 58-year-old man, suddenly
after chronic use. Here, about a week after discontinua- began to hear ‘unusual noises which he believed were
tion, one may see a psychosis with agitation, delusions of caused by wires placed in his house’, and soon after, ‘while
persecution, and hallucinations (Swigar and Bowers 1986), in a restaurant, he suddenly declared that someone had put
which, in one case, was accompanied by a complex move- ground glass into his food. He then ran out of the restaurant
ment disorder, with chorea, tremor, and dystonia being into the street, shouting that his son-in-law had been killed
evident (Kirubakaren et al. 1984). after having been held captive by a gang of criminals’.
Frontal lobe involvement may also be found: in one case of
ENDOCRINOLOGIC PSYCHOSES a ruptured frontal lobe aneurysm, a 23-year-old woman
presented acutely with auditory hallucinations, delusions of
Hypothyroidism may present with psychosis in a condition persecution, and loosening of associations (Hall and Young
known as ‘myxedema madness’, typically characterized by 1992). Finally, thalamic infarction involving the right dorso-
delusions of persecution and reference and by hallucina- medial area was, in one case (Feinberg and Rapcsak 1989),
tions, generally auditory (Asher 1949). The delusions of per- associated with vivid visual hallucinations; indeed, the
secution may at times be so compelling that patients become patient ‘reached down to pat the dog’ that he had halluci-
assaultive (Reed and Bland 1977); in other cases, patients nated at his side.
may be reduced to a seclusive ‘mumbling’ (Karnosh and
Stout 1935). Pertinent clues to the correct diagnosis include Tumors
slowness and a certain ‘fogginess’ of thought, cold intoler- Tumors may present with psychosis, as has been noted with
ance, deepening of the voice, constipation, hair loss, and tumors of the frontal lobe (Strauss and Keschner 1935), cor-
myxedema of the face, supraclavicular fossae, and dorsa of pus callosum (Murthy et al. 1997), and especially the tempo-
the hands and feet. ral lobe (Gal 1958; Keschner et al. 1936; Malamud 1967;
Hyperthyroidism may be accompanied by a psychosis, Strobos 1953; Tucker et al. 1986). In contrast with stroke,
with prominent delusions of persecution: in one case, the the onset here is typically subacute or gradual.
hyperthyroid patient slashed his throat rather than let his
‘persecutors’ capture him (Ingham and Nielsen 1931). Multiple sclerosis
When the psychosis occurs in the setting of ‘thyroid storm’ Multiple sclerosis may cause psychosis (Geocaris 1957;
(Bursten 1961; Greer and Parsons 1968), the prominent Langworthy et al. 1941; Mathews 1979), generally in the
autonomic signs (increased temperature, tachycardia, and company of signs suggestive of disseminated lesions (e.g.,
tremor) immediately suggest the diagnosis; however, when concurrent with nystagmus [Parker 1956]). Rarely, multiple
the responsible hyperthyroidism is milder, the diagnosis sclerosis may present with a psychosis, as in one patient who
may be elusive (Hodgson et al. 1992). developed ‘mystic’ hallucinations and religious delusions,
Cushing’s syndrome may be characterized by a who eventually was found to have compatible lesions on
psychosis, the diagnosis being suggested by the typical magnetic resonance (MR) scanning (Fontaine et al. 1994).
cushingoid habitus of moon facies, truncal obesity, buffalo
hump, violaceous abdominal striae, and so on. One patient Traumatic brain injury
had classic Schneiderian first rank symptoms, including
audible thoughts, thought broadcasting, and thought TBI may also be followed by psychosis (Buckley et al. 1993;
insertion (Trethowan and Cobb 1952), whereas another Hillbom 1951; Nasrallah et al. 1981), and in some cases
presented with auditory hallucinations and delusions of a there may be a long delay, even up to years, between the
grandiose and religious nature (Hertz et al. 1955). injury and the onset of the psychosis (Fujii and Ahmed
Adrenocortical insufficiency is suggested by abdominal 2002; Sachdev et al. 2001).
complaints (nausea, vomiting, diarrhea or constipation,
and abdominal pain) and orthostatic hypotension with Heredodegenerative disorders
postural dizziness. A psychosis may rarely also be seen Of the heredodegenerative disorders capable of causing
(Cleghorn 1951; McFarland 1963). psychosis, Huntington’s disease is the classic example;
others include dentatorubropallidoluysian atrophy, spino-
INTRACRANIAL DISORDERS cerebellar ataxia, and Wilson’s disease. Of note each of
these is also characterized, at some point, by abnormal
The various intracranial disorders capable of causing psy- movements.
chosis include stroke, tumors, multiple sclerosis, traumatic Huntington’s disease is not uncommonly characterized
brain injury (TBI), various heredodegenerative disorders, by a combination of chorea and psychosis (Bolt 1970; Garron
such as Huntington’s disease, and a miscellaneous group. 1973; Heathfield 1967) and, albeit rarely, the disease may
p 07.qxd 3/10/08 9:35 AM Page 242
present with a psychosis (Caine and Shoulson 1983; are delusions and hallucinations (Ellis and Lee 1978; Wells
Garron 1973; James et al. 1969): in such cases, the correct 1975): the diagnosis is suggested by the paroxysmal onset
diagnosis may be suggested by a positive family history and of the psychosis and its relative brevity.
confirmed by genetic testing. Post-ictal psychosis (Briellman et al. 2000; Kanner et al.
Dentatorubropallidoluysian atrophy, another autoso- 1996; Lancman et al. 1994; Leutmezer et al. 2003; Logsdail
mal dominant disorder, may also present with psychosis, and Toone 1988; Nishida et al. 2006; Savard et al. 1991;
accompanied by ataxia and seizures (Adachi et al. 2001). Umbricht et al. 1995) may follow a bout of seizures and, crit-
Spinocerebellar ataxia, also an autosomal dominant dis- ically, is separated from the last seizure by a ‘lucid’ interval,
order characterized by ataxia, may also cause a psychosis lasting from hours to days, during which the patient’s men-
with delusions of persecution (Chandler and Bebin 1956). tal status is ‘clear’. The psychosis itself is characterized by
In one family (Benton et al. 1998), the disorder presented delusions of persecution and hallucinations, most com-
with auditory hallucinations and delusions, eventually monly auditory, and may last for hours or months, although
being joined by abnormal movements. most patients clear spontaneously within a matter of days.
Finally, Wilson’s disease must be considered in young Most patients have a long history of recurrent complex par-
adults with psychosis and a movement disorder (Beard tial seizures.
1959; Gysin and Cooke 1950; Jackson and Zimmerman Chronic interictal psychosis may occur in the setting of
1919). It must also be kept in mind that, albeit rarely, the ini- chronic epilepsy, generally of over a decade in duration.
tial presentation of Wilson’s disease may be with a psychosis, Either insidiously or subacutely, patients develop a psy-
with a movement disorder appearing only much later, as chosis with delusions, often of persecution and reference,
indeed was the case with one of Wilson’s first patients auditory hallucinations and various other symptoms, all of
(Wilson 1912). which occur in the setting of a clear sensorium (Fluger
et al. 2006; Kristensen and Sindrup 1979; Perez and
Miscellaneous Trimble 1980; Slater and Beard 1963a,b).
Of the miscellaneous disorders capable of causing psychosis, Of note post-ictal psychosis and chronic interictal psy-
consideration may first be given to Creutzfeldt–Jakob dis- chosis may exist in the same patient, and in such cases
ease (Brown et al. 1984; Dervaux et al. 2004; Zeng et al. 2001) either the chronic interictal psychosis or post-ictal psy-
(especially the new-variant type [Zeidler et al. 1997a]), choses may appear first (Adachi et al. 2003).
which may present with psychosis, with the diagnosis finally Psychosis of forced normalization is a rare condition,
being suggested by the appearance of myoclonus or a first described by Landolt (1953, 1958) and characterized
dementia. Fatal familial insomnia, a rare inherited prion dis- by the appearance of a psychosis after anti-epileptic drugs
ease, in one case also presented with a psychosis, accompa- (Pakainis et al. 1987) or, in one case, vagus nerve stimula-
nied, true to the name of the disease, by severe insomnia tion (Gatzonis et al. 2000), have controlled the seizure dis-
(Dimitri et al. 2006). order and ‘normalized’ the electroencephalogram (EEG).
Fahr’s syndrome, suggested by extensive calcification of
the basal ganglia, may rarely present with psychosis, as in ENCEPHALITIC AND POST-ENCEPHALITIC
one familial case wherein the illness was manifest symptom- PSYCHOSES
atically with basal ganglia calcification on imaging and a
chronic psychosis (Francis and Freeman 1984). Psychosis may either be directly caused by a viral encephali-
Aqueductal stenosis, one of the causes of non- tis or occur as a sequela.
communicating hydrocephalus, has also been associated Viral encephalitis is suggested by fever, headache, and
with a psychosis (Roberts et al. 1983). lethargy, and may in some cases present with psychosis, as has
been noted with herpes simplex encephalitis (Drachman and
EPILEPTIC PSYCHOSES Adams 1962; Johnson et al. 1972; Williams and Lerner 1978;
Wilson 1976) and infectious mononucleosis (Raymond and
The various psychoses seen in epileptics may be distin- Williams 1948). Encephalitis lethargica may present similarly
guished by their relationship to the seizures experienced by (Kirby and Davis 1921; Meninger 1926; Sands 1928) and is
the patient. Ictal psychoses are in fact seizures and are suggested by sleep reversal and oculomotor pareses.
immediately suggested by their paroxysmal onset. Post-ictal Viral encephalitis may also leave a psychosis in its wake,
psychoses, as the name suggests, follow seizures and, criti- and such postencephalitic psychoses have been noted as
cally, are separated from the last seizure by a ‘lucid’ interval. sequelae to herpes simplex encephalitis (Rennick et al.
The psychosis of forced normalization represents a para- 1973) and encephalitis lethargica (Fairweather 1947).
doxical event in that it appears when the patient’s seizures
are finally brought under control with anti-epileptic treat- MISCELLANEOUS
ment. Finally, chronic interictal psychosis occurs in the set-
ting of a chronically uncontrolled seizure disorder. A large number of miscellaneous causes of psychosis also
Ictal psychosis consists of a complex partial seizure exists, first among which is ‘megaloblastic madness’ due to
wherein, in addition to some defect of consciousness, there vitamin B12 deficiency, with this colorful name being
p 07.qxd 3/10/08 9:35 AM Page 243
7.1 Psychosis 243
derived from the associated megaloblastic anemia. It must be suggested by the characteristic dysmorphic facies with
be borne in mind, however, that this anemia may not be hypertelorism, a bulbous nose, and micrognathia.
present: in one case, the diagnosis became clear only when Vanishing white matter leukoencephalopathy is an
symptoms of subacute combined degeneration appeared autosomal recessively inherited disorder, which, in adults,
(Smith 1929), and in another, the only evidence of vitamin may present with a psychosis very similar to that seen in
B12 deficiency was the psychosis itself: there was no ane- schizophrenia (Denier et al. 2007): the diagnosis may be
mia and no evidence of spinal cord involvement (Evans suggested by evidence of bilateral corticospinal tract dam-
et al. 1983). age, and confirmed by finding extensive white matter dis-
Neurosyphilis rarely presents with a psychosis (Rothschild ease in the cerebral hemispheres.
1940; Schube 1934), and the diagnosis may remain elusive Subacute sclerosing panencephalitis, a vanishingly rare
until other, more typical symptoms appear, such as a demen- disease in developed countries thanks to measles vaccina-
tia, pupillary changes (e.g., Argyll Robertson pupil), tremor, tion, may cause psychosis and myoclonus (Cape et al.
or seizures. 1973; Salib 1988) or may present with a psychosis, the diag-
Acquired immunodeficiency syndrome (AIDS) may nosis only becoming clear with the later appearance of a
cause a psychosis (Bulrich et al. 1988; Harris et al. 1991), delirium (Duncalf et al. 1989; Koehler and Jakumeit 1976).
and the presence of other AIDS-related illnesses, such as Prader–Willi syndrome, a rare disorder characterized by
thrush or Pneumocystis pneumonia may serve to suggest massive obesity and dysmorphic facies, may rarely cause a
the correct diagnosis. Rarely, AIDS may present with psy- psychosis with delusions and hallucinations (Clarke 1993).
chosis (Thomas and Szabadi 1987), and in such cases the
diagnosis may prove elusive until other, more typical, fea-
tures of AIDS make their appearance. Differential diagnosis
Systemic lupus erythematosus may also cause psychosis
(Brey et al. 2002; Devinsky et al. 1988a; Johnson and Delusions and hallucinations may be found in a number of
Richardson 1968; Lim et al. 1988; Miguel et al. 1994) and other syndromes, namely dementia, delirium, depression,
although this usually occurs in the context of other symp- and mania, and thus the first task is to determine if one of
toms, such as arthralgia, rash, pericarditis, or pleurisy, psy- these syndromes is present, and, if so, to then pursue the
chosis may rarely constitute the presenting feature of lupus differential for that syndrome, as discussed in the respec-
(Agius et al. 1997). tive chapters.
Sydenham’s chorea may rarely be complicated by a psy- Dementia and delirium are both marked by significant
chosis with hallucinations and delusions (Hammes 1922; cognitive deficits, such as decreased short-term memory and
Putzel 1879): the diagnosis is immediately suggested by disorientation, and, in the case of delirium, confusion.
the context of subacutely developing chorea in a child or Delusions and hallucinations are quite common in both
adolescent. syndromes, and in some instances, for example diffuse Lewy
Chorea gravidarum, Latin for ‘chorea of pregnant women’, body disease, they may constitute a diagnostic hallmark.
may, rarely, be accompanied by psychosis (Beresford and Both depression and mania, when they are severe, may
Graham 1950; Wilson and Preece 1932). The diagnosis should be characterized by delusions or hallucinations; however, in
be suspected in pregnant women with psychosis, chorea, and a both these instances the delusions or hallucinations occur
history of Sydenham’s chorea. within the context of the mood syndrome, and, upon get-
Hepatic porphyria typically presents in attacks accom- ting a reliable history, one always finds, prior to the onset of
panied by abdominal pain, often with vomiting and consti- the delusions or hallucinations, a prominent and progres-
pation or, less commonly, diarrhea. Rarely, such patients sively worsening depressive or manic syndrome.
may also have a psychosis (Mandoki and Sumner 1994), Finally, simulated psychoses, as seen in malingering,
which, in one case, was accompanied by bizarre behavior factitious illness, and folie à deux must be distinguished
(Hirsch and Dunsworth 1955). from ‘true’ psychoses. Malingerers may simulate a psy-
Metachromatic leukodystrophy, although rare, is of par- chosis in order to avoid unpleasant consequences, as may
ticular interest in that it can cause a psychosis that very occur in prisoners facing trial (Tsoi 1973). Factitious psy-
closely resembles that caused by schizophrenia (Hyde et al. chosis is said to occur when the simulation has the purpose
1992; Muller et al. 1969). Indeed, in some cases, it was not of simply being a patient in the hospital (Pope et al. 1982).
initially possible to distinguish between the two disorders Folie à deux is said to occur when a person with a true psy-
until other symptoms suggestive of metachromatic leuko- chosis, usually paranoid schizophrenia, exerts such a pro-
dystrophy, as for example a peripheral neuropathy found influence on close relatives or acquaintances that
(Manowitz et al. 1978) or a dementia (Betts et al. 1968a; they come to adopt the patient’s own delusional beliefs as
Rauschka et al. 2006; Waltz et al. 1987) developed years later. true. Importantly, in such cases, if the ‘truly’ psychotic per-
Velocardiofacial syndrome has also attracted great inter- son is successfully treated or if a prolonged separation is
est, as it too can cause a psychosis symptomatically quite enforced, the others gradually come to see the falseness of
similar to that caused by schizophrenia (Gothelf et al. 2007; their beliefs (Dewhurst and Todd 1956; Kashiwase and
Ivanov et al. 2003; Murphy et al. 1999). The diagnosis may Kato 1997; Partridge 1950; Waltzer 1963).
p 07.qxd 3/10/08 9:35 AM Page 244
Treatment Disinhibited patients seem to lose regard for customs or

morals: they may eat with gluttony, curse with no regard for
Treatment is directed at the underlying cause; in cases company, and tell coarse and crude jokes. Inappropriate
when that is ineffective or where symptomatic treatment is sexual advances are not uncommon, and patients may, with
required, an antipsychotic is indicated. In general, second- no hint of shame, proposition much younger individuals,
generation antipsychotics are more effective and better even at times children. Some may engage in reckless mas-
tolerated than first-generation agents and, of the second- turbation, at the dinner table or in the front yard.
generation agents, risperidone, olanzapine, or quetiapine Affective changes may have some lateralizing value:
are reasonable choices. In general, and especially in the euphoria is seen more often with right-sided lesions and
elderly or medically frail, or patients with hepatic failure, it depressed mood with left-sided lesions. The euphoria may
is appropriate to ‘start low and go slow’ with regard to ini- occasionally be accompanied by witzelsucht, or a tendency
tial dose and subsequent titrations. In the case of levodopa- to make simple, silly puns.
induced psychosis wherein dose reduction is often not Perseveration is characterized by a tendency to repeat
feasible, good success has been had with clozapine, in the same behavior over and over: examples include repeat-
low doses of 6.25–25 mg/day. In cases where emergent edly uttering the same phrase, opening and closing a book,
treatment is required, one may proceed as described in or buttoning and unbuttoning a shirt.
Section 6.4. Apathy is characterized by a lack of motivation. Although
patients may experience some urges or consider some
actions, their plans, if they occur at all, often come, as it
were, stillborn, and, lacking in motivation, apathetic patients
7.2 PERSONALITY CHANGE
may either never come to the point of action or, if they do
get started, soon find themselves indifferent, after which
Every individual has a definite personality structure,
they give up.
which, once formed in childhood and adolescence, persists
These clinical features often, but not always, coalesce
in a lifelong fashion, being very resistant to any modifica-
into one of two subtypes, namely the orbitofrontal and
tion. Thus, the appearance of a fundamental change in per-
dorsolateral frontal lobe syndromes: the orbitofrontal sub-
sonality, that is to say a far-reaching transformation of the
type is characterized by disinhibition and affective changes
patient’s characteristic personality traits, is an ominous
(often either euphoria or irritability) and the dorsolateral
clinical sign and demands prompt diagnostic evaluation.
type by perseveration and apathy.
The frontal lobe syndrome is also often accompanied by
what is known as the ‘dysexecutive syndrome’, which repre-
Clinical features sents, as one might expect from the name, a disturbance in
‘executive’ abilities. Thus, patients with these executive
The personality change may be non-specific and character- deficits have difficulty in the following areas: formulating and
ized either by a marked exaggeration of pre-existing per- setting goals, developing plans to meet these goals, initiating
sonality traits or by the emergence of altogether new traits, planned behavior, and, lastly, monitoring and correcting
previously foreign to the patient. For example, a character- activity when it gets ‘off course’. Patients with these executive
istically financially prudent person may become stingy to deficits may not come to attention until they are faced with
the point of miserliness. In another example, a previously new, and relatively complex, situations. Thus, patients whose
outgoing and generous person may gradually become lives are passed in fixed routines, where habit rules the day,
withdrawn and miserly; or, conversely, a premorbidly shy may have little difficulty. However, if faced with an unaccus-
and timid person may become freer in personal contacts tomed task, as for example planning a formal dinner or
and even outgoing. In addition to this non-specific person- developing a financial plan, they may find themselves unable
ality change there are also two specific types of personality to successfully complete the work in front of them.
change, namely the frontal lobe syndrome and the inter- Some examples may help to fix the picture of the frontal
ictal personality syndrome, both discussed below. lobe syndrome. The classic case is that of Phineas Gage
Regardless, however, of which kind of personality change (Neylan 1999), who manifested disinhibition and irritabil-
occurs, those around the patient often make comments ity. As reported by his physician (Harlow 1848), on
such as ‘he’s not himself anymore’, and indeed it may be 3 September 1848, while Gage was tamping down an
this realization that leads family members to bring the explosive charge with a special ‘tamping iron’, the charge
patient to medical attention. exploded, blowing the iron rod back up and through his
skull, causing extensive frontal lobe damage. Prior to the
FRONTAL LOBE SYNDROME injury, Gage had been a foreman, capable, well balanced,
and an exemplary worker. Twenty years later, however,
The frontal lobe syndrome is characterized by varying Harlow (1868) found him to be ‘irreverent, indulging at
combinations of disinhibition, affective change (euphoria, times in the grossest profanity (which was not previously
irritability, or depressed mood), perseveration, and apathy. his custom), manifesting but little deference for his
p 07.qxd 3/10/08 9:35 AM Page 245
fellows, impatient of restraint or advice when it conflicts impression of many is that it does occur and that it may have
with his desires . . . In this regard his mind was so radically a profound effect on patients’ lives.
changed . . . that his friends and acquaintances said he was The outstanding characteristic of this syndrome is a
“no longer Gage.” ’ trait known variously as ‘viscosity’, ‘adhesiveness’ or ‘stick-
Mulder et al. (1951) reported another case marked by iness’ (Waxman and Geschwind 1975). In this, patients
disinhibition and irritability. The patient’s wife com- seem unable to break away from a train of thought or a cer-
plained that the patient: tain emotion, thoughts and feelings plodding on and
adhering to one another in a sort of viscous mass. Bleuler
no longer cared about his appearance, that he drove (1924), writing of epileptics in the early part of the twenti-
through red lights, threw bills in the wastebasket eth century, asserted that:
remarking they were ‘only bills’, and frequently
threatened to harm his family. He spilled his food on the most conspicuous anomaly concerns the
his clothing and on the floor, and to his family’s affectivity, which reacts to a morbid degree, and at
dismay, he then picked it up and ate it. He did not the same time shows the peculiarity, that an existing
wait for food to be served, but would snatch it off affect lasts a long time and is difficult to divert by
platters with his fingers as his wife neared the table. new impressions; it is not merely irritability that
His sexual activity became uninhibited, and he shows itself in this manner but the other affects, as
sought intercourse with neighborhood children and attachments, or joy, all take the same course . . . In
prostitutes with no concern for possible speaking and writing we have the same peculiarities:
consequences. the patient does not get anywhere with his talking,
not only because of its slowness, but especially
Another case (Moersch 1925) was marked by persever- because of its circumstantiality, which must depict
ation and apathy. The patient, a 54-year-old man was: all trivialities in repetition and in manifold
expression of the same idea in different forms.
brought to the clinic . . . Because of loss of bladder Besides this the manner of speaking is verbose and
and rectal control, and lack of interest. The patient clumsy, and always vague. (Italics in original.)
himself made no complaint. About three months
before, a gradually increasing mental change had Bear et al. (1982), in addition to this viscosity of thought
been observed. The patient lost his ambition and and emotion, also emphasized an ‘interpersonal adhesive-
interest in work, although he had continued at his ness’ manifest in ‘interpersonal clinging’ and a ‘tendency
trade of carpentry until two weeks before. He had to draw out interpersonal encounters’. In some cases,
become careless in his work, would forget what he patients, on shaking hands while saying goodbye to the
was doing, and seemed little concerned about his physician, will simply continue to ‘hang on’, requiring the
short-comings. For two weeks before his physician to extricate him or herself.
examination he had been content to sit aimlessly at The viscosity of thought may have a written expression
home, or to play with his children. He voided at any in hypergraphia, wherein patients may write voluminous
time and even defecated in his clothes . . . During amounts, far and above what is required for any social or
general examination, the patient was indifferent and professional purposes (Hermann et al. 1988), often writing
aimless, would sit and look at a newspaper, which about philosophic or religious concerns (Waxman and
might be upside down. He was oriented in all Geschwind 1974).
spheres, and his attention might be held for a few In addition to viscosity, patients also tend to be preoc-
moments when aroused. He would follow his son cupied with religious, ethical, or philosophical concerns
about in a fairly good-natured manner, but always and to experience hyposexuality.
object to being examined, saying that he was not Religiosity is, according to Maudsley (1874) ‘often very
sick. He showed considerable perseveration, notable in epileptics’ and Kraepelin (1902), writing in the
repeating movements at times for long periods. For early part of the twentieth century, noted that ‘the religious
example, one evening he sat before a wash bowl for content of [epileptic’s] thought is another striking symp-
over a half hour, turning the faucets on and off. tom, many patients spending a large part of their time in
reading the Bible or praying aloud’. Bear et al. (1982) noted
INTERICTAL PERSONALITY SYNDROME the ‘nascent metaphysical or cosmological preoccupations’
of patients.
The interictal personality syndrome, also known as the Hyposexuality manifests primarily as a loss of libido
Geschwind syndrome, is said to appear insidiously in epilep- (Blumer 1970; Blumer and Walker 1967).
tics after years of uncontrolled complex partial seizures. It As noted earlier, the interictal personality syndrome is a
should be emphasized that this is a controversial entity and controversial entity. Early attempts to validate it (Bear
that it has not as yet been possible to prove conclusively that 1979; Bear and Fedio 1977) made use of a complex rating
such a specific syndrome exists. Nevertheless, the clinical instrument, and subsequent attempts to replicate these
p 07.qxd 3/10/08 9:35 AM Page 246
Table 7.2 Criteria for the diagnosis of the interictal personality Table 7.3 Causes of non-specific personality change
syndrome (all five elements, A–E, must be present)
Subacute or gradual onset
A The patient’s behavior represents an enduring change in Neurodegenerative disorders
personality. Frontotemporal dementia (Seeley et al. 2005)
B The disorder occurs after 3 or more years of repeated Pick’s disease (Mendez et al. 1993)
complex partial seizures. Alzheimer’s disease (Mendez et al. 1993)
C The patient displays viscosity, as manifested by one or Huntington’s disease (Pflanz et al. 1991)
more of: deep and persistent affects; verbose, overly Wilson’s disease (Bridgman and Smyth 1944; Dening and
detailed, and circumstantial speech; or hypergraphia. Berrios 1989; Starosta-Rubinstein et al. 1987; Walshe and
D The patient displays either a preoccupation with religious, Yealland 1992)
ethical ,or philosophical concerns, or hyposexuality. Metachromatic leukodystrophy (Finelli 1985; Hageman
E There are no delusions or hallucinations. et al. 1995)
Adrenoleukodystrophy (Schaumburg et al. 1975)
Tumors
Temporal lobe (Keschner et al. 1936; Strobos 1953)
earlier findings met with no success (Mungas 1982, 1983; Thalamus (Partlow et al. 1992)
Nielsen and Kristensen 1981; Rodin and Schmaltz 1984) or Hypothalamus (Alpers 1937)
only partial success (Bear et al. 1982; Hermann and Reil Other
1981). Provisionally, as I have discussed elsewhere (Moore Normal pressure hydrocephalus (Rice and Gendelman 1973)
1997), the diagnosis should probably be reserved for cases Chronic subdural hematoma (Cameron 1978)
meeting the criteria listed in Table 7.2. Neurosyphilis (Storm-Mathisen 1969)
Vitamin B12 deficiency (Lindenbaum et al. 1988)
Limbic encephalitis (Alamowitch et al. 1997)
Etiology Creutzfeldt–Jakob disease (Brown et al. 1994; Roos et al.
1973; Zeidler et al. 1997a,b)
The etiologies of the various types of personality change, Mercury intoxication (O’Carroll et al. 1995)
namely the non-specific type, the frontal lobe syndrome Manganese intoxication (Abd El Naby and Hassanein 1965)
and the interictal personality syndrome, differ, and hence Acute onset
each is discussed separately. As may be seen, however, in Stroke (Stone et al. 2004)
regard to the non-specific type and the frontal lobe syn-
drome, the most common causes are neurodegenerative Miscellaneous
disorders (e.g., frontotemporal dementia), tumors, and Traumatic brain injury (Brooks et al. 1986; Thomsen 1984)
stroke. Post-viral encephalitis (McGrath et al. 1997)
NON-SPECIFIC PERSONALITY CHANGE

in a similar fashion. Alzheimer’s disease may present with a
The various causes of non-specific personality change are very non-specific personality change. Huntington’s dis-
listed in Table 7.3, which divides them into three groups. ease, rarely, may present with personality change; however,
The first group contains those disorders capable of causing the eventual appearance of chorea will indicate the correct
a personality change of subacute or gradual onset, such as diagnosis. Wilson’s disease may also present with a person-
neurodegenerative disorders, tumors, and others (e.g., ality change; however, in this case the development of var-
normal pressure hydrocephalus). The next group recog- ious abnormal movements will also eventually suggest the
nizes personality change of acute onset, as may occur after diagnosis. It is of interest that Wilson’s first case (Wilson
stroke. Finally, there is a miscellaneous group of disorders, 1912), a 25-year-old woman, presented with a personality
including, notably, TBI. change wherein she became ‘restless, unable to settle to
anything, easily provoked to laughter, constantly smiling
Subacute or gradual onset and unnaturally cheerful’. Metachromatic leukodystrophy
Of the neurodegenerative disorders that may present and adrenoleukodystrophy are two rare disorders that may
with a personality change, perhaps the most important is present with a personality change in adolescence or early
frontotemporal dementia. Frontotemporal dementia occurs adult years.
in two variants, namely the ‘temporal variant’ and the Tumors productive of a non-specific personality change
‘frontal variant’. The frontal variant is discussed below, are most often found in the temporal lobe; rarely a similar
under the frontal lobe syndrome. In the ‘temporal variant’, presentation may occur with tumors of the thalamus or
one may see either a Kluver–Bucy syndrome (as discussed in hypothalamus.
Section 4.12), or a personality change marked by hoarding or The other causes of non-specific personality change are
stereotyped, ritualistic behavior. Pick’s disease may present relatively uncommon. Normal pressure hydrocephalus may
p 07.qxd 3/10/08 9:35 AM Page 247
be suggested by incontinence and a ‘magnetic’ gait. Patients Table 7.4 Causes of the frontal lobe syndrome
with a chronic subdural hematoma may or may not recall any
Subacute or gradual onset
head trauma. Tertiary neurosyphilis may present solely with a
Neurodegenerative disorders
personality change, and the diagnosis may only be suspected
Frontotemporal dementia (Brun et al. 1994; Heutink et al.
when the fluorescent treponemal antibody (FTA) test comes
1997; Neary et al. 1993)
back positive. Vitamin B12 deficiency, likewise, may also pres-
Pick’s disease (Bouton 1940; Litvan et al. 1997; Mendez et al.
ent with a personality change, which may or may not be
1993)
accompanied by a macrocytosis or a peripheral neuropathy.
Alzheimer’s disease (Mega et al. 1996; Petry et al. 1988)
Both limbic encephalitis and Creutzfeldt–Jakob disease (espe-
Amyotrophic lateral sclerosis (Massman et al. 1996)
cially the new-variant type) may present with a subacute per-
Corticobasal ganglionic degeneration (Bergeron et al. 1996)
sonality change; however, in both cases cognitive changes,
Progressive supranuclear palsy (Verny et al. 1996)
either delirium or dementia, supervene fairly quickly.
Multiple system atrophy (olivopontocerebellar type) (Critchley
Mercury intoxication with either elemental mercury (as may
and Greenfield 1948)
occur in factories making thermometers [Vroom and Greer
Spinocerebellar ataxia (Zeman et al. 2004)
1972]) or organic mercury may cause a personality change
Metachromatic leukodystrophy (Rauschka et al. 2006)
known as erethism, with prominent timidity and irritability,
Tumors
often accompanied by tremulousness. Manganism, as may be
Frontal lobe (Avery 1971; Frazier 1936; Hunter et al. 1968;
seen in manganese miners, may present with a personality
Strauss and Keschner 1935; Williamson 1896)
change marked by asthenia, fatigue, irritability, emotional
Corpus callosum (Alpers and Grant 1931; Beling and Martland
lability, and a peculiar unmotivated laughter. One author
1919; Moersch 1925)
(Charles 1927), in commenting on the laughter, noted that
‘excessive smiling without any adequate cause is very com- Acute onset
mon, and the patient, if asked any simple question, will not Stroke
infrequently burst out into hilarious laughter’; parkinsonism, Frontal lobe (Logue et al. 1968)
if not already present, generally supervenes. Caudate nucleus (Mendez et al. 1989; Petty et al. 1996)
Thalamus (Sandson et al. 1991)
Acute onset Mesencephalon (Adair et al. 1996)
Stroke may be followed by a non-specific personality Miscellaneous

change of relatively acute onset, and this may occur with Traumatic brain injury (Oder et al. 1992; Roberts 1976)
both cortical and subcortical infarcts. By and large, Gunshot wounds (Lishman 1973)
patients become irritable, easily frustrated and overall less Multiple sclerosis (Blinkenberg et al. 1996)
easy going. Post-viral encephalitis (Friedman and Allen 1969; Mulder et al.
1951)
Miscellaneous
Both TBI and viral encephalitis (e.g., herpes simplex viral
encephalitis) may have personality change as a sequela, and
in the case of TBI, this may be the most disabling sequela.
years. Alzheimer’s disease may also present with a frontal
lobe syndrome but this is often accompanied early on by
the classic short-term memory loss. Amyotrophic lateral
FRONTAL LOBE SYNDROME sclerosis (ALS) typically, of course, presents with upper and
As noted in Table 7.4, the various causes may be divided lower motor neuron signs, and in about one-tenth of such
into those that produce a frontal lobe syndrome of sub- typical cases a frontal lobe syndrome will eventually follow;
acute or gradual onset, as may be seen with various neu- importantly, albeit rarely, ALS may also present with a
rodegenerative disorders (e.g., frontotemporal dementia), frontal lobe syndrome (Cavalleri and De Renzi 1994; Neary
tumors that produce a frontal lobe syndrome of acute et al. 1990; Peavy et al. 1992). The other neurodegenerative
onset, as may be seen in stroke, and a miscellaneous group, disorders in the list, relative to the foregoing, only rarely
for example TBI. cause the syndrome. Corticobasal ganglionic degeneration
and progressive supranuclear palsy both cause parkinson-
ism and dementia, and the dementia may be accompanied
Subacute or gradual onset by a frontal lobe syndrome. Multiple system atrophy (of the
Of the neurodegenerative disorders capable of producing a olivopontocerebellar type) and spinocerebellar ataxia are
frontal lobe syndrome, the two most important are fronto- both characterized by ataxia and both, rarely, may cause the
temporal dementia and Pick’s disease, both of which may frontal lobe syndrome. Finally, consideration may be given
present with a frontal lobe syndrome, with the advent of to the very rare late-onset form of metachromatic leukody-
significant cognitive deficits being delayed for months to strophy that may present with a frontal lobe syndrome in
p 07.qxd 3/10/08 9:35 AM Page 248
early adult years and which is eventually superseded by a right caudate nucleus (Degos et al. 1993), and the left thala-
dementia. mus (Sandson et al. 1991; Smyth and Stern 1938).
As might be expected, tumors capable of causing the
frontal lobe syndrome are found typically in the frontal
lobes. Anteriorly placed tumors of the corpus callosum INTERICTAL PERSONALITY SYNDROME
may also cause the syndrome; however, it is suspected that
in these cases the syndrome does not occur as a result of If indeed the interictal personality syndrome does exist as a
damage to the corpus callosum but rather to lateral exten- discrete entity, it may then represent a ‘functional hyper-
sion of the tumor into the adjacent medial aspects of the connection’ (Bear 1979; Bear and Fedio 1977) in the limbic
frontal lobes. system, which may in turn occur secondary to the ‘kin-
dling’ effect of frequently repeated seizures (Adamec and
Stark-Adamec 1983).
Acute onset
When the frontal lobe syndrome appears acutely, stroke
should immediately be suspected. Thus, the syndrome may Differential diagnosis
appear after infarction of the frontal lobe (as seen not
uncommonly after subarachnoid hemorrhage [Alexander Personality change must be distinguished from a personal-
and Freedman 1984; Greene et al. 1995]). In addition, ity disorder. Personality disorders, for example borderline
lacunar infarctions of the caudate nucleus, thalamus personality disorder or antisocial personality disorder, do
and, rarely, the mesencephalon, may also produce the syn- not represent a change in the patient’s personality make-
drome. up, but rather have been present, at least in a nascent form,
since childhood or adolescence. Rather than replacing a
pre-existing personality structure, the personality disorder
Miscellaneous just does, in fact, constitute the patient’s lifelong personal-
TBI may leave a frontal lobe syndrome in its wake, often ity. Thus, in the history of an adult patient with a personal-
marked by disinhibition and irritability; indeed such a per- ity disorder, one finds that the various personality traits
sonality change may represent one of the most disabling may be traced back into the patient’s adolescence or child-
sequelae of severe TBI (Thomsen 1984). Gunshot wounds hood in a seamless and continuous fashion: by contrast, in
to the frontal areas may also, as might be expected, create a patient with a personality change, one finds a more or less
the syndrome. In one such case, the substitution of the distinct boundary in the history that separates the patient’s
euphoria of the frontal lobe syndrome for the depression original personality from that which currently exists.
that prompted the suicidal gunshot actually constituted an Relatives and friends may indicate such a change by saying
improvement (Lebensohn 1941). that the patient is ‘not himself’ any more.
Finally, the syndrome may occur secondary to appro- Dementia may be accompanied by an exaggeration of
priately situated plaques in multiple sclerosis and as a pre-existing personality traits, or by the emergence of
sequela to a viral encephalitis. new ones; however, the accompanying cognitive deficits
indicate dementia as the primary syndrome, and the differ-
ential should then be pursued as discussed in Section 5.1.
Comments on the localizing and lateralizing value of Importantly, certain dementing disorders, as noted above,
the frontal lobe syndrome may present not with cognitive deficits but with a person-
The frontal lobe exists in a ‘circuit’ involving the frontal ality change, and the diagnosis may be elusive until, with
cortex, the caudate nucleus, the lenticular nucleus, and the further progression, cognitive deficits make their appear-
thalamus, which eventually sends fibers back to the frontal ance. This is particularly the case, as noted above, with
cortex. The frontal lobe syndrome, in general, localizes to some of the neurodegenerative disorders, most particularly
this circuit, and may be seen with lesions of the frontal lobe frontotemporal dementia.
(Frazier 1936; Williamson 1896), caudate nucleus (Mendez Many psychoses also are accompanied by an alteration
et al. 1989; Petty et al. 1996; Richfield et al. 1987), globus in the sufferer’s personality, this being particularly true of
pallidus (Strub 1989), and thalamus (Sandson et al. 1991; schizophrenia. The psychoses, however, are marked by
Smyth and Stern 1938). The ventral tegmental area of the delusions or hallucinations – symptoms that are not seen
mesencephalon also projects to the frontal cortex and, as in personality change – and their presence should prompt
noted above, infarction of the mesencephalon may also the clinician to refer to the differential diagnosis for psy-
cause the syndrome (Adair et al. 1996). chosis, as discussed in Section 7.1.
The syndrome may not have much lateralizing value: Mood syndromes, namely mania and depression, may
although in most cases, the lesions are bilateral, unilateral suggest the frontal lobe syndrome. The euphoria seen in
lesions may also cause the syndrome, this having been noted mania may, superficially, appear similar to the euphoria
with lesions of either the right or left frontal lobe (Frazier seen in some cases of the frontal lobe syndrome; however,
1936; Strauss and Keschner 1935; Williamson 1896), the there are some clear differences. The euphoria of mania is
p 07.qxd 3/10/08 9:35 AM Page 249
heightened, full, and quite infectious, and this is in marked Table 7.5 Types of seizures
contrast with the shallow, silly euphoria of the frontal lobe Simple partial
syndrome, which lacks any infectiousness. Furthermore, in Complex partial (also known as psychomotor)
mania one also sees pressured speech, increased energy, Petit mal (also known as absence)
decreased need for sleep and hyperactivity – symptoms Grand mal (also known as generalized tonic–clonic)
lacking in the frontal lobe syndrome. A depressed mood Atonic (also known as astatic seizures or ‘drop attacks’)
may suggest the syndrome of depression; however, in the Amnestic
frontal lobe syndrome one does not see the characteristic Reflex
vegetative symptoms of the depressive syndrome, such as Status epilepticus
changes in sleep or appetite, anergia, or anhedonia.
With regard to the interictal personality syndrome, one
must keep in mind that slowly growing tumors in the tem-
poral lobe may present with epilepsy, followed, years later,
by a personality change caused by the tumor itself. Thus, electrical discharge within the cerebral grey matter.
the appearance of a personality change in an epileptic Although, as detailed below, the actual symptomatology
should prompt consideration of an MR scan. seen during a seizure and the cause of the responsible elec-
Finally, there are two syndromes, namely the environ- trical discharge are both extraordinarily varied, the essen-
mental dependency syndrome (also known as ‘utilization tial formal characteristic of the seizure, namely its
behavior’) and the Kluver–Bucy syndrome, which are con- ‘paroxysmal-ness’, remains. The term ‘epilepsy’ is gener-
sidered by some to be personality changes: to me, however, ally reserved for cases in which there has been more than
they are so dissimilar from any conceivable personality trait one seizure and the cause of the seizures is such that one
or type that they are discussed elsewhere, respectively in may reasonably expect that the patient, in the absence of
Sections 4.11 and 4.12. In the environmental dependency definitive treatment, will continue to have seizures. Thus,
syndrome patients appear to lose their autonomy and whereas it might not be proper to consider a patient who
become, as it were, ‘dependent’ on the environment such has only had but one seizure, and that during an episode of
that they feel compelled to make use of whatever comes to severe hypoglycemia, to have epilepsy, it would be appro-
their attention. Thus, if a pen and a piece of paper came to priate in the case of a patient with recurrent seizures and
the patient’s attention, he would feel compelled to pick them mesial temporal sclerosis.
up and write, even although such activity was inappropriate
to the ongoing situation. The Kluver–Bucy syndrome, in
humans, typically manifests with the traits of hyperorality Clinical features
and hypersexuality. In hyperorality, patients put things into
their mouths, whether edible or not, and thus may end up The classification of the various seizure types has changed
eating Styrofoam cups or drinking urine from urinals. over time, as evidenced by the evolution of criteria set forth
Hypersexuality may manifest with public masturbation or by the International League Against Epilepsy (ILAE) in
sexual activity with others, regardless of their gender. 1964 (Gastaut et al. 1964), 1970 (Gastaut 1970), 1981
(Commission of Classification and Terminology 1981),
and 1989 (Commission of Classification and Terminology
Treatment 1989). The 1981 ILAE criteria have proved the most endur-
ing for clinical practice and, with some modification, are
If possible, treatment is directed at the underlying cause. adhered to in this text.
Most patients require some form of supervision, and in The various seizure types are listed in Table 7.5. In dif-
some cases admission to a secure facility may be necessary. ferentiating among these types, the first step is to deter-
Regarding pharmacologic treatment, with the exception of mine the patient’s state of consciousness during the
utilizing carbamazepine for the disinhibition of the frontal seizure. If consciousness remains clear, that is to say the
lobe syndrome (Foster et al. 1989), little is known. In prac- patient remains alert, with intact memory, and without
tice, antipsychotics (e.g., quetiapine) are also used for dis- any clouding or confusion, a simple partial seizure is pres-
inhibition, and antidepressants (e.g., a selective serotonin ent. If, however, consciousness is in some fashion
reuptake inhibitor, SSRI) or anxiolytics (e.g., lorazepam or impaired, but not entirely lost, either a complex partial or
clonazepam) are given when depressed mood or anxiety a petit mal seizure is present. The distinction between
are prominent. complex partial and petit mal seizures, as elaborated fur-
ther in the text, is based on the overall nature of the seizure:
complex partial seizures are often preceded by an aura, last
7.3 SEIZURES AND EPILEPSY several minutes, and are typically followed by some post-
ictal confusion; whereas petit mal seizures occur without an
A seizure, or ictus, is paroxysmal in onset, generally brief in aura, are very brief – lasting only seconds – and terminate
duration, and occurs secondary to an equally paroxysmal abruptly, without any post-ictal confusion. If consciousness
p 07.qxd 3/10/08 9:35 AM Page 250
is entirely lost, one is typically dealing with a grand mal simple partial seizures with psychic symptoms. Furthermore,
seizure, with its accompanying tonic–clonic activity. there is a group, not specified in the ILAE criteria, of miscel-
Atonic seizures may or may not be accompanied by an laneous simple partial seizures.
impairment or loss of consciousness but they are always
characterized by an abrupt loss of muscle tone with, in
most cases, a resulting fall. Amnestic seizures are unusual Simple partial seizures with motor signs
in that they are characterized solely by a paroxysmal amne- These seizures are most commonly characterized by uni-
sia in a clear consciousness. Reflex seizures are said to be lateral clonic or tonic activity, or a combination of the two,
present when any of the foregoing types occurs on a ‘reflex- such motor activity being seen most frequently in the
ive’ basis, being provoked by some specific stimulus, such hand, arm, or face and somewhat less so in the lower
as hearing music or reading. Finally, each of the foregoing extremity (Russell and Whitty 1953). Jacksonian seizures
seizure types may also occur over a prolonged time, in represent a variety of simple partial seizure in which there
which case status epilepticus is said to be present. is a ‘march’ of the ictal symptomatology from one part of
Although any given patient with epilepsy may experi- the body to another. Such marches may begin variously in
ence but one type of seizure during the entire course of the the hands or the fingers, proceed proximally to the face,
illness, the history more often than not reveals different and then march inferiorly; less commonly, they begin in
seizure types at disparate times. Thus, the course of the lower extremity. In most cases, the march is completed
epilepsy may be marked by varying combinations of simple within a matter of minutes (Penfield and Jasper 1954;
partial, complex partial, and grand mal seizures (Devinsky Russell and Whitty 1953). ‘Versive’ seizures represent a
et al. 1988; Golub et al. 1951; Mauguire and Courjon 1978; variety of motor simple partial seizure wherein there is a
Sperling et al. 1989); furthermore, patients with petit mal ‘forced’ tonic version of the head, and sometimes the
epilepsy often also experience grand mal seizures trunk, to one side or the other (Mauguire and Courjon
(Livingston et al. 1965; Sato et al. 1976). Of interest, among 1978; Russell and Whitty 1953). Motor aphasia may be
adults, partial seizures (either simple or complex) are more seen in what the ILAE calls a ‘phonatory’ seizure. Such a
common than grand mal seizures (Gastaut et al. 1975; motor aphasia may constitute the sole manifestation of the
Kotsopoulos et al. 2002). seizure (Labar et al. 1992) or may be accompanied by
Importantly, in many cases, a given ictal event or seizure motor activity on the face. In one case (Williamson et al.
may in fact represent an amalgamation of two different 1985a), the seizure began with right-sided facial twitching
seizure types, the first merging seamlessly into the following followed by muteness: although the patient could follow
one. Thus, a simple partial seizure may immediately pre- commands and was still able to communicate by writing,
cede a complex partial seizure (Bare et al. 1994; Sperling she was unable, much to her distress, to speak. In another
et al. 1989) or, in other cases, a simple partial seizure may case (Walshe 1943), the seizure began with muteness and
precede a grand mal seizure (Mauguire and Courjon 1978; was ‘followed by the advance of the tongue to the line of
Theodore et al. 1994). In such cases, it is customary no the teeth and the utterance of a rapid series of “D” sounds
longer to refer to the ictal event that occurred in clear con- (D-D-D-D-D-D). The throat then “constricts”, the mouth
sciousness as a simple partial seizure but rather to speak of is drawn to the right and finally the head and eyes turn in a
it as an ‘aura’ to the following seizure type. Furthermore, series of jerks to the right’.
complex partial seizures may also transform without inter- Rarely, simple partial seizures with motor signs may be
ruption into grand mal seizures (Theodore et al. 1994; characterized by bilateral motor activity (Kanner et al. 1990;
Tinuper et al. 1996a), and in such cases one speaks of the Tachibana et al. 1996). Such seizures often lead to diagnos-
complex partial seizure undergoing ‘secondary generaliza- tic uncertainty as they ‘break the rule’ that bilateral epilep-
tion’ into a grand mal seizure. tic motor activity is always accompanied by some
Each of the various seizure types noted in Table 7.5 is impairment of consciousness (Morris et al. 1988). In one
now considered in detail. case (Tukel and Jasper 1952): ‘seizures began with a stiffness
in the right arm and leg. The patient then stared and the
right arm raised to the level of the chest. This was followed
SIMPLE PARTIAL SEIZURES by the extension of both arms. There was then adversive
movement of the head and eyes to the right and vocaliza-
Simple partial seizures usually last of the order of a minute or tion. The patient remained conscious throughout . . . she
two, uncommonly extending for up to 5 minutes, and excep- heard herself vocalize but could not speak’.
tionally persevering for as long as 15 minutes (Devinsky et al. Although the motor behavior in these seizures may be
1988b; Mauguire and Courjon 1978). Following the 1981 simple, as in the foregoing example, or perhaps involve
ILAE criteria, they may be subdivided according to their pre- non-directed thrashing (Salanova et al. 1995), it may at
dominant symptomatology into the following subtypes: sim- times be fairly complex (Chassagnon et al. 2003). In one
ple partial seizures with motor signs, simple partial seizures case (Weinberger 1973), the patient’s ‘head and neck
with somatosensory or special sensory symptoms, simple turned to the right. Both arms moved to the right and
partial seizures with autonomic symptoms or signs, and turned rhythmically on their axis at the wrist in a fashion
p 07.qxd 3/10/08 9:35 AM Page 251
best described as turning two door knobs, but in opposite patients (Holmes 1927) had simple partial seizures that
directions’: although the patient ‘was aware of what was ‘commenced with the appearance of several small spheres,
happening to her, and could understand what people were white in the center with an intermediate zone of blue and
saying . . . she could only utter a phrase such as “uh-uh- outside this a ring of red . . . [which] moved either at a uni-
uh” ’. Although in almost all cases such simple partial form rate or in jerks to the left and downwards’.
seizures with bilateral motor signs arise from seizure foci in Hemianopia or blindness may also occur on an ictal basis
the supplemental motor area on the medial aspect of the (Barry et al. 1985; Russell and Whitty 1955). Ictal auditory
frontal lobe, exceptions do occur, as in a case where the hallucinations may consist of such phenomena as buzzing
focus was in the parietal lobe (Bell et al. 1997). or ringing noises (Mauguire and Courjon 1978). Ictal
Inhibitory motor simple partial seizures represent a olfactory hallucinations (Mauguire and Courjon 1978)
kind of ‘inverse’ motor seizure, wherein, rather than seeing tend to be unpleasant, such as the smell of something rot-
tonic or clonic muscle contraction, there is a paroxysmal ten or burning: one of Jackson’s patients (Jackson and
paresis or paralysis. The hand, arm, or leg may be involved Beevor 1890) had ‘a very nasty smell – “burning dirty
(Noachtar and Luders 1999; Russell and Whitty 1953; stuff” ’. Ictal gustatory hallucinations tend likewise to be
Villani et al. 2006), and in some cases hemiparesis may unpleasant, the taste being described as foul or metallic.
result (Globus et al. 1982; Hanson and Chodos 1978). The Ictal vertigo may be characterized either by mere giddiness
spread of epileptic electrical activity from the precentral or by a classic sense of rotation (Kluge et al. 2000; Russell
gyrus to nearby areas may sometimes produce a more and Whitty 1953).
complex picture: in one case, a patient experienced not
only ictal paresis of the right upper extremity, but also an
associated motor aphasia (Lee and Lerner 1990). Simple partial seizures with autonomic
symptoms or signs
Ictal autonomic phenomena include an ill-defined ‘rising’
Simple partial seizures with somatosensory or special epigastric sensation, vomiting (Mitchell et al. 1983; Shukla
sensory symptoms and Mishra 1985), or diarrhea with abdominal cramping
Seizures with somatosensory symptoms are characterized (Zarling 1984).
by generally unilateral paresthesiae, numbness, pain, or a
sensation of warmth or coldness. The hands and fingers are
most frequently affected, followed by the face, foot, or Simple partial seizures with psychic symptoms
entire upper or lower extremity (Mauguire and Courjon These seizures may consist of a variety of experiences: ‘dysm-
1978). Ictal pain may be either diffuse (Wilkinson 1973) or nesic’ phenomena (e.g., déjà vu); ‘cognitive’ disturbances
localized (Young and Blume 1983, 1986) (as for example such as depersonalization; affective experiences such as fear;
with muscle cramping in one extremity [Balkan 1995]) and illusions such as macropsia; and complex, ‘structured’ hallu-
may be quite severe (Russell and Whitty 1953). Although cinations in either the auditory or the visual realms.
the vast majority of somatosensory seizures are unilateral, Dysmnesic phenomena represent a disturbance in the
involving only one side of the body, there may rarely be sense of familiarity, and include déjà vu, jamais vu, déjà
bilateral involvement, for example simultaneous par- entendu and jamais entendu. In déjà vu, patients have the
esthesiae of both hands (Blume et al. 1992). uncanny sense that they have already seen or experienced
Somatosensory simple partial seizures may also undergo something that they are in fact encountering for the first
a Jacksonian ‘march’ (Lende and Popp 1976; Sittig 1925). time; in jamais vu, the opposite phenomenon occurs in
These somatosensory Jacksonian marches tend to follow the that patients, although in the presence of something they
same distribution as motor marches, most often beginning ‘intellectually’ know they have experienced before, yet have
in the hand or fingers (Mauguire and Courjon 1978), but the sense that it is entirely new. Déjà entendu and jamais
they are, unlike motor marches, generally quite rapid, com- entendu represent analagous experiences concerning not
pleting their trek in a matter of seconds (Russell and Whitty sight but hearing. A related phenomenon is the experience
1953). One may at times encounter a kind of ‘mixed’ march of prescience, wherein the seizure is characterize by a sense
with both somatosensory and motor components; interest- that the patient ‘knew’ beforehand what was going to hap-
ingly, in such cases, one almost always finds the sensory pen (Sadler and Rahey 2004).
component appearing first, followed by the motor one Cognitive disturbances most commonly involve deper-
(Penfield and Jasper 1954; Russell and Whitty 1953, Villani sonalization. One of Wilson’s patients (Wilson 1930)
et al. 2006). noted that it was ‘as if my mind were looking at myself
Seizures with special sensory symptoms present with from afar’. In another case (Daly 1958), the patient, while
simple visual, auditory, olfactory, or gustatory hallucina- ‘dissociated from his body’ had the classic sense that he
tions and, at times, with vertigo. Ictal visual hallucinations ‘was looking down on the scene’. In other cases, the cogni-
may consist of such crude phenomena as ‘weaving pat- tive distortion may be difficult to categorize: one of
terns, zigzag lights, showers of sparks or coloured clouds’ Wilson’s (1930) patients described her seizure as an expe-
(Russell and Whitty 1955). One of William Gower’s rience wherein ‘her “thoughts just stopped” ’.
p 07.qxd 3/10/08 9:35 AM Page 252
Affective experiences may include anxiety, depression also reappear in the patient’s dreams (Reami et al. 1991).
or, rarely, euphoria. Anxiety and fear have been frequently Although, in most cases, these complex visual hallucina-
noted (Kennedy 1911; Macrae 1954a,b; Weil 1959; tions occur in only one hemifield, they may at times spread
Williams 1956) and may be quite severe, progressing to a to appear in the entire visual field (Russell and Whitty
full anxiety attack (Alemayehu et al. 1995). In one case, the 1955). Palinopsia may also occur, and one patient’s seizures
seizures were characterized by anxiety, palpitations, dizzi- were characterized by seeing ‘non-existent pedestrians in an
ness, and pallor (Rush et al. 1977), and in another the empty street, having seen these people minutes before in
patient was ‘afraid, perspired and did not want to be left different surroundings’ (Muller et al. 1995). Autoscopy
alone’ (McLachlan and Blume 1980). As might be may occur, in which patients hallucinate an image of them-
expected, some patients may become agoraphobic on the selves (Brugger et al. 1994; Devinsky et al. 1989a). Auditory
basis of such ictal anxiety attacks: one patient, whose ictal structured hallucinations may consist of voices or music:
anxiety attacks lasted of the order of a minute, ‘went to the one patient heard the same song, repeated over and over
emergency room’, and, fearful ‘she could have spells while again (Wieser 1980).
driving, at work, or in social situations . . . confined herself
to home’ (Weilburg et al. 1987). Ictal depressions ‘are char-
Miscellaneous simple partial seizures
acterized by rather sudden let-down of mood and psy-
chomotor retardation . . . from simple listlessness and Various other signs and symptoms may occur on an ictal
apathy to agitated depression with suicidal attempts’ (Weil basis, including prosopagnosia (Agnetti et al. 1978), aso-
1959). One patient’s ictal depressions were ushered in by matognosia (Russell and Whitty 1955; So and Scauble
olfactory hallucinations, like ‘stuffed cabbage in a dirty 2004), and a combination of expressive aprosodia and
outhouse’, and could last for hours, during which the amusia (Bautista and Ciampetti 2003).
patient ‘felt paralyzed inside and couldn’t follow through Other miscellaneous types of simple partial seizures
an act’ (Weil 1955). Euphoria may occur (Williams 1956) include unexplained urges, sexual experiences, involuntary
but in one case was followed, after 10–20 seconds, by an laughing or crying, forced thoughts and, rarely, delusions.
intense depression (Mulder and Daly 1952). In another Inexplicable urges have included impulses to laugh
case (Dewhurst and Beard 1970) the patient had, rather (Sturm et al. 2000) or to run (Strauss 1960).
than simple euphoria, a complex and ecstatic religious Sexual experiences include strong sexual arousal (Erickson
experience: ‘he had a vision in which he was in the cockpit 1945) or orgasm (Reading and Will 1997; Ruff 1980).
of an aeroplane . . . the aircraft gained altitude and brought Seizures characterized by involuntary laughing (‘gelas-
him to a different land, a land of peace. He had no cares tic’ seizures) or crying (‘dacrystic’ seizures) differ from
and no burdens. He felt that the power of God was upon those characterized by ictal emotion (e.g., anxiety or
him and changing him for the better’. The experience was depression, as noted earlier) in that these patients,
so powerful that the patient later converted from Judaism although laughing or crying, do not experience any associ-
to Pentecostalism. ated mirth or sadness. One patient happened to see herself
Illusions may include macropsia, wherein objects in the mirror in the midst of a gelastic seizure and ‘was
appear larger than they are, micropsia, wherein they puzzled by the discrepancy between her facial expression
appear smaller, and various illusory movements of objects and her feelings’ (Arroyo et al. 1993); in another case, the
(Heilman and Howell 1980; Russell and Whitty 1955). smile accompanying the laughter reminded observers of a
Also possible are hyperacusis or hypoacusis, wherein ‘ “toothpaste advertisement” smile’ (Lehtinen and Kivalo
sounds appear louder or fainter, respectively, than they in 1965). Dacrystic seizures manifest with a sad facial expres-
fact are. The supernumerary limb experience may also be sion and tears (Luciano et al. 1993; Marchini et al. 1994), in
included here: one patient had such a strong ictal sense that one case capping off a sensory march that began in the left
his arm was raised above his head that he asked his wife leg, ascended to the left shoulder and was then succeeded
to pull it down even though he acknowledged that he by weeping (Efron 1961).
could in fact see his actual arm at his side (Russell and Forced thoughts may occur and are quite similar to
Whitty 1953). obsessions (Mendez et al. 1996).
Structured hallucinations are characterized by complex Delusions noted during simple partial seizures include
visual or auditory experiences. One of Russell and Whitty’s the Capgras phenomenon (delusion of doubles) (Kanemoto
(1955) patients, wounded in the right occipital area, saw 1997) and a Schneiderian first rank symptom, namely a con-
‘stretcher bearers walking past and then the figures of viction on the patient’s part ‘that his body is being con-
nurses whom he could recognize’, all in the left hemifield; trolled by external forces’ (Mesulam 1981).
another, wounded in the right occipitoparietal area, ‘felt
that as if he was in a dream he was back in Khartoum dur- COMPLEX PARTIAL SEIZURES
ing the war. He saw and recognized friends around him’. In
another case (Sowa and Pituck 1989) the patient saw the Complex partial seizures (Delgado-Escueta et al. 1982;
‘right side of people’s faces missing’ and ‘water coming out Escueta et al. 1977; Golub et al. 1951; Holmes 1984;
of a clock’. Of interest, such ictal visual hallucinations may Theodore et al. 1983) generally last of the order of one to
p 07.qxd 3/10/08 9:35 AM Page 253
several minutes and may or may not be preceded by an of consciousness and automatisms. The patient was in the
aura. The seizure proper is characterized, in all cases, by physician’s office when the seizure occurred. He:
some ‘impairment’ of consciousness, ranging in severity
from the slightest degree of confusion to a more or less suddenly stopped talking, looked off into space,
profound stupor. staring. He slumped down in his chair for a brief
Although, in some cases, the seizure manifests with this moment, then sat up and began to rub his abdomen
impairment of consciousness alone, one will in most cases with both hands. A flashlight was shined into his
also see a ‘motionless stare’ and/or automatisms. The eyes and he turned away. He began to rummage
‘motionless stare’ is characterized by the abrupt appear- about the desk as if looking for something. When
ance of a vacant stare and a complete arrest of all behavior, questioned as to what he wanted, he said, ‘I wanna, I
leaving the patient quite still and unmoving. This stare wanna.’ At this point he took a cigarette from his
occupies only a portion of the seizure itself, and is typically pocket, lit it and started to smoke. He then got up
either followed or, in some cases, preceded, by automa- from his chair, walked out of the office, wandered
tisms. Automatisms range in complexity from such simple, down the hall opening all the doors saying ‘I want a
stereotyped behavior as lip-smacking or chewing to highly toilet.’ Next he walked down the hall, but could not
complex activity, which is, to a greater or lesser degree, be distracted by any outside contact. He then lay
‘reactive’ to the environment. Such reactive automatisms down on the bed and appeared to regain contact
may consist of a more or less faithful continuation of pre- gradually.
ictal behavior or may represent behavior, which, although
still reactive to the environment, represents a break with
the patient’s pre-ictal behavior. Aurae
After the seizure ends, most patients will display a degree As noted earlier, aurae are merely simple partial seizures that
of post-ictal confusion, lasting from one to several minutes, happen to evolve into complex partial seizures: they thus
after which they gradually recover. Patients are subse- include all of the forms of simple partial seizure noted
quently totally, or sometimes only partially, amnestic for above. Several studies (Boon et al. 1991; Gupta et al. 1983;
the events that occurred during the seizure. Kanemoto and Janz 1989; Sperling et al. 1989) provide a
Before discussing in detail the individual clinical aspects rough estimate of the frequency with which various aurae
of complex partial seizures (i.e., aura, impairment of con- are found: the most common is a rising epigastric sensation;
sciousness, motionless stare, and automatisms), some next come dysmnesic symptoms (déjà vu or jamais vu),
descriptions of more or less typical cases are provided to affective symptoms (fear, anxiety, and depression), sensory
give an overall sense of what a complex partial seizure symptoms (visual, tactile, gustatory, olfactory, or auditory
comprises. The first to be considered is Hughlings hallucinations), vertigo, and nausea. Least common are illu-
Jackson’s famous patient, considered by many to be the sions (macropsia, micropsia, hyperacusis, and hypoacusis)
‘paradigm of temporal lobe epilepsy’ (Taylor and Marsh and various unclassified symptoms such as thirst or simply
1980), whom Jackson referred to as ‘Dr Z’ (Jackson 1889; an ‘indescribable’ sensation. In some cases, the aura may be
Jackson and Colman 1898). Dr Z’s first complex partial a combination of two or more symptoms: in an early report,
seizure was preceded by an aura of déjà vu, which was then Anderson (1886) noted an aura compounded of auditory
followed by an impairment of consciousness. In Dr Z’s and visual hallucinations and déjà vu, and Hughlings
own words: Jackson (Jackson and Stewart 1899) noted a combination of
an olfactory hallucination with déjà vu. Although aurae are
I was waiting at the foot of a college staircase, in the typically remembered, amnesia for the aura may be found in
open air, for a friend who was coming down to join approximately one-fourth of all patients upon recovering
me. I was carelessly looking round me, watching from a complex partial seizure (Schulz et al. 1995).
people passing, etc., when my attention was
suddenly absorbed in my own mental state, of which
I know no more than that it seemed to me to be a Impairment of consciousness
vivid and unexpected ‘recollection’; – of what, I do An impairment of consciousness (or, as it is sometimes
not know. My friend found me a minute or two later, referred to, a defect of consciousness) of one sort or
leaning my back against the wall, looking rather another, is present in all cases. As noted by Hughlings
pale, and feeling puzzled and stupid for the moment. Jackson (Taylor 1931), this impairment may involve ‘all
In another minute or two I felt quite normal again, degrees of obscuration of consciousness’, from a profound
and was as much amused as my friend at finding clouding of the sensorium to the slightest trace of confu-
that I could give no distinct account of what had sion or inattention. Indeed, determining the presence of an
happened . . . impairment of consciousness may in some cases be diffi-
cult: Murray Falconer (1954), in commenting on this,
In another case (Golub et al. 1951), the seizure was char- noted that a patient, during a seizure ‘may carry on with
acterized by a motionless stare, followed by an impairment what he is doing, such as playing the piano or driving a car.
p 07.qxd 3/15/08 3:57 PM Page 254
His performance may seem without fault, or he may betray Table 7.6 Common stereotyped automatisms
himself [only] by ignoring the traffic light.’ Chewing or lip-smacking
Looking around
Motionless stare Fumbling with sheets or clothing; groping, or searching
Speaking or mumbling
Although appearing in most complex partial seizures, a Laughing or crying
motionless stare is certainly not seen in all (Delgado- Sitting or standing up
Escueta et al. 1982; Holmes 1984). Some authors have cat- Walking or running
egorized complex partial seizures into two types – ‘type I’ Thrashing or kicking; ‘bicycling’ movements
referring to those seizures that are characterized by the
motionless stare, and ‘type II’ being those without one –
and have gone on to assert that, in type I seizures, the stare
always precedes automatisms (Delgado-Escueta et al. 1982;
Escueta et al. 1977). It appears, however, that this sequenc- (Ames and Enderstein 1975; Gascon and Lombroso 1971),
ing may not be always present, as subsequent work not ‘infectious’ (Sethi and Surya 1976), and has been
(Theodore et al. 1983) has shown that, in type I seizures, described as cackling (Gumpert et al. 1970; Lehtinen and
the motionless stare may be preceded by automatisms. Kivalo 1965). Also, dacrystic seizures may or may not be
accompanied by a sense of sadness (Luciano et al. 1993).
Running, if prominent, may allow one to speak of ‘cur-
Automatisms sive’ epilepsy (Chen and Forster 1973; Sethi and Surya
Automatisms represent behavior that is performed in a more 1976; Sisler et al. 1953). The running is generally uncon-
or less automatic way, such that the patient is, to a greater or trollable: one patient’s seizure consisted of ‘howling and
lesser degree, left in a less adaptive ‘fit’ with the environment. running’ (Marsh 1978).
Spratling (1902) felt that a patient in the midst of an automa- Bicycling movements of the lower extremities exhibit
tism acted ‘like a machine’, and Kraepelin (1902) described varying degrees of coordination and may or may not be
patients as acting in ‘a mechanical or automatic manner’. accompanied by rhythmic movements of the upper
Penfield (Penfield and Jasper 1954) echoed these impres- extremities (Sussman et al. 1989; Swartz 1994).
sions, noting a range in the severity of the automatism such In addition to the foregoing stereotyped automatisms,
that ‘when the condition is severe, the patient acts like an one may, rarely, see other types. In some cases, automa-
automaton or a robot’, but when mild, the patient ‘may be tisms may consist of sexual activity. There may be pelvic
cooperative and only slightly confused, but still unable to thrusting (Geyer et al. 2000), genital manipulation
deal with new problems normally’. Automatisms are cur- (Leutmezer et al. 1999), and sexual arousal and orgasm
rently roughly divided into those that are stereotyped and (Remillard et al. 1983): in one case (Spencer et al. 1983),
those that are still, to some or other degree, ‘reactive’ to the the patient’s seizure consisted of lip-smacking, snorting,
environment. grimacing, thrashing about, uttering obscenities, and mas-
Stereotyped automatisms generally consist of simple, turbation. Coital movements have been noted (Freemon
purposeless behavior. Table 7.6 lists various common and Nevis 1969), and in one remarkable case (Currier et al.
stereotyped automatisms as noted in studies by Delgado- 1971), a 50-year-old woman:
Escueta et al. (1982), Golub (1951), Holmes (1984), and
Gibbs and Gibbs (1952), roughly arranged from most began having what her daughter and husband
(top) to least (bottom) frequent. Chewing or lip-smacking, described as ‘sexual’ seizures. One was as follows.
looking around and fumbling with sheets or clothing are The patient was sitting at the kitchen table with her
fairly straightforward; the other stereotyped automatisms, daughter making out a shopping list. She stopped
however, deserve some comment. making the list, appeared dazed, and gradually
Speaking or mumbling may consist of simple, but slumped to the floor helped by her daughter. She lay
coherent, phrases, such as ‘Oh my God’, or may be charac- on the floor on her back, lifted up her skirt, spread
terized by varying degrees of incoherence (Bell et al. 1990; her knees, and elevated her pelvis rhythmically. She
Serafetinides and Falconer 1963; van der Horst 1953), made appropriate vocalizations for intercourse, such
which may at times be extreme (Gillig et al. 1988; Knight as ‘it feels good’ and ‘further, further.’ . . . Following
and Cooper 1986). In one case, the patient simply repeated these episodes the patient would appear confused
neologisms such as ‘exeverdedeen’ over and over again and have no memory of them.
(Bell et al. 1990).
Laughing or crying may or may not be accompanied by a Other, rare, stereotyped automatisms include the
sense of mirth (Yamada and Yoshida 1977) and may or may Kluver–Bucy syndrome (Nakada et al. 1984) and stuporous
not sound natural: in one case it was ‘identical’ to the catatonia with waxy flexibility (Shah and Kaplan 1980),
patient’s ‘natural laughter’, and in another, it was ‘most con- Reactive automatisms may, as noted earlier, consist
tagious’. More commonly, however, the laughter is unnatural either of behavior that represents a more or less faithful
p 07.qxd 3/10/08 9:35 AM Page 255
continuation of the patient’s pre-ictal behavior or of marked contrast to the solemn expression which he
behavior that, although still ‘reactive’ to the environment, had had prior to the attack. The radio in the room was
represents a definite break with what the patient was doing on and some dance music was being broadcast. The
before the seizure began. patient now approached the female technician and
Examples of ‘continuation’ reactive automatisms include started to dance with her to the tune coming over the
delivering newspapers (Steegmann and Winer 1961) or con- radio. He continued to hum at the same time.
tinuing to drive a car (Falconer 1954). One of Hughlings
Jackson’s patients (Jackson 1889), if she suffered a seizure Before concluding this discussion of reactive automa-
while serving tea, ‘would go on pouring out but would pour tisms, consideration must be given to the possibility of ictal
out wrongly’. In another example, Forster and Liske (1963) violence. Violence during a complex partial seizure is a rare
described ‘a patient, who worked in his father’s shirt and event, and usually only occurs with provocation, as when
pyjama factory as a sorter, [who] would, in the course of a an attempt is made to restrain patients to protect them
seizure, continue to place the shirts, as they came off the line, from harm (Delgado-Escueta et al. 1982). In one case
into the same stack regardless of the size of the shirt. When (Rodin 1973), for example, a patient, during a seizure,
the seizure ended, he would correctly place the shirts coming ‘suddenly lunged forward, having a bewildered and angry
off the line’. In a similar example, Liddell (1953) described a facial expression. An unsuccessful attempt to keep him in
38-year-old clerk who was ‘adding up a column of figures the chair by the attending physician resulted in making the
when the attack would occur. To other people he would patient angrier’; the patient then ‘clenched [his] right fist . . .
appear to carry on as if nothing had happened. When he assumed a boxer-type stance, and violence [seemed] immi-
came to he would discover that he had written in something nent. As soon as the patient was released, however, he
irrelevant or the wrong figures’. merely got out of the chair, then sat down again and began
Reactive automatisms that represent a break with pre-ictal typical fussing type behavior with the pillow’. In other
behavior may be quite startling to observers. One patient, cases, patients may engage in biting, but this is generally
while walking down the street, began to ‘throw away’ his only when someone is injudicious enough to place his or
money (McCarthy 1900); another, a church organist, sud- her hand near the patient’s face (Tassinari et al. 2005).
denly stopped playing the service music and broke out into Spontaneous unprovoked violence is rare and in most
‘hot jazz’ (Forster and Liske 1963). One of Hughling of the reported cases the patient had been accused of a
Jackson’s patients (Taylor 1931), in the middle of an inter- crime, thus raising the question of malingering. Nevertheless,
view, suddenly stopped responding. Jackson: there have been reports of violence occurring during moni-
tored seizures (Delgado-Escueta et al. 1981): two patients
waited a little time, and then, looking at him, I saw ‘shouted and spat at nurses’ and another ‘suddenly knelt on
that he was grinning as if amused at something. the bed and tried to scratch the psychologist’s face’. Such
Next, whilst sitting quietly in his chair, he tore a piece violence may at times be extreme: in another report of
off a packet of prescriptions, and put it in his mouth. I monitored violence (Ashford et al. 1980), the patient:
took it away, but he picked up another piece from the
floor and began to chew it. In about a minute more
when unrestrained in his hospital room . . . would
he came to himself, and then spat out into the fire a
jump up and run around the room. On one occasion
pellet of chewed paper.
he grabbed the drapes next to his bed and kicked out
In a further example, one of Penfield’s patients (Penfield from the wall on them. On another occasion he pulled
and Jasper 1954), a 16-year-old girl, had a complex partial the nurse’s call button out of the wall, ran into the
seizure at a formal ball. During the seizure, she: bathroom and swung it around his head so that it
was crashing against the walls. In all observations, he
proceeded to take her clothing down as though she was locked by himself in a closed room, having no
were about to sit on the toilet. Her friends gathered opportunity to direct aggression against people.
round and tried to hide the performance but she
seemed to come to herself and finding certain articles Other clinical manifestations during complex
of apparel around her ankles, she said, ‘well if they partial seizures
are off we had better take them off completely.’ She
did this and hid them in her handbag. Finally, as Other manifestations that may occur during a complex
complete awareness returned, she was overwhelmed partial seizure include abdominal pain (Peppercorn et al.
by shame and chagrin. 1978), vomiting (Kramer et al. 1988; Panayiotopoulus 1988),
testicular pain (York et al. 1979), fever (Semel 1987), uni-
As a final example, consider a patient of Gloor’s (1975), lateral dystonia (Kotagal et al. 1989), and various
who, during a depth electrode-monitored seizure: arrhthymias, including bradycardia (Britton et al. 2006),
complete A-V block (Wilder-Smith 1992) and asystole
got up from his chair and began to hum and sing . . . (Kiok et al. 1986; Rocamora et al. 2003; Rugg-Gunn et al.
He suddenly looked very cheerful, which was in 2000), which may be followed by syncope (Schufle et al.
p 07.qxd 3/10/08 9:35 AM Page 256
2007; Smaje et al. 1987): in such cases, if seizures cannot be 30 seconds to 1.5 minutes. In some cases, there may be
controlled, placement of a pacemaker may be required. variations, the tonic phase being preceded by a few clonic
jerks, or the tonic phase constituting the majority of the
seizure, with only a few clonic jerks trailing behind. During
PETIT MAL SEIZURES
the tonic activity, respirations cease and cyanosis may
Petit mal seizures (Delgado-Escueta 1979; Penry et al. 1975; appear. There is often incontinence of urine, and, during
Sadleir et al. 2006), also known as absence seizures, are the clonic phase, the tongue may be bitten. Upon cessation
abrupt in onset and occur without an aura; they are very of the seizure proper, most patients remain in a coma or
brief, lasting of the order of 10 seconds, and generally con- stupor for a matter of minutes. A delirium then super-
sist of an arrest of all activity accompanied by a blank stare: venes, with prominent confusion, lasting perhaps 15–30
the seizure ends as abruptly as it began, and there is no post- minutes, after which most patients fall into a deep sleep.
ictal confusion or drowsiness. To the observer, it may
appear that the patient had a ‘blank’ spell or was merely ATONIC SEIZURES
momentarily ‘out of it’ then ‘snapped to’. In some cases,
there may be some myoclonic fluttering of the eyelids and Atonic seizures (Gambardella et al. 1994; Lipinski 1977;
occasionally some myoclonic jerks of the hands. Some Pazzaglia et al. 1985), also known as astatic seizures or
patients will also experience a partial loss of muscle tone: ‘drop attacks’, occur without prodrome or aura and are
the head may drop forwards, or the patient may slump characterized by a sudden loss of motor tone. In most
somewhat, but falls are unusual. Many patients will also cases, this atonus is generalized, and patients fall or slump
have some simple automatisms, such as lip-smacking, to the ground; occasionally, however, the lack of tone may
chewing or fumbling, during the absence (Fuster et al. 1954; be focal, with, for example, only an abrupt drooping of the
Penry and Dreifuss 1969; So et al. 1984, Sadleir et al. 2006). head. The atonus itself generally lasts on the order of a few
There may very rarely be other features, such as auditory or seconds and may or may not be associated with a loss of
visual hallucinations (Guinena and Taher 1955). consciousness. After the restoration of normal tone, most
A variant of petit mal, known as ‘atypical absence’ may patients arise immediately, without any post-ictal confu-
be seen, most commonly in patients with mental retarda- sion; however, others may, for a minute or two, experience
tion. These atypical absences are of more gradual onset and a more or less profound degree of post-ictal confusion.
offset, tend to last longer overall, and may be associated Atonic seizures generally occur only in patients who
with prominent increased muscle tone (Holmes et al. have already suffered from complex partial or grand mal
1987). seizures for many years (Gambardella et al. 1994; Lipinski
1977; Tinuper et al. 1998).
GRAND MAL SEIZURES
AMNESTIC SEIZURES
Grand mal seizures, often referred to as generalized
tonic–clonic seizures, may be preceded by an aura com- Amnestic seizures, also known as ‘pure epileptic amnesia’,
posed of any of the symptoms or signs seen during simple are characterized solely by the appearance of amnesia. As
partial seizures, or may evolve out of a complex partial par- such, they differ from complex partial seizures in that there
tial seizure, a process known as secondary generalization. is no impairment of consciousness, no motionless stare,
As discussed below, under Etiology, it is critical to deter- and no automatic behavior. Typically, the amnesia itself is
mine whether or not grand mal seizures are preceded by an primarily of the anterograde type but, in some cases, the
aura or a complex partial seizure: grand mal seizures pre- amnesia represents a combination of anterograde and ret-
ceded by such events may be assumed to have a ‘focal’ rograde types. Rarely, the seizure will be characterized by
onset, that is to say to be due to a more or less localized retrograde amnesia alone. Examples of each type follow.
lesion, whereas those that lack such preceding events are
more likely to be occurring as part of one of the idiopathic Amnestic seizures of the anterograde type
generalized epilepsies. Caution must be exercised here, These seizures are characterized by the abrupt onset of a
however, before deciding that no ‘focal’ features are pres- loss of short-term memory: patients are able to recall
ent, given that many patients who did, under video–EEG events that occurred up to the onset of the seizure, and
monitoring, clearly have an aura, will be unable, after behave normally during the seizure itself, but subsequent
recovering from the grand mal seizure, to recall the aura to the termination of the seizure, they have no or only
(Schulz et al. 1995). spotty recall of the events that transpired concurrent with
Typical grand mal seizures (Theodore et al. 1994) begin the seizure itself; they generally last from minutes up to an
with an abrupt loss of consciousness, often accompanied hour (Butler et al. 2007; Palmini et al. 1992). Palmini et al.
by an inarticulate ‘cry’: immediately there is tonic activity (1992) provide some interesting examples. In one case, a
in all four extremities. After perhaps 15–20 seconds, the waitress, during her seizure, ‘was able to compute a cus-
tonic activity slowly fades to be gradually replaced by regu- tomer’s bill accurately and to bring him a correct amount
lar clonic activity, which, in turn, may last anywhere from of change’; later, upon recovery, ‘she then realized she had
p 07.qxd 3/10/08 9:35 AM Page 257
a blank in her memory and could not recall her interaction the seizure are in almost all cases lost to memory
with that customer’. In another case, the patient: ‘was in (Deisenhammer 1981).
the cafeteria at his work place, where he had to present a
card and sign a register to pick up his meal. After having Amnestic seizures characterized by retrograde
eaten he presented himself a second time and ate lunch amnesia alone
twice. That same afternoon, the cook telephoned and This type of pure epileptic amnesia is very rare. In these
upbraided him for having eaten two meals. He had no rec- cases, although patients are able to keep track of events
ollection of having done so’. during the seizure itself, they are nevertheless unable to
Finally, there is the case of a young woman, who, during recall events that occurred before the seizure. In one case
a monitored seizure, answered a telephone, spoke with her (Venneri and Caffarra 1998), the retrograde amnesia itself
cousin, and then went to sleep. ‘The next morning she did was limited to only autobiographical events. Thus, during
not recall having received a phone call. When confronted the seizure, the patient, although able to recall public
with the video replay of her seizure, she was incredulous’. events, was unable to recall personal events from her own
The investigators later contacted the cousin, who told past. Once the seizure ended, her recall of personal events
them that ‘their conversation had been entirely normal. He was restored, and she also was able to recall being in the
had not noticed anything amiss with the patient’. seizure itself and having trouble recalling those personal
Of some historical interest is the possibility that events.
Hughlings Jackson’s illustrious ‘Dr Z’ (Jackson 1889) may
also have suffered from amnestic seizures of the antero- REFLEX SEIZURES
grade type. In the midst of examining a patient, Dr Z
remembered: Reflex seizures, though uncommon, are of interest, from
not only a therapeutic point of view, but also a general neu-
taking out my stethoscope and turning away a little ropsychiatric one. Therapeutically, they offer an obvious
to avoid conversation. The next thing I recollect is means of seizure reduction, namely avoiding the precipi-
that I was sitting at a writing-table in the same room, tating stimulus. In general, however, their interest lies in
speaking to another person, and as my consciousness the fact that an experience, sometimes a very complex one
became more complete, recollected my patient, but (as in Penfield’s example below), can ‘spark’ off an equally
saw that he was not in the room. I was interested to complex epileptic event. Various seizure types can be
ascertain what had happened, and had an reflexively induced, including simple partial seizures, com-
opportunity an hour later of seeing him in bed, with plex partial seizures, grand mal and petit mal, and atonic
the note of a diagnosis I had made of ‘pneumonia of seizures.
the left base’. I gathered indirectly from conversation
that I had made a physical examination, written these Reflex simple partial seizures
words, and advised him to take to bed at once. I Reflex simple partial seizures, albeit reported, appear to be
re-examined him with some curiosity, and found that uncommon. In one series, a startling stimulus, generally a
my conscious diagnosis was the same as my loud noise, was noted to cause tonic activity (Manford et al.
unconscious – or perhaps I should say, unremembered 1996), and in another, reading could induce motor phe-
diagnosis had been. I was a good deal surprised, but not nomena such as myoclonic jerking of the jaw or, less
so unpleasantly as I should have thought probable. frequently, alexia (Koutroumaniois et al. 1998). In one
patient, voluntary movement was noted to induce ictal dys-
tonia (Falconer and Driver 1963), and in another writing
Amnestic seizures of anterograde and retrograde types produced clonic activity in the involved upper extremity
In these seizures there is not only a defect of short-term (Tanaka et al. 2006). In one patient, rubbing an arm pro-
memory, but also an inability, during the seizure itself, to duced a sensory Jacksonian march up the arm, immediately
recall events that occurred for a variable period of time followed by a motor march up the same arm (Kanemoto et
before the onset of the seizure proper (Stracciari et al. al. 2001), and in others toothbrushing produced numbness
1990). Such patients may be quite alarmed at their retro- or tingling in the face or tongue followed by clonic move-
grade amnesia and may ask others to fill them in (Zeman ment of the face or upper extremity (D’Souza et al. 2007).
et al. 1998): one patient (Cole et al. 1987) suddenly became In another case, listening to certain kinds of music-induced
unable to recall whether he had gone to work that morn- ictal structured visual hallucinations (Daly and Barry 1957),
ing, long before the seizure began, and repeatedly asked and ictal blindness has been induced by intermittent photic
others whether or not he had shown up for work. Upon stimulation (Barry et al. 1985). Marchini et al. (1994) report
termination of the seizure, the retrograde amnesia resolves, the case of dacrystic seizures induced by speaking and, in a
and patients are once again able to recall what events tran- most unusual case (Falconer 1954; Mitchell et al. 1954),
spired up to the onset of the seizure and are also able to recall gazing at a safety pin was capable of precipitating a simple
events that occurred after the termination of the seizure; partial seizure characterized by a sense of profound, almost
those events, however, which transpired concurrent with sexual, satisfaction.
p 07.qxd 3/10/08 9:35 AM Page 258
Reflex complex partial seizures The dog chased the stick and brought it back to him’. At
Reflex complex partial seizures have, in some cases, earned the age of 17, the patient had his first seizure: ‘he was in a
specific names according to the provoking stimulus; thus crowd of people at the military school which he was
one may speak of ‘musicogenic’, ‘reading’, and ‘eating’ attending [and] watched a demonstration of military tac-
epilepsy. Other stimuli, for example hearing certain people tics in which one of his classmates grabbed a rifle out of the
speak, may also be effective. hands of another man’. At that instant, ‘there immediately
Musicogenic complex partial seizures, although exten- came to the patient’s mind’ a memory of playing with the
sively reported, are rare events (Critchley 1942; Forster dog when he was 13, and ‘in his mind he associated these
1977, Tayah et al. 2006). Critchley (1937) provided an two incidents and tried to put himself into the past mem-
illustrative case: the patient, after hearing ‘a rather loud ory. Following this, he became confused and was unable to
fox-trot with a well defined tempo . . . suddenly became speak for several seconds. Then he evidently lost con-
pale . . . [and] leaned forward in her chair with a frightened sciousness and had a convulsive seizure’. The patient
look in her eyes . . . and . . . began smacking her lips’. In remained well until a half year later, when ‘while in a night
some cases, it appears that only specific kinds of music are club, he heard a man saying, “Give me my hat.” He saw
capable of inducing seizures (Newman and Saunders him grab his hat from the hat-check girl. Immediately the
1980), for example the pealing of church bells (Poskanzer memory of the dog chasing the stick, and the memory of
et al. 1962), organ music (Joynt et al. 1962), ‘a large dance grabbing the stick from the dog’s mouth, came back to
band playing “swing” music’ (Daly and Barry 1957), emo- him. Following that he was confused and behaved in an
tionally laden music (Gastaut and Tassinari 1966), and automatic manner’.
‘Italian’ songs (Wieser et al. 1997). This last case is of inter- Reflex grand mal and petit mal seizures
est in that, upon hearing the Italian song, the patient’s
complex partial seizure was preceded by an aura composed Both grand mal and petit mal seizures may be induced by
of an auditory hallucination of ‘pleasing female murmur- such intermittent photic stimulation as with electronic
ing voices, which took increasing possession of her mind’, video games (Quirk et al. 1995) or watching a flickering tel-
following which she had a complex partial seizure with a evision set (Baykan et al. 2005).
motionless stare. Reflex atonic seizures
Reading-induced complex partial seizures may occur
with ‘silent’ reading (Gastaut and Tassinari 1966) or only Atonic seizure were produced reflexively in the case of one
upon reading aloud (Forster et al. 1969a). In one case girl, whose seizures could be ‘triggered by laughing if she
(Critchley et al. 1959), not just any reading material would was told jokes or watched a comedy on television’ (Jacome
do, but rather it was reading a newspaper, especially the and Risko 1984).
patient’s hometown newspaper, that constituted the effec-
tive stimulus. STATUS EPILEPTICUS
Eating-induced complex partial seizures may occur
regardless of what is eaten (Ahuja et al. 1980; Fiol et al. Status epilepticus is said to be present when, for at least a
1986; Forster 1971) or may occur only with eating certain half-hour, the patient is either undergoing a continuous
foods, in one case, for example, apples (Abenson 1969). seizure or has so many closely spaced seizures that there is
Other stimuli capable of inducing complex partial no time for full recovery between them. Status epilepticus
seizures appear to be highly idiosyncratic: thus there are may be seen with simple partial, complex partial, petit mal,
case reports of seizures induced by hearing the voices of cer- grand mal, and amnestic seizures, and, as the examples
tain specific radio announcers (Forster et al. 1969b), by below demonstrate, may be very prolonged. Although
answering the telephone (Michelucci et al. 2004), engaging most patients, upon recovery, are left without cognitive
in heartfelt prayer (Glass et al. 2007), hearing a vacuum sequelae (Adachi et al. 2005), cognitive impairment, along
cleaner (Carlson and St. Louis 2004), feeling sad (Fenwick with other sequelae, may, as noted below, be found after
and Brown 1989), arching the back (Jacome et al. 1980), status, most especially after grand mal status.
exercising (Sturm et al. 2002), or experiencing orgasm
(Ozkara et al. 2006). More remarkably, albeit very rarely, Simple partial status epilepticus
seizures may also be induced by thinking certain thoughts, Simple partial status epilepticus, although most commonly
as for example, in one case, thinking about home (Martinez presenting with motor signs, has also been reported with
et al. 2001). Finally, there is a fascinating case reported by psychic symptoms such as fear or structured hallucinations.
Penfield (Penfield and Jasper 1954) wherein it appears that Motor simple partial status epilepticus is traditionally
it was the evocation of a memory of a specific event that referred to as epilepsia partialis continua. These seizures
served as the trigger. The history is a bit lengthy and com- typically consist of persistent clonic jerking involving the
plex but worth retelling. face, arm, or leg, and can last any time from hours to years
The patient, when 13 ‘was playing with a dog that (Cockerell et al. 1996; Scholtes et al. 1996a; Seshia et al.
belonged to a neighbor. He remembered grabbing a stick 2005); indeed in one series, the mean duration was 25
out of the mouth of the dog and throwing it to a distance. months, the longest seizure lasting 18 years (Thomas et al.
p 07.qxd 3/10/08 9:35 AM Page 259
1977). Clonic activity may or may not persist into sleep hallucinating, crying out on several occasions, “I am God.”
(Cockerell et al. 1996; Thomas et al. 1977) and may be When placed on a stretcher for transfer . . . she became
accompanied by other symptoms such as aphasia (Cockerell hostile and resistant, screaming “I’m dying” and “They’re
et al. 1996). Although the motor activity is, in the vast taking me to the morgue” ’.
majority of cases, unilateral, there may in a small minority After 2 days, she was eventually treated with an anti-
be bilateral involvement (Ashkenazi et al. 2000; Thomas epileptic drug, ‘with prompt clearing. On recovery, she
et al. 1977). Rarely, inhibitory simple partial status epilepticus described her experience as though recovering from a bad
may occur, with prolonged ictal paresis (Smith et al. 1997). dream’.
Fear or anxiety may be the sole manifestation of simple In other cases, stuporous catatonia has been reported
partial status epilepticus and has been noted to last for (Engel et al. 1978): one patient (Lim et al. 1986) ‘held his
between 10 days (Scott and Masland 1953) and 3 months arms and legs rigidly in the air and would maintain his
(Henriksen 1973). Isolated ictal depression has also been extremities in any bizarre posture indefinitely’.
noted; in one case (Weil 1956), the patient for 2 weeks ‘felt
“blue” and cried, and the smell of fat on a hot stove kept Petit mal status epilepticus
coming back’. Petit mal status epilepticus, which may occur in both child-
Structured hallucinations occurring in status have con- hood and the adult years (Belafsky et al. 1978; Michelucci
sisted of the auditory hallucination of a ‘song’ persisting for et al. 1996; Nightingale and Welch 1982; Novak et al. 1971;
3 hours (Wieser 1980) and a 5-day episode during which Schwab 1953; Thompson and Greenhouse 1968; Tucker
the patient experienced ‘aphasia, acoustic hallucinations and Forster 1958; Zappoli 1955), is characterized by vary-
(strange sounds, music, voices), left sided headache, and ing degrees of confusion, often accompanied by ‘rhythmic
visual hallucinations (red balls in the front of the right eye)’. blinking or small amplitude myoclonic jerking of the face
and arms’, and generally lasts anywhere from half an hour
Complex partial status epilepticus to 2 days (Andermann and Robb 1972). In some cases, the
Complex partial status epilepticus is always characterized confusion may be very slight: in the case of one 30-year-old
by a more or less profound impairment of consciousness, woman seen during petit mal status (Friedlander and
may or may not be accompanied by automatisms, and gen- Feinstein 1956), ‘during the first minute or so of the exam-
erally lasts from an hour or less up to days (Cockerell et al. ination nothing unusual in her manner was noted, but as
1994; Goldensohn and Gold 1960; Mayeux and Lueders she was questioned further it became apparent that there
1978; Rennick et al. 1969; Sheth et al. 2006, Tomson was slowness in comprehending certain questions’, the
et al. 1986, 1992; Van Rossum et al. 1985; Williamson et al. presence of myoclonus of the eyelids and eyebrows sug-
1985b). Longer episodes, however, have been reported, up gested the correct diagnosis.
to 7.5 months in one case (Roberts and Humphrey 1988) Rarely, there may be prominent automatisms. One
and 18 months (Cockerell et al. 1994) in another. patient went for a walk and took a bus while in petit mal
Automatisms seen in complex partial status epilepticus status (Vizioli and Magliocco 1953), and in another case
may be either stereotyped or reactive. Reactive automatisms (Bornstein et al. 1956) a 16-year-old girl, while playing
include such simple behavior as feeding oneself (Jaffe 1962) cards in her dormitory room, ‘suddenly got up, walked out
or wandering off. In one case (Coats 1876), immediately without a coat, went to the airport, and boarded a plane to
after the seizure began, the patient, a craftsman, ‘laid aside New York without a ticket. Upon arrival in New York she
his tools, took off and hung up his leather apron, and after was charged as a stowaway. She was found to be confused
muttering some unintelligible words to the foreman, left and incoherent’.
the shop. He himself remembers nothing of this, but woke
Grand mal status epilepticus
to consciousness to find himself sitting on one of the
benches in George Square’. When the wandering is quite Grand mal status epilepticus (Aminoff and Simon 1980),
prolonged, one speaks of ‘poriomania’: in one case the the most dramatic and life-threatening of all forms of sta-
patient, after a seizure lasting 24 hours, came to find that he tus, is characterized by closely spaced grand mal seizures.
had travelled ‘several hundred miles’ (Mayeux et al. 1979). In some cases, the clinical presentation may evolve into an
In some cases of complex partial status epilepticus, hal- ictal coma, with no motor activity (Lowenstein and
lucinations, delusions, and bizarre behavior may be promi- Aminoff 1992; Towne et al. 2000).
nent (Ballenger et al. 1983; Ellis and Lee 1978; Mikati et al.
1985). In one case (Drury et al. 1985), the patient, an eld- Amnestic status epilepticus
erly clergyman, ‘became agitated and paranoid and had Amnestic status is rare, but has been noted, in some cases
delusional thinking with religious overtones’; 2 days later persisting for days (Zeman et al. 1998).
he was still in status, and when seen ‘was tremulous, had
bizarre posturing and was masturbating’. In another case Sequelae of status
(Wells 1975): ‘the patient became withdrawn . . . refused to Enduring sequelae may be seen after simple partial,
eat . . . grew restless, fitful and irritable; episodes of violent complex partial and, most especially, grand mal status
anger requiring restraints followed. She appeared to be epilepticus.
p 07.qxd 3/10/08 9:35 AM Page 260
Simple partial status epilepticus may, albeit rarely, leave Grand mal status may be followed by either a personal-
sequelae such as hemiparesis (Desbiens et al. 1993) (which ity change or dementia of variable severity in approxi-
may be permanent [Borchert and Labar 1995]) or a motor mately one-fourth of patients (Oxbury et al. 1971, Rowan
aphasia (Scholtes et al. 1996b). and Scott 1970); these symptoms, may, in turn, be related
Complex partial status epilepticus may also have per- to a loss of hippocampal pyramidal cells (DeGiorgio et al.
manent sequelae but this appears to be uncommon. 1992).
Reported sequelae, after 1–3 days of status, include amne-
sia, with or without other cognitive deficits (Krumholz et
al. 1995), and in one case hemianopia and receptive apha- Etiology
sia after an episode that lasted 8 days (Donaire et al. 2006);
in this latter case, autopsy revealed laminar cortical necro- The multiple causes of epilepsy and seizures are listed
sis in the left hemisphere involving the occipital, parietal, in Table 7.7, where they are divided into several groups.
and temporal cortices. The first group, the idiopathic generalized epilepsies (e.g.,
Table 7.7 Causes of epilepsy and seizures
Idiopathic generalized epilepsies Tin

Childhood absence epilepsy Domoic acid
Juvenile absence epilepsy Aspartame
Juvenile myoclonic epilepsy
Alcohol or sedative/hypnotic withdrawal
Idiopathic generalized epilepsy with tonic–clonic seizures only
Alcohol
Metabolic Sedative/hypnotics
Hypoglycemia
Common intracranial causes
Hyperglycemia
Mass lesions
Hyponatremia
Tumors
Hypernatremia
Abscesses
Hypocalcemia
Vascular malformations
Hypomagnesemia
Cerebrovascular disorders
Uremia
Infarction
Toxic Intracerebral hemorrhage
Medications Subarachnoid hemorrhage
Clozapine Neuronal migration disorders
Phenothiazines Mesial temporal sclerosis
Bupropion Traumatic brain injury
Tricyclic antidepressants
Meningoencephalitis
Lithium
Meningitis
Tiagabine
Encephalitis
Baclofen
Acute disseminated encephalomyelitis
Penicillin
Cefipime In association with certain dementing and neurodegenerative
Isoniazid disorders
Busulfan Multi-infarct dementia
Cyclosporine Alzheimer’s disease
Tacrolimus Neurosyphilis
Theophylline AIDS dementia
Meperidine Progressive multifocal leukoencephalopathy
Bismuth Toxoplasmosis
Intoxicants Dentatorubropallidoluysian atrophy
Phencyclidine Choreoacanthocytosis
Cocaine McLeod syndrome
Miscellaneous toxins Wilson’s disease
Iodinated contrast dye Spinocerebellar ataxia
Lead Cerebrotendinous xanthomatosus
(continued)
p 07.qxd 3/10/08 9:35 AM Page 261
Cerebral amyloid angiopathy Systemic lupus erythematosus

Creutzfeldt–Jakob disease Thrombotic thrombocytopenic purpura
Granulomatous angiitis Hyperthyroidism
Metachromatic leukodystrophy Central pontine myelinolysis
Adrenoleukodystrophy Hepatic porphyria
Pantothenate kinase-associated neurodegeneration Wernicke’s encephalopathy
Juvenile Huntington’s disease Sarcoidosis
Subacute sclerosing panencephalitis Marchiafava–Bignami disease
Behçet’s syndrome
Congenital disorders
Wegener’s granulomatosus
Mental retardation
Whipple’s disease
Autism
Celiac disease
Down’s syndrome
Autosomal dominant partial epilepsies
Fragile X syndrome
Multiple sclerosis
Klinefelter’s syndrome
Disorders typically presenting in childhood or adolescence
Sturge–Weber syndrome
Rasmussen’s syndrome
Von Recklinghausen’s disease
Landau–Kleffner syndrome
Rett’s syndrome
Sydenham’s chorea
Tuberous sclerosis
Precipitating events
Prader–Willi syndrome
Post-anoxic encephalopathy
Miscellaneous causes Radiation encephalopathy
Systemic or autoimmune disorders Dialysis dysequilibrium syndrome
Hypertensive encephalopathy Dialysis dementia
Reversible posterior leukoencephalopathy syndrome Eclampsia
Hashimoto’s encephalopathy Post-electroconvulsive therapy
Limbic encephalitis
childhood absence epilepsy, with petit mal seizures), accounts mal seizures may occur either in idiopathic generalized
for approximately one-third of all cases of epilepsy. The epilepsies or secondary to some other cause: grand mal
next three groups include seizures due to metabolic or toxic seizures of non-focal onset suggest one of the idiopathic
factors (such as hypoglycemia or treatment with a medica- generalized epilepsies or a toxic or metabolic factor, whereas
tion such as clozapine) or to alcohol or sedative/hypnotic focal-onset grand mal seizures indicate another cause. As
withdrawal: in these cases, given that seizures generally do noted earlier, the presence of an aura or a complex partial
not recur if the underlying cause is treated, it is not appro- seizure immediately before the grand mal seizure indicates a
priate to speak of epilepsy, a term generally reserved, as focal onset. All the other seizure types, that is to say simple
noted earlier, for cases in whom seizures, in the natural partial, complex partial, atonic and amnestic types, in
course of events, will, in all likelihood, continue to occur. almost all cases will be due to a focal lesion, and amongst
The next group includes common intracranial causes of adults by far the most frequent causes are found in the
epilepsy, including mass lesions (e.g., tumors), cerebrovas- group of common intracranial causes (Currie et al. 1971;
cular disorders (e.g., infarction), neuronal migration Dam et al. 1985; Jensen and Klinken 1976; King and Marsan
disorders (e.g., focal cortical dysplasia), mesial temporal 1977; Loiseau et al. 1990a; Mauguire and Courjon 1978;
sclerosis, and traumatic brain injury. Next are seizures Rasmussen 1963, 1983; Sander et al. 1990; Zentner et al.
occurring due to meningoencephalitis, which, although 1995). Clearly, determining whether the seizures in question
not a common cause, is a diagnosis that must not be are ‘focal’ or ‘non-focal’ facilitates the diagnostic work-up.
missed. The next group includes epilepsy occurring in In evaluating any given patient with seizures, the possibil-
association with certain dementing and neurodegenerative ity must be kept in mind that multiple factors may be
disorders, such as multi-infarct dementia. Following this is involved. Thus, patients with epilepsy, say, due to an intracra-
a group of congenital disorders, such as mental retardation, nial cause such as an infarction, may also have seizures due to
also associated with epilepsy. Finally, there is a large miscel- hypoglycemia occurring with over-vigorous treatment of dia-
laneous group, including such disorders as hypertensive betes mellitus. Or, to take another, not uncommon example,
encephalopathy. seizures in an alcoholic may be due not only to alcohol with-
The diagnostic evaluation is simplified by attending to drawal but also to lesions sustained during the traumatic
the kinds of seizures that the patient has. Petit mal seizures brain injuries that alcoholics are so prone to (Earnest et al.
are seen only in the idiopathic generalized epilepsies. Grand 1988).
p 07.qxd 3/10/08 9:35 AM Page 262
After each of these groups is discussed, attention is then accompanied by autonomic signs (e.g., tremor) or delir-
turned to a suggested diagnostic work-up. ium, it must be borne in mind that a seizure can be the pre-
senting manifestation of hypoglycemia (Hoefer et al. 1946;
IDIOPATHIC GENERALIZED EPILEPSIES Malouf and Brust 1985).
Hyperglycemia, occurring in the syndrome of non-ketotic
The idiopathic generalized epilepsies (IGEs) are genetically hyperosmolar hyperglycemia, has been strongly associated
determined syndromes characterized by generalized seizures with simple partial seizures with either sensory (Maccario
(petit mal, myoclonic, or grand mal) which usually first et al. 1965) or, more commonly, motor symptoms (Grant
appear in childhood or adolescence, and which are usually, and Warlow 1985; Hennis et al. 1992b): in some cases, these
although not always, readily controlled by appropriate anti- simple partial seizures with motor symptoms display a reflex
epileptic drugs (AEDs), such as divalproex. Although there character, being induced by motion (Brick et al. 1989).
is some controversy as to how many, and what types, of Occasionally, simple partial status epilepticus with motor
IGE exist, most authorities describe the following: child- symptoms (epilepsia partialis continua) may occur (Singh
hood absence epilepsy; juvenile absence epilepsy; juvenile et al. 1973; Singh and Strobos 1980). Rarely, simple partial
myoclonic epilepsy; and, idiopathic generalized epilepsy seizures may occur with hyperglycemia during diabetic
with tonic–clonic seizures only. This is a very important ketoacidosis (Placidi et al. 2001).
group, accounting for approximately one-third of all Hyponatremia, with levels at 120 mEq/L or below may
epilepsies seen among adults. cause seizures, often in the context of a delirium (Swanson
Childhood absence epilepsy and juvenile absence and Iseri 1958); seizures secondary to hypernatremia are
epilepsy are similar in that in both disorders all patients very rare, and generally occur only with levels of
have petit mal seizures, and most will also have grand mal 160 mEq/L or higher (Moder and Hurley 1990).
seizures. These disorders differ in their age of onset, with Hypocalcemia may provoke seizures that may or may
childhood absence epilepsy appearing between the ages of not be accompanied by other signs, such as tetany (Glaser
4 and 8 years, and juvenile absence epilepsy between the and Levy 1960). In cases of chronic hypocalcemia second-
ages of 9 and 13 years. In all cases, the EEG shows typical ary to hypoparathyroidism, seizures may be the presenting
interictal generalized spike and dome discharges, especially sign (Berger and Ross 1981) or may be preceded by other
evident during hyperventilation. signs, for example cataracts or parkinsonism (Eraut 1974).
Juvenile myoclonic epilepsy is characterized by general- Hypomagnesemia, in addition to causing delirium and
ized myoclonic seizures, and, in most, by either grand mal myoclonus, may also lead to seizures (Hall and Joffe 1973).
or petit mal seizures; onset is typically between the ages of Uremia may be accompanied by seizures (Tyler 1968),
12 and 18 years. The EEG typically shows interictal gener- with one study finding this to be the case in approximately
alized spike, polyspike, or polyspike and wave discharges. one-third of uremic patients (Locke et al. 1961). Rarely,
Idiopathic generalized epilepsy with tonic–clonic seizures seizures in uremia may be caused not so much by the ure-
only is characterized, as the name suggests, by only grand mal mia per se, but by aluminum intoxication, as occurred in
seizures. Another name for this disorder is epilepsy with gen- some patients with renal failure who had chronically taken
eralized tonic–clonic seizures on awakening, a synonym that antacids (Russo et al. 1992).
calls attention to the fact that in this disorder the grand mal
seizures, although able to occur at any time of the day, are TOXIC
most often seen early in the morning, soon after awakening.
This disorder usually has an onset in adolescence or early Toxic seizures may occur secondary to medications, such as
adult years. As with juvenile myoclonic epilepsy, the EEG in clozapine, intoxicants, such as cocaine, and miscellaneous
this disorder typically shows interictal generalized spike, toxins, such as iodinated contrast dye.
polyspike, or polyspike and wave discharges.
There is some evidence that all of these IGEs share a com- Medications
mon genetic background, differing largely in their age of Of the medications capable of causing seizures perhaps the
onset (Marini et al. 2004; Yenjun et al. 2003). From a general most notorious is clozapine. Clozapine, an atypical antipsy-
clinical point of view, the diagnosis should be suspected in chotic, causes seizures overall in 1.3 percent of patients
all cases characterized by petit mal seizures or by non-focal (Pacia and Devinsky 1994), with a higher incidence found
grand mal seizures with onset between childhood and early in patients with a history of seizures (Wilson and Claussen
adult years, and in any case when the EEG shows generalized 1994): the risk increases with rapid dose titration (Baker
interictal discharges of the spike and dome, spike, polyspike, and Conley 1991; Devinsky et al. 1991) and with high doses,
or polyspike and wave types (Betting et al. 2006). rising to approximately 10 percent in those taking more
than 600 mg daily (Haller and Binder 1990). Phenothiazine
METABOLIC antipsychotics may also cause seizures (Olivier et al. 1982),
especially with higher doses (Logothetis 1967). Of the anti-
Of the metabolic causes of seizures, hypoglycemia is per- depressants, bupropion is most likely to cause seizures:
haps most common, and although such seizures may be among patients treated with 600 mg or more daily, some
p 07.qxd 3/10/08 9:35 AM Page 263
2 percent will have seizures; importantly, seizures are par- mesial temporal sclerosis. Domoic acid is an excitotoxin,
ticularly common in patients with a history of bulimia ner- similar to kainic acid, and in the reported case ingestion
vosa (Davidson 1989; Johnston et al. 1991). Tricyclic was followed by the development of hippocampal atrophy
antidepressants may cause seizures, as has been noted with and complex partial seizures (Cendes et al. 1995). Finally,
amitriptyline (Betts et al. 1968b) and imipramine (Petti and aspartame, taken in very high dose, has been noted, in a
Campbell 1975); maprotilene (Jabbari et al. 1985) and case report, to cause a seizure (Walton 1986).
clomipramine (Clomipramine Collaborative Study Group
1991) are particularly likely to at therapeutic doses, and in the ALCOHOL OR SEDATIVE/HYPNOTIC WITHDRAWAL
case of amoxapine, seizures are very common in overdose
(Litovitz and Troutman 1983). Lithium may cause grand In general hospital practice, alcohol withdrawal seizures
mal seizures (Wharton 1969) and may increase the fre- are quite common, especially among adults in their middle
quency of seizures in those with petit mal epilepsy (Moore years (Sander et al. 1990); the diagnosis, however, often
1981). Interestingly, tiagabine, an AED, has been associated proves elusive as many patients (and their family mem-
with complex partial status epilepticus (Koepp et al. 2005). bers) may deny excessive alcohol use.
Baclofen, in high dosage, caused complex partial status in Alcohol withdrawal seizures are typically of the grand
one case (Zak et al. 1994). Antibiotics known to cause mal type, and are generally seen only in patients with a long
seizures include penicillin (Snavely and Hodges 1984), history of heavy drinking (Lechtenberg and Worner 1992;
cefipine (Dixit et al. 2000, Fernandez-Torre et al. 2005), and Leone et al. 1997; Schuckitt et al. 1993). Seizures may occur
isoniazid (Messing et al. 1984). Chemotherapeutic agents either in an isolated fashion as ‘rum fits’ or in association
associated with seizures include busulfan (Murphy et al. with delirium tremens (Isbell et al. 1955). ‘Rum fits’ are gen-
1992), cyclosporine (Appleton et al. 1989), and tacrolimus erally restricted to the first 48 hours of abstinence, and
(Wijdicks et al. 1996). Other agents include theophylline although repeated seizures, even status, may occur, most
(Messing et al. 1984), meperidine (Kaiko et al. 1983), and patients have only one or two seizures (Earnest et al. 1988;
bismuth: bismuth, as may be used in the treatment of pep- Espir and Rose 1987; Victor and Brausch 1967). Delirium
tic ulcer, is known to cause delirium with myoclonus and tremens, marked by delirium and prominent tremor, gener-
either partial or grand mal seizures (Supino-Viterbo et al. ally appears within the first few days of abstinence, and
1977); uncommonly, bismuth intoxication may present seizures, which may either ‘usher in’ the delirium or occur in
with a seizure (Molina et al. 1989). the midst of it, are seen in between 10 percent (Rosenbaum
et al. 1941) and 20 percent (Lundquist 1961) of patients.
Intoxicants Importantly, although most seizures occurring in a newly
Intoxicants noted to cause seizures include phencyclidine abstinent alcoholic are related to the alcohol withdrawal per
(Alldredge et al. 1989) and cocaine: in the case of cocaine, se, other epileptogenic factors, such as head trauma, hypo-
complex partial status epilepticus was noted (Merriam glycemia, hypomagnesemia, Wernicke’s encephalopathy, or
et al. 1988; Ogunyemi et al. 1989). meningitis may also be present (Earnest et al. 1988;
Lechtenberg and Worner 1992).
Miscellaneous toxins Withdrawal from other sedative/hypnotic agents such
Of the miscellaneous toxins, perhaps the most common as benzodiazepines or barbiturates may also cause grand
offender is iodinated contrast dye, given intravenously mal seizures (Kalinowsky 1942; Levy 1984), and in the case
(Aurahami et al. 1987), intra-arterially (Vickrey and Bahls of barbiturates, status epilepticus is not uncommon.
1989), or intrathecally (Greenberg and Vance 1980;
Shiozawa et al. 1981). Lead intoxication in adults, when COMMON INTRACRANIAL CAUSES
acute, often presents with delirium, abdominal pain, and
seizures, as may be seen in adults who drink illicit ‘moon- In cases when metabolic and toxic factors seem absent,
shine’ whiskey made in old radiators (Morris et al. 1964; withdrawal unlikely, and where the history is not compati-
Whitfield et al. 1972) or, in one case, where adults burned ble with idiopathic generalized epilepsy, consideration
discarded lead storage battery boxes for fuel (Akelaitis should be given to the presence of certain intracranial dis-
1941). Acute lead intoxication in children, as can be seen in orders, the most common of which are mass lesions (e.g.,
those who ingest leaded paint chips, may, when severe, tumors), cerebrovascular disorders (e.g., infarction), mesial
cause seizures and delirium or coma (Jenkins and Mellins temporal sclerosis, neuronal migration disorders, and trau-
1957). Tin intoxication may cause a delirium with seizures, matic brain injury. Each of these is considered in turn.
as has been noted with trimethyl (Fortemps et al. 1978)
and triethyl tin (Alajouanine et al. 1958); in one case, upon Mass lesions
recovery from trimethyl tin intoxication, a patient subse- Tumors, abscesses, and vascular malformations may
quently developed complex partial seizures (Feldman et al. cause seizures, which may be simple or complex partial or
1993). Domoic acid intoxication, as may occur with the grand mal.
ingestion of mussels, is a very rare event but is noted here Seizures occurring secondary to tumors are more likely
because the resulting neuropathology is similar to that of to occur when the tumor involves the cerebral cortex, and
p 07.qxd 3/10/08 9:35 AM Page 264
less so when only the white matter or subcortical gray eventually resulting in a properly laminated and appropri-
structures are involved (Hildebrand et al. 2005; Scott and ately convoluted cortex.
Gibberb 1980). Given their frequency in adults (Dam et al. Disordered migration, depending on its timing and
1985), the clinical ‘rule’ that a new onset seizure disorder in degree, may result in a variety of morphologic changes
an adult is, until proven otherwise, secondary to a tumor, (Raymond et al. 1995). In cases where migration stalls out,
is a sound clinical guide. as it were, either at the periventricular area or in the white
Cerebral abscesses, which may or may not be accompa- matter, one may find misplaced collections of neurons,
nied by fever and leukocytosis, are frequently associated with known as heterotopias, in various locations (d’Orsi et al.
seizures, not only when acute, but also amongst those 2004; Dubeau et al. 1995; Tassi et al. 2005): thus there may
patients who survive (Legg et al. 1973); in this regard it may be periventricular nodular heterotopias (Battaglia et al.
be noted that neurocysticercosis, a common cause of seizures 2006; D’Agostino et al. 2002; Kothare et al. 1998) and what
in developing countries, may be emerging in developed are known as ‘band’ or ‘laminar’ heteropias, wherein the
countries, such as Portugal (Monteiro et al. 1995) and the heterotopia extends in a band through a greater or lesser
United States (Wallin and Kurtzke 2004). portion of the white matter (Barkovich and Kjos 1992;
Vascular malformations, such as arteriovenous malfor- Ono et al. 1997); in many cases one also finds an excessive
mations and various angiomas, are a common cause of number of isolated neurons scattered throughout the
seizures, which may indeed constitute their sole clinical white matter. The overlying cortex may also be malformed,
expression (Kramer and Awad 1994), even in the absence and this malformation may be either macroscopic or
of any symptomatic hemorrhage. microscopic. Macroscopic malformations include pacyh-
gyria (a grossly thickened cortex), polymicrogyria (with
Cerebrovascular disorders multiple, small and highly convoluted gyri), or lissencephaly
Simple partial, complex partial, and grand mal seizures (a ‘smooth’ cortex, with little or no gyrification visible)
(Labovitz et al. 2001) may occur after infarction (Brodtkorb et al. 1992). Microscopic abnormalities include
(Bogousslavsky et al. 1992; Daniele et al. 1989; Kilpatrick microdysgenesis (with dyslamination) (Armstrong 1993;
et al. 1990, 1992; Richardson and Dodge 1954; So et al. Meencke and Janz 1984) or focal cortical dysplasia (with
1996), intracerebral hemorrhage (Passero et al. 2002), or dyslamination accompanied by dysmorphic neurons)
subarachnoid hemorrhage and it is customary to divide (Fauser et al. 2006; Lawson et al. 2005; Palmini et al. 1991;
these seizures into three types, depending on when they Siegel et al. 2005; Sisodiya et al. 1995; Taylor et al. 1971).
occur: (i) immediate seizures during the first day; (ii) early Various seizure types may occur secondary to disor-
seizures during the following two weeks; and (iii) late dered neuronal migration, including complex partial, sim-
seizures during the following months and years. ple partial, and grand mal, and, with the advent of MRI, it
After cerebral infarction immediate and early seizures has become apparent that disordered neuronal migration
are seen in less than 3 percent of patients; late-appearing is one of the most common causes of focal epilepsy
seizures are seen in a little more than 3 percent of cases, (Barkovich et al. 1995; Raymond et al. 1995; Sisodiya et al.
and generally appear within the first 2 years or so post 1996): in these cases the onset of seizures ranges from
stroke (Lamy et al. 2003): those with severe stroke seem at childhood to early adult years.
higher risk for late-appearing epilepsy (Lamy et al. 2003); Before ending this discussion of disordered neuronal
the occurrence of an immediate or early seizure may migration, mention should be made of a rare condition
(Lamy et al. 2003) or may not (Lossius et al. 2005) increase known as hypothalamic hamartoma. In this condition one
the likelihood of a late-appearing one. finds one or more nodules, or hamartomas, composed of
Intracerebral hemorrhage is more likely to cause otherwise normal neurons, within the hypothalamus.
seizures when the hemorrhage is lobar, rather than subcor- Classically, these present in childhood with precocious
tical (Passero et al. 2002), and immediate or early seizures puberty and simple partial seizures of the gelastic type (Ames
are seen in up to 25 percent of cases. and Enderstein 1980; Berkovic et al. 1988; Breningstall
Subarachnoid hemorrhage likewise may cause immedi- 1985; Cascino et al. 1993a; Kuzniecky et al. 1997). Further
ate or early seizures in some 25 percent of cases; late experience, however, has demonstrated that the onset may
appearing seizures are seen in less than 10 percent, and be delayed until adult years, that precocious puberty may
appear more common in cases complicated by infarction not be present, and that various other seizure types, includ-
(Claasen et al. 2003). ing complex partial and grand mal, may also be seen
(Boudreau et al. 2005; Castro et al. 2007; Mullatti et al. 2003).
Neuronal migration disorders The interictal EEG in hypothalamic hamartoma may show
Neuronal migration disorders comprise a large group of interictal epileptiform discharges in the temporal or
conditions, all of which result from defective neuronal frontal areas; importantly the ictal EEG during a gelastic
migration during embryogenesis. In the normal course of seizure, as is the case in most simple partial seizures, is typ-
embryogenesis, neurons migrate along radially oriented ically unremarkable (Leal et al. 2003). In reviewing the
glial fibers from the periventricular area to the overlying MRI in cases of gelastic seizures, although finding a nodu-
cortical plate, where they come to rest in an orderly fashion, lar mass in the hypothalamus is highly suggestive of an
p 07.qxd 3/10/08 9:35 AM Page 265
hamartoma, one must keep in mind that other lesions, dysplasia, a significant minority will also be found to have
such as a ganglioglioma, may appear similar (List et al. mesial temporal sclerosis (Fauser et al. 2006). Third, there
1958). are clearly documented cases wherein patients with normal
hippocampi have developed mesial temporal sclerosis after
Mesial temporal sclerosis experiencing seizures from other causes (Parmar et al. 2006;
Mesial temporal sclerosis is characterized by sclerosis of Worrell et al. 2002). Finally, although not all studies agree
one or more of the structures on the medial aspect of the (Liu et al. 2002), there is evidence from prospective volu-
temporal lobe, including the hippocampus, amygdala, and metric studies that progressive hippocampal atrophy occurs
parahippocampal gyrus (Cavenaugh et al. 1956; Cendes in patients who continue to experience complex partial or
et al. 1993a; Falconer 1971; Hudson et al. 1993), as illus- grand mal seizures (Briellmann et al. 2002; Fuerst et al. 2003;
trated in Figure 7.1. Ammon’s horn (cornu Ammonis) is Salmenpara et al. 2005).
an older term for the hippocampus, and some authors,
rather than using the term ‘hippocampal sclerosis’, will Traumatic brain injury
speak of ‘Ammon’s horn sclerosis’. Seizures occurring after traumatic brain injury may appear
Among patients with a seizure focus in the temporal early (within the first week) or late (at any time thereafter)
lobe, mesial temporal sclerosis is the most common cause (Jennett 1973; Jennett et al. 1973). Early seizures are seen in
(Bruton 1988; Engel et al. 1975; Falconer 1971; Falconer from 2 percent to 15 percent of cases, and late seizures,
et al. 1964; Margerison and Corsellis 1966; Sano and generally appearing within the first year post injury
Malamud 1953). Given that most (but certainly not all) (Mazzini et al. 2003), in 5–10 percent of cases. Several fac-
cases of complex partial seizures result from a focus in the tors increase the likelihood that patients will have late
temporal lobe, mesial temporal sclerosis turns out to be the seizures, including the following: the occurrence of an
most common cause of this type of seizure. early seizure; the presence of contusions or intracerebral
The etiology of mesial temporal sclerosis is not known hemorrhages; any intracranial operations; and dural pene-
with certainty. In some cases, albeit rare, it is familial tration by metal fragments or by bone (Annegers et al.
(Kobayashi et al. 2002, 2003). With regard to the remaining 1980; Annegers et al. 1998; Ashcroft 1941; Caveness 1976;
large group of non-familial cases, a popular theory holds Englander et al. 2003; Jennett 1975; Lishman 1968;
that seizures occurring secondary to other causes (e.g., McQueen et al. 1983; Mazzini et al. 2003; Russell and
childhood febrile seizures) may, via excitotoxic mecha- Whitty 1952; Salazar et al. 1985).
nisms, induce damage in the hippocampus, with the result-
ing sclerotic area then becoming epileptogenic in its own MENINGOENCEPHALITIS
right. There is some evidence to support this. First, although
certainly not all patients with mesial temporal sclerosis have The occurrence of a grand mal or, less commonly, simple
a history of childhood febrile seizures, such events are more partial or complex partial seizure in the context of an illness
common in these patients than in the general population characterized by fever, headache and delirium should always
(Adam et al. 1994; Cendes et al. 1993b; French et al. 1993; raise the diagnostic possibility of meningitis or encephalitis
Saygi et al. 1994). Second, among patients with focal cortical (Annegers et al. 1988). Both arbovirus encephalitis, and
Figure 7.1 Coronal magnetic resonance imaging scan demonstrating mesial temporal sclerosis on the right. On the T1-weighted scan,
atrophy of the hippocampus, indicated by the arrow, is fairly apparent, increased signal intensity being seen in the same area on the
T2-weighted scan. (Reproduced from Hopkins et al. 1995.)
p 07.qxd 3/10/08 9:35 AM Page 266
herpes simplex encephalitis may present in this fashion Achilles tendon enlargement or cataracts, may also cause
(Haymaker 1949; Kennedy 1988; Williams and Lerner seizures (Fiorelli et al. 1990).
1978), and seizures have also been noted during infectious Cerebral amyloid angiopathy, classically causing lobar
mononucleosis (Gautier-Smith 1965; Silverstein et al. 1972). hematomas and, in some cases, a dementia, may also man-
In those who survive, seizures may occur as sequelae ifest with simple partial seizures, which may occur before
(Marks et al. 1992), and this appears to be especially likely in any lobar hemorrhages and either before or concurrent
cases in which the acute phase was characterized by seizures with a dementia (Greenberg et al. 1993).
(Annegers et al. 1988) and when there are other sequelae Creutzfeldt–Jakob disease, typically characterized by
indicative of cerebral damage (Pomeroy et al. 1990). dementia or delirium with myoclonus, may also, albeit
In this regard, it may also be noted that acute dissemi- uncommonly and late in the course of the disease, cause
nated encephalomyelitis, occurring in the days or weeks partial or grand mal seizures (Brown et al. 1986).
following a viral illness, may also be characterized by Granulomatous angiitis, or isolated angiitis of the cen-
seizures (Paskavitz et al. 1995; Tenenbaum et al. 2002). tral nervous system, presents subacutely with headache,
which is quite prominent, and delirium, and may, in a
IN ASSOCIATION WITH CERTAIN DEMENTING OR minority, be accompanied by seizures (Vollmer et al. 1993).
NEURODEGENERATIVE DISORDERS Certain degenerative disorders of relatively early onset,
from childhood to early adult years, may also cause partial
Although partial and grand mal seizures may occur sec- or grand mal seizures, including metachromatic leukodys-
ondary to various dementing or neurodegenerative disor- trophy (Alves et al. 1986; Betts et al. 1968a; Hageman et al.
ders, overall these disorders account for only a small 1995; Haltia et al. 1980; Lima et al. 2006; Rauschka et al.
minority of all seizure cases; furthermore, relative to other 2006), adrenoleukodystrophy (Moser et al. 1984), pan-
symptoms caused by these disorders, the seizures play but tothenate kinase-associated neurodegeneration (Rozdilsky
a minor role in the overall clinical picture. et al. 1968), juvenile Huntington’s disease (Campbell et al.
Multi-infarct dementia may be associated with seizures 1961; Siesling et al. 1997), and, especially, subacute scleros-
at any point in its evolution (Rosenberg et al. 1979); in ing panencephalitis (Koehler and Jakumeit 1976; Kornberg
Alzheimer’s disease, however, seizures typically occur only et al. 1991; Prashanth et al. 2006).
late in its course, and long after the dementia is well-estab-
lished (Amatniek et al. 2006; Goodman 1953; Hauser et al. CONGENITAL DISORDERS
1986; Romanelli et al. 1990).
Neurosyphilis, in particular general paresis of the insane Mental retardation, of severe or profound degree, is com-
(GPI), may cause either grand mal or partial seizures, most monly associated with seizures (Steffenburg et al. 1996),
especially simple partial seizures with a Jacksonian march and over one-third of patients with autism will also have
(Merritt et al. 1932; Storm-Mathisen 1969). Importantly, seizures, which may be seen both in those with and without
the Jarisch–Herxheimer reaction to penicillin treatment retardation (Danielsson et al. 2005; Gillberg 1991; Olsson
may also be characterized by seizures (Hahn et al. 1959; et al. 1988).
Zifko et al. 1994). Various specific congenital disorders, most associated
AIDS dementia may, late in its course, be accompanied with mental retardation, also cause seizures, with each one
by seizures (Navia et al. 1986a). Other disorders, often seen being marked by various distinctive features.
in association with AIDS, must also be considered, includ- Down’s syndrome, typified by a variable degree of mental
ing progressive multifocal leukoencephalopathy and toxo- retardation and a characteristic dysmorphism with narrowed
plasmosis (Navia et al. 1986b; Porter and Sande 1992). palpebral fissures, epicanthal folds, and a small mouth, often
Various movement disorders, typically accompanied by with a large protruding tongue, may be accompanied by par-
dementia, may also cause partial or grand mal seizures, tial or grand mal seizures in adults (Pueschel et al. 1991), the
notably the choreiform disorders dentatorubropalli- proportion affected rising from about one-tenth of young
doluysian atrophy (Porter et al. 1995; Warner et al. 1995), adults, to about one-half of those over 50 years old
choreoacanthocytosis (Feinberg et al. 1991; Hardie et al. (McVicker et al. 1994), and to over three-quarters of those
1991; Lossos et al. 2005) (which may present with complex who go on to develop a dementia (Lai and Williams 1989).
partial seizures years before the onset of chorea [Al-Asmi Fragile X syndrome, seen generally, but not always, in
et al. 2005]), and the McLeod syndrome (Danek et al. 2001). males, is typified by a variable degree of mental retardation,
In the case of seizures occurring in a young person with a macro-orchidism, and a characteristic dysmorphism, with a
movement disorder (with chorea, parkinsonism, tremor), long, narrow face, prominent forehead, and large ears.
consideration must also always be given to Wilson’s disease A minority of these patients will also have either partial or
(Dening et al. 1988). Spinocerebellar ataxia, characterized by grand mal seizures (Finelli et al. 1985; Wisniewski et al. 1985).
a slowly progressive ataxia, in certain of its types, may also Klinefelter’s syndrome, characterized by tall stature and
cause seizures (Grewal et al. 2002; Rasmussen et al. 2001) eunuchoidism in post-pubertal males, may, albeit rarely,
Cerebrotendinous xanthomatosis, typified by a combi- be accompanied by complex partial or grand mal seizures
nation of either mental retardation or dementia with (Tatum et al. 1998).
p 07.qxd 3/10/08 9:35 AM Page 267
Sturge–Weber syndrome is classically characterized by a present with delirium and either partial or grand mal
unilateral facial port-wine stain, hemiplegia contralateral seizures; in the case of limbic encephalitis, seizures may
to the port-wine stain, mental retardation, and seizures constitute either the presentation (Brennan and Craddock
(Bebin and Gomez 1988; Pascual-Castroviejo et al. 1993). 1983; Corsellis et al. 1968), or, rarely, the primary clinical
Importantly, there is an association between frequent expression of the disease (Shavit et al. 1999; Tsukamoto
seizures and dementia in this disorder (Lichenstein 1954; et al. 1993). Systemic lupus erythematosus may likewise
Petermann et al. 1958), an association that underlines the cause partial or grand mal seizures (Devinsky et al. 1988a)
importance of seizure control. in well over 10 percent of patients (Appenzeller et al. 2004).
Von Recklinghausen’s disease (neurofibromatosis type Thrombotic thrombocytopenic purpura should be sus-
I) is characterized by neurofibromas and café au lait spots: pected in cases of seizures occurring in the context of delir-
seizures may occur in 4–5 percent of sufferers (Korf et al. ium and thrombocytopenia (Blum and Drislane 1996).
1993; Kulkantrakorn and Geller 1998). Hyperthyroidism, rarely, may directly cause seizures, and
Rett’s syndrome (Hagberg et al. 1983), seen virtually is suggested by the accompanying autonomic symptoms
only in females, is suggested by a typical evolution of (Korczyn and Bechar 1976; Jabbari and Huott 1980).
symptoms in childhood, resulting in microcephaly and Central pontine myelinolysis, suggested by the occurrence
mental retardation. In a minority of adults either partial or of quadriplegia or abnormal movements in the setting of
grand mal seizures may be seen. rapid correction of hyponatremia, may also, rarely, cause
Tuberous sclerosis classically presents in childhood with seizures (Karp and Laureno 1993). Hepatic porphyria may
the triad of seizures, adenoma sebaceum, and mental retar- be suspected when seizures occur in the context of abdom-
dation (Critchley and Early 1932). Seizures generally, but inal pain and delirium (Byelsjo et al. 1996). Wernicke’s
not always, precede the appearance of adenoma sebaceum encephalopathy, presenting with variable combinations
(Alsen et al. 1994; Ross and Dickerson 1943), and although of nystagmus, ataxia, and delirium in the setting of nutri-
generally of the ‘salaam’ type in infancy, manifest with typ- tional deficiency (as in chronic alcoholism), may, rarely,
ical grand mal or partial seizures by early or mid-childhood also cause seizures (Harrison et al. 2006). Marchiafava–
(Pampiglione and Moynahan 1976). Tuberous sclerosis Bignami disease, a very rare disorder also associated with
may rarely present in the adult years: in one case, a 26-year- chronic alcoholism, may present with delirium and seizures
old developed adenoma sebaceum, followed, at the age of (Ironside et al. 1961; Koeppen and Barron 1978). Sarcoidosis
31, by partial seizures (Kofman and Hyland 1959). is immediately suggested by typical findings on chest radi-
Prader–Willi syndrome is characterized by extreme ograph (Ferriby et al. 2001; Krumholz et al. 1991; Oksanen
obesity secondary to a ravenous hunger. Dysmorphic fea- 1986). Other, rare, causes include: Behçet’s syndrome, sug-
tures are common, with a narrow head, almond-shaped gested by delirium accompanied by oral or genital aphthous
eyes, a thin upper lip, thin arms, and, in males, micropenis ulcers (Aykutlu et al. 2002); Wegener’s granulomatosus
and cryptorchidism. Perhaps one-half will also have men- (Nishino et al. 1993), suggested by a combination of upper
tal retardation, generally of a mild degree. Seizures may respiratory and renal disease; Whipple’s disease, suggested by
occur in about one-fifth of these patients (Bray et al. 1983). abdominal pain and arthralgia (Louis et al. 1996; Romanul et
al. 1977); and celiac disease, also known as gluten enteropa-
MISCELLANEOUS CAUSES thy, suggested by abdominal pain or bloating (Chapman
et al. 1978) or by the finding of occipital calcification (Gobbi
The miscellaneous causes may be divided into various et al. 1992; Tinuper et al. 1996b).
groups; these include: systemic or autoimmune disorders,
such as hypertensive encephalopathy or Hashimoto’s Autosomal dominant partial epilepsies
encephalopathy; the autosomal dominant partial epilepsies; Autosomal dominant partial epilepsy should be suspected
multiple sclerosis; certain disorders typically presenting in in cases of partial seizures, with or without grand mal
childhood or adolescence, such as Rasmussen’s syndrome; seizures, which exhibit a family history consistent with
and, finally, a group characterized by obvious precipitating autosomal dominant inheritance, and wherein the MR
events, such as cerebral anoxia. scan is normal. Three, more or less distinct, types have
been recognized, including autosomal dominant lateral
Systemic or autoimmune disorders temporal lobe epilepsy (also known as autosomal domi-
Various systemic or autoimmune disorders may cause par- nant partial epilepsy with auditory features), autosomal
tial or grand mal seizures. Hypertensive encephalopathy dominant nocturnal frontal lobe seizures, and familial par-
(Chester et al. 1978; Healton et al. 1982) and the reversible tial epilepsy with variable foci. Autosomal dominant lateral
posterior leukoencephalopathy syndrome (Hinchey et al. temporal lobe epilepsy is suggested clinically by complex
1996) both present with headache, delirium, and seizures, partial seizures occurring with an auditory aura, which
and should be suspected in cases of severe hypertension may range from simple buzzing to, at times, complex
or treatment with immunosuppressants. Hashimoto’s auditory hallucinations, such as music or voices (Berkovic
encephalopathy (Henchey et al. 1995; Shaw et al. 1991) and et al. 2004a; Brodtkorb et al. 2005; Hedera et al. 2004;
limbic encephalitis (Alamowitch et al. 1997) may both Michelucci et al. 2003; Ottman et al. 1995; Poza et al. 1999;
p 07.qxd 3/10/08 9:35 AM Page 268
Winawer et al. 2000). Autosomal dominant nocturnal frontal encephalopathy (Shewmon and Masdeu 1980), during the
lobe seizures is a syndrome distinguished by complex partial dialysis dysequilibrium syndrome or as part of the now
seizures that arise from sleep (Combi et al. 2005; vanishingly rare dialysis dementia (Burks et al. 1976;
Gambardella et al. 2000; Hayman et al. 1997; Hirose et al. Garrett et al. 1988; Lederman and Henry 1978; O’Hare
1999; Oldani et al. 1998; Phillips et al. 2000; Saenz et al. 1999; et al. 1983), or during eclampsia (Manfredi et al. 1997) or,
Scheffer et al. 1994, 1995; Willoughby et al. 2003). In both very rarely, as a sequela to electroconvulsive therapy (ECT)
these types, the seizure type generally ‘runs true’ among (Devinsky and Duchowny 1983; Varma and Lee 1992).
family members; in familial partial epilepsy with variable
foci, however, there is a marked heterogeneity in seizure DIAGNOSTIC WORK-UP
types among family members (Berkovic et al. 2004b), and
it is this heterogeneity which distinguishes this disorder. In The diagnostic work-up, in part, is determined by the kinds
addition to these three well-recognized type, there are also of seizures the patient has. Cases characterized by an onset
reports of other, less clear-cut autosomal dominant types in childhood or adolescence of petit mal and/or non-focal
of partial epilepsy (Brodtkorb et al. 2002; Depondt et al. grand mal seizures probably represent one of the idiopathic
2002; Picard et al. 2000; Provini et al. 1999), and many generalized epilepsies, and in such cases generally an inter-
researchers believe that what has been discovered so far ictal EEG is indicated: if it shows the typical findings dis-
represents merely the tip of the iceberg. cussed below, no further work-up may be required. In cases
of non-focal grand mal seizures of later onset, and in all
Multiple sclerosis cases of focal seizures (i.e., grand mal seizures with focal
Multiple sclerosis, rarely, may cause seizures (Nicoletti et al. features and all cases of either simple partial, complex par-
2003; Thompson et al. 1993; Trouillas and Courjon 1972) tial seizures, atonic, or amnestic seizures) one should
and in one very rare case, multiple sclerosis presented with assume that a lesion is present and take steps to determine
simple partial status epilepticus with motor signs secondary its location and nature (King et al. 1999). These steps, dis-
to a plaque in the precentral gyrus (Spatt 1995). cussed below, include an EEG, neuroimaging (preferably
using MRI), and a specifically focused history and examina-
tion, looking for certain distinctive lateralizing and localiz-
Disorders typically presenting in childhood or
ing symptoms and signs. Lumbar puncture is reserved for
adolescence
cases of suspected meningitis or encephalitis. Additionally,
Certain disorders typically presenting in childhood or adoles- one should always be alert to toxic or metabolic factors or
cence may also be considered, including Rasmussen’s substance withdrawal, which may cause grand mal seizures
encephalitis, the Landau–Kleffner syndrome, and Sydenham’s in otherwise normal individuals and may precipitate
chorea. Rasmussen’s encephalitis typically presents with par- seizures in patients with epilepsy of any cause. If, after a
tial seizures, with or without secondary generalization; over thorough work-up, the cause of the patient’s epilepsy
time seizures are joined by a progressive hemiparesis, and, in remains obscure it is customary to make a diagnosis of
some cases, a dementia (Aguilar and Rasmussen 1960; Bien ‘cryptogenic’ epilepsy. Such a diagnosis, however, should
et al. 2002; Granata et al. 2003; Rasmussen and Andermann not be taken for more than it is, a mere confession of our
1989; Rasmussen et al. 1958); motor simple partial status ignorance, and the clinician should remain alert to the
epilepticus is not uncommon. Although pathologic studies emergence of new clinical features that may ultimately
have revealed an underlying encephalitic process consistent reveal the underlying cause.
with an autoimmune etiology (Pardo et al. 2004); the nature
of this autoimmune disorder remains, as yet, unknown. Electroencephalogram
Although the onset is generally in childhood under the age An EEG (discussed in detail in Section 1.5) should be
of 10 years, adult onsets, albeit rare, may also be seen obtained in all cases. An interictal EEG is, in the vast major-
(McLachlan et al. 1993). Landau–Kleffner syndrome is char- ity of cases, sufficient, and should include hyperventilation,
acterized by a childhood onset of aphasia with seizures, photic stimulation, and a sleep recording. Ictal EEGs,
which may be either partial or grand mal in type (Hirsch et al. although helpful, are generally not required except for pre-
1990; Landau and Kleffner 1957; Mantovani and Landau surgical work-ups; however, in cases of reflex seizures, con-
1980; Paquier et al. 1992). Sydenham’s chorea is suggested by sideration may be given to inducing a seizure with the
the onset of chorea in childhood or adolescence, and may appropriate reflexive stimulus (Fariello et al. 1983).
also, albeit rarely, cause seizures (Nausieda et al. 1980). Idiopathic generalized epilepsies are associated with gen-
Interestingly, and again, very rarely, epilepsy may occur as a eralized, bilaterally symmetric, and synchronous interictal
sequela to Sydenham’s chorea (Aron et al. 1965). epileptiform discharges. Patients with petit mal seizures will
have classic spike and dome discharges, and patients with
Precipitating events non-focal grand mal seizures will generally have spike and
Seizures may also occur after certain, obvious, precipitat- wave, polyspike, or polyspike and wave discharges.
ing events, such as in the context of either post-anoxic Focal epilepsies typically display focal or multifocal
encephalopathy (Krumholz et al. 1988) or post-radiation interictal epileptiform discharges; however, it may require
p 07.qxd 3/10/08 9:35 AM Page 269
up to four routine EEGs to capture them, and even this may be able to provide a sufficiently clear history, however
strategy, as noted below, may fail. In cases where a focus is in the case of complex partial and grand mal seizures, this is
suspected in one of the temporal lobes, consideration not possible, and one must rely on a history provided by
should be given to the use of supplemental leads: ‘true’ other observers. When this is not reliable, consideration may
anterior temporal leads are routinely appropriate in these be given to asking family members to videotape seizures
cases, while invasive sphenoidal or nasopharyngeal leads (Newmark 1981; Samuel and Duncan 1994) or, if this is
are typically held in reserve for particularly difficult cases. unsuccessful, to admission for video–EEG monitoring.
As important as the finding of interictal or ictal activity Before discussing the lateralizing and localizing features
is, its absence does not rule out the diagnosis of focal peculiar to each seizure type, mention should be made of
epilepsy. In the case of simple partial seizures, both interictal two post-ictal features, either of which can be seen with
(Devinsky et al. 1989b; Mauguire and Courjon 1978) and any of these three seizure types and which both have strong
ictal (Bare et al. 1994; Devinsky et al. 1988b, 1989b) EEGs lateralizing value. The first of these is a post-ictal unilateral
are often normal. In the case of complex partial seizures, Babinski sign. Although it is well recognized that this may
interictal EEGs may likewise be normal (Goodin et al. be found after a grand mal seizure, it also occurs post-
1990); furthermore, although ictal EEGs are more likely to ictally after approximately 20 percent of complex partial
be abnormal, even here the EEG may be normal during a seizures (Walczak and Rubinsky 1994). The second is
seizure, especially when the seizure focus is on the medial Todd’s paralysis. This phenomenon, first described by
surface of the frontal (Williamson and Spencer 1986; Todd in 1855, is characterized by a unilateral post-ictal
Williamson et al. 1985c) or temporal (Lieb et al. 1976) lobe. paresis, usually of the upper extremity, which may range in
In these limiting cases when routine EEGs remain unreveal- severity from a total paralysis to a mere drift of the upper
ing, consideration may be given to admission to an epilepsy extremity and which lasts for from seconds up to almost
monitoring unit, or, more simply, to the utilization of a half an hour. It may be found after simple partial seizures
computer-assisted 24-hour ambulatory EEG. with motor symptomatology, complex partial or grand
mal seizures (Gallmetzer et al. 2004; Kellinghaus and
Neuroimaging Kotagal 2004). Both of these features reliably lateralize the
lesion to the contralateral hemisphere.
Neuroimaging should, whenever possible, be performed
Simple partial seizures often display both lateralizing
using MRI rather than computed tomography (CT) scan-
and localizing signs. In the case of simple partial seizures
ning, as MR scanning is far more sensitive (Franceschi et al.
with either motor or somatosensory signs, the focus is typ-
1989; Swartz et al. 1992). When MR scanning is utilized, it
ically, but not always (Herskowitz and Swerdlow 1972),
is important to obtain coronal images as these are superior
lateralized to the hemisphere contralateral to the side on
to axial or sagittal images for the detection of mesial tem-
which the patient is experiencing the symptoms (Mauguire
poral sclerosis (Berkovic et al. 1991). Furthermore, it must
and Courjon 1978). With regard to localization to a partic-
be borne in mind that in some cases of mesial temporal
ular lobe, in most cases motor signs suggest the frontal
sclerosis the temporal lobes and their contents may appear
lobe, somatosensory symptoms the parietal lobe, simple
quite symmetric, and the only abnormality may be
visual hallucinations or hemianopia the occipital lobe,
increased signal intensity on the T2-weighted scan (Jackson
structured visual hallucinations the occipitoparietal or
et al. 1994). Although MRI is more sensitive, a normal MRI
occipitotemporal region, and most ‘psychic’ symptoms the
examination certainly does not rule out a focal lesion, such
temporal lobe (Acharya et al. 1998; Bien et al. 2000;
as a small area of focal cortical dysplasia (Devinsky et al.
Mauguire and Courjon 1978; Morris et al. 1988; Nystrom
1988; Williamson et al. 1993).
1966; Russell and Whitty 1955; Salanova et al. 1995). In
In evaluating the MRI, it must be kept in mind that, albeit
cases in which more than one sort of symptom is seen,
rarely, seizures themselves may induce reversible changes.
careful attention must be paid to which occurred first as
For example, after complex status epilepticus the mesial
this is the one with most localizing value: for example, a
aspect of the temporal lobe may demonstrate increased sig-
simple partial seizure that began with a crude visual hallu-
nal intensity on diffusion weighted imaging (Parmar et al.
cination and was immediately followed by a motor sign
2006; Szabo et al. 2005) and T2-weighted imaging (Henry
would indicate a focus in the occipital rather than the
et al. 1994; Kramer et al. 1987). CT scanning may also be
frontal lobe (Salanova et al. 1992; Williamson et al. 1992a).
misleading in the same situation, revealing a transient radio-
Complex partial seizures, like simple partial seizures,
lucency (Kramer et al. 1987; Sammaritano et al. 1985).
may also display both lateralizing and localizing signs.
Lateralizing features include: speech; unilateral ictal clonic,
Lateralizing and localizing symptoms and signs tonic, or dystonic movements or paresis; unilateral automa-
Certain aspects of simple partial, complex partial or focal tisms; possibly ictal head version; and, finally, interictal emo-
grand mal seizures may be helpful in both lateralizing and tional facial palsy. Speech may occur either during an aura,
localizing the responsible lesion, and consequently a good during the seizure itself, or post-ictally, and may be either
grasp of the clinical symptomatology of the patient’s seizure coherent or aphasic. Ictal speech that is coherent suggests a
is very helpful. In the case of simple partial seizures, patients focus in the non-dominant hemisphere (Fakhoury et al.
p 07.qxd 3/10/08 9:35 AM Page 270
1994; Gabr et al. 1989; Koerner and Laxer 1988; Marks and ‘bicycling’ movements. Some have held that these indicate a
Laxer 1998; Yen et al. 1996); however, exceptions to this frontal lobe onset (Williamson et al. 1985c), but such move-
rule do occur (Kaiboriboon et al. 2006). Aphasic speech ments have also been noted in complex partial seizures of
occurring either as an aura (Kanemoto and Janz 1989) or temporal lobe origin (Sussman et al. 1989; Swartz 1994).
post-ictally (Ajmone-Marsan and Ralston 1957; Devinsky Grand mal seizures may also display lateralizing and
et al. 1994a; Fakhoury et al. 1994; Gabr et al. 1989; Koerner localizing features. A post-ictal Babinski sign or Todd’s
and Laxer 1988; Marks and Laxer 1998; Privitera et al. paralysis, as described above, may lateralize to the con-
1991; Serafetinides and Falconer 1963) suggests a focus in tralateral hemisphere, and any aurae may localize, as
the dominant hemisphere. Unilateral ictal clonic, tonic or described for simple partial seizures, above.
dystonic movement (Kotagal et al. 1989; Marks and Laxer
1998; Rusu et al. 2005) and unilateral paresis (Oestreich
et al. 1995) all suggest a focus on the contralateral side. DIFFERENTIAL DIAGNOSIS
Unilateral automatisms (Janszky et al. 2006; Marks and In differentiating between seizures and other disorders
Laxer 1998) or unilateral ictal eye-blinking (Benbadis et al. capable of producing a more or less similar clinical picture,
1996) both generally indicate an ipsilateral focus. Head two features are generally helpful. The first feature to con-
version at the start of a seizure is of controversial lateraliz- sider is the exquisitely paroxysmal onset of all seizure
ing significance: some studies (e.g., Quesney et al. 1990; types, occurring over seconds: such an onset is rare in other
Salanova et al. 1995) report that the head turns away from disorders. Second, one should always, in obtaining a his-
the side with the focus, whereas others (e.g., Geier et al. tory, search for other seizure types, as their occurrence
1977; Ochs et al. 1984) have not found such a relationship. strongly suggests that the event in differential question is
With regard to this controversy over the lateralizing signif- likewise a seizure. Additional differential considerations
icance of head version, one study offered a potential solu- specific for each of the seizure types are discussed in turn,
tion by noting first that there are two types of head version: below, followed by a discussion of pseudoseizures.
in one the head turning is casual, whereas in the other it is
forced and unnatural and often accompanied by hemi- Simple partial seizures
facial clonic movements on the side toward which the head
is turning. Cases with forced head version lateralized to the A transient ischemic attack or a migrainous aura may
hemisphere away from which the head turned (Rheims mimic most of the symptoms seen in simple partial
et al. 2005). Interictal emotional facial palsy suggests that seizures. Transient ischemic attacks (TIAs), of course, are
the focus is contralateral to the side with the palsy (Cascino unlikely in the young; however, when the clinical event in
et al. 1993b; Jacob et al. 2003; Remillard et al. 1977). question occurs in an elderly patient with various vascular
Localization of the focus of a complex partial seizure risk factors, the differential becomes quite problematic.
may not be as straightforward as was once thought. In the A prototypical case involves patients with episodes of
not-too-distant past, the assumption that complex partial paralysis of a limb, which could represent either a TIA or
seizures all originated from foci in the temporal lobe was so an inhibitory motor simple partial seizure. The EEG, if
unquestioned that some authors used the terms ‘complex productive of an interictal epileptiform discharge, is help-
partial epilepsy’ and ‘temporal lobe epilepsy’ synony- ful, but a negative EEG still leaves the differential open, for,
mously. It has become clear, however, that even though as noted earlier, EEGs are typically normal in patients with
most complex partial seizures do arise from foci in the simple partial seizures. In doubtful cases, consideration
temporal lobe (Nystrom 1966), they may also occur sec- may be given to empirical treatment with either an anti-
ondary to foci in the frontal (Geier et al. 1977; Rasmussen platelet agent or an AED. In the case of migraine, the dif-
1983; Salanova et al. 1995; Sutherling et al. 1990; ferential is much simpler: most migrainous aurae are
Williamson et al. 1985c), occipital (Ludwig and Marsan followed by a typical migraine headache, and in those cases
1975; Salanova et al. 1992; Williamson et al. 1992a), or of migrainous aura without headache, the history will
parietal (Cascino et al. 1993c; Ho et al. 1994; Williamson reveal typical events, with headache, in the past.
et al. 1992b) lobes. In cases where the focus is in a site other Some further considerations come into play in cases of
than the temporal lobe, electrical activity spreads rapidly hallucinations or anxiety. Simple partial seizures constitute
from the originating lobe to the temporal lobes, thus pro- but one of many disorders capable of causing isolated hal-
ducing the symptomatology of the complex partial seizure lucinations, and the differential for these events, as dis-
itself. As suggested by Jackson (1894), it stands to reason cussed in Section 4.30, should be pursued. In a similar
that, in such cases, the aura to the complex partial seizure vein, simple partial seizures, likewise, are but one cause of
may indicate the lobe of origin, and this does in fact appear anxiety attacks, and the differential for these, as outlined in
to be the case (Boon et al. 1991; Palmini and Gloor 1992), Section 6.5, should also be consulted.
the various aurae having the same localizing value as dis-
cussed for simple partial seizures, above. Finally, before leav- Complex partial seizures
ing the subject of localization in complex partial seizures, Relatively brief episodes of confusion may be caused not
note should be made of the significance of ictal bilateral only by complex partial seizures, but also by TIAs when
p 07.qxd 3/10/08 9:35 AM Page 271
the ischemia is found in one of the temporal lobes or in the Amnestic seizures
thalamus. The differential here proceeds much as dis- Amnestic seizures must be distinguished from transient
cussed immediately above for simple partial seizures; how- global amnesia and alcoholic blackouts, a differential dis-
ever, here the EEG may be more useful, as interictal cussed in Section 5.4.
epileptiform discharges are more common in cases of
complex partial seizures. Atonic seizures
Brief episodes of confusion arising from sleep may rep-
resent either a nocturnal complex partial seizure or a para- Atonic seizures may be mimicked by cataplexy or by syn-
somnia such as REM sleep behavior disorder, night terrors, cope. In this differential, a good history is essential as in
or somnambulism. REM sleep behavior disorder may be almost all cases of atonic seizures one will find a long his-
readily identified, as patients with this disorder will, upon tory of other seizure types.
‘coming to’, report a vivid dream that explains their behav- Cataplectic attacks are always preceded by some strong
ior during the event. Night terrors and somnambulism, emotion and are accompanied by preservation of con-
however, lack such distinctive clues, and may be closely sciousness, and although atonic seizures, as discussed
mimicked by nocturnal complex seizures (Boller et al. above, may share the same characteristics, this is very rare.
1975; Pedley and Guilleminault 1977; Plazzi et al. 1995); Syncope may be difficult to distinguish from an atonic
consequently, polysomnography may be required. seizure (Lempert et al. 1994). A ‘swoon’, in contrast with the
Brief episodes of unprovoked and uncharacteristic vio- ‘stricken’ fall of an atonic seizure, suggests a vasovagal syn-
lence may suggest either a complex partial seizure or an copal episode, and syncope upon standing suggests
entity known as intermittent explosive disorder. This is a hypotension. Cardiac syncope may be very similar to an
controversial entity putatively characterized by episodes atonic seizure, and Holter monitoring may be required.
wherein patients, either without any precipitants or with Furthermore, as noted earlier, some cases of complex partial
only trivial ones, experience a growing sense of tension and seizures are accompanied by sinus arrest, and in such cases
irritability, culminating in an explosion of violence, after an AED, rather than anti-arrhythmic, drug, is in order.
which they have only a spotty memory of the event; impor-
tantly, at other times in the patients’ lives, there are no sig- Pseudoseizures
nificant abnormalities (e.g., no chronic irritability). As Pseudoseizures are paroxysmal events that, rather than
demonstrated by the examples provided earlier regarding occurring on the basis of an electrical paroxysm in the brain,
violence during complex partial seizures, it is clear that the represent a simulation of a seizure, and may be seen in con-
similarities between the putative intermittent explosive version disorder, malingering, and factitious disorder
disorder and a complex partial seizure with reactive (including ‘epileptic Munchausen’s syndrome’ [Savard et al.
automatisms may be compelling. In fact, some believe that 1988]). In practice, this differential possibility comes to mind
intermittent explosive disorder is in fact a species of com- when patients present with episodes that, although resem-
plex partial epilepsy. Resolving this nosologic question will bling either grand mal or complex partial seizures, have some
require further research; in the meantime, one should, atypical features. After discussing some of these atypical fea-
when evaluating patients with sporadic, seemingly unmo- tures, consideration will be given to an appropriate work up.
tivated episodes of violence, enquire closely regarding the Pseudo-grand mal seizures may begin with a cry, but
all-important history of other seizure types. unlike the inarticulate brief cry of a ‘true’ grand mal
Prolonged episodes of confusion may represent com- seizure, this cry may involve words and may persist long
plex partial status epilepticus; however, in such cases the into the event. The movements seen in a pseudo-grand mal
differential becomes quite large as it encompasses the seizure may be thrashing rather than rhythmic, and if
syndrome of delirium, and in such cases that differential, attempts are made to restrain these movements the patient
as discussed in Section 5.3, should be considered. with a pseudoseizure may show active resistance. Patients
with pseudoseizures may bite their lips, but the tongue is
Petit mal seizures usually spared; furthermore, urinary incontinence is rare
during a pseudoseizure.
Apart from complex partial seizures, there is little else that
Pseudo-complex partial seizures often come into the dif-
can even come close to mimicking typical petit mal
ferential when the behavior during the event is quite complex.
seizures. The presence of an aura or a duration longer than
Although this indeed is suggestive, as most ‘true’ complex
10 or 15 seconds points toward a diagnosis of a complex
partial seizures are characterized by simple stereotyped
partial seizure; in doubtful cases, an interictal EEG will
automatisms, it is not definitive: as indicated by the examples
resolve the issue.
cited earlier in the chapter, some of the reactive automatisms
seen in complex partial seizures are quite complex indeed.
Grand mal seizures The work up in such cases proceeds in a fashion similar
Apart from pseudoseizures, discussed below, there is very to that described earlier, and should include the following:
little that can reduplicate the tonic–clonic activity of a typ- testing for a post-event Babinski sign; appropriately timed
ical grand mal seizure. testing for prolactin, neuron-specific enolase and, when
p 07.qxd 3/10/08 9:35 AM Page 272
grand mal seizures are in question, creatine phosphokinase seizures. Interpretation here must proceed with some cau-
(CPK) levels; EEG; neuroimaging; consideration of placebo tion, however: in some cases, epileptogenic lesions (e.g.,
induction, and, in selected cases, single photon emission small areas of focal cortical dysplasia) may be very difficult
computed tomography (SPECT) or positron emission to detect on MRI and, conversely, not all lesions, even
tomography (PET) imaging. although they are easily detected (e.g., a small convexity
A temporary Babinski sign may, as noted earlier, be seen meningioma), are likely to cause seizures.
after both grand mal and complex partial seizures As this Placebo induction, for example with saline infusion
phenomenon will generally lie outside the knowledge of (Cohen and Suter 1982; Devinsky et al. 1996; Walczak et al.
most pseudoseizure patients, even medically sophisticated 1994), has been used as a diagnostic test for pseudoseizures
ones, its presence is a reliable sign of epileptic activity. Its on the not-implausible assumption that placebos are
absence, of course, is of little diagnostic import. unlikely to induce paroxysmal electrical activity. It must be
The serum prolactin level rises with depth-electrode stim- borne in mind, however, that placebo may, albeit rarely,
ulation of either the hippocampus or the amygdala induce ‘true’ seizures (Lesser et al. 1983).
(Gallagher et al. 1987; Parra et al. 1980; Sperling and Wilson Cumulatively, the absence of a Babinski sign, normal
1986), thus serving as a marker for paroxysmal activity in prolactin and neuron-specific enolase levels (and CPK levels
these or related structures and as an indicator that the clinical when grand mal seizures are in question), and a normal ictal
event in question is a ‘true’ rather than a ‘pseudo’ seizure EEG and MR scan, coupled with a reproduction of the event
(Laxer et al. 1985; Pritchard et al. 1985a). Prolactin elevation in question by placebo induction would, when present in
is, however, not entirely specific to epileptic events, as such combination, argue very strongly for the diagnosis of pseu-
elevations may also be seen after hypotensive syncope (Oribe doseizure. It must, however, be borne in mind that some
et al. 1996). A twofold or greater rise in serum prolactin level ‘true’ seizures will, albeit very rarely, ‘slip by’ all these tests.
is found about 15 minutes post-ictally in most cases of com- Consequently, in doubtful cases, consideration may be given
plex partial seizures with temporal lobe onset (Bauer et al. to ictal SPECT or PET recordings. Essentially, in the work
1994; Sperling et al. 1986) and in grand mal seizures (Wyllie up of a suspected pseudoseizure, one is attempting to ‘prove
et al. 1984). However, with seizures arising from foci outside a negative’, that is, to ‘prove’ that the event in question is not
the temporal lobe, whether complex partial (Meierkord et al. accompanied by a paroxysmal electrical discharge. Given
1992) or simple partial (Dana-Haeri et al. 1983; Laxer et al. that one can never definitively prove a negative, however,
1985; Sperling et al. 1986), prolactin elevation is less likely to the diagnosis of pseudoseizure should always remain some-
occur. Furthermore, after frequent seizures (Jackel et al. what tentative.
1987; Malkowitz et al. 1995) or after status epilepticus A further complication in the diagnostic work up of
(Tomson et al. 1989) one may find a normal prolactin level, pseudoseizures is the fact that it is not uncommon for
presumably reflecting an exhaustion of the pituitary pro- patients to have both pseudoseizures and ‘true’ seizures
lactin stores secondary to prolonged stimulation. (Krumholz and Niedermeyer 1983). Thus, simply demon-
Neuron-specific enolase is a marker of neuronal injury, strating that a patient has had a pseudoseizure does not
and, in contrast with the prolactin level, which tends to be mean that the patient does not also have epilepsy.
normal after status epilepticus, the level of enolase is elevated
in such situations (DeGiorgio et al. 1999), peaking at one
(DeGiorgio et al. 1995) to two days (Rabinowicz et al. 1995). Treatment
Neuron-specific enolase may at times also be elevated after
single complex partial or grand mal seizures (Rabinowicz This section will begin with a discussion of non-emergent
et al. 1996). treatment, followed by a consideration of status epilepticus.
CPK levels rise with muscle injury, and in cases when the
differential is between a ‘true’ grand mal seizure and a pseu- NON-EMERGENT TREATMENT
doseizure, this should be determined. Rises occur within 3
hours and tend to peak at a day and a half (Chesson et al. In non-emergent cases, when treatment of the underlying
1983; Libman et al. 1991). cause is either not possible or ineffective, utilization of an
An EEG, if possible, should be obtained concurrent AED is appropriate. The first step in choosing among the
with a typical event, as the finding of ictal electrical activity many AEDs available today is to determine the etiology, as
is obviously very important. The absence of any electrical seizures due to one of the idiopathic generalized epilepsies
change, however, does not unequivocably argue against an respond differently than do focal seizures.
epileptic etiology given that, albeit very rarely, the ictal Idiopathic generalized epilepsies generally respond to
EEG during a complex partial seizure may be normal treatment with valproic acid, and this is a reasonable first
despite clear paroxysmal activity on depth recordings (Lieb choice for patients with petit mal seizures (Sato et al. 1982)
et al. 1976; Morris et al. 1988; Williamson et al. 1986). and/or non-focal grand mal seizures (Marson et al. 2002) with
Neuroimaging, preferably by MR scanning, should be onset from childhood to early adult years. Ethosuximide is
considered to determine whether or not a lesion is present also effective for petit mal seizures but is not for grand mal
that could, with some probability, be expected to cause seizures and, given that most patients with childhood or
p 07.qxd 3/10/08 9:35 AM Page 273
juvenile onset absence epilepsy also, in addition to petit mal drug–drug interactions becomes so high that side-effects
seizures, have grand mal seizures, valproic acid seems prefer- are often unacceptable. Furthermore, with such ‘triple ther-
able. Importantly, certain other AEDs, such as phenytoin apy’ regimens there may be an exacerbation of the epilepsy:
(Genton et al. 2000), carbamazepine (Genton et al. 2000; not uncommonly, patients on triple therapy who carry a
Thomas et al. 2006), and oxcarbazepine (Gelisse et al. 2004) diagnosis of ‘treatment-resistant epilepsy’ enjoy a substan-
may worsen seizure control in patients with idiopathic gener- tial decrease in seizure frequency after one or more of their
alized epilepsies and therefore should be avoided. In cases AEDs are discontinued.
where valproic acid is only partially effective, further The mechanism or mechanisms underlying treatment
improvement may be obtained by adding topiramate (Biton resistance are not clear. Recent research has focused on the
et al. 1999), lamotrigine (Biton et al. 2005), or levetiracetam role of what are known as multidrug resistance proteins.
(Grunewald 2005). In patients who get little benefit from val- These proteins are normally found on capillary endothelial
proic acid or in whom it is poorly tolerated, consideration cells and serve to maintain the blood–brain barrier by
may be given to utilizing one of these ‘add-on’ drugs as pumping out foreign substances (such as AEDs) from the
monotherapy; however, it should be borne in mind that as yet interstitial fluid back into the blood: one theory holds that
there are no double-blind studies supporting this practice. they are up-regulated in patients with treatment resistance
Epilepsy characterized by focal seizures may respond to (Aronica et al. 2004). Regardless of the cause of treatment
monotherapy with any of the following: phenytoin or car- resistance, several options are open. In some cases, epilepsy
bamazepine (Heller et al. 1995; Mattson et al. 1985; surgery is appropriate, as for example in those with mesial
Ramsey et al. 1983; Rowan et al. 2005; Simonsen et al. 1976; temporal sclerosis (Engel 1996; Wiebe et al. 2001) or cer-
Troupin et al. 1977), oxcarbazepine (Beydoun et al. 2000; tain cases of focal cortical dysplasia (Kral et al. 2003). Vagal
Schacter et al. 1999), valproic acid (Beydoun et al. 1997; nerve stimulation (Handforth et al. 1998; Salinsky et al.
Callaghan et al. 1985; Heller et al. 1995; Mattson et al. 1996) may also be considered, and there is also some very
1992), gabapentin (Rowan et al. 2005), topiramate, or lam- preliminary evidence for the efficacy of transcranial mag-
otrigine (Brodie et al. 1995; Rowan et al. 2005) and leve- netic stimulation in patients with various cortical dys-
tiracetam (Brodie et al. 2007). The choice among these is plasias (Fregni et al. 2006).
guided by considerations of the patient’s general medical In cases where patients have been seizure free for two or
condition, potential drug–drug interactions with other more years, the possibility of tapering and discontinuing
medications, anticipated side-effects, etc. In cases where AEDs may be entertained. The decision to embark on this
patients fail to respond to monotherapy, one may choose course, however, is complex. To begin with, consideration
either to try monotherapy with a different AED or to add should be given to the consequences of a recurrence of
on an AED to the one already in place. In cases where the seizures and to the burden imposed by ongoing treatment.
first AED used as monotherapy was relatively ineffective or In patients with only simple partial seizures, the conse-
simply not tolerated, then a switch to another monother- quences of another seizure may not be severe, and if side-
apy agent is reasonable, however when the first AED had effects from current AED treatment are bothersome then
definite benefit and was well-tolerated, then it is reasonable discontinuation may seem attractive; on the other hand a
to consider an ‘add-on’ strategy. Most of the ‘add-on’ stud- history of grand mal seizures and a lack of side-effects
ies have been performed with patients already on either might give one pause. Another consideration, of course, is
phenytoin or carbamazepine, however, admittedly, there is the likelihood of recurrence, and several factors may enable
no consistency over all these studies. Consideration may be one to make a rough estimate in this regard (Callaghan et al.
given to the following as ‘add-on’ AEDs: valproic acid 1988; Cardoso et al. 2006; Spooner et al. 2006), including
(Willmore et al. 1996), gabapentin (Fuerstein et al. 1994; the presence or absence of a lesion, the frequency of seizures
Sivenius et al. 1991; US Gabapentin Study Group 1993), and the difficulty encountered in initially controlling
pregabalin (Beydoun et al. 2005; Elger et al. 2005), topira- them, the kinds of seizures experienced by the patient, and
mate (Faught et al. 1996; Privitera et al. 1996), lamotrigine the presence of interictal epileptiform discharges (IEDs).
(Binnie et al. 1989; Boas et al. 1996; Jawad et al. 1989; Not unreasonably, the presence of a lesion, such as mesial
Loiseau et al. 1990b; Matsuo et al. 1993; Messenheimer et al. temporal sclerosis, increases the risk; by contrast, patients
1994), and levetiracetam (Cereghino et al. 2000; Leppik with idiopathic generalized epilepsies appear to be at lower
et al. 2003; Tsai et al. 2006) (which appears to be at times risk. A history of very frequent seizures coupled with great
very effective [Stefan et al. 2006]). In choosing among these, difficulty in controlling them (as evidenced by the number
particular attention must be paid to potential drug–drug of trials of AEDs required to do so) suggests a more severe
interactions. In cases when patients fail to respond to treat- underlying process and this also increases the risk of recur-
ment with two AEDs, various options are open. First, one rence. The kinds of seizures experienced by the patient also
may try either monotherapy with a different agent or try a may serve as an indicator of the severity of the underlying
different combination of two agents. In some cases, patients process. Thus, a history of complex partial seizures with
have responded to treatment with a combination of three secondary generalization poses a higher risk than does a
AEDs but this strategy is very problematic: the risk of history of simple or complex partial seizures without sec-
both pharmacokinetic and, especially, pharmacodynamic ondary generalization or a history of non-focal grand mal
p 07.qxd 3/10/08 9:35 AM Page 274
seizures (as seen in the idiopathic generalized epilepsies). development of the seizure by ‘forcing his thoughts with
Finally, the presence of IEDs on an EEG obtained close to ‘might and main’ into some other channel’. Other tech-
the end of the 2-year seizure-free period indicates ongoing niques have been reported: one patient, whose aura con-
activity of the underlying disorder and suggests an increased sisted of an olfactory hallucination, was able to prevent a
risk of recurrence. Although some patients may fall at the complex partial seizure by the application of a ‘strong odor’
extremes of these risk factors, most fall in between and, con- (Efron 1956, 1957), and another patient, whose aura con-
sequently, much clinical judgment should be utilized in bal- sisted of an auditory hallucination of music, was able to
ancing these various risk factors. If a decision is made to abort the seizure by ‘imagining himself fishing, his favorite
taper and discontinue AEDs the process should be a slow leisure pursuit’ (Pritchard et al. 1985b).
one, generally extending over 3–6 months, and if more than
one AED is in place, only one should be tapered at a time. Status epilepticus
In addition to the foregoing, some general measures are Status epilepticus is approached differently depending on
appropriate in all cases. First, certain non-specific stresses the kind of seizure involved. Grand mal status epilepticus
may aggravate epilepsy and these should be avoided or is an acutely life-threatening event that also, in those who
treated. They include poor sleep, irregular dietary habits, survive, entails significant sequelae; thus it requires emer-
dehydration, febrile illnesses, hyperventilation, and exces- gent treatment. Complex partial status epilepticus, in con-
sive alcohol use. Second, there are certain specific disorders trast, is not life-threatening and, although sequelae have
which also aggravate epilepsy, including migraine, sleep been noted, they are uncommon and, consequently, emer-
apnea and, in some females, the menstrual cycle. Although, gency treatment may not be required. Simple partial status,
of itself, migraine probably does not cause seizures, there is petit mal status and amnestic status are, of themselves,
evidence that migraine may be able to precipitate seizures benign events and may be approached non-emergently.
in patients with epilepsy. In particular, it appears that a In all cases of status, regardless of the seizure type, a fin-
migraine aura may trigger either a partial or a grand mal ger stick glucose level is determined and if the level is low
seizure, the seizure being intercalated between the migraine then 50 mL of D50 W is given. Thiamine, 100 mg i.v.,
aura and the migraine headache (Marks and Ehrenberg should also be given if there is any suspicion of alcoholism
1993): in such cases effective migraine prophylaxis is essen- or severe malnutrition. Blood is sent for determination of
tial and either valproic acid or topiramate are logical glucose, sodium, potassium, calcium, magnesium, blood
choices as they are effective not only as AEDs, but also as urea nitrogen (BUN), and, if appropriate, AED levels.
prophylaxis against migraine. Obstructive sleep apnea may In cases requiring emergent treatment, intravenous
aggravate seizures and treatment of the apnea with contin- access is obtained and lorazepam is given in a total dose of
uous positive airway pressure may be very effective in ⬃0.07 mg/kg at a rate no faster than 2 mg/min; as a rule,
reducing seizure frequency (Devinsky et al. 1994b). Finally, fosphenytoin should then be administered in a total dose
some women will experience an increase in seizure fre- of 15–25 mg/kg at a rate of 100–150 mg/min (Browne et al.
quency either toward the end of the follicular phase or dur- 1996; Lowenstein et al. 1998; Ramsey and DeToledo 1996;
ing menstrual flow (Backstrom 1976), and although oral Treiman et al. 1998). Exceptions to this rule include the
contraceptives have been advocated in such situations following: allergy; a history of non-response to adequate
(Mattson et al. 1986) this is controversial (Dana-Haeri and levels of phenytoin; current treatment with phenytoin with
Richens 1983). blood levels in the therapeutic range; and cases where the
Reflex seizures, of course, constitute an invitation to the grand mal seizures are occurring as part of one of the idio-
utilization of common-sense measures at avoiding the pathic generalized epilepsy syndromes. In cases where one
reflex stimulus itself. In cases where this is not feasible, it of these exceptions obtain, consideration should be given
may be possible, in certain cases, to blunt the provocative to intravenous valproate in a total dose of 15–25 mg/kg
effect of the stimulus by repeatedly exposing the patient to (Misra et al. 2006): although current recommendations
that stimulus, as has been demonstrated in cases of suggest infusing this at a rate no faster than 20 mg/min (or
musicogenic (Forster et al. 1967) and reading (Forster et al. over a total of 60 min, whichever is longer), recent work
1969a) epilepsies. suggests that much faster infusions, at 3–10 mg/kg/min are
Remarkably, albeit rarely, some patients have found it effective and well tolerated (Boggs et al. 2000; Limdi et al.
possible to abort partial seizures. Thus, in some cases of 2007; Wheless et al. 2004). Regardless of whether fos-
simple partial seizures that undergo a Jacksonian march, phenytoin or valproate is given, an AED blood level should
the seizure may be aborted by vigorously rubbing the part be obtained approximately 2 hours after the infusion is
of the body that lies just proximal to the advancing march, completed, with subsequent doses based on levels and
and this holds true not only for motor (Russell and Whitty response. When all of these measures are under way the
1953; Symonds 1959), but also for sensory (Efron 1961; patient must be closely monitored, preferably in an intensive
Sutherling et al. 1990) marches. In the case of complex care unit (ICU). In cases when status persists despite these
partial seizures, Penfield (Penfield and Jasper 1954) noted measures, consideration may be given to utilizing two
that, when the aura consisted of some ‘change in the stream AEDs: thus, if a patient had been given fosphenytoin and
of thought’, the patient might be able to prevent the failed to respond, valproate could be added; alternatives
p 07.qxd 3/10/08 9:35 AM Page 275
7.4 Stroke 275
include levetiracetam (Patel et al. 2006) or phenobarbital, arteries arise the vertebral arteries. Under normal circum-
in a total dose of 20 mg/kg, at a rate no faster than stances, the entire blood supply to the brain is derived from
100 mg/min. In cases resistant to these measures, coma may the internal carotid arteries and the vertebral arteries, as
be induced with pentobarbital, midazolam, or propofol. described below: in clinical work, arteries derived from the
Non-emergent treatment may involve oral loading with internal carotid arteries are referred to as part of the ‘anterior
phenytoin, or, in cases of petit mal status, valproic acid. circulation’, whereas those derived from the vertebral arteries
Phenytoin may be loaded in a dose of 15–25 mg orally, and are referred to as part of the ‘posterior circulation’.
valproic acid likewise in a dose of 15–25 mg/kg (impor- Both common carotid arteries bifurcate at the level of
tantly, divalproex should not be used emergently given the the thyroid cartilage into an external carotid artery and an
long time required to obtain peak blood levels). internal carotid artery (ICA). The internal carotid artery
Alternatively, if the current episode of status occurred sec- may then be divided into four segments, namely cervical,
ondary to non-compliance with an AED other than phenyt- intrapetrosal, intracavernous, and supraclinoid. The cervi-
oin or valproic acid, and the patient had a clear history of cal segment rises from the bifurcation and passes up
response to that AED, one might simply load the patient through the neck, without giving off any branches. Upon
with this previously effective agent. arriving at the skull, the internal carotid artery then enters
the petrous portion of the temporal bone via the foramen
lacerum and passes through the temporal bone as the
7.4 STROKE intrapetrosal segment. The artery emerges from the tempo-
ral bone into the cavernous sinus, and passes horizontally
Stroke is defined as the more or less sudden occurrence of a through the sinus close to its medial wall. This intra-
neuropsychiatric deficit occurring secondary to a vascular cavernous portion bears important relations to the other
event, such as an ischemic infarction or an intracerebral hem- occupants of the cavernous sinus, namely the third, fourth
orrhage, and the diagnosis should be suspected in any patient and sixth cranial nerves, and the first and second divisions
with the acute onset of virtually any of the signs, symptoms or of the fifth cranial nerve. After passing through the cav-
syndromes described in the preceding chapters including, ernous sinus, the internal carotid artery then swings superi-
most especially, weakness (such as hemiparesis), sensory orly and emerges medial to the anterior clinoid process as
changes, aphasia, agnosia, neglect, or delirium. The evalua- the supraclinoid segment.
tion and care of stroke patients has undergone revolutionary After emerging from the cavernous sinus, the internal
advances in the recent past and, especially in acute cases, carotid artery gives off several branches, including the oph-
patients should generally be referred to stroke specialists. thalmic, posterior communicating, and anterior choroidal
arteries. The ophthalmic artery passes forward in relation
to the optic nerve and enters the orbit via the optic fora-
Clinical features men. The posterior communicating artery passes posteri-
orly, and forms part of the circle of Willis, described below.
Given that the clinical features of stroke are determined, in The anterior choroidal artery also passes posteriorly, giving
large part, by the vessel involved, this discussion will begin off important central branches, also described below. After
with a review of the arterial supply and venous drainage of giving off these three branches, the internal carotid artery
the brain. Once this is in mind, attention is then turned to then bifurcates into the anterior cerebral artery (ACA) and
the most common cause of stroke, namely ischemic infarc- the middle cerebral artery (MCA).
tion, followed by discussions of less common causes such The anterior cerebral artery passes anteriorly and medi-
as intracerebral hemorrhage and subarachnoid hemorrhage ally, crossing superior to the optic nerve, to reach the inter-
and, finally, of two rare causes, namely intraventricular hemispheric fissure. Before passing into the fissure, it is
hemorrhage and cerebral venous thrombosis. Finally, atten- joined to its partner on the opposite side by the anterior
tion is directed to various sequelae of stroke, such as demen- communicating artery. After passing into the interhemi-
tia and post-stroke depression. spheric fissure, the ACA, traveling inferior to the rostrum
and genu of the corpus callosum, gives off orbitofrontal
branches and a frontopolar artery. After rising over the
ARTERIAL SUPPLY AND VENOUS DRAINAGE OF THE BRAIN genu, the ACA then bifurcates into a callosomarginal
artery and a pericallosal artery, which extends along the
Arterial supply body of the corpus callosum all the way to the splenium.
In tracing the arterial supply to the brain (Tatu et al. 1996, Although this overall description of the ACA holds true in
1998), one may begin at the aortic arch, from which arises most cases, important normal variations may occur. In a
first the innominate artery, which, in turn, bifurcates into the few percent of cases, the ICA on one side does not give rise
right common carotid artery and the right subclavian artery. to an ACA, and in this situation the ACA on that side arises
Passing further along the aortic arch, the left common from the anterior communicating artery, such that both
carotid artery arises and, a little after that, the aortic arch ACAs draw their blood from one ICA. Another very
gives off the left subclavian artery. From both subclavian important variation is the fact that in over one-third of
p 07.qxd 3/10/08 9:35 AM Page 276
individuals a given ACA will supply not only its own hemi- occipital artery. The temporo-occipital artery courses later-
sphere, but also will send various branches to the opposite ally to supply the inferior surface of the temporal lobe and
hemisphere. Finally, in perhaps 5 percent of individuals, adjacent occipital lobe, including the occipitotemporal gyrus
there may be only one ACA: this azygous, or unpaired, ACA and the lingual gyrus. The internal occipital artery bifurcates
then supplies the medial aspect of both hemispheres. into the parieto-occipital artery and the calcarine artery. The
The MCA passes laterally, inferior to the anterior perfo- parieto-occipital artery, in addition to supplying the medial
rated substance, to reach the lateral cerebral fissure, where it aspect of the occipital and parietal lobes, also supplies the
typically bifurcates into superior and inferior divisions. The splenium of the corpus callosum. The calcarine artery sup-
superior division gives rise to the orbitofrontal artery, pre- plies the medial aspect of the occipital lobe, including the
Rolandic artery, Rolandic artery, anterior parietal artery, critically important calcarine cortex. An important normal
posterior parietal artery and, in about one-half of variant of the posterior cerebral artery, seen in about 10 per-
individuals, the angular artery. The inferior division in turn cent of individuals, consists of a ‘fetal’ pattern of circulation
gives rise to the temporopolar artery, the anterior temporal wherein one of the PCAs, rather than arising from the basilar
artery, the middle temporal artery, the posterior temporal artery, originates from the internal carotid artery, as it were
artery, and, in the other one-half of normal individuals, the replacing the posterior communicating artery.
angular artery. In a small percentage of individuals, rather The anterior, middle, and posterior cerebral arteries
than bifurcating, the MCA may undergo a trifurcation, or, supply most of the cerebral cortex. Subcortical structures,
in an even smaller percentage, may directly divide into the including the basal ganglia and the thalamus, are supplied
numerous branches just named. by various central branches, most, but not all, of which
Turning now to the vertebral arteries (which have arise from the circle of Willis. The first component of the
arisen from the subclavian arteries in the neck): these rise circle of Willis to consider is the posterior communicating
to the level of the sixth cervical vertebra where they enter artery, which, as noted earlier, arises from the ICA. The
the transverse foramina; subsequently, they rise through posterior communicating artery courses posteriorly to
the transverse foramina of the remaining cervical vertebrae anastamose with the PCA. Subsequent components of the
to eventually enter the cranium through the foramen mag- circle include the ipsilateral PCA, the contralateral PCA,
num. Once inside the cranium, they initially ascend on the contralateral posterior communicating artery, the con-
either side of the medulla, and eventually merge at the tralateral ACA, the anterior communicating artery, and the
junction of the medulla and pons to form the basilar ipsilateral ACA, which then brings us full circle. In addi-
artery. Before merging, however, in addition to giving off tion to some central branches, discussed immediately
numerous small penetrating branches to the medulla, they below, the circle of Willis also gives off multiple very small
also give rise to several large branches, namely the poste- penetrating branches that nourish, among other struc-
rior spinal artery, the posterior inferior cerebellar artery, tures, the hypothalamus and portions of the midbrain.
and the anterior spinal artery. The posterior spinal arteries The central branches to be considered now include the
move posteriorly and descend along the posterior aspect of following: the thalamopolar artery, the thalamo-perforating
the spinal cord. The posterior inferior cerebellar artery artery, the thalamogeniculate artery, the posterior
courses along the lateral aspect of the medulla and then choroidal artery, the recurrent artery of Heubner, the
reaches the inferior aspect of the cerebellum. The anterior lenticulostriate arteries, and the anterior choroidal artery.
spinal artery is formed by two branches, arising from both The thalamopolar artery arises from the posterior
vertebral arteries, which meet in the midline to form this communicating artery and supplies anterior and lateral
artery; the artery then descends along the anterior midline portions of the thalamus, including the dorsomedial
of the medulla to the cord below. nucleus, ventral lateral nucleus, and portions of the mam-
The basilar artery, arising from the junction of the two millothalamic tract. In a small minority of cases, both thala-
vertebral arteries, ascends along the ventral surface of the mopolar arteries may arise from a common pedicle arising
pons and onto the ventral surface of the midbrain where- from one or the other posterior communicating artery.
upon it bifurcates into the two posterior cerebral arteries. The thalamoperforating artery arises from the PCA
The basilar artery gives off numerous branches. The ante- medial to its junction with the posterior communicating
rior inferior cerebellar artery arises first and supplies the artery, and supplies the central portion of the thalamus,
inferior surface of the cerebellum. Penetrating branches including the intralaminar nuclei and portions of the mam-
are given off throughout the course of the basilar artery millothalamic tract. In a small minority of cases both thala-
and include paramedian, short circumferential, and long moperforating arteries may arise from a common pedicle.
circumferential arteries. Just before the basilar artery bifur- The thalamogeniculate artery arises from the posterior
cates into the posterior cerebral arteries (PCAs) it gives off cerebral artery lateral to the junction with the posterior
the superior cerebellar arteries, which nourish the superior communicating artery and supplies portions of the lateral
surface of the cerebellum. geniculate body and both the ventral posterolateral and
The PCA courses around the surface of the midbrain and ventral posteromedial nuclei of the thalamus.
passes superiorly medial to the tentorium, after which it The posterior choroidal artery arises from the PCA
bifurcates into a temporo-occipital artery and an internal lateral to the origin of the thalamogeniculate artery. The
p 07.qxd 3/10/08 9:35 AM Page 277
7.4 Stroke 277
posterior choroidal artery bifurcates into a medial poste- The next dural sinus to consider is the cavernous sinus,
rior choroidal artery and a lateral posterior choroidal which lies lateral to the sella turcica and its enclosed pitu-
artery. The medial posterior choroidal artery courses itary gland. The cavernous sinus, in turn, drains posteri-
medially to gain the medial aspect of the thalamus, where it orly by two other sinuses, the superior petrosal and inferior
supplies the anterior thalamic nuclei and the choroid petrosal sinuses, which connect, respectively, with the
plexus of the third ventricle. The lateral posterior choroidal transverse sinus and the internal jugular vein.
artery courses laterally and enters the choroidal fissure of The superficial cerebral veins lie on the cortex and drain
the temporal lobe to supply portions of the choroid plexus into the various nearby dural sinuses. Importantly, these
of the inferior horn of the lateral ventricle and portions of superficial cerebral veins are interconnected by various
the hippocampus. anastamotic veins that, by providing alternative outflows,
The recurrent artery of Heubner arises from the ACA minimize the consequences of a single occlusion. The deep
and gives off branches that, after arising through the ante- cerebral veins drain subcortical structures and the medial
rior perforated substance, supply the ventral portion of the aspects of the temporal lobes: the two most important
head of the caudate, the inferior portion of the anterior types of these veins are the internal cerebral veins and the
limb of the internal capsule, and the anterior portion of the basal vein of Rosenthal, which join to form the great vein
putamen. of Galen – as noted earlier this vein drains into the straight
The lenticulostriate arteries arise from the stem of the sinus.
MCA before it reaches the lateral cerebral fissure. These
arteries rise up through the anterior perforated substance, ISCHEMIC INFARCTION
after which they supply the superior portion of the poste-
rior limb of the internal capsule, the lateral portion of the Ischemic infarctions of the brain may be subdivided into
globus pallidus, and most of the putamen. the following groups: large vessel syndromes, occurring sec-
The anterior choroidal artery, as noted earlier, arises ondary to occlusion of one of the large pial vessels, such as
from the internal carotid artery. It courses posteriorly, lat- the MCA; low-flow (watershed) infarctions located in the
eral to the midbrain and then turns laterally to pierce the boundary zone between the areas of distribution of two
choroidal fissure of the temporal lobe and supply portions large vessels, for example the MCAs and ACAs; and lacunar
of the choroid plexus of the inferior horn of the lateral ven- syndromes resulting from occlusion of central or penetrat-
tricle and portions of the hippocampus. Before turning lat- ing arteries. Attention is then turned to transient ischemic
erally, however, the anterior choroidal artery also gives off attacks (TIAs), which occur due to temporary occlusion of
branches that supply the inferior portion of the posterior a vessel, and, finally, to so-called ‘silent’ infarctions.
limb of the internal capsule, the retrolenticular portion of
the posterior limb of the internal capsule and portions of Large vessel syndromes
the lateral geniculate body. A branch also supplies a por- In the following paragraphs, the typical syndromes seen
tion of the globus pallidus. with occlusion of the large cerebral vessels, namely the
middle, anterior, and posterior cerebral arteries, the ante-
Venous drainage rior choroidal artery, and the basilar and vertebral arteries,
Venous drainage of the brain is accomplished via the are discussed. It must be borne in mind, however, that
superficial and deep cerebral veins, which in turn drain more often than not only fragments of these syndromes are
into the dural venous sinuses. seen. This is particularly the case with embolic infarction,
Of the dural sinuses, the first to consider is the superior wherein, rather than occluding the large vessel at or close
sagittal sinus, which extends posteriorly along the superior to its origin, the embolus travels up the artery to lodge in a
edge of the falx cerebri to reach the sinus confluens. The smaller branch.
inferior sagittal sinus extends posteriorly along the free edge MCA infarction may be only partial, involving only the
of the falx cerebri to the edge of the tentorium cerebelli, superior division or the inferior division, or may be com-
where it joins with the great vein of Galen to form the plete, involving both divisions. Infarction in the area of dis-
straight sinus. The straight sinus, in turn, runs posteriorly tribution of the superior division typically produces a
in the junction of the falx cerebri and tentorium cerebelli to contralateral hemiparesis and hemisensory loss, with prefer-
eventually join the terminus of the superior sagittal sinus at ential involvement of the face and upper extremity. When
the sinus confluens. The sinus confluens then gives rise to the right hemisphere is affected, left neglect and anosognosia
the transverse sinuses, each of which courses anteriorly (Hier et al. 1983) are commonly seen; other signs that may
along the outer edge of the tentorium cerebelli. In a major- appear include asomatagnosia, constructional and dressing
ity of cases, the straight sinus enters directly into the left apraxia, and aprosodia. With involvement of the left hemi-
transverse sinus, whereas the superior sagittal sinus drains sphere a motor aphasia typically occurs: in cases of left-sided
directly into the right transverse sinus. The transverse sinus, infarction where the angular artery arises from the superior
upon reaching the junction of the occipital and petrosal division, the additional involvement of Wernicke’s area will
bones, empties into the sigmoid sinus, which curves down- produce a global aphasia; other signs that may occur include
ward to drain into the internal jugular vein. ideomotor or ideational apraxia and Gerstmann’s syndrome.
p 07.qxd 3/10/08 9:35 AM Page 278
Infarction in the area of distribution of the inferior division Vertebral artery occlusion or occlusion of a posterior
generally causes a contralateral hemianopia or quadran- inferior cerebellar artery (or occlusion of one of the perfo-
topia. With right-sided infarction, a delirium, often accom- rating branches of either of these arteries) may give rise to
panied by agitation (Caplan et al. 1986) is common and the classic Wallenberg or ‘lateral medullary’ syndrome (Kim
prosopagnosia may also be seen. With left-sided infarction, 2003; Sacco et al. 1993). Infarction of the lateral medulla typ-
in cases where the angular artery arises from the inferior ically involves the following structures: inferior cerebellar
division, one typically sees a sensory aphasia; delirium may peduncle, spinothalamic tract, the spinal tract and nucleus
also occur but is less common than with right-sided infarc- of the fifth cranial nerve, the nucleus ambiguus, vestibular
tion. Complete infarction, involving both the upper and nuclei, and descending sympathetic fibers. Respectively, the
lower divisions, is often a catastrophic event (Heinsius et al. corresponding symptoms are: ipsilateral ataxia; contralat-
1998) and, in addition to a profound hemiplegia, such a eral hemianesthesia of the extremities; ipsilateral anesthesia
‘malignant MCA infarction’ may also be accompanied by of the face (which may be accompanied by pain); hoarseness
stupor and vasogenic edema developing over the following and dysphagia; nausea, vomiting, and vertigo; and an ipsilat-
2–5 days may cause uncal or tentorial herniation with coma eral Horner’s syndrome. Occlusion of one of the originating
and death (Hacke et al. 1996): in such cases, decompressive branches of the anterior spinal artery may produce the
hemicraniectomy may be life-saving. ‘medial medullary’ syndrome (Kim et al. 1995). Here,
ACA infarction, classically, produces a contralateral infarction of the pyramid and of the emerging fibers of the
hemiplegia and hemianesthesia preferentially affecting the twelfth cranial nerve give rise to an ipsilateral paresis of the
lower extremity (Critchley 1930); when the left hemisphere tongue and a contralateral hemiparesis.
is involved, a transcortical motor aphasia may also appear. Cerebellar artery occlusion, including the posterior
When the corpus callosum is infarcted, one may also see a inferior, anterior inferior, and superior cerebellar arteries,
‘disconnection syndrome’ with left-sided, but not right- may cause vertigo, nausea, nystagmus, or ipsilateral ataxia.
sided, agraphia, tactile agnosia or apraxia, and, rarely, the Large infarctions, with attendant vasogenic edema, may,
alien hand syndrome. In cases of bilateral infarction (e.g., as by compressing the underlying brainstem, cause stupor or
may occur with an azygous ACA), paraplegia may occur, as coma, and in such cases emergent neurosurgical interven-
may abulia, a frontal lobe syndrome, or akinetic mutism. tion may be required (Jensen et al. 2005).
PCA infarction typically causes a contralateral hemi-
anopia (Castaigne et al. 1973; Pessin et al. 1987). If the infarc- Low-flow (watershed) infarctions
tion is on the left, one may also see alexia with agraphia, Watershed infarctions typically present with more or less
visual agnosia, and, if the temporal lobe is involved, a delir- atypical fragments of some of the large vessel syndromes.
ium. Infarctions on the right side that also involve the tempo- Thus, ACA–MCA watershed infarcts involving the pre-
ral lobe may be accompanied by prosopagnosia, and, in some frontal cortex and subjacent white matter may present with
cases a delirium (Medina et al. 1974). Bilateral infarction is brachial or crural paresis, and, when the left hemisphere is
signaled by cortical blindness, which may or may not be involved one may see mutism, initially, which resolves into
accompanied by Anton’s syndrome, with denial of the blind- a transcortical motor aphasia. MCA–PCA watershed
ness. In cases of bilateral infarction when both temporal infarcts may present with hemianesthesia, hemianopia,
lobes are involved, patients may also be left with a and, if the left hemisphere is involved, a transcortical sen-
Korsakoff ’s syndrome. As described earlier, central branches sory aphasia. ACA–MCA infarcts involving the centrum
arise from the PCA (i.e., thalamoperforating, thalamogenic- semiovale present with a variable mixture of either of the
ulate, and posterior choroidal) and if these are also occluded, foregoing syndromes. ‘Internal’ watershed infarcts in the
the typical symptoms just described will be joined by the syn- border zone between the MCA and lenticulostriate arteries
dromes peculiar to occlusion of these central branches, as may present with hemiparesis with or without hemi-
described below, under ‘lacunar syndromes’. Furthermore, anesthesia (Kumral et al. 2004).
when some of the very small penetrating branches to the
mesencephalon are involved, there may be hemiparesis, ocu- Lacunar syndromes
lomotor disturbances, and abnormal movements. Lacunes are small cavities, ranging in size from 1 to 20 mm,
Anterior choroidal artery infarction is marked by con- which typically represent infarctions in the area of distribu-
tralateral hemiplegia and hemianopia (Helgason et al. 1986). tion of one of the central or perforating branches described
Importantly, however, there is no accompanying aphasia or earlier (Fisher 1965, 1982; Mohr 1982). Although the clini-
neglect, and generally no, or only transient, hemianesthesia, cal presentation of lacunar infarctions is quite varied,
and it is the absence of these symptoms that distinguishes depending on the location of the lacune (Arboix et al.
these infarctions from those that occur secondary to occlu- 2006), certain presentations are quite distinctive and highly
sion of the MCA. suggestive of lacunar infarction. These ‘classic’ lacunar syn-
Basilar artery occlusion is often a catastrophic event dromes include ‘pure motor stroke’, ‘ataxic hemiparesis’,
(Caplan 1979; von Campe et al. 2003). Involvement of the ‘dysarthria-clumsy hand’, and ‘pure sensory stroke’.
basis pontis produces a quadriparesis, and involvement of Pure motor stroke, as the name suggests, is characterized
the midbrain will add diplopia. by a hemiparesis in the absence of sensory changes or other
p 07.qxd 3/10/08 9:35 AM Page 279
7.4 Stroke 279
symptoms such as aphasia or neglect. Typically, the upper Caudate lacunes (Caplan et al. 1990; Mendez et al. 1989),
and lower extremities are more or less equally involved (with as may occur with occlusion of the recurrent artery of
or without involvement of the ipsilateral lower face) and this Heubner, are typically characterized by frontal lobe symp-
pattern helps distinguish hemiplegia due to lacunar infarc- toms, especially abulia, and, less commonly, by chorea. Early
tion from hemiplegia due to middle or anterior cerebral on there may also be a dysarthria or mild hemiparesis, both
artery infarction wherein either, respectively, the upper or transient, and agitation or restlessness, especially when the
lower extremity is preferentially involved. The responsible lacune is in the right caudate nucleus.
lacune in pure motor stroke may be found in the contralat- Finally, and before leaving this discussion of lacunar
eral corona radiata, internal capsule, cerebral peduncle, basis syndromes, mention should be made of a condition known
pontis, or medullary pyramid. In cases where the lacune is in either as a ‘giant lacune’ or a ‘striatocapsular infarction’
the brainstem, one may see contralateral cranial nerve (Weiller et al. 1990). Here, all, or almost all, of the lenticu-
palsies, helping to further localize it: a third nerve palsy sug- lostriate arteries on one side are occluded, resulting in a
gests a midbrain location; a sixth nerve palsy, a pontine loca- relatively large infarction involving the posterior limb of
tion; and a twelfth nerve palsy, a medullary one. the internal capsule and the putamen. These infarctions are
In cases when pure motor stroke is characterized by typically larger than 20 mm in diameter and thus, techni-
either a monoparesis (of either the upper or the lower cally, do not qualify as ‘lacunes’. Their discrete shape and
extremity) or an isolated facial paresis, the responsible subcortical location, however, tempt one to use the word
lacune may not only be due to infarction in the area of dis- ‘lacune’ in referring to them, and this linguistic tension has
tribution of the central or perforating arteries and located given rise to the compromise term ‘giant lacune’. Symptom-
in the areas just described, but may also occur secondary to atically, as might be expected, such a giant lacune generally
infarction due to occlusion of terminal branches of the presents with a contralateral hemiplegia that may be
MCA (or, less commonly, the ACA), producing small accompanied, if the lesion is on the left, by a transcortical
infarctions in the motor cortex (Maeder-Ingvar et al. 2005; motor aphasia or, if the lesion is on the right, by left neglect.
Paciaroni et al. 2005). The mechanism underlying such a ‘giant lacune’ varies
Ataxic hemiparesis manifests with a combination of according to the anatomy of the lenticulostriate arteries in
ataxia and hemiparesis and the lacune is typically found in question. As noted earlier, in most cases the lenticulostriate
the corona radiata, internal capsule, or basis pontis. arteries arise sequentially from along the stem of the mid-
Dysarthria clumsy hand presents not only with dle cerebral artery, and in these cases the responsible lesion
dysarthria and clumsiness of the hand but also with a lower is generally an embolus that lodges in the MCA stem prox-
facial paresis ipsilateral to the clumsy hand; the lacune is imal to the origin of the first of the lenticulostriate arteries.
typically found in the corona radiata, internal capsule (near In such a scenario, the lack of collateral supply to the area
the genu), or the rostral basis pontis (Arboix et al. 2004). nourished by the lenticulostriate arteries leads to infarc-
Pure sensory stroke is characterized by hemianesthesia tion, whereas the cerebral cortex, being supplied with rich
occurring in isolation, and in the absence of motor weak- collaterals, may escape infarction. In other cases, all the
ness or other symptomatology. In such cases, a lacune is lenticulostriate arteries arise from one common pedicle
typically found in the ventrolateral thalamus: occasionally, arising from the MCA stem, and in these cases the occlusion
when the lacune is surrounded by a substantial amount of of this one pedicle, either by lipohyalinosis or encroach-
edema, involvement of the adjacent posterior limb of the ment of an atherosclerotic plaque, may do the job.
internal capsule may cause a contralateral hemiplegia,
which, however, is usually relatively mild and clears as the
edema resolves. In the months following a pure sensory Transient ischemic attacks
stroke, a minority of patients may begin to experience A TIA represents the results of fully reversible neuronal
chronic painful dysesthesiae in the involved limbs. ischemia due to a transient reduction in blood supply.
Other, less ‘classic’ lacunar syndromes may occur with Clinically, patients may experience any of the symptoms of
infarction of other portions of the thalamus or with lacu- ischemic infarction just described, with one critical differ-
nar infarction of the caudate nucleus. ence: after a brief period of time, the symptoms resolve
Lacunes affecting the anterior or central portions of the completely, with a full restoration of prior functional abil-
thalamus (Bogousslavsky et al. 1988; Giannopoulos et al. ity. There has been some controversy regarding the dura-
2006; Graff-Radford et al. 1985), as may occur with occlu- tion of symptoms seen in a TIA. In the past, it was felt that
sion of the thalamopolar or thalamoperforating arteries, symptoms could persist for up to 24 hours; however, more
typically present acutely with delirium or somnolence. recent studies with diffusion-weighted imaging (DWI) MR
Over time, patients typically become alert but are left with scanning have revealed that in cases when symptoms last
memory deficits (reflecting involvement of the mammil- much longer than 30 minutes (Inanatomia et al. 2004), and
lothalamic tract) or a frontal lobe syndrome (with involve- certainly for an hour or more (Ay et al. 2005), that actual
ment of the dorsomedial nucleus); furthermore, when the infarction has generally occurred. Thus, it is probably best
lacune is on the left, aphasia may occur and, when on the to reserve this diagnosis for cases where symptoms last no
right, neglect may be seen. longer than a half hour, and in no case for more than an
p 07.qxd 3/10/08 9:35 AM Page 280
hour, and, if MR scanning is performed, for cases in which In some cases, the hemorrhage will extend into one of
DWI is negative. the ventricles, generally producing a catastrophic worsen-
The transient reduction in blood flow may be due to ing clinically, with increased headache, decreased level
either an embolus that fragments and passes on in a few of consciousness, and stiff neck. Such ventricular extension
minutes, or to temporary low flow past a thrombus or is most common when the hemorrhage is close to a ventri-
through a stenosed artery, as may occur during an episode cle, as may be seen with a caudate hemorrhage secondary
of systemic hypotension. One very important kind of TIA, to rupture of the recurrent artery of Heubner or a thalamic
not mentioned earlier, is amaurosis fugax (‘fleeting blind- hemorrhage secondary to rupture of the thalamo-
ness’, also referred to as transient monocular blindness), perforating artery; putaminal hemorrhages, secondary to
wherein the patient experiences partial or complete blind- rupture of a lenticulostriate artery, may also extend into
ness for a matter of minutes in one eye: such episodes the nearby lateral ventricle.
are highly suggestive of a disease in the ipsilateral carotid In cases of cerebellar hemorrhage, the proximity of the
artery proximal to the origin of the ophthalmic artery. hemorrhage to the brainstem sets the stage for another
TIAs may herald either embolic or thrombotic infarc- mechanism of catastrophic worsening, namely compression
tions, including lacunar infarctions. Indeed, in one study of the underlying brainstem. When this occurs, coma and
(Rothwell et al. 2005), approximately 20 percent of TIA death may occur, and surgical decompression is mandatory.
patients went on to have a stroke: in 17 percent of those who
did develop stroke, the stroke occurred on the same day as SUBARACHNOID HEMORRHAGE
the TIA, in 9 percent on the next day, and in 43 percent over
the following week. These are sobering figures and serve to Most cases of subarachnoid hemorrhage present in a cata-
stress that a TIA is not a benign event but rather constitutes strophic fashion (Suarez et al. 2006): the eruption of blood
a serious warning of impending stroke. Given this, it is at arterial pressure within the subarachnoid space causes a
appropriate, if one is not already done, to immediately insti- very rapid rise in intracranial pressure, with severe
tute a work up, as described below, just as if the patient had headache, nausea and vomiting, delirium, stupor, or coma.
already had an ischemic infarction, and then to pursue The headache may rise to its maximal intensity over sec-
appropriate treatment. onds, and is often described by patients as the worst in
their lives. Neck stiffness is common but may not appear
‘Silent’ infarctions immediately. In some cases when the arterial eruption is
directed toward the parenchyma, a jet of blood may pierce
It is important to note that ischemic infarctions may be into the brain, causing an intracerebral hemorrhage.
‘silent’, that is to say they either, in and of themselves, pro- In 20–40 percent of cases, this full picture may be pre-
duce no symptoms or produce symptoms of such mildness ceded by transient ‘sentinel’ headaches occurring second-
that no attention is brought to them. This may be a com- ary to minor ‘warning leaks’ that terminate spontaneously
mon occurrence; indeed in patients who have a clinical his- (Ostergaard 1990).
tory of stroke, MR scanning with DWI reveals subsequent Seizures may complicate the clinical picture within the
silent infarctions in approximately one-third of all cases first 24 hours, and are seen in up to one-fifth of all patients.
within the first 5 days, with approximately one-fifth of all Patients who survive the initial event are at risk for sig-
cases going on to have silent infarcts in the 30- to 90-day nificant complications (Hijdra 1988) over the following
period (Kang et al. 2006). weeks, including rebleeding, vasospasm with cerebral
Despite being individually ‘silent’, these infarctions infarction, and the development of hydrocephalus.
should not be considered as benign, given that, with an Rebleeding may occur in up to 20 percent of patients and,
accumulation of them, a multi-infarct or a lacunar demen- although it is most common within the first 24 hours, the
tia (as discussed in Sections 10.1 and 10.2, respectively) risk extends for two or more weeks. Vasospasm of cerebral
may eventually develop. arteries passing through the subarachnoid blood may
occur, leading to clinically evident ischemic infarction in
INTRACEREBRAL HEMORRHAGE approximately one-third of all patients (Hijdra et al. 1986):
serial MR scans have demonstrated that approximately a
Clinically, intracerebral hemorrhage is typified by the further fifth of patients will have ‘silent’ ischemic infarcts
gradual evolution, over from 30 minutes to many hours, of (Shimoda et al. 2001). The risk for vasospasm appears
headache, nausea, and vomiting, and a focal deficit appro- within the first few days, peaks at 5–10 days and then sub-
priate to the location of the enlarging hemorrhage; with sides by 2 weeks. Acute hydrocephalus, with headache and
large putaminal or thalamic hemorrhages, stupor may also lethargy, may be seen in up to 20 percent of patients within
occur. In a significant minority seizures may also occur the first hours or days, and occurs secondary to blockage,
during the initial presentation (Caplan 1988). Such hem- by clotted blood, of the exit foramina of the fourth ventri-
orrhages are readily visualized on CT scanning and their cle. Chronic hydrocephalus, secondary to restricted passage
location gives a strong clue to the underlying mechanism of cerebrospinal fluid (CSF) through the arachnoid villi,
of the bleed. may occur in the weeks or months following the initial
p 07.qxd 3/10/08 9:35 AM Page 281
7.4 Stroke 281
bleed, presenting with dementia, incontinence, and gait SEQUELAE OF STROKE

disturbance.
Other complications include arrhythmias and hypo- The sequelae of stroke include dementia, depression, anxi-
natremia. The hyponatremia, in turn, may be secondary to ety, and other sequelae, such as emotional incontinence, the
either the syndrome of inappropriate ADH secretion catastrophic reaction, the frontal lobe syndrome, and,
(SIADH), or, more commonly, cerebral salt wasting (CSW) much less commonly, mania or psychosis.
(Rabinstein and Wijdicks 2003). Differentiating SIADH
Dementia
from CSW is critical, as the treatments are radically differ-
ent. In SIADH there is an increased release of ADH, with With multiple ischemic infarctions or intracerebral hem-
consequent increased renal reabsorption of water leading to orrhages, patients may be left demented. This may occur
hyponatremia in the setting of volume expansion. By con- with either cortical or white matter infarcts, producing a
trast, in CSW a release of natriuertic factors leads to renal multi-infarct dementia (discussed further in Section 10.1),
sodium and fluid loss and a hyponatremia in a setting of or with lacunes, producing a lacunar dementia (discussed
volume contraction. SIADH is treated by fluid restriction, in Section 10.2). Typically, in such cases, one finds a his-
whereas CSW is treated by the administration of saline. tory of repeated stroke; however, occasionally, a ‘strategi-
cally’ placed single infarction or hemorrhage may leave the
patient with a dementia, as for example with infarcts or
INTRAVENTRICULAR HEMORRHAGE
hemorrhages within either temporal lobe or a hemorrhage
Intraventricular hemorrhage presents in a fashion similar or lacune in the thalamus.
to subarachnoid hemorrhage. Chronic communicating Subarachnoid hemorrhage may also be followed by a
hydrocephalus is a common sequela. dementia, due either to chronic hydrocephalus or multiple
infarctions due to vasospasm. When infarction is at fault,
one may find either a relatively small number of large ves-
CEREBRAL VENOUS THROMBOSIS
sel infarcts or a myriad of ‘microinfarcts’ occurring sec-
Thrombosis of one of the dural sinuses (most commonly ondary to spasm of small vessels. CT scanning, although
the superior sagittal or the transverse sinus) may or may quite capable of demonstrating the large infarcts, will miss
not be followed by cerebral infarction, depending both on the smaller ones, and hence MRI may be required.
whether drainage of a cerebral vein is blocked by the Cerebral venous thrombosis, if accompanied by multi-
thrombus and on whether or not the vein in question lacks ple venous infarctions, may also leave patients demented;
the anastamotic connections that might ensure adequate in the absence of these, most patients, if they survive, do so
venous drainage. When these unfavorable conditions are without cognitive sequelae.
met, venous congestion of the subserved area occurs with
the gradual appearance of a hemorrhagic infarction and Post-stroke depression
the appearance, clinically (Bousser et al. 1985; Cantu and In the weeks or months following stroke, close to one-half
Barregarrementeria 1993; Gosk-Bierska et al. 2006), of the of all patients will develop a depression of variable severity.
gradual onset of headache, focal deficits appropriate to the The location of the infarct or hemorrhage plays a part here,
infarcted area, and, in a significant minority, seizures. with lesions in the anterior portions of the frontal lobes
Thrombosis of the vein of Galen, although uncommon, being more likely to cause depression. Of interest, in cases
may be given special consideration here, given its clinical where the depression appears relatively early on, within
expression. In these cases, the thalami, which are drained the first week or two, left frontal lesions are more likely,
by the internal cerebral veins, may undergo hemorrhagic whereas in cases where the onset is delayed for months,
infarction, and this may result in stupor or coma (van den lesions are found with approximately equal frequency in
Bergh et al. 2005) or, in milder cases, a subacute onset of either the left or the right frontal area. Depression has also
dementia (Krolak-Salmon et al. 2006). been noted with lesions of the left basal ganglia.
Thrombosis of the superior sagittal sinus, by causing an In evaluating a patient for possible post-stroke depres-
elevation of intracranial pressure, may cause symptoms even sion, toxic and metabolic factors must also be considered.
in the absence of venous infarction, and patients may pres- Medications (e.g., metoclopramide or nifedipine) may
ent with the gradual evolution of headache and delirium. cause depression, and fatigue and loss of appetite are very
Thrombosis of the cavernous sinuses produces a dis- common with infections and certain metabolic disorders,
tinctive syndrome with proptosis secondary to impaired including hyponatremia and uremia.
venous drainage from the eye, and ophthalmoplegia, sec- Treatment with either citalopram (Anderson et al.
ondary to compression of the third and fourth cranial 1994) or nortriptyline (Lipsey et al. 1984; Robinson et al.
nerves found in the wall of the sinus itself. 2000) is effective; fluoxetine was found effective in one
The evolution of symptoms seen with venous infarction study (Wiart et al. 2000) but not in another (Robinson
is very gradual, spanning days or even weeks. This leisurely et al. 2000)
onset reflects the gradual propagation of the clot and the Of interest, given the frequency with which post-stroke
equally gradual failure of collateral drainage. depression occurs, efforts have been made to determine if
p 07.qxd 3/10/08 9:35 AM Page 282
antidepressants can prevent the appearance of depression. venous thrombosis, and each of these is discussed in turn.
In this regard, both nortriptyline and fluoxetine were found Certain rare or unusual other causes of stroke, such as cere-
effective; notably, however, when these medicines were dis- bral autosomal dominant arteriopathy with subcortical
continued after approximately 2 years of continuous treat- infarcts and leukoencephalopathy (CADASIL), are then
ment, whereas the fluoxetine-treated patients did well, the discussed, followed by a suggested work up for the new
nortriptyline-treated patients were more likely to subse- stroke patient.
quently develop a depression (Narushima et a. 2002).
Sertraline has also been studied, with one study (Rasmussen ISCHEMIC INFARCTION
et al. 2003) demonstrating prophylactic efficacy and another
not (Almeida et al. 2006). Ischemic infarction occurs when arterial blood supply is
reduced below that required for tissue viability and such
Anxiety reductions may occur via a variety of mechanisms. First,
Chronic anxiety is seen in a small minority of stroke embolic infarctions occur when an embolus, say from the
patients and appears to be more common with right hemi- heart, lodges in an artery, thus occluding it. Second, throm-
sphere infarctions. botic infarctions occur when a thrombus forms inside an
In most cases of anxiety seen after stroke, the anxiety, artery, typically on top of an ulcerated atherosclerotic
rather than occurring in an isolated fashion, rather is part plaque, causing occlusion. These two mechanisms account
of a post-stroke depression and in such cases an additional for most large vessel syndromes, and may also underlie cer-
diagnosis should not be made. Other differential possibili- tain of the lacunar syndromes. Third, low-flow (watershed)
ties include alcohol or benzodiazepine withdrawal, and infarctions occur secondary, not to occlusion, but to a crit-
general medical conditions such as chronic obstructive ical reduction in perfusion pressure. Fourth, and finally,
pulmonary disease or hypocalcemia. small penetrating arteries may be subject to lipohyalinosis,
Benzodiazepines are often prescribed: caution should leading to their gradual occlusion and producing a lacunar
be exercised here, however, as post-stroke patients may be syndrome.
more likely to develop cognitive deficits or lethargy sec-
ondary to these medications. Embolic infarctions
Emboli may be either cardiogenic (Caplan et al. 1983),
Other sequelae arising from the heart, or ‘artery-to-artery’ wherein they
Emotional incontinence, discussed further in Section 4.7, is arise from a thrombus on an arterial wall and travel down-
characterized by displays of uncontrollable laughter or cry- stream to eventually plug a smaller caliber artery. The most
ing without any corresponding emotion and occurs second- common cause of cardiogenic embolic infarction is atrial
ary to bilateral interruption of the corticobulbar tracts. fibrillation, wherein thrombi form within either the left
Nortriptyline (Robinson et al. 1993) and citalopram in doses atrium or atrial appendage. Emboli are also seen in the sick
of 10–20 mg/day (Andersen et al. 1993) are both effective. sinus syndrome; however, here the increased risk is proba-
A catastrophic reaction, as discussed further in Section bly due to the associated atrial fibrillation. Atrial myxomas,
4.24, may be seen in close to 20 percent of patients and although rare, are very prone to fragment and undergo
appears to be particularly common with infarction of the embolization. Valvular disease is also associated with
anterior left hemisphere or the left basal ganglia. emboli. In the case of mitral stenosis, this increased
The frontal lobe syndrome, discussed in Section 7.2, risk may be related simply to the commonly associated
may be seen with infarction or hemorrhage of the frontal atrial fibrillation; however, in both infective endocarditis
lobes, caudate nucleus, or thalamus. Patients may present (Anderson et al. 2003) and Libman–Sacks endocarditis, actual
with varying combinations of disinhibition, perseveration, embolization from the affected valves does occur. Prosthetic
and affective changes. valves may be complicated by thrombus formation with
Mania is a rare sequela to stroke and, as discussed in embolization, and this is much more likely with mechani-
Section 6.3, may be seen after infarction of the midbrain, cal than with bioprosthetic valves. Myocardial infarction is
thalamus, anterior limb of the internal capsule, and adjacent associated with thrombus formation and embolization,
head of the caudate nucleus, or the frontal or temporal lobes. both acutely and in the chronic phase. Acutely, thrombi
Psychosis, likewise, is a rare sequela, and, as discussed in may form on the damaged endocardium, and the period of
Section 7.1, may occur with infarction of the frontal or risk here extends up through the first month or so post
temporal cortex, or the thalamus. myocardial infarction. Chronically, thrombi may form in
cases characterized by ventricular aneurysm or large areas
of reduced cardiac contractility. Another cardiac condition
Etiology favoring thrombus formation is dilated cardiomyopathy.
In all the foregoing cardiac conditions, emboli arise from
The etiology of stroke varies according to whether it is due the left side of the heart: there is another condition, known
to ischemic infarction, intracerebral hemorrhage, subarach- as ‘paradoxical embolization’ wherein emboli travel first
noid hemorrhage, intraventricular hemorrhage, or cerebral through the right heart. In these cases, one most commonly
p 07.qxd 3/10/08 9:35 AM Page 283
7.4 Stroke 283
finds a patent foramen ovale; other defects allowing for clinical change during hemorrhagic transformation: it is
such paradoxical embolization include atrial septal defect, clinically ‘silent’.
ventricular septal defect, and pulmonary arteriovenous
fistulae. Thrombotic infarctions
Artery-to-artery emboli typically have their origin in a Atherosclerotic occlusion of an artery, after embolus, is the
thrombus atop an atherosclerotic plaque. Typical scenarios next most common cause of cerebral infarction.
include emboli arising from the origin of the ICA and trav- Atherosclerosis is most likely to occur at areas of turbulent
eling downstream to occlude a branch of the MCA, or aris- blood flow (Moosey 1966). In the anterior circulation, this
ing from the basilar artery, then traveling downstream to includes the origin of the common carotid artery, its bifur-
eventually occlude a branch of the PCA. cation into the internal and external carotid arteries, the
Emboli may also occur in association with cardiac sur- intracavernous portion of the internal carotid artery, and
gery, especially valve replacement and coronary bypass the proximal portions of the middle cerebral and anterior
grafting. Such cases are often associated with significant cerebral arteries. In the posterior circulation, the likely
arteriosclerosis of the aorta, and when the aorta is clamped areas include the origins of the subclavian arteries, the ori-
and unclamped, showers of embolic material may be dis- gin of the vertebral arteries, the proximal portion of the
lodged. Mere cardiac catheterization may also cause embolic intracranial vertebral artery, the distal portion of the
infarction, either secondary to dislodgment of a portion of intracranial vertebral artery, the basilar artery, and the prox-
an aortic plaque or secondary to thrombus formation on the imal portion of the PCA. The formation and enlargement of
tip of the catheter (Khatri and Kasner 2006). the atherosclerotic plaques is a slow process, extending over
Carotid artery dissection, although occurring across the from months to years, and as this gradual encroachment of
lifespan, should be especially considered in any patient the arterial lumen occurs, collateral circulation forms to
under the age of 45 years who has had an embolic infarc- supply the downstream cerebral tissues that are being grad-
tion (Ahl et al. 2004). With dissection of the carotid artery ually deprived of their blood supply. The development of
and rupture of the intima, a thrombus forms, which may such collateral circulation explains why atherosclerotic
serve as a source for emboli (Fisher et al. 1978). Suggestive occlusion of an artery may, even if complete, cause no
clinical evidence includes headache, neck pain, and, due to symptoms at all. When, however, a thrombus forms on top
compression of ascending sympathetic fibers, Horner’s of a cracked or ulcerated atherosclerotic plaque, the stage is
syndrome, all occurring ipsilaterally to the infarction (Lee set for infarction. One mechanism, as noted above, is
et al. 2006). embolization of a portion of the thrombus downstream to
Regardless of the source of the embolus, whether it is car- plug a smaller caliber artery. Another mechanism involves
diac or from an upstream artery, the sequence of events in occlusion of the artery by the developing thrombus itself.
embolic infarction is essentially the same. In all cases, the Such thrombotic occlusion generally occurs over hours or
embolus is borne downstream, through arteries of progres- a day or more, and thus most strokes due to thrombotic
sively smaller caliber, until finally it lodges in an artery, caus- occlusion, as compared with embolic infarctions, have a
ing its occlusion. Clinically, such plugging of an artery gives relatively leisurely onset. An exception to this rule is when
rise to a rapid onset of symptoms, over from seconds to hemorrhage occurs inside an atherosclerotic plaque: here,
minutes. In some cases, the embolic plug remains in place; enlargement of the plaque into the lumen may occur rap-
however, in many cases the embolic thrombus fragments, idly, with occlusion occurring within minutes.
dislodges, and passes further downstream, either to plug yet In cases of thrombotic infarction when traditional risk fac-
a smaller artery or, if the fragments are sufficiently small, to tors, such as hypertension, hyperlipidemia, and diabetes mel-
pass through the capillary bed into the venous circulation. In litus are absent, or when the patient is under 45 years old, it is
cases when such dislodgement occurs early, before tissue appropriate to look for other causes of thrombus formation.
infarction occurs, one may see clinical improvement, which These include deficiencies of the naturally occurring anti-
in some cases is dramatic: the so-called ‘spectacular shrink- thrombotic agents protein S, protein C, and anti-thrombin
ing deficit’ (Minematsu et al. 1992), wherein the clinical III, and mutations in factor V Leiden (Bertina et al. 1994;
symptomatology undergoes a dramatic improvement as the Nedeltchev et al. 2005). The anti-phospholipid syndrome
embolus dislodges and travels downstream. However, in should also be tested for. This syndrome (Bailey et al. 1989),
cases when infarction has already occurred, the passage of when fully developed, is characterized by a history of throm-
the embolus downstream, rather than leading to clinical bophlebitis, miscarriage, stroke and heart attack, and by the
improvement, is followed by ‘hemorrhagic transformation’ presence of Libman–Sacks endocarditis, thrombocytopenia,
of the infarct (Okada et al. 1989). Here, with the renewed and a false-positive VDRL test: laboratory testing reveals ele-
presence of blood flow in the infarcted area at arterial pres- vations of anti-cardiolipin antibodies (both IgG and IgM) and
sure, multiple petechial hemorrhages form within the area lupus anticoagulant. Consideration should also be given to
of infarction. Such hemorrhagic transformation occurs in carotid artery dissection. As noted above, such dissection may
about one-third of cases, and although it generally takes be followed by thrombus formation with embolization but, in
places within the first 2 days, transformation may occur for some cases, rather than embolization, the thrombus may pro-
up to 10 days post-stroke. Importantly, there is usually little ceed to occlude the carotid artery itself.
p 07.qxd 3/10/08 9:35 AM Page 284
Low-flow (watershed) infarctions INTRACEREBRAL HEMORRHAGE

‘Low-flow’ infarctions differ from embolic and thrombotic When the hemorrhage involves subcortical structures (e.g.,
infarctions in that the arteries serving the infarcted area are putamen, caudate, or thalamus), brainstem (typically the
not, in fact, occluded. Certain portions of the cerebral cor- pons) or cerebellum, the bleeding has usually occurred sec-
tex lie at the very periphery of the areas of distribution of ondary to rupture of a microaneurysm on one of the cen-
major cerebral arteries and these areas are quite vulnerable. tral or penetrating arteries (Cole and Yates 1967), which, in
Perfusion pressure falls as one travels further down the turn has usually developed on the basis of longstanding
arterial tree and at these peripheries pressure is relatively uncontrolled hypertension.
quite low. Consequently, whenever there is a substantial By contrast, when the hemorrhage is ‘lobar’, that is to say
reduction of pressure upstream, the pressure at the periph- situated in one of the lobes of the cerebrum, a variety of
ery may fall below that required for tissue viability and causes may be at fault, including cerebral amyloid angiopa-
infarction may occur. Such upstream reductions may thy, hemorrhage into a tumor, rupture of a vascular malfor-
occur with gradual artherosclerotic narrowing, with sys- mation (e.g., an arteriovenous malformation, a cavernous
temic hypotension (as may occur with cardiac arrest or as a angioma, or a venous angioma), vasculitis, or in the setting
side-effect of numerous drugs), or a combination of these of anticoagulant or thrombolytic treatment: patients
mechanisms. Such ‘low-flow’ infarctions are generally treated with warfarin may experience lobar hemorrhages
referred to as either ‘watershed’ or ‘border zone’ infarctions secondary to minor trauma and intracerebral hemorrhage
and have a characteristic location. Watershed infarctions at is a feared complication of treatment with tissue plasmino-
the border zone of the anterior and middle cerebral arter- gen activator. Other possible causes include vasculitis or use
ies (ACA–MCA) occur either at the dorsolateral prefrontal of sympathomimetic agents, such as cocaine.
cortex or extend through the central portion of the
centrum semiovale. Those occurring at the border zone of
the middle cerebral and posterior cerebral arteries SUBARACHNOID HEMORRHAGE
(MCA–PCA) are typically found in the parieto-occipital Subarachnoid hemorrhage (van Gijn and Rinkel 2001) is
cortex. Finally, there is an ‘internal’ border zone, lying most often due to rupture of a berry aneurysm. Other
between the lenticulostriate arteries and pial branches of causes include mycotic aneurysms, trauma, rupture of an
the MCA: infarctions in this border zone are typically arteriovenous malformation into the subarachnoid space,
found in the periventricular white matter. In cases of uni- vasculitidies, and a condition known as perimesencephalic
lateral watershed infarction, there is generally an associated hemorrhage (van Gijn et al. 1985). This last entity is char-
tight stenosis of the internal carotid artery; simultaneous acterized by hemorrhage surrounding the midbrain and
bilateral watershed infarcts generally only occur with dra- pons; symptoms are typically mild and it is suspected that
matic systemic hypotension, for example with cardiac the bleeding in this case, unlike all the other causes, is
arrest. venous.
Lipohyalinosis
INTRAVENTRICULAR HEMORRHAGE
Lipohyalinosis is generally considered to occur secondary
to hypertension and affects the central branches, described Hemorrhage into a ventricle may, as noted earlier, occur
above, and the penetrating branches arising from the secondary to extension of an intracerebral hemorrhage.
vertebral and basilar arteries. With occlusion of one of these ‘Primary’ intraventricular hemorrhage may also occur: this
small arteries, a correspondingly small infarction, known as is rare, and generally due to bleeding from a vascular mal-
a ‘lacune’ typically occurs. Occlusion of central and pene- formation adjacent to the ventricle.
trating arteries, while most commonly due to lipo-
hyalinosis, may also occur secondary to atherosclerosis CEREBRAL VENOUS THROMBOSIS
(Caplan 1989) and, rarely, to embolic occlusion.
Atherosclerosis, as noted earlier, often involves the basilar Cerebral venous thrombosis, as noted earlier, generally is
artery, and in such a case an atherosclerotic plaque may, as seen as a complication of thrombosis of one of the dural
it gradually enlarges, slowly lap over the ostium of the pen- sinuses. Such thrombosis, in turn, may be due to a number
etrating artery, thus occluding this innocent bystander. A of causes (Gosk-Bierska et al. 2006), such as Behçet’s syn-
similar sequence of events may occur in the stem of the drome, the anti-phospholipid syndrome, deficiencies of
MCA, leading to occlusion of one or all of the lenticulostri- anti-thrombin III or of proteins S or C, systemic lupus ery-
ate arteries. Embolic occlusion of a small central or pene- thematosus, the puerperium, paroxysmal nocturnal hemo-
trating artery is unusual given that most emboli are borne globinuria, in association with certain malignancies, during
along in the mainstream of the large parent artery and sim- treatment with oral contraceptives, and in association with
ply do not make the midstream turn required to enter cen- certain infections: otitis or mastoiditis may lead to throm-
tral or penetrating arteries, which generally arise at a more bosis of the transverse sinus, and facial or sinus infection to
or less right angle to their parent artery. thrombosis of the cavernous sinus.
p 07.qxd 3/10/08 9:35 AM Page 285
7.4 Stroke 285
OTHER CAUSES OF STROKE severe headache. Embolic infarctions are generally of acute
onset, with the maximal clinical deficit being reached rapidly,
Other rare or relatively uncommon causes of stroke over minutes; by contrast thrombotic infarctions are typi-
include CADASIL, moyamoya disease, vasculitidies (e.g., cally of gradual or ‘stuttering’ onset, over hours or longer.
cranial arteritis and systemic lupus erythematosus), com- Strokes due to intracerebral hemorrhage are relatively grad-
plicated migraine, and subclavian steal. CADASIL is sug- ual in onset and are generally accompanied by significant
gested by a history of migraine and by the presence of headache. Strokes due to subarachnoid hemorrhage are of
leukaraiosis in the external capsule and temporal lobe. very acute onset, sometimes over seconds, and are typified by
Moyamoya disease (Chiu et al. 1998; Mineharu et al. 2006) very severe headache; intraventricular hemorrhage shares
is characterized by stenosis of the terminal portions of both these characteristics. Stroke due to cerebral venous thrombo-
internal carotid arteries with development of a large num- sis is generally of leisurely onset, over days or longer, and is
ber of collateral vessels from the circle of Willis: the name generally accompanied by a more or less severe headache.
of this disorder is Japanese for ‘puff of smoke’, which is the Although these clinical features are helpful, exceptions
appearance generated by these numerous collaterals as are not uncommon to these guidelines, and hence imaging
seen on arteriography. Clinically, patients present with is indispensible. Although MR scanning with DWI is far
both subcortical infarctions and subcortical hemorrhages. more sensitive than CT scanning (Chalela et al. 2007;
Moyamoya disease may be either primary or secondary to Lansberg et al. 2000), CT scanning is generally utilized
such conditions as Down’s syndrome, von Recklinghausen’s first, not only because of its speed and ready availability but
disease, or irradiation. Cranial arteritis is suggested by con- also because it is at least as sensitive as is MRI for the detec-
current headache and an elevated erythrocyte sedimentation of the blood characteristic of hemorrhage transforma-
tion rate (ESR), and systemic lupus erythematosus by tion of an ischemic infarction, intracerebral hemorrhage,
associated symptoms such as arthralgia and rash. Other vas- subarachnoid hemorrhage, intraventricular hemorrhage,
culitidies to consider include Sjögren’s syndrome, suggested or cerebral venous thrombosis.
by dryness of the eyes and mouth, and Sneddon’s syndrome, In ischemic infarction, the CT scan is generally normal
heralded by livedo reticularis. Complicated migraine is sug- early on. By 1 hour, some indistinctness of the gray-white
gested by the appearance of stroke in the setting of a migraine boundary may occur, and in patients with occlusion of the
headache. The subclavian steal syndrome (Hennerici et al. MCA a ‘hyperdense MCA sign’ may be seen in about one-
1988) occurs secondary to stenosis of the subclavian artery half of cases. Beginning 6 hours after onset, an increasing
proximal to the origin of the vertebral artery on either the proportion of cases will demonstrate radiolucency in the
left, or, less commonly, the right side. With flow through area of the infarction, and up to 50 percent of cases will
the subclavian artery reduced, any exercise of the ipsilateral demonstrate this by 12 hours. If hemorrhagic transforma-
arm, with its concomitant increased blood demand, will tion occurs one may see either stippled areas of radiodensity
‘steal’ blood from the vertebral artery and thus reduce flow in the area of infarction, representing petechial hemor-
to the brainstem. Symptoms include ‘claudication’ of the rhages, or, if the infarction is large, an actual hematoma.
ipsilateral arm with exercise-induced aching, and symp- If MR scanning is performed, at a minimum T2, fluid-
toms suggestive of brainstem TIA, such as vertigo, ataxia, attenuated inversion recovery (FLAIR) and DWI sequences
or diplopia: actual brainstem infarction is rare. The clue to with apparent diffusion coefficient (ADC) mapping should
the diagnosis is found by taking the radial pulse on both be obtained. Diffusion-weighted imaging may indicate an
arms simultaneously: on the affected side the pulse will be area of ischemic infarction within minutes of the event
delayed and reduced. (Hjort et al. 2005) and tends to remain positive for 7–14
days; T2 and FLAIR images gradually become positive and
SUGGESTED WORK UP then remain so chronically. If cerebral venous thrombosis is
suspected, MR venography should be ordered.
In the initial evaluation of a patient with acute stroke, one Many hospitals also offer either perfusion CT or perfu-
of the primary goals is to determine the cause of the stroke sion MRI, and these procedures may be very useful in cases
and to do this rapidly. Most strokes are secondary to of ischemic infarction. In such cases, the ischemic tissue
ischemic infarction: ischemic infarction in the area of dismay be divided into an ischemic ‘core’, which is destined to
tribution of one of the large pial vessels (either embolic, or, undergo necrosis no matter what treatment is offered, and
less commonly, thrombotic in nature) is most common, an ischemic ‘penumbra’, consisting of ‘stunned’ tissue,
followed by lacunar infarctions and watershed infarctions. which, although not functional, is capable of recovery.
Intracerebral hemorrhage is the next most common cause Identifying such a penumbra is of great import, for it invites
of stroke, followed by subarachnoid hemorrhage, intraven- therapies designed to restore circulation and thus salvage
tricular hemorrhage, and cerebral venous thrombosis. the stunned tissue, and such an identification is enabled by
Both the mode of onset and the presence or absence of the use of either perfusion CT or perfusion MRI (Schramm
severe headache help to differentiate the various causes of et al. 2004; Wintermark et al. 2002a,b). In this regard, per-
stroke. Strokes due to ischemic infarction may be either acute fusion CT may have an advantage as it takes only about 15
or gradual in onset but are generally not accompanied by minutes and can be performed in the emergency room.
p 07.qxd 3/10/08 9:35 AM Page 286
Once imaging has been accomplished, and a decision Patients with spontaneous subarachnoid hemorrhage
has been made as to whether treatment with tissue plas- require arteriography to demonstrate the source of the
minogen activator (discussed below) should be offered, arterial bleeding.
further laboratory evaluation is undertaken to determine
the mechanism of the stroke.
In cases of ischemic infarction, the following tests should Differential diagnosis
be considered: Holter monitoring, echocardiography,
duplex doppler studies of the carotid arteries, and either Ischemic infarction may be mimicked by multiple sclerosis
MR angiography or CT angiography. Holter monitoring or a Bell’s palsy. Multiple sclerosis is distinguished by
is required to detect intermittent atrial fibrillation. imaging and CSF findings. Bell’s palsy may suggest a ‘pure
Echocardiography may be either trans-thoracic (TTE) or motor’ lacunar syndrome but only until recognition that
trans-esophageal (TEE): although TEE is invasive, it is the forehead is involved declares the lesion to be in the
superior to TTE for imaging the left atrium, left atrial facial nerve.
appendage, any atrial septal defects, and the aortic arch Intracerebral hemorrhage may be mimicked by compli-
(Daniel and Mugge 1995; Sen et al. 2004). Duplex doppler cated migraine; however, in complicated migraine the
studies identify plaques and stenotic lesions of the carotid headache is usually delayed for from 30 to 60 minutes after
arteries; MRA, and CTA, are likewise useful in this regard the onset of focal signs, whereas in intracerebral hemor-
and also allow imaging of the larger intracranial vessels. If rhage, the headache evolves more or less simultaneously
an embolic source is present, it is usually demonstrated by with focal signs. Epidural or acute subdural hematomas may
one or more of these tests. There are, however, exceptions. likewise mimic an intracerebral hemorrhage, and in the
In some cases, the entire emboligenic lesion, for example a absence of a history of trauma the diagnosis may depend on
small atrial thrombus, may undergo embolization, leaving imaging. Hypertensive encephalopathy may closely mimic
nothing behind to detect. Hence, some clinical judgment is intracerebral hemorrhage, with headache, nausea and vom-
required in interpreting these tests. For example, as noted iting, and seizures. Finding a grossly elevated blood pressure
earlier, a stroke which is ‘maximal’ at the onset is likely may or may not be helpful here, as this may be common to
embolic in nature. Furthermore, ischemic infarction in both conditions. Delirium and visual loss favor hypertensive
one of the distal branches of the cerebral arteries is also encephalopathy; however, here the diagnosis often depends
likely embolic: thrombotic infarctions usually occur at on imaging: although there may be petechial hemorrhages
areas of atherosclerotic plaque formation, which, as noted in hypertensive encephalopathy, one does not see the large,
earlier, are generally in the more proximal portions of the well-circumscribed collection of blood characteristic of
arterial tree; by contrast, smaller emboli may readily pass intracerebral hemorrhage.
distally to occlude an artery further downstream. Finally, if Subarachnoid and primary intraventricular hemor-
there is more than one acute infarction, and these infarc- rhage, with the associated hyperacute onset of ‘worst-ever’
tions are in different arterial territories then an embolic headache, are rarely imitated by any other disorder. Both
mechanism is a more likely explanation (Baird et al. 2000): meningitis and severe migraine might be considered, but
multiple emboli, say, from a cardiac source, may course up imaging will quickly resolve the issue.
different arteries, whereas it is unlikely that multiple differ- Cerebral venous thrombosis may be mimicked by suba-
ent stenotic arteries would simultaneously give off emboli. cute subdural hematoma, a brain tumor (e.g., glioblastoma
In thrombotic infarction, the underlying etiology is usually multiforme) or a cerebral abscess, with, again, imaging
atherosclerosis, and one typically finds evidence of hyper- resolving the question.
lipidemia, diabetes mellitus, hypertension, or smoking. When TIAs may be mimicked, with varying degrees of faith-
these are absent, or the patient is under 45 years old, other fulness, by partial seizures, ‘transient tumor attacks’, mul-
causes must be considered, as discussed earlier, and consider- tiple sclerosis, transient global amnesia, and either hyper-
ation should be given to the following tests: protein S, or hypoglycemia. Inhibitory motor simple partial seizures
protein C, anti-thrombin III, factor V Leiden, anti-cardiolipin are suggested by their exquisitely paroxysmal onset, over
antibodies (IgG and IgM), and lupus anticoagulant. The anti- seconds, and by their association with other seizure types.
phospholipid syndrome may occur on an idiopathic basis or A post-ictal Todd’s paralysis may also enter the differential
be secondary to systemic lupus erythematosus and, conse- but this is immediately suggested by the history of the pre-
quently, in the presence of anti-cardiolipin antibodies or ceding seizure. ‘Transient tumor attacks’ occur in associa-
lupus anticoagulant, an ANA test should also be ordered. tion with cerebral tumors, which are immediately apparent
In patients with intracerebral hemorrhage, re-imaging on imaging. Multiple sclerosis is suggested by the early
with MRI (including a T2* sequence to detect evidence of adult onset, and may be confirmed by imaging and CSF
old petechial hemorrhages in cases of suspected cerebral analysis. Transient global amnesia (TGA) is, relative to a
amyloid angiopathy) should be undertaken after a few TIA, long-lasting; furthermore, there is no heminanopia or
weeks have passed, by which time enough blood will have blindness in TGA, findings that would be expected in a TIA
been resorbed to allow the detection of most of the possi- occurring secondary to ischemia in the area of distribution
ble underlying causes. of the PCAs. Finally, hyperglycemia (as may be seen in
p 07.qxd 3/10/08 9:35 AM Page 287
7.4 Stroke 287
hyperosmolar non-ketotic hyperglycemia) and hypo- In cases of embolic infarction when systemic t-PA fails,
glycemia may both present with focal signs, which resolve consideration may be given to local, intra-arterial throm-
promptly with restoration of euglycemia. bolysis or to mechanical embolectomy (Gobin et al. 2004).
Patients should also be given aspirin in a dose of 325 mg
for the first 2 weeks, as this reduces the risk of recurrent
Treatment stroke within that timeframe (Chen et al. 2000): if t-PA is
not given, aspirin should be given immediately; in cases
This section will focus first on certain aspects of the acute where t-PA is utilized, aspirin may be started after
treatment of ischemic infarction, intracerebral hemorrhage, 24 hours.
subarachnoid hemorrhage, intraventricular hemorrhage, and Some authors advocate the use of heparin in cases of
cerebral venous thrombosis, followed by certain recom- thrombotic infarction, in the hope of preventing propaga-
mended routine measures appropriate in most cases of tion of the offending thrombus. As yet, however, there is
stroke. It should be emphasized that the acute treatment no convincing evidence for the effectiveness of heparin and
of stroke typically requires admission to a specialized the risks attendant on its use argue against this practice.
unit. Most patients with ischemic infarction will also have
hypertension, and it cannot be stressed enough that rigid
ACUTE TREATMENT control of blood pressure is not indicated in the acute
phase of stroke treatment (Caplan 1976). The risks of neu-
Ischemic infarction ronal ischemia secondary to systemic hypotension are sim-
The acute treatment of patients with ischemic infarction ply too great; indeed, in cases of watershed infarction, a
may involve the use of tissue-type plasminogen activator case may be made for allowing the pressure to run a little
(t-PA). Normally, plasminogen is converted by endoge- high. Recent work has also indicated that in acute patients,
nous tissue plasminogen activator to plasmin, which in lying flat in bed, as compared to sitting up, not only
turn is a fibrinolytic enzyme. The administration of t-PA, improves flow within the MCA territory, but may also be
by increasing fibrinolysis, may dissolve a clot (whether part followed, in some cases, by prompt clinical improvement
of an embolus or occurring on an atherosclerotic plaque in (Wojner-Alexandrov et al. 2005).
a large vessel), thus restoring flow to cerebral tissue, which, Obstructive sleep apnea is a common condition, and
although ‘stunned’ by ischemia, has not as yet undergone recent work indicates that obstructive apneas are associ-
necrosis. Acute ischemic infarctions, as noted earlier, con- ated with early clinical worsening (Iranzo et al. 2002).
sist of a ‘core’ of tissue that has been irreversibly damaged Given this, it appears appropriate to ensure, if possible,
and a surrounding ‘ischemic penumbra’ of tissue, which, that all patients with obstructive sleep apnea receive appro-
although ‘stunned’ and not functioning, may still survive if priate treatment.
blood flow is promptly restored. The window of opportu- Once acute treatment is accomplished, preventive treat-
nity for restoration of blood flow is narrow, measured in ment should be instituted: in addition to control of risk
hours, and thus decisions must be made rapidly. Current factors such as diabetes mellitus, hypertension, hyper-
guidelines set the outside limit for treatment with t-PA at 3 lipidemia, and smoking cessation, consideration may be
hours post onset; however, this may not be appropriate in given to secondary stroke prevention with either warfarin
all cases: as noted earlier, both perfusion CT and perfusion or antiplatelet agents. Warfarin is indicated in cases of
MRI studies allow for a demonstration of the ischemic embolic infarction secondary to atrial fibrillation, atrial or
penumbra, and this may persist well past 3 hours (Albers ventricular thrombi, cardiomyopathy, and mechanical
et al. 2006; Parsons et al. 2002). prosthetic valves. In other cases, or when warfarin is con-
Even in cases of ischemic infarction when an ischemic traindicated, antiplatelet agents are indicated. A time-release
penumbra is present not all patients should receive t-PA, combination of aspirin and dipyridamole (Aggrenox) is
given the risk of causing an intracerebral hemorrhage. superior to aspirin alone (Halkes et al. 2006; Sacco et al.
Contraindications to t-PA include: stroke, head trauma, or 2005), and clopidogrel (Plavix) is equal in efficacy to aspirin:
myocardial infarction within 3 months; major surgery the combination of clopidogrel and aspirin should proba-
within 2 weeks; a history of gastrointestinal or genitouri- bly not be used, as it carries an increased risk of hemor-
nary bleeding within 3 weeks; a history of intracerebral rhage. If aspirin is used alone, the best dose, whether 81 mg
hemorrhage at any time; thrombocytopenia (with a platelet or 325 mg is uncertain; whichever dose is used, an enteric-
count below 100 000), anticoagulation (with an INR >1.7), coated preparation should be utilized. In patients on
or use of heparin within 48 hours (and a prolonged aPTT); aspirin, it is important to avoid treatment with ibuprofen,
grossly elevated blood pressure (systolic over 180 mmHg or which inhibits aspirin’s antiplatelet effect (Catella-Lawson
diastolic over 110 mmHg); and, finally, evidence of a large et al. 2001).
infarct: large infarcts, for example infarcts encompassing In cases when carotid artery stenosis is present at greater
the entire area of distribution of the MCA, are more likely that 70 percent, consideration may be given to carotid
to undergo hemorrhagic transformation and thus treat- endarterectomy (Barnett et al. 1998; Chaturvedi et al.
ment may do more harm than good. 2005) or carotid stenting (Yadav et al. 2004).
p 07.qxd 3/10/08 9:35 AM Page 288
Intracerebral hemorrhage endoscopic gastrostomy tube placement), physical ther-

As yet there are no specific treatments for intracerebral apy, prevention or treatment of aspiration, decubiti, uri-
hemorrhage: recent work suggests a role for recombinant nary tract infections, and deep venous thrombosis. A close
activated factor VII to reduce the growth of the watch should be kept early on for a worsening neurologic
hemorrhage (Mayer et al. 2005); however, this has not as deficit. In ischemic infarction, recurrent emboli may lead
yet been approved for clinical use. In cases when the hem- to new infarctions, as may propagation of a thrombus. In
orrhage is causing significant herniation or compressing intracerebral hemorrhage renewed bleeding may occur
critical structures, treatment with dexamethasone, manni- (Kazui et al. 1996), and in subarachnoid hemorrhage either
tol, or furosemide may be indicated. In emergent situa- ischemic infarction secondary to vasospasm or renewed
tions, surgery may be required to remove the clot. There is bleeding may occur. Vasogenic edema typically appears
debate as to whether surgery is safe in cases of cerebral within the first few days, and, if substantial, this too may
amyloid angiopathy, given the widespread vascular cause a clinical downturn; typically the edema resolves
fragility; however, on balance, even here surgery may be within a week or two. A deterioration in the patient’s gen-
worth the risk. In cases where there is doubt as to the etiol- eral medical condition, by compromising the functioning
ogy of the bleed, as for example may occur with lobar hem- of ‘stunned’ neuronal structures, may also cause a worsen-
orrhages, follow-up MRI is indicated to detect underlying ing of the initial deficit, and a close watch should be kept
neoplasms or vascular malformations. for hypoglycemia, hyponatremia, infections (e.g., pneu-
monia or urinary tract infections) and for any toxicity
from such commonly administered medications as
Subarachnoid hemorrhage
opioids, benzodiazepines, or antipsychotics.
Patients with subarachnoid hemorrhage should be treated Treatment with anti-epileptic drugs (e.g., phenytoin),
in an ICU. Various measures are undertaken (Naidech may or may not be required. Seizures may be immediate,
et al. 2005; Suarez et al. 2006): benzodiazepines (e.g., early (within the first 2 weeks) or late (from 2 weeks to
lorazepam), are given for agitation, nimodipine to reduce 2 years). Early and immediate seizures occur in about 5
vasospasm, and either phenytoin or valproate for seizure percent of patients with ischemic infarction, and up to 25
prophylaxis; serial transcranial doppler studies are made to percent of patients with intracerebral hemorrhage: they
monitor the development of vasospasm, and should this generally occur only in those with cortical involvement
appear, consideration is given both to ‘triple-H’ therapy and are rare in those with lacunar infarctions or hemor-
(hypertension, hypervolemia, hemodilution) to facilitate rhages confined to subcortical structures. In the case of
flow through constricted arteries, and to angioplasty. Serial subarachnoid hemorrhage, early and immediate seizures
CT scans are also indicated to monitor for the develop- may be seen in up to 25 percent of patients, and in cerebral
ment of hydrocephalus and external ventricular drainage venous thrombosis, about 15 percent. The EEG may help
may be required. Arteriography is generally performed to in predicting seizures: periodic lateralized epileptiform dis-
identify the bleeding source, and when, as is usually the charges (PLEDs) and focal spikes are strongly associated
case, an aneurysm is identified, patients should be consid- with their development (Gupta et al. 1988; Holmes 1980).
ered for endovascular coiling (International Subarachnoid In the case of ischemic infarction, treatment with an AED
Aneurysm Trial [ISAT] Collaborative Group 2002) or neu- is generally withheld until a seizure occurs, but in cases of
rosurgical clipping. intracerebral hemorrhage with cortical involvement or
subarachnoid hemorrhage or venous thrombosis the risk is
Intraventricular hemorrhage so high that prophylactic treatment with phenytoin is gen-
In the case of intraventricular hemorrhage, treatment in an erally given for the first 2 weeks. Should a seizure occur
ICU is generally required, as is external ventricular drainage. after stroke, it is not clear how long treatment should con-
tinue: a prudent course would be to continue prophylactic
Cerebral venous thrombosis treatment until 2 years had passed without seizure.
Once the patient is medically stable, consideration
For cerebral venous thrombosis, there is debate as to should also be given to transfer to a rehabilitation facility.
whether patients should be treated with heparin. Although
increased hemorrhage is a risk, it appears that, in this case,
the benefits obtained by preventing thrombus propagation 7.5 TRAUMATIC BRAIN INJURY
may outweigh it. Increased intracranial pressure, as is often
seen with thrombosis of the superior sagittal sinus, may Traumatic brain injury (also known as closed head injury)
require treatment with dexamethasone and mannitol. occurs in the United States with a yearly incidence of
approximately 120/100 000. Two age peaks are found,
ROUTINE MEASURES between 15 and 24 years of age, wherein motor vehicle acci-
dents are the most common cause, and over the age of 64
Routine measures include proper nutrition (utilizing, years, wherein falls are most common. Males are more
if necessary, nasogastric tube feedings or percutaneous commonly affected than females at all ages, and alcohol
p 07.qxd 3/10/08 9:35 AM Page 289
intoxication is a very common factor, being found in from monitoring is often indicated, and treatment with intra-
one-third to one-half of all cases (Corrigan 1995). Although venous sedation, mannitol, and other agents may be
multiple forms of brain injury may occur, this syndrome required to reduce pressure. Intubation is often required,
refers primarily to cases occurring with sudden ‘accelera- and pneumonia is a frequent occurrence.
tion–deceleration’, as during a motor vehicle accident or a Treatment of delirium, in all cases, involves simple envi-
fall or blow to the head; trauma due to gunshot wounds and ronmental measures designed to reduce confusion. These
crush injuries are not considered here. This chapter will dis- include, whenever possible, having the patient in a quiet
cuss the clinical features and treatment of the various room, with a window. Large calendars and digital clocks
aspects of traumatic brain injury, the etiology of these clin- should be in full view, and the nurse’s call button should be
ical features, and the differential diagnosis between trau- readily available. Sleep is essential and consequently the
matic brain injury and concussion. room should be darkened and very quiet at night, and all
non-emergency procedures (e.g., vital signs, weights, baths,
laboratory testing) should be forbidden during the sleeping
Clinical features and treatments hours. Restraints may occasionally be required and can be
life-saving. For patients prone to get out of bed unsuper-
In considering the clinical features (and their treatments) vised, keeping the bedrails up may be sufficient; if not, or if
of traumatic brain injury, it is convenient to divide them these are impractical, utilizing a ‘low-boy’ bed, surrounded
into two groups, namely an acute phase and a chronic phase. by mats, may help prevent injury. In some cases, round-
The acute phase, from a neuropsychiatric point of view, is the-clock sitters may be required.
often dominated by a delirium; as the confusion clears, In cases where these environmental measures are ineffec-
patients gradually enter into the chronic phase, which in tive, pharmacologic treatment may be considered with either
turn may be characterized by numerous sequelae, includ- an antipsychotic or, in certain emergent cases, lorazepam.
ing cognitive deficits that may, at times, be severe enough Antipsychotics are indicated for treatment of hallucinations
to constitute a dementia. or delusions, and are also effective for agitation. A second-
generation agent, such as risperidone, is often used, and, in
ACUTE PHASE practice quetiapine and olanzapine are also utilized. Initial
doses should generally be low, for example 0.5–1 mg of
Almost all patients with significant traumatic brain injury risperidone, 12.5–25 mg of quetiapine, and 2.5–5 mg of olan-
will sustain a loss of consciousness, of variable duration, zapine. The first-generation agent haloperidol is also often
immediately after the injury. Those who do survive will used, with initial doses of 2–5 mg. Repeat doses, in approxi-
typically emerge into a delirium. This delirium, in addition mately similar milligram amounts, may then be given every
to such characteristic symptoms as confusion, disorienta- hour or so until the patient is calm, limiting side-effects
tion, and decreased short-term memory, is also often occur, or a maximum dose is reached: rough guidelines for
marked by hallucinations, delusions, and, especially, agita- dose maxima are 5 mg for risperidone, 150 mg for que-
tion, which is seen in the majority of cases (Rao and tiapine, 20 mg for olanzapine, and 20 mg for haloperidol. In
Lyketsos 2000; van der Naalt et al. 2000). cases when the patient responds satisfactorily, a regular daily
It must be borne in mind that although the delirium in dose is ordered for the next day (with the total daily dose
such cases is generally due to the intracranial injuries directly approximately equivalent to the total required initially),
caused by the trauma, that other factors, as discussed in divided into two or three doses. Provision is also made for
Section 5.3, may also be involved as the hospitalization pro- further as-needed doses, with the total daily dose being
ceeds. Toxicity from such medications as opioids, baclofen, adjusted according to the amount needed in p.r.n. doses. The
anticholinergics, metoclopramide, and even amantadine eventual maintenance dose is then continued until the
must be considered, along with metabolic factors, such as patient has been stable for a significant period of time, at
hyponatremia, hypoglycemia, hypomagnesemia, and systemic which point it may be gradually tapered. Lorazepam is very
effects of infections, such as pneumonia. Other metabolic commonly used, and given the rapidity of its effectiveness
factors to consider relate to the frequency with which alco- when given intravenously, has a place in emergent situations;
holism is involved, and include Wernicke’s encephalopathy however, given that lorazepam may also worsen confusion, it
due to thiamine deficiency and delirium tremens. Considera- is appropriate to substitute another agent as soon as this is
tion may also be given to the effects of global cerebral practical. If lorazepam is used, one may give anywhere from
ischemia secondary to severe hypotension and, in those with 0.5 to 2 mg i.v. every hour as needed until the patient is calm,
fractures of long bones, to the fat embolism syndrome. limiting side-effects (such as sedation) occur, or a maximum
Treatment of patients during the acute phase is, at least of approximately 12 mg is reached.
initially, generally undertaken in either a trauma unit or an Once patients have been stabilized, general rehabilita-
ICU. Neurosurgical treatment may be required for evacuation efforts may be started, including physical, speech, and
tion of epidural or subdural hematomas or large contu- occupational therapy. Eventually, most patients are trans-
sions or intracerebral hemorrhages, and serial CT scans ferred to a specialized rehabilitation facility, where these
are obtained. In comatose patients, intracranial pressure general efforts are continued.
p 07.qxd 3/10/08 9:35 AM Page 290
Two rating scales have come into widespread use in the cannot and should not take the place of a detailed narrative
evaluation of patients with traumatic brain injury: the description of the patient’s clinical condition.
Glasgow Coma Scale and the Rancho Los Amigos Cognitive Post-traumatic seizures may occur during the acute
Scale. The Glasgow Coma Scale (Teasdale and Jennett phase, and these are discussed further, below.
1974) is designed for evaluating patients in the acute phase,
and involves assessing three clinical features: eye opening, Chronic phase
motor response, and verbal response, with, as noted in As the delirium gradually clears, almost all patients will be
Table 7.8 a numerical score described for the various left with one or more chronic sequelae (Rao and Lyketos
responses. Patients with total scores of ⭐8 are said to have a 2000), and these are discussed below, beginning with cog-
severe injury, those with scores from 9 to 12, a moderate nitive deficits, which are almost universal.
injury, and those with scores of from 13 to 15, a mild injury.
The Rancho Los Amigos scale, described in Table 7.9 may Cognitive deficits
also be utilized early on; however, it is often also employed Cognitive deficits typically remain after the confusion of
as an instrument for following patients during the chronic delirium clears, and generally include inattentiveness, poor
phase. Although these scales are useful as a ‘shorthand’ they short-term memory (or simple ‘forgetfulness’), poor concen-
tration, and decreased abstracting ability (Levin et al. 1979;
Table 7.8 The Glasgow Coma Scale van Zomeren and van den Burg 1985). In some cases these
may be quite mild and not terribly limiting; however, in oth-
Eye opening
ers they amount to a clear, and disabling, dementia. Most
Spontaneous 4
patients show improvement over the first 6 months, with
To speech 3
some further, but not as impressive, gains over the next
To pain 2
6 months: however, after 12 months, little further sponta-
Nil 1
neous recovery can be expected. Importantly, in assessing
Best motor response
patients with cognitive deficits it is critical to check for the
Obeys commands 6
presence of depression, which, in and of itself, may cause
Localizes 5
cognitive impairment. Pharmacologic treatment may include
Withdraws 4
donepezil, amantadine, bromocriptine, or methylphenidate.
Abnormal flexion 3
Donepezil, in doses of 10 mg/day, improves memory and
Extensor response 2
attention (Morey et al. 2003; Zhang et al. 2004) (rivastigmine
Nil 1
does not appear to be effective [Silver et al. 2006]).
Verbal response
Amantadine, in doses of 100 mg in the morning and 100 mg
Oriented 5
in the early afternoon, may likewise improve cognitive per-
Confused conversation 4
formance (Meythaler et al. 2002), but not all studies support
Inappropriate words 3
this (Schneider et al. 1999). Bromocriptine, in one double-
Incomprehensible sounds 2
blind study (McDowell et al. 1998) had some positive effect
Nil 1
on executive functioning. Methylphenidate, titrated to a dose
Table 7.9 The Ranchos Los Amigos Scale*

I No response: unresponsive to any stimulus
II Generalized response: limited, inconsistent, and non-purposeful responses – often to pain only
III Localized response: purposeful responses; may follow simple commands; may focus on presented object
IV Confused, agitated: heightened state of activity; confusion and disorientation; aggressive behavior; unable to perform self
care; unaware of present events; agitation appears related to internal confusion
V Confused, inappropriate: non-agitated, appears alert; responds to commands; distractible; does not concentrate on task;
agitated responses to external stimuli; verbally inappropriate; does not learn new information
VI Confused, appropriate: goal-directed behavior, needs cueing; can relearn old skills as activities of daily living; serious
memory problems, some awareness of self and others
VII Automatic, appropriate: appears appropriately oriented; frequently robot-like in daily routine; minimal or absent confusion;
shallow recall; increased awareness of self and interaction with environment; lacks insight into condition; decreased
judgment and problem solving; lacks realistic planning for future
VIII Purposeful, appropriate: alert and oriented; recalls and integrates past events; learns new activities and can continue
without supervision; independent in home and living skills; capable of driving; defects in stress tolerance, judgment and
abstract reasoning persist; may function at reduced levels in society
* Reprinted with permission from the Adult Brain Injury Service of the Rancho Los Amigos Medical Center, Downey, California
p 07.qxd 3/10/08 9:35 AM Page 291
of 0.3 mg/kg b.i.d., may improve attention and speed of Pharmacologic treatment of agitation may include AEDs,
information processing (Whyte et al. 2004), but, as with amantadine, antipsychotics, propranolol, lithium, and anti-
amantadine, not all studies support this (Speech et al. 1993). depressants. In non-blind studies or case reports, carba-
Overall, it may be prudent to begin with either donepezil or mazepine (Azouvi et al. 1999; Chatham-Showalter 1996),
amantadine, holding methylphenidate as a distant reserve. valproic acid (Chatham-Showalter and Kimmel 2000;
Wroblewski et al. 1997), and lamotrigene (Pachet et al. 2003)
Post-traumatic amnesia all appear effective. Amantadine, in a case report, was also
‘Post-traumatic amnesia’ is defined differently by different effective (Chandler et al. 1988). Antipsychotics, such as the
authors. Some include under this rubric the decreased short- second-generation agents risperidone, quetiapine, or olanza-
term memory seen during delirium, whereas others restrict pine, may be utilized. Although first-generation agents (e.g.,
the definition to cases wherein a short-term memory loss haloperidol) have been associated with cognitive decrement
persists after resolution of delirium and, importantly, persists (Stanislav 1997), and the same may be true with second-gen-
in relative ‘isolation’, being generally unaccompanied by eration agents, the benefits of treatment with antipsychotics
other cognitive deficits. Utilizing the latter definition, Levin typically outweigh these cognitive side-effects. Propranolol
et al. (1988) found such a residual amnestic disturbance in also appears effective (Brooke et al. 1992): treatment is com-
approximately one-quarter of patients. menced at low doses, perhaps 20 mg/day, and increased
gradually, in increments of perhaps 60 mg every few days, to
Anosognosia clinical effectiveness, tolerance, or a maximum dose of
Anosognosia is characterized by a failure to appreciate the 800 mg/day. Lithium has also been used (Glenn et al. 1989).
severity of a deficit, or even its existence. Clinically signifi- Amitriptyline, in a large case series, has also been effective
cant anosognosia is found as a persistent symptom in (Mysiw et al. 1988), and in the author’s experience, mirta-
almost one-half of patients (Flashman and McAllister zapine has been remarkably effective; however, high doses of
2002). Interestingly, the anosognosia appears selective, in 60–90 mg may be required.
that although patients tend to acknowledge such deficits as Given the lack of head-to-head studies, choosing among
hemiplegia, they are much less likely to appreciate their these agents is not straightforward. In my opinion, AEDs
cognitive deficits (Sbordone et al. 1998) or the existence of are a good first choice, and among these, preference may
mood changes or a personality change (Fahy et al. 1967). be given to either valproic acid or carbamazepine. Antipsy-
Distinguishing anosognosia from denial may be difficult. chotics are probably a second choice, and among these, que-
One helpful point is the affect accompanying the patient’s tiapine is generally very well tolerated. Propranolol, given the
response to questions about deficits: in anosognosia the high doses often required, should probably be held in reserve,
affect is often bland or matter of fact, whereas in denial and the same may be said of lithium, which is often poorly
there may be a degree of indignation or angry protest. tolerated by patients with brain injuries. Amitriptyline, given
Importantly, given the high prevalence of anosognosia, it is its anticholinergic effects and possible negative effects on
critical, in the long-term treatment of these patients, to always cognition, might also be held in reserve; as noted, the author
question others, such as family members or friends, regarding has found mirtazapine quite effective, and with no significant
the patient’s condition. Relying on the anosognosic patient’s adverse effects.
report could lead to disastrous underdiagnosing.
Sympathetic storms
Focal signs and symptoms Sympathetic storms, as described in Section 4.23, consist of
Focal signs and symptoms that persist after resolution of episodes characterized by profuse diaphoresis, tachycardia,
the delirium may include not only hemiplegia and various tachypnea, pupillary dilation, and, in some, rigid extensor
movement disorders, but also ‘cortical’ signs and symp- posturing. The diaphoresis is indeed impressive, with
toms such as neglect and aphasia. Aphasia is particularly beads of sweat dripping from the head. During the episode,
common, and, to a variable degree, is found in the vast patients may grimace as if in pain, and family members
majority of cases (Levin et al. 1976; Sarno et al. 1986). and other observers may become quite alarmed. The
episodes themselves last from minutes to hours, and termi-
Agitation nate slowly.
Agitation is common and tends to fluctuate in severity, and The distinction of these ‘storms’ from agitation is gener-
may occur in up to two-thirds of all patients in the first few ally based on their course: the ‘storms’ come in discrete
months (Nott et al. 2006). Up to one-third of patients may episodes, whereas agitation, although perhaps waxing and
also exhibit aggressiveness, which may be either verbal or waning in intensity, usually does not assume an episodic
physical (Tateno et al. 2004). In evaluating agitated course. In addition, sympathetic symptoms, such as impres-
patients, consideration must be given to the possibility that sive diaphoresis, although typical of sympathetic storms, are
the agitation in question is not directly due to the head generally absent, or relatively minimal, during agitation.
injury but is rather secondary to other causes, such as pain, Treatment with propranolol or bromocriptine usually
delusions of persecution, akathisia or disinhibition sec- prevents further attacks; alternatives include gabapentin
ondary to alcohol or benzodiazepines. and morphine.
p 07.qxd 3/10/08 9:35 AM Page 292
Personality change 10 percent of patients (Tateno et al. 2004; Zeilig et al. 1996).
Personality change is very common, and over the long Citalopram is effective here, sometimes in as little as 2 or 3
term may constitute one of the most disabling of residual days (Muller et al. 1999).
symptoms (Thomsen 1984). A full or partial frontal lobe Apathy
syndrome is typical, with disinhibition being the most
common symptom; affective changes and perseveration Apathy may occur (Kant et al.1998) and is distinct from either
may also occur. Before making this diagnosis, due regard abulia or depression. Patients with abulia, if supervised, may
must be paid to the patient’s premorbid personality, with complete tasks at a normal rate, whereas patients with apathy
special attention to the presence of either an antisocial or do not. Patients with depression may also complete tasks
borderline personality disorder. Pharmacologic treatment slowly; however, here, in contrast with apathy, there is a
of the frontal lobe syndrome may include treatment with depressed mood. Apathy may respond to bromocriptine
carbamazepine or an antipsychotic, such as quetiapine. (Powell et al. 1996), amantadine (Van Reekum et al. 1995), or
selegeline (Newburn and Newburn 2005).
Depression
Fatigue
Depression appears during the first 2 years in up to one-
Fatigue may be present in up to one-third of patients
half of patients, and may either remit spontaneously or
(Hillier et al. 1997). When severe, consideration may be
persist (Jorge et al. 1993, 2004); of the typical symptoms of
given to treatment with methylphenidate or amphet-
depression (i.e., depressed mood, fatigue, loss of interest,
amines; however, these agents should be given cautiously,
loss of appetite, difficulty with concentration, and insom-
if at all, in cases where they might be abused.
nia), fatigue and poor concentration are often especially
problematic (Kreutzer et al. 2001). Mania
Importantly, in considering a diagnosis of depression,
in this population one must keep in mind that transient Mania may occur in the year following injury, but is rela-
displays of depressed mood or affect, as may be seen in tively uncommon (Nizamie et al. 1988; Starkstein et al.
emotionalism or emotional incontinence, simply do not 1990); it appears to be more likely when the polar regions
qualify. Furthermore, both apathy and abulia must be kept of the temporal lobes have been involved, as for example
in mind as other possibilities: in both cases, the requisite by contusions. The episodes themselves tend to be rela-
depressed mood is not present. Other differential possibil- tively short, lasting on average 2 months (Jorge et al. 1993),
ities to keep in mind include medications (e.g., steroids and may occur soon after the injury or after a latent inter-
or metoclopramide) and a premorbid major depressive val lasting months. In evaluating a patient suspected of
disorder. having post-traumatic mania, it is important to differenti-
Treatment generally includes an antidepressant, such as ate manic exuberance from the disinhibition that is seen in
sertraline (Fann et al. 2000) or some other SSRI. Tricyclic the frontal lobe syndrome: the main differential point here
antidepressants, although effective (e.g., desipramine is that whereas mood is heightened in mania, it is not in the
[Wroblewski et al. 1996]) should be used with caution, frontal lobe syndrome. Furthermore, before attributing
given that they lower the seizure threshold (Wroblewski mania to head injury, a careful history is required to
et al. 1990). Methylphenidate may also be considered, and exclude a premorbid bipolar disorder. Treatment should
in one double-blind study was similar to sertraline (Lee generally include a mood stabilizer, such as divalproex or
et al. 2005). carbamazepine; lithium may also be considered, however,
as noted earlier, patients with head injury may be especially
Emotionalism prone to develop side-effects to this agent.
Emotionalism is relatively common after head injury (Sloan Sleep disturbances
et al. 1992). Typically, patients find themselves uncharacter- Sleep disturbances occur in the majority of patients and
istically prone to sadness and tearfulness. Importantly, may include hypersomnia, excessive daytime sleepiness or
although patients, especially males, may complain of their insomnia (Baumann et al. 2007).
lack of emotional restraint, they do not complain that the Hypersomnia may be directly related to the head injury
sadness is unmotivated or out of place. Antidepressants, but consideration must also be given to the use of any
especially SSRIs, such as fluoxetine (Sloan et al. 1992), may sedating medications.
be effective in this regard. Excessive daytime sleepiness may be likewise be directly
related to the head injury or may be due to sleep apnea,
Emotional incontinence which in turn may be either central or obstructive (Castriotta
Emotional incontinence (Muller et al. 1999) is character- and Lai 2001; Masel et al. 2001); periodic limb movements of
ized by the involuntary appearance of a sad or happy affect sleep may also occur and, rarely, there may be post-traumatic
in the absence of any corresponding sense of sadness or narcolepsy (Lankford et al. 1994). Given that these latter dis-
mirth, and as such differs from emotionalism. Such ‘empty’ orders have specific treatments, it is reasonable to request
displays of affect may be seen as a late sequela in from 5 to polysomnography in any brain injury patient who complains
p 07.qxd 3/10/08 9:35 AM Page 293
of excessive daytime sleepiness. In cases of excessive daytime Consequently, phenytoin may be preferable for early pro-
sleepiness occurring directly secondary to head injury, a case phylaxis. Importantly, neither of these agents provides pro-
may be made for a trial of either methylphenidate or phylaxis after the first week: consequently, if the patient has
modafinil. gone through the first week without a seizure, the AED may
Insomnia may occur secondary to pain, or as part of generally be discontinued.
depression, or exist independently (Beetar et al. 1996; In cases where a seizure has occurred, whether early or late,
Fichtenberg et al. 2000); treatment generally involves med- treatment recommendations are not as clearly worked out. If
ications such as zolpidem or trazodone (typically effective a patient had an early seizure despite prophylactic treatment
in low doses of from 25 to 50 mg). with phenytoin at therapeutic levels, some clinicians would
continue phenytoin, on the assumption that it will decrease
Psychosis the frequency of later-occurring seizures, whereas others
would opt for a different AED. In cases where there were no
Psychosis, that is to say a condition characterized by delu-
seizures during the first week, but one occurred later, perhaps
sions and/or hallucinations in the absence of delirium or
much later, there are no firm guidelines regarding treatment,
dementia, is reported, albeit rarely, as a long-term sequela to
and consideration could be given not only to phenytoin or
traumatic brain injury (Fujii and Ahmed 2002; Sachdev et al.
valproate, but also to other agents, such as levetiracetam, car-
2001); however, this assertion must be viewed with some
bamazepine, oxcarbazepine, gabapentin, etc.
caution. In the reported cases, latencies of 1–5 or more years
are reported between the head injury and the gradual onset Endocrinologic changes
of the psychosis, and a family history of schizophrenia was
found to be a significant risk factor (Sachdev et al. 2001). Endocrinologic changes appear in a majority of traumatic
Given these findings, the argument may be made that the brain injury patients, and may occur secondary to either
psychosis represents merely the coincidental occurrence of hypothalamic (Crompton 1971) or pituitary damage
schizophrenia in a patient with a history of traumatic brain (Edwards and Clark 1986; Salehi et al. 2007). Diabetes
injury. Treatment involves use of an antipsychotic, prefer- insipidus, with hypernatremia, may occur early on; other
ably one of the better-tolerated second-generation agents, endocrinologic changes, such as hypothyroidism or
such as risperidone or quetiapine. gonadal failure, may not become evident for months to
years after the injury. In this regard, it is prudent to check a
thyroid profile in any patient who develops depression,
Post-traumatic seizures
apathy or fatigue, and a testosterone level in patients who
Post-traumatic seizures may be defined as occurring early, develop decreased libido.
during the first 7 days post-injury, or late, occurring at any
time thereafter. Early seizures are reported in anywhere Post-traumatic stress disorder
from 2 to 15 percent of cases, and are most likely to occur Post-traumatic stress disorder may occur after any major
within the first 24 hours. Late seizures are seen in from 5 to trauma, and traumatic brain injury is no exception. Indeed,
10 percent of cases, and in those destined to have a late anywhere from 6 percent (Bombardier et al. 2006) to 20
seizure, the first one usually occurs within the first year percent (Hibbard et al. 1998) of these patients will develop
post-injury (Mazzini et al. 2003): the range here, however, this disorder at some point.
is wide, from weeks to up to 15 years. Several features Before making a diagnosis of post-traumatic stress dis-
increase the risk of occurrence of a late seizure, including order, however, careful consideration must be given to the
the following: having an early seizure; the presence of con- fact that certain symptoms suggestive of this disorder may
tusions or intracerebral hemorrhages; intracranial opera- also occur as direct sequela of the brain injury itself,
tions; and dural penetration with bone or metal fragments including poor concentration, insomnia, and fatigue.
(Englander et al. 2003; Mazzini et al. 2003; McQueen et al.
1983; Messori et al. 2005). Importantly, although the vast
majority of seizures occurring post-traumatically are due Etiology
to the intracranial pathology itself, other possibilities must
also be kept in mind: in the case of early seizures, metabolic In traumatic brain injury, a variety of lesions may be seen
causes, such as hyponatremia, hypocalcemia, or hypomag- (Freytag 1963; Jenkins et al. 1986), including diffuse axonal
nesemia are not uncommon. Simple partial, complex par- injury, contusions, intracerebral hemorrhage, subarach-
tial, and grand mal seizures may all occur. noid hemorrhage, epidural or subdural hematomas, or
With regard to treatment, two aspects exist: prophylaxis infarctions. Cerebral edema accompanies most of these,
against an early seizure, and treatment after a seizure, and, in combination with space-occupying lesions, may
whether early or late, has occurred. cause uncal or subfalcine herniation. In some cases, hydro-
With regard to prophylaxis of early seizures during the cephalus may appear. Fractures may or may not accom-
first week, both phenytoin (Temkin et al. 1990) and valproate pany these lesions.
(Temkin et al. 1999) are effective; however, there was an Diffuse axonal injury (Adams et al. 1982), occurring sec-
apparent trend toward increased mortality with valproate. ondary to the tremendous shearing and rotational forces
p 07.qxd 3/10/08 9:35 AM Page 294
occurring during acceleration/deceleration, is characterized the presence of a fracture and the presence of brain damage;
by axonal rupture or damage. Although these effects are indeed in many cases of devastating traumatic brain injury,
widespread throughout the cerebrum, certain areas are most there is no fracture at all. Linear, depressed and compound
vulnerable, including the junction between the cortex and fractures may all be seen, but of these linear fractures, typi-
white matter, the corpus callosum, and dorsolateral quad- cally at the base of the skull, are most common.
rants of the midbrain. In almost all cases, this diffuse axonal In addition to these direct effects of trauma, the occur-
injury is also accompanied by diffuse vascular injury, rence of hypoxia and hypotension at the scene may lead,
wherein small penetrating arterioles, subjected to the same respectively, to global anoxic brain damage or, as noted
shearing and rotational forces, undergo rupture, producing earlier, watershed infarcts.
widespread petechial hemorrhages. In determining which of these injuries have occurred, it
Contusions occurring in acceleration–deceleration must be borne in mind that MR scanning is more sensitive
injuries typically occur along the inferior surfaces of the than CT scanning for diffuse axonal injury, contusions,
frontal and temporal lobes, as they slide along the bony pro- subdural and epidural hematomas, infarcts, and global
tuberances at the base of the skull. In cases where there has anoxic injury (Mittl et al. 1994; Orrison et al. 1994).
been a blow to the head, a contusion may form under the
point of impact (the ‘coup’ contusion) and also contralater-
ally, at the area where the brain is flung up against the inner
surface of the skull (the ‘contre-coup’ contusion).
Concussion is said to occur when, after an acceleration–
Intracerebral hemorrhages occur with rupture of rela-
deceleration injury or a blow to the head, there is either a very
tively large penetrating arteries, and although these hemo-
brief loss of consciousness or merely a sense of being dazed;
rrhages may be lobar in location they are most commonly
there may also be an associated amnesia for the event. The
seen in the basal ganglia (Katz et al. 1989; Macpherson et al.
post-concussion syndrome (discussed in Section 11.5), seen
1986). Rarely, intracerebral hemorrhages may be delayed in
in a minority of patients after concussion, is characterized by
appearance for up to 2 days post-injury.
minor cognitive deficits.
Subarachnoid hemorrhage may occur secondary to
shearing of vessels traversing the subarachnoid space or due
to leakage of blood from an area of contused or hemorrhagic
7.6 ACUTE ENCEPHALITIS
cortex. In such cases, vasospasm of arteries traversing the
bloody subarachnoid space may lead to ischemic infarction
Although, technically, the term ‘encephalitis’ refers to any
of subserved tissue.
inflammation of the brain parenchyma, whether focal or
Subdural hematomas occur in about one-fifth of patients,
diffuse, of any cause, in common clinical practice to say that
and may range in size from thin, inconsequential crescents to
a patient has an encephalitis is to imply that they are suffer-
large, life-threatening lesions. Epidural hematomas may also
ing from an acute and generalized infection. Most cases are
occur, but are far less common.
due to viruses; bacterial and protozoal encephalitidies are
Infarctions may occur secondary to herniations,
much less common (Chaudhuri and Kennedy 2002).
vasospasm arterial dissection, or, if severe hypotension
Acute encephalitis constitutes a medical emergency, and
occurred, via a ‘watershed’ phenomenon (Marino et al.
hence recognizing the cardinal signs of encephalitis, namely
2006).
fever, headache and delirium, is critically important.
Cerebral edema is common, and adds considerably to the
clinical expression of diffuse axonal injury, contusions and
intracerebral hemorrhages. Herniation may occur, with, as Clinical features
just noted, possible infarction secondary to vascular com-
pression: with uncal herniation, such infarction may occur In most cases, the encephalitis is preceded by a non-specific
in the area of distribution of the posterior cerebral artery, prodrome, lasting perhaps a few days, of fatigue, malaise,
whereas with subfalcine herniation, infarction may occur in and fever. The encephalitis itself generally presents acutely,
the area of distribution of the anterior cerebral artery. over hours, or at the most a day, with headache and delir-
Hydrocephalus may occur via a number of mecha- ium. In addition to confusion and variable disorientation,
nisms. Acute hydrocephalus may occur secondary to com- the delirium may also be accompanied by agitation, halluci-
pression of the foramen of Monro by an expanding lesion, nations (typically visual), and delusions. Focal findings,
such as a contusion, or, when subarachnoid hemorrhage such as hemiparesis, aphasia, or hemianesthesia, may or
has occurred, secondary to a clot obstructing outflow from may not be present, and there may also be partial or grand
the exit foramina of the fourth ventricle. Chronic hydro- mal seizures. In most, but certainly not all, cases, signs of
cephalus, presenting weeks or months after the injury, may meningeal inflammation may also be present, with stiff
occur secondary to outflow obstruction at the arachnoid neck or photophobia. With progression, stupor or coma
villi of the superior sagittal sinus. may supervene.
Fractures may or may not occur, and it is important to Lumbar puncture is indicated in virtually every case
keep in mind that there is not a good correlation between (Steiner et al. 2005). Glucose is normal in viral infections,
p 07.qxd 3/10/08 9:35 AM Page 295
7.6 Acute encephalitis 295
and decreased in bacterial and other causes. The total pro- (Lanska 2002), mycoplasma pneumoniae infection, lep-
tein is increased. Essentially all cases will have a pleocytosis, tospirosis, listerosis, and cat scratch fever.
ranging from 5 to 10 up to a 1000 white cells or more. In Protozoal causes include toxoplasmosis (Section 14.21),
viral cases the pleocytosis is generally lymphocytic, whereas generally seen only in the severely immunocompromised,
bacterial encephalitidies are generally marked by the pres- and cerebral malaria (Section 14.20).
ence of polymorphonuclear cells: an exception to this
occurs with certain arbovirus infections wherein there may
be a substantial number of polymorphonuclear cells for Differential diagnosis
the first day or two; a persistent polymorphonuclear pre-
dominance after this time, however, is much more charac- Acute disseminated encephalomyelitis, as discussed in
teristic of bacterial infections. Gram stain and culture are Section 14.11, represents an autoimmune encephalitis trig-
performed routinely. Polymerase chain reactions (PCR) gered by a preceding viral or bacterial infection. Clinically,
assay has revolutionized the identification of responsible this syndrome may be indistinguishable from acute infec-
organisms, and is useful in detecting herpes simplex, vari- tious encephalitis, and the differential may hinge on
cella-zoster, Epstein–Barr, cytomegalovirus, enterovirus, demonstrating the characteristic latent interval between a
and various bacteria. preceding infectious illness and the onset of the delirium.
MRI, with contrast, should be performed; if this is not Toxic and metabolic deliria are very common, and
possible then CT scanning represents an alternative. Given often occur in patients who have headache and fever due to
the emergent nature of encephalitis, imaging should be a general medical illness, such as pneumonia or sepsis.
promptly performed so as not to delay lumbar puncture. Considerable clinical judgment is required here in deciding
Importantly, early on, in the first day or two, imaging may whether to perform a lumbar puncture; however, if the
not be impressive in the case of viral encephalitidies. metabolic abnormalities are relatively mild, and the toxic-
Electroencephalography typically shows generalized ity of current medications generally low, and the patient is
slowing, with or without interictal epileptiform discharges. not septic, one might lean toward obtaining CSF.
Focal slowing in the temporal areas, with or without peri- Subdural empyema, cerebritis or cerebral abscess, and
odic complexes, is highly suggestive of herpes simplex cerebral thrombophlebitis are each apparent on magnetic
encephalitis. resonance imaging.
The neuroleptic malignant syndrome (Section 22.1) is
suggested by the presence of rigidity and coarse tremor in
Etiology the proper pharmacologic setting: initiation or increased
dose of an antipsychotic, or discontinuation or substantial
As noted earlier, most cases of acute encephalitis are due to dose decrease of a dopaminergic preparation, such as
viral infection (Koskiniemi et al. 2001). Herpes simplex levodopa.
virus encephalitis (Section 14.5) is the most common cause
of sporadic viral encephalitis, and, given its treatability, it
should be high on the differential. Arboviral encephaliti- Treatment
dies (Section 14.4) occur in both an epidemic and endemic
fashion. Zoster encephalitis (Section 14.9) is suggested by a Most patients should be admitted to an ICU, with strict
concurrent, generally widespread, zosteriform eruption; attention to fluid and electrolyte balance: both diabetes
mumps encephalitis (Section 14.8) by an associated paroti- insipidus and the syndrome of inappropriate antidiuretic
tis, and infectious mononucelosis (Section 14.7) by its hormone (ADH) secretion may occur. Intracranial pres-
occurrence in the setting of typical ‘mono’ with sore throat sure monitoring may be required. Seizures may be treated
and cervical adenopathy. Rabies (Section 14.10) is sug- with fosphenytoin, and the general treatment of delirium is
gested by the presence of parasthesiae near the site of the as discussed in Section 5.3.
fateful bite (which may have occurred weeks or months Some encephalitidies have specific treatments, as dis-
earlier) and hypersalivation with hydrophobia. Other viral cussed in the respective chapters. Given the devastating
causes include influenza, enteroviruses, and adenoviruses. nature of herpes simplex encephalitis and its eminent
In the immunoincompetent patient, for example those with treatability, it is customary to administer acyclovir pending
AIDS or those under treatment with steroids or immunosup- the results of PCR testing.
pressants, one must also consider cytomegalovirus (Section Patients who survive may or may not be left with seque-
14.2). Furthermore, early on during human immunodefi- lae (Arciniegas and Anderson 2004), depending on the
ciency virus (HIV) infection, a brief encephalitis may accom- causative organism, the severity of the infection, and the
pany seroconversion. age of the patient: both the very young and the elderly are
Bacterial causes include Rocky Mountain spotted fever more likely to have sequelae. Focal deficits may persist, and
(Section 14.19) and typhus, suggested by a concurrent epilepsy may ensue. There may also be personality change,
rash, stage II Lyme disease (Section 14.16), suggested by a dementia, and various movement disorders. Specifics are
concurrent cranial or peripheral neuropathy, anthrax discussed in the respective chapters.
p 07.qxd 3/10/08 9:35 AM Page 296
7.7 SOMATOFORM DISORDERS middle of the forearm, and ends abruptly at a boundary that
describes a perfect circle around the forearm. There simply
Somatoform disorders are characterized by complaints that is no lesion of either the central or peripheral nervous sys-
either, as in the case of conversion disorder or somatization tem that could conceivably produce such a pattern of anes-
disorder, have no basis in the anatomic or physiologic facts thesia. In the following paragraphs, each of these common
of the matter, or, as in hypochondriasis, although having conversion symptoms is discussed in turn, with special
some basis in anatomy or physiology, yet are exaggerated attention to the associated ‘violations’ that one may find.
far beyond what would be expected. Each of these is consid- Conversion paralysis may mimic monoplegia, hemiple-
ered in turn. gia, or paraplegia. In conversion monoplegia involving, for
example, the upper limb, one may find a non-physiologic
pattern of weakness, involving perhaps the forearm and
Conversion disorder hand with complete strength maintained in the shoulder
and arm. In conversion hemiplegia, one may find a positive
Conversion disorder is characterized by symptoms that Hoover test (Hoover 1908). The Hoover test may be per-
meet two criteria: first, they suggest a specific lesion of the formed by having the patient lie supine on the bed, posi-
central or peripheral nervous system; and, second, further tioning yourself at the foot of the bed and placing one hand
investigation either reveals symptomatology that ‘violates’ under the heel of the ‘bad’ leg and the other on top of the
the laws of anatomy or physiology, or demonstrates con- ankle of the ‘good’ leg. At this point ask the patient to lift
clusively that the suspected lesion does not, in fact exist. the ‘good’ leg up in the air against the resistance of your
Furthermore, and again despite thorough investigation, no hand. As the patient attempts to lift the ‘good’ leg, you will
motive can be discovered for the conversion symptom in feel the normal compensatory downward pressure of the
question. This last point is critical, as it distinguishes con- contralateral leg on your hand as it lies under the heel of
version disorder from malingering, when the motive for the ‘bad’ leg. Once this maneuver has been accomplished,
the symptomatology, whether it be financial gain or avoid- ask the patient to rest the ‘good’ leg down and then switch
ance of some unpleasant task, is fairly obvious. the position of your hands, now placing one hand under
A synonym for conversion disorder is hysteria (or, ‘hyster- the heel of the ‘good’ leg and placing the other hand on top
ical neurosis’): both terms, to a degree, are unfortunate, as of the ‘bad’ leg. At this point, encourage the patient to exert
both indicate etiologic theories that have not been substanti- the greatest effort possible in raising the ‘bad’ leg up against
ated. ‘Conversion’ implies a mechanism whereby emotionally the resistance of your hand. In a positive Hoover test one
charged ideas are in some unconscious way ‘converted’ into finds two things: first, the ‘bad’ leg moves little, if at all; sec-
‘physical’ symptoms. ‘Hysteria’, an ancient term, suggests that ond, one fails to feel any of the normally expected down-
the disorder is in some way related to having a hystera (Greek ward pressure on the hand underneath the heel of the
for ‘womb’), which is clearly not the case; although females ‘good’ leg, indicating that, in fact, the patient is putting no
are more likely to have this disorder than males (by a factor of effort into the task of lifting the ‘bad’ leg. Recently, a simi-
from 2:1 up to 10:1), it clearly also occurs in males. lar test, designed to elict the ‘abductor sign’ has been
The lifetime prevalence of conversion disorder is not described (Sonoo 2004). In this test, with the patient with
known with certainty: reported figures range from 0.01 to conversion hemiplegia supine in bed, stand at the foot of
0.5 percent of the general population. the bed, facing the patient, and place your hands on the lat-
eral aspects of both of the patient’s legs, maintaining a light
CLINICAL FEATURES inward pressure. At this point, ask the patient to abduct the
‘bad’ leg as forcefully as possible against the light pressure
Although conversion disorder may first appear anywhere of your hand. In conversion paralysis, there is no move-
from childhood to old age, most patients first experience ment of the ‘bad’ leg, and, critically, there is also no abduc-
symptoms in either adolescence or early adult years. In tion of the ‘good’ leg either. In patients with ‘true’
most cases, the onset is abrupt and typically follows closely hemiplegia one would appreciate the expected synergistic
upon a stressful life event. abduction of the ‘good’ leg, and it is the absence of this in
Although a large number of conversion symptoms are conversion that indicates that, in fact, the patient is not
possible, most patients have only one at a time. Common putting effort into the task. Observing the patient on
conversion symptoms include paralysis, anesthesia, ataxia, attempted ambulation is also helpful: when asked to walk,
tremor, deafness, blindness, parkinsonism, syncope, coma, patients with conversion hemiparesis tend to drag the
and seizures. As noted above, one of the distinctive features affected leg, pulling it up behind them, rather than circum-
of conversion symptoms is that, in some way or other, they ducting it. Furthermore, patients with conversion hemi-
‘violate’ the laws of anatomy or physiology, and it is this plegia may also display the ‘wrong-way’ tongue, with
‘violation’ that often alerts the examiner to the conversion deviation of the protruded tongue away from the weak
nature of the symptom in question (Stone et al. 2002). An side, rather than toward it, as one would expect with stroke
example would be a patient who complained of an area of (Keane 1986). In both conversion monoplegia and hemi-
anesthesia that involves the entire hand, extends up to the plegia one typically also finds symmetric deep tendon
p 07.qxd 3/10/08 9:35 AM Page 297
reflexes and bilaterally down-going toes. One may also find Conversion deafness, if bilateral and complete, is
‘give-way’ or ‘collapsing’ weakness. Here, the patient may suggested by observing a blink reflex to an unexpected
be asked to flex the forearm after which the examiner, and loud sound, thus demonstrating intactness of the
grasping the patient’s hand, attempts to extend the fore- brainstem.
arm. In ‘collapsing’ weakness, one finds that an initial resist- Conversion blindness may be either monocular or
ance is followed by an abrupt giving away of any resistance, bilateral. In both cases, an intact direct and consensual
as if the arm had suddenly become flaccid. Although this pupillary response demonstrates that the visual pathways
sign is useful, it must be borne in mind that a degree of col- to the lateral geniculate bodies are intact. In cases of bilat-
lapsing weakness may at times be found in patients with eral conversion blindness, one finds that the patient does
hemiparesis due to stroke. Conversion paraplegia is sug- not sustain injury while attempting to navigate around the
gested by normal reflexes, muscle tone, sensation, and office or hospital room. In doubtful cases, one may have to
sphincter function (Baker and Silver 1987). resort to visual evoked potentials to demonstrate that the
Conversion anesthesia is suggested by the non- post-geniculate visual pathways are intact.
physiologic boundaries of the ‘anesthetic’ area. Thus, Conversion parkinsonism (Lang et al. 1995) may pres-
patients with a ‘glove and stocking’ pattern may complain ent with tremor, loss of associated arm movements, and
of a precise boundary, with the anesthesia ending abruptly postural instability; however, all of these may be accompa-
at a circular boundary just above the ankles or hands, nied by atypical features. Tremor may persist or even
rather than displaying the gradual ‘fade’ seen in a periph- increase with action, and the arms, upon ambulation, are
eral polyneuropathy. Furthermore, in such cases one may often held tightly against the patient’s sides. Postural insta-
find a negative Romberg test. In cases where the conver- bility may be tested, provided adequate help is available in
sion anesthesia suggests a mononeuropathy, one finds that the case of a fall, by standing in front of the patient and
the anesthetic area simply does not match any known der- then administering an abrupt and forceful push against the
matomal pattern. Finally, in cases suggesting central sen- patient’s sternum. In such cases, if the patient does fall
sory loss, one may see a hemianesthesia with a boundary back, there may be a tell-tale and distinctive fluid upswing
that precisely and exactly bisects the midline (care must be of the arms, a movement that does not appear in bradyki-
taken in interpreting this finding, however, for there are netic patients.
rare cases of hemianesthesia secondary to thalamic lesions Conversion syncope is suggested by a lack of autonomic
wherein such a precise bisection is actually seen). changes, such as pallor, and by a typical, dramatic swoon
Before moving on to the next conversion symptom, it is that does not result in any injury.
worth remarking that the oft-stated rule that conversion Conversion coma is suggested by a number of findings.
paralysis and anesthesia are more likely to occur on the left First, eye movements, as observed under the closed lids,
than the right side does not, in fact, appear to hold true. are, rather than roving, typically saccadic. Next, upon gen-
Conversion ataxia is suggested by elaborate lurching tly stroking the eyelashes, one may see a responsive flutter-
movements of the legs, which may be accompanied by simi- ing of the eyelids, and if one attempts to open the eyes by
larly exaggerated flinging of the arms. In severe cases of con- pulling up the lids, there is typically some more or less
version ataxia one may find astasia–abasia, that is to say, an forceful resistance; furthermore, one finds that the pupil-
inability to both walk and to stand. In such cases, one typically lary responses are normal. Finally, when the eyes are allowed
finds that, when supine on the bed, patients can perform fin- to close, they do so abruptly or with a jerky motion, in con-
ger-to-nose and heel-to-knee-to-shin testing adequately. Care trast to the smooth lowering seen in coma. If doubt
must be taken here, however, for in some cases of lesions of remains, one may raise the patient’s flaccid arm, hold it
the anterior vermis such a discrepancy may be found. over the head and then let it drop, observing carefully to
Conversion tremors are typically of large amplitude, see if the arm is pulled to the side to avoid injuring the face.
and most importantly, vary in amplitude and frequency One may also consider the ice cube test, wherein, without
over small periods of time or with distraction; further- warning, one touches an ice cube to a sensitive area,
more, when a weight is applied to the tremulous extremity, perhaps the cheek, whereupon one typically sees an abrupt
one often finds an exacerbation, rather than the expected turning of the head away from the stimulus.
diminution. In cases of unilateral tremor, the tremor may Conversion seizures, also referred to as ‘pseudo-
diminish when the patient is asked to perform a complex seizures’, ‘psychogenic non-epileptic seizures’, or simply
action with the contralateral extremity, for example touch- ‘psychogenic seizures’, may mimic either grand mal or
ing the third, first, and fourth fingers with the thumb. One complex partial seizures. Conversion grand mal seizures,
may also attempt to elicit a phenomenon known as ‘chas- like true grand mal seizures, may begin with a cry, but,
ing the tremor’. In cases of ‘true’ tremor, say, of a hand, unlike the inarticulate cry of a grand mal seizure, this cry
when one grasps the hand the tremor diminishes and does may be more of a scream, and may involve words; further-
not appear elsewhere. In conversion tremor, however, after more, the scream may persist well past the initial part of
grasping the hand, the forearm may begin to tremble, then, the episode. The movements seen in a conversion grand
if the forearm is grasped, the tremor may appear in the mal seizure, rather than being symmetric and rhythmic,
upper arm, as if one were ‘chasing’ it. are typically asymmetric and may involve wild thrashing
p 07.qxd 3/10/08 9:35 AM Page 298
and rocking from side to side; furthermore, if attempts are ETIOLOGY

made to restrain the patient, these are generally met with
some resistance. In a conversion grand mal seizure, some The experience of patients with conversion symptoms is
patients may bite their lips, but the tongue is generally quite remarkable. Although it may be clear to the examining
spared; furthermore, it is very rare to see urinary inconti- physician that the symptoms are, in some sense or other,
nence during a conversion seizure. After the event one typ- ‘produced’ by the patient, the patient is not aware of doing
ically does not see any confusion, nor does one find a so: for the patient, the symptom simply appeared, and did so
positive Babinski sign. Conversion complex partial seizures not on the basis of any motivation or intention that the
are more difficult to diagnose given, as discussed in Section patient was aware of. Various theories have been proposed to
7.3, the extraordinary range of symptomatology seen in explain this. Some invoke the concept of dissociation or sug-
true complex partial seizures. In general, however, as the gest an association with hypnotic phenomena, whereas oth-
behavior becomes more complex and the episode lasts ers involve unconscious motivations. For example, in
longer, well past 5 minutes, the greater the likelihood is explaining of conversion paralysis, say, of the right arm, one
that the event represents a conversion seizure. Laboratory might speculate that the patient experienced a number of
testing, including video–EEG and serum prolactin, neu- events unconsciously, including anger and a desire to strike
ron-specific enolase and CPK levels, may be required to out, guilt at entertaining such a notion and a sense of shame
confirm the diagnostic impression, and these are discussed at not acting decisively. Here, the ‘paralysis’ of the arm serves
further in Section 7.3. two purposes: it effectively prevents the patient from hurting
Other conversion symptoms, of course, are possible, and anyone, thus avoiding guilt, but also provides a ready excuse
these include aphonia, anosmia, nystgmus, convergence why decisive action cannot be taken, thus avoiding shame.
spasm, and ageusia. Although such theories have a strong intuitive appeal, there is
Demonstrating a ‘violation’ may at times require consid- not, as yet, compelling evidence in their support.
erable ingenuity on the part of the examining physician, Imaging studies have provided some interesting results.
and in all cases requires a thorough and detailed neurologic SPECT scanning has revealed decreased activity in the stria-
examination coupled with a firm grasp of the anatomy and tum and thalamus contralateral to conversion paralysis,
physiology of the nervous system. Whether or not investi- with this asymmetry resolving with remission of the paraly-
gation beyond the clinical examination is required, for sis (Vuilleumier et al. 2001). Positron emission tomography
example with MR scanning, evoked potentials or EEGs, is a (PET) scanning has revealed underactivation of the motor
question that should be decided on a case-by case basis. cortex contralateral to conversion paralysis when patients
Certainly, if the ‘violation’ is questionable, such investiga- are requested to move the limb, with associated increased
tion should be considered. activation of the orbitofrontal and anterior cingulate cortex
Although conversion disorder may occur in isolation, (Marshall et al. 1997), and, in a similar vein, functional MR
most patients have other disorders (Binzer et al. 1997), scanning revealed decreased activity in the sensory cortex
most commonly either a depression or a personality disor- contralateral to conversion anesthesia (Ghaffar et al. 2006).
der of the histrionic, passive–aggressive, borderline, or Finally, in one study, MR scanning revealed slight atrophy
antisocial types. Another feature often said to occur in of both striata and the right thalamus in patients with con-
association with conversion symptoms is ‘la belle indiffer- version disorder (Atmaca et al. 2006).
ence’, that is to say a casual indifference to symptoms, such Overall, it may be prudent to say that the appearance of
as blindness or hemianesthesia, which would normally conversion symptoms involves dysfunction of the cortico-
provoke considerable alarm. Unfortunately, this is not a striato-thalamic circuitry, which, in some as yet unknown
reliable symptom, as it may either be absent or seen in fashion, is associated with behavior whose motivation is
other disorders (Stone et al. 2006). Furthermore, it may be unknown to the patient.
confused with anosognosia. DIFFERENTIAL DIAGNOSIS
COURSE The most important differential to make, of course, is

between conversion symptoms and ‘true’ symptoms that
Conversion disorder may pursue either an episodic or are, in fact, occurring on the basis of central or peripheral
chronic course (Mace and Trimble 1996). In episodic cases, nervous system disease. In this regard, it must be borne in
recovery is seen typically in a matter of weeks or months; this mind that, despite thorough investigation, a small minority
favorable turn of events is more likely in younger patients, of patients who receive the diagnosis of conversion disorder
those of good intelligence, and in cases wherein the onset is will, on follow-up, be found to have lesions missed during
acute, and occurs shortly after a major emotional stress. In the initial evaluation (Binzer and Kullgren 1998; Moene
those who do recover, however, recurrences are common in et al. 2000). Consequently, the importance of a detailed and
the following years; when recurrences do occur, the symp- thorough examination, coupled with appropriate imaging
toms may or may not be the same. Chronicity may be antic- and laboratory testing, cannot be overemphasized.
ipated when initial symptoms persist much beyond Conversion symptoms may occur not only in conversion
6 months. disorder, but also in Briquet’s syndrome and schizophrenia.
p 07.qxd 3/10/08 9:35 AM Page 299
Conversion disorder is characterized solely by conversion earlier, multiple complaints are heard, implicating multiple
symptoms. By contrast, in these two other disorders one sees organ systems, including the gastrointestinal tract, the gen-
multiple other symptoms. In Briquet’s syndrome there are itourinary system, central and peripheral nervous systems,
multiple complaints referable to organ systems other than the and the musculoskeletal system. There is debate as to how
central nervous system, and hence one typically hears of com- many symptoms and how many organ systems are required
plaints regarding pulmonary, gastrointestinal, and muscu- to make a diagnosis: a conservative approach requires at
loskeletal functioning. In schizophrenia, one sees a variable least one unexplained complaint from each system.
mixture of psychotic symptoms, such as delusions, hallucina- Gastrointestinal complaints often center on vague and
tions, loosened associations, and overall bizarreness. poorly localized abdominal pain, often accompanied by nau-
Malingering is distinguished from conversion disorder sea and bloating. Constipation is common, diarrhea some-
in that, in the case of malingering, the patient does inten- what less so, and patients often complain of multiple food
tionally, and with full awareness, feign the symptom that, intolerances. Rectal pain or burning may also be present.
in turn, clearly answers to an obvious motivation. For Of genitourinary complaints, irregular, painful or heavy
example, a patient who had been in a minor motor vehicle menstrual flow is prominent, and patients who have been
accident might feign a paralysis, and maintain that weak- pregnant may complain of having had severe, intractable
ness until a large legal settlement had been obtained. vomiting throughout the entire pregnancy. Decreased
Factitious disorder must also be considered, and here the libido is common; females may complain of decreased vagi-
motivation is simply to be a patient in the hospital. nal lubrication and dyspareunia, and males may complain
of erectile dysfunction. Dysuria and partial urinary reten-
TREATMENT tion may also occur.
Musculoskeletal complaints include backache, arthral-
After the diagnosis is made, one should inform the patient in gia, and diffuse chest pain.
a calm and quietly authoritative way that the investigation Central and peripheral nervous system complaints
and testing indicate that the nervous system is intact and not include paralysis, anesthesia, ataxia, deafness, blurry vision,
damaged. One may then go on to add that although it is not diplopia, blindness, dizziness, fainting, pseudoseizures,
known why these symptoms have appeared, it is known that, globus hystericus, aphonia, and headache.
with time, most patients recover. In some cases, especially The large number of complaints, and the inability of the
those with conversion symptoms involving motor function, physician to pin the patient down as to details, often make
such as paralysis, engaging the patient in a course of physical the interview very frustrating for the physician, and it is
therapy may be followed by a rapid resolution of symptoms typical to find chart entries indicating merely that the
(Watanabe et al. 1998). Hypnosis and psychotherapy have review of systems was ‘diffusely positive’. Many physicians
both been utilized, and, anecdotally, with success. turn to the physical examination with some relief, hoping
to determine some definite findings. Generally, however, if
there are any findings, they are typically minor and not
Somatization disorder indicative of any disease or condition that could possibly
account for the patient’s multitudinous complaints.
Somatization disorder, also known as Briquet’s syndrome When physicians attempt to reassure patients regarding
(in honor of Pierre Briquet, who first described it in 1859), the benign nature of the examination, they are often met
is characterized by multiple complaints, referable to multi- with disbelief, if not hostility, and patients typically
ple organ systems, all occurring in the absence of any demand tests, and when basic tests are unremarkable, the
disease entity that could reasonably account for them demands persist. Some physicians may call it quits at this
(Perley and Guze 1962). These complaints persist chroni- point, but others will proceed to invasive procedures or
cally, and typically occasion multiple evaluations, hospital- even to surgery. In some cases, patients have welcomed so
izations, and often-needless diagnostic procedures or many abdominal surgeries that they finally develop a ‘battle-
surgeries. Conservative estimates indicate a lifetime preva- field abdomen’. ‘Doctor shopping’ is common, as exasper-
lence in females of from 0.2 to 2 percent; although Briquet’s ated physicians ‘fire’ their patients, or patients, dissatisfied
syndrome may also occur in males, this is probably very with the diagnostic approach offered by their physicians,
uncommon, if not rare (Smith et al. 1985). move on to find a more aggressive diagnostician.
In addition to these multiple complaints, depression
CLINICAL FEATURES and panic attacks are common, as is alcohol abuse or alco-
holism. Personality disturbances of the borderline, histri-
This syndrome generally first appears in teenage years; onic, or antisocial type, are also common.
onset past the age of 30 is extremely rare.
Patients tend to be excessively vague or dramatic in COURSE
relating their history, often moving restlessly from one
symptom to another, never lingering long enough on one Briquet’s syndrome typically pursues a chronic course,
symptom to give an adequately detailed account. As noted with the intensity and variety of complaints fluctuating
p 07.qxd 3/10/08 9:35 AM Page 300
gradually over the lifespan of the patient; spontaneous before the appearance of multiple complaints. In doubtful
remissions are very uncommon. cases, it may be appropriate to attempt a ‘diagnosis by
treatment response’ by prescribing an antidepressant and
ETIOLOGY watching to see if the multiple complaints subside.
Schizophrenia may also be associated with multiple
Briquet’s syndrome may have both environmental and complaints, but these typically have a bizarre cast to them,
genetic determinants. The prevalence in first-degree rela- and are associated with other typical psychotic symptoms,
tives of females with this syndrome is increased to as high such as delusions, hallucination, etc.
as 20 percent, and adoption studies of females have
demonstrated an increased prevalence of alcohol abuse TREATMENT
and antisocial behavior in their biological fathers (Bohman
et al. 1984; Golding et al. 1992; Guze et al. 1986). It has A conservative medical approach is appropriate, and, if at
been suggested that Briquet’s syndrome and antisocial per- all possible, patients should remain under the care of one
sonality disorder result from a common genetic back- physician, either an internist or family practitioner; psychi-
ground, with sex-mediated expression. atric consultation to the primary care physician has also
been demonstrated to improve patient care (Smith et al.
DIFFERENTIAL DIAGNOSIS 1986). Preliminary work suggests that cognitive behavior
therapy may also be beneficial (Allen et al. 2001).
The most important differential consideration, of course,
is one, or perhaps an unfortunate combination of diseases,
that could produce a ‘diffusely positive’ review of systems Hypochondriasis
with few informative findings on physical examination.
Possibilities include multisystem diseases such as systemic In hypochondriasis (Barsky 2001), patients, on the basis of
lupus erythematosus and sarcoidosis. Consequently, it is minor symptoms or signs, come to believe, or, at the very
necessary to evaluate each new complaint on its own mer- least, strongly suspect, that they have a serious, perhaps even
its, before deciding that it can be ascribed to Briquet’s. In life-threatening, disease. Their concerns occasion multiple
this regard, when complaints referable to the central or consultations, often with multiple physicians, and, impor-
peripheral nervous system are present, the techniques sug- tantly, despite negative examinations and earnest reassur-
gested in the preceding section, on conversion disorder, ances regarding their condition, these patients remain beset
may be helpful. by their concerns. This condition probably has a lifetime
Conversion disorder may also be considered on the dif- prevalence of between 1 and 5 percent, and is equally com-
ferential but is ruled out on two counts: first, rather than a mon among males and females.
multitude of symptoms, there are generally only one, or
perhaps two; and, second, rather than a multitude of organ CLINICAL FEATURES
systems, only one is involved in conversion disorder,
namely the nervous system. Although the onset of hypochondriasis may occur at any
Malingering and factitious disorder, like conversion dis- point between adolescence and old age, most patients first
order, generally are not associated with multiple complaints; begin to experience their concerns in their twenties or thir-
furthermore, the complaints are intentionally feigned with a ties. Although in most cases there does not appear to be a
more or less obvious motive behind them. precipitating event, occasionally the onset may be triggered
Hypochondriasis may also be considered, as hypochon- either by observing a serious illness in an acquaintance or
driacal patients often have multiple complaints referable to personally suffering one. A good example of the latter is the
multiple organ systems. The difference here, however, relates ‘cardiac cripple’ who remains an invalid, consumed by
to the patients’ attitude toward the complaint. In hypochon- hypochondriacal concerns after recovering from a heart
driasis, rather than being concerned about any suffering asso- attack, despite reassurances from the cardiologist.
ciated with the complaint, patients are worried about what Patients come to the physician already convinced that
the symptom implies, namely the presence of a serious, but their symptoms, no matter how mild or trivial, indicate the
undiagnosed, disease. In Briquet’s syndrome, however, the presence of a severe disease. A mild, non-productive cough
focus is more on the suffering associated with the symptom. means they have pneumonia, or perhaps lung cancer; a few
Depression may be associated with multiple unex- palpitations indicate that the heart is about to fail; slight
plained complaints, and thus can present a picture similar nausea is a sure sign that an ulcer has eaten through the
to Briquet’s syndrome. To complicate matters further, as stomach, and simple constipation can only mean that
noted above, patients with Briquet’s syndrome often do colon cancer has finally appeared.
have concurrent depression. The key to making the differ- Patients often present their complaints in minute and
ential here lies in the time course: in cases where the com- maddening detail. If they have been to other physicians, as is
plaints are secondary to depression, one finds the onset of typically the case, they may present copies of prior evalua-
depressed mood and associated vegetative symptoms well tions coupled with accusations that the prior physicians did
p 07.qxd 3/10/08 9:35 AM Page 301
not take their complaints with sufficient seriousness: the in a matter of weeks, and in any case, persist no longer than
often thinly-veiled hostility of such patients may put the 6 months.
current physician on guard, as if he or she is under attack. Depression is perhaps the most important differential
An appropriate history and examination is typically unre- to consider. Especially in the elderly, depression may man-
vealing, or, if findings are noted, they are usually indicative ifest with hypochondriacal concerns; indeed, such patients
of an often trivial condition. Rather than being reassured, may limit their presentation to such complaints, and not
however, patients are often upset. They want more tests, and spontaneously report the accompanying vegetative symp-
if the physician expresses some skepticism regarding this, toms, such as anergia, anhedonia, anorexia, and insomnia.
they may become demanding. Predictably, ‘doctor shop- These ‘masked depressions’ may at times be difficult to
ping’ is common. diagnose, as in some cases patients may deny feeling
The expression of hypochondriacal concerns is not con- depressed.
fined to hospital or doctor visits but permeates these Briquet’s syndrome is distinguished both by the nature
patients’ lives. They may share their worries about their of the patients’ complaints and by the manner in which
health at the dinner table, the office, or at social gatherings, they are made. In Briquet’s syndrome, patients typically
anxiously going from person to person until they find a have a multitude of complaints, and here, it is not so much
sympathetic listener who will tolerate their complaints. In a concern that the symptoms indicate a serious underlying
some cases, their complaints are so wearying that others disease as it is with the debilitating nature of the symptom
begin to avoid these patients, who become isolated and itself. Thus, whereas a hypochondriacal patient complain-
even more miserable. Some, paralyzed by their concerns, ing of constipation may admit that it is mild, and relieved
will opt to enter a nursing home in order to be sure that with simple fiber laxatives, the patient with Briquet’s syn-
medical care is immediately available. drome may complain that it is painful, unbearable, and
Depression or panic disorder are present in a majority impossible to overcome. Further, whereas the hypochon-
of cases (Noyes et al. 1994). driacal patient typically reports complaints in precise
detail, the patient with Briquet’s syndrome is for the most
part vague, and difficult to pin down.
COURSE Conversion disorder is likewise suggested by the nature
Hypochondriasis, in the majority of cases, appears to be of the complaint. In conversion disorder, the complaint
chronic, with symptoms waxing and waning in intensity always refers to the nervous system: in hypochondriasis,
over the years (Barsky et al. 1998). Although it appears that such complaints may also be heard, but other organ sys-
spontaneous full remissions do occur, the frequency with tems are more commonly implicated. Furthermore, in
which this occurs is not clear. conversion disorder the patients’ concerns are not so much
related to a fear of some undiagnosed and underlying dis-
ease, as is the case in hypochondriasis, as they are to the
ETIOLOGY effects of the symptom itself, such as an inability to walk
because of conversion paralysis.
Hypochondriasis does not appear to run in families (Noyes Malingering and factitious disorder are both distin-
et al. 1997), and the etiology is as yet unclear. Although guished by the fact that these patients either intentionally
these patients recall having more serious illnesses in child- lie about symptoms or intentionally inflict wounds, all in
hood and going through more emotionally traumatic the service of an understandable goal, such as financial
events (Barsky et al. 1994; Noyes et al. 2002), there have gain, or, in the case of factitious disorder, merely being a
been no prospective studies, and hence these findings may patient in the hospital.
well be due to recall bias. Finally, one must remain alert to the possibility that
Based on the similarity between the persistent recurring new complaints, rather than being hypochondriacal, may
concerns seen in hypochondriasis and obsessions seen in signal a serious underlying disease: each new complaint
obsessive–compulsive disorder, there has been speculation must be evaluated on its own merits.
that hypochondriasis is but one example of the ‘obses-
sive–compulsive spectrum’ disorders but as yet proof of
this is lacking. TREATMENT
Cognitive–behavioral therapy is effective (Barsky and

DIFFERENTIAL DIAGNOSIS Ahern 2004), and paroxetine is roughly equivalent to cog-
nitive–behavioral therapy, with both being better than
Hypochondriasis must be distinguished from transient placebo (Greeven et al. 2007). In cases where such therapy
hypochondriacal concerns, which are very common in the is either not available or when patients refuse to enter
general population: the notorious ‘Doctor’s diseases’ suf- treatment, it is appropriate to maintain a conservative
fered by medical students are a good example. The differ- medical approach and to see patients in regularly sched-
ential here rests on the duration of hypochondriacal uled follow-up visits. Should depression or panic disorder
concerns: most transient concerns resolve spontaneously be present, these must be treated.
p 07.qxd 3/10/08 9:35 AM Page 302
7.8 MALINGERING AND FACTITIOUS ILLNESS their way around the jail and to do those things that are nec-
essary to maintain a certain degree of comfort and safety.
Both malingering (LoPiccolo et al. 1999) and factitious ill- All in all, these individuals are acting out the ‘popular’ con-
ness (Krahn et al. 2003) are characterized by the inten- ception of ‘insanity’, and once the trial is over, or the sen-
tional feigning of illness; they are distinguished from one tence imposed, this ‘insanity’ clears up quickly.
another by the motive underlying this behavior. In malin- Several features may alert the physician to the possibility
gering the motive is readily understandable, as for example of malingering. First, look for obvious gains should the
when someone complains of a ‘bad back’ to get out of work individual be certified as ‘ill’, such as obtaining insurance
or to obtain narcotics. In factitious illness, however, the payments or narcotics, or winning a lawsuit. Second, be
motive is a little more obscure, in that the goal of these alert to inconsistencies in the clinical presentation. In this
individuals is merely to be a patient in the hospital, and to regard, when neurologic complaints are heard, the diagnos-
assume, as it were, the ‘sick role’. tic tips discussed in the Section 7.7 for conversion disorder
Before making a diagnosis of malingering or factitious may be kept in mind. Third, be suspicious when patients
illness, one must be reasonably certain that there is no true are uncooperative with treatment, or when the offering of a
underlying illness that could reasonably account for the good prognosis is met with thinly veiled hostility.
individual’s complaints. Furthermore, one must also dis- In doubtful cases, obtaining collateral history may be
tinguish malingering and factitious illness from conversion very helpful. For example, if, on interviewing the spouse of
disorder, Briquet’s syndrome, and hypochondriasis; these an individual who complains of incapacitating back pain,
differential possibilities are distinguished by the lack of any one gathers a history that the ‘patient’ spends his weekends
associated intentionality and by the lack of any recogniz- playing volleyball, the diagnostic evaluation is essentially
able ‘goal’. Thus, in the case of ‘paralysis’, the malingerer complete. Laboratory testing may be helpful, as for exam-
and the individual with factitious illness both consciously ple neuroimaging in cases of feigned paralysis; however,
and intentionally feign weakness, with the goal, respec- most malingerers tend to feign illnesses that lack distinc-
tively, of either an understandable gain (e.g., winning a tive laboratory findings.
lawsuit) or of simply being a patient on the neurologic What the physician should do, once it becomes clear
ward. By contrast, in the case of, say, conversion disorder, that malingering is present, is not clear. Some advocate a
the ‘paralysis’ simply appears, without any planning or simple, but non-judgmental, discussion of the facts, and
intention on the part of the patient, and persists despite indeed some malingerers may respond favorably to this.
there being no advantage to the patient. Most, however, will not and indeed may become even
more demanding or hostile. Regardless of what approach is
taken, however, it is important to ‘do no harm’, and in this
Malingering regard, one should not prescribe narcotics, certify non-
existent illnesses, or do anything else that reinforces the
Some malingerers may limit their dissimulation to simply patient’s deception.
voicing more or less convincing complaints. Others may
take advantage of an actual illness, and embellish their
symptoms out of all proportion to the actual underlying Factitious illness
disease or condition. Some may go so far as to actually
stage an accident or inflict a wound and then go on to exag- The illnesses feigned here tend to be severe, as might be
gerate their effects. Falsification of medical records may expected, given that the goal of the dissimulation is admis-
also occur. sion to the hospital. Typically, the patient arrives at the
Neurologic, psychiatric, and rheumatologic illnesses are emergency room with a very convincing presentation (Reich
often chosen as models. Malingerers may complain of and Gottfried 1983). Some may complain of several episodes
headaches, anesthesia, paralysis, ‘whiplash’, and pain, espe- of severe chest pain, suggesting crescendo angina. Others
cially low back pain. Depression, post-traumatic stress dismay report having had a ‘seizure’, and even bite their tongue
order, and psychosis may also be feigned. A peculiar form to make the picture more convincing. Others may swallow
of malingering may be seen in prisoners awaiting trial or blood and then vomit, thus simulating hematemesis,
sentencing, known as the ‘Ganser syndrome’ (Carney et al. whereas others may hold the blood in their mouths and then
1987; Tsoi 1973). Also known as the ‘nonsense syndrome’, cough, producing a picture of hemoptysis. A urine specimen
this is characterized by ‘nonsense’ responses to questions, may be contaminated with feldspar to mimic renal calculi,
which are always just off the mark or past the point. For or with feces to suggest a severe urinary tract infection. More
example, if the individual is asked to add 5 plus 3, he may malignantly, feces may be injected to create a septic picture.
respond ‘7’; with coaching and encouragement he may give Laxatives may be taken to induce diarrhea, furosemide to
other responses, such as ‘6’ or ‘9’, but never the correct one. create hypokalemia, myelosuppressants to mimic aplastic
In a similar vein, if asked how many legs a horse has, the anemia, thyroid hormone to produce hyperthyroidism, and
response may be ‘3’. Typically, although these individuals either insulin or oral antidiabetic agents to produce hypo-
appear confused and dazed, they are generally able to find glycemia and raise the question of an insulinoma; in this last
p 07.qxd 3/10/08 9:35 AM Page 303
References 303
case, determining simultaneous insulin and C-peptide levels 1977; Pope et al. 1982; Popli et al. 1992). Individuals may
is helpful to rule out surreptitious injection of insulin: in an report suicidal or homicidal ideation, or may complain of
insulinoma both are elevated, whereas when insulin is voices, visions, deep depression, or post-traumatic stress.
injected the C-peptide level will be normal (Grunberger Given that laboratory testing is generally irrelevant in such
et al. 1988). cases, unmasking the dissimulation may take a little longer;
Once admitted, these individuals may make frequent however, eventually inconsistencies become apparent. In
demands for narcotics, and staff are often split and played such cases, when confronted by the physician’s suspicions,
off, one against the other. Diagnostic tests are welcomed, these individuals may, like those with ‘physical’ symptoms,
even demanded, and as the tests become ever more inva- become indignant and demand discharge, or they may ‘up
sive and dangerous, these individuals often become the ante’ by making a suicidal gesture.
calmer, even content. As more and more tests come back As with malingering, it is not clear what the best
negative or inconsistent (Wallach 1994), the complaints approach is to factitious illness. Some advocate confronta-
may change: chest pain may fail to recur, but now abdom- tion, whereas others will attempt to engage the individual
inal pain and diarrhea come to the forefront. Eventually, in some form of psychotherapy. In cases of ‘proxy’ illness,
when told by the physician that there is ‘nothing wrong’, legal authorities must be involved.
these individuals typically become angry, accuse the physi-
cian of incompetence, and leave the hospital abruptly,
often against medical advice. REFERENCES
The majority of individuals with factitious illness are
female; most are in their twenties or thirties, and most have Abd El Naby S, Hassanein M. Neuropsychiatric manifestations of
some medical background, having worked as aides, nurses, chronic manganese poisoning. J Neurol Neurosurg Psychiatry
or therapists of one sort or other. In these cases, the fre- 1965; 28:282–8.
quency with which hospitalization is sought varies over Abenson MH. Epileptic fits provoked by taste. Br J Psychiatry
time, and is often related to stressful events. In most cases, 1969; 115:123.
the dissimulation eventually stops after a matter of years. Acharya V, Acharya J, Luders H. Olfactory epileptic auras.
In a minority of cases, however, the course is chronic Neurology 1998; 51:56–61.
and severe, and in such cases one speaks of ‘Munchausen’s Adachi N, Arima K, Kato M et al. Dentatorubral-pallidoluysian
syndrome’, named after the famous German baron who atrophy (DRPLA) presenting with psychosis. J Neuropsychiatry
traveled from city to city telling elaborate tales about him- Clin Neurosci 2001; 13:258–60.
self (Asher 1951). In contrast with the typical individual Adachi N, Kato M, Sekimoto M et al. Recurrent postictal psychosis
with factitious illness, these individuals tend to be male after remission of interictal psychosis: further evidence of
and middle-aged, and to have a history of traveling from bimodal psychosis. Epilepsia 2003; 44:1218–22.
city to city with, at times, literally hundreds of hospital Adachi N, Kanemoto K, Muramatsu R et al. Intellectual prognosis
admissions. Also known as ‘hospital hoboes’ (Clarke and of status epilepticus in adult epilepsy patients: analysis with
Melnick 1958) or ‘hospital addicts’ (Barker 1962), these Wechsler Adult Intelligence Scale-revised. Epilepsia 2005;
individuals have made being a patient into a way or life. 46:1502–9.
A particularly loathsome variant of factitious illness (or Adair JC, Williamson DJG, Schwartz RL et al. Ventral tegmental
Munchausen’s syndrome) is that which occurs ‘by proxy’ area injury and frontal lobe disorder. Neurology 1996;
(Souid et al. 1998). Here, a parent, typically the mother, 46:442–3.
may induce illness in a young child by any of the means Adam C, Baulac M, Saint-Hilaire J-M et al. Value of magnetic
noted above, and use the result as a ticket for the child’s resonance imaging-based measurements of hippocampal
admission. These parents may, at least initially, seem formation in patients with partial epilepsy. Arch Neurol 1994;
appropriately concerned; however, suspicions may be 51:130–8.
aroused when staff note a certain satisfaction, even con- Adamec DE, Stark-Adamec C. Limbic kindling in animal behavior:
tentment, on the parent’s part as the child is subjected to implications for human psychopathology associated with
ever more invasive diagnostic procedures. In some cases, complex partial seizures. Biol Psychiatry 1983; 18:269–74.
laboratory results may clinch the diagnosis, whereas in Adams JH, Graham DI, Murray Al et al. Diffuse axonal injury due
others it may be necessary to resort to covert video surveil- to nonmissile head injury in humans: an analysis of 45 cases.
lance to ‘catch’ the parent injecting or otherwise harming Ann Neurol 1982; 12:557–63.
the child (Hall et al. 2000). Although such ‘proxy’ facti- Agius MA, Chan JW, Chung S et al. Role of antiribosomal P
tious illness most often involves a parent and child, there protein antibodies in the diagnosis of lupus isolated to the
have also been cases where adults have induced illness, central nervous system. Arch Neurol 1997; 54:862–4.
either in their spouses or, more commonly, their elderly Agnetti V, Carreras M, Pinna L et al. Ictal prosopagnosia and
parents. epileptogenic damage of the dominant hemisphere. Cortex
Although most cases of factitious illness involve ‘physi- 1978; 14:50–7.
cal’ signs and symptoms, cases may also occur where ‘psy- Aguilar MJ, Rasmussen T. Role of encephalitis in pathogenesis of
chological’ signs and symptoms are feigned (Gelenberg epilepsy. Arch Neurol 1960; 2:663–76.
p 07.qxd 3/10/08 9:35 AM Page 304
Ahl B, Bokemeyer M, Ennen JC et al. Dissection of the brain Ames FR, Enderstein O. Ictal laughter: a case report with clinical,
supplying arteries over the life span. J Neurol Neurosurg cinefilm, and EEG observations. J Neurol Neurosurg Psychiatry
Psychiatry 2004; 75:1194–6. 1975; 38:11–17.
Ahuja GK, Mohandas S, Narayanaswamy AS. Eating epilepsy. Ames FR, Enderstein O. Gelastic epilepsy and hypothalamic
Epilepsia 1980; 21:85–9. hamartoma. S Afr Med J 1980; 58:163–5.
Ajmone-Marsan C, Ralston BL. The epileptic seizure: its functional Aminoff MJ, Simon RP. Status epilepticus. Causes, clinical
morphology and diagnostic significance. IL: Springfield, features and consequences in 98 patients. Am J Med 1980;
Charles C. Thomas, 1957. 69:657–66.
Akelaitis AJ. Lead encephalopathy in children and adults. J Nerv Andermann F, Robb JP. Absence status: a reappraisal following
Ment Dis 1941; 93:313–32. review of thirty-eight patients. Epilepsia 1972; 13:177–87.
Alajouanine T, DeRobert L, Thieffry S. Etude clinique de 210 cas Andersen G, Vestergaard K, Riis J. Citalopram for poststroke
d’intoxication par les sels organiques d’etain. Rev Neurol 1958; pathological crying. Lancet 1993; 342:837–9.
98:85–96. Andersen G, Vestergaard K, Lauritzen L. Effective treatment of
Alamowitch S, Graus F, Uchuya M et al. Limbic encephalitis and poststroke depression with the selective serotonin reuptake
small cell lung cancer: clinical and immunological features. inhibitor citalopram. Stroke 1994; 25:1099–104.
Brain 1997; 120:923–8. Anderson DJ, Goldstein LB, Wilkinson WE et al. Stroke location,
Al-Asmi A, Jansen AC, Badhwar AP et al. Familial temporal lobe characterization, severity, and outcome in mitral vs aortic
epilepsy as a presenting feature of choreoacanthocytosis. valve endocarditis. Neurology 2003; 61:1334–6.
Epilepsia 2005; 46:1256–63. Anderson G, Vestergaard F, Lauritzen L. Effective treatment of
Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance poststroke depression with the selective serontonin reuptake
imaging profile predict clinical response to early reperfusion: inhibitor citalopram. Stroke 1994; 25:1099–104.
the diffusion and perfusion imaging evaluation for Anderson J. On sensory epilepsy. A case of cerebral tumour,
understanding stroke evolution (DEFUSE) study. Ann Neurol affecting the left temporo-sphenoidal lobe, and giving rise to
2006; 60:508–17. a paroxysmal taste-sensation and dreamy state. Brain 1886;
Albert A, Mirza S, Mirza KAH et al. Morbid jealousy in alcoholics. 8:385–95.
Br J Psychiatry 1996; 167:668–72. Andrews E, Ballard J, Walter-Ryan WG. Monosymptomatic
Alemayehu S, Bergey GK, Barry E et al. Panic attacks as ictal hypochondriacal psychosis manifesting as delusion of
manifestations of parietal lobe seizures. Epilepsia 1995; infestation: case studies of treatment with haloperidol. J Clin
36:824–30. Psychiatry 1986; 47:188–90.
Alexander MP, Freedman M. Amnesia after anterior communicating Annegers JF, Grabow JD, Groover RD et al. Seizures after head
artery aneurysm rupture. Neurology 1984; 34:752–7. trauma: a population study. Neurology 1980; 30:683–9.
Alldredge BK, Lowenstein DH, Simon RP. Seizures associated with Annegers JF, Hauser WA, Beghi E et al. The risk of unprovoked
recreational drug abuse. Neurology 1989; 39:1037–9. seizures after encephalitis and meningitis. Neurology 1988;
Allen LA, Woolfoldk RL, Lehrer PM et al. Cognitive behavior 38:1407–10.
therapy for somatization disorder: a preliminary investigation. Annegers JF, Hauser A, Coan SP et al. A population-based study of
J Behav Ther Exp Psychiatry 2001; 32: 53–62. seizures after traumatic brain injuries. N Engl J Med 1998;
Allen RM, Young SJ. Phencyclidine induced psychosis. Am J 383:20–4.
Psychiatry 1978; 135:1081–4. Appenzeller S, Cendes F, Costallat LTL. Epileptic seizures in
Almeida OP, Waterreus A, Hankey GJ. Preventing depression after systemic lupus erythematosus. Neurology 2004; 63:1808–12.
stroke: results from a randomized, placebo-controlled trial. J Appleton RE, Farrell K, Teal P et al. Complex partial status
Clin Psychiatry 2006; 67:1104–9. epilepticus associated with cyclosporin-A therapy. J Neurol
Almeida S, Ranjith G. Using pramipexole in neuropsychiatry: a Neurosurg Psychiatry 1989; 52:1068–71.
cautionary tale. J Neuropsychiatry Clin Neurosci 2006; 18:556–7. Arboix A, Bell Y, Garcia-Eroles L et al. Clinical study of 35 patients
Alpers BJ. Relation of the hypothalmus to disorders of personality: with dysarthria-clumsy hand syndrome. J Neurol Neurosurg
report of a case. Arch Neurol Psychiatry 1937; 38:291–303. Psychiatry 2004; 75:231–4.
Alpers BJ, Grant FC. The clinical syndrome of the corpus callosum. Arboix A, Lopez-Grau M, Casanovas C et al. Clinical study of 39
Arch Neurol Psychiatry 1931; 25:67–86. patients with atypical lacunar syndromes. J Neurol Neurosurg
Alsen G, Gillberg IC, Lindblom R et al. Tuberous sclerosis in Psychiatry 2006; 77:381–4.
Western Sweden: a population study of cases with early Arcineagas DB, Anderson CA. Viral encephalitis: neuropsychiatric
childhood onset. Arch Neurol 1994; 51:76–81. and neurobehavioral aspects. Curr Psychiatry Rep 2004;
Alves D, Pires MM, Guimaraes A et al. Four cases of late onset 6:372–9.
metachromatic leukodystrophy in a family: clinical, Armstrong DD. The neuropathology of temporal lobe epilepsy. J
biochemical and neuropathological studies. J Neurol Neuropathol Exp Neurol 1993; 52:499–506.
Neurosurg Psychiatry 1986; 49:1417–22. Aron AM, Freeman JM, Carter S. The natural history of
Amatniek JC, Hauser WA, DelCastillo-Castenada C et al. Incidence Sydenham’s chorea. Am J Med 1965; 38:83–95.
and predictors of seizures in patients with Alzheimer disease. Aronica E, Gorter JA, Ramkema M et al. Expression and cellular
Epilepsia 2006; 47:867–72. distribution of multidrug resistance-related proteins in the
p 07.qxd 3/10/08 9:35 AM Page 305
References 305
hippocampus of patients with mesial temporal lobe epilepsy. Barkovich AJ, Kjos BO. Gray matter heterotopias: MR
Epilepsia 2004; 45:441–5. characteristics and correlation with developmental and
Arroyo S, Lesser RP, Gordon B. Mirth, laughter and gelastic neurologic manifestations. Radiology 1992; 182:493–9.
seizures. Brain 1993; 116:757–80. Barkovich AJ, Rowley HA, Andermann F. MR in partial epilepsy:
Ashcroft PB. Traumatic epilepsy after gunshot wounds in the value of high-resolution volumetric techniques. AJNR 1995;
head. BMJ 1941; 1:739–44. 16:339–43.
Asher R. Myxoedematous madness. BMJ 1949; 2:555–62. Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a
Asher R. Munchausen’s syndrome. Lancet 1951; 1:339–41. review and phenomenological survey. J Neurology Neurosurg
Ashford JW, Schulz SC, Walsh GO. Violent automatism in a partial Psychiatry 2001; 70:727–33.
complex seizure: report of a case. Arch Neurol 1980; Barnett HJM, Taylor DW, Eliasziw M et al. Benefit of carotid
37:120–2. endarterectomy in patients with symptomatic moderate or
Ashkenazi A, Kaufman Y, Ben-hur T. Bilateral focal motor status severe stenosis. N Engl J Med 1998; 339:1415–25.
epilepticus with retained consciousness after stroke. Barry E, Sussman NM, Bosley TM et al. Ictal blindness and status
Neurology 2000; 54:976–8. epilepticus amauroticus. Epilepsia 1985; 26:577–84.
Atmaca M, Aydin A, Texcan E et al. Volumetric investigation of Barsky AJ. The patient with hypochondriasis. N Engl J Med 2001;
brain regions in patients with conversion disorder. Prog 345:1395–9.
Neuropsychopharmacol Biol Psychiatry 2006; 30:708–13. Barsky AJ, Ahern DK. Cognitive behavior therapy for
Aurahami E, Weiss-Peretz J, Cohn AF. Focal epileptic activity hypochondriasis: a randomized controlled trial. JAMA 2004;
following intravenous contrast material injection in patients 291:1464–70.
with metastatic brain disease. J Neurol Neurosurg Psychiatry Barsky AJ, Wool C, Barnett MC et al. Histories of childhood
1987; 50:221–3. trauma in adult hypochondriacal patients. Am J Psychiatry
Avery TL. Seven cases of frontal tumor with psychiatric 1994; 151:397–401.
presentation. Br J Psychiatry 1971; 119:19–23. Barsky AJ, Fama JM, Bailey ED et al. A prospective 4- to 5-year
Ay H, Koroshetz WJ, Benner T et al. Transient ischemic attack with study of DSM-III-R hypochondriasis. Arch Gen Psychiatry
infarction: a unique syndrome. Ann Neurol 2005; 57:679–83. 1998; 55:737–44.
Aykutlu E, Baykan B, Serdaroglu P et al. Epileptic seizures in Battaglia G, Chiapparini L, Fransceschetti S et al. Periventricular
Behcet’s disease. Epilepsia 2002; 43:832–5. nodular heterotopia: classification, epileptic history, and
Azouvi P, Jokic C, Attal N et al. Carbamazepine in agitation and genesis of epileptic discharges. Epilepsia 2006; 47:86–97.
aggressive behavior following severe closed-head injury: Bauer J, Kaufmann P, Elger CE et al. Similar postictal serum
results of an open trial. Brain Inj 1999; 13:797–804. prolactin response in complex partial seizures of temporal or
Backstrom T. Epileptic seizures in women related to plasma frontal lobe onset. Arch Neurol 1994; 51:645.
estrogen and progesterone during the menstrual cycle. Acta Baumann CR, Werth E, Stocker R et al. Sleep-wake disturbances 6
Neurol Scand 1976; 54:321–47. months after traumatic brain injury: a prospective study. Brain
Bagedahl-Strindlund M. Postpartum mental illness: timing of 2007;130:1873–83.
illness onset and its relation to symptoms and Bautista RE, Ciampetti MZ. Expressive aprosody andamuia as a
sociodemographic characteristics. Acta Psychiatr Scand 1986; manifestation of right hemisphere seizures. Epilepsia 2003;
74:490–6. 44:466–7.
Bailey DP, Coull BM, Goodnight SH. Neurological disease Baykan B, Matur Z, Gurses C et al. Typical absence seizures
associated with antiphospholipid antibodies. Ann Neurol 1989; triggered by photosensitivity. Epilepsia 2005; 46:159–63.
25:221–7. Bear DM. Temporal lobe epilepsy: a syndrome of sensory-limbic
Baird AE, Lovblad KO, Schlaug G et al. Multiple acute stroke hyperconnection. Cortex 1979; 15:357–69.
syndrome: marker of embolic disease? Neurology 2000; Bear DM, Fedio P. Qualitative analysis of interictal behavior in
54:674–8. temporal lobe epilepsy. Arch Neurol 1977; 34:454–67.
Baker JH, Silver JR. Hysterical paraplegia. J Neurol Neurosurg Bear DM, Levin K, Blumer D et al. Interictal behavior in
Psychiatry 1987; 50: 375–82. hospitalized temporal lobe epileptics: relationship to
Baker RW, Conley RR. Seizures during clozapine therapy. Am J idiopathic psychiatric syndromes. J Neurol Neurosurg
Balkan S. Painful unilateral epileptic seizure. Acta Neurol Scand Beard AW. The association of hepatolenticular degeneration with
1995; 91:414–16. schizophrenia. Acta Psychiatr Neurol Scand 1959; 34:411–28.
Ballenger CE, King DW, Gallagher BB. Partial complex status Bebin EM, Gomez ER. Prognosis in Sturge–Weber disease:
epilepticus. Neurology 1983; 33:1545–52. comparison of unihemispheric and bihemispheric involvement.
Bare MA, Burnstine TH, Fisher RS et al. Electroencephalographic J Child Neurology 1988; 3:181–4.
changes during simple partial seizures. Epilepsia 1994; Beetar JT, Guilmette TJ, Sparadeo FR. Sleep and pain complaints
35:715–20. in symptomatic traumatic brain injury and neurologic
Barker JC. The syndrome of hospital addiction (Munchausen populations. Arch Phys Med Rehabil 1996; 77:1288–302.
syndrome): a report on the investigation of seven cases. J Belafsky MA, Carwille S, Miller P et al. Prolonged epileptic
Ment Sci 1962; 108:167–82. twilight states: continuous recordings with nasopharyngeal
p 07.qxd 3/10/08 9:35 AM Page 306
electrodes and videotape analysis. Neurology 1978; Beydoun A, Sackellares JC, Shu V et al. Safety and efficacy of
28:239–45. divalproex sodium monotherapy in partial epilepsy: a double-
Beling CC, Martland HS. A case of tumor of the corpus callosum blind, concentration–response design clinical trial. Neurology
and frontal lobes. J Nerv Ment Dis 1919; 50:425–32. 1997; 48:182–8.
Bell DS. The experimental reproduction of amphetamine Beydoun A, Sachdeo R, Rosenfeld WE et al. Oxcarbazepine
psychosis. Arch Gen Psychiatry 1973; 29:35–40. monotherapy for partial-onset seizures: a multicenter, double-
Bell WL, Harmes J, Logue P et al. Neologistic speech automatisms blind, clinical trial. Neurology 2000; 54:2245–51.
during complex partial seizures. Neurology 1990; 40:49–52. Bicknell JN, Moore RA. Psychological meaning of disulfiram
Bell WL, Walczak TS, Shin C et al. Painful generalized clonic and (Antabuse) therapy. Arch Gen Psychiatry 1960; 2:661–8.
tonic seizures with retained consciousness. J Neurol Neurosurg Bien CG, Benniger FO, Urbach H et al. Localizing value of epileptic
Psychiatry 1997; 63:792–5. visual auras. Brain 2000; 123:244–53.
Benbadis SR, Kotagal P, Klem GH. Unilateral blinking: a Bien CG, Widman G, Urbach H et al. The natural history of
lateralizing sign in partial seizures. Neurology 1996; 46:45–8. Rasmussen’s encephalitis. Brain 2002; 125:1751–9.
Benton CS, de Silva R, Rutledge SL et al. Molecular and genetic Binnie LD, Debets RMC, Engelsman M et al. Double-blind
studies in SCA-7 define a broad clinical spectrum and the crossover trial of lamotrigene (Lamictal) as add-on therapy in
infantile phenotype. Neurology 1998; 51:1081–6. intractable epilepsy. Epilepsia Res 1989; 4:222–9.
Bercel NA, Travis LE, Olinger LB et al. Model psychoses induced by Binzer M, Kullgren G. Motor conversion disorder. A prospective 2-
LSD-25 in normals. I. Psychophysiological investigations, with to 5-year follow-up study. Psychosomatics 1998; 39:519–27.
special reference to the mechanism of the paranoid reaction. Binzer M, Andersen PM, Kullgren G. Clinical characteristics of
Arch Neurol Psychiatry 1956; 75:588–611. patients with motor disability due to conversion disorder: a
Beresford OD, Graham AM. Chorea gravidarum. J Obs Gynecol Br prospective control group study. J Neurol Neurosurg Psychiatry
Emp 1950; 57:616–25. 1997; 63: 83–8.
Berger JR, Ros DB. Reversible Parkinson syndrome Biton V, Montouris GD, Ritter F et al. A randomized, placebo-
complicating postoperative hypoparathyroidism. Neurology controlled study of topiramate in primary generalized tonic-
1981; 31:81–2. clonic seizures. Neurology 1999; 52:1330–7.
Bergeron C, Pollanen MS, Weyer L et al. Unusual clinical Biton V, Sackellares JC, Vuong A et al. Double-blind, placebo-
presentation of cortical-basal ganglionic degeneration. Ann controlled study of lamotriginein primary generalized tonic-
Neurol 1996; 40:893–900. clonic seizures. Neurology 2005; 65:1737–43.
van den Bergh MW, van der Schaaf I, van Gijn J. The spectrum of Bleuler E. Textbook of psychiatry, 1924. New York: Arno Press,
presentations of venous infarction caused by deep cerebral 1976.
vein thrombosis. Neurology 2005; 65:192–6. Blinkenberg M, Rune K, Jonsson A et al. Cerebral metabolism in a
Berkovic SF. Andermann F, Melanson D et al. Hypothalamic case of multiple sclerosis with acute mental disorder. Acta
hamartomas and associated ictal laughter: evolution of the Neurol Scand 1996; 94:310–13.
characteristic epileptic syndrome and diagnostic value of Blum AS, Drislane FW. Nonconvulsive status epilepticus in
magnetic resonance imaging. Ann Neurol 1988; 23:429–39. thrombotic thrombocytopenic purpura. Neurology 1996;
Berkovic SF, Andermann F, Olivier A et al. Hippocampal sclerosis 47:1079–81.
in temporal lobe epilepsy demonstrated by magnetic Blume WT, Jones DC, Young GB et al. Seizures involving secondary
resonance imaging. Ann Neurol 1991; 29:175–82. sensory and related areas. Brain 1992; 115:1509–20.
Berkovic SF, Izzillo P, McMahon JM et al. LGI1 mutations in Blumer D. Hypersexual episodes in temporal lobe epilepsy. Am J
temporal lobe epilepsy. Neurology 2004a; 62:1115–19. Psychiatry 1970; 126:1099–106.
Berkovic SF, Serratosa JM, Phillips HA et al. Familial partial Blumer D, Walker AE. Sexual behavior in temporal lobe epilepsy.
epilepsy with variable foci: clinical features and linkage to Arch Neurol 1967; 16:37–43.
chromosome 22q12. Epilepsia 2004b; 45:1054–60. Boas J, Dam M, Friis ML et al. Controlled trial of lamotrigene
Bertina RM, Koelman BPC, Rosendall FR et al. Mutation in the (Lamictal) for treatment-resistant partial seizures. Acta Neurol
blood coagulation factor factor V associated with resistance Scand 1996; 54:247–52.
to protein C. Nature 1994; 369:64–7. Boggs J, Preis K. Successful initiation of combined therapy with
Betting LE, Mory SB, Lopes-Cendes I et al. EEG features in valproate sodium injection and divalproex sodium extended-
idiopathic generalized epilepsy: clues to diagnosis. Epilepsia release tablets in the epilepsy monitoring unit. Epilepsia 2000;
2006; 47:523–8. 46:940–51.
Betts TA, Smith WT, Kelly RE. Adult metachromatic Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical
leukodystrophy (sulphatide lipidosis) simulating schizophrenia. syndromes, etiology, and prognosis. Neurology 1988;
Neurology 1968a; 18:1140–2. 38:837–48.
Betts TA, Kalra PL, Cooper R et al. Epileptic fits as a possible side- Bogousslavsky J, Martin R, Regli F et al. Persistent worsening of
effect of amitriptyline. Lancet 1968b; 1:390–2. stroke sequelae after delayed seizures. Arch Neurol Psychiatry
Beydoun A, Uthman BM, Kugler AR et al. Safety and efficacy of 1992; 49:385–8.
two pregabalin regimens for add-on treatment of epilepsy. Bohman M, Cloninger CR, von Knorring AL et al. An adoption
Neurology 2005; 64:475–80. study of somatoform disorders. III. Cross-fostering analysis
p 07.qxd 3/10/08 9:35 AM Page 307
References 307
and genetic relationship to alcoholism and criminality. Arch Brodtkorb E, Nilsn G, Smevik O et al. Epilepsy and anomalies of
Gen Psychiatry 1984; 41:872–8. neuronal migration: MRI and clinical aspects. Acta Neurol
Boller F, Wright DG, Cavalieri R et al. Paroxysmal ‘nightmares’: Scand 1992; 86:24–32.
sequel of a stroke responsive to diphenylhydantoin. Neurology Brodtkorb E, Gu W, Nakken KO et al. Familial temporal lobe
1975; 25:1026–8. epilepsy with aphasic seizures and linkage to chromosome
Bolt JMW. Huntington’s disease in the West of Scotland. Br J 10q22–q24. Epilepsia 2002; 43:228–35.
Psychiatry 1970; 116:259–70. Brodtkorb E, Michler RP, Gu W et al. Speech-induced aphasic
Bombardier CH, Fann JR, Temkin N et al. Posttraumatic stress seizures in epilepsy caused by LGI1 mutations. Epilepsia 2005;
disorder symptoms during the first six months after traumatic 46:963–6.
brain injury. J Neuropsychiatry Clin Neurosci 2006; 18:501–8. Brooke MM, Patterson DR, Questad KA et al. The treatment of
Boon PA, Williamson PD, Fried I et al. Partial seizures: an agitation during initial hospitalization after traumatic brain
anatomoclinical, neuropsychological, and surgical correlation. injury. Arch Phys Med Rehabil 1992; 73:917–21.
Epilepsia 1991; 32:467–76. Brooks N, Campsie L, Symington C et al. The five year outcome of
Borchert CD, Labar DR. Permanent hemiparesis due to partial severe blunt head injury: a relative’s view. J Neurol Neurosurg
status epilepticus. Neurology 1995; 45:187–8. Psychiatry 1986; 49:764–70.
Bornstein M, Coddon D, Song S. Prolonged alterations in behavior Brown P, Rodgers-Johnson P, Cathala F et al. Creutzfeldt–Jakob
associated with a continuous electroencephalographic (spike disease of long duration: clinicopathological characteristics,
and dome) abnormality. Neurology 1956; 6:444. biotransmissability, and differential diagnosis. Ann Neurol
Boudreau EA, Liow K, Frattali CM et al. Hypothalamic hamartomas 1984; 16:295–304.
and seizures: distinct natural history of isolated and Pallister- Brown P, Cathala F, Castaigne P et al. Creutzfeldt–Jakob disease:
Hall syndrome cases. Epilepsia 2005; 46:42–7. clinical analysis of a consecutive series of 230
Bousser M-G, Chiras J, Bories J et al. Cerebral venous thrombosis: neuropathologically verified cases. Ann Neurol 1986;
a review of 38 cases. Stroke 1985; 16:199–213. 20:597–602.
Bouton SM. Pick’s disease. J Nerv Ment Dis 1940; 91:9–30. Brown P, Gibbs CJ, Rodgers-Johnson P et al. Human spongiform
Brady KT, Lydiard RB, Malcolm R et al. Cocaine-induced psychosis. encephalopathy: the National Institutes of Health series of
J Clin Psychiatry 1991; 52:509–12. 300 cases of experimentally transmitted disease. Ann Neurol
Bray GA, Dahms WT, Swerdhoff RS et al. The Prader–Willi 1994; 35:513–29.
syndrome: a study of 40 patients and a review of the Browne TR, Kugler AR, Eldon MA. Pharmacology and
literature. Medicine 1983; 62:59–88. pharmacokinetics of fosphenytoin. Neurology 1996; 46(suppl.
Breningstall GN. Gelastic seizures, precocious puberty, and 1):3–7.
hypothalamic hamartoma. Neurology 1985; 35:1180–3. Brugger P, Agosti R, Regard M et al. Heautoscopy, epilepsy and
Brennan LV, Craddock PR. Limbic encephalopathy as a non- suicide. J Neurol Neurosurg Psychiatry 1994; 57:838–9.
metastatic complication of oat cell lung cancer: its reversal Brun A, Englund B, Gustafson L et al. Clinical and
after treatment of the primary lung lesion. Am J Med 1983; neuropathological criteria for frontotemporal dementia. J
75:518–20. Neurol Neurosurg Psychiatry 1994; 57:416–18.
Brey RL, Holliday SL, Saklad AR et al. Neuropsychiatric syndromes Bruton CJ. The neuropathology of temporal lobe epilepsy. Oxford:
in lupus. Prevalence using standardized definitions. Neurology Oxford University Press, 1988.
2002; 58:1214–20. Buckley P, Stack JP, Madigan C et al. Magnetic resonance imaging
Brick JF, Gutrecht JA, Ringel RA. Reflex epilepsy and non-ketotic of schizophrenia-like psychoses associated with cerebral
hyperglycemia in the elderly. Neurology 1989; 39:394–9. trauma: clinicopathological correlates. Am J Psychiatry 1993;
Briellman RS, Kalnins RM, Hopwood MJ et al. TLE patients with 150:146–8.
postictal psychosis: mesial dysplasia and anterior hippocampal Bulrich N, Cooper DA, Freed A. HIV infection associated with
preservation. Neurology 2000; 55:1027–30. symptoms indistinguishable from functional psychosis. Br J
Briellmann RS, Berkovic SF, Syngeniotis A et al. Seizure-associated Psychiatry 1988; 152:649–53.
hippocampal volume loss: a longitudinal magnetic resonance Burks JS, Alfrey AC, Huddlestone J et al. A fatal encephalopathy in
study of temporal lobe epilepsy. Ann Neurol 2002; 51:641–4. chronic hemodialysis patients. Lancet 1976; 1:764–8.
Britton JW, Ghearing GR, Benarroch EE et al. The ictal bradycardia Bursten B. Psychoses associated with thyrotoxicosis. Arch Gen
syndrome: localization and lateralization. Epilepsia 2006; Psychiatry 1961; 4:267–73.
47:374–84. Butler CR, Graham KS, Hodges JR et al. The syndrome of transient
Bridgman O, Smyth FS. Progressive lenticular degeneration. J Nerv epileptic amnesia. Ann Neurol 2007; 61:587–98.
Ment Dis 1944; 99:534–43. Byelsjo I, Forsgren L, Lithner F et al. Epidemiology and clinical
Brodie MJ, Richens A, Yuen AW. Double-blind comparison of characteristics of seizures in patients with acute intermittent
lamotrigene and carbamazepine in newly diagnosed epilepsy. porphyria. Epilepsia 1996; 37:230–5.
Lancet 1995; 345:476–9. Caine ED, Shoulson I. Psychiatric syndromes in Huntington’s
Brodie MJ, Perucca E, Ryvlin P et al. Comparison of levetiracetam disease. Am J Psychiatry 1983; 140:728–33.
and controlled-release carbamazepine in newly diagnosed Callaghan N, Kenny RA, O’Neill B et al. A prospective study
epilepsy. Neurology 2007; 68:402–8. between carbamazepine, phenytoin and sodium valproate in
p 07.qxd 3/10/08 9:35 AM Page 308
previously untreated and recently diagnosed patients with Cavalleri F, De Renzi E. Amyotrophic lateral sclerosis with
epilepsy. J Neurol Neurosurg Psychiatry 1985; 48:639–44. dementia. Acta Neurol Scand 1994; 89:391–4.
Callaghan N, Garrett A, Goggin T. Withdrawal of anticonvulsant Caveness WF. Epilepsy, a product of trauma in our time. Epilepsia
drugs in patients free of seizures for two years. A prospective 1976; 17:207–15.
study. N Engl J Med 1988; 318:942–6. Celesia GG, Barr AN. Psychosis and other psychiatric manifestations
Cameron MM. Chronic subdural hematoma: a review of 114 of levodopa therapy. Arch Neurol 1970; 23:193–200.
cases. J Neurol Neurosurg Psychiatry 1978; 41:834–9. Cendes F, Andermann F, Gloor P et al. Atrophy of medial
von Campe G, Regli F, Bogousslavsky J. Heralding manifestations structures in patients with temporal lobe epilepsy: cause or
of vascular artery occlusion with lethal or severe stroke. J consequence of repeated seizures? Ann Neurol 1993a;
Campbell AMG, Corner B, Norman RM et al. The rigid form of Cendes F, Andermann F, Dubeau F et al. Early childhood prolonged
Huntington’s disease. J Neurol Neurosurg Psychiatry 1961; febrile convulsions, atrophy and sclerosis of medial structures,
24:71–7. and temporal lobe epilepsy: an MRI volumetric study.
Cantu C, Barinagarrementeria F. Cerebral venous thrombosis Neurology 1993b; 43:1083–7.
associated with pregnancy and puerperium. Review of 67 Cendes F, Andermann F, Carpenter S et al. Temporal lobe epilepsy
cases. Stroke 1993; 24:1880–4. caused by domoic acid intoxication: evidence for glutamate
Cape CA, Martinez AJ, Robertson JT et al. Adult onset of subacute receptor-mediated excitotoxicity in humans. Ann Neurol 1995;
sclerosing panencephalitis. Arch Neurol 1973; 28:124–7. 37:123–6.
Caplan LR. Positional cerebral ischemia. J Neurol Neurosurg Cereghino JJ, Biton V, Abou-Khalil B et al. Levetiracetam for
Psychiatry 1976; 39:385–91. partial seizures: results of a double-blind, randomized clinical
Caplan LR. Occlusion of the vertebral or basilar artery. Stroke trial. Neurology 2000; 55:236–42.
1979; 10:272–82. Chalela JA, Kidwell CS, Nentwich LM et al. Magnetic resonance
Caplan LR. Intracerebral hemorrhage revisited. Neurology 1988; imaging and computed tomography in emergency assessment
38:624–7. of patients with suspected acute stroke: a prospective
Caplan LR. Intracranial branch atheromatous disease. Neurology comparison. Lancet 2007; 369:293–8.
1989; 39:1246–50. Chandler JH, Bebin J. Hereditary cerebellar ataxia:
Caplan LR, Hier DB, D’Cruz I. Cerebral embolism in the Michael olivopontocerebellar type. Neurology 1956; 6:187–95.
Reese Stroke Registry. Stroke 1983; 14:530–6. Chandler MC, Barnhill JL, Gualtieri CT. Amantadine for the
Caplan LR, Kelly M, Kase CS et al. Infarcts of the inferior division agitated head-injury patient. Brain Inj 1988; 2:309–11.
of the right middle cerebral artery. Neurology 1986; Chapman RWG, Laidlow JM, Colin-Jones D et al. Increased
36:1015–20. prevalence of epilepsy in coeliac disease. BMJ 1978; 2:250–1.
Caplan LR, Schmahmann JD, Kase CS et al. Caudate infarcts. Arch Charles JR. Manganese toxaemia, with special reference to the
Neurol 1990; 47:133–43. effects of liver feeding. Brain 1927; 50:30–43.
Cardoso TAM, Coan AC, Kobayashi E et al. Hippocampal Chassagnon S, Minotti L, Kremer S et al. Restricted frontomesial
abnormalities and seizure recurrence after antiepileptic drug epileptogenic focus generates dyskinetic behavior and
withdrawal. Neurology 2006; 67:134–6. laughter. Epilepsia 2003; 44:859–63.
Carlson C, St. Louis EK. Vacuum cleaner epilepsy. Neurology 2004; Chatham-Showalter PE. Carbamazepine for combativeness in
63:190–1. acute traumatic brain injury. J Neuropsychiatry Clin Neurosci
Carney MW, Chary TK, Robotis P et al. Ganser syndrome and its 1996; 8:96–9.
management. Br J Psychiatry 1987; 151:697–700. Chatham-Showalter PE, Kimmel DN. Agitated symptom response
Cascino GD, Andermann F, Berkovic SF et al. Gelastic seizures and to divalproex following acute brain injury. J Neuropsychiatry
hypothalamic hamartomas. Neurology 1993a; 43:747–50. Clin Neurosci 2000; 12:395–7.
Cascino GD, Luckstein RR, Sharbrough FW et al. Facial asymmetry, Chaturvedi S, Bruno A, Feasby T et al. Carotid endarterectomy –
hippocampal pathology, and remote symptomatic seizures. an evidence-based review. Neurology 2005; 65:794–801.
Neurology 1993b; 43:725–7. Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral
Cascino GD, Hulihan JF, Sharbrough FW et al. Parietal lobe encephalitis. Postgrad Med J 2002; 78:575–83.
lesional epilepsy: electroclinical correlation and operative Chen R-C, Forster FM. Cursive epilepsy and gelastic epilepsy.
outcome. Epilepsia 1993c; 34:522–7. Neurology 1973; 23:1019–29.
Castaigne P, Lhermitte F, Gautier J et al. Arterial occlusion in the Chen ZM, Sandercock P, Pan HC et al. Indications for early aspirin
vertebral-basilar system. Brain 1973; 96:133–54. use in acute ischemic stroke: a combined analysis of 40 000
Castriotta RJ, Lai JM. Sleep disorders associated with traumatic randomized patients from the Chinese acute stroke trial and
brain injury. Arch Phys Med Rehabil 2001; 82:1403–6. the international stroke trial. Stroke 2000; 31:1240–9.
Castro LH, Ferreira LK, Teles LR et al. Epilepsy syndromes associated Chesson AL, Kasarkis EJ, Small VW. Postictal elevation of serum
with hypothalamic hamartomas. Seizure 2007;16:505–8. creatine kinase level. Arch Neurol 1983; 40:315–17.
Catella-Lawson F, Reilly MP, Kapoor SC et al. Cyclooxygenase Chester EM, Agamanolis DP, Banker BQ et al. Hypertensive
inhibitors and the antiplatelet effects of aspirin. N Engl J Med encephalopathy: a clinicopathologic study of 20 cases.
2001; 345:1809–17. Neurology 1978; 28:928–39.
p 07.qxd 3/10/08 9:35 AM Page 309
References 309
Chopra HD, Beatson JA. Psychotic symptoms in borderline Critchley M, Cobb W, Sears TA. On reading epilepsy. Epilepsia
personality disorder. Am J Psychiatry 1986; 143:1605–7. 1959; 1:403–17.
Chouinard G, Jones BD. Neuroleptic-induced supersensitivity Crompton M. Hypothalamic lesions following closed head injury.
psychosis. Am J Psychiatry 1980; 137:16–21. Brain 1971; 94:165–72.
Cittandi E, Goadsby PJ. Psychiatric side effects during Currie S, Heathfield KWG, Henson RA et al. Clinical course and
methysergide treatment. J Neurol Neurosurg Psychiatry 2005; prognosis of temporal lobe epilepsy: a survey. Brain 1971;
76:1037–8. 97:173–90.
Chiu D, Shedden P, Bratina P et al. Clinical features of Moyamaya Currier RD, Little SC, Suess SJ et al. Sexual seizures. Arch Neurol
disease in the United States. Stroke 1998; 29:1347–51. 1971; 25:260–4.
Clarke DJ. Prader–Willi syndrome and psychoses. Br J Psychiatry D’Agostino MD, Bernasconi A, Das S et al. Subcortical band
1993; 163:680–4. heterotopia (SBH) in males: clinical, imaging and genetic
Clarke E, Melnick SC. The Munchausen syndrome or the problem findings in comparison with females. Brain 2002;
of hospital hoboes. Am J Med 1958; 25:6–12. 125:2507–22.
Classen J, Peery S, Kreiter KT et al. Predictors and clinical import Daly D. Ictal affect. Am J Psychiatry 1958; 115:97–108.
of epilepsy after subarachnoid hemorrhage. Neurology 2003; Daly DD, Barry MJ. Musicogenic epilepsy: report of three cases.
60:208–14. Psychosom Med 1957; 19:399–408.
Cleghorn RA. Adrenal cortical insufficiency: psychological and Dam AM, Fuglsang-Fredricksen A, Svarre-Olsen U et al. Late-onset
neurological observations. CMAJ 1951; 65:445–57. epilepsy: etiologies, types of seizure, and value of clinical
Clomipramine Collaborative Study Group. Clomipramine in the investigation, EEG and computerized tomography scan.
treatment of patients with obsessive-compulsive disorder. Epilepsia 1985; 26:227–31.
Arch Gen Psychiatry 1991; 48:730–8. Dana-Haeri J, Richens A. Effect of norethisterone on seizures
Coats J. A study of two illustrative cases of epilepsy. BMJ associated with menstruation. Epilepsia 1983; 24:377–81.
1876:647–9. Dana-Haeri J, Trimble MR, Oxley J. Prolactin and gonadotropin
Cockerell OC, Walker MC, Sander JWAS et al. Complex partial changes following generalized and partial seizures. J Neurol
status epilepticus: a recurrent problem. J Neurol Neurosurg Neurosurg Psychiatry 1983; 46:331.
Psychiatry 1994; 57:835–7. Danek A, Rubio JP, Rampoldi L et al. McLeod neuroacanthocytosis:
Cockerell OC, Tothwell J, Marsden CD et al. Clinical and genotype and phenotype. Ann Neurol 2001; 50:755–64.
physiological features of epilepsia partialis continua: cases Daniel WG, Mugge A. Transesophageal echocardiography. N Engl J
ascertained in the UK. Brain 1996; 116:393–407. Med 1995; 332:1268–79.
Cohen RJ, Suter C. Hysterical seizures: suggestion as a Daniele O, Mattaliano A, Tassinari CA et al. Epileptic seizures and
provocative EEG test. Ann Neurol 1982; 11:391–5. cerebrovascular disease. Acta Neurol Scand 1989; 80:117–22.
Cole AJ, Gloor P, Kaplan R. Transient global amnesia: the Danielsson S, Gillberg C, Billstedt E et al. Epilepsy in young adults
electroencephalogram at onset. Ann Neurol 1987; with autism: a prospective population-based follow-up study
22:721–2. of 120 individuals diagnosed in childhood. Epilepsia
Cole F, Yates, P. Intracerebral microaneurysms and small 2005;46:918–23.
cerebrovascular lesions. Brain 1967; 90:759–68. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry
Combi R, Dalpra L, Ferini-Strambi L et al. Frontal lobe epilepsy and 1989; 50:256–61.
mutations of the corticotropin-releasing hormone gene. Ann DeGiorgio CM, Tomiyasu U, Gott PS, et al. Hippocampal pyramidal
Neurol 2005; 58:899–904. cell loss in human status epilepticus. Epilepsia 1992;33:23–7.
Commission of Classification and Terminology of the International DeGiorgio CM, Correale JD, Gott PS et al. Serum neuron-specific
League Against Epilepsy. Epilepsia 1981; 22:489–501. enolase in human status epilepticus. Neurology 1995;
Commission of Classification and Terminology of the International 45:1134–7.
League Against Epilepsy. Epilepsia 1989; 30:389–99. DeGiorgio CM, Heck CN, Rabinowicz AL et al. Serum neuron-
Corrigan JD. Substance abuse as a mediating factor in outcome specific enolase in the major subtypes of status epilepticus.
from traumatic brain injury. Arch Phys Med Rehabil 1995; Neurology 1999; 52:746–9.
76:302–9. Degos J-D, da Fonseca N, Gray F et al. Severe frontal syndrome
Corsellis JAN, Golberg GJ, Norton AR. ‘Limbic encephalitis’ and its associated with infarcts of the left anterior cingulate gyrus
association with carcinoma. Brain 1968; 91:481–96. and the head of the right caudate nucleus. Brain 1993;
Critchley M. The anterior cerebral artery, and its syndromes. Brain 116:1541–8.
1930; 53:120–65. Deisenhammer E. Transient global amnesia as an epileptic
Critchley M, Early CJC. Tuberose sclerosis and allied conditions. manifestation. J Neurol 1981; 225:289–92.
Brain 1932; 55:311–46. Delgado-Escueta AV. Epileptogenic paroxysms: modern
Critchley M. Musicogenic epilepsy. Brain 1937; 60:13–27. approaches and clinical correlations. Neurology 1979;
Critchley M. Two cases of musicogenic epilepsy. J Royal Navy Med 29:1014–22.
Serv 1942; 27:182–4. Delgado-Escueta AV, Mattson RH, King L et al. The nature of
Critchley M, Greenfield JG. Olivo-ponto-cerebellar atrophy. Brain aggression during epileptic seizures. N Engl J Med 1981;
1948; 71:343–64. 305:711–16.
p 07.qxd 3/10/08 9:35 AM Page 310
Delgado-Escueta AV, Bascal FE, Treiman DM. Complex partial Drachman DA, Adams RD. Herpes simplex and acute inclusion-
seizures on closed-circuit television and EEG: a study of 691 body encephalitis. Arch Neurol 1962; 7:45–63.
attacks in 79 patients. Ann Neurol 1982; 11:292–300. Drury I, Klass DW, Westmoreland BF et al. An acute syndrome
Denier C, Orgibet A, Foffi F et al. Adult-onset vanishing white with psychiatric symptoms and EEG abnormalities. Neurology
matter leukoencephalopathy presenting as psychosis. 1985; 35:911–14.
Neurology 2007; 68:1538–9. D’Souza WJ, O’Brien TJ, Murphy M et al. Toothbrushing-induced
Dening TR, Berrios GE. Wilson’s disease: psychiatric symptoms in epilepsy with structural lesions in the primary somatosensory
195 cases. Arch Gen Psychiatry 1989; 46:1126–34. area. Neurology 2007; 68:769–71.
Dening TR, Berrios GE, Walshe JM. Wilson’s disease and epilepsy. Dubeau F, Tampieri E, Carpenter S et al. Periventricular and
Brain 1988; 111:1139–55. subcortical nodular heterotopia: a study of 33 patients. Brain
Depondt C, Van Paesschen W, Matthijs G et al. Familial temporal 1995; 118:1273–87.
lobe epilepsy with febrile seizures. Neurology 2002; Duncalf CM, Kent JNG, Harbord M et al. Subacute sclerosing
58:1429–33. panencephalitis presenting as schizophreniform psychosis. Br J
van Der Naalt J, van Zomeren AH, Sluiter WJ et al. Acute Psychiatry 1989; 155:557–9.
behavioral disturbances related to imaging studies and Earnest MP, Feldman H, Marx JA et al. Intracranial lesions shown
outcome in mild-to-moderate head injury. Brain Inj 2000; by CT scans in 259 cases of first alcohol-related seizures.
14:781–8. Neurology 1988; 38:1561–5.
Dervaux A, Laine H, Czermak M et al. Creutzfeldt-Jakob disease Edwards OM, Clark JDA. Post-traumatic hypopituitarism: six
presenting as psychosis. Am J Psychiatry 2004; 161:1307–8. cases and a review of the literature. Medicine 1986;
Desbiens R, Berkovic S, Dubeau F et al. Life-threatening focal 65:281–90.
status epilepticus due to occult cortical dysplasia. Arch Neurol Efron R. The effect of olfactory stimuli in arresting uncinate fits.
1993; 50:695–700. Brain 1956; 79:267–81.
Devinsky O, Duchowny MS. Seizures after convulsive therapy: a Efron R. The conditioned inhibition of uncinate fits. Brain 1957;
retrospective case series. Neurology 1983; 33:921–5. 80:251–62.
Devinsky O, Petito CK, Alonso DR. Clinical and neuropathological Efron R. Post-epileptic paralysis: theoretical critique and report of
findings in systemic lupus erythematosus: the role of a case. Brain 1961; 84:381–94.
vasculitis, heart emboli and thrombotic thrombocytopenic Eisen JL, Rasmussen SA. Obsessive compulsive disorder with
purpura. Ann Neurol 1988a; 23:380–4. psychotic features. J Clin Psychiatry 1993; 54:373–9.
Devinsky O, Kelley K, Porter RJ et al. Clinical and Ellis JM, Lee SI. Acute prolonged confusion in later life as an ictal
electroencephalographic features of simple partial seizures. state. Epilepsia 1978; 19:119–28.
Neurology 1988b; 38:1347–52. Elger CE, Brodie MJ, Anhut H et al. Pregabalin add-on treatment
Devinsky O, Felmann E, Burrowes K et al. Autoscopic phenomena in patients with partial seizures. A novel evaluation of
with seizures. Arch Neurol 1989a; 46:1080–8. flexible-dose and fixed-dose treatment in a double-blind,
Devinsky O, Sato O, Kufta CV et al. Electroencephalographic placebo-controlled study. Epilepsia 2005; 46:1926–36.
studies of simple partial seizures with subdural electrode Engel J. Surgery for seizures. N Engl J Med 1996; 334:647–52.
recordings. Neurology 1989b; 39:527–33. Engel J, Driver MV, Falconer MA. Electrophysiological correlates of
Devinsky O, Honigfield G, Patin J. Clozapine-related seizures. pathology and surgical results in temporal lobe epilepsy. Brain
Neurology 1991; 41:369–71. 1975; 98:129–56.
Devinsky O, Kelley K, Yacubian EMT et al. Postictal behavior. Arch Engel J, Ludwig BI, Fetele M. Prolonged partial complex status
Neurol 1994a; 51:254–9. epilepticus: EEG and behavioral observations. Neurology 1978;
Devinsky O, Ehrenberg B, Barthlen GM et al. Epilepsy and sleep 28:863–9.
apnea syndrome. Neurology 1994b; 44:2060–4. Englander J, Bushnik T, Duong TT et al. Analyzing risk factors for
Devinsky O, Sanchez-Villasenor F, Vazquez B et al. Clinical profile late posttraumatic seizures: a prospective, multicenter
of patients with epileptic and nonepileptic seizures. Neurology investigation. Arch Phys Med Rehabil 2003; 84:365–73.
1996; 46:1530–3. Eraut D. Idiopathic hypoparathyroidism presenting as dementia.
Dewhurst K, Beard AW. Sudden religious conversions in temporal BMJ 1974; 1:429–30.
lobe epilepsy. Br J Psychiatry 1970; 117:497–507. Erickson TC. Erotomania (nymphomania) as an expression of
Dewhurst K, Todd J. The psychosis of association – folie a deux. J cortical epileptiform discharge. Arch Neurol Psychiatry 1945;
Nerv Ment Dis 1956; 124:451–9. 53:226–31.
Dimitri D, Jehel L, Durr A et al. Fatal familial insomnia presenting Espir ML, Rose FC. Alcohol, seizures and epilepsy. J R Soc Med
as psychosis in an 18-year-old man. Neurology 2006; 1987; 9:542–3.
67:363–4. Escueta AV, Kunze U, Waddell G et al. Lapse of consciousness and
Dixit S, Kurle P, Buyan-Dent L et al. Status epilepticus associated automatisms in temporal lobe epilepsy: a videotape analysis.
with cefipime. Neurology 2000; 54:2153–5. Neurology 1977; 27:144–55.
Donaire A, Carreno M, Gomez B et al. Cortical laminar necrosis Evans DL, Edelsohn GA, Golden RN. Organic psychosis without
related to prolonged focal status epilepticus. J Neurol dementia or spinal cord symptoms in patients with vitamin
Neurosurg Psychiatry 2006; 77:104–6. B12 deficiency. Am J Psychiatry 1983; 140:218–21.
p 07.qxd 3/10/08 9:35 AM Page 311
References 311
Fahy TJ, Irving MJ, Millac P. Severe head injuries. A six-year Finelli PF. Metachromatic leukodystrophy manifesting as a
follow-up. Lancet 1967; 2:475–9. schizophrenic disorder: computed tomographic correlation.
Fairweather DS. Psychiatric aspects of the post-encephalitic Ann Neurol 1985; 18:94–5.
syndrome. J Ment Sci 1947; 93:201–54. Finelli PF, Pueschel SM, Padre-Mendoza T et al. Neurological
Fakhoury T, Abou-Khalil B, Peguero E. Differentiating clinical findings in patients with the fragile-X syndrome. J Neurol
features of right and left temporal lobe seizures. Epilepsia Neurosurg Psychiatry 1985; 45:150–63.
1994; 35:1038–44. Fiol ME, Leppik IE, Pretzel K. Eating epilepsy: EEG and clinical
Falconer MA. Clinical manifestations of temporal lobe epilepsy study. Epilepsia 1986; 27:441–5.
and their recognition in relation to surgical treatment. BMJ Fiorelli M, Di Piero V, Bastianello S et al. Cerebrotendinous
1954; 2:939–44. xanthomatosis: clinical and MRI study (a case report). J Neurol
Falconer MA. Genetic and related aetiological factors in temporal Neurosurg Psychiatry 1990; 53:76–8.
lobe epilepsy. Epilepsia 1971; 12:13–31. Fisher CM. Lacunes: small deep cerebral infarcts. Neurology 1965;
Falconer MA, Driver MV, Serafetinides EA. Seizures induced by 15:774–84.
movement: report of a case relieved by operation. J Neurol Fisher CM. Lacunar strokes and infarcts: a review. Neurology
Neurosurg Psychiatry 1963; 26:300–7. 1982; 32:871–6.
Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and Fisher CM, Ojemann R, Robertson G. Spontaneous dissection of
pathogenesis of temporal lobe epilepsy. Arch Neurol 1964; cervico-cerebral arteries. Can J Neurol Sci 1978; 5:9–19.
10:233–48. Flashman LA, McAllister TW. Lack of awareness and its impact in
Fann JR, Uomoto JM, Katon WJ. Sertaline in the treatment of traumatic brain injury. NeuroRehabilitation 2002; 17:285–96.
major depression following mild traumatic brain injury. J Flugel D, Cerlignani M, Symms MR et al. Diffusion tensor imaging
Neuropsychiatry Clin Neurosci 2000; 12:226–32. findings and their correlation with neuropsychological deficits
Fariello RG, Booker HE, Chun RWM et al. Reenactment of the in patients with temporal lobe epilepsy and interictal
triggering situation for the diagnosis of epilepsy. Neurology psychosis. Epilepsia 2006; 47:941–4.
1983; 33:878–84. Fontaine B, Seilhean D, Tourbah A et al. Dementia in two
Faught E, Wilder BJ, Famsay RE et al. Topiramate placebo- histologically confirmed cases of multiple sclerosis: one with
controlled dose-ranging trial in refractory partial epilepsy isolated dementia and one case associated with psychiatric
using 200–, 400–, and 600–mg daily dosages. Neurology symptoms. J Neurol Neurosurg Psychiatry 1994; 57:353–9.
1996; 46:1684–90. Forster FM. Epilepsy associated with eating. Trans Am Neurol Assn
Fauser S, Huppertz H-J, Bast T et al. Clinical characteristics in 1971; 96:106–7.
focal cortical dysplasia: a retrospective evaluation in a series Forster FM. Reflex epilepsy, behavioral therapy and conditioned
of 120 patients. Brain 2006; 129:1907–16. reflexes. IL: Springfield, Charles C. Thomas, 1977.
Feinberg TE, Cianci CD, Morrow JS et al. Diagnostic Forster FM, Liske E. Role of environmental clues in temporal lobe
tests for choreoacanthocytosis. Neurology 1991; epilepsy. Neurology 1963; 13:301–5.
41:1000–6. Forster FM, Booker HE, Gascon G. Conditioning in musicogenic
Feinberg WM, Rapcsak SZ. ‘Peduncular hallucinosis’ following epilepsy. Trans Am Neurol Assn 1967; 92:236–7.
paramedian thalamic infarction. Neurology 1989; Forster FM, Paulsen WA, Baughman FA. Clinical therapeutic
39:1535–6. conditioning in reading epilepsy. Neurology 1969a;
Feldman RG, White RF, Eriator II. Triethyltin encephalopathy. Arch 19:717–23.
Neurol 1993; 50:1320–4. Forster FM, Hansotia P, Cleeland CS et al. A case of voice-induced
Fenelon G, Mahieux F, Huon R et al. Hallucinations in Parkinson’s epilepsy treated by conditioning. Neurology 1969b;
disease: prevalence, phenomenology and risk factors. Brain 19:325–31.
2000; 123:733–45. Fortemps E, Amand G, Bomboir A et al. Trimethyltin poisoning.
Fenton WS, McGlashen TH. Natural history of schizophrenia Report of two cases. Int Arch Occupat Environment Hlth 1978;
subtypes. I. Longitudinal study of paranoid, hebephrenic, and 41:1–6.
undifferentiated schizophrenia. Arch Gen Psychiatry 1991; Foster HG, Hillbrand M, Chi CC. Efficacy of carbamazepine in
48:969–77. assaultive patients with frontal lobe dysfunction. Prog
Fenwick PBC, Brown SW. Evoked and psychogenic seizures. Acta Neuropsychopharmacol Biol Psychiatry 1989; 13:865–74.
Neurol Scand 1989; 80:535–40. Franceschi M, Triulzi F, Ferini-Strambi L et al. Focal cerebral
Fernandez-Torre JL, Martinez-Martinez M, Gonzalez-Rato J et al. lesions found by magnetic resonance imaging in cryptogenic
Cephalosporin-induced nonconvulsive status epilepticus: nonrefractory temporal lobe epilepsy patients. Epilepsia 1989;
clinical and electroencephalographic features. Epilepsia 2005; 30:540–6.
46:1550–2. Francis A, Freeman H. Psychiatric abnormality and brain
Ferriby D, de Seze J, Stojkovic T et al. Long-term follow-up of calcification over four generations. J Nerv Ment Dis 1984;
neurosarcoidosis. Neurology 2001; 57:927–9. 172:166–70.
Fichtenberg NL, Millis SR, Mann NR et al. Factors associated with Frazier CH. Tumor involving the frontal lobe alone: a symptomatic
insomnia among post-acute traumatic brain injury survivors. survey of one hundred and five verified cases. Arch Neurol
Brain Inj 2000; 14:659–67. Psychiatry 1936; 35:525–51.
p 07.qxd 3/10/08 9:35 AM Page 312
Freemon FR, Nevis AH. Temporal lobe sexual seizures. Neurology Gastaut H. Clinical and electroencephalographic classification of
1969; 19:87–90. epileptic seizures. Epilepsia 1970; 11:102–13.
Fregni F, Otachi PTM, de Valle A et al. A randomized clinical trial Gastaut H, Tassinari CA. Triggering mechanisms in epilepsy: the
of repetitive transcranial magnetic stimulation in patients electroclinical point of view. Epilepsia 1966; 7:85–138.
with refractory epilepsy. Ann Neurol 2006; 60:447–55. Gastaut H, Caveness WF, Landolt H et al. Epilepsia 1964;
French JA, Williamson PD, Thadani VM et al. Characteristics of 5:297–306.
medial temporal lobe epilepsy: I. Results of history and Gastaut H, Gastaut JL, Goncalves E et al. Relative frequency of
physical examination. Ann Neurol 1993; 34:774–80. different types of epilepsy: a study employing the
Freytag E. Autopsy findings in head injuries from blunt forces: classification of the International League Against Epilepsy.
statistical evaluation of 1,367 cases. Arch Pathol 1963; Epilepsia 1975; 16:457–61.
75:402–13. Gatzonis SD, Stamboulis E, Siafakis A. Acute psychosis and EEG
Friedlander WJ, Feinstein GH. Petit mal status: Epilepsia minoris normalization after vagus nerve stimulation. J Neurol
continua. Neurology 1956; 6:357–62. Neurosurg Psychiatry 2000; 69:278–9.
Friedman A, Sienkiewicz J. Psychotic complications of long-term Gautier-Smith PC. Neurological complications of glandular fever
levodopa treatment of Parkinson’s disease. Acta Neurol Scand (infectious mononucleosis). Brain 1965; 88:323–34.
1991; 84:111–13. Geier S, Bancaud J, Talairach J et al. The seizures of frontal lobe
Friedman HM, Allen N. Chronic effects of complete limbic lobe epilepsy: a study of clinical manifestations. Neurology 1977;
destruction in man. Neurology 1969; 19:679–90. 27:951–8.
Fuerst D, Shah J, Shah A et al. Hippocampal sclerosis is a Gelenberg AJ. Munchausen’s syndrome with a psychiatric
progressive disorder: a longitudinal volumetric MRI study. Ann presentation. Dis Nerv Syst 1977; 38:378–80.
Neurol 2003; 53:413–16. Gelisse P, Genton P, Kuate C et al. Worsening of seizures by
Fuerstein TJ, Sauerman W, Anhut H et al. Gabapentin (Neurontin) oxcarbazepine in juvenile idiopathic generalized epilepsies.
as add-on therapy in patients with partial seizures: a double- Epilepsia 2004; 45:1282–6.
blind placebo-controlled study. Epilepsia 1994; 35:795–801. Genton P, Gelisse P, Thomas P et al. Do carbamazepine and
Fujii DE, Ahmed I. Risk factors in psychosis secondary to traumatic phenytoin aggravate juvenile myoclonic epilepsy? Neurology
brain injury. J Neuropsychiatry Clin Neurosci 2001; 13:61–9. 2000; 55:1106–9.
Fujii DE, Ahmed I. Characteristics of psychotic disorders due to Geocaris K. Psychotic episodes heralding the diagnosis of multiple
traumatic brain injury: an analysis of case studies in the sclerosis. Bull Men Clin 1957; 21:107–16.
literature. J Neuropsychiatry Clin Neurosci 2002; 14:130–40. Geyer JD, Payne TA, Drury I. The value of pelvic thrusting in the
Fuster B, Castells C, Rodriguez B. Psychomotor attacks (primary diagnosis of seizures and pseudoseizures. Neurology 2000;
automatisms) of subcortical origin. Arch Neurol Psychiatry 54:227–9.
1954; 71:455–72. Ghaffar O, Stains R, Feinssein A et al. Unexplained neurologic
Gabr M, Luders H, Dinner D. Speech manifestations in symptoms: an fMRI study of sensory conversion disorder.
lateralization of temporal lobe seizures. Ann Neurol 1989; Neurology 2006; 67:2036–8.
25:82–7. Giannopoulos S, Kostadima V, Selvi A, et a. Bilateral paramedian
Gal P. Mental symptoms in cases of tumor of the temporal lobe. thalamic infarcts. Arch Neurol 2006; 63:1652.
Am J Psychiatry 1958; 115:157–60. Gibbs FA, Gibbs EC. Atlas of electroencephalography, Vol. II.
Gallagher BB, Flanigan HF, King DW et al. The effect of electrical Epilepsy. London: Addison-Wesley, 1952.
stimulation of medial temporal lobe structures in epileptic van Gijn J, Rinkel GJ. Subarachnoid hemorrhage: diagnosis, causes
patients upon ACTH, prolactin, and growth hormone. and management. Brain 2001; 124:249–78.
Neurology 1987; 37:299–303. van Gijn J, van Dongen KJ, Vermeulen M et al. Perimesencephalic
Gallmetzer P, Leutezer F, Serles W et al. Postictal paresis in focal hemorrhage: a nonaneurysmal and benign form of
epilepsies: incidence, duration and causes. Neurology 2004; subarachnoid hemorrhage. Neurology 1985; 35:493–7.
62:2160–4. Gillberg C. Outcome in autism and autistic-like conditions. J Am
Gambardella A, Reutens DC, Andermann F et al. Late onset drop Acad Child Adolesc Psychiatry 1991; 30:375–82.
attacks in temporal lobe epilepsy. Neurology 1994; Gillig P, Sackellares JC, Greenberg HS. Right hemisphere partial
44:1074–8. complex seizures: mania, hallucinations, and speech
Gambardella A, Annesi G, De Fusco M et al. A new locus for disturbances during ictal events. Epilepsia 1988; 29:26–9.
autosomal dominant nocturnal frontal lobe epilepsy maps to Glaser GH, Levy LL. Seizures and idiopathic hypoparathyroidism.
chromosome 1. Neurology 2000; 55:1467–71. Epilepsia 1960; 4:454–65.
Garrett PJ, Mulcahy D, Carmody M et al. Aluminum Glass HC, Prieur B, Molnar C et al. Micturition and emotion-
encephalopathy: clinical and immunologic findings. Q J Med induced reflex epilepsy: case report and review of the
1988; 69:775–83. literature. Epilepsia 2007; 47:2180–2.
Garron D. Huntington’s chorea and schizophrenia. Adv Neurol Glenn MB, Wroblewski B, Parziale J et al. Lithium carbonate
1973; 1:729–34. for aggressive behavior or affective instability in ten
Gascon GG, Lombroso CT. Epileptic (gelastic) laughter. Epilepsia brain-injured patients. Am J Phys Med Rehabil 1989;
1971; 12:63–76. 68:221–6.
p 07.qxd 3/10/08 9:35 AM Page 313
References 313
Globus M, Lavi E, Fich E et al. Ictal hemiparesis. Eur Neurol 1982; Greer S, Parsons V. Schizophrenia-like psychosis in thyroid crisis.
21:165–8. Br J Psychiatry 1968; 114:1357–62.
Gloor P. Electrophysiological studies of the amygdala (stimulation Greeven A, van Balkom AJLM, Visser S et al. Cognitive behavioral
and recording): their possible contribution to the therapy and paroxetin in the treatment of hypochodriasis: a
understanding of neural mechanisms of aggression. In: Fields randomized controlled trial. Am J Psychiatry 2007; 164:91–9.
WS, Sweet WH eds. Neural bases of violence and aggression. St Grewal RP, Achari M, Matsuura T et al. Clinical features and ATTC
Louis: C.V. Mosby, 1975. repeat expansion in spinocerebellar ataxia type 10. Arch
Gobbi G, Bouquet F, Greco L et al. Coeliac disease, epilepsy, and Neurol 2002; 59:1285–90.
cerebral calcification. Lancet 1992; 340:439–43. Griffith JD, Cavanaugh J, Held J et al. Dextroamphetamine:
Gobin YP, Starkman S, Duckwiler GR et al. MERCI 1: a phase 1 evaluation of psychotomimetic properties in man. Arch Gen
study of Mechanical Embolus Removal in Cerebral Ischemia. Psychiatry 1972; 26:97–100.
Stroke 2004; 35:2848–54. Grunberger G, Weiner JL, Silverman R et al. Factitious
Goetz CG, Fan W, Leurgans S et al. The malignant course of hypoglycemia due to surreptitious administration of insulin.
‘benign hallucinations’ in Parkinson disease. Arch Neurol 2006; Diagnosis, treatment, and long-term follow-up. Ann Intern
63:713–16. Med 1988; 108:252–7.
Golden RN, James S, Sherer M et al. Psychoses associated with Grunewald R. Levetiracetam in the treatment of idiopathic
bupropion treatment. Am J Psychiatry 1985; 142:1459–62. generalized epilepsies. Epilepsia 2005; 46(suppl. 9):154–60.
Goldensohn ES, Gold AP. Prolonged behavioral disturbances as Guinena YH, Taher Y. Psychosensory seizures ‘visual and auditory’
ictal phenomena. Neurology 1960; 10:1–9. of primary subcortical origin. Electroencephalogr Clin
Golding JM, Rost K, Kashner TM et al. Family psychiatric history of Neurophysiol 1955; 7:425–8.
patients with somatization disorder. Psychiatr Med 1992; Gumpert J, Hansotia P, Upton A. Gelastic epilepsy. J Neurol
Golub LM, Guhlman HV, Merlis JK. Seizure patterns in Gunderson JG, Kolb JE. Discriminating features of borderline
psychomotor epilepsy. Dis Nerv Syst 1951; 12:73–6. patients. Am J Psychiatry 1978; 135:792–6.
Goodin DS, Aminoff MJ, Laxer KD. Detection of epileptiform Gupta AK, Jeavons PM, Hughes RC et al. Aura in temporal lobe
activity by different noninvasive EEG methods in complex epilepsy: clinical and electroencephalographic correlation. J
partial epilepsy. Ann Neurol 1990; 27:330–4. Neurol Neurosurg Psychiatry 1983; 46:1079–83.
Goodman L. Alzheimer’s disease: a clinico-pathologic analysis of Gupta SR, Nasheedy MH, Elias D et al. Postinfarction seizures: a
twenty-three cases with a theory on pathogenesis. J Nerv clinical study. Stroke 1988; 19:1477–81.
Ment Dis 1953; 118:97–130. Guze SB. Cloninger CR, Martin RL et al. A follow-up and family
Gordon A. Transition of obsessions into delusions. Am J Psychiatry study of Briquet’s syndrome. Br J Psychiatry 1986; 149:17–23.
1950; 107:455–8. Gysin WM, Cooke ET. Unusual mental symptoms in a case of
Gosk-Bierska I, Wysokinski W, Brown RD et al. Cerebral venous hepatolenticular degeneration. Dis Nerv Syst 1950; 28:305–9.
sinus thrombosis. Incidence of venous thrombosis recurrence Hacke W, Schwab S, Horn M et al. ‘Malignant’ middle cerebral
and survival. Neurology 2006; 67:814–19. artery territory infarction: clinical course and prognostic signs.
Gothelf D, Feinstein C, Thompson T et al. Risk factors for the Arch Neurol 1996; 53:309–15.
emergence of psychotic disorders in adolescents with 22q11.2 Hagberg B, Aicardi J, Ramos O. A progressive syndrome of autism,
deletion syndrome. Am J Psychiatry 2007; 164:663–9. ataxia, and loss of purposeful hand use in girls: Rett’s
Graff-Radford NR, Damasio H, Yamada T et al. Non-hemorrhagic syndrome: report of 35 cases. Ann Neurol 1983; 14:471–9.
thalamic infarction. Brain 1985; 108:495–516. Hageman ATM, Gabreels FJM, de Jong JGN et al. Clinical
Graham JM, Gruenwald RA, Sagar HJ. Hallucinosis in idiopathic symptoms of adult metachromatic leukodystrophy and
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; arylsulfatase A pseudodeficiency. Arch Neurol 1995;
63:434–40. 52:408–13.
Granata T, Gobbi G, Spreafico R et al. Rasmussen’s encephalitis. Hahn RD, Webster B, Weickhardt G et al. Penicillin treatment of
Early characteristics allow diagnosis. Neurology 2003; general paresis (dementia paralytica). Arch Neurol Psychiatry
60:422–5. 1959; 81:557–90.
Grant C, Warlow C. Focal epilepsy in diabetic non-ketotic Halkes PH, van Gijn J, Kappelle LJ et al. Aspirin plus dipyridamole
hyperglycemia. BMJ 1985; 290:1204–5. versus aspirin alone after cerebral ischaemia of arterial origin
Greenberg MK, Vance SC. Focal seizure disorder complicating (ESPRIT): randomized controlled trial. Lancet 2006;
iodophenylate myelography. Lancet 1980; 1:312–13. 367:1665–73.
Greenberg SM, Vonsattel JPG, Stakes JW et al. The clinical Hall DE, Eubanks L, Meyyaxhagan LS et al. Evaluation of covert
spectrum of cerebral amyloid angiopathy: presentations video surveillance in the diagnosis of Munchausen syndrome
without lobar hemorrhage. Neurology 1993; 43:2073–9. by proxy: lessons from 41 cases. Pediatrics 2000;
Greene KA, Marciano FF, Dickman CA et al. Anterior 105:1305–12.
communicating aneurysm paraparesis syndrome: clinical Hall DP, Young SA. Frontal lobe cerebral aneurysm rupture
manifestations and pathologic correlates. Neurology 1995; presenting as psychosis. J Neurol Neurosurg Psychiatry 1992;
45:45–50. 55:1207–8.
p 07.qxd 3/10/08 9:35 AM Page 314
Hall RCW, Joffe JR. Hypomagnesemia: physical and psychiatric Hennerici M, Klemm C, Rautenberg W. The subclavian steal
symptoms. JAMA 1973; 224:1749–51. phenomenon: a common vascular disorder with rare
Haller E, Binder RL. Clozapine and seizures. Am J Psychiatry 1980; neurologic deficits. Neurology 1988; 38:669–73.
147:1069–71. Hennis A, Corbin D, Fraser H. Focal seizures and non-ketotic
Haltia T, Palo J, Haltia M et al. Juvenile metachromatic dystrophy: hyperglycemia. J Neurol Neurosurg Psychiatry 1992; 55:195–7.
clinical, biochemical, and neuropathologic studies in nine new Henriksen GF. Status epilepticus partialis with fear as clinical
cases. Arch Neurol 1980; 37:42–5. expression: report of a case and EEG findings. Epilepsia 1973;
Hammes EM. Psychoses associated with Sydenham’s chorea. J Am 14:39–46.
Med Assoc 1922; 79:804–7. Henry TR, Drury I, Brunberg JA et al. Focal cerebral magnetic
Handforth A, DeGiorgio CM, Schacter SC et al. Vagus nerve resonance changes associated with partial status epilepticus.
stimulation therapy for partial-onset seizures: a randomized Epilepsia 1994; 35:35–41.
active-control trial. Neurology 1998; 51:48–55. Hermann BP, Riel P. Interictal personality and behavioral traits in
Hanson PA, Chodos R. Hemiparetic seizures. Neurology 1978; temporal lobe and generalized epilepsy. Cortex 1981;
28:920–3. 17:125–8.
Hardie RJ, Pullon HWH, Harding AE et al. Neuroacanthocytosis: a Hermann BP, Whitman S, Wyler AR et al. The neurological,
clinical, haematological and pathological study of 19 cases. psychosocial and demographic correlates of hypergraphia in
Brain 1991; 114:13–49. patients with epilepsy. J Neurol Neurosurg Psychiatry 1988;
Harlow JM. Passage of an iron rod through the head. Bost Med 51:203–8.
Surg J 1848; 39:389–93. Herskowitz A, Swerdlow M. Focal seizures – a false lateralizing
Harlow JM. Recovery from passage of an iron bar through the sign. Dis Nerv Syst 1972; 33:523–5.
head. J Mass Med Soc 1868; 2:327–47. Hertz PE, Nadas E, Wojtkowski H. Case report: Cushing’s
Harris MJ, Jeste DV, Gleghorn A et al. New-onset psychosis in syndrome and its management. Am J Psychiatry 1955;
HIV-infected patients. J Clin Psychiatry 1991; 52:369–76. 112:144–5.
Harrison RA, Vu T, Hunter AJ. Wernicke’s encephalopathy in a Heutink P, Stevens M, Rizzu P et al. Hereditary frontotemporal
patient with schizophrenia. J Gen Int Med 2006; 21:1338. dementia is linked to chromosome 17q21–q22: a genetic and
Hauser WA, Morris ML, Hewston LL et al. Seizures and myoclonus clinicopathological study of three Dutch families. Ann Neurol
in patients with Alzheimer’s disease. Neurology 1986; 1997; 41:150–9.
36:1226–30. Hibbard MR, Uysal S, Kepler K et al. Axis I psychopathology in
Haymaker W. Herpes simplex encephalitis in man. J Neuropathol individuals with traumatic brain injury. J Head Trauma Rehabil
Exp Neurol 1949; 8:132–54. 1998; 13:24–39.
Hayman M, Scheffer IE, Chinvarun Y et al. Autosomal dominant Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after
nocturnal frontal lobe epilepsy: demonstration of focal frontal right hemisphere stroke. Neurology 1983; 33:337–44.
onset and intrafamilial variation. Neurology 1997; 49:969–75. Hijdra A, Van Gijn J, Stefanko S et al. Delayed cerebral ischemia
Healton EB, Brust JC, Feinfeld DA et al. Hypertensive after aneurysmal subarachnoid hemorrhage: clinico-anatomic
encephalopathy and the neurologic manifestations of correlations. Neurology 1986; 36:329–33.
malignant hypertension. Neurology 1982; 32:127. Hijdra A, van Gijn J, Nagelkerke NJD et al. Prediction of delayed
Heathfield KWG. Huntington’s chorea. Investigation into the cerebral ischemia, rebleeding and outcome after aneurismal
prevalence of this disease in the area covered by the North subarachnoid hemorrhage. Stroke 1988; 19:1250–6.
East Metropolitan Regional Hospital Board. Brain 1967; Hildebrand J, Lecaille C, Perennes J et al. Epileptic seizures during
90:203–32. follow-up of patients treated for primary brain tumor.
Hedera P, Abou-Khalil B, Cronk AE et al. Autosomal dominant Neurology 2005; 65:212–15.
lateral temporal epilepsy: two families with novel mutations in Hillbom E. Schizophrenia-like psychoses after brain trauma. Acta
the LGI1 gene. Epilepsia 2004; 45:218–22. Psychiatr Neurol Scand 1951(suppl. 60):36–47.
Heilman KM, Howell GJ. Seizure-induced neglect. J Neurol Hillier SL, Sharpe MH, Metzer J. Outcomes 5 years post-traumatic
Neurosurg Psychiatry 1980; 43:1035–40. brain injury (with further reference to neurophysical
Heinsius T, Bogousslavsky J, van Melle G. Large infarcts in the impairment and disability). Brain Inj 1997; 11:661–75.
middle cerebral artery territory. Etiology and outcome Hinchey J, Chaves C, Appignani B et al. A reversible posterior
patterns. Neurology 1998; 50:341–50. leukoencephalopathy syndrome. N Engl J Med 1996;
Helgason C, Caplan LR, Goodwin J et al. Anterior choroidal artery 334:494–500.
territory infarction. Arch Neurol 1986; 43:681–6. Hirose S, Iwata H, Akiyoshi H et al. A novel mutation of CHRNA4
Heller AJ, Chesterman P, Elwes RDC et al. Phenobarbitone, phenytoin, responsible for autosomal dominant nocturnal frontal lobe
carbamazepine, or sodium valproate for newly diagnosed adult epilepsy. Neurology 1999; 53:1749–53.
epilepsy: a randomized comparative monotherapy trial. J Neurol Hirsch E, Marescaux C, Maquet P et al. Landau-Kleffner syndrome:
Neurosurg Psychiatry 1995; 58:44–50. a clinical and EEG study of five cases. Epilepsia 1990;
Henchey R, Cibula J, Helveston W et al. Electroencephalographic 31:756–67.
findings in Hashimoto’s encephalopathy. Neurology 1995; Hirsch S, Dunsworth FA. An interesting case of porphyria. Am J
45:977–81. Psychiatry 1955; 111:703.
p 07.qxd 3/10/08 9:35 AM Page 315
References 315
Hjort N, Christensen S, Solling C et al. Ischemic injury detected by report of a second case in Great Britian. Brain 1961;
diffusion imaging in 11 minutes. Ann Neurol 2005; 58:462–5. 84:212–30.
Ho SS, Berkovic SF, Newton MR et al. Parietal lobe epilepsy: Isbell H, Fraser HF, Wickler A et al. An experimental study of
clinical features and seizure localization by SPECT. Neurology etiology of ‘rum fits’ and delirium tremens. Q J Study Alcohol
1994; 44:2277–84. 1955; 16:1–33.
Hodgson RE, Murray D, Woods MR. Othello’s syndrome and Ivanov D, Kirov G, Norton N et al. Chromosome 22q11 deletions,
hyperthyroidism. J Nerv Ment Dis 1992; 180:663–4. velo-cardio-facial syndrome and early onset psychosis. Br J
Hoefer PFA, Guttman SA, Sands IJ. Convulsive states and coma in Psychiatry 2003;183:409–13.
cases of islet cell carcinoma of the pancreas. Am J Psychiatry Iwanami A, Sugiyama A, Kuroki N et al. Patients with
1946; 102:486–95. methamphetamine psychosis admitted to a psychiatric
Holmes G. Local epilepsy. Lancet 7 May 1927; 957–73. hospital in Japan. Acta Psychiatr Scand 1994; 89:428–32.
Holmes GL. The electroencephalogram as a predictor of seizures Jabbari B, Huott AD. Seizures in thyrotoxicosis. Epilepsia 1980;
following cerebral infarction. Clin Electroencephalogr 1980; 21:91–6.
11:83–6. Jabbari B, Bryan GE, Marsh EE et al. Incidence of seizures with
Holmes GL. Partial complex seizures in children: an analysis of 69 tricyclic and tetracyclic antidepressants. Arch Neurol 1985;
seizures in 24 patients using EEG FM radiotelemetry and 42:480–1.
videotape recordings. Electroencephalogr Clin Neurophysiol Jackel RA, Malkowitz D, Trivedi R et al. Reduction of prolactin
1984; 57:13–20. response with repetitive seizures. Epilepsia 1987; 28:588.
Holmes GL, McKeever M, Adamson M. Absence seizures in Jackson GD, Kuzniecky RI, Cascino GD. Hippocampal sclerosis
children: clinical and electroencephalographic features. Ann without detectable hippocampal atrophy. Neurology 1994;
Neurol 1987; 21:268–73. 44:42–6.
Hoover CF. A new sign for detection of malingering and Jackson JA, Zimmerman SL. A case of pseudosclerosis associated
functional paresis of the lower extremities. J Am Med Assoc with a psychosis. J Nerv Ment Dis 1919; 49:5–13.
1908; 51:1309–10. Jackson JH. On a particular variety of epilepsy (‘intellectual aura’).
Hopkins A, Shorvon S, Cascino G. Epilepsy, 2nd edn. London: One case with symptoms of organic brain disease. Brain 1889;
Arnold 1995. 11:179–207.
van der Horst L. Affective epilepsy. J Neurol Neurosurg Psychiatry Jackson JH. Neurological fragments. Lancet 1894; 2:182–3.
1953; 16:25–9. Jackson JH, Beevor CE. Case of tumour of the right temporo-
Hudson EA, Munoz DG, Miller L et al. Amygdaloid sclerosis in sphenoidal lobe bearing on the localization of the sense of
temporal lobe epilepsy. Ann Neurol 1993; 33:622–31. smell and on the interpretation of a particular variety of
Hunter R, Blackwood W, Bull J. Three cases of frontal epilepsy. Brain 1890; 12:346–57.
meningiomas presenting psychiatrically. BMJ 1968; Jackson JH, Colman WJ. Case of epilepsy with tasting movements
3:9–16. and ‘dreamy state’ – very small patch of softening in the left
Hyde TM, Ziegler JL, Weinberger DR. Psychiatric disturbances in uncinate gyrus. Brain 1898; 21:580–91.
metachromatic leukodystrophy: insights into the neurobiology Jackson JH, Stewart P. Epileptic attacks with a warning of a crude
of psychosis. Arch Neurol 1992; 49:401–6. sensation of smell and with the intellectual aura (dreamy
Inanatomia Y, Kimura K, Yonehara T et al. DWI abnormalities and state) in a patient who had symptoms pointing to gross
clinical characteristics in TIA patients. Neurology 2004; organic disease of the right temporo-sphenoidal lobe. Brain
62:376–80. 1899; 22:534–49.
Ingham SD, Nielsen JM. Thyroid psychosis: difficulties in Jacob A, Cherian PJ, Radhakrishnan K et al. Emotional facial
diagnosis. J Nerv Ment Dis 1931; 74:271–7. paresis in temporal lobe epilepsy: its prevalence and
Insel TR, Akiskal HS. Obsessive-compulsive disorder with psychotic lateralizing value. Seizure 2003; 12:60–4.
features: a phenomenologic analysis. Am J Psychiatry 1986; Jacome DE, Risko M. Pseudocataplexy: gelastic–atonic seizures.
143:1527–33. Neurology 1984; 34:1381–3.
International Subarachnoid Aneurysm Trial (ISAT) Collaborative Jacome DE, McLain W, Fitzgerald R. Postural reflex gelastic
Group. International subarachnoid aneurysm trial (ISAT) on seizures. Arch Neurol 1980; 37:249–51.
neurosurgical clipping versus endovascular coiling in 2143 Jaffe R. Ictal behavior as the only manifestation of seizure
patients with ruptured intracranial aneurysm: a randomized disorder: case report. J Nerv Ment Dis 1962; 134:470–6.
trial. Lancet 2002; 360:1267–74. James WE, Mefferd RB, Kimbell I. Early signs of Huntington’s
Inzelberg R, Kipervasser S, Korczyn AD. Auditory hallucinations in chorea. Dis Nerv Syst 1969; 30:550–9.
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998; Janszky J, Fogarai A, Magalova V et al. Unilateral hand automatisms
64:533–5. in temporal lobe epilepsy. Seizure 2005; 15:393–6.
Iranzo A, Santamaria J, Berenguer J et al. Prevalence and clinical Jawad S, Richens A, Goodwin G et al. Controlled trial of
importance of sleep apnea in the first night after cerebral lamotrigene (Lamictal) for refractory partial seizures. Epilepsia
infarction. Neurology 2002; 58:911–16. 1989; 30:356–63.
Ironside R, Bosanquet FD, McMenemy WH. Central demyelination Jenkins CD, Mellins RB. Lead poisoning in children: a study of
of the corpus callosum (Marchifava–Bignami disease): with forty-six cases. Arch Neurol Psychiatry 1957; 77:70–8.
p 07.qxd 3/10/08 9:35 AM Page 316
Jenkins A, Teasdale G, Hadley MD et al. Brain lesions detected by Kant R, Duffy JD, Pivovarnik A. Prevalence of apathy following
magnetic resonance imaging in mild and severe head injuries. head injury. Brain Inj 1998; 12:87–92.
Lancet 1986; 2:445–6. Karnosh LJ, Stout RE. Psychoses of myxedema. Am J Psychiatry
Jennett B. Early traumatic epilepsy. Arch Neurol 1973; 30:394–8. 1935; 91:1263–74.
Jennett B. Epilepsy and acute traumatic intracranial haematoma. Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a
J Neurol Neurosurg Psychiatry 1975; 38:378–81. neurologic disorder following rapid correction of
Jennett B, Teather D, Bennie S. Epilepsy after head injury. Lancet hyponatremia. Medicine 1993; 72:359–73.
1973; 2:652–3. Kashiwase H, Kato M. Folie a deux in Japan – analysis of 97 cases
Jensen I, Klinken L. Temporal lobe epilepsy and neuropathology. in the Japanese literature. Acta Psychiatr Scand 1997;
Acta Neurol Scand 1976; 54:391–414. 96:231–4.
Jensen MB, St. Louis EK. Management of acute cerebellar stroke. Katz DI, Alexander MP, Seliger GM et al. Traumatic basal ganglia
Arch Neurol 2005; 62:537–44. hemorrhage: clinicopathologic features and outcome.
Johnson KP, Rosenthal MS, Lerner PI. Herpes simplex encephalitis. Neurology 1989; 39:862–3.
Arch Neurol 1972; 27:103–8. Kazui S, Naritomi H, Yamamoto H et al. Enlargement of
Johnson RI, Richardson EP. The neurological manifestations of spontaneous intracerebral hemorrhage: incidence and time
systemic lupus erythematosus. Medicine 1968; 47:337–69. course. Stroke 1996; 27:1983–7.
Johnston JA, Lineberry CG, Archer JA et al. A 102–center Keane JR. Wrong-way deviation of the tongue with hysterical
prospective study of seizure in association with bupropion. J hemiparesis. Neurology 1986; 36:1406–7.
Clin Psychiatry 1991; 52:450–6. Kellinghaus C, Kotagal P. Lateralizing value of Todd’s palsy in
Jorge RE, Robinson RG, Arndt SV et al. Comparison between patients with epilepsy. Neurology 2004; 62:289–91.
acute-and delayed-onset depression following traumatic brain Kendler KS. The nosological validity of paranoia (simple delusional
injury. J Neuropsychiatry Clin Neurosci 1993; 5:43–9. disorder): a review. Arch Gen Psychiatry 1980; 37:699–706.
Jorge RE, Robinson RG, Moser D et al. Major depression following Kendler KS, McGuire M, Gruenberg AM et al. Outcome and family
traumatic brain injury. Arch Gen Psychiatry 2004; 61:42–50. study of the subtypes of schizophrenia in the West of Ireland.
Joynt J, Green D, Gren R. Musicogenic epilepsy. JAMA 1962; Am J Psychiatry 1994; 151:849–56.
179:501–4. Kennedy F. The symptomatology of temporosphenoidal tumors.
Kaiboriboon K, Parent JM, Barbaro NM et al. Speech preservation Arch Int Med 1911; 8:317–50.
during language-dominant, left temporal lobe seizures: report Kennedy PGE. A retrospective analysis of forty-six cases of herpes
of a rare, potentially misleading finding. Epilepsia 2006; simplex encephalitis seen in Glasgow between1962 and 1985.
47:1343–6. Q J Med 1988; 68:533–40.
Kaiko RF, Foley KM, Grabinski PY et al. Central nervous system Keschner M, Bender MB, Strauss I. Mental symptoms in cases of
excitatory effects of meperidine in cancer patients. Ann Neurol tumor of the temporal lobe. Arch Neurol Psychiatry 1936;
1983; 13:180–5. 35:572–96.
Kalinowsky LB. Convulsions in nonepileptic patients on Khatri P, Kasner SE. Ischemic strokes after cardiac catheterization.
withdrawal of barbiturates, alcohol and other drugs. Arch Opportune thrombolysis candidates? Arch Neurol 2006;
Kanemoto K. Periictal Capgras syndrome after clustered ictal Kilpatrick CJ, Davis SM, Tress BM et al. Epileptic seizures in acute
fear: depth-electroencephalogram study. Epilepsia 1997; stroke. Arch Neurol 1990; 47:157–60.
38:847–50. Kilpatrick CJ, Davis SM, Hopper JL et al. Early seizures after acute
Kanemoto K, Janz D. The temporal sequence of aura-sensations in stroke: risk of late seizures. Arch Neurol 1992; 49:509–11.
patients with complex partial focal seizures with particular Kim JS. Pure lateral medullary infarction: clinical-radiological
attention to ictal aphasia. J Neurol Neurosurg Psychiatry 1989; correlation of 130 acute, consecutive patients. Brain 2003;
52:52–6. 126:1864–72.
Kanemoto K, Watanabe Y, Tsuji T et al. Rub epilepsy: a Kim JS, Kim HG, Chung CS. Medial medullary syndrome: report of
somatosensory evoked reflex epilepsy induced by prolonged 18 new patients and a review of the literature. Stroke 1995;
cutaneous stimulation. J Neurol Neurosurg Psychiatry 2001; 26:1548–52.
70:541–3. King DW, Marsan CA. Clinical features and ictal patterns in
Kang D-W, Lattimore SU, Latour LL et al. Silent ischemic lesion epileptic patients with EEG temporal lobe foci. Ann Neurol
recurrence on magnetic resonance imaging predicts 1977; 2:138–47.
subsequent clinical vascular events. Arch Neurol 2006; King MA, Newton MR, Jackson GD et al. Epileptology of the first
63:1730–3. seizure presentation: a clinical, electroencephalographic, and
Kanner AM, Morris HH, Dinner DS et al. Supplementary motor magnetic resonance imaging study of 300 consecutive
seizures mimicking pseudoseizures: some clinical differences. patients. Lancet 1999; 352:1007–11.
Neurology 1990; 40:1404–7. Kiok MC, Terrence CF, Fromm GH et al. Sinus arrest in epilepsy.
Kanner AM, Stagno S, Kotagal P et al. Postictal psychiatric events Neurology 1986; 36:115–16.
during prolonged video-electroencephalographic monitoring Kirby GH, Davis TK. Psychiatric manifestations of epidemic
studies. Arch Neurol 1996; 53:258–63. encephalitis. Arch Neurol Psychiatry 1921; 5:491–555.
p 07.qxd 3/10/08 9:35 AM Page 317
References 317
Kirubakaren V, Mayfield D, Rengachary S. Dyskinesia and Krahn LE, Li H, O’Connor MK. Patients who strive to be ill:
psychosis in a patient following Baclofen withdrawal. Am J factitious disorder with physical symptoms. Am J Psychiatry
Psychiatry 1984; 141:692–3. 2003; 160:1163–8.
Kluge M, Beyenburg S, Fernandez G et al. Epileptic vertigo: Kral T, Clusman H, Blumcke I et al. Outcome of epilepsy surgery in
evidence for vestibular representation in human frontal cortex. focal cortical dysplasia. J Neurol Neurosurg Psychiatry 2003;
Neurology 2000; 55:1906–8. 74:183–8.
Knight RT, Cooper J. Status epilepticus manifesting as reversible Kramer DL, Awad IA. Vascular malformations and epilepsy: clinical
Wernicke’s aphasia. Epilepsia 1986; 27:301–4. considerations and basic mechanisms. Epilepsia 1994;
Kobayashi E, Li LM, Lopes-Cendes I et al. Magnetic resonance 35(suppl. 6):30–43.
imaging evidence of hippocampal sclerosis in asymptomatic, Kramer RE, Lesser RP, Weinstein MR et al. Transient focal
first-degree relatives of patients with familial mesial temporal abnormalities of neuroimaging studies during focal status
lobe epilepsy. Arch Neurol 2002; 59:1891–4. epilepticus. Epilepsia 1987; 28:528–32.
Kobayashi E, D’Agostino MD, Lopes-Cendes I et al. Hippocampal Kramer RE, Luders H, Goldstick LP et al. Ictus emeticus: an
atrophy an T2-weighted signal changes in familial mesial electroclinical study. Neurology 1988; 38:1048–52.
temporal lobe epilepsy. Neurology 2003; 60:405–9. Kreutzer JS, Seel RT, Gourley E. The prevalence and symptom rates
Kober D, Gabbard GO. Topiramate-induced psychosis. Am J of depression after traumatic brain injury: a comprehensive
Psychiatry 2005; 162:1542. examination. Brain Inj 2001; 15:561–2.
Koehler K, Jakumeit U. Subacute sclerosing panencephalitis Kristensen O, Sindrup EH. Psychomotor epilepsy and psychosis. III:
presenting as Leonhard’s speech-prompt catatonia. Br J Social and psychological correlates. Acta Neurol Scand 1979;
Psychiatry 1976; 129:29–31. 59:1–9.
Koepp MJ, Edwards M, Collins J et al. Status epilepticus and Krolak-Salmon P, Montanont A, Hermier A et al. Thalamic venous
tiagabine therapy revisited. Epilepsia 2005; 46:1625–32. infarction as a cause of subacute dementia. Neurology 2006;
Koeppen AH, Barron KD. Marchiafava–Bignami disease. Neurology 58:1689–91.
1978; 28:290–4. Kroll P. Psychoses associated with marijuana abuse in Thailand. J
Koerner M, Laxer KD. Ictal speech, postictal language dysfunction, Nerv Ment Dis 1975; 161:149–56.
and seizure lateralization. Neurology 1988; 38:634–6. Krumholz A, Niedermeyer E. Psychogenic seizures: a clinical study
Kofman O, Hyland HH. Tuberous sclerosis in adults with normal with follow-up data. Neurology 1983; 33:498–502.
intelligence. Arch Neurol Psychiatry 1959; 81:557–90. Krumholz A, Stern BJ, Weiss HD. Outcome from coma after
Korczyn AD, Bechar M. Convulsive fits in thyrotoxicosis. Epilepsia cardiopulmonary resuscitation: relation to seizures and
1976; 17:33–4. myoclonus. Neurology 1988; 38:401–5.
Korf BR, Carrazana E, Holmes GL. Patterns of seizures observed in Krumholz A, Stern BJ, Stern EG. Clinical implications of seizures in
association with neurofibromatosis. I. Epilepsia 1993; neurosarcoidosis. Arch Neurol 1991; 48:842–4.
34:616–20. Krumholz A, Sung GY, Fisher RS et al. Complex partial status
Kornberg AJ, Harvery AS, Shield LK. Subacute sclerosing epilepticus accompanied by serious morbidity and mortality.
panencephalitis presenting as simple partial seizures. J Child Neurology 1995; 45:1499–504.
Neurol 1991; 6:146–9. Kulkantrakorn K, Geller TJ. Seizures in neurofibromatosis. 1.
Koskiniemi M, Rantalaiho T, Piiparinen H et al. Infections of Pediatr Neurology 1998; 19:347–50.
the central nervous system of suspected viral origin: a Kumral E, Ozdemirkiran T, Alper Y. Strokes in the subinsular
collaborative study from Finland. J Neurovirol 2001; territory. Clinical, topographical, and etiological patterns.
7:400–8. Neurology 2004; 63:2429–32.
Kossoff EH, Bergey GK, Freeman JM et al. Levetiracetam psychosis Kuramochi H, Takahashi R. Psychopathology of LSD intoxication:
in children with epilepsy. Epilepsia 2001; 42:1611–13. study of experimental psychosis induced by LSD-25:
Kotagal P, Luders H, Morris HH et al. Dystonic posturing in description of LSD symptoms in normal Oriental subjects. Arch
complex partial seizures of temporal lobe onset: a new Gen Psychiatry 1964; 11:151–61.
lateralizing sign. Neurology 1989; 39:196–204. Kuzniecky R, Guthrei B, Mountz J et al. Intrinsic epileptogenesis of
Kothare SV, VanLandingham K, Armon C et al. Seizure onset from hypothalamic hamartomas in gelastic epilepsy. Ann Neurol
periventricular nodular heterotopias: depth-electrode study. 1997; 42:60–7.
Neurology 1998; 51:1723–7. Labar DR, Solomon GR, Wells CR. Aphasia as the sole
Kotsopoulos IAW, van Merode T, Kessels FGH et al. Systematic manifestation of simple partial status epilepticus. Epilepsia
review and meta-analysis of incidence studies of epilepsy and 1992; 33:84–7.
unprovoked seizures. Epilepsia 2002; 43:1402–9. Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of
Koutroumaniois M, Koepp MJ, Richardson MP et al. The variants early seizure and status epilepticus after first stroke.
of reading epilepsy: a clinical and video-EEG study of 17 Neurology 2001; 57:200–6.
patients with reading-induced seizures. Brain 1998; Lai F, Williams RS. A prospective study of Alzheimer’s disease in
121:1409–27. Down syndrome. Arch Neurol 1989; 46:849–53.
Kraepelin E. Clinical psychiatry 1902. Delmar, NY: Scholar’s Lambert MT. Paranoid psychoses after abuse of proprietary cold
Facsimiles and Reprints, 1981. remedies. Br J Psychiatry 1987; 151:548–50.
p 07.qxd 3/10/08 9:35 AM Page 318
Lamy C, Domigo V, Semah F et al. Early and late seizures after Lende RA, Popp AJ. Sensory Jacksonian seizures. J Neurosurg
cryptogenic stroke in young adults. Neurology 2003;60:400–4. 1976; 44:706–11.
Lancman ME, Craven WJ, Asconape JJ et al. Clinical management Leone M, Bottacchi E, Beghi E et al. Alcohol use is a risk factor for
of recurrent postictal psychosis. J Epilepsy 1994; 7:47–51. a first generalized tonic-clonic seizure. Neurology 1997;
Landau WM, Kleffner FR. Syndrome of acquired aphasia with 48:614–20.
convulsive disorder in children. Neurology 1957; 7:523–30. Leppik IE, Biton V, Sander JWA et al. Levetiracetam and partial
Landolt H. Some clinical electroencephalographic correlations in seizure subtypes: pooled data from three randomized,
epileptic psychoses (twilight states). Electroencephalogr Clin placebo-controlled trials. Epilepsia 2003; 44:1585–7.
Neurophysiol 1953; 5:121. Lesser RP, Lueders H, Conomy JP et al. Sensory seizure mimicking
Landolt H. Serial electroencephalographic investigations during a psychogenic seizure. Neurology 1983; 33:800–2.
psychotic episodes in epileptic patients and during Leutmezer F, Serles W, Bacher J et al. Genital automatisms in
schizophrenic attacks. In: de Haas AML ed. Lectures on complex partial seizures. Neurology 1999; 52:1188–91.
epilepsy. London: Elsevier, 1958. Leutmezer F, Podreka I, Asenbaum S et al. Postictal psychosis in
Lang AE, Koller WC, Fahn S. Psychogenic parkinsonism. Arch temporal lobe epilepsy. Epilepsia 2003; 44:582–90.
Neurol 1995; 52:802–10. Levin HS, Grossman RG, Kelly PJ. Aphasic disorder in patients with
Langworthy OR, Kolb LC, Androp S. Disturbances of behavior in closed head injury. J Neurol Neurosurg Psychiatry 1976;
patients with disseminated sclerosis. Am J Psychiatry 1941; 39:1062–70.
98:243–9. Levin HS, Grossman RG, Rose JE et al. Long-term
Lankford DA, Wellman JJ, O’Hara C. Posttraumatic narcolepsy in neuropsychological outcome of closed head injury. J
mild to moderate closed head injury. Sleep 1994; 17(suppl. Neurosurg 1979; 50:412–22.
8):S25–S28. Levin HS, Goldstein FC, High WM et al. Disproportionately severe
Lansberg Mg, Albers GW, Beaulieu C et al. Comparison of memory deficit in relation to normal intellectual functioning
diffusion-weighted MRI and CT in acute stroke. Neurology after closed head injury. J Neurol Neurosurg Psychiatry 1988;
2000; 54:1557–61. 51:1294–301.
Lanska DJ. Anthrax meningoencephalitis. Neurology 2002; Levy AB. Delirium and seizures due to abrupt alprazolam
59:327–34. withdrawal: case report. J Clin Psychiatry 1984; 45:38–9.
Lawson JA, Birchansky S, Pacheo E et al. Distinct clinicopathologic Libman MD, Potvin L, Coupal L et al. Seizure v. syncope:
subtypes of cortical dysplasia of Taylor. Neurology 2005; measuring serum creatine kinase in the emergency
64:55–61. department. J Gen Intern Med 1991; 6:408–12.
Laxer KD, Mullooly JP, Howell B. Prolactin changes after seizures Lichenstein BW. Sturge–Weber–Dimitri syndrome: cephalic form
classified by EEG monitoring. Neurology 1985; 35:31–5. of neurocutaneous hemangiomatosus. Arch Neurol Psychiatry
Leal AJR, Moreira A, Robalo C et al. Different electroclinical 1954; 71:291–301.
manifestations of the epilepsy associated with hamartomas Liddell DW. Observations on epileptic automatisms in a mental
connecting to the middle or posterior hypothalamus. Epilepsia hospital population. J Ment Sci 1953; 99:732–48.
2003; 44:1191–5. Lieb JP, Walsh JO, Babb TL et al. A comparison of EEG seizure
Lebensohn ZM. Self-inflicted bullet wound of frontal lobes in a patterns with surface and depth electrodes in patients with
depression with recovery. Am J Psychiatry 1941; 48:56–62. temporal lobe epilepsy. Epilepsia 1976; 17:137–60.
Lechtenberg R, Worner TM. Total ethanol consumption as a Lim J, Yagnik P, Schraeder P et al. Ictal catatonia as a
seizure risk factor in alcoholics. Acta Neurol Scand 1992; manifestation of nonconvulsive status epilepticus. J Neurol
Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann Lim L, Ron MA, Omerod IEC et al. Psychiatric and neurological
Neurol 1978; 4:199–204. manifestations in systemic lupus erythematosus. Q J Med
Lee H, Lerner A. Transient inhibitory seizures mimicking crescendo 1988; 66:27–38.
transient ischemic attacks. Neurology 1990; 40:165–6. Lima MA, Drislane FW, Kuralnik IJ. Seizures and their outcome in
Lee H, Kim SW, Kim JM et al. Comparing effects of progressive multifocal leukoencephalopathy. Neurology 2006;
methyphenidate, sertraline and placebo on neuropsychiatric 66:262–4.
sequelae in patients with traumatic brain injury. Hum Limdi Na, Knowlton RK, Cofield SS et al. Safety of rapid
Psychopharmacol 2005; 20:97–104. intravenous loading of valproate. Epilepsia 2007;
Lee VH, Brown RD, Madrekar JN et al. Incidence and outcome of 48:478–83.
cervical artery dissection. Neurology 2006; 67:1809–12. Lin J T-Y, Ziegler DK. Psychiatric symptoms with initiation of
Legg NJ, Gupta PC, Scott DF. Epilepsy following cerebral abscess. A carbidopa-levodopa treatment. Neurology 1976;
clinical and EEG study of 70 patients. Brain 1973; 96:259–68. 26:699–700.
Lehtinen L, Kivalo A. Laughter epilepsy. Acta Neurol Scand 1965; Lindenbaum J, Healton EB, Savage DG et al. Neuropsychiatric
41:255–61. disorders caused by cobalamin deficiency in the absence of
Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis anemia or macrocytosis. N Engl J Med 1988; 318:1720–8.
of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994; Lipinski CG. Epilepsies with astatic seizures of late onset. Epilepsia
36:233–7. 1977; 18:13–20.
p 07.qxd 3/10/08 9:35 AM Page 319
References 319
Lipsey JD, Robinson RG, Pearlson GD et al. Nortriptyline treatment Lundquist G. Delirium tremens: a comparative study of
of post-stroke depression: a double-blind study. Lancet 1984; pathogenesis, course and prognosis with delirium tremens.
1:297–300. Acta Psychiatr Neurol Scand 1961; 36:443–66.
Lishman WA. Brain damage in relation to psychiatric disability Maccario M, Messis CP, Vastola EF. Focal seizures as a
after head injury. Br J Psychiatry 1968; 114:373–410. manifestation of hyperglycemia without ketoacidosis. A report
Lishman WA. The psychiatric sequelae of head injury: a review. of seven cases with review of the literature. Neurology 1965;
Psychol Med 1973; 3:304–18. 15:195–206.
List CF, Dowman CE, Bagchi BK et al. Posterior hypothalamic Mace CJ, Trimble MR. Ten-year prognosis of conversion disorder.
hamartomas and gangliogliomas causing precocious puberty. Br J Psychiatry 1996; 169:282–8.
Neurology 1958; 8:164–74. Macpherson P, Teasdale E, Dhakar S et al. The significance of
Litovitz TL, Troutman WG. Amoxapine overdose: seizures and traumatic hematoma in the region of the basal ganglia. J
fatalities. JAMA 1983; 250:1069–71. Neurol Neurosurg Psychiatry 1986; 49:29–34.
Litvan IL, Agid Y, Sastrj N et al. What are the obstacles to the Macrae D. Isolated fear: a temporal lobe aura. Neurology 1954a;
accurate clinical diagnosis of Pick’s disease? Neurology 1997; 4:497–505.
49:62–9. Macrae D. On the nature of fear, with reference to its occurrence
Liu RSN, Lemieux L, Bell GS et al. The structural consequences of in epilepsy. J Nerv Ment Dis 1954b; 120:385–93.
newly diagnosed seizures. Ann Neurol 2002; 52:573–80. McCarthy DJ. Epileptic ambulatory automatism. J Nerv Ment Dis
Livingston S, Torres I, Pauli L et al. Petit mal epilepsy. Results of a 1900; 27:143–9.
prolonged follow-up of 117 patients. JAMA 1965; McDowell S, Whyte J, D’Esposito M. Differential effect of a
194:227–32. dopaminergic agent on prefrontal function in traumatic brain
Locke J, Merrill JP, Tyler HR. Neurologic complications of uremia. injury patients. Brain 1998; 121:1155–64.
Arch Int Med 1961; 108:519–30. McElroy SL, Phillips KA, Keck PE et al. Body dysmorphic disorder:
Logothetis J. Spontaneous epileptic seizures and does it have a psychotic subtype? J Clin Psychiatry 1993;
electroencephalographic changes in the course of 54:389–95.
phenothiazine therapy. Neurology 1967; 17:869–77. McFarland HR. Addisons’s disease and related psychoses. Compr
Logsdail SJ, Toone BK. Postictal psychoses: a clinical and Psychiatry 1963; 4:90–5.
phenomenological description. Br J Psychiatry 1988; 152:246–52. McGrath N, Anderson NE, Croxson MC et al. Herpes simplex
Logue V, Durward M, Pratt RTC et al. The quality of survival after encephalitis treated with acyclovir: diagnosis and long term
rupture of an anterior cerebral aneurysm. Br J Psychiatry 1968; outcome. J Neurol Neurosurg Psychiatry 1997; 63:321–6.
114:137–60. McLachlan RS, Blume WT. Isolated fear in complex partial status
Loiseau J, Loiseau P, Duche B et al. A survey of epileptic disorder epilepticus. Ann Neurol 1980; 8:639–41.
in southwest France: seizures in elderly patients. Ann Neurol McLachlan RS, Girvin JP, Blume WT et al. Rasmussen’s chronic
1990a; 27:232–7. encephalitis in adults. Arch Neurol 1993; 50:269–74.
Loiseau P, Yuen AWC, Duche B et al. A randomized double-blind, McQueen JK, Blackwood DH, Harris P et al. Low risk of late post-
placebo-controlled crossover add-on trial of lamotrigene in traumatic seizures following severe head injury: implications
patients with treatment-resistant partial seizures. Epilepsia for clinical trials of prophylaxis. J Neurol Neurosurg Psychiatry
Res 1990b; 7:136–45. 1983; 46:899–904.
LoPiccolo CJ, Goodkin K, Baldewicz TT. Current issues in the McVicker RW, Shanks OEP, McClelland RJ. Prevalence and
diagnosis and management of malingering. Ann Med 1999; associated features of epilepsy in adults with Down’s
31:166–74. syndrome. Br J Psychiatry 1994; 164:528–32.
Lossius MI, Ronning OM, Slapo GD et al. Poststroke epilepsy: Maeder-Ingvar M, van Melle G, Bogousslavsky J. Pure
occurrence and predictors: a long-term prospective controlled monoparesis. A particular stroke subgroup? Arch Neurol 2005;
study. Epilepsia 2005; 46:1246–51. 62:1221–4.
Lossos A, Dobson-Stone C, Monaco AP et al. Early clinical Malamud N. Psychiatric disorder with intracranial tumors of
heterogeneity in choreoacanthocytosis. Ann Neurol 2005; limbic system. Arch Neurol 1967; 17:113–23.
62:611–14. Malkowitz DE, Legido A, Jackel RA et al. Prolactin secretion
Louis ED, Lynch T, Daufmann P et al. Diagnostic guidelines in central following repetitive seizures. Neurology 1995; 45:448–52.
nervous system Whipple’s disease. Ann Neurol 1996; 40:561–8. Malouf R, Brust JCM. Hypoglycemia: causes, neurological
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med manifestations and outcome. Ann Neurol 1985; 17:421–30.
1998; 338:970–6. Mandalos GE, Szarek BL. Dose-related paranoid reaction
Lowenstein DH, Aminoff MJ. Clinical and EEG features of status associated with fluoxetine. J Nerv Ment Dis 1990; 178:57–8.
epilepticus in comatose patients. Neurology 1992; 42:100–4. Mandoki MW, Sumner GS. Psychiatric manifestations of
Luciano D, Devinsky O, Perrine K. Crying seizures. Neurology 1993; hereditary coproporphyria in a child. J Nerv Ment Dis 1994;
43:2113–17. 182:117–18.
Ludwig BI, Marsan CA. Clinical ictal patterns in epileptic patients Manford MRA, Fish DR, Shorvon SD. Startle provoked epileptic
with occipital electroencephalographic foci. Neurology 1975; seizures: features in 19 patients. J Neurol Neurosurg Psychiatry
25:463–71. 1996; 61:151–6.
p 07.qxd 3/10/08 9:35 AM Page 320
Manfredi M, Beltramello A, Bongiovanni LG et al. Eclamptic Mattson RH, Cramer JA, Collins JF et al. A comparison of
encephalopathy: imaging and pathogenetic considerations. valproate with carbamazepine for the treatment of complex
Acta Neurol Scand 1997; 96:277–82. partial seizures and secondarily generalized tonic-clonic
Manowitz P, Kling A, Kohn H. Clinical course of adult seizures in adults. N Engl J Med 1992; 327:765–71.
metachromatic leukodystrophy presenting as schizophrenia: a Maudsley H. Responsibility in mental disease. New York: D.
report of two living cases in siblings. J Nerv Ment Dis 1978; Appleton, 1874.
166:500–6. Mauguire F, Courjon J. Somatosensory epilepsy: a review of 127
Mantovani JF, Landau WM. Acquired aphasia with convulsive cases. Brain 1978; 101:307–32.
disorder: course and prognosis. Neurology 1980; 30:524–9. Mayer SA, Brun SC, Begtrup K et al. Recombinant activated factor
Marchini C, Romito D, Lucci B et al. Fits of weeping as an unusual VII for acute intracerebral hemorhage. N Engl J Med 2005;
manifestation of speaking: case report. Acta Neurol Scand 352:777–85.
1994; 90:218–21. Mayeux R, Lueders H. Complex partial status epilepticus: case
Margerison JH, Corsellis JAN. Epilepsy and the temporal lobes. report and proposal for diagnostic criteria. Neurology 1978;
Brain 1966; 89:499–530. 28:957–61.
Marini C, Scheffer IE, Crossland KM et al. Genetic architecture of Mayeux R, Alexander MP, Benson DF et al. Poriomania. Neurology
idiopathic generalized epilepsy: clinical genetic analysis of 55 1979; 29:1616–19.
multiplex families. Epilepsia 2004; 45:467–78. Mazzini L, Cossa FM, Angelino E et al. Posttraumatic epilepsy:
Marino R, Gasparotti R, Pinelli L et al. Posttraumatic cerebral neuroradiologic and neuropsychological assessment of long-
infarction in patients with moderate or severe head trauma. term outcome. Epilepsia 2003; 44:569–74.
Neurology 2006; 67:1165–71. Medina J, Rubino F, Ross E. Agitated delirium caused by
Marks DA, Ehrenberg BC. Migraine-related seizures in adults with infarctions of the hippocampal formation and fusiform and
epilepsy, with EEG correlation. Neurology 1993; 43:2476–83. lingual gyri: a case report. Neurology 1974; 24:1181–3.
Marks DA, Laxer KD. Semiology of temporal lobe seizures: value in Meencke HJ, Janz D. Neuropathological findings in primary
lateralizing the seizure focus. Epilepsia 1998; 39:721–6. generalized epilepsy: a study of eight cases. Epilepsia 1984;
Marks DA, Kim J, Spencer D et al. Characteristics of intractable 25:8–21.
seizures following meningitis and encephalitis. Neurology Mega MS, Cummings JL, Fiorello T et al. The spectrum of
1992; 42:1513–18. behavioral changes in Alzheimer’s disease. Neurology 1996;
Marsh GG. Neuropsychological syndrome in a patient with 46:130–5.
episodic howling and violent motor behavior. J Neurol Meierkord H, Shorvon S, Lightman S et al. Comparison of the
Neurosurg Psychiatry 1978; 41:366–9. effects of frontal and temporal lobe partial seizures on
Marshall JC, Halligan PW, Fink GR et al. The functional anatomy prolactin levels. Arch Neurol 1992:49:225–30.
of a hysterical paralysis. Cognition 1997; 64:1–8. Mendez MF, Adams NL, Lewandowski KS. Neurobehavioral
Marson AG, Williamson PR, Clough H et al. Carbamazepine versus changes associated with caudate lesions. Neurology 1989;
valproate monotherapy for epilepsy: a meta-analysis. Epilepsia 39:349–54.
2002; 43:505–13. Mendez MF, Selwood A, Mastri AR et al. Pick’s disease versus
Martinez O, Reisin R, Andermann F et al. Evidence for reflex Alzheimer’s disease: a comparison of clinical characteristics.
activation of experiential complex seizures. Neurology 2001; Neurology 1993; 43:289–92.
56:121–3. Mendez MF, Chernier MM, Perryman KM. Epileptic forced thinking
Masel BE, Scheibel RS, Kimbark T et al. Excessive daytime from left frontal lesions. Neurology 1996; 47:79–83.
sleepiness in adults with brain injuries. Arch Phys Med Rehabil Meninger KA. Influenza and schizophrenia. Am J Psychiatry 1926;
2001; 82:1526–32. 82:469–529.
Massman PJ, Sims J, Cooke N et al. Prevalence and correlates of Merriam AE, Medalia A, Levine B. Partial complex status
neuropsychological deficits in amytrophic lateral sclerosis. J epilepticus associated with cocaine abuse. Biol Psychiatry
Neurol Neurosurg Psychiatry 1996; 61:450–5. 1988; 23:515–18.
Mathews WB. Multiple sclerosis presenting with acute remitting Merritt HH, Springlova M. Lissauer’s dementia paralytica: a
psychiatric symptoms. J Neurol Neurosurg Psychiatry 1979; clinical and pathologic study. Arch Neurol Psychiatry 1932;
42:859–63. 27:987–1030.
Matsuo F, Beren D, Faught E et al. Placebo-controlled study of the Messenheimer J, Ramsey RE, Willmore LJ et al. Lamotrigene
efficacy and safety of lamotrigene in patients with partial therapy for partial seizures: a multicenter, placebo-controlled,
seizures. Neurology 1993; 43:2284–91. double-blind, cross-over trial. Epilepsia 1994; 35:113–21.
Mattson RH Cramer JA, Collins JF et al. Comparison of Messing RO, Closson RG, Simon RP. Drug-induced seizures: a
carbamazepine, phenobarbital, phenytoin, and primidone in 10–year experience. Neurology 1984; 34:1582–6.
partial and secondarily generalized tonic-clonic seizures. N Messori A, Polonara G, Carle F et al. Predicting posttraumatic
Engl J Med 1985; 313:145–51. epilepsy with MRI; prospective longitudinal morphologic study
Mattson RH, Cramer JA, Darney PD et al. Use of oral in adults. Epilepsia 2005; 46:1472–81.
contraceptives by women with epilepsy. JAMA 1986; Mesulam M-M. Dissociative states with abnormal temporal lobe
255:238–40. EEG. Arch Neurol 1981; 38:176–81.
p 07.qxd 3/10/08 9:35 AM Page 321
References 321
Meythaler JM, Brunner RC, Johnson A et al. Amantadine to Moore DP. Partial seizures and interictal disorders. Boston:
improve neurorecovery in traumatic brain injury-associated Butterworth-Heinemann, 1997.
diffuse axonal injury: a pilot double-blind randomized trial. J Moosey J, Morphology, sites and epidemiology of cerebral
Head Trauma Rehabil 2002; 17:300–13. atherosclerosis. Res Publ Assoc Res Nerv Ment Dis 1966; 51:1–22.
Michelucchi R, Rubboli G, Passarelli D et al. Electroclinical Morey CE, Cilo M, Berry J et al. The effect of Aricept in persons
features of idiopathic generalized epilepsy with persisting with persistent memory disorder following traumatic brain
absences in adult life. J Neurol Neurosurg Psychiatry 1996; injury: a pilot study. Brain Inj 2003; 17:809–15.
61:471–7. Morris CE, Heyman A, Pozefsky T. Lead encephalopathy caused by
Michelucchi R, Poza JJ, Sovia V et al. Autosomal dominant lateral ingestion of illicitly distilled whiskey. Neurology 1964;
temporal lobe epilepsy: clinical spectrum, new epitempin 14:493–9.
mutations, and genetic heterogeneity in seven European Morris HH, Dinner DS, Luders H et al. Supplementary motor
families. Epilepsia 2003; 44:1289–97. seizures: clinical and electroencephalographic findings.
Michelucchi R, Gardella E, de Haan G-J et al. Telephone-induced Neurology 1988; 38:1075–82.
seizures: a new type of reflex epilepsy. Epilepsia 2004; 45:280–3. Moser HW, Moser AE, Singh I et al. Adrenoleukodystrophy: survey
Miguel EC, Rodriguez Pereira RM, de Braganca Pereira CA et al. of 303 cases: biochemistry, diagnosis and therapy. Ann Neurol
Psychiatric manifestations of systemic lupus erythematosus: 1984; 16:628–41.
clinical features, symptoms and signs of central nervous Moskovitz C, Moses H, Klawans HL. Levodopa-induced psychosis:
system activity in 43 patients. Medicine 1994; 73:224–32. a kindling phenomenon. Am J Psychiatry 1978; 135:669–75.
Mikati MA, Lee WL, DeLong GR. Epileptiform encephalopathy: an Motamedi M, Nguyen DK, Zaatreh M et al. Levetiracetam efficacy
unusual form of partial complex status epilepticus. Epilepsia in refractory partial-onset seizures, especially after failed
1985; 26:563–77. epilepsy surgery. Epilepsia 2003; 44:211–14.
Mineharu Y, Takenada K, Yamakawa H et al. Inheritance pattern Mula M, Trimble MR, Yuen A et al. Psychiatric adverse events
of familial Moyamoya disease: autosomal dominant mode and during levetiracetam therapy. Neurology 2003; 61:704–6.
genetic imprinting. J Neurol Neurosurg Psychiatry 2006; Mulder DW, Daly D. Psychiatric symptoms associated with lesions
77:1025–9. of temporal lobe. JAMA 1952; 150:173–6.
Minematsu K, Yamaguchi T, Omae T. Spectacular shrinking deficit: Mulder DW, Parrott M, Thaler M. Sequelae of western equine
rapid recovery from a major hemispheric syndrome by encephalitis. Neurology 1951; 1:318–27.
migration of an embolus. Neurology 1992; 42:157–62. Mullatti N, Selway R, Nashef L et al. The clinical spectrum of
Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in epilepsy in children and adults with hypothalamic hamartoma.
status epilepticus: a pilot study. Neurology 2006; 67:340–2. Epilepsia 2003; 44:1310–19.
Mitchell C. Successful treatment of chronic delusional Muller D, Pilz H, Ter Meulen V. Studies on adult metachromatic
parasittosis. Br J Psychiatry 1989; 155:556–7. leukodystrophy. I. Clinical, morphological and histochemical
Mitchell W, Falconer MA, Hill D. Epilepsy with fetishism relieved observations in two cases. J Neurol Sci 1969; 9:567–84.
by temporal lobectomy. Lancet 1954; 2:626–30. Muller T, Buttner TH, Kuhn W et al. Palinopsia as sensory epileptic
Mitchell WG, Messenheimer JA, Greenwood RS. Abdominal phenomenon. Acta Neurol Scand 1995; 91:433–6.
epilepsy. Cyclic vomiting as the major symptom of simple Muller U, Murai T, Bauer-Wittmund T et al. Paroxetine versus
partial seizures. Arch Neurol 1983; 40:251–2. citalopram treatment of pathological crying after brain injury.
Mittle RL, Grossman RI, Hiehle JF et al. Prevalence of MR evidence Brain Inj 1999; 13:805–11.
of diffuse axonal injury in patients with mild head injury and Mungas D. Interictal behavior abnormality in temporal lobe
normal head CT findings. AJNR 1994; 15:1583–9. epilepsy. Arch Gen Psychiatry 1982; 39:108–11.
Moder KG, Hurley DL. Fatal hypernatremia from exogenous salt Murphy CP, Harden EA, Thompson JM. Generalized seizures
intake: report of a case and review of the literature. Mayo Clin secondary to high dose busulfan therapy. Ann Pharmacother
Proc 1990; 65:187–94. 1992; 26:30–1.
Moene FC, Landberg EH, Hoogduin KA et al. Organic syndromes Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in
diagnosed as conversion disorder: identification and frequency adults with velo-cardio-facial syndrome. Arch Gen Psychiatry
in a study of 85 patients. J Psychosom Res 2000; 49:7–12. 1999; 56:940–5.
Moersch FP. Psychic manifestations in cases of brain tumors. Am J Murthy P, Jayakumar PN, Sampat S. Of insects and eggs: a case
Psychiatry 1925; 81:707–24. report. J Neurol Neurosurg Psychiatry 1997; 63:522–3.
Mohr JP. Lacunes. Stroke 1982; 13:3–11. Mysiw WJ, Jackson RD, Corrigan JD. Amitriptyline for post-
Molina JA, Calandre L, Bermejo F. Myoclonic encephalopathy due traumatic agitation. Am J Phys Med Rehabil 1988; 67:29–33.
to bismuth salts: treatment with dimercaprol and analysis of Naidech AM, Janjua N, Kreiter KT et al. Predictors and impact of
CSF transmitters. Acta Neurol Scand 1989; 79:200–3. aneurysm rebleeding after subarachnoid hemorrhage. Arch
Monteiro L, Nunes B, Mendonca D et al. Spectrum of epilepsy in Neurol 2005; 62:410–16.
neuroacanthocytosis: a long-term follow-up of 143 patients. Nakada T, Lee H, Kwee IL et al. Epileptic Kluver–Bucy syndrome:
Acta Neurol Scand 1995; 92:33–40. case report. J Clin Psychiatry 1984; 45:87–8.
Moore DP. A case of petit mal epilepsy aggravated by lithium. Am Narushima K, Kosier JT, Robinson R. Preventing poststroke
J Psychiatry 1981; 138:690–1. depression: a 12-week double-blind randomized treatment
p 07.qxd 3/10/08 9:35 AM Page 322
trial and 21-month follow-up. J Nerv Ment Dis 2002; Noyes R, Holt CS, Happel RL et al. A family study of
190:296–303. hypochondriasis. J Nerv Ment Dis 1997; 185:223–32.
Nasrallah HA, Fowler RC, Judd LL. Schizophrenia-like illness Noyes R, Sturat S, Langbehn DR et al. Childhood antecedents of
following head injury. Psychosomatics 1981; 22:359–61. hypochondriasis. Psychosomatics 2002; 43:282–9.
Nausieda PA, Grossman BJ, Koller WC et al. Sydenham chorea: an Nystrom HM. Relationship between location of cerebral lesion
update. Neurology 1980; 30:331–4. and epilepsy. A statistical study of 350 cases. Acta Neurol
Navia BA, Jordan BD, Price RW. The AIDS dementia complex. I. Scand 1966; 42:191–206.
Clinical features. Ann Neurol 1986a; 19:517–24. O’Carroll RE, Masterton G, Dougall N et al. The neuropsychiatric
Navia BA, Petito CK, Gold JWM et al. Cerebral toxoplasmosis sequelae of mercury poisoning: the Mad Hatter’s disease. Br J
complicating the acquired immune deficiency syndrome: Psychiatry 1995; 167:95–8.
clinical and neuropathological findings in 27 patients. Ann Ochs R, Gloor P, Quesney F et al. Does head-turning during a
Neurol 1986b; 19:224–38. seizure have lateralizing or localizing significance? Neurology
Neary D, Snowden JS, Mann DMA et al. Frontal lobe dementia and 1984; 34:884–90.
motor neuron disease. J Neurol Neurosurg Psychiatry 1990; Oder W, Goldenberg G, Spatt J et al. Behavioral and psychosocial
53:23–32. sequelae of severe closed head injury and regional cerebral
Neary D, Snowden JS, Mann DMA. Familial progressive atrophy: blood flow: a SPECT study. J Neurol Neurosurg Psychiatry
its relationship to other forms of lobar atrophy. J Neurol 1992; 55:475–80.
Neurosurg Psychiatry 1993; 56:1122–5. Oestreich LJ, Berg MJ, Bachmann DL et al. Ictal contralateral
Nedeltchev K, der Maur TA, Georgiadis D et al. Ischemic stroke in paresis in complex partial seizures. Epilepsia 1995; 36:671–5.
young adults: predictors of outcome and recurrence. J Neurol Ogunyemi AO, Locke GE, Kramer LD et al. Complex partial status
Neurosurg Psychiatry 2005; 76:191–5. epilepticus provoked by ‘crack’ cocaine. Ann Neurol 1989;
Newburn G, Newburn D. Selegeline in the management of apathy 26:785–6.
following traumatic brain injury. Brain Inj 2005; 19:149–54. O’Hare JA, Callaghan NM, Murnaghan DJ. Dialysis
Newman P, Saunders M. A unique case of musicogenic epilepsy. encephalopathy. Clinical, electroencephalographic, and
Arch Neurol 1980; 37:244–5. interventional aspects. Medicine 1983; 62:129–41.
Newmark ME. Diagnosis of epilepsy with home video-cassette Okada Y, Yamaguchi T, Minematsu K et al. Hemorrhagic
recorder. N Engl J Med 1981; 305:769. transformation in cerebral embolism. Stroke 1989; 20:598–603.
Neylan TC. Frontal lobe function: Mr. Phineas Gage’s famous Oksanen V. Neurosarcoidosis: clinical presentations and course in
injury. J Neuropsychiatry Clin Neurosci 1999; 11:281–3. 50 patients. Acta Neurol Scand 1986; 73:283–90.
Nicoletti A, Sofia V, Biondi R et al. Epilepsy and multiple sclerosis Oldani A, Zucconi M, Asselta R et al. Autosomal dominant
in Italy: a population-based study. Epilepsia 2003; 44:1445–8. nocturnal frontal lobe epilepsy: a video-polysomnographic and
Nielsen H, Kristensen O. Personality correlates of sphenoidal EEG genetic appraisal of 40 patients and delineation of the
foci in temporal lobe epilepsy. Acta Neurol Scand 1981; epileptic syndrome. Brain 1998; 121:205–23.
64:289–300. Olivier AP, Luchins DJ, Wyatt RJ. Neuroleptic-induced seizures.
Nightingale S, Welch JL. Psychometric assessment in absence Arch Gen Psychiatry 1982; 39:206–9.
status. Arch Neurol 1982; 39:516–19. Olsson I, Steffenberg S, Gillberg C. Epilepsy in autism and
Nishida T, Kudo T, Inoue Y et al. Postictal mania versus postictal autistic-like conditions. Arch Neurol 1988; 45:666–8.
psychosis: differences in clinical features, epileptogenic zone, Ono J, Mano T, Andermann E et al. Band heterotopia or double
and brain functional changes during postictal period. Epilepsia cortex in a male: bridging structures suggest abnormality of
2006; 47:2104–14. the radial glial system. Neurology 1997; 48:1701–3.
Nishino H, Rubino FA, DeRemee RA et al. Neurological involvement Opjordsmoen S, Rettersol N. Delusional disorder: the predictive
in Wegener’s granulomatosis: an analysis of 324 consecutive validity of the concept. Acta Psychiatr Scand 1991; 84:250–4.
patients at the Mayo clinic. Ann Neurol 1993; 33:4–9. Oribe E, Rohullah A, Nissenbaum E et al. Serum prolactin
Nizamie SH, Nizamie A, Borde M et al. Mania following head concentrations are elevated after syncope. Neurology 1996;
injury: case reports and neuropsychological findings. Acta 47:60–2.
Psychiatr Scand 1988; 77:637–9. Orrison WW, Gentry LR, Stimae GK et al. Blinded comparison of
Noachtar S, Luders HO. Focal akinetic seizures as documented by cranial CT and MR in closed head injury evaluation. AJNR
electroencephalography and video recordings. Neurology 1994; 15:351–6.
1999; 53:427–9. d’Orsi G, Tinuper P, Bisulli F et al. Clinical features and long term
Nott MT, Chapparo C, Baguley IJ. Agitation following traumatic outcome of epilepsy in periventricular nodular heterotopia.
brain injury: an Australian sample. Brain Inj 2006; Simple compared with plus forms. J Neurol Neurosurg
20:1175–82. Psychiatry 2004; 75:873–8.
Novak J, Corke P, Fairley N. ‘Petit mal status’ in adults. Dis Nerv Ostergarrd JRl Warning lead in subarachnoid hemorrhage. BMJ
Syst 1971; 32:245–8. 1990; 301:190–1.
Noyes R, Kathol RG, Fisher MM et al. Psychiatric comorbidity Ottman R, Risch N, Hauser WA et al. Localization of a gene for
among patients with hypochondriasis. Gen Hosp Psychiatry partial epilepsy to chromosome 10q. Nat Genet 1995;
1994; 16:78–87. 10:56–60.
p 07.qxd 3/10/08 9:35 AM Page 323
References 323
Oxbury JM, Whitty CWM. Causes and consequences of status Paskavitz JF, Anderson CA, Filley CM et al. Acute arcuate fiber
epilepticus in adults: a study of 86 cases. Brain 1971; demyelinating encephalopathy following Epstein–Barr virus
94:733–44. infection. Ann Neurol 1995; 38:127–31.
Ozkara C, Ozdemir S, Yilmaz A et al. Orgasm-induced seizures: a Passero S, Rocchi R, Rossi S et al. Seizures after spontaneous
study of six patients. Epilepsia 2006; 47:2193–7. supratentorial intracerebral hemorrhage. Epilepsia 2002;
Pachet A, Friesen S, Winkelaar D et al. Beneficial behavioral 43:1175–80.
effects of lamotrigene in traumatic brain injury. Brain Inj Patel NC, Landan IR, Levin J et al. The use of levetiracetam in
2003; 17:715–22. refractory status epilepticus. Seizure 2006; 15:137–41.
Pacia SV, Devinsky O. Clozapine-related seizures: experience with Pazzaglia P, D’Alessandro R, Ambrosetto G et al. Drop attacks: an
5,629 patients. Neurology 1994; 44:2247–9. ominous change in the evolution of partial epilepsy. Neurology
Paciaroni M, Caso V, Milia P et al. Isolated monoparesis following 1985; 35:1725–30.
stroke. J Neurol Neurosurg Psychiatry 2005; 76:805–7. Peavy GM, Herzog AG, Rubin NP et al. Neuropsychological aspects
Pakainis A, Drake ME, John K et al. Forced normalization: acute of dementia of motor neuron disease: a report of two cases.
psychosis after seizure control in seven patients. Arch Neurol Neurology 1992; 42:1004–8.
1987; 44:289–92. Pedley TA, Guilleminault C. Episodic nocturnal wanderings
Palmini A, Gloor P. The localizing value of auras in partial responsive to anticonvulsant drug therapy. Ann Neurol 1977;
seizures: a prospective and retrospective study. Neurology 2:30–5.
1992; 42:801–8. Penfield W, Jasper H. Epilepsy and the functional anatomy of the
Palmini A, Andermann F, Olivier A et al. Focal neuronal migration human brain. Boston: Little, Brown, 1954.
disorders and intractable partial epilepsy: a study of 30 Penry JK, Dreifuss FE. Automatisms associated with the absence
patients. Ann Neurol 1991; 30:741–9. of petit mal epilepsy. Arch Neurol 1969; 21:142–9.
Palmini AL, Gloor P, Jones-Gotman M. Pure amnestic seizures in Penry JK, Porter RJ, Dreifuss FE. Simultaneous recording of
temporal lobe epilepsy. Brain 1992; 115:749–69. absence seizures with video tape and electroencephalography:
Pampiglione G, Moynahan EJ. The tuberous sclerosis syndrome: a study of 374 seizures in 48 patients. Brain 1975; 98:427–40.
clinical and EEG studies in 100 children. J Neurol Neurosurg Peppercorn MA, Herzog AG, Dichter MA et al. Abdominal epilepsy:
Psychiatry 1976; 39:666–73. a case of abdominal pain in adults. JAMA 1978; 240:2450–1.
Panayiotopoulus CP. Vomiting as an ictal manifestation of Perez NM, Trimble MR. Epileptic psychosis – diagnostic
epileptic siezures and syndromes. J Neurol Neurosurg comparison with process schizophrenia. Br J Psychiatry 1980;
Psychiatry 1988; 51:1448–51. 137:245–9.
Paquier PF, Van Dongen HR, Loonen CB. The Landau–Kleffner Perley M, Guze B. Hysteria: the stability and usefulness of clinical
syndrome or ‘acquired aphasia with convulsive disorder’: long- criteria: a quantitative study based on a 6–8 year follow-up of
term follow-up of six children and a review of the recent 39 patients. N Engl J Med 1962; 266:421–6.
literature. Arch Neurol 1992; 49:354–9. Peroutka SJ, Sohmer BH, Kumer AJ et al. Hallucinations and
Pardo CA, Vining SPG, Guo L et al. The pathology of Rasmussen delusions following a right temporo-parietal-occipital
syndrome: stages of cortical involvement and infarction. Johns Hopkins Med J 1982; 151:181–5.
neuropathological studies in 45 hemispherectomies. Epilepsia Pessin MS, Lathi E, Cohen M et al. Clinical features and mechanism
2004; 45:516–26. of occipital infarction. Ann Neurol 1987; 21:290–9.
Parker N. Disseminated sclerosis presenting as schizophrenia. Med Petermann AF, Hayles AB, Dockerty MB et al. Encephalotrigeminal
J Aust 1956; 1:405–7. angiomatosis (Sturge–Weber disease). Clinical study of thirty-
Parmar H, Lim S-H, Tan NCK et al. Acute symptomatic seizures five cases. J Am Med Assoc 1958; 167:2169–76.
and hippocampal damage: DWI and MRS findings. Neurology Petry S, Cummings JL, Hill MA et al. Personality alterations in
2006; 66:1732–5. dementia of the Alzheimer type. Arch Neurol 1988; 45:1187–90.
Parra A, Velasco M, Cervantes C et al. Plasma prolactin increase Petti TA, Campbell M. Imipramine and seizures. Am J Psychiatry
following electrical stimulation of the amygdala in humans. 1975; 132:538–40.
Neuroendocrinology 1980; 31:60–5. Petty RG, Bonner D, Mouratoglou V et al. Acute frontal lobe
Parsons MW, Barber PA, Chalk J et al. Diffusion- and perfusion- syndrome and dyscontrol associated with bilateral caudate
weighted MRI response to thrombolysis in stroke. Ann Neurol infarctions. Br J Psychiatry 1996; 168:237–40.
2002; 51:28–37. Pflanz S, Besson JAO, Ebmeier KP et al. The clinical manifestations
Partlow GD, del Carpio-ODonovan R, Melanson D et al. Bilateral of mental disorder in Huntington’s disease: a retrospective
thalamic glioma: review of eight cases with personality case record study of disease progression. Acta Psychiatr Scand
change and mental deterioration. AJNR 1992; 13:1125–30. 1991; 83:53–60.
Partridge M. One operation cures three people: effect of Phillips HA, Marini C, Scheffer IE et al. A de novo mutation in
prefrontal leukotomy on a case of folie a deux et demie. Arch sporadic nocturnal frontal lobe epilepsy. Ann Neurol 2000;
Pascual-Castroviejo I, Diaz-Gonzalez G, Garcia-Melian RM et al. Picard F, Baulac S, Kahane P et al. Dominant partial epilepsies: a
Sturge–Weber syndrome: study of 40 patients. Pediatr clinical, electrophysiological and genetic study of 19 European
Neurology 1993; 9:283–8. families. Brain 2000; 123:1247–62.
p 07.qxd 3/10/08 9:35 AM Page 324
Placidi F, Floris R, Bozzao A et al. Ketotic hyperglycemia and Quirk JA, Fish DR, Smith SJM et al. First seizures associated with
epilepsia partialis continua. Neurology 2001; 57:534–7. playing electronic screen games: a community-based study in
Plazzi G, Tinuper P, Montagna P et al. Epileptic nocturnal Great Britian. Ann Neurol 1995; 37:733–7.
wanderings. Sleep 1995; 18:749. Rabinowicz AL, Correale JD, Bracht KA et al. Neuron specific
Pomeroy SL, Holmes SJ, Dodge PR et al. Seizures and other enolase is increased after nonconvulsive status epilepticus.
neurologic sequelae of bacterial meningitis in children. N Engl Epilepsia 1995; 36:475–9.
J Med 1990; 323:1651–7. Rabinowicz AL, Correale J, Boutros RB. Neuron-specific enolase is
Pope HG, Katz DL. Affective and psychotic symptoms associated increased after single seizures during inpatient video/EEG
with anabolic steroid use. Am J Psychiatry 1988; monitoring. Epilepsia 1996; 37:122–5.
145:487–90. Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill
Pope HG, Jonas JM, Jones B. Factitious psychosis: neurological patients. Neurologist 2003; 9:290–300.
phenomenology, family history and long-term outcome of Ramsey RE, DeToledo J. Intravenous administration of
nine patients. Am J Psychiatry 1982; 139:1480–3. fosphenytoin: options for the management of seizures.
Popli AP, Masand PS, Dewan MJ. Factitious disorders with Neurology 1996; 46(suppl. 1):17–19.
psychological symptoms. J Clin Psychiatry 1992; 53:315–18. Ramsey RE, Wilder BJ, Berger JR et al. A double-blind study
Porter NT, Meyer MA, Zimmerman AW et al. Molecular and comparing carbamazepine with phenytoin as initial seizure
clinical findings in a family with dentatorubral-pallidoluysian therapy in adults. Neurology 1983; 33:904–10.
atrophy. Ann Neurol 1995; 37:273–7. Rao V, Lyketsos C. Neuropsychiatric sequelae of traumatic brain
Porter SB, Sande MA. Toxoplasmosis of the central nervous injury. Psychosomatics 2000; 41:95–103.
system in the acquired immunodeficiency syndrome. N Engl J Rasmussen A, Matsuura T, Ruano L et al. Clinical and genetic
Med 1992; 327:1643–8. analysis of four Mexican families with spinocerebellar ataxia
Poskanzer DC, Brown AE, Miller H. Musicogenic epilepsy caused type 10. Ann Neurol 2001; 50:234–9.
only by a discrete frequency band of church bells. Brain 1962; Rasmussen A, Lunde M, Poulsen DL et al. A double-blind, placebo-
85:7–92. controlled study of sertraline in the prevention of depression
Powell JH, al-Adawi S, Morgan J et al. Motivational deficits after in stroke patients. Psychosomatics 2003; 44:216–21.
brain injury: effects of bromocriptine in 11 patients. J Neurol Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to
Neurosurg Psychiatry 1996; 60:416–21. chronic localized encephalitis. Neurology 1958; 8:435–45.
Poza JJ, Saenz A, Martinez-Gil A et al. Autosomal dominant Rasmussen T. Surgical therapy of frontal lobe epilepsy. Epilepsia
lateral temporal lobe epilepsy: clinical and genetic study of a 1963; 4:181–98.
large Basque pedigree linked to chromosome 10q. Ann Neurol Rasmussen T. Characteristics of a pure culture of frontal lobe
1999; 45:182–8. epilepsy. Epilepsia 1983; 24:482–93.
Prashanth LK, Taly AB, Ravi V et al. Adult subacute sclerosing Rasmussen T, Andermann F. Update on the syndrome of ‘chronic
panencephalitis: clinical profile of 39 patients from a encephalitis’ and epilepsy. Cleve Clin J Med 1989; 56(suppl.
tertiary care center. J Neurol Neurosurg Psychiatry 2006; 2):181–4.
77:630–3. Rauschka H, Colsch B, Baumann N et al. Late-onset
Pritchard PB, Wannamaker BB, Sagel J et al. Serum prolactin and metachromatic leukodystrophy. Genotype strongly influences
cortisol levels in evaluation of pseudoepileptic seizures. Ann phenotype. Neurology 2006; 67:859–63.
Neurol 1985a; 18:87–9. Raymond AA, Fish DR, Sisodiya SM et al. Abnormalities of
Pritchard PB, Holmstrom VL, Giacinto J. Self-abatement of gyration, heterotopias, tuberous sclerosis, focal cortical
complex partial seizures. Ann Neurol 1985b; 18:265–7. dysplasia, microdysgenesis, dysembroplastic neuroepithelial
Privitera MD, Morris GL, Gilliam F. Postictal language assessment tumor and dysgenesis of the archicortex in epilepsy. Clinical,
and lateralization of complex partial seizures. Ann Neurol EEG and neuroimaging findings. Brain 1995; 118:629–60.
1991; 30:391–6. Raymond RW, Williams RL. Infectious mononucleosis with
Privitera MD, Fincham R, Penry J et al. Topiramate placebo- psychosis. N Engl J Med 1948; 239:542–4.
controlled dose-ranging trial in refractory partial epilepsy Reading PJ, Will RG. Unwelcome orgasms. Lancet 1997; 350:1747.
using 600-, 800-, and 1,000-mg daily dosages. Neurology Reami DO, Silva DF, Albuquerque M et al. Dreams and epilepsy.
1996; 46:1678–83. Epilepsia 1991; 32:51–3.
Provini F, Plazzi G, Tinuper P et al. Nocturnal frontal lobe epilepsy: Reed K, Bland RL. Masked ‘myxedema madness’. Acta Psychiatr
a clinical and polygraphic overview of 100 consecutive cases. Scand 1977; 56:421–6.
Brain 1999; 122:1017–31. van Reekum R, Bayley M, Garner S et al. N of 1 study: amantadine
Pueschel SM, Louis S, McKnight P. Seizure disorders in Down for the amotivational syndrome in a patient with traumatic
syndrome. Arch Neurol 1991; 48:318–20. brain injury. Brain Inj 1995; 9:49–53.
Putzel L. Cerebral complications of chorea. New York Medical Reich P, Gottfried LA. Factitious disorders in a teaching hospital.
Record 1879; (6 Sept):220–2. Ann Intern Med 1983; 99:240–7.
Quesney LF, Constain M, Fish DR et al. The clinical differentiation Remillard GM, Andermann F, Rhi-Sausa A et al. Facial assymetry
of seizures in the parasaggital and anterolateral frontal in patients with temporal lobe epilepsy. Neurology 1977;
convexities. Arch Neurol 1990; 47:677–9. 27:109–14.
p 07.qxd 3/10/08 9:35 AM Page 325
References 325
Remillard GM, Andermann F, Testa GF et al. Sexual ictal Rothschild D. Dementia paralytica accompanied by manic-
manifestations predominate in women with temporal lobe depressive and schizophrenic psychoses. Am J Psychiatry 1940;
epilepsy: a finding suggesting sexual dimorphism in the 96:1043–60.
human brain. Neurology 1983; 33:323–30. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke. Time
Rennick PM, Perez-Borja C, Rodin EA. Transient mental deficits window for prevention is very short. Neurology 2005;
associated with recurrent prolonged epileptic clouded state. 64:817–20.
Epilepsia 1969; 10:397–405. Rowan AJ, Scott DF. Major status epilepticus: a series of 42
Rennick PM, Noland DC, Bauer RB et al. Neuropsychologic and patients. Acta Neurol Scand 1970; 46:573–84.
neurologic follow-up after herpes hominis encephalitis. Rowan AJ, Ramsey RE, Collins JF et al. New onset geriatric
Neurology 1973; 23:42–7. epilepsy. A randomized study of gabapentin, lamotrigine, and
Rheims S, Demarquay G, Isnard J et al. Ipsilateral head deviation carbamazepine. Neurology 2005; 64:1868–73.
in frontal lobe seizures. Epilepsia 2005; 46:1750–3. Rozdilsky B, Cummings JN, Huston AF. Hallervorden–Spatz
Rice E, Gendelman S. Psychiatric aspects of normal pressure disease: late infantile and adult type, report of two cases. Acta
hydrocephalus. JAMA 1973; 223:409–12. Neuropathologica 1968; 10:1–16.
Richardson EP, Dodge PR. Epilepsy in cerebral vascular disease. Ruff RL. Orgasmic epilepsy. Neurology 1980; 30:1252.
Epilepsia 1954; 3:49–74. Rugg-Gunn FJ, Duncan JS, Smith SJM. Epileptic cardiac asystole.
Richfield EK, Twyman R, Berent S. Neurological syndrome J Neurol Neurosurg Psychiatry 2000; 68:108–10.
following bilateral damage to the head of the caudate nuclei. Rush JL, Everett BA, Adams AH et al. Paroxysmal atrial
Ann Neurol 1987; 22:768–71. tachycardia and frontal lobe tumor. Arch Neurol 1977;
Roberts AH. Sequelae of closed head injuries. Proc R Soc Med 34:578–80.
1976; 69:137–41. Russell WR, Whitty CWM. Studies in traumatic epilepsy. 1.
Roberts JKA, Trimble MR, Robertson M. Schizophrenic psychosis Factors influencing the incidence of epilepsy after brain
associated with aqueductal stenosis in adults. J Neurol wounds. J Neurol Neurosurg Psychiatry 1952; 15:93–8.
Neurosurg Psychiatry 1983; 46:892–8. Russell WR, Whitty CWM. Studies in traumatic epilepsy. 2. Focal
Roberts MA, Humphrey PRD. Prolonged complex partial status motor and somatic sensory fits: a study of 85 cases. J Neurol
epilepticus: a case report. J Neurol Neurosurg Psychiatry 1988; Neurosurg Psychiatry 1953; 16:73–97.
51:586–8. Russell WR, Whitty CWM. Studies in traumatic epilepsy. 3. Visual
Robinson RG, Parikh RM, Lipsey JR et al. Pathological laughing fits. J Neurol Neurosurg Psychiatry 1955; 18:79–96.
and crying after stroke: validation of a measurement scale and Russo LS, Beace G, Sandroni S et al. Aluminum intoxication in
a double-blind treatment study. Am J Psychiatry 1993; undialysed adults with chronic renal failure. J Neurol
Robinson RG, Schultz SK, Castillo C et al. Nortriptyline versus Rusu V, Chassoux F, Landre E et al. Dystonic posturing in seizures
fluoxetine in the treatment of depression and in short-term of mesial temporal origin. Electroclinical and metabolic
recovery after stroke: a placebo-controlled, double-blind pattern. Neurology 2005; 65:1612–19.
study. Am J Psychiatry 2000; 157:658–60. Sacco RL, Freddo L, Bello JA et al. Wallenberg’s lateral medullary
Rocamora R, Kurthen M, Lickfett L et al. Cardiac asystole in syndrome. Clinical-magnetic resonance imaging correlations.
epilepsy: clinical and neurophysiologic features. Epilepsia Arch Neurol 1993; 50:609–14.
2003; 44:179–85. Sacco RL, Sivenius J, Diener H-C. Efficacy of aspirin plus
Rodin E, Schmaltz S. The Bear–Fedio personality inventory and extended-release dipyridamole in preventing recurrent
temporal lobe epilepsy. Neurology 1984; 34:591–6. stroke in high-risk populations. Arch Neurol 2005;
Rodin EA. Psychomotor epilepsy and aggressive behavior. Arch 62:403–8.
Gen Psychiatry 1973; 28:210–13. Sachdev P, Smith JS, Cathcart S. Schizophrenia-like psychosis
Romanelli MF, Morris JC, Ashkin K et al. Advanced Alzheimer’s following traumatic brain injury: a chart-based descriptive and
disease is a risk factor for late-onset seizures. Arch Neurol case-control study. Psychol Med 2001; 31:231–9.
1990; 47:847–50. Sadleir LG, Farrell K, Smith S et al. Electroclinical features of
Romanul FCA, Radvany J, Rosales RK. Whipple’s disease confined absence seizures in childhood absence epilepsy. Neurology
to the brain: a case confirmed clinically and pathologically. J 2006; 67;413–18.
Neurol Neurosurg Psychiatry 1977; 40:901–9. Sadler RM, Rahey S. Prescience as an aura of temporal lobe
Roos R, Cajdusek DC, Gibbs CJ. The clinical characteristics of epilepsy. Epilepsia 2004; 45:982–4.
transmissible Creutzfeldt–Jakob disease. Brain 1973; 96:1–20. Saenz A, Galan J, Caloustian C et al. Autosomal dominant
Rosenbaum M, Lewis M, Piker P et al. Convulsive seizures in nocturnal frontal lobe epilepsy in a Spanish family with a
delirium tremens. Arch Neurol Psychiatry 1941; 45:486–93. SER252PHE mutation in the CHRNA4 gene. Arch Neurol 1999;
Rosenberg GA, Kornfeld M, Stovring J et al. Subcortical 56:1004–9.
arteriosclerotic encephalopathy (Binswanger’s): computerized Salanova V, Andermann F, Olivier A et al. Occipital lobe epilepsy:
tomography. Neurology 1979; 29:1102–6. electroclinical manifestations, electrocorticography, cortical
Ross AT, Dickerson WW. Tuberous sclerosis. Arch Neurol Psychiatry stimulation and outcome in 42 patients treated between 1930
1943; 50:233–57. and 1991. Brain 1992; 115:1655–80.
p 07.qxd 3/10/08 9:35 AM Page 326
Salanova V, Morris HH, Van Ness P et al. Frontal lobe seizures: Sbordone RJ, Seyranian GD, Ruff RM. Are the subjective
electroclinical syndromes. Epilepsia 1995; 36:16–24. complaints of traumatically brain injured patients reliable?
Salazar AM, Jabbari B, Vance SC et al. Epilepsy after penetrating Brain Inj 1998; 12:505–15.
head injury. I. Clinical correlates: a report of the Viet Nam Schacter SC, Vazquez B, Fisher RS et al. Oxcarbazepine: double-
head injury study. Neurology 1985; 35:1406–14. blind, randomized, placebo-controlled monotherapy trial for
Salehi F, Kovacs K, Scheihauer BW et al. Histologic study of the partial seizures. Neurology 1999; 52:732–7.
human pituitary gland in acute traumatic injury. Brain Inj Schaumburg HH, Powers JM, Raine CS et al.
2007; 21:651–6. Adrenoleukodystrophy: a clinical and pathological study of 17
Salib EA. Subacute sclerosing panencephalitis (SSPE) presenting cases. Arch Neurol 1975; 32:577–91.
at the age of 21 as a schizophrenia-like state with bizarre Scheffer IE, Bhatia KP, Lopes-Cendes I et al. Autosomal dominant
dysmorphophobic features. Br J Psychiatry 1988; 152:709–10. nocturnal frontal epilepsy misdiagnosed as a sleep disorder.
Salinsky MC, Uthman BM, Ristanovic RK et al. Vagus nerve Lancet 1994; 343:515–17.
stimulation for the treatment of medically intractable Scheffer IE, Bhatia KP, Lopes-Cendes I et al. Autosomal dominant
seizures: results of a 1–year open-extension trial. Arch Neurol nocturnal frontal lobe epilepsy: a distinctive clinical disorder.
1996; 53:1176–80. Brain 1995; 118:61–73.
Salmenpara T, Kononen M, Roberts N et al. Hippocampal damage Schneider WN, Drew-Cates J, Wong TM et al. Cognitive and
in newly diagnosed focal epilepsy: a prospective MRI study. behavioral efficacy of amantadine in acute traumatic brain
Neurology 2005; 64:62–8. injury: an initial double-blind placebo-controlled study. Brain
Sammaritano M, Andermann F, Melanson D et al. Prolonged focal Inj 1999; 13:863–72.
cerebral edema associated with partial status epilepticus. Scholtes FB, Renier WO, Meinardi H. Simple partial status
Epilepsia 1985; 26:334–9. epilepticus: causes, treatment, and outcome in 47 patients. J
Samuel M, Duncan JS. Use of hand held video camcorder in the Neurol Neurosurg Psychiatry 1996a; 61:90–2.
evaluation of seizures. J Neurol Neurosurg Psychiatry 1994; Scholtes FB, Renier WO, Meinardi H. Non-convulsive status
57:1417–18. epilepticus: causes, treatment and outcome in 65 patients. J
Sander JWAS, Hart YM, Johnson AL et al. National General Neurol Neurosurg Psychiatry 1996b; 61:93–5.
Practice Study of Epilepsy: newly diagnosed epileptic seizures Schramm P, Schelliger PD, Klotz E et al. Comparison of perfusion
in a general population. Lancet 1990; 336:1267–71. computed tomography and computed tomography
Sander JWAS, Hart YM, Trimble MR et al. Vigabatrin and angiography source images with perfusion-weighted imaging
psychosis. J Neurol Neurosurg Psychiatry 1991; 54:435–9. and diffusion-weighted imaging in patients with acute stroke
Sands IJ. The acute psychiatric type of epidemic encephalitis. Am J of less than 6 hours’ duration. Stroke 2004; 35:1652–8.
Psychiatry 1928; 84:975–87. Schube PG. Emotional states of general paresis. Am J Psychiatry
Sandson TA, Daffner KR, Carvalho PA et al. Frontal lobe 1934; 91:625–38.
dysfunction following infarction of the left-sided medial Schuckitt MA, Smith TL, Anthenelli R et al. Clinical course of
thalamus. Arch Neurol 1991; 48:1300–3. alcoholism in 636 male inpatients. Am J Psychiatry 1993;
Sano K, Malamud N. Clinical significance of sclerosis of cornu 150:786–92.
Ammonis. Arch Neurol Psychiatry 1953; 70:40–53. Schufle SU, Bermeo AC, Alexopoulos AV et al. Video-
Sarno MT, Buonaguro A, Levita E. Characteristics of verbal electrographic and clinical features in patients with ictal
impairment in closed head injury patients. Arch Phys Med asystole. Neurology 2007; 69:439–41.
Rehabil 1986; 67:400–5. Schulz R, Luders HO, Noachtar S et al. Amnesia of the epileptic
Satel SL, Southwick SM, Gawin FH. Clinical features of cocaine- aura. Neurology 1995; 45:231–5.
induced paranoia. Am J Psychiatry 1991; 148:495–8. Schwab RS. A case of status epilepticus in petit mal.
Sato S, Dreifuss FE, Penry JK. Prognostic factors in absence Electroencephalogr Clin Neurophysiol 1953; 5:441–2.
seizures. Neurology 1976; 26:788–96. Scott GM, Gibberb FB. Epilepsy and other factors in the prognosis
Sato S, White BG, Penry JK et al. Valproic acid versus of gliomas. Acta Neurol Scand 1980; 61:227–39.
ethosuximide in the treatment of absence seizures. Neurology Scott JS, Masland RL. Occurrence of ‘continuous symptoms’ in
1982; 32:157–3. epilepsy patients. Neurology 1953; 3:297–301.
Savard G, Andermann F, Teitelbaum J et al. Epileptic Seeley WW, Bauer AM, Miller BL et al. The natural history of
Munchausen’s syndrome: a form of pseudoseizures temporal variant frontotemporal dementia. Neurology 2005;
distinct from hysteria and malingering. Neurology 1988; 64:1384–90.
38:1628–9. Semel JD. Complex partial status epilepticus presenting as fever
Savard G, Andermann F, Olivier A et al. Postictal psychoses after of unknown origin. Arch Int Med 1987; 147:1571–2.
partial complex seizures: a multiple case study. Epilepsia Sen S, Laowatana S, Lima J et al. Risk factors for intracardiac
1991; 32:225–31. thrombus in patients with recent ischemic cerebrovascular
Saygi S, Spencer SS, Scheyer R et al. Differentiation of events. J Neurol Neurosurg Psychiatry 2004; 75:1421–5.
temporal lobe ictal behavior associated with hippocampal Serafetinides EA, Falconer MA. Speech disturbance in temporal
sclerosis and tumor of the temporal lobe. Epilepsia 1994; lobe seizures: a study in 100 epileptic patients submitted to
35:737–42. anterior temporal lobectomy. Brain 1963; 86:333–46.
p 07.qxd 3/10/08 9:35 AM Page 327
References 327
Serby M, Angrist B, Lieberman A. Mental disturbances during Sisodiya SM, Stevens JM, Fish DR et al. The demonstration of
bromocriptine and lergotrile treatment of Parkinson’s disease. gyral abnormalities in patients with cryptogenic partial
Am J Psychiatry 1978; 135:1227–9. epilepsy using three-dimensional MRI. Arch Neurol 1996;
Seshia SS, McLachlan RS. Aura continua. Epilepsia 2005; 46:454–5. 53:28–34.
Sethi PK, Surya R. Gelastic, quiritarian, and cursive epilepsy. J Sittig O. A clinical study of sensory Jacksonian fits. Brain 1925;
Shah P, Kaplan SL. Catatonic symptoms in a child with epilepsy. Sivenius J, Kalviainen R, Ylinen A et al. Double-blind study of
Am J Psychiatry 1980; 137:738–9. gabapentin in the treatment of partial seizures. Epilepsia
Shavit YB, Graus F, Probst A et al. Epilepsia partialis continua: a 1991; 32:539–42.
new manifestation of anti-Hu associated paraneoplastic Slater E, Beard AW. The schizophrenia-like psychoses of epilepsy.
encephalomyelitis. Ann Neurol 1999; 45:255–8. I. Psychiatric aspects. Br J Psychiatry 1963a; 109:95–112.
Shaw PJ, Walls TJ, Newman PK et al. Hashimoto’s Slater E, Beard AW. The schizophrenia-like psychoses of epilepsy.
encephalopathy: a steroid-responsive disorder associated with V. Discussion and conclusion. Br J Psychiatry 1963b;
high anti-thyroid antibody titers – report of 5 cases. 109:143–50.
Neurology 1991; 41:228–33. Sloan RL, Brown KW, Pentland B. Fluoxetine as a treatment
Sherer MA, Kumor KM, Cone EJ et al. Suspiciousness induced by for emotional lability after brain injury. Brain Inj 1992;
four-hour intravenous infusion of cocaine. Preliminary 6:315–19.
findings. Arch Gen Psychiatry 1988; 45:673–7. Smaje JC, Davidson C, Teasdale GM. Sino-atrial arrest due to
Sheth RD, Drazkowski JF, Sirven JI. Protracted ictal confusion in temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 1987;
elderly patients. Arch Neurol 2006; 63:529–32. 50:112–13.
Shewmon DA, Masdeu JC. Delayed radiation necrosis of the brain Smith GR, Monson RA, Livingston RL. Somatization disorder in
contralateral to original tumor. Arch Neurol 1980; 37:592–4. men. Gen Hosp Psychiatry 1985; 7:4–8.
Shimoda M, Takeuchi M, Tominaga J et al. Asymptomatic versus Smith GR, Monson RA, Ray DC. Psychiatric consultation in
symptomatic infarcts from vasospasm in patients with somatization disorder. A randomized controlled study. N Engl J
subarachnoid hemorrhage: serial magnetic resonance imaging. Med 1986; 314:1407–13.
Neurosurgery 2001; 49:1341–8. Smith LH. Mental and neurologic changes in pernicious anemia.
Shiozawa Z, Sasaki H, Ozaki Y et al. Epilepsia partialis continua Arch Neurol Psychiatry 1929; 22:551–7.
following metrizamide cisternography. Ann Neurol 1981; Smith RF, Devinsky O, Luciano D. Inhibitory motor status: two
10:400–1. new cases and a review of inhibitory motor seizures. J Epilepsy
Shukla GD, Mishra DN. Vomiting as sole manifestation of simple 1997; 10:15–21.
partial seizure. Arch Neurol 1985; 42:626. Smyth GE, Stern K. Tumours of the thalamus: a clinico-
Siegel AM, Cascino GD, Elger CE et al. Adult-onset epilepsy in pathological study. Brain 1938; 61:339–74.
focal cortical dysplasia of Taylor type. Neurology 2005; Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents.
64:1771–4. Ann Int Med 1984; 101:92–104.
Siegel RK. Cocaine hallucinations. Am J Psychiatry 1978; So EL, Schauble BS. Ictal asomatognosia as a cause of epileptic
135:309–14. falls. Simultaneous video, EMG, and invasive EEG. Neurology
Silver JM, Koumaras B, Chen M et al. Effects of rivastigmine on 2004; 63:2153–4.
cognitive function in patients with traumatic brain injury. So EL, King DL, Muruin AJ. Misdiagnosis of complex absence
Neurology 2006; 67:748–55. seizures. Arch Neurol 1984; 41:640–1.
Siesling S, Vegter-van der Vlis M, Roos RAC. Juvenile Huntington’s So EL, Annegers JF, Hauser WA et al. Population-based study of
disease in the Netherlands. Pediatr Neurol 1997; 17:34–43. seizure disorders after cerebral infarction. Neurology 1996;
Silverstein A, Steinberg G, Nathanson M. Nervous system 46:350–1.
involvement in infectious mononucleosis. Arch Neurol 1972; Sonoo M. Abductor sign: a reliable new sign to detect unilateral
26:353–8. non-organic paresis of the lower limb. J Neurol Neurosurg
Simonsen N, Olsen PZ, Kuhl V et al. A comparative controlled Psychiatry 2004; 75:121–5.
study between carbamazepine and diphenylhydantoin in Souid AK, Keith DV, Cunningham AS. Munchausen syndrome by
psychomotor epilepsy. Epilepsia 1976; 17:169–76. proxy. Clin Pediatr 1998; 37:497–503.
Singh BM, Strobos RJ. Epilepsia partialis continua associated with Sowa MV, Pituck S. Prolonged spontaneous visual hallucinations
nonketotic hyperglycemia: clinical and biochemical profile of and illusions as ictal phenomena. Epilepsia 1989; 30:524–6.
21 patients. Ann Neurol 1980; 8:155–60. Soyka M. Psychopathological characteristics in alcohol
Singh BM, Gupta DR, Strobos RJ. Nonketotic hyperglycemia and hallucinosis and paranoid schizophrenia. Acta Psychiatr Scand
epilepsia partialis continua. Arch Neurol 1973; 29:187–90. 1990; 81:255–9.
Sisler GC, Levy LL, Roseman E. Epilepsia cursiva: syndrome of Soyka M, Naber G, Volcker A. Prevalence of delusional jealousy in
running fits. Arch Neurol Psychiatry 1953; 69:73–9. different psychiatric disorders. Br J Psychiatry 1991;
Sisodiya SM, Free SL, Stevens JM et al. Widespread cerebral 158:549–53.
structural changes in patients with cortical dysgenesis and Spatt J. Epilepsia partialis continua in multiple sclerosis. Lancet
epilepsy. Brain 1995; 118:1039–50. 1995; 345:658–9.
p 07.qxd 3/10/08 9:35 AM Page 328
Speech TJ, Rao SM, Osmon DC et al. A double-blind controlled Strauss I, Keschner M. Mental symptoms in cases of tumor of the
study of methylphenidate treatment in closed head injury. frontal lobe. Arch Neurol Psychiatry 1935; 33:986–1007.
Brain Inj 1993; 7:333–8. Strobos RRJ. Tumors of the temporal lobe. Neurology 1953;
Spencer SS, Spencer DD, Williamson PD et al. Sexual automatisms 3:752–60.
in complex partial epilepsy. Neurology 1983; 33:527–33. Strub RL. Frontal lobe syndrome in a patient with bilateral globus
Sperling MR, Wilson CL. The effect of limbic and extralimbic pallidus lesions. Arch Neurol 1989; 46:1024–7.
electrical stimulations upon prolactin secretion in humans. Sturm JW, Andermann F, Berkovic SF. ‘Pressure to laugh’: an
Brain Res 1986; 371:293–7. unusual epileptic symptom associated with small
Sperling MR, Pritchard PB, Engel J et al. Prolactin in partial hypothalamic hamartomas. Neurology 2000; 54:971–3.
epilepsy: an indicator of limbic seizures. Ann Neurol 1986; Sturm JW, Fedi M, Berkovic SF et al. Exercise induced temporal
20:716–22. lobe epilepsy. Neurology 2002; 59:1246–8.
Sperling MR, Lieb JP, Engel J et al. Prognostic significance of Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid
independent auras in temporal lobe seizures. Epilepsia 1989; hemorrahge. N Engl J Med 2006; 354:387–96.
30:322–31. Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic
Spooner CG, Berkovic SF, Mitchell LA et al. New-onset temporal encephalopathy due to ingestion of bismuth salts: clinical and
lobe epilepsy in children. Lesion on MRI predicts poor seizure EEG studies of 45 patients. J Neurol Neurosurg Psychiatry
control. Neurology 2006; 67:2147–53. 1977; 40:748–52.
Spratling WP. Epilepsy, its etiology, pathology and treatment Sussman NM, Jackel RA, Kaplan LR et al. Bicycling movements as
briefly considered. JAMA 1902; 38:1126–30. a manifestation of complex partial seizures of temporal lobe
Stanislav SW. Cognitive effects of antipsychotic agents in persons origin. Epilepsia 1989; 30:527–31.
with traumatic brain injury. Brain Inj 1997; 11:335–41. Sutherling WW, Risinger MW, Crandall PH et al. Focal functional
Starkstein SE, Mayberg HS, Berthier ML et al. Mania after brain anatomy of dorsolateral frontocentral seizures. Neurology
injury: neuroradiological and metabolic findings. Ann Neurol 1990; 40:87–98.
1990; 27:652–9. Swanson AG, Iseri OA. Acute encephalopathy due to water
Starosta-Rubinstein S, Young AB, Kluin K et al. Clinical intoxication. N Engl J Med 1958; 258:831–4.
assessment of 31 patients with Wilson’s disease: correlations Swartz BE. Electrophysiology of bimanual-bipedal automatisms.
with structural changes on magnetic resonance imaging. Arch Epilepsia 1994; 35:264–74.
Neurol 1987; 44:365–70. Swartz BE, Tomiyasu U, Delgado-Escueta AV et al. Neuroimaging
Steegmann AT, Winer B. Temporal lobe epilepsy resulting from in temporal lobe epilepsy: test sensitivity and relationships to
ganglioglioma. Neurology 1961; 11:406–12. pathology and postoperative outcome. Epilepsia 1992;
Stefan H, Wang-Tilz Y, Pauli E et al. Onset of action of 33:624–34.
levetiracetam; a RCT trial using therapeutic intensive seizure Swigar ME, Bowers MB. Baclofen withdrawal and
analysis. Epilepsia 2006; 47:516–22. neuropsychiatric symptoms: a case report and review of other
Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in case literature. Compr Psychiatry 1986; 27:394–400.
children and adolescents with mental retardation and active Symonds C. Excitation and inhibition in epilepsy. Brain 1959;
epilepsy. Arch Neurol 1996; 53:904–12. 82:133–46.
Steiner I, Budka H, Chaudhuri A et al. Viral encephalitis: a review Szabo K, Poepel A, Pohlmann-Eden B et al. Diffusion-weighted
of diagnostic methods and guidelines for management. Eur J and perfusion MRI demonstrates parenchymal changes in
Neurol 2005; 12:331–43. complex partial status epilepticus. Brain 2005; 128:1369–76.
Steiner W, Laporta M, Chouinard G. Neuroleptic-induced Tachibana N, Shinde A, Ikede A et al. Supplementary motor area
supersensitivity psychosis in patients with bipolar affective seizure resembling sleep disorder. Sleep 1996; 19:811–16.
disorder. Acta Psychiatr Scand 1990; 81:437–40. Tanaka N, Sakurai K, Kamada K et al. Neuromagnetic source
Stone J, Zeman A, Sharpe M. Functional weakness and localization of epileptiform actitivity in patients with
sensory disturbance. J Neurol Neurosurg Psychiatry 2002; graphigenic epilepsy. Epilepsia 2006; 47;1963–7.
73:241–5. Tassi L, Colombo N, Cossu M et al. Electroclinical, MRI and
Stone J, Townend E, Kwan J et al. Personality change after stroke: neuropathological study of 10 patients with nodular
some preliminary observations. J Neurol Neurosurg Psychiatry heterotopia, with surgical outcomes. Brain 2005; 128:321–37.
2004; 75:1708–13. Tassinari CA, Tassi L, Calandra-Buonaura G et al. Biting behavior,
Stone J, Smyth R, Carson A et al. La belle indifference in aggression, and seizures. Epilepsia 2005; 46:654–63.
conversion symptoms and hysteria: systematic review. Br J Tateno A, Jorge RE, Robinson RG. Pathological laughing and
Psychiatry 2006; 188:204–9. crying after traumatic brain injury. J Neuropsychiatry Clin
Storm-Mathisen A. General paresis: a follow-up study of 203 Neurosci 2004; 16:126–34.
patients. Acta Psychiatr Scand 1969; 45:118–32. Tatu L, Moulin T, Bogousslavsky J et al. Arterial territories of human
Stracciari A, Ciucci G, Bianchedi G et al. Epileptic transient brain: brainstem and cerebellum. Neurology 1996; 47:1125–35.
amnesia. Eur Neurol 1990; 30:176–9. Tatu L, Moulin T, Bogousslavsky J et al. Arterial territories of
Strauss H. Paroxysmal convulsive running and the concept of human brain: cerebral hemispheres. Neurology 1998;
epilepsia cursiva. Neurology 1960; 10:341–4. 50:1699–708.
p 07.qxd 3/10/08 9:35 AM Page 329
References 329
Tatum WO, Passaro EA, Elia M et al. Seizure in Klinefelter’s Tinuper P, Cerullo A, Marini C et al. Epileptic drop attacks in
syndrome. Pediatr Neurology 1998; 19:275–82. partial epilepsy: clinical features, evolution, and prognosis. J
Tayah TF, Abou-KhalilB, Gilliam FG et al. Musicogenic seizures Neurol Neurosurg Psychiatry 1998; 64:231–7.
can arise from multiple temporal lobe foci: intracranial Todd R. Clinical lectures on paralysis, diseases of the brain, and
EEG analyses of three patients. Epilepsia 2006; other affections of the nervous system. Philadelphia: Lindsay &
47:1402–6. Blakiston, 1855.
Taylor DC, Marsh SM. Hughlings Jackson’s Dr. Z: the paradigm of Tomson T, Svanborg E, Wedlund J-E. Nonconvulsive status
temporal lobe epilepsy revealed. J Neurol Neurosurg Psychiatry epilepticus: high incidence of complex partial status. Epilepsia
1980; 43:758–67. 1986; 27:276–85.
Taylor DC, Falconer MA, Bruton CJ et al. Focal dysplasia of the Tomson T, Lindbom U, Nilsson BY et al. Serum prolactin during
cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry status epilepticus. J Neurol Neurosurg Psychiatry 1989;
1971; 34:369–87. 52:1435–7.
Taylor J ed. Selected writings of John Hughlings Jackson. London: Tomson T, Lindbom U, Nilsson BY. Nonconvulsive status
Hodder & Stoughton, 1931. epilepticus in adults. Thirty-two consecutive patients from a
Teasdale G, Jennett B. Assessment of coma and impaired general hospital population. Epilepsia 1992; 33:829–35.
consciousness. A practical scale. Lancet 1974; 2:81–4. Towne AR, Waterhouse EJ, Boggs JG et al. Prevalence of
Temkin NR, Dikmen SS, Wilensky AJ et al. A randomized, double- nonconvulsive status epilepticus in comatose patients.
blind study of phenytoin for the prevention of post-traumatic Neurology 2000; 54:340–5.
seizures. N Engl J Med 1990; 323:497–502. Treiman DM, Meyers PD, Walton NY et al. A comparison of four
Temkin NR, Dikmen SS, Anderson GD et al. Valproate therapy for treatments for generalized convulsive status epilepticus.
prevention of posttraumatic seizures: a randomized trial. J Veterans Affairs Status Epilepticus Cooperative Study Group. N
Neurosurg 1999; 91:593–600. Engl J Med 1998; 339:792–8.
Tenembaum S, Chamoles N, Fejerman N. Acute disseminated Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing’s
encephalomyelitis. A long-term follow-up study of 84 syndrome. Arch Neurol Psychiatry 1952; 67:283–309.
pediatric patients. Neurology 2002; 59:1224–31. Trouillas P, Courjon J. Epilepsy with multiple sclerosis. Epilepsia
Thacore VR, Shukla SRP. Cannabis psychosis and paranoid 1972; 13:325–33.
schizophrenia. Arch Gen Psychiatry 1976; 33:383–6. Troupin A, Ojemann LM, Halpern L et al. Carbamazepine – a
Theodore WH, Porter RJ, Penry JK. Complex partial seizures: double-blind comparison with phenytoin. Neurology 1977;
clinical characteristics and differential diagnosis. Neurology 27:511–19.
1983; 33:1115–21. Tsai JJ, Yen DJ, Hsih MS et al. Efficacy and safety of levetiracetam
Theodore WH, Porter RJ, Albert P et al. The secondarily (up to 2000 mg/day) in Taiwanese patients with refractory
generalized tonic-clonic seizure: a videotape analysis. partial seizures: a multicenter, randomized, double-blind,
Neurology 1994; 44:1403–7. placebo-controlled study. Epilepsia 2006; 47:72–81.
Thomas CS, Szabadi E. Paranoid psychosis as the first presentation Tsoi WF. The Ganser syndrome in Singapore: a report on ten cases.
of a fulminating lethal case of AIDS. Br J Psychiatry 1987; Br J Psychiatry 1973; 123:567–72.
151:693–5. Tsukamoto T, Mochizuki R, Mochizuki H et al. Paraneoplastic
Thomas JE, Reagen TJ, Klass DW. Epilepsia partialis continua. A cerebellar degeneration and limbic encephalitis in a patient
review of 32 cases. Arch Neurol 1977; 34:266–75. with adenocarcinoma of the colon. J Neurol Neurosurg
Thomas P, Valton L, Genton P. Absence and myoclonic status Psychiatry 1993; 56:713–16.
epilepticus precipitated by antiepileptic drugs in idiopathic Tucker GJ, Price TRP, Johnson VB et al. Phenomenology of
generalized epilepsies. Brain 2006; 129:1281–92. temporal lobe dysfunction: a link to atypical psychosis: a
Thompson AJ, Kermode AG, Moseley JF et al. Seizures due to series of cases. J Nerv Ment Dis 1986; 174:348–56.
multiple sclerosis: seven patients with MRI correlations. J Tucker WM, Forster FM. Petit mal epilepsy occurring in status.
Neurol Neurosurg Psychiatry 1993; 56:1317–20. Arch Neurol Psychiatry 1958; 64:823–7.
Thompson GN, Nielsen JM. The organic paranoid syndrome. J Nerv Tukel K, Jasper H. The electroencephalogram in parasaggital
Ment Dis 1949; 110:478–96. lesions. Electroencephalogr Clin Neurophysiol 1952;
Thompson SW, Greenhouse HH. Petit mal status in adults. Ann 4:481–94.
Intern Med 1968; 68:1271–9. Tyler RH. Neurologic disorders in renal failure. Am J Med 1968;
Thomsen IV. Late outcome of very severe blunt head trauma: a 44:734–48.
10–15 year second follow-up. J Neurol Neurosurg Psychiatry Umbricht D, Degreef G, Barr WB et al. Postictal and chronic
1984; 47:260–8. psychoses in patients with temporal lobe epilepsy. Am J
Tinuper P, Provini F, Marini C et al. Partial epilepsy of long Psychiatry 1995; 152:224–31.
duration: changing semiology with age. Epilepsia 1996a; US Gabapentin Study Group. Gabapentin as add-on therapy in
37:162–4. refractory partial epilepsy: a double-blind, placebo-controlled,
Tinuper P, Plazzi G, Provini F et al. Celiac disease, epilepsy, and parallel-group study. Neurology 1993; 43:2292–8.
occipital calcification: histopathological study and clinical Van Rossum J, Groeneveld-Ockhuysen AAW, Arts RJHM.
outcome. J Epilepsy 1996b; 9:206–9. Psychomotor status. Arch Neurol 1985; 42:989–93.
p 07.qxd 3/10/08 9:35 AM Page 330
Varma NK, Lee SI. Nonconvulsive status epilepticus following hemiparesis: a report of four cases. Arch Phys Med Rehabil
electroconvulsive therapy. Neurology 1992; 42:263–4. 1998; 79:1482–3.
Venneri A, Caffarra P. Transient autobiographic amnesia: EEG and Waxman SG, Geschwind M. Hypergraphia in temporal lobe
single-photon emission CT evidence of an organic etiology. epilepsy. Neurology 1974; 24:629–36.
Neurology 1998; 50:186–91. Waxman SG, Geschwind N. The interictal behavior syndrome of
Verny M, Jellinger KA, Hauw J-J et al. Progressive supranuclear temporal lobe epilepsy. Arch Gen Psychiatry 1975; 32:1580–6.
palsy: a clinicopathological study of 21 cases. Acta Weil AA. Depressive reactions associated with temporal
Neuropathologica 1996; 61:427–31. lobe–uncinate seizures. J Nerv Ment Dis 1955; 121:505–10.
Vickrey BG, Bahls FH. Nonconvulsive status epilepticus following Weil AA. Ictal depression and anxiety in temporal lobe disorders.
cerebral angiography. Ann Neurol 1989; 25:199–201. Am J Psychiatry 1956; 113:149–57.
Victor M, Brausch J. The role of abstinence in the genesis of Weil AA. Ictal emotions occurring in temporal lobe dysfunction.
alcohol epilepsy. Epilepsia 1967; 8:1–20. Arch Neurol Psychiatry 1959; 1:101–11.
Victor M, Hope JM. The phenomenon of auditory hallucinations in Weilburg JB, Bear DM, Sachs G. Three patients with concomitant
chronic alcoholism. J Nerv Ment Dis 1958; 126:451–8. panic attacks and seizure disorder: possible clues to the
Videbech T. Chronic olfactory paranoid syndrome. Acta Psychiatr neurology of anxiety. Am J Psychiatry 1987; 144:1053–6.
Scand 1966; 42:183–213. Weiller C, Ringelstein EB, Reiche W et al. The large striatocapsular
Villani F, D’Amico D, Pincherle A et al. Prolonged focal negative infarct: a clinical and pathological entity. Arch Neurol 1990;
motor seizures: a video-EEG study. Epilepsia 2006; 47:1085–91.
47:1949–52. Weinberger J. Simultaneous bilateral focal seizures without loss
Vizioli R, Magliocco EB. A case of prolonged petit mal seizures. of consciousness. Mt Sinai J Med 1973; 40:693–6.
Electroencephalogr Clin Neurophysiol 1953; 5:439–40. Wells CE. Transient ictal psychosis. Arch Gen Psychiatry 1975;
Vollmer TL, Guarnaccia J, Harrington W et al. Idiopathic 32:1201–3.
granulomatous angiitis of the central nervous system: Wharton RM. Grand mal seizures with lithium treatment. Am J
diagnostic challenges. Arch Neurol 1993; 50:925–30. Psychiatry 1969; 125:1446.
Vroom FQ, Greer M. Mercury vapor intoxication. Brain 1972; Wheless JW, Vazquez BR, Kanner AM et al. Rapid infusion with
95:305–18. valproate sodium is well-tolerated in patients with epilepsy.
Vuilleumier P, Chicherio C, Assal F et al. Functional Neurology 2004; 63:1507–8.
neuroanatomical correlates of hysterical sensorimotor loss. Whitfield CL, Ch’ien LT, Whitehead JD. Lead encephalopathy in
Brain 2001; 124:1077–90. adults. Am J Med 1972; 52:289–98.
Wallin WT, Kurtzke JF. Neurocysticercosis in the United States. Whyte J, Hart T, Vaccaro M et al. Effects of methylphenidate on
Review of an important emerging infection. Neurology 2004; attention deficits after traumatic brain injury: a
63:1559–64. multidimensional, randomized, controlled trial. Am J Phys Med
Walczak TS, Rubinsky M. Plantar responses after epileptic Rehabil 2004; 83:401–20.
seizures. Neurology 1994; 44:2191–3. Wiart L, Petit H, Joseph PA et al. Fluoxetine in early poststroke
Walczak TS, Williams DT, Berten W. Utility and reliability of depression: a double-blind placebo-controlled study. Stroke
placebo infusion in the evaluation of patients with seizures. 2000; 31:1829–32.
Neurology 1994; 44:394–9. Wiebe S, Blume WT, Girvin JP et al. A randomized, controlled trial
Walshe FMR. On the mode of representation of movements in the of surgery for temporal-lobe epilepsy. N Engl J Med 2001;
motor cortex, with special reference to ‘convulsions beginning 345:311–18.
unilaterally’ (Jackson). Brain 1943; 66:104–39. Wieser HG. Temporal lobe or psychomotor status epilepticus. A
Walshe JM, Yealland M. Wilson’s disease: the problem of delayed case report. Electroencephalogr Clin Neurophysiol 1980;
diagnosis. J Neurol Neurosurg Psychiatry 1992; 55:692–6. 48:558–72.
Wallach J. Laboratory diagnosis of factitious disorders. Arch Int Wieser HG, Hungerbuhler H, Siegel AM et al. Musicogenic
Med 1994; 154:1690–6. epilepsy: review of the literature and case report with ictal
Walton RG. Seizure and mania after high intake of aspartame. single photon emission computed tomography. Epilepsia 1997;
Psychosomatics 1986; 27:218–20. 38:200–7.
Waltz G, Harik SI, Kaufman B. Adult metachromatic Wijdicks EFM, Plevak DJ, Wiesner RH et al. Course and outcome of
leukodystrophy: value of computed tomographic scanning and seizures in liver transplant patients. Neurology 1996;
magnetic resonance imaging of the brain. Arch Neurol 1987; 47:1523–5.
44:225–7. Wilder-Smith E. Complete atrio-ventricular block during complex
Waltzer H. A psychotic family – folie a douze. J Nerv Ment Dis partial seizure. J Neurol Neurosurg Psychiatry 1992; 55:734–6.
1963; 137:67–75. Wilkinson HA. Epileptic pain. An uncommon manifestation with
Warner TT, Williams LD, Walker RWH et al. A clinical and localizing value. Neurology 1973; 23:518–20.
molecular genetic study of dentatorubropallidoluysian atrophy Williams BB, Lerner AM. Some previously unrecognized features
in four European families. Ann Neurol 1995; 37:452–9. of herpes simplex encephalitis. Neurology 1978; 28:1193–6.
Watanabe TK, O’Dell MW, Togliatti TJ. Diagnosis and Williams D. The structure of emotions reflected in epileptic
rehabilitation strategies for patients with hysterical experiences. Brain 1956; 79:29–67.
p 07.qxd 3/10/08 9:35 AM Page 331
References 331
Williamson PD, Spencer SS. Clinical and EEG features of complex tomography, at the time of emergency room admission, in
partial seizures of extratemporal origin. Epilepsia 1986; acute stroke patients. Ann Neurol 2002b; 51:417–32.
27(suppl. 2):46–63. Wisniewski KE, Frency JH, Fernando S et al. Fragile X syndrome:
Williamson PD, Spencer DD, Spencer SS et al. Episodic aphemia associated neurological abnormalities and developmental
and epileptic focus in the nondominant hemisphere: relieved disabilities. Ann Neurol 1985; 18:665–9.
by section of the corpus callosum. Neurology 1985a; Wojner-Alexandrov AW, Garami Z, Chernyshev OY et al. Heads
35:1069–71. down. Flat positioning improves blood flow velocity in acute
Williamson PD, Spencer DD, Spencer SS et al. Complex partial ischemic stroke. Neurology 2005; 64:1354–7.
status epilepticus: a depth-electrode study. Ann Neurol 1985b; Worrell GA, Sencakova D, Jack CR et al. Rapidly progressive
18:647–54. hippocampal atrophy: evidence for a seizure-induced
Williamson PD, Spencer DD, Spencer SS et al. Complex partial mechanism. Neurology 2002; 58:1553–6.
seizures of frontal lobe origin. Ann Neurol 1985c; Wroblewski BA, McColgan K, Smith K et al. The incidence of
18:497–504. seizures during tricyclic antidepressant drug treatment in a
Williamson PD, Thadani VM, Darcey TM et al. Occipital lobe brain-injured population. J Clin Psychopharmacol 1990;
epilepsy: clinical characteristics, seizure spread patterns, and 10:124–8.
results of surgery. Ann Neurol 1992a; 31:3–13. Wroblewski BA, Joseph AB, Cornbatt RR. Antidepressant
Williamson PD, Boon PA, Thadani VM et al. Parietal lobe epilepsy: pharmacotherapy and the treatment of depression in patients
diagnostic considerations and results of surgery. Ann Neurol with severe traumatic brain injury: a controlled, prospective
1992b; 31:193–201. study. J Clin Psychiatry 1996; 57:582–7.
Williamson PD, French JA, Thadani VM et al. Characteristics of Wroblewski BA, Joseph AB, Kupfer J et al. Effectiveness of
medial temporal lobe epilepsy. II. Interictal and ictal scalp valproic acid on destructive and aggressive behaviors in
electroencephalography, neuropsychological testing, patients with acquired brain injury. Brain Inj 1997;
neuroimaging, surgical results, and pathology. Ann Neurol 11:37–47.
1993; 34:781–7. Wyllie E, Luders H, MacMillan JP et al. Serum prolactin levels
Williamson RT. On the symptomatology of gross lesions (tumours after epileptic seizures. Neurology 1984; 34:1601–3.
and abscesses) involving the pre-frontal regions of the brain. Yadav JS, Wholex MH, Kuntz RE et al. Protected carotid artery
Brain 1896; 19:346–65. stenting versus endarterectomy in high-risk patients. N Engl J
Willmore LJ, Shu V, Wallin B. Efficacy and safety of add-on Med 2004; 351:1493–1501.
divalproex sodium in the treatment of complex partial Yamada H, Yoshida H. Laughing attack: a review and
seizures. Neurology 1996; 46:49–53. report of nine cases. Folia Psychiatr Neurol Japonica 1977;
Willoughby JO, Pope KJ, Eaton V. Nicotine as an antiepileptic 31:129–37.
agent in ADNFLE: an N-of-one study. Epilepsia 2003; Yen D-J, Su M-S, Shih Y-H et al. Ictal speech manifestations in
44:1238–40. temporal lobe epilepsy: a video-EEG study. Epilepsia 1996;
Wilson LG. Viral encephalopathy mimicking functional psychosis. 37:45–9.
Am J Psychiatry 1976; 133:165–70. Yenjun S, harvey AS, Marini C et al. EEG in adult-onset idiopathic
Wilson P, Preece AA. Chorea gravidarum. Arch Intern Med 1932; generalized epilepsy. Epilepsia 2003; 44:252–6.
49:671–97. York GK, Gabor AJ, Dreyfuss PM. Paroxysmal genital pain: an
Wilson SAK. Progressive lenticular degeneration: a familial unusual manifestation of epilepsy. Neurology 1979;
nervous disease associated with cirrhosis of the liver. Brain 29:516–19.
1912; 34:295–509. Young GB, Blume WT. Painful epileptic seizures. Brain 1983;
Wilson SAK. Nervous semiology, with special reference to 106:537–44.
epilepsy. BMJ 1930; 2:50–4. Young GB, Blume WT. Painful epileptic seizures involving the
Wilson WH, Claussen AM. Seizures associated with clozapine secondary sensory area. Ann Neurol 1986; 19:412.
treatment in a state hospital. J Clin Psychiatry 1994; Zak R, Solomon G, Petito F et al. Baclofen-induced generalized
55:184–8. nonconvulsive status epilepticus. Ann Neurol 1994;
Winawer MR, Ottman R, Hauser A et al. Autosomal dominant 36:113–14.
partial epilepsy with auditory features: defining the Zappoli R. Two cases of prolonged twilight state with almost
phenotype. Neurology 2000; 54:2173–6. continuous ‘wave-spikes’. Electroencephalogr Clin
Winokur G. Delusional disorder (paranoia). Compr Psychiatry Neurophysiol 1955; 7:421–3.
1977; 18:511–21. Zarling EJ. Abdominal epilepsy: an unusual cause of recurrent
Wintermark M, Reichart M, Cuisenaire O et al. Comparison of abdominal pain. Am J Gastroenterol 1984; 79:687–8.
admission perfusion computed tomography and qualitative Zeidler M, Johnstone EC, Bamber RWK et al. New variant
diffusion- and perfusion weighted magnetic resonance Creutzfeldt–Jakob disease: psychiatric features. Lancet 1997a;
imaging in acute stroke patients. Stroke 2002a; 350:908–10.
33:2025–31. Zeidler M, Stewart GE, Barraclough CR et al. New variant
Wintermark M, Reichart M, Thiran J-P et al. Prognostic accuracy Creutzfeldt–Jakob disease: neurological features and
of cerebral blood flow measurement by perfusion computed diagnostic tests. Lancet 1997b; 350:903–7.
p 07.qxd 3/10/08 9:35 AM Page 332
Zeilig G, Drubach DA, Katz-Zeilig M et al. Pathological laughter Zentner J, Hufnagel A, Wolf HK et al. Surgical treatment of
and crying in patients with closed traumatic brain injury. temporal lobe epilepsy: clinical, radiological, and
Brain Inj 1996; 10:591–7. histopathological findings in 178 patients. J Neurol Neurosurg
Zeman A, Stone J, Porteous M et al. Spinocerebellar ataxia type 8 Psychiatry 1995; 58:666–73.
in Scotland: genetic and clinical features in seven unrelated Zhang L, Plotkin RC, Wang G et al. Cholinergic augmentation with
cases and a review of published reports. J Neurol Neurosurg donepezil enhances recovery in short-term memory and
Psychiatry 2004; 75:459–65. sustained attention after traumatic brain injury. Arch Phys
Zeman AZJ, Boniface SJ, Hodges JR. Transient epileptic amnesia: a Med Rehabil 2004; 85:1050–5.
description of the clinical and neuropsychological features in Zifko U, Lindner K, Wimberger D et al. Jarisch–Herxheimer
10 cases and a review of the literature. J Neurol Neurosurg reaction in a patient with neurosyphilis. J Neurol Neurosurg
Zeng S, Kim CH, Rahman H. Psychotic symptoms presented in van Zomeren AH, van den Berg W. Residual complaints of patients
familial Creutzfeldt-Jakob disease, subtype E200K. J Clin two years after severe head injury. J Neurol Neurosurg
Psychiatry 2001; 62:735. Psychiatry 1985; 48:21–8.
p 08.qxd 3/10/08 9:38 AM Page 333
PART III
SPECIFIC DISORDERS
8 Neurodegenerative and movement disorders 335 15 Prion diseases 525

9 Congenital , developmental, and other 16 Endocrinologic disorders 534
childhood-onset disorders 403 17 Immune-related disorders 544
10 Vascular disorders 433 18 Sleep disorders 569
11 Trauma 454 19 Brain tumors and hydrocephalus 596
12 Hypoxic disorders 462 20 Idiopathic psychotic, mood, and anxiety disorders 606
13 Nutritional, toxic and metabolic disorders 466 21 Substance use disorders 656
14 Infectious and related disorders 493 22 Medication and substance-induced disorders 683
p 08.qxd 3/15/08 4:37 PM Page 335
8
Neurodegenerative and movement disorders
8.1 Alzheimer’s disease 335 8.18 Pantothenate kinase-associated neurodegeneration 364

8.2 Pick’s disease 340 8.19 Dopa-responsive dystonia 365
8.3 Frontotemporal dementia 341 8.20 Primary torsion dystonia 366
8.4 Amyotrophic lateral sclerosis 342 8.21 Idiopathic cervical dystonia 366
8.5 Parkinson’s disease 344 8.22 Task-specific dystonia 367
8.6 Diffuse Lewy body disease 350 8.23 Meige’s syndrome 368
8.7 Progressive supranuclear palsy 352 8.24 Spasmodic dysphonia 368
8.8 Corticobasal ganglionic degeneration 354 8.25 Tourette’s syndrome 369
8.9 Multiple system atrophy 354 8.26 Myotonic muscular dystrophy 371
8.10 Huntington’s disease 356 8.27 Cerebrotendinous xanthomatosis 373
8.11 Choreoacanthocytosis 358 8.28 Thalamic degeneration 374
8.12 FXTAs 358 8.29 Metachromatic leukodystrophy 374
8.13 Senile chorea 359 8.30 Adrenoleukodystrophy 376
8.14 Benign hereditary chorea 360 8.31 Kufs’ disease 377
8.15 Dentatorubropallidoluysian atrophy 360 8.32 Essential tremor 377
8.16 Wilson’s disease 361 8.33 Hyperekplexia 378
8.17 Spinocerebellar ataxia 362 References 379
8.1 ALZHEIMER’S DISEASE Clinical features

Alzheimer’s disease is the most common cause of dementia Although onsets in early adulthood may occur, the vast
in the elderly, accounting for about one-half of all cases in majority of cases present gradually and insidiously past the
this age group. The prevalence of Alzheimer’s disease age of 50 years. In the vast majority of cases, the presenta-
increases with age: in those under 65 years approximately tion is with a progressively worsening amnesia; in most of
1 percent will be affected, whereas in those aged 65 years these cases, the amnesia is joined by a gradually progressive
some 5–10 percent will have the disease, and in those 85 personality change.
years or older the prevalence rises to 20–40 percent. With amnesia as the presenting feature, patients gradu-
Women are slightly more likely to be affected than men. ally become more and more forgetful (Bowler et al. 1997;
The first known case of this disease occurred in a 51-year- Didic et al. 1998; Linn et al. 1995): the location of keys, wal-
old woman, Auguste D, who was initially seen by lets, or purses is forgotten, and patients may have difficulty
Alois Alzheimer in 1901 at the Frankfurt State Asylum. recollecting what has happened earlier in the day; eventu-
Alzheimer subsequently moved to Munich to work with ally, disorientation to time and place occur. Over time, as
Kraepelin and, after Auguste D died, he presented his find- this anterograde component of the amnesia grows more
ings on 3 November 1906 at the 37th annual meeting of the profound, it is typically joined by a progressively worsen-
Southwest German Psychiatrists in Tubingen; these finding retrograde component: patients may forget where they
ings were published in 1907 (Alzheimer 1907). Alzheimer have worked, the names of their children, the fact that they
himself was diffident about lending his name to the dis- have been married, where they went to high school, etc.
ease, and it was only at the urging of Kraepelin that he The fact that the amnesia is of the declarative or ‘episodic’
agreed, thus giving us now the most famous of all medical form, rather than the ‘procedural’ type, can make for some
eponyms (Amaducci et al. 1986; Maurer et al. 1997). startling contrasts in the clinical picture. Thus, profoundly
p 08.qxd 3/10/08 9:38 AM Page 336
336 Neurodegenerative and movement disorders
amnestic patients may still ‘remember’ how to play card in from 10 percent (Mega et al. 1996) to 35 percent (Klatka
games or musical instruments (Beatty et al. 1994). For et al. 1996) of patients and are more commonly visual than
example, one patient (Crystal et al. 1989), a professional auditory (Burns et al. 1990b; Forstl et al. 1993; Ropacki and
musician, although unable to remember the names of var- Jeste 2005). Delusions are found in from 16 percent (Burns
ious musical pieces or their composers, was nevertheless et al. 1990c) to 53 percent (Klatka et al. 1996). Common
still able to play Beethoven’s fifth symphony flawlessly on delusional themes (Binetti et al. 1993; Burns et al. 1990c;
the piano. Devanand et al. 1997; Forstl et al. 1993; Hirono et al. 1998)
Personality change may take various forms: apathy, include misidentification, theft, the Capgras phenomenon,
indifference, and withdrawal are most common. Patients and the phantom boarder. Patients may misidentify other
may also develop a frontal lobe syndrome, with coarseness, people and sometimes their own homes. They may insist
impulsivity, and disinhibition (Mega et al. 1996; Petry et al. that things have been stolen or taken from them, and
1988). they may be terrified that family members are actually
Rarely, Alzheimer’s disease may present with an aphasia imposters who have come to annoy or torment them;
that may be expressive or, much less commonly, receptive, some may insist that someone, perhaps someone malevo-
which gradually worsens as dementia supervenes (Clark lent, is in fact hiding in the house, perhaps in the attic or
et al. 2003; Galton et al. 2000; Green et al. 1990; Greene the cellar. In some cases, misidentification may be quite
et al. 1996; Karbe et al. 1993; Knibb et al. 2006). Even more remarkable, and patients may insist that their own reflec-
rarely, the presentation may be with a gradually worsening tion in the mirror is in fact not them (Forstl et al. 1993).
apraxia (Ross et al. 1996). Interestingly, although it is very rare for Alzheimer’s dis-
With gradual progression, further cognitive deficits ease to present with psychosis, this was in fact the presen-
accrue to eventually complete the clinical syndrome of tation in Alzheimer’s first patient, Auguste D, who
dementia. Attempts have been made to subdivide the presented, at the age of 51 years, with a delusion of jealousy
course of the dementia of Alzheimer’s disease into various regarding her husband (Maurer et al. 1997; Wilkins and
stages, such as ‘mild’, ‘moderate’, and ‘severe’ and, although Brody 1969a).
this has some merit, it must be kept in mind that there Other symptoms may appear as the dementia pro-
is substantial overlap among these stages. The mild stage gresses, including ‘frontal release’ signs (such as snout and
is characterized primarily by cognitive deficits: in addition grasp reflexes), astereognosis, and agraphesthesia (Huff
to the amnesia, one also finds a decrease in abstracting and et al. 1987). Anosognosia is seen in a minority early on, but
calculating abilities; there is also often a degree of anomia becomes common with disease progression (Starkstein
and apraxia. In the moderate stage, cognitive ability deteri- et al. 1997). Parkinsonism may be seen late in the course in
orates further and speech may deteriorate into a fluent a minority of cases, being typically characterized by rigidity
aphasia (Faber-Langendoen et al. 1988; Price et al. 1993). In and bradykinesia, with tremor being relatively rare (Clark
the severe stage there is a profound cognitive deficit, and et al. 1997; Scarmeas et al. 2004). Seizures may also occur
patients are often totally dependent on others for their care; in a small minority (Amatniek et al. 2006; Goodman 1953);
mutism may occur, or there may be echolalia or palilalia. these tend to be grand mal and occur late in the course of
In addition to cognitive deficits most patients will also the disease (Romanelli et al. 1990). Very late in the course,
develop mood changes and psychotic symptoms, generally a minority may also have myoclonus (Benesch et al. 1993;
during the moderate stage. Mood changes may include Chen et al. 1991; Faden and Townsend 1976). Other possi-
depression, apathy, anxiety and irritability, agitation, and ble symptoms include emotional incontinence (Starkstein
euphoria (Mega et al. 1996). Depressive symptoms are fairly et al. 1995), the Kluver–Bucy syndrome (Lilly et al. 1983),
common, with prevalence figures noted of 14 percent and, very rarely, hemiparesis (Jagust et al. 1990).
(Klatka et al. 1996), 24 percent (Burns et al. 1990a) and 52 Magnetic resonance imaging (MRI) and computed
percent (Starkstein et al. 2005), and these symptoms tend to tomography (CT) scanning reveal cortical atrophy and ven-
persist over a long follow-up period (Starkstein et al. 1997). tricular dilation. Early on in the course, the degree of this
The severity of the depression varies from mild to that change may still be within the broadly defined limits of nor-
encountered in the depressive episodes of a major depres- mal for the elderly population, but with progression, the
sion (Migliorelli et al. 1995). Apathy may accompany changes become quite pronounced, as illustrated in Figures
depression, but it may also be seen in a pure form in roughly 8.1 and 8.2. The electroencephalogram is typically normal
one-third of all patients (Starkstein et al. 2006). Anxiety and in mild disease; however, with progression generalized
irritability are about as common as depression, being found theta, and eventually delta, slowing appears. Although rou-
in a little less than one-half of patients (Litvan et al. 1996a; tine cerebrospinal fluid (CSF) studies are normal, measure-
Mega et al. 1996). Agitation is very common, found in over ment of CSF beta-amyloid and tau protein may be of
one-half of patients (Lopez et al. 2003). Euphoria, by con- diagnostic import. As noted below, Alzheimer’s disease is
trast, is uncommon, being found in from 4 percent (Burns characterized pathologically by neuritic plaques composed
et al. 1990a) to 8 percent (Mega et al. 1996) of cases. of an amyloid core, and by neurofibrillary tangles com-
Psychotic symptoms include hallucinations, either posed of hyperphosphorylated tau protein. CSF studies
visual or auditory, and delusions. Hallucinations are noted have demonstrated both a decreased level of beta-amyloid
p 08.qxd 3/10/08 9:38 AM Page 337
Course
Although a small minority of patients may experience tem-
porary plateaus, Alzheimer’s disease, for the most part, is
relentlessly and steadily progressive, death occurring for
most within 5–15 years. At the end, patients are vegetative,
bedfast, and incontinent. Although it is generally held that
cases with an early onset, before the age of 65 years, tend to
run a more rapid course (Koss et al. 1996), not all studies
agree on this (Bracco et al. 1994).
Etiology
Macroscopically, as illustrated in Figure 8.1, there is wide-

Figure 8.1 Note the relative sparing of the pre- and post- spread cortical atrophy affecting primarily the temporal,
central gyri compared with the rest of the cortex in this case of parietal, and frontal lobes, with prominent sparing of the
Alzheimer’s disease. (Reproduced from Rees et al. 1996.) pre- and post-central gyri; relative to the other lobes the
occipital lobe is less affected. Within the temporal lobe,
the hippocampus (as illustrated in Figure 8.2) and amyg-
dala are also very prominently involved. Subcortical and
brainstem nuclei, including the nucleus basalis of Meynert
(especially its cholinergic neurons) (Whitehouse et al.
1981), the locus ceruleus (Mann et al. 1984), and the dor-
sal raphe nucleus (Yamamoto and Hirano 1985), also
undergo significant damage.
Microscopically (Kidd 1964) there are widespread neu-
rofibrillary tangles and neuritic plaques (also known as
senile plaques) accompanied by neuronal loss (Terry et al.
1981). Neurofibrillary tangles are fibrillar structures found
in the neuronal cytoplasm that, by electron microscopy,
are seen to be composed of paired helical filaments. These
paired helical filaments are composed of hyperphosphory-
lated tau proteins, which are one of the microtubule-asso-
ciated proteins (MAP) that ensure the integrity and
stability of the cellular microtubules. Neuritic plaques are
spherical extracellular structures composed of an amyloid
Figure 8.2 This T1-weighted magnetic resonance imaging scan core surrounded by ‘neurites’, or swollen axonal frag-
demonstrates the cortical atrophy and ventricular dilation found ments. The amyloid core of the neuritic plaque is com-
in advanced Alzheimer’s disease. Note in particular that the posed primarily of beta-amyloid.
hippocampus, indicated by the arrows, has shrunk down to a thin Interestingly, although the clinical severity of Alzheimer’s
remnant. (Reproduced from Gillespie and Jackson 2000.) disease correlates with the number of neurofibrillary
tangles, there is little correlation with the number of neu-
ritic plaques (Arriagada et al. 1992; Bierer et al. 1995).
Furthermore, it appears that, in general, there is an
and an increased level of tau protein (Andreasen et al. 2001; orderly appearance of neurofibrillary tangles during the
Galasko et al. 1998; Hampel et al. 2004), and a recent course of the disease, beginning first in the transentorhinal
autopsy study demonstrated a good correlation between cortex and then progressing sequentially to the entorhinal
CSF levels of tau protein and the burden of neurofibrillary cortex, hippocampus, temporal cortex, parietal and pre-
tangles (Buerger et al. 2006). frontal cortex, and finally all neocortical areas (Braak
Although single photon emission computed tomogra- and Braak 1991; Delacourte et al. 1999). This progression
phy (SPECT) scanning may show areas of decreased activ- appears to supply a pathologic underpinning to the
ity in association with neocortical areas, this technique is evolution of clinical features noted above, in that damage
probably not appropriate for routine clinical work as in an to medial temporal structures would be expected to
autopsy control study (McNeill et al. 2007) it added little to cause an amnesia, whereas later damage to cortical areas
diagnostic accuracy over and above a good history and would account for the appearance of further cognitive
examination. deficits.
p 08.qxd 3/10/08 9:38 AM Page 338
In addition, there appears to be a correlation between plaques remain unclear. One current hypothesis (the ‘amy-
the depth of the memory loss in Alzheimer’s disease and loid cascade hypothesis’) focuses on the neurotoxicity of
the extent of damage in the cholinergic nucleus basalis of one form of beta-amyloid, the 42-amino acid form. APP is
Meynert (Neary et al. 1986; Rasool et al. 1986; Whitehouse a transmembrane protein that is normally cleaved by sev-
et al. 1982). There is also a correlation between depression eral secretases, namely alpha, beta, and gamma secretase.
and cell loss in the superior central nucleus (Zweig et al. Depending on which secretases are involved, different
1988) and probably the locus ceruleus (Zubenko and fragments are produced; when cleavage is via beta and then
Moosy 1988; Zweig et al. 1988), although not all have repli- gamma secretase it appears that two forms of beta-amyloid
cated this finding (Hoogendijk et al. 1999). are produced, a 40-amino acid form and a 42-amino acid
Much progress has been made in the search for the etiol- form. The 42-amino acid form of beta-amyloid is relatively
ogy of Alzheimer’s disease, especially with regard to genetic insoluble and undergoes fibrillization to form what are
factors. In a small minority of cases, probably less than 1 per- known as ‘diffuse’ plaques. These diffuse plaques prompt
cent, especially those of early onset before the age of 50 years, an inflammatory response and are neurotoxic; according
Alzheimer’s disease is clearly inherited in an autosomal to the theory, this neurotoxicity leads both to the break-
dominant fashion. Mutations have been identified in three down of axons, thus creating neurites that surround the
genes (Janssen et al. 2003): the APP (amyloid precursor pro- ‘diffuse’ plaques, thereby creating classic neuritic plaques,
tein) gene on chromosome 21 (Brouwers et al. 2006; and to the formation of neurofibrillary proteins in surviv-
Chartier-Harlin et al. 1991), the presenilin-1 gene on chro- ing neurons. This amyloid cascade hypothesis gains sup-
mosome 14 (Bird et al. 1996; Wasco et al. 1995), and the port from several quarters. First, it is well known that
presenilin-2 gene on chromosome 1 (Levy-Lahad et al. 1995). patients with Down’s syndrome, should they survive past
The role of genetic factors in the remaining vast majority of the age of 40 years, almost always develop Alzheimer’s dis-
cases of apparently sporadic Alzheimer’s disease is not clear. ease (Evenhuius 1990; Jervis 1948; Lai and Williams 1989;
Some (Bergem et al. 1997; Breitner et al. 1995; Gatz et al. Olson and Shaw 1969). Down’s syndrome occurs second-
1997), but not all (Cook et al. 1981), studies support a higher ary to an extra chromosome 21, with a consequent extra
concordance among monozygotic than dizygotic twins. gene for APP; this leads in turn to an overproduction of
Likewise, whereas some studies indicate a higher prevalence APP, which would ‘start’ the amyloid cascade going from
of Alzheimer’s disease among the first-degree relatives of the top. Second, as noted earlier, there are rare inherited
probands than among the equivalent relatives of controls, cases of Alzheimer’s disease that are caused by mutations
others do not. One of the reasons for these discordant results in the gene for APP, which, again, could start the cascade
might be that, although Alzheimer’s disease may be inher- going. Third, it appears that presenilin interacts with
ited, there is such great intrafamily variability in the age of its gamma secretase and, as noted earlier, there are also rare
expression that most cases among relatives are missed in inherited forms of Alzheimer’s disease that occur second-
cross-sectional studies. Life-table studies support this ary to mutations in the genes for presenilin-1 or -2; con-
notion; indeed, studies using the life-table approach have ceivably, if these mutations lead to an increased activity of
found that the projected risk among first-degree relatives is gamma secretase, this would lead to an overproduction of
approximately 50 percent (Mohs et al. 1987), just what beta-amyloid, specifically of the neurotoxic 42-amino acid
would be expected if sporadic Alzheimer’s disease was, in form. Finally, it also appears that the epsilon-4 form of
fact, an autosomal dominant disorder. apolipoprotein E increases the rate of beta-amyloid pro-
Another gene associated with Alzheimer’s disease is that duction. Although taken together these considerations
for apolipoprotein E on chromosome 19. Apolipoprotein lend considerable weight to the ‘amyloid cascade’ hypoth-
E occurs in several forms, depending on which alleles are esis, it should be borne in mind that the hypothesis
present – epsilon-2, epsilon-3, or epsilon-4 – and there is a remains simply that, an hypothesis, and as yet has not
correlation between which alleles are present and the risk been proven.
of Alzheimer’s disease. Thus, the risk for patients with one
or two of the epsilon-4 alleles is substantially higher
(Corder et al. 1993; Saunders et al. 1993) than that for Differential diagnosis
patients who lack this allele. Importantly, the presence of
the epsilon-4 allele is merely a ‘risk factor’: patients with- As noted above, the typical presentation of Alzheimer’s
out this allele can and do get the disease and, conversely, disease is characterized by the gradual onset of amnesia,
those with it may never develop Alzheimer’s. with a subsequent accrual of other cognitive deficits; a per-
In contrast to these positive results in genetic studies, sonality change may occur, but usually only after cognitive
efforts to identify environmental causes have generally been deficits have become prominent, and, at least in the mild
unsuccessful, with possibly one exception: it does appear stage of the disease, there are few distinctive features. The
that a history of significant head trauma may increase the differential diagnosis for such a dementia of gradual onset,
risk of Alzheimer’s disease (Schofield et al. 1997). lacking in distinctive features, as detailed in Section 5.1 and
The actual mechanism or mechanisms responsible for Table 5.1, is fairly wide, but certain considerations enable
the formation of neurofibrillary tangles and neuritic one to narrow it down.
p 08.qxd 3/10/08 9:38 AM Page 339
Diffuse Lewy body disease may present in a similar fash- that may reduce the risk of getting the disease or reduce
ion, but, within the first year, one sees several features that symptoms.
are not typical for early Alzheimer’s disease, namely Agents that may reduce the risk of the disease include
parkinsonism, visual hallucinations, and spontaneous con- non-steroidal anti-inflammatory drugs and, possibly,
fusional episodes. estrogen replacement therapy. With regard to the use of
Binswanger’s disease and lacunar dementia may be sug- non-steroidal anti-inflammatory drugs (primarily ibupro-
gested by a history of stroke; however, this may at times be fen), several epidemiologic studies have suggested a
absent, especially in the case of Binswanger’s disease. decreased risk with chronic use (Aisen and Davis 1994;
Magnetic resonance scanning, however, will typically in t’ Veld et al. 2001; MacKenzie and Munoz 1998;
resolve the issue, revealing severe white matter disease in McGeer et al. 1996; Stewart et al. 1997). With regard to
the case of Binswanger’s disease, and a dozen or more sub- estrogens, some (Scooter et al. 1999; Tang et al. 1996;
cortical infarcts in the case of lacunar dementia. Multi- Zandi et al. 2002), but not all (Roberts et al. 2006; Seshadri
infarct dementia is often listed in the differential at this et al. 2001), studies suggest that, in post-menopasual
point, but this entity is always characterized by a history of women, estrogen replacement therapy may also reduce the
stroke, typically multiple strokes, and either CT or MRI risk. It is not clear whether, and to whom, these treatments
will reveal appropriately placed lesions. should be recommended, if at all; certainly in the case of
Pick’s disease and frontotemporal dementia both typi- ibuprofen, the risks may well outweigh any putative
cally present with a personality change, which dominates benefits. Pending prospective studies it might,
the clinical picture for a long time before cognitive deficits however, be reasonable to discuss them with patients who
appear; as noted earlier, although a personality change may are at high risk, such as those with a family history of
occur in Alzheimer’s disease, this typically has an onset Alzheimer’s disease or those with two epsilon-4 alleles of
only after cognitive deficits are well established. apolipoprotein E.
Tumors of the frontal lobes, corpus callosum, or dien- Agents capable of causing a modest symptomatic
cephalon may be considered, but are immediately revealed improvement include the acetylcholinesterase inhibitors
by imaging. donepezil (Feldman et al. 2001; Greenberg et al. 2000;
Cerebral amyloid angiopathy, although typically pre- Rogers and Friedhoff 1996; Rogers et al. 1998), rivastigmine
senting with lobar intracerebral hemorrhage, may, at (Rosler et al. 1999), and galantamine (Rockwood et al.
times, present with a gradually progressive dementia due 2001). As noted above, there is a correlation between the
to miliary microbleeds. The differential in such cases may loss of cholinergic neurons in the nucleus basalis of
depend on performing MR scanning with gradient recall Meynert and memory loss, and it is probably by partly
imaging to detect these lesions. restoring cholinergic tone that the acetylcholinesterase
Vitamin B12 and folate deficiency may be clinically inhibitors exert their therapeutic effect. Another agent to
indistinguishable from Alzheimer’s disease, and, although consider is the N-methyl-D-aspartic acid (NMDA) antago-
these are uncommon, they should always be tested for, nist memantine (Cummings et al. 2006), which may be
given their eminent treatability. used either alone or, more commonly, as an ‘add-on’ drug
Depression in the elderly may manifest with prominent to one of the cholinesterase inhibitors, such as donepezil.
cognitive deficits and thus enters the differential. Clinical Importantly, with treatment with a cholinesterase inhibitor
features suggestive of this include the following: a history or memantine, one sees not only some cognitive improve-
of typical depressive symptoms predating the onset of cog- ment but also some improvement in other clinical features,
nitive deficits; a history of prior episodes of depression; such as mood changes and, in some cases, delusions or hal-
and, on mental status examination, a lack of effort on the lucinations. Finally, some studies suggest benefit from
patient’s part in attempting cognitive tasks. As noted ear- D-cycloserine (Schwartz et al. 1996; Tsai et al. 1999), and
lier, Alzheimer’s disease itself may cause depression; how- some (Le et al. 1997; Mazza et al. 2006; Oken et al. 1998),
ever, in contrast to the dementia syndrome of depression, but not all (Schneider et al. 2005), also suggest benefit from
the depression seen in Alzheimer’s disease occurs not Ginkgo biloba. The optimum strategy with regard to these
before the onset of cognitive failure but only well after cog- medications has not as yet been established. In my opinion
nitive deficits have been thoroughly established. In cases in it is reasonable to begin with a cholinesterase inhibitor, for
which a reliable history is lacking it is appropriate to example donepezil, and then monitor for a matter of
attempt a ‘diagnosis by treatment response’ and to pre- months; if there has been some improvement but, as is usu-
scribe an antidepressant and then observe the course of ally the case, there is room for further improvement,
both the depressive and cognitive symptoms. memantine may then be added. The place of d-cycloserine
and Gingko biloba has simply not been elucidated; however,
during a time of relative clinical stability, one may consider
Treatment adding one of these.
Other symptoms that may respond to pharmacologic
In addition to the routine environmental measures discussed treatment include depression, insomnia, apathy, agitation,
in Section 5.1, certain medications may be considered and delusions and hallucinations. Depression may respond
p 08.qxd 3/10/08 9:38 AM Page 340
to treatment with an antidepressant, and a selective sero- Clinical features

tonin reuptake inhibitor (SSRI; e.g., escitalopram), given
their tolerability, should receive consideration. Insomnia The onset is gradual and insidious, typically occurring in
may, of course, be part of a depressive syndrome and, as the fourth through the seventh decades; onsets as young as
such, may eventually respond to treatment with an antide- 21 (Lowenberg et al. 1939) or 25 (Coleman et al. 2002)
pressant; in cases in which a hypnotic is required, consid- years of age have, however, been noted. In most cases, the
eration may be given to melatonin or zolpidem. Apathy presentation is with a personality change, typically of the
in Alzheimer’s disease, as discussed in Section 6.2, may frontal lobe type, with disinhibition, coarsening of behav-
respond to methylphenidate. Agitation, as discussed in ior, and perseveration (Bouton 1940; Ferraro and Jervis
Section 6.4, may respond to risperidone or olanzapine; in 1936; Litvan et al. 1997a; Mendez et al. 1993; Munoz et al.
my opinion it is reasonable to begin with a low dose of 1993; Munoz-Garcia and Ludwin 1984; Nichols and
risperidone (e.g., 0.25–0.5 mg/day) and to titrate it slowly Weigner 1938); elements of the Kluver–Bucy syndrome,
and carefully. Although quetiapine has been associated such as hyperorality and hypersexuality, are also common
with sedation, in my experience this agent, if started at a (Cummings and Duchen 1981; Mendez et al. 1993; Munoz
low dose (e.g., 6.25–12.5 mg) and titrated very carefully, et al. 1993; Munoz-Garcia and Ludwin 1984). Some
may be extremely useful. With regard to the use of patients may also be prone to restless wandering; however,
antipsychotics, concern has been raised that they may in contrast to patients with Alzheimer’s disease, who tend
accelerate cognitive decline; however, at least in the case to wander off and get lost, patients with Pick’s disease tend
of risperidone, this does not appear to be the case to get back to their starting point (Mendez et al. 1993;
(Livingston et al. 2007). Carbamazepine, as pointed out in Munoz et al. 1993). Eventually, cognitive deficits appear,
Section 6.4, is also effective for agitation, although the side- such as short-term memory loss, concreteness, and diffi-
effect burden of this agent may give one pause. Delusions culty with calculations; in many cases an aphasia, typically
and hallucinations, whether accompanied by agitation or of the expressive type, will supervene, and, in a small
not, may respond to the same antipsychotics as used for minority, seizures may occur.
agitation; however, as with all symptoms, one must be Rarely, Pick’s disease may present with a slowly progres-
sure that these delusions or hallucinations are sufficiently sive aphasia (Graff-Radford et al. 1990; Kertesz et al. 1994;
troubling to warrant the risk attendant on the use of Knibb et al. 2006; Wechsler et al. 1982), amnesia (Wisniewski
antipsychotics. et al. 1972), or apraxia (Fukui et al. 1996).
Computed tomography or MR scanning reveals lobar
atrophy (Knopman et al. 1989; Wechsler et al. 1982), typi-
cally affecting the frontal and anterior temporal lobes; in
8.2 PICK’S DISEASE some cases the atrophy is so severe as to present a ‘knife-
blade’ appearance.
Pick’s disease, first described by the neuropsychiatrist
Arnold Pick in 1892 (Pick 1892), is a rare cause of demen-
tia in which the dementia is distinguished by its presenta- Course
tion with a personality change of the frontal lobe type or by
a more or less complete Kluver–Bucy syndrome; it is prob- Pick’s disease is relentlessly progressive, leading to a pro-
ably equally common in men and women. found dementia with death within 5–10 years (Robertson
Before proceeding with this discussion, it is necessary to et al. 1958), generally from an intercurrent pneumonia.
mention nomenclature. Pick’s disease has been well-
described, both clinically and pathologically, for about a
century. More recently it has become apparent that a fairly Etiology
large number of different pathologic entities may cause a
similar clinical picture, and some authors have recom- Pick’s disease is an example of ‘lobar’ atrophy, with the
mended grouping all of these disorders together with frontal and temporal lobes bearing the brunt of the disease
Pick’s disease, with different authors suggesting different process. Interestingly, even when the temporal lobes are
names for the resulting collection: some have proposed the very hard hit, the posterior two-thirds of the superior tem-
term ‘Pick complex’, whereas others favor ‘frontotemporal poral gyrus is generally spared, often to a remarkable
dementia’. In this area of uncertain nomenclature, it is my degree, as illustrated in Figure 8.3. Although in most cases
opinion that we should preserve Pick’s disease as an inde- both the frontal and the temporal lobes are clearly affected,
pendent entity while leaving these newer disorders with in a minority only one lobe will be macroscopically abnor-
similar clinical presentations provisionally grouped under mal (Sjorgen et al. 1952). Microscopically one sees wide-
the rubric of frontotemporal dementia until, with further spread neuronal loss and gliosis. Pick cells (large, ballooned
work, they become clearly differentiated, both clinically neurons) and Pick bodies (rounded or oval argentophilic
and pathologically, at which time they may be regarded as intracytoplasmic inclusions) may be seen in affected areas;
independent entities on their own. the Pick bodies are composed of neurofilaments that are
p 08.qxd 3/10/08 9:38 AM Page 341
8.3 Frontotemporal dementia 341
regarding nomenclature. To begin with it must be empha-

sized that the term ‘frontotemporal dementia’ refers not to a
discrete disease but rather to a syndrome that in turn results
from multiple different diseases. The syndrome itself, as
noted below, is characterized initially by a personality
change, with, in most cases, the eventual development of a
dementia. As noted in the discussion of Pick’s disease,
some authors would subsume Pick’s disease under the
rubric of frontotemporal dementia; however, in my opinion
this represents inappropriate ‘lumping’ and in this text
Pick’s disease is treated as a disease in its own right (see
Section 8.2). As noted in the section on etiology below,
recent work has begun to identify some of the specific dis-
ease entities responsible for frontotemporal dementia, and it
is hoped that, with further study, our understanding of
Figure 8.3 Sparing of the posterior two-thirds of the superior these will mature to the point where they are as
temporal gyrus relative to the frontal lobe and the rest of the well-described as Pick’s disease and thus eventually merit
temporal lobe in a case of Pick’s disease. (Reproduced from sections in their own right. Frontotemporal dementia,
Graham and Lantos 1996.) among the neurodegenerative disorders, is a relatively com-
mon cause of dementia.
straight or twisted (Murayama et al. 1990; Rewcastle and
Ball 1968; Zhukareva et al. 2002). Clinical features
Although most cases of Pick’s disease are sporadic
(Malamud and Waggoner 1943), hereditary cases do occur The onset is insidious and generally in the sixth decade.
(Groen and Endtz 1982; Heston et al. 1987) and are usually Clinically (Heutink et al. 1997; Mann et al. 1993a; Neary
consistent with dominant inheritance (Sjorgen et al. 1952). et al. 1998), a personality change is usually the first sign of
Most of these familial cases are associated with mutations the disease, and, depending on the kind of personality
in the tau gene (Bronner et al. 2005; Neumann et al. 2001; change present, one may speak of a ‘frontal variant’ fron-
Pickering-Brown et al. 2000); however, a case has also been totemporal dementia or a ‘temporal variant’ frontotempo-
reported secondary to a mutation in presenilin-1 ral dementia.
(Dermaut et al. 2004). The frontal variant, as might be expected, is character-
ized by the frontal lobe syndrome, with varying mixtures of
Differential diagnosis disinhibition, mood changes, perseveration, and overall
coarsening of behavior; some patients may become quite
Both Pick’s disease (Litvan et al. 1997a) and fronto- gluttonous and some will show a pronounced taste
temporal dementia are distinguished from most other for sweets. In some cases the environmental dependency
dementing disorders by their presentation with a personal- syndrome may occur; as discussed in Section 4.11,
ity change; at present, a reliable differentiation of Pick’s such patients may compulsively utilize objects that come
and frontotemporal dementia from each other on clinical into view.
grounds may not be possible. Tumors of the frontal or The temporal variant, in turn, is characterized by ele-
temporal lobes may mimic these disorders, but are imme- ments of the Kluver–Bucy syndrome (with hypersexuality
diately identified by imaging. and hyperorality, wherein patients will eat or drink almost
anything, including, in one case, coffee grounds or banana
peels [Edwards-Lee et al. 1997]) and by ritualistic and
Treatment compulsive behaviors, which may include collecting or
hoarding things. Patients with the temporal variant may
The general treatment of dementia is discussed in Section also exhibit an anomia, and in such cases the term ‘seman-
5.1, of the frontal lobe syndrome in Section 7.2, and of the tic dementia’ is often used (Davies et al. 2005).
Kluver–Bucy syndrome in Section 4.12. There is no spe- Over time, and well after the personality change has
cific treatment for Pick’s disease itself. become established, a dementia supervenes, which, how-
ever, may remain relatively mild. Judgment and abstract
thinking fail, and eventually there may be amnestic fea-
8.3 FRONTOTEMPORAL DEMENTIA tures. Over time, many patients will also develop an
expressive aphasia (Neary et al. 1993; Snowden et al. 1992);
At the outset it must be recognized that, with regard gradually, this aphasia worsens, gathers receptive elements,
to frontotemporal dementia, there is considerable confusion and finally leads to mutism.
p 08.qxd 3/10/08 9:38 AM Page 342
Subsequent to the onset of the personality change, some on clinical grounds, to differentiate it from Pick’s disease.
patients may also gradually develop parkinsonism or a syn- Tumors of the frontal or temporal lobes may cause a
drome similar to amyotrophic lateral sclerosis, with upper similar presentation but are immediately identified on
or lower motor neuron signs. imaging.
Uncommonly, frontotemporal dementia may present When frontotemporal dementia is accompanied by
with an expressive aphasia (Bak et al. 2001; Turner et al. parkinsonism, the possibility of diffuse Lewy body disease
1996) or with a progressive amnesia (Graham et al. 2005). may be raised. Clinical features preceding the development
Computed tomography or MR scanning reveals atro- of parkinsonism, however, enable a differential: in
phy of the frontal or temporal lobes, or both. This may be frontotemporal dementia one sees a personality change,
quite pronounced, to the point of a ‘knife-blade’ appear- whereas in diffuse Lewy body disease one sees a dementia
ance of remaining gyri; in some cases the posterior portion marked by visual hallucinations and confusional episodes.
of the superior temporal gyrus may be spared.
Treatment
Course
There are no well-established symptomatic treatments spe-
Frontotemporal dementia is gradually progressive, with
cific for frontotemporal dementia: one open study sup-
most patients dying within 5–10 years.
ported the use of rivastigmine (Moretti et al. 2004),
whereas another open study reported no cognitive benefit
Etiology from donepezil and a behavioral worsening (Mendez et al.
2007); one blind study reported behavioral improvement
Macroscopically (Heutink et al. 1997; Mann et al. 1993a) with low-dose trazodone (Lebert et al. 2004), whereas
there is cortical atrophy in the frontal and temporal lobes; another blind study reported that with paroxetine there
microscopically, neuronal loss, gliosis, and spongiform was no behavioral improvement but a cognitive decrement
change are seen primarily in the superficial layers of the (Deakin et al. 2004).
frontal and temporal cortices. Similar, although less severe, Given that the personality change is generally the focus
changes may be seen in the insula, cingulate cortex, hip- of treatment, consideration may be given to carbamazepine
pocampus, basal ganglia, substantia nigra, and, in some, or a second-generation antipsychotic, as discussed in
anterior horn cells. Importantly, there are no Pick cells and Section 7.2 on the frontal lobe syndrome and Section 4.12
no Pick bodies. Appropriate staining, however, may reveal on the Kluver–Bucy syndrome. Dementia, as noted, is often
intracytoplasmic inclusions. In some cases these inclusions mild, and treatment considerations are discussed in
are tau positive, whereas in others they are tau negative but Section 5.1.
ubiquitin positive.
Both sporadic and familial, autosomal dominant cases
occur. Autosomal dominant cases may be divided into those
8.4 AMYOTROPHIC LATERAL SCLEROSIS
that have tau-positive inclusions and those that have inclu-
sions which are tau negative but ubiquitin positive. Tau-
Amyotrophic lateral sclerosis (ALS), first clearly delineated
positive inclusions are seen in frontotemporal dementia with
by the French neurologist Jean-Martin Charcot in 1874, is
parkinsonism linked to chromosome 17 (FTDP-17), a
classically characterized by a combination of upper and
disorder secondary to mutations in the MAPT gene on chro-
lower motor neuron signs; recent work, however, has indi-
mosome 17 (Janssen et al. 2002; Lantos et al. 2002; Pickering-
cated additional involvement of the frontal and temporal
Brown et al. 2000; Yasuda et al. 2005). Tau-negative,
cortices in this disease, with, in a substantial minority of
ubiquitin-positive inclusions may be seen in several disor-
patients, the development of a dementia. In Europe, ALS is
ders, including frontotemporal lobar dementia with motor
often referred to as Charcot’s disease or motor neuron dis-
neuron disease (FTLD-MND) (Josephs et al. 2006) and fron-
ease, and in the United States it is, at times, colloquially
totemporal lobar dementia-ubiquitinated (FTLD-U), due to
referred to as Lou Gehrig’s disease, after the famous base-
mutations in the gene for progranulin, also on chromosome
ball player who, in 1939, was forced to retire as the disease
17 (Bruni et al. 2007; Mackenzie et al. 2006; Mesulam et al.
took its toll.
2007; Snowden et al. 2006). As might be expected from
ALS has a lifetime prevalence of roughly 4–6 per 100 000
the names of these disorders, FTDP-17 is associated with the
and is more common in men than women by a ratio of
later appearance of parkinsonism, and FTLD-MND with the
approximately 1.5:1.
later appearance of upper and lower motor neuron signs.
Differential diagnosis Clinical features
When, as is typically the case, frontotemporal dementia Onset is gradual, most patients falling ill between the ages
presents with a personality change, it may not be possible, of 40 and 70 years. Classically, patients present with weak-
p 08.qxd 3/10/08 9:38 AM Page 343
8.4 Amyotrophic lateral sclerosis 343
ness in one of the upper extremities, often in the hand, and Course
there may be difficulty buttoning clothes or using small
tools; over time other limbs become involved. Eventually, ALS is almost invariably progressive, with death, often
with involvement of both upper and lower neurons, one from respiratory failure or an intercurrent pneumonia,
finds the distinctive combination of brisk deep tendon generally occurring within about 3 years; survival past
reflexes with atrophic muscular weakness and fascicula- 5 years is quite uncommon (del Aguila et al. 2003).
tions. With involvement of the upper motor neurons des-
tined for the cranial nerve nuclei, a ‘pseudobulbar palsy’
may appear, with dysarthria, dysphagia, and ‘emotional Etiology
incontinence’ with forced laughter and crying (Gallagher
1989; Ironside 1956); the jawjerk reflex tends also to be As noted, the motor symptomatology of ALS reflects
quite brisk. With involvement of the lower motor neurons involvement of both the upper and lower motor neurons
in the cranial nerve nuclei, the tongue may become (Brownell et al. 1970): the upper motor neurons include
atrophic and demonstrate fasciculation. Sensory changes those sending fibers into both the corticospinal and corti-
are generally absent. cobulbar tracts, whereas the lower motor neurons include
Subsequent to the onset of the upper and lower motor those found in certain lower brainstem cranial nerve nuclei
neuron symptoms, a dementia may gradually appear in up (especially the hypoglossal nucleus and the nucleus
to one-quarter of all patients, and in a significant minority ambiguus) and in the anterior horn of the spinal cord.
of others there will be a cognitive decrement of less severe Concurrent with the degeneration of the upper motor neu-
degree, characterized by poor short-term memory and rons, Wallerian degeneration leads to a thinning of both the
judgment (Rippon et al. 2006). corticospinal and corticobulbar tracts, and with degenera-
Although most patients present with a combination of tion of the anterior horn cells, there is subsequent atrophy of
upper and lower motor neuron signs and symptoms, in a the ventral roots. Cognitive deficits reflect cell loss in the
small minority of cases the presentation will be heavily frontal and temporal cortices (Wilson et al. 2001). In
weighted toward either the upper motor neuron (produc- remaining cells one typically finds tau-negative, unbiquitin-
ing a syndrome known as primary lateral sclerosis) or the positive inclusions.
lower motor neuron (producing progressive muscular Ninety percent of all cases of ALS are sporadic; roughly
atrophy). Primary lateral sclerosis (Pringle et al. 1992) is 10 percent are inherited in an autosomal dominant fashion,
characterized clinically by a progressive spastic paresis, secondary to mutations in the gene for superoxide dismu-
accompanied in roughly one-half of patients by a pseudo- tase on chromosome 21 (Rosen et al. 1993; Siddique et al.
bulbar palsy (Kuipers-Upmeijer et al. 2001). Progressive 1991), and there are very rare cases of inheritance on a reces-
muscular atrophy, in contrast, presents with progressive sive basis. Although the mechanism underlying cell loss in
weakness, atrophy, and fasciculations. In most cases, ALS is not known, excitotoxicity is strongly suspected.
patients with progressive lateral sclerosis or progressive
muscular atrophy go on to develop clear clinical evidence
of involvement of both upper and motor neurons (e.g., the Differential diagnosis
eventual development of fasciculations in patients with
progressive lateral sclerosis [La Forestier et al. 2001]), thus Diseases capable of causing diagnostic confusion are best
leaving no doubt as to the correct diagnosis. However, in a grouped according to whether they mimic classic ALS, pri-
small minority of cases the clinical picture throughout life mary lateral sclerosis, progressive muscular atrophy, or the
persistently demonstrates involvement of only the upper dementia seen in ALS.
motor neuron or only the lower motor neuron, and these Classic ALS, with evidence of both upper and lower
cases have raised the question as to whether primary lateral motor neuron damage, may be mimicked by cervical
sclerosis and progressive muscular atrophy might each be a spondylosis and syringomyelia; rarely, a similar picture
disease sui generis and distinct from ALS. Autopsy studies, may occur on a paraneoplastic basis or secondary to lym-
however, have indicated subclinical involvement of both phoma (Younger et al. 1991). Finally, there is a rare disor-
the upper and lower motor neurons in these cases, thereby der known as amyotrophic lateral sclerosis–parkinsonism
justifying their inclusion under the overall rubric of ALS dementia complex of Guam, found in Guam, parts of
(Brownell et al. 1970; Lawyer and Netsky 1953). Japan, and other Pacific islands (Garruto et al. 1981;
Electromyography typically reveals evidence of dener- Hirano et al. 1967; Malamud et al. 1961).
vation, and nerve condition velocity studies are typically Primary lateral sclerosis may be mimicked by multiple
normal. sclerosis, adrenoleukodystrophy, hereditary spastic para-
T2-weighted or fluid-attenuated inversion recovery plegia, and vitamin B12 deficiency.
(FLAIR) MR imaging may reveal increased signal intensity Progressive muscular sclerosis is very closely mimicked
bilaterally in the centrum semiovale, corresponding to the by two rare, recessively inherited disorders, namely spinal
corticospinal tracts; rarely, atrophy may be noted in the muscular atrophy type III (or the Kugelberg–Welander syn-
prefrontal gyrus. drome [Kugelberg and Welander 1956]), which presents in
p 08.qxd 3/10/08 9:38 AM Page 344
adolescence or early adulthood with proximal muscle weak- develop depression. Furthermore, of patients treated with
ness, and X-linked spinal muscular atrophy (or Kennedy’s levodopa or direct-acting dopaminergics, a majority will
disease [Harding et al. 1982; Kennedy et al. 1968]), which develop significant neuropsychiatric side-effects, most
presents in the middle years with progressive weakness and notably visual hallucinations.
fasciculations, often accompanied by a degree of gyneco- This is a common disease, with a prevalence of roughly
mastia. Consideration may also be given to various periph- 0.2 percent in the general population; it is slightly more
eral motor neuropathies; however, these are immediately common in men than women, by a ratio of roughly 1.5:1.
identified on nerve conduction velocity studies.
As noted earlier, dementia occurring in ALS appears
after the motor signs and symptoms are well-established, Clinical features
and this distinguishes this dementia from certain of the
frontotemporal dementias. As noted in Section 8.3, certain The onset of Parkinson’s disease is gradual and insidious,
of the frontotemporal dementias are accompanied by with symptoms generally first appearing in the mid-50s;
upper and lower motor neuron signs; however, these the range, however, is wide, from 20 to 80 years.
motor signs occur well after the personality change and As just noted, the disease initially manifests with parkin-
dementia have appeared. However, this neat division, sonism (Hoehn and Yahr 1967; Hughes et al. 1993; Martin
based on the evolution of signs and symptoms, has been et al. 1973): patients typically present with asymmetric
brought into question by the discovery of certain families tremor or rigidity affecting an upper or, less commonly,
in which some members have ALS that is later complicated lower extremity. Over time, the opposite side becomes
by a dementia, whereas others have developed a dementia involved, and eventually all four limbs are affected.
first, followed by an ALS-like picture (Vance et al. 2006). Once fully established, Parkinson’s disease leaves a
Further research is clearly needed here. stamp on patients that is, once recognized, almost unforget-
table. Patients stand in a stooped, ‘flexion’ posture, with
their arms and knees in flexion. A rhythmic, 3–7 cycles per
Treatment second (cps) rest tremor is present, most noticeably in the
hands but also evident, when seated, in the feet; the jaw is
Meticulous general medical care goes far to ensure an opti- also often tremulous; of note, although the tremor typically
mum quality of life as the disease progresses. Physical ther- resolves with sleep, in a minority it may persist (April 1966;
apy is helpful for spasticity and, when this is severe, a trial of Stern et al. 1968). The face is often ‘masked’ and expres-
baclofen may be considered. Emotional incontinence, as sionless, and there is a reduced frequency of blinking; there
discussed in Section 4.7, may respond to a combination of may also be copious drooling. Speech is hypophonic,
30 mg of dextromethorphan and 30 mg of quinidine, given soft, monotonous, and lacking in emotional inflection.
twice daily; consideration may also be given to a trial of Handwriting undergoes a ‘micrographic’ change, produc-
citalopram, nortriptyline, or amitriptyline. As respiratory ing scratchy, small letters. Passive extension of the limbs
insufficiency supervenes, bi-level positive airway pressure reveals the rigidity, which, although often of the ‘cogwheel’
(BIPAP) is indicated. At some point the question of a feed- type, may at times be ‘lead pipe’ in character.
ing tube must be considered, and in most cases this is appro- While walking there is reduced arm swing and patients
priate. Eventually one must also discuss tracheostomy, often display ‘marche a petit pas’, wherein they take small,
which is perhaps the most difficult decision of all. shuffling steps; furthermore, they often display ‘festination’
Tracheostomy clearly prolongs life but, as the disease pro- in which, as they walk, their steps become ever more rapid
gresses, patients may become completely ‘locked in’. For and closely spaced, to the point at which a catastrophic fall
some patients this amounts to a ‘living death’ and, rather forward seems almost inevitable. Upon evaluating the sta-
than risk this, they may forego tracheostomy. Eventually, tion of these patients, one typically finds retropulsion,
hospice care is appropriate. wherein a gentle push on the patient’s chest will induce a
Riluzole may also be considered. This agent both gradual toppling backward that the patient cannot keep up
inhibits pre-synaptic release of glutamate and blocks post- with by backward steps. Another important symptom is
synaptic glutamate receptors, and has been shown to retard bradykinesia, which manifests as a slowness in virtually any
the progression of the disease. At most, however, it gener- activity. For example, even in the absence of tremor or sig-
ally adds only a few months to the patient’s life. nificant rigidity, it may take many minutes to fasten a but-
ton. A related phenomenon is bradyphrenia, in which
thoughts, although coherent and logical, move very slowly,
8.5 PARKINSON’S DISEASE as if stuck in molasses.
Another curious phenomenon is ‘freezing’: in this,
Parkinson’s disease, also known as idiopathic parkinson- patients on the brink of an intentional act suddenly
ism or paralysis agitans, presents with a classic parkinson- become ‘frozen’ and unable to move at all (Giladi et al.
ism; over time, however, the majority of patients will 1992). For example, a patient standing in a doorway and
develop a dementia, and a significant minority will also desirous of walking down the hall may be unable to lift a
p 08.qxd 3/10/08 9:38 AM Page 345
foot, take a step, or move at all. Amazingly, however, such depressive symptoms are more likely when the right side of
‘freezing’ may be prevented by providing appropriate the body is affected compared with the left, indicating an
visual ‘cues’. For example, if the hallway is marked off with involvement of the left hemisphere in the genesis of depres-
pieces of tape set about one footstep apart, the patient may sion (Starkstein et al. 1990).
well be able to begin and finish the walk down the hall Rapid eye movement (REM) sleep behavior disorder is
without any difficulty; furthermore, in some cases, patients fairly common in patients with Parkinson’s disease, and
may be able to lyse their own frozen state by simply imag- may either precede or follow the onset of motor symptoms
ining such cues (Morris et al. 1996). (Gagnon et al. 2002; Iranzo et al. 2005).
Finally, akathisia may occur in Parkinson’s disease
(Comella and Goetz 1994) and may appear early in the
course of the disease, before any pharmacologic treatment Course
(Lang and Johnson 1987).
Autonomic symptoms such as dysphagia, constipation, Untreated, most patients become incapacitated within
urinary frequency or incontinence, and nocturia are com- 8–10 years, with death often from pneumonia; with treat-
mon, being seen in well over one-half of patients after 10 or ment, however, survival of 15 or more years may be
more years of disease (Verbaan et al. 2007). expected.
Dementia is more common in patients with Parkinson’s
disease than in age-matched controls (Biggins et al. 1992),
with overall prevalence figures of 11 percent (Mayeux et al. Etiology
1988), 17 percent (Aarsland et al. 1996), 18 percent (Tison
et al. 1995), 19 percent (Marder et al. 1995), 29 percent Macroscopically, there is depigmentation of the substantia
(Marttila and Rinne 1976), and 41 percent (Mayeux et al. nigra (as illustrated in Figure 8.4) and the locus ceruleus.
1992) being noted. The prevalence of dementia in Microscopically (Hughes et al. 1993), neuronal loss is pres-
Parkinson’s disease rises with age: Mayeux et al. (1992) ent not only in these structures but also in the dorsal raphe
noted a prevalence of 0 percent for those under 50 years and
69 percent for those over 80 years. In a similar vein, over an 8-
year follow-up, Aarsland et al. (2003) noted that 78 percent
became demented. It also appears that dementia is more
likely in those with more severe motor symptoms (Kuzis
et al. 1997; Marder et al. 1995). Importantly, the dementia
does not appear until after the motor symptoms have been
well established: one study found that the onset of demen-
tia occurred at a mean of 13 years after the appearance of
motor symptoms, with a range of 6–21 years (Aarsland et al.
2005). It is of interest that James Parkinson, who described
this disease in 1817 (Ostheimer 1922; Wilkins and Brody
1969b), maintained that dementia did not occur, an opin-
ion that was echoed in textbooks for over one and one-half
centuries. This mistake of his may be forgiven, based as it
was on the observation of a mere six patients, two of whom
were encountered only ‘casually’ and one of whom was
‘seen only at a distance’. The dementia itself is fairly non-
specific: patients may experience difficulty with memory
and concentration, and, less commonly, such focal deficits
as aphasia or apraxia may appear.
Depressive symptoms of sufficient severity to meet the
criteria for a depressive episode as set out in DSM-III
(American Psychiatric Association 1980) have been noted
in 3 percent (Hantz et al. 1994), 5 percent (Tandberg et al.
1996), and, in two separate studies (Mayeux et al. 1984;
Starkstein et al. 1990), 21 percent of patients; minor depres-
sive symptomatology may be found in others (Tandberg
et al. 1996), indeed up to 20 percent (Mayeux et al. 1986;
Starkstein et al. 1990). As might be expected, the presence of Figure 8.4 Note the depigmentation, especially evident in the
depression worsens the cognitive deficits in those also substantia nigra, in the case of Parkinson’s disease on the left
demented (Kuzis et al. 1997). Of interest, it appears that in compared with a normal control on the right. (Reproduced from
patients with primarily unilateral motor symptomatology, Stern 1990.)
p 08.qxd 3/10/08 9:38 AM Page 346
Figure 8.5 Lewy bodies in surviving neurons of the substantia nigra. (Reproduced from Stern 1990.)
nucleus, the pedunculopontine nucleus, the dorsal motor with cell loss and Lewy bodies in the cortex (Aarsland
nucleus of the vagus, the thalamus, hypothalamus, nucleus et al. 2005; Apaydin et al. 2002; Braak et al. 2005; Hurtig
basalis of Meynert, the amygdala, and in various areas of the et al. 2000), and depression with similar changes in the
cortex, including the temporal, insular, and cingulate cor- locus ceruleus (Chan-Palay and Asan 1989) and the
tices. Remaining neurons typically display the hallmark of dorsal raphe nucleus (Becker et al. 1997); of note, the dor-
Parkinson’s disease, namely the Lewy body, which, as illus- sal raphe nucleus serves as one of the main sources of sero-
trated in Figure 8.5, is an intracytoplasmic inclusion, com- tonergic innervation to the cortex and a correlation has
posed of alpha-synuclein, neurofilaments, and ubiquitin. been found between CSF levels of 5-hydroxyindoleacetic
Motor symptoms correlate with cell loss in the substan- acid, a metabolite of serotonin, and the presence of depres-
tia nigra, and generally do not appear until 60 percent or sion in patients with Parkinson’s disease (Mayeux et al.
more of these cells have been lost. Dementia correlates 1984, 1986).
p 08.qxd 3/10/08 9:38 AM Page 347
Table 8.1 Genetic forms related to Parkinson’s disease
Inheritance
pattern Chromosome Locus Gene Protein Onset Parkinsonism
AD 12p11-q13 PARK8 LRRK2 Leucine-rich repeat kinase 2 Late Typical

AD 4q21 PARK1 SCNA Alpha-synuclein Early to late Typical or atypical
AD 4q21 PARK4 SCNA Alpha-synuclein Early to late Typical or atypical
AD 4p14 PARK5 UCH-L1 Ubiquitin C-terminal hydrolase Late Typical
AD 2p13 PARK3 ? ? Late Typical
AD 1p PARK11 ? ? Late Typical
AR 6q25.2–27 PARK2 PRKN Parkin Early to late Atypical
AR 1p36 PARK6 PINK1 PTEN-induced putative kinase 1 Early to late Typical
AR 1p36 PARK7 DJ-1 DJ-1 Early Typical
AR 1p36 PARK9 ? ? Early Atypical
? 1p PARK10 ? ? Late Typical
AD, autosomal dominant; AR, autosomal recessive.
Although the mechanism or mechanisms underlying cell majority of cases that do not exhibit a clear-cut familial
loss and Lewy body formation are not known, it is theorized basis, as they may not have the same pathology as that
that, perhaps related to mitochondrial respiratory chain described above. For example, although Lewy bodies, the
dysfunction, there is an increased formation of free radicals pathologic hallmark of Parkinson’s disease, are found in
with subsequent cell damage. Genetic factors and environ- some cases of PARK8 (Papapetropoulos et al. 2006) and
mental factors may both be involved. Although idiopathic PARK2 (Farrer et al. 2001; Pramstaller et al. 2005), they are
Parkinson’s disease has long been thought to be sporadic, not found in other cases, both of PARK8 (Funayama et al.
recent epidemiologic work strongly suggests familial factors 2002; Gaig et al. 2007) and PARK2 (Mori et al. 1998;
(Sveinbjornsdottir et al. 2000). Furthermore, fluorodopa Takahashi et al. 1994).
positron emission tomography has demonstrated not only The place of genetic testing, at present, is uncertain.
reduced dopamine uptake in the striatum of patients but Where a strong family history exists, a case could be made
also a reduced uptake in their clinically unaffected co-twins, for testing to allow for genetic counselling; otherwise, such
suggesting that the co-twins had asymptomatic disease testing is probably best reserved for research settings.
(Piccini et al. 1999). Environmental toxins have long been
suspected, and suspicion has focused on exposure to pesti-
cides (Ascherio et al. 2006). Of interest, it also appears that Differential diagnosis
cigarette smoking appears to reduce the risk of developing
Parkinson’s disease (Thacker et al. 2007). Parkinson’s disease constitutes only one of many different
Interest in genetic factors has recently been stimulated causes of parkinsonism, and the full differential for
by the investigation of cases having a clear-cut, unequivo- parkinsonism is discussed at length in Section 3.8. Of the
cal familial basis (Feany 2004; Klein 2006; Tan and disorders noted there, several should especially come to
Jankovic 2006). These constitute only a small percentage of mind when considering a diagnosis of Parkinson’s disease,
cases, no more than 10 percent, and the pattern of inheri- including diffuse Lewy body disease, multiple system atro-
tance may be either autosomal dominant or autosomal phy, progressive supranuclear palsy, corticobasal gan-
recessive. Table 8.1 lists the various forms that have been glionic degeneration, and vascular parkinsonism.
discovered, grouping them according to whether they Diffuse Lewy body disease may present with a classic
are dominantly or recessively inherited. As noted these parkinsonism; however, within a year of onset of the
cases may be either early (under 40 years) or late onset, and movement disorder, this disease also causes a dementia
the parkinsonism may be typical or have atypical aspects. marked by confusional episodes and visual hallucinations.
Two of the more common forms are PARK8, due to muta- Although most patients with Parkinson’s disease will also
tions in LRRK, and PARK2, due to mutations in PRKN. develop a dementia, this, as noted above, is a late occur-
PARK8 cases may be clinically indistinguishable from rence, appearing only many years after the onset of the
idiopathic Parkinson’s disease (Gaig et al. 2007; movement disorder, and it is this disparity in time of onset
Papapetropoulos et al. 2006); PARK2 cases may also be of the dementia which is most helpful in distinguishing
indistinguishable or may present with a combination of these two disorders.
parkinsonism and foot dystonia (Khan et al. 2003; Lucking Multiple system atrophy may cause a fairly classic
et al. 2000). It is unclear at present how relevant these dis- parkinsonism; however, these patients will also typically
coveries are to an understanding of the overwhelming have evidence of either cerebellar degeneration with ataxia,
p 08.qxd 3/10/08 9:38 AM Page 348
or autonomic failure with postural dizziness, erectile dys- increasing the amount available in the striatum and
function and either urinary incontinence or retention. thereby exerting a modest therapeutic effect. Although
Progressive supranuclear palsy may cause parkinsonism, perhaps controversial, there is also evidence that both
but this is usually accompanied by certain atypical features, selegiline (Palhagen et al. 2006) and rasagiline (Parkinson
such as the early occurrence of frequent, unexplained falls, Study Group 2004) may have a ‘neuroprotective’ effect and
a symmetric onset, an extension (rather than flexion) pos- may, to a modest degree, slow the progression of the dis-
ture, and, most importantly, the appearance within several ease. As there have been no ‘head to head’ comparisons of
years of a supranuclear ophthalmoplegia. these two agents, it is not clear which one should be used.
Corticobasal ganglionic degeneration, like Parkinson’s Anticholinergics, although useful for tremor, have a lim-
disease, causes a parkinsonism of asymmetric onset. ited effect on bradykinesia and rigidity, and in some
However, here the onset is markedly asymmetric and, patients may cause confusion or a memory deficit. In light
furthermore, the rigidity often has a dystonic aspect to it of this, they are generally reserved for cases in which tremor
and is typically accompanied by cortical sensory loss and is prominent, with due regard for any emerging cognitive
apraxia. deficits.
Vascular parkinsonism, occurring in the setting of mul- Amantadine, in a dose of 200–300 mg/day, may have a
tiple lacunar infarctions, produces a somewhat atypical mild effect on motor symptoms, but the effect may be short-
parkinsonism in that tremor is often absent and the rigid- lived, with little benefit seen after a matter of months
ity and bradykinesia are accompanied by evidence of dam- (Thomas et al. 2004; Timberlake and Vance 1978). Given this
age to the corticospinal tracts (e.g., hyper-reflexia and limited benefit, and the side-effects seen with amantadine,
Babinski signs) and corticobulbar tracts (e.g., pseudobul- routine use is probably not justified. There may, however, be
bar palsy with emotional incontinence). a place for amantadine in the treatment of levodopa-induced
One very important clue in the differential of parkin- dyskinesias (Verhagen Metman et al. 1998).
sonism is the presence or absence of ‘levodopa responsive- Levodopa is the most effective treatment for the motor
ness’. The parkinsonism of Parkinson’s disease is almost symptomatology of Parkinson’s disease, and is generally
always robustly responsive to levodopa; although parkin- given in combination with a peripheral aromatic amino
sonism seen in other disorders may also respond, this is acid decarboxylase inhibitor (carbidopa or benzaride) in
not as common and the response is typically not robust, order to prolong its effect: both regular and sustained-
hence a lack of a robust response to levodopa should release preparations are available. The initial response to
prompt a reconsideration of the diagnosis. levodopa/carbidopa is generally quite gratifying, but as lev-
odopa does not retard the progression of the disease, a
dosage increase is necessary over time, and most patients
Treatment eventually begin to show motor fluctuations: such fluctua-
tions can be ‘peak dose’ with dyskinesias, ‘end of dose’ with
The treatment of Parkinson’s disease begins with its motor an early wearing off of effectiveness, or unpredictable.
symptoms; over time, as noted earlier, dementia and depres- When fluctuations appear, using lower and more closely
sion typically appear and require their own treatments. spaced doses of levodopa may help, or one may add tol-
Each aspect of treatment is discussed in turn, beginning capone. Tolcapone is a peripheral catechol-O-methyltrans-
with motor symptoms. ferase inhibitor that extends the duration of levodopa’s
effect and also allows for a lowering of the levodopa dose
MOTOR SYMPTOMS (Adler et al. 1998; Brooks and Sagar 2003; Kurth et al. 1997;
Rajput et al. 1997; Waters et al. 1997); although hepatotox-
Motor symptoms may be treated with a variety of agents, icity is a concern (Baas et al. 1997), the medication may
including monoamine oxidase inhibitors (e.g., selegiline be used safely with appropriate monitoring (Olanow et al.
and rasagiline), anticholinergics (e.g., benztropine and tri- 2000). Recently a ‘triple combination’ preparation, con-
hexyphenidyl), amantadine, levodopa/carbidopa (with or taining levodopa, carbidopa, and tolcapone, has become
without entacapone), and direct-acting dopamine agonists available. Attention should also be paid to the possibility of
(bromocriptine, cabergoline, pramipexole, and ropinirole). Helicobacter pylori infection; in patients with confirmed
Each of these agents will be discussed in turn, followed by a infection, successful treatment with omeprazole, amoxi-
discussion of an overall treatment strategy. Treatment with cillin, and clarithromycin was followed by increased absorp-
levodopa or dopamine agonists eventually causes significant tion of levodopa and increased on-time (Pierantozzi
neuropsychiatric side-effects (e.g., visual hallucinations) in et al. 2006).
most patients, and these are discussed further below. As noted above, dopamine agonists include a number of
The monoamine oxidase inhibitors selegiline (used in different agents: although bromocriptine is the oldest
doses of 10 mg or less daily) (Myllyla et al. 1997; Palhagen member of this group, problematic side-effects, combined
et al. 1998) and rasagiline (Parkinson Study Group 2005) with the fact that newer agents (e.g. ropinirole [Korczyn
are both selective against monoamine oxidase type B and, et al. 1999]) may be more effective, have limited its use.
as such, inhibit intracellular metabolism of levodopa, thus Dopamine agonists have been used as monotherapy in early,
p 08.qxd 3/10/08 9:38 AM Page 349
mild Parkinson’s disease, and include cabergoline (Rinne and to allow a dose reduction and a reduction in levodopa-
et al. 1997), pramipexole (Parkinson Study Group 1997; induced dyskinesias.
Shannon et al. 1997), ropinirole (Adler et al. 1997; Korczyn In treating patients with levodopa or dopaminergic
et al. 1999; Rascol et al. 2000), and, most recently, transder- agents, it is important to avoid suddenly stopping them as
mal rotigotine (Jankovic et al. 2007). Dopamine agonists are this may precipitate a neuroleptic malignant syndrome, as
also used as ‘add-on’ drugs to levodopa, both to smooth out has been reported for levodopa (Sechi et al. 1984; Toru et al.
levodopa fluctuations and to allow for a levodopa dose 1981), the combination of levodopa and bromocriptine
reduction, this effect having been shown for cabergoline (Figa-Talamanca et al. 1985), and amantadine (Cunningham
(Hutton et al. 1996; Inzelberg et al. 1996), pramipexole et al. 1991; Harsch 1987).
(Guttman et al. 1997; Lieberman et al. 1997; Pinter et al. When motor symptoms become severe and resistant to
1999), and ropinirole (Lieberman et al. 1998). Of these pharmacologic treatment, consideration may be given to
dopamine agonists, cabergoline has been strongly associated deep brain stimulation or to electroconvulsive therapy
with cardiac valvular disease (Zanettini et al. 2007) and, (ECT). Deep brain stimulation of the subthalamic nucleus
hence, if an oral dopamine agonist is used, consideration is is effective (Deep Brain Stimulation for Parkinson’s
best given to either pramipexole or ropinirole. When Disease Study Group 2001; Rodriguez-Oroz et al. 2004),
dopamine agonists are used, patients should be cautioned somewhat more so than stimulation of the pars interna
that sleep attacks may occur (Avorn et al. 2005; Ferreira et al. of the globus pallidus (Deep Brain Stimulation for
2000; Frucht et al. 1999; Hauser et al. 2000); they should Parkinson’s Disease Study Group 2001). In emergent situ-
generally avoid driving or using hazardous machinery until, ations, or in cases where neurosurgical intervention is not
with prolonged use, it has become apparent whether or not possible, consideration should be given to ECT. ECT has
this side-effect will occur. been shown in a double-blind study (Andersen et al. 1987)
The optimum overall treatment strategy is still a matter to improve motor symptoms regardless of whether
of some debate, and although the strategy recommended patients are depressed or not, and the results are at times
here is intended as a middle of the road approach, not all dramatic. As such, ECT may be life-saving, and although
authors will be in agreement. maintenance ECT may be required to prolong the benefit,
In general, pharmacologic treatment should not be ini- this may, in selected cases, be a reasonable price to pay in
tiated until the motor symptomatology significantly inter- light of the increased mobility.
feres with the patient’s ability to function. In mild cases Most patients treated with levodopa or dopamine ago-
one may begin with one of the monoamine oxidase nists will eventually develop significant neuropsychiatric
inhibitors and, when tremor is prominent, some clinicians side-effects. The most common of these are visual halluci-
advocate the use of an anticholinergic. With disease pro- nations; others include psychosis, anxiety (during wearing
gression, however, one must at some point add either lev- off of levodopa), and certain other, much less common,
odopa or a dopamine agonist, and the question of which to phenomena, including impulsive behaviors, stereotypies,
use first has not been settled. Given the sometimes stun- euphoria (with, rarely, mania), and delirium. Each of these
ning effectiveness of levodopa, some advocate using this is discussed in turn.
first, especially when a prompt response is required, for Visual hallucinations are very common with prolonged
example when a patient is threatened with job loss. Others, treatment with either levodopa or dopamine agonists: in
however, with an eye towards delaying the emergence of one 6-year study, the percentage of patients with hallucina-
levodopa-induced dsykinesias, advocate starting with tions gradually increased until, at the end of the study, fully
dopamine agonist monotherapy and adding levodopa only 62 percent were experiencing them (Goetz et al. 2005). The
as the disease progresses. hallucinations are typically complex, involving scenes, ani-
All other things being equal, it may be prudent to begin mals or people, and may last from minutes to hours or
with a dopamine agonist, either pramipexole or ropinirole, even days; importantly, early on, patients retain insight
increasing the dose as required until limiting side-effects into the hallucinatory nature of these experiences and rec-
occur or further dose increases are not effective, and then, ognize that they are not ‘real’ (Barnes and David 2001;
with disease progression, to add levodopa. Between the Fenelon et al. 2000; Friedman and Sienkiewicz 1991;
regular and sustained-release preparations of levodopa, the Graham et al. 1997; Inzelberg et al. 1998). Auditory hallu-
sustained-release preparation may be preferable as it may cinations, or even olfactory or gustatory hallucinations,
allow for a longer duration of effect; given its slower onset may also occur, but these are much less common (Goetz
of action, however, some patients may have to take a ‘reg- et al. 2005; Holroyd et al. 2001). Of note, although it has
ular’ release preparation first thing in the morning in order traditionally been taught that visual hallucinations in
to ‘jump start’ themselves (Pahwa et al. 1996). When patients with Parkinson’s disease occur, as noted here, as
fluctuations in levodopa responsiveness begin to appear, side-effects, recent work suggests that, in a very small
the addition of tolcapone may be considered. If one begins minority of patients, visual hallucinations may occur
with levodopa rather than with dopamine agonist before any treatment is administered (Biousse et al. 2004).
monotherapy, at some point one will generally have to add Furthermore, it appears that patients with greater cell loss
a dopamine agonist to smooth out the effect of levodopa and Lewy body pathology in the amygdala are more likely
p 08.qxd 3/10/08 9:38 AM Page 350
to develop hallucinations when treated with levodopa medication, symptoms resolve within days to months
(Harding et al. 2002a). It may well be that amygdalar (Dodd et al. 2005).
pathology not only renders patients more sensitive to the Stereotypies seen with treatment may be complex and
hallucinogenic effects of levodopa and dopamine agonists socially disabling. Known as ‘punding’, these may include
but may also, if severe enough, independently cause repeatedly taking apart and putting together machinery or
hallucinations. engaging in other purposeless behaviors (Evans et al.
Psychosis is said to be present when patients either 2004).
experience hallucinations without insight or develop delu- Euphoria may occur, and some patients may escalate
sions. As just noted, visual hallucinations with preserved the dose in order to achieve this side-effect (Giovannoni et
insight are very common; however, over a matter of several al. 2000); in some cases, albeit rarely, a manic episode may
years, the majority of patients who do have hallucinations occur (Celesia and Barr 1970; O’Brien et al. 1971).
will lose insight and begin to react to the visual hallucina- Delirium has been noted as a side-effect (Celesia and
tions as if they were real (Goetz et al. 2006). Delusions, Barr 1970; Friedman and Sienkiewicz 1991; Serby et al.
often of persecution, may also occur, but are much less 1978), but this is rare.
common (Holroyd et al. 2001).
Treatment of hallucinations or psychosis should gener- DEMENTIA
ally involve an attempt at dose reduction of levodopa
and/or dopamine agonists. These side-effects are generally Dementia may be treated with either donepezil (Emre et al.
dose-responsive and in some cases it may be possible to 2004; Ravina et al. 2005) or rivastigmine (Aarsland et al.
reduce the dose sufficiently to allow for a substantial resolu- 2002); donepezil may be preferred as there was no worsen-
tion of them without sacrificing control of the parkinson- ing of parkinsonism with donepezil, in contrast to riva-
ism. When dose reduction is either ineffective or stigmine, which did cause motor worsening, in particular
impractical, consideration may be given to treatment with an an increase in tremor. The overall treatment of dementia is
antipsychotic. Various second-generation agents have been discussed in Section 5.1.
used. Quetiapine, in doses of 50–150 mg/day, in non-blind
(Fernandez et al. 1999; Weiner et al. 2000) and single-blind DEPRESSION
(Merims et al. 2006) studies, appeared promising; however,
a double-blind study failed to show any superiority to Depression may be treated with antidepressants such as ser-
placebo (Rabey et al. 2006). Olanzapine, in doses of traline (Antonini et al. 2006) or nortriptyline (Andersen
2.5–15 mg in double-blind studies, was no better than et al. 1980); however, to date, there is no double-blind evi-
placebo and less effective than clozapine, and tended to dence to support their efficacy. Of interest, it appears that
aggravate parkinsonism (Breier et al. 2002; Goetz et al. pramipexole may be more effective than sertraline in this
2000). Risperidone, in a dose of 1–2 mg, was comparable to regard; however, again this was an unblind study (Barone
clozapine in a double-blind study but, in contrast to cloza- et al. 2006). Mirtazapine should be used only with caution,
pine, worsened parkinsonism (Ellis et al. 2000). Clozapine, as it may precipitate REM sleep behavior disorder in these
in doses of 6.25–50 mg, is clearly effective in double-blind patients (Onofrj et al. 2003). In treatment-resistant cases,
studies (Parkinson Study Group 1999, Pollak et al. 2004) consideration may be given to either ECT or transcranial
and, rather than worsening parkinsonism, may actually magnetic stimulation (TMS). In a naturalistic study
improve it (Durif et al. 2004; Parkinson Study Group 1999). (Douyon et al. 1989) ECT was effective, and, as noted earlier,
On the basis of efficacy and motor effects, clozapine is ECT also improves motor symptoms. In a sham-controlled,
clearly preferable; however, the risk of agranulocytosis and double-blind study (Fregni et al. 2004), TMS was as effective
the need for regular blood counts make most clinicians as fluoxetine and did not aggravate motor symptomatology.
pause before recommending it. A reasonable strategy might
be to try another agent first, for example risperidone, keep-
ing clozapine in reserve. 8.6 DIFFUSE LEWY BODY DISEASE
Anxiety may be seen during motor fluctuations of the
‘wearing off’ type, and full anxiety attacks may occur Diffuse Lewy body disease, also known as dementia with
(Hillen and Sage 1996; Vazquez et al. 1993); other symp- Lewy bodies, Lewy body dementia, cortical Lewy body dis-
toms seen during the ‘off’ period include depressed mood, ease, and senile dementia of the Lewy body type, is a rela-
irritability, and various other symptoms, including sweat- tively recently described (Okazaki et al. 1961) cause of
ing (Raudino 2001). dementia, now recognized in both autopsy (Barker et al.
Impulsive behaviors, including pathologic gambling, 2002) and clinical (Rahkonen et al. 2003) studies to be the
compulsive shopping, and hypersexuality, may occur as second most common cause of dementia in the elderly,
side-effects of treatment in a few percent of patients, and accounting for nearly 20 percent of all cases. Clinical stud-
appear more likely in those treated with dopamine agonists ies have also indicated that, in the general population, dif-
(Dodd et al. 2005; Pontone et al. 2006; Voon et al. 2006a,b); fuse Lewy body disease is the second most common cause
with discontinuation of treatment with the offending of parkinsonism (Pineda et al. 2000).
p 08.qxd 3/10/08 9:38 AM Page 351
8.6 Diffuse lewy body disease 351
Diffuse Lewy body disease is distinctive in that it may [Louis et al. 1997]), autonomic dysfunction (with urinary
present in one of two ways, either with a dementia or incontinence, constipation, and orthostatic hypotension
with parkinsonism; eventually, all patients will display [Horimoto et al. 2003]) and REM sleep behavior disorder,
both features. which may actually constitute a very early presentation of
the disorder, appearing long before any other symptoms
(Boeve et al. 1998).
Clinical features Magnetic resonance scanning may reveal cortical atro-
phy and atrophy of medial temporal structures; however,
The onset is gradual, generally in the seventh decade, and, the degree of atrophy tends to be relatively mild (Tam et al.
as noted, the presentation may be with either a dementia or 2005). The EEG may reveal generalized slowing with tem-
parkinsonism (Byrne et al. 1989). poral theta transients (Briel et al. 1999); frontal intermit-
The dementia of diffuse Lewy body disease is character- tent delta activity (FIRDA) (Calzetti et al. 2002) and
ized initially by difficulty in sustaining attention and by periodic spike and slow-wave complexes (Doran and
executive dysfunction, with deficits in judgment and Larner 2004) have also been reported.
decision-making; over time, these symptoms are joined by
short-term memory loss. There are two other features of
the dementia of diffuse Lewy body disease that deserve Course
note, as they are helpful, as discussed later, in distinguish-
ing diffuse Lewy body disease from other dementias: these The course is one of gradual progression, with death on
two features are early-onset hallucinations or delusions average within 12–13 years.
and spontaneous episodes of confusion.
Hallucinations seen in diffuse Lewy body disease are
typically visual, complex and well-formed, and are experi- Etiology
enced without insight (Ala et al. 1997; Ballard et al. 1997,
1999, 2001; Crystal et al. 1990; Tiraboschi et al. 2006; Microscopically (Gibb et al. 1987, Gomez-Tortosa et al.
Weiner et al. 1996). Auditory hallucinations may also 1999, Hansen et al. 1990, Lennox et al. 1989, Lippa et al.
occur, but are less common. Delusions are somewhat less 1994) there is cell loss and Lewy bodies in surviving
common than hallucinations, and tend to be persecutory neurons in the substantia nigra, nucleus basalis of
in nature (Marantz and Verghese 2002). As noted, these Meynert, amygdala, and the cortex. Dementia correlates
symptoms tend to appear early on, and indeed may occur not only with cortical Lewy bodies but also with the pres-
at presentation. ence of Lewy bodies in the nucleus basalis of Meynert. The
Confusional episodes are common and occur early on nucleus basalis provides cholinergic innervation to the cor-
(Ballard et al. 2001, McKeith et al. 1994a); they tend to last in tex, and there is a good correlation between loss of cortical
the order of hours and, importantly, occur spontaneously, choline acetyltransferase activity and the severity of the
without any precipitating events (Bradshaw et al. 2004). dementia (Tiraboschi et al. 2002). In turn, there is also a
Depression may occur during the course of the demen- good correlation between the occurrence of visual halluci-
tia (Burkhardt et al. 1988) and indeed has been noted in up nations and the burden of Lewy bodies in the amygdala,
to one-half of all patients (Klatka et al. 1996). parahippocampus, and inferior temporal cortex (Harding
The parkinsonism of diffuse Lewy body disease is very et al. 2002b).
similar to the classic parkinsonian picture seen in It appears that most cases are sporadic, with only a few
Parkinson’s disease, with bradykinesia, rigidity, and pos- familial instances being reported (Galvin et al. 2002).
tural instability (Hely et al. 1996); tremor, however, is
somewhat less commonly present (Louis et al. 1995, 1997).
Like all parkinsonian patients, those with diffuse Lewy Differential diagnosis
body disease are apt to experience a worsening of their
parkinsonism upon exposure to antipsychotics; however, The differential considerations vary depending on whether
in diffuse Lewy body disease, the exacerbation tends to be the presentation of diffuse Lewy body disease is with
quite severe, a phenomenon known as ‘neuroleptic sensi- dementia or with parkinsonism.
tivity’ (McKeith et al. 1992a,b; Weiner et al. 1996). In some In cases that present with dementia, consideration, as
cases, the exacerbation may persist long after the antipsy- discussed in Section 5.1, must be given to certain other dis-
chotic has been discontinued, and fatalities have occurred. orders capable of causing a dementia of gradual onset,
In cases that present with dementia, parkinsonism typi- including Alzheimer’s disease, Binswanger’s disease, and
cally appears within a matter of years. In cases that present lacunar dementia. Several features of diffuse Lewy body
with parkinsonism, a dementia supervenes relatively soon disease facilitate this differential. The most important is the
thereafter, typically within a year. early appearance, within a year of the onset of the demen-
Other symptoms seen in diffuse Lewy body disease tia, of parkinsonism. Other distinctive features are the
include myoclonus (seen in about one-fifth of patients early and prominent nature of visual hallucinations and
p 08.qxd 3/10/08 9:38 AM Page 352
the occurrence of confusional episodes. Although confu- 25 to 75 mg/day, was beneficial in the majority of cases but
sional episodes may occur, for example, in Alzheimer’s dis- frequently caused sedation and orthostatic hypotension.
ease, they generally appear later and typically occur only in Risperidone, at a dose of 1 mg/day, was beneficial in a case
stressful situations (e.g., when a patient is confronted with report (Kato et al. 2002). Interestingly, clozapine, at a dose
a cognitively demanding task), in contrast to the confu- of 6.25 mg/day, was not only ineffective but also actually
sional episodes of diffuse Lewy body disease, which appear worsened the hallucinations and delusions (Burke et al.
spontaneously. Neuroleptic sensitivity may also provide a 1998). Clearly, more work is needed here.
clue: in some cases of diffuse Lewy body disease that pres- With regard to the treatment of depression, there are no
ent with dementia, there may be a subclinical parkinson- controlled studies. Consideration may be given to an anti-
ism, and in these patients treatment with an antipsychotic depressant, such as an SSRI (McKeith et al. 2005), or, in
may be followed by a florid, and totally unexpected, severe and treatment-resistant cases, ECT (Rasmussen
parkinsonism (McKeith et al. 1992c, 1994b). et al. 2003). In case reports, patients with REM sleep
In cases that present with parkinsonism, other neurode- behavior disorder have responded well to both clonazepam
generative disorders, as discussed in Section 3.8, must be and donepezil (Massironi et al. 2003).
considered, including Parkinson’s disease, multiple system The parkinsonism of diffuse Lewy body disease may
atrophy, progressive supranuclear palsy, and corticobasal respond to combination treatment with levodopa/
ganglionic degeneration. With regard to Parkinson’s dis- carbidopa (Byrne et al. 1989); however, the response is
ease, the most important distinguishing feature is what has generally not as robust as that seen in Parkinson’s disease
come to be known as the ‘1-year rule’. As noted earlier, in (Molloy et al. 2005). There is little published experience
cases of diffuse Lewy body disease that present with regarding the use of dopamine agonists such as pramipex-
parkinsonism, there will generally be a dementia within ole or ropinirole.
1 year; although Parkinson’s disease may also cause demen-
tia, the dementia typically ‘breaks’ the 1-year rule in that
many years pass before cognitive features appear. Multiple
system atrophy is suggested by concurrent ataxia; progres- 8.7 PROGRESSIVE SUPRANUCLEAR PALSY
sive supranuclear palsy by frequent falls, an extension pos-
ture, and supranuclear ophthalmoplegia; and corticobasal Progressive supranuclear palsy, also known as the Steele–
ganglionic degeneration by a strikingly asymmetric parkin- Richardson–Olszewski syndrome, is characterized by an
sonism accompanied by dystonia and cortical sensory loss. atypical parkinsonism, which is accompanied in most cases
by a supranuclear ophthalmoplegia and, in about half of
cases, by a dementia. This is an uncommon disorder, found
Treatment somewhat more frequently in men than women.
The dementia may be treated with rivastigmine: doses of

6–12 mg not only improved cognition but also reduced the Clinical features
severity and frequency of hallucinations and delusions
(McKeith et al. 2000, Wesnes et al. 2002); open-label stud- The general clinical features have been described in several
ies also suggest benefit from donepezil (Thomas et al. reports (Birdi et al. 2000; Collins et al. 1995; Litvan et al.
2005) and galantamine (Edwards et al. 2004). Memantine 1996b; Maher and Lees 1986; Messert and Van Nuis 1966;
should probably be avoided, as it has been reported to Steele 1972; Steele et al. 1964). The onset is insidious, gen-
worsen cognition (Sabbagh et al. 2005) and hallucinations erally in the sixth decade, and the disease typically presents
and delusions (Ridha et al. 2005). In cases in which hallu- with frequent unexplained falls due to postural instability.
cinations and delusions persist despite treatment with An atypical parkinsonism then gradually appears, charac-
rivastigmine, and which are clinically troubling, considera- terized by a more or less symmetric onset of rigidity, gen-
tion may be given to using an antipsychotic. Given the erally without tremor, and an abnormal gait typified by a
neuroleptic sensitivity characteristic of diffuse Lewy body wide-based stance with short, shuffling steps. Importantly,
disease, first-generation agents, such as haloperidol, are rather than the typical flexion posture seen in most cases of
best avoided, as they are more likely to cause parkinsonism parkinsonism, patients with progressive supranuclear
than the second-generation agents. Second-generation palsy typically display a dystonic axial rigidity, which may
agents used in diffuse Lewy body disease include olanzap- also affect the neck. Dystonic rigidity also affects the facial
ine, quetiapine, and risperidone. Olanzapine, in a post hoc musculature, at times creating an ‘astonished’ appearance,
analysis of a larger study, was effective at doses from 5 to as seen in Figure 8.6.
10 mg, but not at doses of 15 mg (Cummings et al. 2002); Classically, from 1 to 3 years after the parkinsonism is
an open study of olanzapine using doses from 2.5 to 7.5 mg established, one also sees a supranuclear ophthalmoplegia
reported either intolerable side-effects or minimal benefit for vertical gaze, wherein patients have difficulty voluntar-
(Walker et al. 1999). In two case series (Fernandez et al. ily looking down, a difficulty that may make walking down
2002, Takahashi et al. 2003), quetiapine, in doses from stairs particularly treacherous. This feature, however, may
p 08.qxd 3/10/08 9:38 AM Page 353
8.7 Progressive supranuclear palsy 353
the mesencephalic tectum, periaqueductal gray matter,

locus ceruleus, substantia nigra, dentate nucleus, red
nucleus, thalamus (especially in the caudal intralaminar
nuclei), globus pallidus, subthalamic nucleus, and the tem-
poral and inferior frontal cortices. This cell loss is accom-
panied by a gliosis and, in surviving neurons, one finds
neurofibrillary tangles that are dissimilar to those found in
Alzheimer’s disease (Takahashi et al. 1989).
Although definite autosomal dominantly inherited
cases have been identified (Brown et al. 1993; Rojo et al.
1999; Ros et al. 2005a,b; Stanford et al. 2000; de Yebenes et
al. 1995), the vast majority of cases appear to be sporadic.
There does, however, appear to be a ‘susceptibility geno-
type’, composed of normal variants in the gene for tau,
which predisposes to classic progressive supranuclear palsy
(Higgins et al. 1999; Morris et al. 2002).
As discussed in detail in Section 3.8, progressive supra-

nuclear palsy must be distinguished from certain other
Figure 8.6 ‘Astonished’ facial appearance in progressive neurodegenerative disorders capable of causing a parkin-
supranuclear palsy. (Reproduced from Stern 1990.) sonism of gradual onset and slow progression, including
Parkinson’s disease, diffuse Lewy body disease, multiple
system atrophy (of the striatonigral variant), and corti-
cobasal ganglionic degeneration. Three clinical features of
be delayed for many years, and in some cases may never progressive supranuclear palsy, if present, generally allow
appear (Birdi et al. 2002; Daniel et al. 1995). for an accurate differentiation from all of these other disor-
Dementia occurs in about one-half of all patients, gen- ders, namely postural instability, frequent unexplained
erally well after the parkinsonism has become established: falls, and supranuclear ophthalmoplegia; if all three of
patients have difficulty with concentration and memory, these are present during the first year of illness, the diagno-
and there may be elements of a frontal lobe syndrome sis of progressive supranuclear palsy is almost assured
(Verny et al. 1996) with prominent apathy (Litvan et al. (Litvan et al. 1996c, 1997b). As noted above, however,
1996a). Rarely, dementia may constitute the presenting supranuclear palsy may be delayed for years, and in some
symptom of progressive supranuclear palsy (Davis et al. pathologically proven cases it may never have appeared. In
1985). Over time, pseudobulbar palsy with emotional such cases, one may look to other distinguishing features,
incontinence (Menza et al. 1995) may occur, and seizures namely the fact that Parkinson’s disease, diffuse Lewy body
may occur in a small minority (Nygaard et al. 1989). disease, multiple system atrophy, and corticobasal gan-
Aphasia, agnosia, and apraxia are rare. glionic degeneration are all characterized by an asymmet-
Magnetic resonance scanning may reveal atrophy of the ric onset of parkinsonism with, if anything, a flexion
midbrain and, in some cases, of the frontal and temporal posture, in marked contrast to progressive supranuclear
cortices. palsy, in which one sees a symmetric onset with an exten-
sion posture.
Course
Progressive supranuclear palsy is progressive, with death Treatment

within 5–7 years (Golbe et al. 1988; Maher and Lees 1986).
Levodopa or dopamine agonists may offer some benefit for
the parkinsonism, but this is modest at best and any bene-
Etiology fit is generally short-lived (Birdi et al. 2002). Interestingly,
amitriptyline, in low doses from 25 to 50 mg, improves the
Macroscopically there is atrophy of the midbrain, globus parkinsonism, especially regarding gait (Kvale 1982;
pallidus and, in some cases, the frontotemporal cortex. Newman 1985). Donepezil provided very modest benefit
Microscopically (Collins et al. 1995; Henderson et al. 2000; for dementia but worsened the parkinsonism, and on bal-
Litvan et al. 1996b; Steele et al. 1964), cell loss is noted in ance may not be beneficial (Litvan et al. 2001).
p 08.qxd 3/10/08 9:38 AM Page 354
8.8 CORTICOBASAL GANGLIONIC to the contralateral side, and the temporal lobes and ante-
DEGENERATION rior portions of the frontal lobes may become involved.
Microscopically, changes are seen in these areas and in the
Corticobasal ganglionic degeneration, also know as corticobasal ganglia and substantia nigra, consisting of neuronal
basal degeneration, is a rare disorder, apparently equally loss and astrocytosis; surviving neurons are large, ballooned,
common in men and women. It is characterized by an and achromatic and contain tau-positive filaments. The
atypical parkinsonism, a dementia, or both. vast majority of cases are sporadic.
Clinical features Differential diagnosis
The onset is gradual, usually in the sixth or seventh decade. When the presentation is with parkinsonism, considera-
Clinically (Litvan et al. 1997c; Riley et al. 1990; Rinne et al. tion may be given to Parkinson’s disease, diffuse Lewy
1994a; Wenning et al. 1998), most patients present with a body disease, multiple system atrophy, and progressive
strikingly asymmetric rigid akinetic parkinsonism affecting supranuclear palsy, as outlined in Section 3.8. Several fea-
an upper limb; dystonic rigidity may also be present tures set corticobasal ganglionic degeneration apart from
(Vanek and Jankovic 2001). Cortical sensory loss and these disorders, including the striking asymmetry of the
apraxia are common, as is myoclonus. Dementia occurs in parkinsonism and the accompanying sensory loss and
about one-half of patients and, although this usually fol- apraxia. When the presentation is with dementia, consid-
lows the motor disturbance by years, it may at times be the eration, as discussed in Section 5.1, must be given to other
presenting feature (Bergeron et al. 1996; Schneider et al. disorders capable of causing a dementia of subacute or
1997); indeed, in two series (Grimes et al. 1999; Murray gradual onset, such as Alzheimer’s disease, diffuse Lewy
et al. 2007), the majority of patients presented with demen- body disease, Binswanger’s disease, etc. The correct diag-
tia. In patients who do develop dementia, depression is nosis here may remain elusive until the asymmetric
common; apathy and irritability may also occur (Litvan parkinsonism appears. In cases that present with aphasia,
et al. 1998). Corticobasal ganglionic degeneration may the differential diagnosis of primary progressive aphasia, as
rarely present with a primary progressive aphasia (Geda discussed in Section 2.1, should be considered.
et al. 2007; Ikeda et al. 1996) or with a personality change
with frontal lobe features (Geda et al. 2007). Many authors
also comment on the presence of an alien hand sign in cor- Treatment
ticobasal ganglionic degeneration, but, as pointed out in
Section 4.13, this sign is not in fact well described in this The general treatment of dementia is discussed in Section
disorder: rather, patients display such purposeless move- 5.1. Supportive measures, including physical and occupa-
ments as grasping, ‘wandering’ (Rinne et al. 1994a; Sawle tional therapy, may be beneficial for the movement disor-
et al. 1991), or levitation (Gibb et al. 1994; Riley et al. der; the parkinsonism generally does not respond to
1990). levodopa (Rinne et al. 1994a).
MRI scanning may reveal asymmetric cortical atrophy
affecting primarily the parietal and frontal cortices.
8.9 MULTIPLE SYSTEM ATROPHY
Course Multiple system atrophy, as the name suggests, is charac-
terized pathologically by involvement of multiple systems.
Over a long period of time, the parkinsonism gradually This involvement, however, does not proceed evenly, and
becomes bilateral; in some cases cerebellar signs may consequently the disease may present in different fashions,
appear and, rarely, a supranuclear ophthalmoplegia has depending on which system is involved first (Papp and
been noted. Death typically occurs within 6–10 years, gen- Lantos 1994; Quinn 1989). Three variants are generally
erally secondary to aspiration pneumonia. recognized, namely the striatonigral variant, the olivopon-
tocerebellar variant, and the Shy–Drager variant.
This is an uncommon disease and is somewhat more
Etiology frequent in men than women.
The pathology of corticobasal ganglionic degeneration has

been described in a number of papers (Gibb et al. 1994; Clinical features
Rebeiz et al. 1968; Riley et al. 1990; Rinne et al. 1994a).
Macroscopically there is asymmetric cortical atrophy, The onset is gradual and typically occurs in the sixth
affecting primarily the parietal lobe and the posterior por- decade. As noted, this disease may present in one of three
tion of the frontal lobe; over time, the atrophy may spread fashions, each described below.
p 08.qxd 3/10/08 9:38 AM Page 355
8.9 Multiple system atrophy 355
The striatonigral variant (Colosimo et al. 1995; Etiology

Watanabe et al. 2002; Wenning et al. 1995), seen when the
striatum and substantia nigra are most involved, is charac- Macroscopically there is variable atrophy of the cerebral
terized by the gradual onset of parkinsonism. The parkin- cortex (particularly the frontal area), striatum (more so
sonism is similar to that seen in Parkinson’s disease, with the putamen than the caudate), pons, inferior olives, and
the exceptions that the flexion posture is often extreme and cerebellum (Ozawa et al. 2004; Wenning et al. 1996).
tremor is seen in only a minority and is typically not of the Microscopically, cell loss and astrocytosis are seen not only
classic pill-rolling type. Furthermore, patients with the stri- in these areas but also in the substantia nigra, locus ceruleus,
atonigral variant may have other signs not typical of ventrolateral medulla (Benarroch et al. 1998), and interme-
Parkinson’s disease, such as hyper-reflexia and extensor diolateral gray matter of the spinal cord. Cytoplasmic inclu-
plantar responses, myoclonus, and, rarely, supranuclear sions containing alpha-synuclein are seen in oligodendroglia
ophthalmoplegia for downward gaze (Wenning et al. 1995). and in surviving neurons.
The olivopontocerebellar variant (Watanabe et al. 2002), Multiple system atrophy is a sporadic disorder of
seen with involvement of the inferior olives, basis pontis, unknown cause.
and cerebellar cortex, is characterized by the gradual onset
of ataxia, intention tremor, dysarthria, and scanning speech;
reflex myoclonus is also commonly seen (Rodriguez et al.
1994) and a recent study found emotional incontinence in
roughly one-third of all cases (Parvizi et al. 2007).
Differential considerations vary according to the variant
The Shy–Drager variant (Shy and Drager 1960), seen
with which multiple system atrophy presents. In cases of the
when the intermediolateral gray matter of the spinal cord is
striatonigral variant, consideration, as discussed in Section
heavily involved, is characterized by evidence of auto-
3.8, must be given to certain other neurodegenerative disor-
nomic failure, such as urinary retention or incontinence,
ders capable of causing parkinsonism, such as Parkinson’s
postural dizziness or syncope, erectile dysfunction, and,
disease, diffuse Lewy body disease, progressive supra-
rarely, fecal incontinence (Wenning et al. 1994).
nuclear palsy, and corticobasal ganglionic degeneration.
Dementia may occur in a minority of patients with multi-
Although a relatively pure case of the striatonigral variant
ple system atrophy and may be distinguished by elements of
might be difficult to distinguish from other causes of classic
a frontal lobe syndrome (Robbins et al. 1992). Rarely, multi-
parkinsonism, especially Parkinson’s disease or diffuse
ple system atrophy may present with a personality change
Lewy body disease, the eventual appearance of evidence of
and dementia, as has been noted in a case of the olivoponto-
other system involvement, for example the appearance of
cerebellar variant (Critchley and Greenfield 1948).
ataxia, will secure the diagnosis. In cases of the olivoponto-
Regardless of which variant the disease presents with,
cerebellar variant, consideration is given to alcoholic or
over a matter of years most patients will eventually display
paraneoplastic cerebellar degeneration, and to spinocere-
features of all three variants. Many patients also eventually
bellar ataxia, which is distinguished by its autosomal domi-
develop laryngeal stridor.
nant inheritance; fragile X-associated tremor/ataxia
Interestingly, there is a strong association between mul-
syndrome (FXTAS) may be difficult to distinguish on clini-
tiple system atrophy and REM sleep behavior disorder
cal grounds, and genetic testing may be required.
(Iranzo et al. 2005): one report (Plazzi et al. 1997) noted
that the vast majority of patients with multiple system
atrophy had this disorder, which could precede the devel-
opment of typical symptomatology by years. Treatment
Magnetic resonance scanning may reveal atrophy of the
striatum, pons, inferior olives, and cerebellum. In some Parkinsonism may be treated with levodopa, but the
cases, especially those with the striatonigral variant, the response is neither prolonged nor robust and side-effects
putamen displays decreased signal intensity on T2- are common (Wenning et al. 1995). Interestingly, there is a
weighted scanning but laterally has a surrounding rim of double-blind study that demonstrated an improvement in
increased signal intensity. In other cases, especially those parkinsonism after treatment with paroxetine, in doses of
with the olivopontocerebellar variant, the basis pontis will up to 60 mg/day (Freiss et al. 2006). There is no known
display the ‘hot cross bun sign’ on axial T2-weighted treatment for the cerebellar symptoms. Postural dizziness
images, wherein the base of the pons is marked by lines that may respond to fludrocortisone or midodrine. Erectile dys-
give it the appearance of a hot cross bun seen from above. function has been treated with sildenafil; however, this was
often not tolerated because of an aggravation of hypoten-
sion (Hussain et al. 2001). The general treatment of demen-
Course tia is discussed in Section 5.1. Continuous positive airway
pressure (CPAP) or BIPAP may be helpful in cases of laryn-
The disease is gradually progressive, with death, often from geal stridor; however, tracheostomy may eventually be
aspiration pneumonia, generally within 6–9 years. required.
p 08.qxd 3/10/08 9:38 AM Page 356
8.10 HUNTINGTON’S DISEASE through the hair, as if the purpose had all along been to
straighten the hair. Dysarthria often occurs, as does dys-
Huntington’s disease, also known as Huntington’s chorea phagia, which may lead to aspiration (Leopold and Kagel
or chorea major, is an autosomal dominantly inherited dis- 1985). The chorea eventually makes almost all purposeful
order that is characterized, in its full expression, by a com- activity, whether eating, dressing, or walking, almost
bination of chorea and dementia. This disorder was first impossible, and patients eventually become chairbound or
clearly characterized by George Huntington in 1872, who bedridden. At the end, the chorea may gradually disappear,
observed a number of affected families in East Hampton to be replaced by a rigid, akinetic state (Feigin et al. 1995).
on Long Island (Brody and Wilkins 1967; Huntington In advanced cases, seizures may also occur.
1872). Although the lifetime prevalence is not high (from The personality change presents with poor judgment,
0.004 to 0.008 among white populations, and only one- impulsivity, irritability, and an overall coarsening of behav-
third of that in black populations and one-tenth among ior. Over time, as noted earlier, a dementia develops, char-
Japanese populations), these patients are not uncommonly acterized by deficits in memory, concentration, calculation,
seen in hospital and clinic. and abstraction; focal signs, such as aphasia and apraxia, are
generally not seen. Associated symptoms are found in the
vast majority of patients (Caine and Shoulson 1983;
Clinical features Folstein et al. 1983; Paulsen et al. 2001). These include
depression of variable severity in roughly half, agitation,
The onset is generally highly insidious and may occur any- irritability, apathy and anxiety, and, in a minority, euphoria
where from childhood to the eighth decade, with most or, rarely, mania. Delusions, generally of persecution, and,
patients falling ill in their 30s. The presentation may be less commonly, hallucinations may be seen in a small
with either chorea or a personality change; over time, in minority, and, albeit rarely, Huntington’s disease may pres-
the vast majority of patients, both these syndromes will ent with a psychosis (Caine and Shoulson 1983). Suicidal
become present and be joined by the gradual development ideation is common (Paulsen et al. 2005), and suicide itself
of a dementia (Pflanz et al. 1991). Exceptions to this rule occurs in a significant minority (Schoenfeld et al. 1984).
do occur, especially in those with late onset in the sixth As noted earlier, Huntington’s disease may present in
decade or beyond, when one may see primarily chorea, childhood or adolescence, and when it does one often sees
with little or no cognitive deficit (Britton et al. 1995). what is known as the Westphal variant of Huntington’s
Chorea may initially present as fidgetiness, clumsiness, or disease, in which, rather than chorea, there is often a rigid,
a tendency to drop things; obvious choreiform movements akinetic state that is generally accompanied by severe
are generally first visible on the face (including the fore- dementia, often with seizures, myoclonus, and ataxia (Bird
head), from where they spread to involve the trunk and and Paulson 1971; Campbell et al. 1965; Hansotia et al.
extremities. There may be facial grimacing, brow wrinkling, 1968; Jervis 1979; Siesling et al. 1997); in other cases, rather
and blinking; upper extremity involvement may lead to than parkinsonism, the presentation may be with chorea,
shoulder shrugging, abrupt flinging of the arms, or purpose- myoclonus, or dementia (Ribai et al. 2007).
less ‘piano-playing’ movements of the hands. In shaking the Computed tomography or axial MR scanning may be
patient’s hand, one may note the classic ‘milkmaid’ grip, normal early in the course of the disease; over time, however,
wherein the patient’s grasping of the examiner’s hand feels because of atrophy of the caudate nuclei, there is a character-
as if the patient is attempting to milk a cow. Lower extrem- istic dilation of the frontal horns of the lateral ventricles,
ity involvement may lead to a lurching, staggering, or ‘danc- yielding a characteristic ‘butterfly’ configuration. Cortical
ing and prancing’ gait, which in some cases may so resemble atrophy, especially of the frontal lobes, may also be seen.
the gait seen in alcohol intoxication that patients have been As noted below, Huntington’s disease is a fully pene-
arrested for public intoxication (Lesse 1946). Importantly, trant, autosomal dominant disease, and genetic testing is
these choreiform movements are quite brief, appearing and highly specific and sensitive (International Huntington
disappearing on a random basis from one location to Association 1994; Kremer et al. 1994). A positive family his-
another with lightning-like rapidity. Interestingly, although tory is almost universally found, and in one American fam-
some patients seem fully aware of their chorea, it is not at all ily it was possible to trace the disease back to an ancestor
uncommon to find patients with obvious chorea denying who arrived with the Puritans (Vessie 1932). Exceptions to
that anything is amiss. The depth of this denial is at times this rule may occur secondary to rarely occurring sponta-
extreme: I have seen patients with chorea of such severity as neous mutations or, more commonly, to uncertain parent-
to preclude safe ambulation who nevertheless stoutly deny age (Ramos-Arroyo et al. 2005).
that anything at all is amiss.
Early on in the course of the disease, patients may
attempt, with varying degrees of success, to disguise the Course
choreic movements by merging them with purposeful
movements: for example, a choreic fling of the arm up to Huntington’s disease is relentlessly progressive: most
the head may be purposefully extended to draw the fingers patients die within 10–30 years of onset, with an average
p 08.qxd 3/10/08 9:38 AM Page 357
8.10 Huntington’s disease 357
life expectancy of about 15 years. Those with an earlier age Differential diagnosis
of onset, for example those with the Westphal variant,
experience a more rapid course, with death within about Genetic testing has greatly simplified the differential diag-
10 years; conversely, those with a late onset, in the fifth nostic task, and should be considered in any patient with
decade or beyond, typically experience a more leisurely the gradual onset of chorea in late adolescence or early
course. adult years. The other disorders to consider in the differen-
tial are discussed in Section 3.4, and certain clinical fea-
tures, atypical for Huntington’s disease, should suggest a
Etiology close look. These include tics, dystonia or lip-biting (seen
in choreoacanthocytosis), ataxia (in dentatorubropalli-
Huntington’s disease is a fully penetrant autosomal domi- doluysian atrophy), dystonia or parkinsonism (in Fahr’s
nant disorder: the affected gene codes for a protein known syndrome), and dystonia or tremor (in Wilson’s disease).
as huntingtin and is located on chromosome 4. The gene Another differential possibility to consider is schizo-
normally contains anywhere from 10 to 29 CAG trinu- phrenia, especially when this is complicated by tardive
cleotide repeats, whereas in Huntington’s disease, any- dyskinesia. As noted above, the dementia of Huntington’s
where from 36 to 121 repeats may be found (Kremer et al. disease may be complicated by delusions or hallucinations,
1994). Very rarely, sporadic cases may occur: in such cases, and in some cases these symptoms may be very prominent,
it appears that the patient’s father, himself unaffected, har- thus creating a clinical syndrome of psychosis and chorea,
boured a number of CAG repeats that, although still within which, at first glance, may appear similar to that seen when
the bounds of normal, were unstable and underwent schizophrenia is complicated by tardive dyskinesia. Certain
expansion (Myers et al. 1993). Although an inverse corre- features of the chorea seen in these two situations, however,
lation has been found with the number of repeats and the may enable a clinical differentiation. The chorea of tardive
age of onset (Marder et al. 2002), there is apparently no dyskinesia is generally stereotyped and repetitive, almost
correlation with the appearance of mood changes or delu- never involves the forehead, and generally leaves gait rela-
sions or hallucinations (Tsuang et al. 2000; Zappacosta tively unaffected. This is in contrast to the chorea of
et al. 1996). Huntington’s disease, which is mercurial, flitting from one
Macroscopically, atrophy is noted in the caudate (as body part to another in an unpredictable fashion, and
illustrated in Figure 8.7), less so in the putamen, and to a which typically affects the forehead and gait.
degree in the frontal and parietal cortices. Neuronal loss
and reactive astrocytosis is noted in these areas; in the cau-
date nucleus in particular, spiny neurons are lost first Treatment
(Mann et al. 1993b; Myers et al. 1988). Surviving neurons
may display intranuclear inclusions, which contain the The severity of chorea may be reduced by treatment with
huntingtin protein. antipsychotics. Of the antipsychotics, the first-generation
agent haloperidol is most often used, in doses from 1 to
10 mg/day (Barr et al. 1988). Akathisia may occur with
haloperidol and, hence, second-generation agents, such as
olanzapine (Bonelli et al. 2002; Dipple 1999; Paleacu et al.
2002), are also being used. Tetrabenazine, a dopamine
depleter not available in the United States, is also beneficial
(Huntington Study Group 2006). Amantadine may have a
place here also. Although a double-blind study of amanta-
dine, in a dose of 300 mg/day, found no benefit relative to
placebo (O’Suilleabhain and Dewey 2003), another study
(Verhagen Metman et al. 2002) did find a benefit, but only
with a higher dose of 400 mg/day.
The general treatment of dementia is discussed in
Section 5.1. In cases complicated by agitation or delusions
or hallucinations, antipsychotics may also be useful.
Depression may respond to an antidepressant, such as an
SSRI. With progression of the disease, institutionalization
becomes almost inevitable.
Ongoing research efforts are underway to find treat-
Figure 8.7 Marked atropy of the caudate, with compensatory ments that may retard the progression of the disease, and
ventricular dilation, in a case of Huntington’s disease compared many patients are highly motivated to participate.
with a control brain on the right. (Reproduced from Graham and As noted earlier, genetic testing is now available, and
Lantos 1996.) should be offered to patients with a compatible clinical
p 08.qxd 3/10/08 9:38 AM Page 358
picture and to unaffected relatives. Extensive counselling chromosome 9q21 (formerly known as CHAC), which
resources should be available for instances when the test is codes for a protein known as chorein. There may be con-
positive. siderable phenotypic heterogeneity in the same family.
Macroscopically, there is atrophy of the caudate, puta-
men, and, to a lesser degree, the globus pallidus. Micro-
8.11 CHOREOACANTHOCYTOSIS scopically, neuronal loss and gliosis are seen in these
structure and in the substantia nigra (Rinne et al. 1994b).
Choreoacanthocytosis, also known as chorea-acantho- Axonal loss occurs in the peripheral nerves (Hardie et al.
cytosis, is a rare autosomal recessively inherited disorder 1991; Ohnishi et al. 1981).
that typically manifests with chorea, as well as dementia in
roughly half of cases; in all cases one also finds an excessive
percentage of acanthocytic red blood cells. This last Differential diagnosis
characteristic, namely acanthocytosis, qualifies choreo-
acanthocytosis as one member of a larger group of disor- The differential for chorea is discussed in Section 3.4; of
ders known as the neuroacanthocytoses, which, as noted the disorders considered there, several others, in addition
below in the discussion on differential diagnosis, includes to choreoacanthocytosis, present with chorea in early
such conditions as the McLeod syndrome. adult years and must be distinguished from choreo-
acanthocytosis. Huntington’s disease is marked by autoso-
mal dominant inheritance and an absence of a peripheral
Clinical features neuropathy and, critically, a lack of acanthocytosis. As noted
earlier, other disorders, in addition to choreoacanthocytosis,
The onset is generally in the late twenties or early thirties may also present with chorea and acanthocytosis, and these
but may occur anywhere from late childhood to the sev- include the McLeod syndrome and Huntington’s disease-
enth decade. Clinically (Critchley et al. 1968; Feinberg et al. like 2 (Walker et al. 2002). The McLeod syndrome is distin-
1991; Hardie et al. 1991; Kartsounis and Hardie 1996; guished by X-linked inheritance and Huntington’s
Lossos et al. 2005; Sakai et al. 1981), most cases present with disease-like 2 by an autosomal dominant pattern of inheri-
a gradually progressive chorea, which, over time, is often tance. Genetic testing is available for all of these disorders.
joined by other abnormal movements, such as tics, dystonia,
or a mild parkinsonism. A classic symptom, seen, however,
in only a minority, is self-mutilating lip- or tongue-biting. Treatment
Importantly, this self-mutilation is outside the patient’s
control: one patient (Medalia et al. 1989), despite attempt- As for Huntington’s disease, chorea may be treated with
ing to ‘restrain herself . . . by placing her fingers or a folded antipsychotics; the general treatment of dementia is dis-
towel in her mouth . . . nevertheless had bleeding and cussed in Section 5.1.
scarred lesions of her oral mucosa and lips’. Most patients
will also develop a sensorimotor peripheral poly-neuropa-
thy, and, in a minority, seizures may occur. Roughly half of 8.12 FXTAS
all patients will also develop a personality change, a
dementia, or both. FXTAS, also known as the fragile X-associated tremor/ataxia
Acanthocytosis to a degree of 10 percent or more is seen syndrome, is a recently described inherited disorder charac-
on peripheral smears; importantly, the smears must be terized by the gradual development of tremor, ataxia, and, in
fresh wet preparations and, given the chance of false a minority, dementia in middle-aged or older adults. This is
negatives, at least three smears should be examined not an uncommon disorder, and although cases have been
(Hardie et al. 1991). Genetic testing is available. reported in women (Hagerman et al. 2004), it is far more
Creatinine kinase is elevated in most cases and MR common in men.
scanning may reveal atrophy of the caudate nucleus.
Course Clinical features
Clinical features have been described in a number of

The disease is gradually progressive, with death, on aver-
papers (Greco et al. 2006; Hagerman et al. 2001; Hall et al.
age, after 14 years.
2005). Although the age of onset ranges from the fourth to
the ninth decade, most patients fall ill in the seventh
Etiology decade with the gradual onset of ataxia and tremor. The
tremor, although typically of the intention type, may also
Choreoacanthocytosis is an autosomal recessive condition have a rest or postural component. Over time, a mild
occurring secondary to mutations in the VPS13A gene on parkinsonism may also accrue, with rest tremor, rigidity,
p 08.qxd 3/10/08 9:38 AM Page 359
8.13 Senile chorea 359
and bradykinesia. A peripheral neuropathy is common, Differential diagnosis

and some patients may experience autonomic symptoms,
such as erectile dysfunction. Spinocerebellar ataxia is suggested by the autosomal dom-
Cognitive deficits eventually appear, and anywhere inant pattern of inheritance. Multiple system atrophy may
from one-quarter to one-half of all patients may eventually be difficult to distinguish on clinical grounds, and the dif-
become demented: short-term memory loss, poor concen- ferential may rest on genetic testing.
tration, concreteness, and poor judgment are common. One clue to the diagnosis rests in the family history.
Frontal lobe symptomatology may also be seen, with disin- When the diagnosis is considered in a middle-aged or eld-
hibition, perseveration, and inappropriate jocularity, and erly man, one should inquire whether any of his grand-
mood changes are common, with agitation, irritability, children have mental retardation. If the middle-aged or
apathy, or depression (Bacalman et al. 2006; Bourgeois elderly man in question does have FXTAS, then any daugh-
et al. 2007). ters would also have the ‘pre-mutation’. Increases in repeat
Magnetic resonance scanning may reveal both cerebral length are likely during oogenesis and, consequently, a
and cerebellar cortical atrophy. The most characteristic daughter may have passed on a ‘full’ mutation to one of her
finding, however, is the ‘middle cerebellar peduncle’ sign: children, who, in turn, might express the fragile X syn-
on T1-weighted scans these peduncles show decreased sig- drome with mental retardation. As noted above, FXTAS is
nal intensity, and on T2-weighted scans there is increased much less likely in females and, when it does occur, it is less
signal intensity (Brunberg et al. 2002). This sign, although severe; this is probably due to the fact that females who do
not universally present, becomes more likely later in the have the ‘pre-mutation’ also have a normal gene on the
course of the disease. Genetic testing is available. other X chromosome. In cases of middle-aged or elderly
women suspected of having FXTAS, the family history may
also help; however, here one looks only to the children and
Course not the grandchildren for the telltale finding of mental
retardation.
Symptoms progress very slowly.
Treatment
Etiology
The general treatment of dementia is described in Section
As might be gathered from the name of this syndrome, 5.1; as yet there are no controlled studies focusing on
FXTAS bears a relationship to the fragile X syndrome: both FXTAS itself.
occur as the result of a mutation in the fragile X mental
retardation 1 (FMR1) gene, located on the long arm of the
X chromosome. 8.13 SENILE CHOREA
Normally, the FMR1 gene contains anywhere from 5 to
55 CGG trinucleotide repeats. The mutation in question Senile chorea is a rare disorder characterized by the gradual
involves an increase in the number of these repeats beyond onset of chorea late in life, in the absence of a family history.
the normal range. Increases into the range of 55 to 200
repeats have traditionally been termed a ‘premutation’
whereas increases above 200 repeats have been considered
Clinical features
to constitute a ‘full’ mutation. Individuals with full muta-
The onset is insidious and generally in the seventh decade.
tions, especially men, typically develop the fragile X syn-
Clinically, one sees the gradual progression of a mild
drome, with mental retardation. Until recently, it had been
chorea, generally involving the upper extremities or the
thought that those with a ‘premutation’ were merely carri-
face (Delwaide and Desseilles 1977; Klawans and Barr
ers who remained free of any symptoms. The recognition
1981; Shinotoh et al. 1994; Varga et al. 1982). There are no
of FXTAS, however, has now made it clear that this ‘pre-
other abnormal movements and no dementia.
mutation’, rather than being benign, may cause symptoms
in its own right. Indeed, among men with the premutation,
the penetrance progressively rises from roughly 20 percent Course
in those from 50 to 59 years of age up to 75 percent in those
aged 80 or above (Jacquemont et al. 2004). The disorder is very gradually progressive.
Macroscopically, there is cerebral and cerebellar cortical
atrophy. Microscopically (Greco et al. 2002, 2006), there is
neuronal loss in these areas, and status spongiosus in the Etiology
cerebellar white matter and the middle cerebellar pedun-
cles. Intranuclear inclusions are found in both astrocytes Microscopically, neuronal loss is noted in the caudate. The
and surviving neurons. mechanism is not known.
p 08.qxd 3/10/08 9:38 AM Page 360
Differential diagnosis Differential diagnosis

Of the disorders capable of causing chorea, discussed in Other disorders capable of causing chorea in childhood, as
Section 3.4, special consideration should be given to the discussed in Section 3.4, include Sydenham’s chorea and
following (Warren et al. 1998): late-onset Huntington’s cerebral palsy. The autosomal dominant pattern displayed,
disease, the anti-phospholipid syndrome, tardive dyskine- and the course, however, are quite distinctive.
sia, and Fahr’s syndrome; of these, Huntington’s disease is
the most likely and, hence, genetic testing is in order
(Garcia Ruiz et al. 1997). Edentulousness should also be
Treatment
considered, as it may be accompanied by orofacial move-
ments that resemble chorea (Koller 1983).
There are no established treatments; in case reports, lev-
odopa was beneficial (Asmus et al. 2005). Consideration
Treatment may also be given to treatment with antipsychotics, as dis-
cussed for Huntington’s disease.
In general, no treatment other than simple reassurance is
required. In those rare cases in which the chorea becomes
severe enough to interfere with functioning, consideration
may be given to treatment with antipsychotics, as 8.15 DENTATORUBROPALLIDOLUYSIAN
described for Huntington’s disease. ATROPHY
The unwieldy name of this disorder is derived from the
8.14 BENIGN HEREDITARY CHOREA main structures that show pathological changes, namely
the dentate nucleus, the nucleus rubor (the red nucleus),
This is a rare autosomal dominantly inherited disorder, the globus pallidus, and the corpus Luysii (the subthalamic
characterized by a childhood-onset chorea that is generally nucleus). Dentatorubropallidoluysian atrophy, also known
non-progressive. as dentatorubralpallidoluysian atrophy or simply DRPLA,
is a rare autosomal dominantly inherited disorder, which
may present early, in childhood or adolescence, or late, in
Clinical features adult years: among adult-onset cases, one typically sees a
movement disorder, with chorea or ataxia, and a dementia.
Onset may be anywhere from infancy to late childhood, Some authorities consider DRPLA to be one of the spino-
and is characterized by a generalized chorea that may be cerebellar ataxias; however, in this author’s opinion, given
accompanied by a subtle degree of ataxia (Breedveld et al. that DRPLA may be characterized by chorea rather than
2002; Fernandez et al. 2001); hypothyroidism may also ataxia, this seems to be inappropriate nosologic ‘lumping’
occur (Asmus et al. 2005). There is no dementia (Behan and the disorders are considered separately in this text.
and Bone 1977).
After a period in which the chorea becomes established, The onset is gradual, regardless of whether it is early or late,
although in most cases there is no change over time, one and the clinical features are strongly influenced by the age
may see in a minority either a mild progression (Kleiner- of onset. Early-onset cases (Becher et al. 1997) are charac-
Fisman et al. 2003) or, conversely, in adolescence or early terized by ataxia, myoclonus, seizures, and a dementia.
adult years, a partial remission of symptoms (Fernandez Late-onset cases (Becher et al. 1997; Iizuka et al. 1984;
et al. 2001). Nielsen et al. 1996; Villani et al. 1998; Warner et al. 1994,
1995; Yoshii et al. 1998) are typified by either chorea or
ataxia (or a combination of these); in a minority of cases
Etiology one may also see a mild degree of dystonia or parkinson-
ism. In adults one also sees the eventual development of a
As noted, this is an autosomal dominant condition and dementia, which may be accompanied by prominent hal-
mutations have been found in the thyroid transcription lucinations and delusions; rarely, DRPLA may present with
factor 1 gene (TITF1) (Asmus et al. 2005). Neuronal loss a psychosis in adult years (Adachi et al. 2001). A small
has been reported in the striatum (Kleiner-Fisman et al. minority of adults may also have seizures. Magnetic reso-
2005) and astrocytosis has been noted in the globus pal- nance scanning may reveal atrophy of the superior cerebel-
lidus, thalamus, hypothalamus, and periaqueductal gray lar peduncle and, on T2-weighted scans, increased signal
(Kleiner-Fisman et al. 2003). intensity in the globus pallidus.
p 08.qxd 3/10/08 9:38 AM Page 361
8.16 Wilson’s disease 361
Course the range is wide, from early childhood to the sixth decade.
The presentation may be with a movement disorder, psy-
DRPLA is a gradually progressive disorder. chosis, personality change, or dementia; over time, most
patients eventually develop a combination of these features.
Other symptoms include seizures, a Kayser–Fleischer ring,
Etiology hepatitis, and anemia.
The movement disorder may consist of dystonia, chorea,
As noted earlier, DRPLA is an autosomal dominantly tremor, or parkinsonism; dysarthria may also appear.
inherited disorder: mutations exist in the gene for Dystonia may present with torticollis, dystonia of the upper
atrophin-1, found on chromosome 12, which consist of an or lower extremity, oculogyric crisis (Lee et al. 1999), or
expansion of a normally occurring CAG trinucleotide facial dystonia; classically, there is a fixed, vacuous, wide-
repeat (Nagafuchi et al. 1994). There is considerable phe- mouthed dystonic smile. Chorea may involve either the
notypic heterogeneity both within and between families upper or the lower extremities. The tremor may be rhyth-
(Potter et al. 1995). Neuronal loss is found not only in the mic or irregular; at times, one may see the classic ‘wing-
namesakes of this disorder (the dentate nuclei, red nucleus, beating’ tremor in which a rhythmic elevation and lowering
globus pallidus, and subthalamic nucleus) but also in the of the upper extremities, combined with flexion at the
striatum, substantia nigra, inferior olives, thalamus, and elbows, gives an overall appearance of a frightened bird
cerebral cortex (Becher et al. 1997; Goto et al. 1982; Iizuka flapping its wings.
et al. 1984; Warner et al. 1994). In surviving neurons, Personality change is generally characterized by lability,
intranuclear inclusions, formed of abnormal atrophin-1, disinhibition, and, at times, bizarre behavior (Bridgman
may be found. and Smyth 1944; Dening and Berrios 1989; Walshe and
Yealland 1992).
Psychosis is characterized by hallucinations and delu-
Differential diagnosis sions (Dening and Berrios 1989; Gysin and Cooke 1950)
and may be quite bizarre, with Schneiderian first rank
In adults, the differential is influenced by the nature of the symptoms. Indeed, one of Wilson’s (1912) patients heard
movement disorder: when chorea is prominent, consider- ‘God and the devil talking to him simultaneously’ and said
ation is given to Huntington’s disease, and when ataxia is that he was ‘influenced, willed or hypnotized to do certain
foremost, spinocerebellar ataxia enters the differential. things’. In one case (Davis and Borde 1993), stuporous
Genetic testing is often required to make the differential. catatonia dominated the presentation.
Seizures may occur but are rare, occurring in about 5
percent of patients (Dening et al. 1988).
Treatment The Kayser–Fleischer ring is a golden-brown discol-
oration of the corneal limbus, visible either on slit-
There is no specific treatment. The general treatment of lamp examination or to the naked eye. Although this
dementia is discussed in Section 5.1; in cases in which Kayser–Fleischer ring is present in the overwhelming major-
chorea is problematic, treatment with antipsychotics, as ity of cases, cases of unequivocal Wilson’s disease (with a
for Huntington’s disease, may be considered. movement disorder) without a Kayser–Fleischer ring do
occur (Demirkiran et al. 1996).
Hepatic damage may lead to clinical hepatitis, with fever,
8.16 WILSON’S DISEASE malaise, abdominal pain, and elevated transaminase levels.
With significant hepatic dysfunction, hepatic encephalopa-
Wilson’s disease, also known as hepatolenticular degenera- thy may occur (Starosta-Rubinstein et al. 1987).
tion, is an autosomal recessively inherited disorder charac- A Coombs-negative hemolytic anemia may occur.
terized pathologically by copper deposition in the liver and The ceruloplasmin and total serum copper levels are
brain. Although relatively rare, occurring in perhaps both low, but the serum free copper is elevated, as is the
1–2/100 000 population, it is an important diagnosis given 24-hour urinary copper; in a small minority, the ceruloplas-
its eminent treatability. min level may be normal. Liver biopsy reveals an elevated
copper level.
Magnetic resonance scanning may reveal charac-
Clinical features teristic findings (Sinha et al. 2006). On T2-weighted scans,
increased signal intensity may be seen in the head of the
The clinical features of Wilson’s disease have been caudate and lateral aspect of the putamen, with decreased
described in several large series (Dening and Berrios 1989; signal intensity in the globus pallidus; in the midbrain,
Machado et al. 2006; Starosta-Rubinstein et al. 1987; Taly T2-weighted scanning may reveal the ‘face of the giant panda’
et al. 2007; Walshe and Yealland 1992). The onset is typi- sign, with increased signal intensity in the tegmentum and
cally between late childhood and early adulthood, although decreased signal intensity in the red nuclei. On T1-weighted
p 08.qxd 3/10/08 9:38 AM Page 362
scans, increased signal intensity may be seen in the caudate Treatment

and the putamen.
Given the large number of possible mutations, genetic Treatment is aimed at reducing the total copper burden.
testing is not practical. Several methods are available, including chelation with
penicillamine, trientine, or tetrathiomolybdate; treatment
with zinc; and limiting copper intake.
Course Chelation has traditionally been accomplished with
penicillamine; however, this agent has multiple, severe
Although there may be partial, temporary remissions, the
side-effects and also, in a significant minority of patients,
overall course is one of progression, with death within
will either exacerbate pre-existing symptoms (Starosta-
5–10 years.
Rubinstein et al. 1987) or, in pre-symptomatic patients,
cause them (Brewer et al. 1994; Glass et al. 1990).
Etiology Consequently, attention has shifted to two other chelating
agents, namely trientine and tetrathiomolybdate; of these,
Wilson’s disease is essentially a disease of copper metabo- tetrathiomolybdate is more effective than trientine
lism. Normally, after copper is absorbed from the intestine, (Brewer et al. 2006), and is generally well-tolerated (Brewer
it is bound to hepatic ceruloplasmin and then for the most et al. 1996).
part undergoes biliary excretion. In Wilson’s disease biliary Zinc induces intestinal metallothionein, which in turn
excretion is deficient and copper accumulates, first in the binds copper and prevents its absorption; it is less effective
liver, where it causes hepatitis, and then, once it spills over than chelating agents. Zinc is given in a dose of 50 mg three
into the systemic circulation, in the brain, where copper times daily, before meals (Hoogenraad et al. 1987).
deposition occurs primarily in a pericapillary distribution. Dietary restriction of copper is the least effective of the
Macroscopically (Howard and Royce 1919), there is atro- treatment measures and requires an avoidance of shellfish,
phy and a brownish discoloration of the striatum, with, in legumes, nuts, grains, coffee, chocolate, and organ meats.
advanced cases, cavitation (Wilson 1912) and a mild degree On balance, symptomatic patients should probably be
of cortical atrophy. Microscopically, there is neuronal loss treated with tetrathiomolybdate and zinc. Asymptomatic
and astrocytosis in the striatum (more so the putamen than patients, with no evidence of liver or brain involvement,
the caudate) and to a lesser degree in the globus pallidus; might be treated with zinc, with careful monitoring. With
other affected structures include the cerebral cortex (espe- chelation treatment of symptomatic patients, recovery is
cially the frontal lobes [Barnes and Hurst 1926]), thalamus, slow, and up to a year or more may be required to see full
red nucleus, substantia nigra, dentate nucleus, and cerebel- improvement. The degree of recovery varies with the sever-
lar cortex. Copper deposition in Descemet’s membrane ity of symptoms before treatment; in mild cases there may
gives rise to the classic Kayser–Fleischer ring. be complete recovery, whereas in severe cases, some degree
As noted earlier, Wilson’s disease is an autosomal reces- of residual symptomatology is to be expected.
sive disease, and it results from mutations in the ATP7B A final alternative is liver transplantation, which, as it
gene on chromosome 13 that codes for the copper-binding restores the body’s ability to handle copper, is curative.
ATPase (Bull et al. 1993; Chelly and Monaco 1993); multi- This should be considered in either treatment-resistant or
ple different mutations have been identified (Thomas et al. fulminant cases (Bax et al. 1998; Stracciari et al. 2000).
1995). Symptomatic treatment of dementia is discussed in
Section 5.1, of personality change in Section 7.2, and of
psychosis in Section 7.1. Given that almost all patients with
Differential diagnosis Wilson’s disease will have some degree of hepatic failure,
doses of hepatically metabolized medications must be
Given the pleomorphic symptomatology of Wilson’s dis- adjusted accordingly.
ease, the differential diagnosis is large. In practice, given All of the patient’s siblings should be offered testing for
the availability of treatment, and the consequent impor- copper and ceruloplasmin levels and, in doubtful cases,
tance of not missing the diagnosis, it is appropriate to test consideration should be given to liver biopsy.
for Wilson’s disease in any young person with a clinical
presentation consistent with Wilson’s disease that cannot
be readily and fully accounted for by another disease 8.17 SPINOCEREBELLAR ATAXIA
process. One disorder in particular deserves mention as it
may mimic Wilson’s disease not only clinically but also Spinocerebellar ataxia (SCA), also known as autosomal
with respect to laboratory values. Hereditary ceruloplasmin dominant cerebellar ataxia, is an uncommon, dominantly
deficiency, like Wilson’s disease, is characterized by low inherited disorder characterized, in most cases, by a slowly
ceruloplasmin and total serum copper levels, but, unlike progressive ataxia, joined, over time, by various other fea-
Wilson’s disease, it is characterized by a low 24-hour uri- tures, which may include dementia, personality change, or
nary copper level (Kawanami et al. 1996). delusions or hallucinations.
p 08.qxd 3/10/08 9:38 AM Page 363
8.17 Spinocerebellar ataxia 363
Some words are required regarding the synonym for this clinical picture (Giunti et al. 1998; Schols et al. 1998; Tang
disorder, namely autosomal dominant cerebellar ataxia or et al. 2000).
ADCA. This name was initially utilized by Harding (1982, Magnetic resonance scanning may reveal atrophy of the
1984), who went on to divide ADCA into three different cerebellum, pons, and inferior olives (Arpa et al. 1999;
subtypes, namely types III, II, and I. Type III was described Ueyama et al. 1998).
as being characterized solely by cerebellar signs, without
any associated features. Types II and I, by contrast, did
encompass associated features, the difference between type Etiology
II and type I being that type II could be accompanied by
pigmentary retinopathy, whereas type I cases were specifi- As noted, SCA is an autosomal dominantly inherited syn-
cally free of this sign. The nosologic status of this proposed drome, and 26 different loci have been identified (Duenas
subdivision is, however, in doubt, on both clinical and etio- et al. 2006): SCA1 on chromosome 6 (Goldfarb et al. 1989,
logic grounds. From a clinical point of view, it appears that 1996; Sasaki et al. 1996; Schols et al. 1997a; Tang et al.
type III cases are exceedingly rare, perhaps (with a suffi- 2000), SCA2 on chromosome 12 (Adams et al. 1997; Burk
ciently long follow-up) non-existent, and that, when com- et al. 1999; Giunti et al. 1998; Hsieh et al. 1999; Schols et al.
paring types II and I, type I patients (that is to say, those 1997a,b; Tang et al. 2000; Ueyama et al. 1998; Zhou et al.
with associated features but without pigmentary retinopa- 1998), SCA3 (also known as Machado–Joseph disease) on
thy) comprise the overwhelming majority. Furthermore, chromosome 14 (Durr et al. 1996; Lopes-Cendes et al.
from an etiologic point of view, it appears that this subdivi- 1996; Schols et al. 1996, 1997b; Takiyama et al. 1994; Tang
sion does not ‘cleave’ nature at the genetic ‘joints’, in that et al. 2000; Zhou et al. 1997), SCA4 on chromosome 16
mutations at the same gene locus may cause two different (Nagaoka et al. 2000), SCA5 on chromosome 11 (Stevanin
clinical types (e.g., spinocerebellar ataxia type 6 [SCA6] is et al. 1999), SCA6 on chromosome 19 (Arpa et al. 1999;
associated with both type III [Ishikawa et al. 1999] and type Ikeuchi et al. 1997; Ishikawa et al. 1999; Kaseda et al. 1999;
I [Schols et al. 1998]). Given this nosologic uncertainty, it Matsumara et al. 1997; Schols et al. 1998; Stevanin et al.
may be prudent, for the time being, to refrain from sub- 1997), SCA7 on chromosome 3 (Benton et al. 1998; Jobsis
typing cases as III, II, or I, but rather to concentrate on et al. 1997; Modi et al. 2000), SCA8 on chromosome 13
making sure that one has a case of ADCA and then proceed- (Ikeda et al. 2000), SCA10 on chromosome 22 (Grewal
ing to identify the responsible genetic locus. et al. 2002; Matsuura et al. 1999), SCA11 on chromosome 15
(Worth et al. 1999), SCA12 on chromosome 5 (Seltzer et al.
1999), SCA13 on chromosome 19, SCA14 on chromosome
Clinical features 19 (Yamashita et al. 2000), SCA 15 on chromosome 3,
SCA16 on chromosome 8, SCA17 on chromosome 6
The clinical hallmark of SCA is the appearance of a gradu- (Lasek et al. 2006; Maltecca et al. 2003; O’Hearn et al.
ally progressive cerebellar ataxia, which is generally accom- 2001), SCA18 on chromosome 7, SCA19 on chromosome
panied by dysarthria and nystagmus. The onset, although 1, SCA20 on chromosome 11, SCA21 on chromosome
generally in the early to mid-adult years, may occur any- 7, SCA23 on chromosome 20, SCA24 on chromosome 1,
where from childhood to senescence. With disease pro- SCA25 on chromosome 2, SCA26 on chromosome 19,
gression, almost all patients will also develop one or more SCA27 on chromosome 13, and SCA28 on chromosome
of the following associated features: hyper-reflexia and 18. Some authors also include dentatorubropallidoluysian
extensor plantar responses; decreased vibratory sense, atrophy among the SCAs (specifying it as ‘SCA9’), but
atrophy, and fasciculations; supranuclear ophthalmople- given that patients with dentatorubropallidoluysian atro-
gia; tremor (including titubation), dystonia, chorea, phy may have little or no ataxia, and often have prominent
myoclonus or parkinsonism; or pigmentary retinopathy. chorea, this inclusion may not be warranted, and, in this
Seizures may also occur; however, they are uncommon and text, dentatorubropallidoluysian atrophy is discussed sepa-
may be grand mal, simple, or complex partial in type. rately, in its own section.
Dementia may occur in a minority as may a personality Most of the known mutations involve trinucleotide
change (often of the frontal lobe type), and some patients repeat expansions, as has been found for SCA1, -2, -3, -6,
may develop delusions and hallucinations. Rarely, SCA may -7, -12, and -17; a CTG trinucleotide repeat expansion has
present with dementia, a personality change, or a psychosis. been noted for SCA8, a pentancleotide repeat expansion
The plenitude of these associated features should not, for SCA10, and missense mutations for SCA5, -23, -14,
however, distract attention from the central feature of this and -27.
syndrome, namely a progressive cerebellar ataxia; the associ- The pathologic hallmark of this syndrome is atrophy of
ated features, usually few in number in any given case, gen- the cerebellum, pons, and inferior olives; in addition to
erally play only a minor part in the overall clinical picture. these findings, associated atrophy may also be found in one
Genetic testing is available. Interestingly, given the wide or more of the following structures: the spinocerebellar
phenotypic heterogeneity, it does not appear possible to tracts, Clarke’s column, the globus pallidus, the sub-
reliably predict which SCA type is present based on the thalamic nucleus, the substantia nigra, and the cerebral
p 08.qxd 3/10/08 9:38 AM Page 364
cortex (Durr et al. 1996; Ikeuchi et al. 1997; Ishikawa et al. are generally characterized by a slowly progressive dystonic
1999; Jobsis et al. 1997; Takiyama et al. 1994). rigidity, prominent in both the extremities and the face;
although this dystonia may be unilateral initially, bilateral
involvement eventually occurs. Over time, other abnormal
Differential diagnosis movements may appear, including tremor or choreo-
athetosis; tics have also been noted in a small minority, as
Two autosomal dominant disorders to consider include den- have obsessions and compulsions. Over time, a dementia
tatorubropallidoluysian atrophy and Gerstmann–Straussler– gradually appears.
Scheinker disease. Dentatorubropallidoluysan atrophy is Adult-onset cases (Alberca et al. 1987; Jankovic et al.
marked, in many cases, by prominent chorea, and this may 1985; Rozdilsky et al. 1968) may present with parkinson-
be a clue, but genetic testing is typically required to rule out ism, dystonia, or athetosis. Over time, and with progression
both these disorders. Friedrich’s ataxia is suggested by an of the abnormal movements, a dementia may occur. Rarely
autosomal recessive mode of inheritance and a typically early the presentation may be with dementia, followed years
age of onset. Multiple system atrophy of the olivopontocere- later by a movement disorder (Cooper et al. 2000; Dooling
bellar type is suggested by concurrent autonomic signs and et al. 1974; Murphy et al. 1989; Rozdilsky et al. 1968). In
by its sporadic nature. Other sporadic disorders to consider some cases depressive symptomatology may occur or,
include vitamin B12 deficiency, hypothyroidism, paraneo- rarely, delusions and hallucinations.
plastic cerebellar degeneration, and alcoholic cerebellar In addition to the abnormal movements, many patients
degeneration. may also develop signs of spasticity, with hyper-reflexia
and the Babinski sign; in a minority pigmentary retinopa-
thy may occur.
Treatment Magnetic resonance scanning generally reveals the dis-
tinctive ‘eye of the tiger’ sign (Angelini et al. 1992). On T2-
In one double-blind study (Botez et al. 1996), amantadine weighted scans, increased signal intensity is seen in the
reduced ataxia in patients with SCA1 and SCA2. The lateral aspect of the globus pallidus, whereas on the inner
general treatment of dementia is discussed in Section 5.1, aspect there is a gross loss of signal intensity: the overall
of personality change in Section 7.2, and of psychosis in effect, seen on axial imaging, is of looking a tiger in the eye.
Section 7.1.
Genetic testing should be offered to at-risk relatives.
Course
8.18 PANTOTHENATE KINASE-ASSOCIATED Childhood-onset cases show gradual progression, with

NEURODEGENERATION death occurring within 10–15 years; adult-onset cases tend
to pursue a much more leisurely course, and some patients
Pantothenate kinase-associated neurodegeneration is a rare may remain ambulatory for decades.
autosomal recessively inherited disease due to mutations in
the gene for panthothenate kinase. It typically presents in
childhood or adolescence with a movement disorder, gen- Etiology
erally dystonia, followed, in most, by a dementia.
The original name for this disease was Haller- As noted earlier, this is a recessively inherited disorder, and
vorden–Spatz disease; however, the use of this eponym is mutations are found in the gene for pantothenate
now discouraged on ethical grounds (Shevell 2003). kinase, PANK2, found on chromosome 20 (Zhou et al.
Although there is no dispute that Drs Hallervorden and 2001). Macroscopically, the globus pallidus is atrophic and
Spatz originally described this disease, concerns have been exhibits a rust-brown discoloration. Microscopically, iron
raised about honoring them with an eponym, given their deposition and axonal spheroids are seen not only in the
participation in the extraordinarily unethical euthanasia globus pallidus but also in the pars reticulata of the sub-
programs practiced in Germany during the Third Reich. stantia nigra and in the cerebral cortex (Dooling et al.
1974).
Clinical features
The onset is typically gradual and, although most patients
fall ill in childhood or adolescence, adult-onset cases may In childhood- or adolescent-onset cases, consideration
occur. The clinical symptomatology is heavily influenced must be given to Wilson’s disease, idiopathic torsion dys-
by the age of onset. tonia, and dopa-responsive dystonia. In adult-onset cases,
Childhood-onset cases (Dooling et al. 1974, 1980; given the variety of abnormal movements seen, the differ-
Hayflick et al. 2003; Pellecchia et al. 2005; Swaiman 1991) ential is very wide and the reader is directed to Sections 3.5,
p 08.qxd 3/10/08 9:38 AM Page 365
8.19 Dopa-responsive dystonia 365
3.7, and 3.8 for athetosis, dystonia, and parkinsonism obsessions and compulsions without any abnormal move-
respectively. ments (Hahn et al. 2001; Van Hove et al. 2006).
One finding that is very helpful in the differential diag-
nosis is the ‘eye of the tiger’ sign. This is seen in almost all
cases and indeed may be found before the onset of symp- Course
toms (Hayflick et al. 2001). Consequently, the sensitivity of
this sign is very high. The specificity is also fairly high, In childhood-onset cases the dystonia eventually general-
although there are some cases that are clinically similar to izes over about 3 or 4 years, after which it remains static.
pantothenate kinase-associated neurodegeneration, even
to the point of demonstrating the ‘eye of the tiger’ sign, but
which are not apparently associated with mutations in the Etiology
pantothenate kinase gene (Hartig et al. 2006). The noso-
logic status of these cases is not clear. Dopa-responsive dystonia is a genetically heterogenous
syndrome and, at present, three different diseases have
been described, namely DYT5a, DYT5b, and DYT14.
Treatment
DYT5a, also known as the Segawa syndrome, is an auto-
somal dominant disorder and constitutes the most com-
Pharmacologic treatment of the abnormal movements
mon cause of dopa-responsive dystonia. In DYT5a there is
may be attempted as described in Sections 3.5, 3.7, and 3.8;
a mutation in the gene for guanosine triphosphate cyclo-
however, the responses are generally not robust. In severe
hydrolase 1 (GCH1) on chromosome 14 (Bandmann et al.
cases, success has been reported with deep brain stimula-
1998; Illarioshkin et al. 1998; Ohye et al. 1994; Steinberger
tion of the globus pallidus (Castelnau et al. 2005). The gen-
et al. 2000). GCH1 is the rate-limiting enzyme for the syn-
eral treatment of dementia is discussed in Section 5.1.
thesis of tetrahydrobiopterin, which in turn is an essential
co-factor for tyrosine hydroxylase, the rate-limiting enzyme
in the production of dopamine. The net result of this muta-
8.19 DOPA-RESPONSIVE DYSTONIA tion is a reduction in the production of dopamine.
DYT5b is an autosomal recessive disorder caused by a
Dopa-responsive dystonia is an uncommon inherited syn- mutation in the gene for tyrosine hydroxylase on chromo-
drome that classically presents in childhood with a dysto- some 11 (Furukawa et al. 2001; Schiller et al. 2004).
nia which, as the name indicates, is quite responsive to DYT14 is an autosomal dominant disorder linked to a
levodopa. Given its eminent treatability, it is a diagnosis site on chromosome 14 (Grotzch et al. 2002); the gene has
that must not be missed. not as yet been identified.
Pathologic studies have demonstrated a reduction in
melanin pigment in the substantia nigra, without cell loss,
Clinical features in both DYT5a (Rajput et al. 1994) and DYT14 (Grotzch
et al. 2002).
Although the classic onset is in childhood, later onsets in
adolescence or adult years have also been reported.
Regardless of the age of onset, symptoms generally both
appear and accrue gradually. Differential diagnosis
Childhood-onset cases (Deonna 1986; Harwood et al.
1994; Nygaard and Duvoisin 1986; Nygaard et al. 1990, The full differential diagnosis for dystonia is discussed in
1991) generally present with an intermittent dystonia of one Section 3.7: of the disorders noted there, primary torsion
foot; over time the dystonia spreads, eventually involving dystonia is highest on the differential. A key feature in
the other lower extremity and then the upper extremities; making the diagnosis is the responsiveness to levodopa,
truncal and cervical dystonia may also eventually appear. A and an attempt at a ‘diagnosis by treatment response’ is
characteristic feature of the dystonia has been termed ‘sleep warranted in most cases of childhood-onset dystonia.
benefit’: after a good night’s sleep, the dystonia may be very
mild, or even absent, only to gradually reappear and worsen
as the day wears on. In some cases, a mild parkinsonism may Treatment
appear; myoclonus has also been noted. The movement dis-
order may, in some cases, be accompanied by depression or As indicated earlier, the dystonia of dopa-responsive dys-
obsessions and compulsions. tonia responds well to levodopa, and generally only low
Later-onset cases, although at times presenting similarly doses are required; of note, and in contrast to other condi-
to childhood-onset cases, may also be marked by a more tions treated with levodopa, such as Parkinson’s disease,
prominent parkinsonism (Harwood et al. 1994); in some the response to levodopa is sustained over long periods,
cases the syndrome may present with depression or with little need for dosage increases (Nygaard et al. 1991).
p 08.qxd 3/10/08 9:38 AM Page 366
8.20 PRIMARY TORSION DYSTONIA (Ozelius et al. 1997); penetrance is low, of the order of
30–40 percent. Although the underlying pathology is not
Primary torsion dystonia, also known as dystonia muscu- known, one study found neuronal inclusion bodies in the
lorum deformans, is a syndrome characterized classically pedunculopontine nucleus, the cuneiform nucleus, and the
by the onset of a focal dystonia in childhood or adolescence periaqueductal gray (McNaught et al. 2004).
that eventually generalizes. As noted below, however, atyp- DYT6 has been linked to chromosome 8 and tends to
ical presentations may also occur. have an atypical presentation, often with a cervical dysto-
nia (Almasy et al. 1997).
DYT13 is linked to chromosome 1 and also has an atyp-
Clinical features ical presentation, with dystonia of an upper limb or a cer-
vical dystonia (Bentivoglio et al. 1997; Valente et al. 2001).
Classic cases (Johnson et al. 1962; Marsden and Harrison
1974) are characterized by an onset of dystonia between the
ages of 5 and 15 years, appearing first in one of the lower Differential diagnosis
extremities. Typically, and only intermittently, the young
patient may experience some dystonic inversion and plan- The full differential diagnosis of dystonia is discussed in
tar flexion of the foot while walking. Curiously, this dysto- Section 3.7. Of the disorders noted there, the most impor-
nia is not present at rest, and it may also be absent when tant for the differential diagnosis is dopa-responsive dysto-
walking backwards or dancing. Over time, however, the nia; given that this disorder may be clinically
dystonia becomes more frequent and begins to involve indistinguishable from primary torsion disorder, a ‘diag-
more proximal portions of the lower extremities, often with nosis by treatment response’, as discussed above (Section
flexion at the knees and hips. With progression of the dis- 8.19), should be attempted by giving levodopa.
ease, the dystonia becomes more and more constant and
spreads not only to the upper extremities but also to the
trunk, producing lordosis and tortipelvis. In a small minor-
Treatment
ity, the face may be involved, with dystonic grimacing.
Perhaps the best-established pharmacologic treatment is
Atypical presentations (Bressman et al. 1989; Fletcher
trihexyphenidyl: children and adolescents may do well
et al. 1990; Gasser et al. 1998; Johnson et al. 1962) are more
with this and, in contrast to adults, may tolerate high doses
common with later onset in adolescence or early adult
of 30 mg or more per day (Burke et al. 1986). In severe
years; patients may present with focal dystonias, such as
cases, consideration may be given to intrathecal baclofen
writer’s cramp or a cervical dystonia. Although such cases
or to deep brain stimulation of the globus pallidus
may show some spread, generalization of the sort seen in
(Vidhailet et al. 2005).
classic cases is not common.
Genetic testing is available for the most common cause
of this syndrome, namely DYT1, and should be considered
in any patient with an early-onset dystonia that has gener-
8.21 IDIOPATHIC CERVICAL DYSTONIA
alized (Brassat et al. 2000; Bressman et al. 2000).
Idiopathic cervical dystonia, also known as spasmodic tor-
ticollis or ‘wry neck’, is the most common of the primary
Course focal dystonias and is somewhat more frequent in women.
When progression does occur it typically reaches a maxi-

mum after some 5–10 years, after which the course is more Clinical features
or less static. In a very small minority partial remissions
may occur, but these are generally only temporary. Clinically (Chan et al. 1991; Jankovic et al. 1991; Rondot
et al. 1991; Sorensen and Hamby 1966), the onset is gener-
ally between the ages of 20 and 60 years, with most patients
Etiology falling ill in their forties. The presentation is generally with
some intermittent dystonia of the neck musculature,
Three different autosomal dominant diseases have been pulling the head into a dystonic posture. The most com-
identified that can cause the syndrome of primary torsion mon position is torticollis, the head being rotated to one
dystonia, namely DYT1, DYT6, and DYT13; the remaining side or the other; other positions, in order of decreasing
cases, as yet, are considered idiopathic. Of the known frequency, include lateralcollis, with the head tilted to one
causes, DYT1 was the first to be recognized and is by far the side, retrocollis, with the head bent back, or anterocollis,
most common and the most likely to cause a classic pres- with the head pulled down toward the chest. Isolated posi-
entation (Kramer et al. 1990; Ozelius et al. 1992). tions are the exception: most patients exhibit a combina-
DYT1, also known as Oppenheim disease, occurs second- tion, such as torticollis and lateralcollis. Pain is a common
ary to a mutation in the gene for torsin A on chromosome 9 accompaniment.
p 08.qxd 3/10/08 9:38 AM Page 367
8.22 Task-specific dystonia 367
In most cases patients are able to use a geste antagoniste to occasions the dystonia; thus we have writer’s cramp, typ-
temporarily relieve the dystonia (Jahanshahi 2000; Muller ist’s cramp, musician’s cramp, etc.
et al. 2001a). These ‘tricks’ consist of lightly touching a spe-
cific body part, such as the chin, face, or occiput, resulting in
a prompt, but temporary, relief of the dystonic stiffness. Clinical features
Over time, the dystonia becomes more constant and
sustained, and will, in a minority, undergo segmental Task-specific dystonias generally appear in adulthood
spread to an adjacent part such as the arm. between the ages of 20 and 50 years, and typically only after
A tremor of the head, similar to that seen in essential the patient has been engaging in the task in question for at
tremor, is present in a substantial minority of patients. least a number of years.
Writer’s cramp (Cohen and Hallett 1988; Jedynak et al.
2001; Sheehy and Marsden 1982) is perhaps the most com-
Course mon of the task-specific dystonias and manifests as a dys-
tonic cramping of the hand upon using a pen or pencil.
In most cases there is a gradual progression with, as noted, Although early on in the course the dystonia may appear
some segmental spread in a minority; generalization, how- only after the patient has been writing for a while, with
ever, does not occur. There may be remissions in some time the dystonia appears earlier and earlier until it may
10–20 percent of patients during the first few years (Chan manifest as soon as the patient picks up the pen; further-
et al. 1991; Friedman and Fahn 1986; Jayne et al. 1984); more, and again with time, the dystonia may spread to
however, most of these patients eventually relapse within involve the forearm. Some patients may try and evade the
5 years (Dauer et al. 1998). cramping by writing with their non-dominant hand; how-
ever, in a minority, the dystonia will reappear on this
opposite side. Musician’s cramp may appear in the hands
Etiology of violinists or pianists, and it may also appear in the oro-
facial musculature in wind-instrument players. This latter
Both familial (Bressman et al. 1996; Chan et al. 1991; type of musician’s cramp is referred to as embouchure dys-
Jankovic et al. 1991) and sporadic cases occur. In some tonia or, colloquially, as ‘loss of lip’, and manifests vari-
familial cases, a genetic cause has been identified, for exam- ously with lip dystonia or dystonic jaw movements (Frucht
ple the DYT7 locus, mapped to chromosome 18 (Leube et al. et al. 2001).
1997). The neuropathology is unknown.
Differential diagnosis Course
The full differential for dystonia is discussed in Section 3.7. The dystonia gradually worsens over perhaps years and
Of the disorders noted there, special consideration should then typically remains static; remissions are unusual.
be given to an atypical presentation of primary torsion
dystonia.
Etiology
Treatment Most cases are sporadic. Familial cases are generally consis-
tent with an autosomal dominant mode of inheritance. Of
Local injection of botulinum toxin (Greene et al. 1990) is interest, in some familial cases different family members
effective; although some patients may benefit from treat- may manifest different subtypes of task-specific dystonia
ment with trihexyphenidyl, botulinum toxin is more effec- (Schmidt et al. 2006). In one family, writer’s cramp
tive (Brans et al. 1996). In severe, treatment-resistant cases, occurred as part of DYT7 with linkage to chromosome 18
consideration may be given to deep brain stimulation of (Bhidayasiri et al. 2005). The neuropathologic basis of this
the globus pallidus (Hung et al. 2007). disorder is not known.
8.22 TASK-SPECIFIC DYSTONIA Differential diagnosis
Task-specific dystonia, one of the primary dystonias, is Writer’s cramp has been noted as an atypical presentation
characterized by the occurrence of a dystonia upon of both primary torsion dystonia (Gasser et al. 1998) and
attempting to perform a learned task. Also known as occu- dopa-responsive dystonia (Deonna et al. 1997), and these
pational dystonia, this movement disorder is typically disorders should be considered whenever task-specific dys-
divided into several subtypes depending on the task that tonic movements occur in children or adolescents.
p 08.qxd 3/10/08 9:38 AM Page 368
Treatment that these last two cases represented atypical presentations

of diffuse Lewy body disease or some variant thereof.
Writer’s cramp has been treated with botulinum toxin
injections (Kruisdijk et al. 2007; Rivest et al. 1991), biofeed-
back, retraining, splint immobilization for 4–5 weeks
(Priori et al. 2001), and placement of a transcutaneous elec-
The full diagnosis of dystonia is discussed in Section 3.7,
trical nerve stimulation (TENS) unit (Tinazzi et al. 2005).
and several of the disorders discussed there deserve consid-
Similar strategies may be considered for musician’s cramp
eration. Brueghel’s syndrome, another primary dystonia, is
involving the hand (Jabusch et al. 2005).
distinguished by the fact that it presents with oromandibu-
lar dystonia in the absence of blepharospasm (Gilbert
1996). Atypical presentations of primary torsion dystonia
8.23 MEIGE’S SYNDROME may be characterized by blepharospasm (Bressman et al.
1994; Ozelius et al. 1989). Tardive dyskinesia may present
Meige’s syndrome (also known as essential blepharospasm
with blepharospasm, but the diagnosis is immediately sug-
or primary blepharospasm), first described by the French
gested by the appearance of symptoms in the context of
neurologist Henri Meige in 1910 (Tolosa and Klawans
long-term treatment with antipsychotics (Weiner et al.
1979), is one of the primary dystonias and is characterized,
1981). Blepharospasm has also been reported secondary to
as the synonyms indicate, by blepharospasm.
lesions in the basal ganglia (Jankovic 1986) or brainstem
(Jankovic and Patel 1983).
Non-dystonic disorders to consider include hemifacial
Clinical features
spasm, distinguished by its strictly unilateral occurrence,
and facial tics, distinguished by their fleeting, unsustained
Clinical features have been described in a number of series
nature. Ocular pathology must also be considered, as
(Grandas et al. 1988; Paulson 1972; Tolosa 1981). Onset is
inflammation of the lid, conjunctiva or iris may all be asso-
usually in middle years, and the primary symptom is bilat-
ciated with blepharospasm.
eral blepharospasm. Initially the blepharospasm is neither
prolonged nor frequent, but over time it becomes persist-
ent, forceful, and at times almost constant. Over a year or Treatment
two, the adjacent musculature, especially the jaw and
mouth, may also become involved and, in a small minor- Botulinum toxin represents standard treatment; when this
ity, the neck musculature may likewise be affected (Defazio fails, case reports and case series suggest a usefulness for
et al. 1999). The blepharospasm may be worsened by anticholinergics (Tanner et al. 1982) (e.g., trihexyphenidyl
bright light or sometimes by walking, and may be lessened or benztropine), clonazepam (Hipola et al. 1984), lev-
by yawning, talking, or singing (Weiner and Nora 1984). etiracetam (Yardimci et al. 2006), and, interestingly, quetiap-
Gestes antagonistes, such as touching the eyebrow or the ine (Reeves and Liberto 2003). In severe, treatment-resistant
temple, may relieve the blepharospasm. cases, consideration may be given to deep brain stimulation
of the globus pallidus (Houser and Waltz 2005).
Course
8.24 SPASMODIC DYSPHONIA
Symptoms tend to worsen over the first few years and then
remain static. Spontaneous remissions may occur in Spasmodic dysphonia, also at times referred to as spastic
roughly 10 percent of patients, usually within the first dysphonia, represents a focal dystonia of the laryngeal
5 years (Castelbuono and Miller 1998). musculature that renders speech dysphonic.
Etiology Clinical features

A positive family history is found in only a small minority Clinical features have been described in a number of
(Defazio et al. 2006), and the remaining cases appear spo- reports (Aminoff et al. 1978; Bicknell et al. 1968; Pool et al.
radic. Several cases have come to autopsy, however, it is 1991). The onset is typically in middle or later years, and
not clear how representative they are. In three patients no may be subacute or gradual. Dystonic spasm of the laryn-
clear abnormalities were found (Gibb et al. 1988); in one geal musculature may occur either in adduction or abduc-
case neuronal loss and gliosis were found in the striatum tion, and the quality of the dysphonia differs in these two
(Altrocchi and Forno 1983); and in two cases neuronal loss forms. Adductor spasm, which is by far more common,
and Lewy bodies were found in brainstem nuclei renders the voice high-pitched, strained, and strangulated;
(Kulisevsky et al. 1988; Mark et al. 1994). It may well be with abductor spasm, the voice is more breathy and
p 08.qxd 3/10/08 9:38 AM Page 369
8.25 Tourette’s syndrome 369
whispering. Some patients may find improvement with Nee et al. 1980; Regeur et al. 1986); it has also become
singing, or even with shouting. apparent that sensory tics, once thought to be unusual, are
also present in most patients.
Motor tics are usually the first to appear. Simple motor
Course tics include blinking, brow wrinkling, grimacing, and
shoulder shrugging; complex motor tics may include
After a period of progression of variable duration, the dys- touching, smelling, hopping, throwing, clapping, bending
phonia generally remains chronic. over, squatting, or even such very complex acts as
echopraxia or copropraxia (wherein patients make obscene
gestures). Motor tics usually appear first in the face or head
Etiology and then spread in a caudal direction. In most cases, before
having a tic, patients first experience an urge to tic (Lang
Spasmodic dysphonia is considered one of the primary 1991), an urge that may at times be resisted, albeit with dif-
dystonias; the etiology is not known. ficulty. Furthermore, some patients are able to abort a
motor tic with a geste antagoniste, such as placing a hand
under the chin to prevent the emergence of a tic of the head
(Wojcieszek and Lang 1995).
Vocal tics, like motor tics, may also be simple or com-
Dysphonia may result from lesions in the central or periph-
plex. Simple vocal tics include snorting, hissing, coughing,
eral nervous system or in the larynx itself. Dysphonia has
throat-clearing, grunting, and, classically, barking.
been noted with a putaminal lesion (Lee et al. 1996), lesions
Complex vocal tics include the utterance of words, simple
of the nucleus ambiguus or the vagus or recurrent laryngeal
phrases, or entire sentences. Echolalia or palilalia may
nerves, and with various intrinsic laryngeal lesions.
occur and, in a minority, classic coprolalia, or involuntary
Dysphonia has also been reported as a side-effect of val-
swearing, may be seen.
proic acid (Oh et al. 2004) and gabapentin (Reeves et al.
Sensory tics occur in the majority of patients and appear
1996), and has also occurred as part of tardive dyskinesia
to exist in two forms. In one there is simply the experience
(Lieberman and Reife 1989).
of an itch or a tingle (Chee and Sachdev 1997), and this is
seen in perhaps one-quarter of patients. In the other the
Treatment sensory tic appears more as a premonitory urge to a motor
tic (Cohen and Leckman 1992; Leckman et al. 1993), and
Botulinum injection of the laryngeal musculature generally this has been reported in over 90 percent of cases
provides relief. In treatment-resistant cases, consideration (Leckman et al. 1993). Remarkably, in one case a premon-
may be given to lesioning the recurrent laryngeal nerve. itory urge to itch was experienced by a patient as residing
in another person, whom the patient then proceeded to
scratch (Karp and Hallett 1996).
8.25 TOURETTE’S SYNDROME Rarely, dystonic movements, especially cervical or facial
dystonias, may appear in the course of Tourette’s syn-
Tourette’s syndrome, first describe by the French neurolo- drome, but not until 10–38 years have passed (Stone and
gist Georges Gilles de la Tourette in 1885 (de la Tourette Jankovic 1991).
1885), is the classic cause of chronic tics; this is a not Obsessions and compulsions are common in Tourette’s
uncommon disorder, with a lifetime prevalence of about syndrome, eventually appearing in nearly one-half of all
0.05 percent, and is about three times more common in patients (Frankel et al. 1986; Robertson et al. 1988); they
males than females. Synonyms for this disorder include typically begin to appear about 5 years into the course.
maladie des tics and tic convulsiv. Interestingly, compulsions experienced by patients with
Tourette’s syndrome often center on getting things ‘just
right’ (Leckman et al. 1994).
Clinical features Attention deficit/hyperactivity disorder (ADHD) very
commonly accompanies Tourette’s syndrome and, in
The onset of Tourette’s syndrome is typically with a simple those cases of Tourette’s syndrome in which it does occur,
tic, more often motor than verbal, and more often on the the hyperactivity usually precedes the tics by a little over a
head or face than elsewhere. Although the age of onset year (Cardoso et al. 1996).
may be anywhere from infancy to the early adult years
(Marneros 1983), most patients fall ill in childhood,
around the age of 7 years. Course
In its fully developed form, both motor and verbal tics
are present, and these may be either simple or complex In most cases, symptoms gradually worsen over a matter of
(Cardoso et al. 1996; Lang et al. 1993; Lees et al. 1984; a few years, peaking in severity around the age of 10 years;
p 08.qxd 3/10/08 9:38 AM Page 370
subsequently there is a gradual and progressive remission Differential diagnosis

of symptoms, such that by the age of 18 years roughly one-
half of patients are left with either no, or only trivial, tics The full differential for tics is provided in Section 3.3, and
(Leckman et al. 1998; Pappert et al. 2003). In those cases of the causes noted there, several deserve special consider-
where full remissions do occur, relapses may appear, some- ation. Autism may be complicated by tics, and this diagno-
times decades later (Chouinard and Ford 2000; Klawans sis is suggested by the other features seen in autism, such as
and Barr 1985). the machine-like relationships patients have with others.
Sydenham’s chorea may occur in children, but is suggested
by concurrent chorea; Huntington’s disease and choreo-
Etiology acanthocytosis may also cause tics, but these too are associ-
ated with chorea and generally have an onset in adult years.
Tourette’s syndrome is clearly familial, with concordance Technically, a diagnosis of Tourette’s syndrome should
rates rising from about 5 percent in siblings to approxi- not be made until the patient has both motor tics and vocal
mately 10 percent in dizygotic twins and 50 percent in tics. Patients with only motor or only vocal tics are said to
monozygotic twins; indeed if one accepts the presence of have ‘transient tic disorder’ if the tics last no longer than a
simple tics as evidence of the disorder, the monozygotic year, or ‘chronic motor or vocal tic disorder’ if they last
concordance rises to over 75 percent (Price et al. 1985). longer than a year. This distinction may be unwarranted,
Although earlier studies supported an autosomal dominant however, as it appears that these ‘disorders’ merely repre-
mode of inheritance (Eapen et al. 1993; Pauls and Leckman sent formes frustes of the full Tourette’s syndrome
1986; Pauls et al. 1990), more recent work has indicated that (Golden 1978; Kurlan et al. 1988).
Tourette’s syndrome is a complex genetic disorder.
Imaging and neuropathologic studies have focused on
the basal ganglia. MRI studies strongly suggest a reduced Treatment
size of the basal ganglia (Bloch et al. 2005; Hyde et al. 1995;
Peterson et al. 1993; Singer et al. 1993). Although neu- Various medications are effective, including second-gener-
ropathologic studies have not revealed distinctive micro- ation antipsychotics (olanzapine [Onofrj et al. 2000],
scopic findings, immunologic studies have revealed a ziprasidone [Sallee et al. 2000], risperidone [Bruggeman
decreased number of dopamine reuptake sites in the stria- et al. 2001; Dion et al. 2002; Scahill et al. 2003]), first-
tum (Singer et al. 1991) and a decrease in dynorphin stain- generation antipsychotics (haloperidol and pimozide [Sallee
ing in fibers coursing from the striatum to the globus et al. 1997; Shapiro et al. 1989]), alpha-2 autoreceptor ago-
pallidus (Haber et al. 1986). nists (clonidine [Cohen et al. 1980; Leckman et al. 1991]
Although the mechanism or mechanisms underlying and guanfacine [Scahill et al. 2001]), desipramine (Spencer
these changes in the basal ganglia are not clear, some et al. 2002), and pergolide (Gilbert et al. 2003). Each is dis-
research suggests that, at least in a certain minority of cussed in turn, followed by a discussion of overall pharma-
cases, Tourette’s syndrome may be an autoimmune dis- cologic strategy.
ease, triggered, in turn, by a preceding beta-hemolytic Of the antipsychotics, olanzapine is begun at a dose of
streptococcal infection. Swedo et al., in 1998, considered 5 mg/day and increased, if necessary, 2 weeks later to a dose
Tourette’s to be part of a syndrome that they named PAN- of 10 mg/day. The starting dose for ziprasidone is 5 mg, for
DAS (pediatric autoimmune neuropsychiatric disorders risperidone 0.5 mg, for haloperidol 0.25–0.5 mg, and for
associated with streptococcal infections). In this condition, pimozide 1 mg, and each agent may be increased in similar
similar to Sydenham’s chorea, a preceding group A beta- increments every week or two until a satisfactory response,
hemolytic streptococcal pharyngitis triggers an immune limiting side-effects, or a maximum dose is reached.
response that cross-reacts with the basal ganglia, leading Dosage ranges (and average effective doses) are as follows:
to, among other symptomatologies, tics; increased levels of ziprasidone, 5–40 mg (30 mg); risperidone, 1–6 mg (3 mg);
anti-streptococcal antibodies in patients with Tourette’s haloperidol, 1–10 mg (4 mg); pimozide, 1–10 mg (4 mg).
syndrome support this notion (Church et al. 2003; Muller Choosing between the various antipsychotics is not
et al. 2001b; Rizzo et al. 2006). Furthermore, most (Church entirely straightforward. Although the second-generation
et al. 2003; Rizzo et al. 2006; Singer et al. 1998), but not all agents olanzapine, ziprasidone, and risperidone are, over-
(Singer et al. 2005), studies have also found an increased all, better tolerated than the first-generation agents, both
incidence of serum anti-basal ganglia antibodies in olanzapine and risperidone are associated with weight
patients with Tourette’s compared with controls. Although gain, hyperlipidemia, and even diabetes mellitus, and
speculative, it is tempting to suggest that in Tourette’s risperidone may cause dysphoria (Margolese et al. 2002).
syndrome what is inherited is either a susceptibility to Haloperidol and pimozide are less likely to cause weight
streptococcal infections or to the development of a partic- gain but carry the liabilities of akathisia (which may mani-
ular immune response to such infections, with symptoms fest with an increase in the frequency of tics [Weiden and
then appearing secondary to autoimmune damage to the Bruun 1987]), tardive dyskinesia, dysphoria (Bruun 1988),
basal ganglia. and, in children, the capacity to cause severe separation
p 08.qxd 3/10/08 9:38 AM Page 371
8.26 Myotonic muscular dystrophy 371
anxiety to the point where ‘school phobia’ sets in (Linet followed, if necessary, by another, and perhaps another, is
1985; Mikkelsen et al. 1981). Furthermore, pimozide car- most appropriate.
ries the further risk of prolonging the corrected QT inter- In considering treatment of Tourette’s, one should
val, with the possibility of torsades de pointe. All other also keep in mind the possibility that some cases do occur
things being equal, it may be prudent to begin with a sec- as part of PANDAS, that is to say, on an autoimmune
ond-generation agent; if the initial choice fails then basis after a beta-hemolytic streptococcal pharyngitis.
another might be tried, or one could switch to a first-gen- This should be suspected in cases in which there is a tem-
eration agent such as haloperidol. poral relationship between either the onset of tics (or their
Of the two alpha-2 autoreceptor agonists, clonidine is exacerbation) and a preceding ‘sore throat’, keeping in
the best studied. The total daily starting dose for clonidine mind that weeks or months may be required for the
is 0.1 mg and for guanfacine is 1 mg. Dosage increases may mounting of the autoimmune response. When suspicion is
be made in similar increments every week or so until one high, it is appropriate to determine ASO (anti-streptolysin
begins to see an initial response, limiting side-effects, or a O) and anti-DNAase B levels to confirm a preceding strep-
maximum dose is reached of 1 mg for clonidine and 4 mg tococcal infection. In cases in which it appears likely that
for guanfacine. In all cases the total daily dose should be the Tourette’s is occurring as part of PANDAS, considera-
divided into two or three doses. Importantly, in contrast to tion may be given to chronic penicillin treatment to
antipsychotics, where the response is fairly prompt, with prevent future exacerbations, and, in severe cases, to
the alpha-2 autoreceptor agonists the full response may plasmapheresis to acutely reduce symptoms (Perlmutter
take weeks or months to develop. Consequently, in titrat- et al. 1999).
ing the dose it makes sense, as soon as an initial response is Finally, in severe and treatment-resistant cases, neuro-
seen, to pause and see how things develop before increas- surgical intervention, for example deep brain stimulation of
ing the dose further. It must also be borne in mind that the globus pallidus, may be considered (Shahed et al. 2007).
these agents must not be abruptly discontinued, as this As noted earlier, ADHD is commonly seen in patients
may be followed by a prolonged and severe ‘rebound’ of with Tourette’s and, should an alpha-2 autoreceptor ago-
tics (Leckman et al. 1986): a gradual tapering, over weeks, nist (or desipramine in adults) not prove effective, consid-
is required. In making the choice between clonidine and eration may then be given to utilizing a stimulant, such as
guanfacine, although there is more experience with the use methylphenidate. Despite the fact that stimulants may
of clonidine, guanfacine may be better tolerated. cause tics (Denckla et al. 1976), it appears that, in practice,
Desipramine, a tricyclic antidepressant, may be started the risk is negligible (Gadow et al. 1992, 1999); indeed, in
at a dose of 25 mg and increased every few days to 100 mg, one study tics actually decreased with methylphenidate
after which the patient should be observed for a few weeks treatment (Tourette’s Syndrome Study Group 2002).
to see what sort of response emerges. Importantly, as Furthermore, given that in patients with combined
desipramine has been associated with lethal arrhythmias in Tourette’s and ADHD it is the symptomatology of the
children, its use should be restricted to adults. ADHD that is often most problematic, it is critical to not
Pergolide has recently been shown to be effective. Given withhold effective treatment.
the association between pergolide and cardiac valvu-
lopathy, however, its use cannot be recommended. If
ropinirole or pramipexole are found to be effective, this
will open up an exciting new therapeutic option. 8.26 MYOTONIC MUSCULAR DYSTROPHY
Overall, in children one should begin with either an
antipsychotic or an alpha-2 autoreceptor agonist. Although Of the several disorders capable of causing myotonia and
the antipsychotics are by and large more effective, the bur- muscular dystrophy, the classic example, described by
den of long-term side-effects is significant, and, based on Batten and Gibb in 1909, has had several names over the past
that, some clinicians prefer to begin with an alpha-2 auto- century. The original name, bestowed by Batten and Gibb
receptor agonist, holding the antipsychotics in reserve. (1909), was myotonia atrophica; a similar one is myotonia
Furthermore, if the patient also has ADHD that requires dystrophica. Subsequently, this disease was referred to as
treatment, special consideration should be given to an myotonic muscular dystrophy or, simply, myotonic dystro-
alpha-2 autoreceptor agonist, as these agents, unlike the phy. Recently it became apparent that some other disorders
antipsychotics, are also effective in ADHD. In adults, simi- (as discussed below under differential diagnosis) could pro-
lar considerations apply; however, here one may also con- duce a similar clinical picture and, in an effort to standardize
sider desipramine, which, like the alpha-2 autoreceptor terminology, a recent conference proposed renaming
agonists, is effective not only for Tourette’s but also for myotonic muscular dystrophy as myotonic dystrophy type 1
ADHD. It must be emphasized that the foregoing constitute (or DM1), with similar disorders named myotonic dystro-
suggestions only: there simply are not enough comparative phy type 2 (DM2), etc. (International Myotonic Dystrophy
studies to allow for definitive recommendations. In many Consortium 2000). Ongoing use of the name ‘myotonic
cases, a methodical approach, giving one agent a good muscular dystrophy’ for DM1 was not forbidden, however,
trial (at an adequate dose and for an adequate duration), and it is retained in this text.
p 08.qxd 3/10/08 9:38 AM Page 372
Myotonic muscular dystrophy is a not uncommon dismay be born with ‘congenital’ myotonic muscular dystro-
order, with a lifetime prevalence of about 5 per 100 000; it phy, characterized, among other symptoms, by mental
is equally common in males and females. retardation (Koch et al. 1991).
Both CT (Avrahami et al. 1987) and MRI (Antonini et al.
2004) scanning may reveal a mild degree of cortical atrophy.
Clinical features On MR scanning patchy areas of increased signal intensity
on T2-weighed scans may be seen in the white matter (Di
The onset is gradual and insidious and, although most Costanzo et al. 2002). Genetic testing is available.
patients fall ill in their late teens or early twenties, the range
of age of onset is wide, from childhood up to the sixth
decade. Course
The cardinal symptoms of the disease are myotonia and
weakness. Myotonia may go unnoticed by the patient, or The disease is gradually progressive and, although those
may manifest in difficulty in letting go of, for example, a with later onsets and milder symptoms may experience a
doorknob, or in disengaging from a handshake. On physi- normal lifespan, cases of early onset and severe symptoms
cal examination, myotonia may be elicited by tapping the are often associated with premature death in early or middle-
thenar eminence with a percussion hammer and observing adult years, often from cardiac or respiratory causes.
for the characteristic muscle dimpling. Weakness is even-
tually accompanied by atrophy and, importantly, this is Etiology
more prominent distally, being seen first in the upper
extremities. Other signs may also accrue. Many patients Myotonic muscular dystrophy is inherited in an autosomal
have a distinctive ‘myopathic facies’, with frontal balding, dominant fashion with almost 100 percent penetrance but
ptosis, and wasting of the face and neck musculature; the a quite variable expressivity, even within the same family
voice often also becomes nasal and monotone. Cataracts (Pryse-Phillips et al. 1982). Mutations consist of an expan-
are seen in over 90 percent of patients, and there may be sion of a normally occurring CTG triplet in the DMPK
deafness (Wright et al. 1988) and gonadal failure, with gene on chromosome 19, which codes for the myotonic
erectile dysfunction or menstrual irregularity. Cardiac dystrophy protein kinase (Brook et al. 1992). As in many
conduction abnormalities and arrhythmias may occur, inherited disorders due to triplet expansions, ‘anticipation’
including atrioventricular block, fascicular block, intra- may occur, in which in succeeding generations, and with
ventricular conduction block, atrial fibrillation, and ven- expansion of the triplet repeat, the disease becomes more
tricular premature contractions; a cardiomyopathy with severe and has an earlier onset. Although anticipation is
congestive heart failure may also occur, but is less com- more likely with maternal transmission, it has been noted
mon. Alveolar hypoventilation may also occur. in paternal cases (Nakagawa et al. 1994).
Cognitive impairment is eventually seen in a majority of Neuropathologic studies are few. Neuronal hetero-
patients (Modoni et al. 2004; Perini et al. 1989) and, although topias have been noted in the cerebral cortex (Rosman and
this is generally quite mild, it may progress to a dementia Kakulas 1966) and neurofibrillary tangles in the hip-
(Huber et al. 1989). Personality change may also occur and, pocampus (Maurage et al. 2005). In cases characterized by
although it tends to be mixed in type, avoidant traits may be hypersomnolence, cell loss was noted in the superior cen-
predominant (Delaporte et al. 1998; Winblad et al. 2005). tral nucleus of the midbrain (Ono et al. 1998), and, in cases
Apathy appears to be more common than among compara- marked by alveolar hyperventilation, cell loss was seen in
ble controls (Rubinsztein et al. 1998). Although depression the medullary reticular formation (Ono et al. 1996).
may occur, it appears, in contrast to apathy, to be no more
common among these patients than comparable controls: in
considering the diagnosis of depression, one must guard Differential diagnosis
against misinterpreting the expressionless ‘myopathic facies’
as a depressed affect (Adie and Greenfield 1924; Billings and As noted earlier, myotonic muscular dystrophy, or DM1, is
Ravin 1941; Bungener et al. 1998). but one of several causes of myotonia and weakness.
Hypersomnia is not uncommon (Manni et al. 1991) DM2, also known as the PROMM syndrome (or proximal
and indeed may be the presenting complaint (Hansotia myotonic myopathy), although similar to myotonic mus-
and Frens 1981): some patients may literally sleep for days cular dystrophy, may be distinguished clinically by the pat-
(Phemister and Small 1961). Although some of these tern of weakness, which is proximal rather than distal, and
hypersomnic patients demonstrate sleep apnea (of either by the presence of myalgia, which is not seen in myotonic
the central or obstructive type), the number of apneic muscular dystrophy (Day et al. 2003; Ricker et al. 1994,
episodes is not high enough to account for the degree of 1995, 1999). Recently a third disorder, namely DM3, was
hypersomnolence (van der Meche et al. 1994). described, which, like the PROMM syndrome, is also char-
As noted below, ‘anticipation’ may occur in this disease acterized by proximal weakness; it also apparently is
(Harper et al. 1992; Howeler et al. 1989), and some children notable for a prominent dementia (Le Ber et al. 2004).
p 08.qxd 3/10/08 9:38 AM Page 373
8.27 Cerebrotendinous xanthomatosis 373
Another disorder to consider is myotonia congenita. Mahloudji 1975; Soffer et al. 1995; Verrips et al. 2000a,b;
This is an inherited, non-progressive condition character- Watts et al. 1996) is characterized by dementia, seizures,
ized by myotonia and, rather than weakness and atrophy, long-tract signs, ataxia, a peripheral sensorimotor polyneu-
by a degree of muscular hypertrophy: autosomal dominant ropathy, gross tendon enlargement, especially evident in
cases are referred to as Thomsen’s disease and recessive the Achilles tendon, cataracts, and chronic diarrhea.
cases as the Becker variant. Because the phenomenon of Although the disease may present with any one of these var-
myotonia may be the only symptom of myotonic muscular ious features, in most cases the presentation will be with
dystrophy for many years, the clinical differential between juvenile cataracts or with chronic, intractable diarrhea.
myotonic muscular dystrophy and myotonia congenita T2-weighted or, especially, FLAIR MR scanning will
may depend on long-term follow-up, watching closely for reveal increased signal intensity in the cerebral and cerebel-
other symptoms to appear (Maas and Paterson 1950). lar white matter; increased signal intensity may also be seen
in the cerebellar dentate nuclei (De Stefano et al. 2001;
Swanson and Cromwell 1986).
Treatment Serum cholestanol levels are grossly increased; choles-
terol levels are either normal or decreased (Salen 1971).
There is no specific treatment for the disease. Hyper- Genetic testing is available (Meiner et al. 1994).
somnolence, which, in some cases, may be the most dis-
tressing feature of the disease, responds to modafinil
(MacDonald et al. 2002; Wintzen et al. 2007); open work Course
also suggests a usefulness for methylphenidate (van der
Meche et al. 1994). Myotonia may respond to various med- This is a very slowly progressive disorder. In those with an
ications, including phenytoin, disopyramide, pro- early age of onset and severe symptoms, death typically
cainamide, and nifedipine, but given that myotonia rarely occurs within 10 to 20 years, whereas those with later
causes distress or disability, these agents are typically not onsets and milder symptoms may experience a normal
required. The general treatment of dementia is discussed in lifespan.
Section 5.1. Yearly electrocardiograms (ECGs) are required
and, if there is suspicion of significant arrhythmia, a 24-
hour Holter monitor is appropriate; some patients may Etiology
require a pacemaker. As noted earlier, alveolar hypoventila-
tion may occur; these patients do not appear to tolerate Cerebrotendinous xanthomatosis occurs secondary to
general anesthesia well, hence surgery, if possible, should be mutations in CYP27, a gene on chromosome 2 that codes for
avoided. Hearing aids and cataract surgery may be required. an enzyme known as sterol 27-hydroxylase (Verrips et al.
Genetic counseling is appropriate and, given the vari- 2000a). With defective activity of this enzyme, cholestanol
able expression of the disease, it may be appropriate to accumulation occurs in the cerebral and cerebellar white
offer testing to apparently unaffected relatives. matter, the cerebellar dentate nuclei, and peripheral
nerves, tendons, and corneae (Menkes et al. 1968). Within
the brain, widespread demyelinization occurs and, in some
8.27 CEREBROTENDINOUS XANTHOMATOSIS cases, actual xanthomas may form (Schimschock et al. 1968).
Cerebrotendinous xanthomatosis is a rare, recessively

inherited lipid storage disease that may, in some cases, Differential diagnosis
cause a dementia. Also known as cholestanolosis,
cholestanol storage disease or Van Bogaert’s disease, the Whenever dementia occurs in the setting of juvenile
current name is a felicitous one, given that it draws atten- cataracts, chronic diarrhea, or, classically, Achilles
tion to the hallmarks of the disease, namely xanthomatous tendon enlargement, the diagnosis of cerebrotendinous
deposits in the cerebrum and tendons, most particularly xanthomatosis is very likely. When these are not present,
the Achilles tendon. or are overlooked, consideration may be given to
metachromatic leukodystrophy in children, and to spin-
ocerebellar ataxia in adults.
Clinical features
The onset is very gradual and, although most patients Treatment
begin to have symptoms in late childhood or early adoles-
cence, the range in age of onset is wide, from infancy to Chenodeoxycholic acid, at a dose of 750 mg/day, taken
middle years (Swanson and Cromwell 1986). chronically, dramatically reduces serum cholestanol levels
Fully developed, classic cerebrotendinous xantho- and leads to a either a stabilization of symptoms or to a
matosis (Bencze et al. 1990; Canelas et al. 1983; Farpour and degree of remission (Berginer et al. 1984). Pravastatin and
p 08.qxd 3/10/08 9:38 AM Page 374
simvastatin, although ineffective by themselves, enhance 8.29 METACHROMATIC LEUKODYSTROPHY

the effect of chenodeoxycholic acid.
At-risk relatives should be offered genetic testing. Metachromatic leukodystrophy is a rare, recessively inher-
ited disorder that occurs secondary to mutations in the
gene for arylsulfatase A, with a resulting accumulation of
8.28 THALAMIC DEGENERATION sulfatides in the brain, peripheral nerves, kidneys, and gall-
bladder. It is of particular interest in that, when appearing
Thalamic degeneration is a very rare syndrome character- in adolescents or adults, it may present with a psychosis,
ized clinically by dementia and pathologically by relatively personality change, or a dementia.
selective degeneration of the thalamus, in the absence of
known causes such as Creutzfeldt–Jakob disease. In all like-
lihood, this syndrome subsumes several or more different Clinical features
disease processes, which, to date, have not been isolated.
Three forms are recognized based on the age of onset: the
late infantile form presents in infants up to the age of 4
Clinical features years, the juvenile form from the age of 4 to 16 years, and
the adult form from the age of 16 years onwards. In the
As might be expected, there is considerable variability in adult form, although most cases present before the age of
the clinical features of this syndrome (Martin et al. 1983). 30 years, cases presenting as late as the seventh decade have
The age of onset may range from adolescence to the sev- been noted (Bosch and Hart 1978). Each of these forms
enth decade, and the mode of onset from subacute to differs in their typical clinical symptomatology.
insidious. Dementia is a common denominator in all cases, The late infantile form is characterized by hypotonia,
and this may be accompanied by apathy and somnolence weakness, and seizures (Brain and Greenfield 1950).
(Janssen et al. 2000; Stern 1939), emaciation (Martin et al. The juvenile form (Haltia et al. 1980) may present with
1983), or myoclonus (Little et al. 1986). In one case a dementia or with a personality change that merges into a
(Deymeer et al. 1989), a 46-year-old woman presented dementia. Ataxia, spasticity, and a peripheral neuropathy
with ‘bizarre behavior and paranoid ideas’, eventually fol- may also constitute the presentation, or, in cases that pres-
lowed by a dementia accompanied by fasciculations. ent with a dementia or personality change, any one or all of
these features may emerge later in the course of the disease.
The adult-onset form may present with psychosis, per-
Course sonality change, or dementia: in those cases that present
with a psychosis or a personality change, a dementia gener-
Survival ranges from a matter of several months (Stern ally ensues (Hageman et al. 1995; Rauschka et al. 2006).
1939) to up to 20 years (Martin et al. 1983). Other symptoms and signs may also constitute presenting
features, or may emerge in the context of psychosis, per-
sonality change or dementia, including ataxia, spasticity,
Etiology seizures, or a peripheral neuropathy (Rauschka et al. 2006).
It must be emphasized that in cases which do present with
Both familial (Little et al. 1986) and sporadic cases have
psychosis, personality change, or dementia, these other
been reported. Autopsy studies reveal neuronal loss and
symptoms and signs may not appear for years.
gliosis in the thalamus, especially the dorsomedial (Janssen
The psychosis seen in the adult form is very similar to
et al. 2000; Moosey et al. 1987) and anterior (Martin et al.
that seen in schizophrenia. One patient developed bizarre
1983) nuclei. Other structures may also be affected, includ-
delusions, auditory hallucinations, loosening of associa-
ing the cerebral cortex, cerebral white matter, and inferior
tions, and flat affect at the age of 19 years, and the diagnosis
olives (Stern 1939), as well as the basal ganglia and nucleus
became apparent only 12 years later when a peripheral
basalis of Meynert (Moosey et al. 1987).
polyneuropathy was noted (Manowitz et al. 1978).
Another, at the age of 28 years, developed ‘bizarre elation,
Differential diagnosis true auditory hallucinations, and poorly formulated para-
noid ideas’, followed by a gradually progressive dementia
Creutzfeldt–Jakob disease and fatal familia insomnia are over the next 4 years (Betts et al. 1968). In a third example
often included in the differential. (Waltz et al. 1987), a 31-year-old man began to talk to him-
self and pace the floor; he was eventually fired from his job
and his wife left him. By the age of 38 years he had ‘poor con-
Treatment centration, inappropriate smiling and laughing, . . . irrelevant
remarks . . . with non sequiturs, restlessness and occasional
The general treatment of dementia is discussed in auditory hallucinations’. The diagnosis was eventually sug-
Section 5.1. gested when nerve conduction velocity studies showed mild
p 08.qxd 3/10/08 9:38 AM Page 375
8.29 Metachromatic leukodystrophy 375
slowing. In some cases, the psychosis may have a distinct normally converts sulfatides into cerebroside, which is a
manic flair: one patient (Besson 1980) was ‘grandiose . . . normal constituent of myelin; with decreased activity of
and called out the fire brigade’, and another (Van Bogaert arylsulfatase A, there is an increase in sulfatide levels and a
and Dewulf 1939) ‘had ideas of grandeur, thought he was decrease in cerebroside levels, with resulting demyelin-
going to become an ambassador and gave himself honorary ization. Of interest, the increased sulfatide content in
titles’. In both these cases, the patients eventually became peripheral nervous tissue and renal epithelial cells accounts
demented. for the metachromasia. Sulfatides are positively charged,
The personality change may be non-specific; however, a and their excessive presence reorients the negatively
frontal lobe syndrome may be prominent (Austin et al. charged molecules of cresyl violet or toluidine blue, thereby
1968; Finelli 1985; Wulff and Trojaborg 1985) with disin- changing their color.
hibition, perseveration, irritability, and socially inappro- Within the central nervous system, widespread
priate behavior. demyelinzation is seen, and this is especially evident in the
As might be suspected, in addition to cognitive deficits, centrum semiovale. In severe cases, the white matter of the
the dementia seen in metachromatic leukodystrophy is centrum semiovale may be shrunken down to a thin gliotic
also often marked by delusions, hallucinations, and frontal remnant, with only relative sparing of the U-fibers, such
lobe symptomatology (Alves et al. 1986; Bosch and Hart that there is very little intervening tissue between the
1978; Hirose and Bass 1972; Hyde et al. 1992; Reider- depths of the sulci and the lateral ventricles. The cerebellar
Grosswasser and Bornstein 1987; Shapiro et al. 1994). white matter is affected in a similar fashion, and there is
T2-weighted MR scanning reveals ventricular dilation also peripheral demyelinization.
and widespread increased signal intensity in the white mat- Rarely, rather than occurring secondary to a mutation
ter (Reider-Grosswasser and Bornstein 1987; Rauschka in the gene for arylsulfatase A, metachromatic leukodys-
et al. 2006). Nerve conduction velocity studies may reveal trophy may occur secondary to a mutation in a gene on
slowing in patients who lack clinical evidence of a periph- chromosome 10 coding for a sulfatide activator protein
eral neuropthy; however, it must be kept in mind that such (Schlote et al. 1991). This protein acts as an essential cofac-
studies may be normal. Lumbar puncture may reveal nor- tor for arylsulfatase A and, in its absence, all of the bio-
mal CSF or, especially in those with late infantile or juve- chemical defects seen with mutations in the gene for
nile forms, an increased total protein. arylsulfatase A also accrue.
An often mentioned, but rarely seen, finding in
metachromatic leukodystrophy is non-filling of the gall-
bladder on cholecystography, which occurs secondary to
infiltration of the gallbladder by sulfatides. Differential diagnosis
Assays of leukocytes reveal decreased aryl sulfatase A
activity, and assays of peripheral nerve tissue (obtained at Differential diagnostic considerations vary according to
sural nerve biopsy) or of urinary sediment will reveal the age of the patient.
increased sulfatide content. The phenomenon of metachro- Juvenile-onset cases may be confused with adreno-
masia, from which this disorder derives its name, may also leukodystrophy; however, in adrenoleukodystrophy one
be observed in peripheral nervous tissue or urinary sedi- also sees either a hemianopia or cortical blindness, findings
ment. Both cresyl violet and toluidine blue undergo a chro- not seen in metachromatic leukodystrophy.
matic metamorphosis, turning from violet or blue to brown Adult-onset cases may, depending on their presenta-
or golden-brown, respectively, when applied to affected tion, raise several differential considerations. Presentations
cells in the peripheral nerve or urinary sediment. with psychosis may be indistinguishable from schizophre-
nia until other signs and symptoms, such as ataxia or
peripheral neuropathy, emerge, or until a dementia super-
venes. Presentations with a personality change of the
Course frontal lobe type or with a dementia may raise the possibil-
ity of frontotemporal dementia, and the differential here
The disease is gradually progressive, with death within
may also rest on the emergence of a peripheral neuropathy
2–10 years in the late infantile or juvenile forms; in the
or ataxia.
adult form, death may be delayed for up to 15 years.
As noted earlier, diagnosis rests on demonstrating
decreased aryl sulfatase A activity in leukocytes and in find-
ing increased sulfatide content in peripheral tissues, and it
Etiology must be stressed that both tests must be positive. Finding a
decreased aryl sulfatase A activity by itself is not diagnostic,
As noted, metachromatic leukodystrophy is a recessively because in about 10 percent of the general population there
inherited disorder, and occurs secondary to any of a large is a ‘pseudodeficiency’ of arylsulfatase A activity that is not
number of mutations in the gene for arylsulfatase A, found associated with sulfatide accumulation or with any symp-
on chromosome 22 (Barth et al. 1993). Arylsulfatase A tomatology (Hageman et al. 1995).
p 08.qxd 3/10/08 9:38 AM Page 376
Treatment whereas in others there may be melanoderma, nausea,

vomiting, abdominal pain, diarrhea, and hyperkalemia. It
Bone marrow transplantation may retard or halt the pro- must be kept in mind that, in some cases with cerebral or
gression of the disease (Kidd et al. 1998; Krivit et al. 1987; cord involvement, adrenal function may be normal.
Navarro et al. 1996). The general treatment of psychosis is Phenotypic variability is the rule in adrenoleukodystro-
discussed in Section 7.1, of personality change in Section phy, and even members of the same family may have dif-
7.2, and of dementia in Section 5.1. ferent presentations (Erlington et al. 1989). Indeed, even
monozygotic twins may exhibit phenotypic heterogeneity
(Sobue et al. 1994), to the point of one twin being affected
8.30 ADRENOLEUKODYSTROPHY while the other is not (Korenke et al. 1996).
Female heterozygotes may occasionally have mild
Adrenoleukodystrophy is a rare, X-linked disorder charac- symptoms.
terized pathologically by the accumulation of very-long- Computed tomography scanning in patients with cere-
chain fatty acids in the brain, spinal cord, peripheral bral involvement may reveal areas of radiolucency in the
nerves, and adrenal glands, and clinically by a variable white matter: typically these first appear in the occipital
combination of dementia, spasticity, and adrenal failure. lobes and then spread anteriorly into the parietal and tem-
poral lobes. With contrast administration, enhancement is
seen at the boundary between the areas of radiolucency
Clinical features and normal tissue. T2-weighted MR scanning reveals
increased signal intensity in the white matter, following the
Clinically (Moser et al. 1984), adrenoleukodystrophy may same pattern as seen on CT scans, with the same pattern of
be characterized according to either the age of onset or the enhancement upon administration of gadolinium.
primary site of pathology. Thus, onset may be in childhood Cerebrospinal fluid analysis may reveal a mild lymphocytic
(at an average age of 8 years), adolescence, or adult years, pleocytosis and an elevated total protein. In patients with
and the primary site may be cerebral, spinal, or adrenal. adrenal involvement, there may be hyperkalemia and
Childhood-onset adrenoleukodystrophy usually pres- decreased cortisol and increased adrenocorticotropic hor-
ents with cerebral symptomatology, often with a personal- mone (ACTH) levels. The diagnosis is confirmed by find-
ity change and visual symptoms. These patients may ing elevated levels of very-long-chain fatty acids in plasma
become withdrawn and irritable, and school performance or cultured skin fibroblasts. Given the very large number of
declines. Varying degrees of hemianopia or cortical blind- mutations, genetic testing is not practical.
ness may occur, followed by a dementia accompanied by
spasticity (Moser et al. 1984; Schaumburg et al. 1975).
Adolescent-onset adrenoleukodystrophy tends to present Course
in a fashion similar to that of the childhood-onset form.
Adult-onset adrenoleukodystrophy tends to present Childhood-onset cases generally progress fairly rapidly,
with spinal cord involvement, adrenal failure or, less com- death supervening within 3–5 years; adolescent- and adult-
monly, with cerebral involvement; in cases that present onset cases, especially those with the adrenomyeloneu-
with cord involvement or adrenal failure, long-term fol- ropathy syndrome, may progress very slowly. There may
low-up reveals the development of cerebral involvement in rarely be periods of partial remission, only to be followed
a significant minority (van Geel et al. 2001). Cord involve- eventually by relapse (Walsh 1980).
ment yields a syndrome known as adrenomyeloneuropa-
thy (Griffin et al. 1977), wherein gait becomes clumsy and
stiff, and a spastic paraplegia eventually appears. Cerebral Etiology
involvement produces a dementia that may be non-
specific in character, or which may be marked by manic Adrenoleukodystrophy is an X-linked disorder (Mosser
symptoms (Weller et al. 1992) or a Kluver–Bucy syndrome et al. 1994) that occurs secondary to any of a large number
(Powers et al. 1980). of different mutations in the ALD gene on the X chromo-
Peripheral nerve involvement tends to be mild and may some. These mutations cause defective functioning of a
in some cases only be apparent with nerve conduction peroxisome membrane-associated protein, which in turn
velocity studies. leads to an accumulation of very-long-chain fatty acids in
Seizures occur in about one-fifth of all patients, usually the white matter of the brain or spinal cord, in the periph-
late in the course of the disease. eral nerves, and in the adrenal cortex.
Adrenal involvement may occur at any age and may Within the brain (Schaumburg et al. 1975), one typi-
indeed be the sole presentation of adrenoleukodystrophy cally finds an advancing wave of demyelinization that
(O’Neill et al. 1982). In some cases, the only evidence of begins in the occipital lobe and then moves forward into
adrenal cortical involvement may be a decreased cortisol the parietal and temporal lobes; the frontal lobes are
level or an increased adrenocorticotrophic hormone level, broached in only a minority. An inflammatory response is
p 08.qxd 3/10/08 9:38 AM Page 377
8.32 Essential tremor 377
seen at the border between the demyelinization and the Magnetic resonance scanning may be normal or may
normal tissue, behind which much of the white matter is reveal cortical atrophy.
replaced by gliotic tissue. Importantly, the subcortical U- In those with dementia, generalized slowing is seen on
fibers are generally spared, as is the gray matter. the EEG; when seizures are present, the EEG typically reveals
Demyelinization also occurs in the spinal cord, especially generalized spike-and-wave discharges, and there may be a
in the corticospinal tracts, and the peripheral nerves may pronounced photosensitivity (Vadlamudi et al. 2003).
also be involved, albeit generally to a much lesser extent. Diagnosis is confirmed by rectal, muscle, or skin biopsy,
which reveals characteristic fingerprint or granular osmio-
philic deposits on electron microscopy (Berkovic et al. 1988).
In children or adolescents, a diagnosis of metachromatic Course

leukodystrophy may be considered; however, the presence
of visual symptoms and adrenal insufficiency favor The disease is relentlessly progressive, with death occurring
adrenoleukodystrophy. In adults, multiple sclerosis is often on average after 12 years.
considered. Adrenal insufficiency suggests adrenoleukodys-
trophy; however, in its absence the differential may rest on
the determination of very-long-chain fatty acid levels. Etiology
The neuronal ceroid lipofuscinoses occur in four forms,

Treatment namely infantile (CLN1), late infantile (CLN2), juvenile
(CLN3), and the adult form, Kufs’ disease (CLN4). Kufs’
There was much hope that reducing very-long-chain fatty disease may occur on a sporadic or an inherited basis.
acid levels by means of ‘Lorenzo’s oil’ would be curative; Although most heritable cases occur on an autosomal
however, this hope does not seem to have been borne out. recessive basis (Berkovic et al. 1988), families with domi-
Although Lorenzo’s oil does indeed reduce plasma very- nant inheritance have been reported (Burneo et al. 2003;
long-chain fatty acid levels, and uncontrolled studies suggest Nijssen et al. 2002). Although the genetic defect for most
that it may delay expression of the disease in asymptomatic cases of Kufs’ disease is not known, there is one case report
boys (Moser et al. 2005), a controlled study in symptomatic of adult-onset neuronal ceroid lipofuscinosis occurring
patients failed to display any benefit (van Geel et al. 1999). secondary to a mutation typically associated with the
Bone marrow transplantation, if undertaken very early in infantile form (van Diggelen et al. 2001).
the course of the disease, may halt its progression or even Neuronal loss occurs, and in surviving neurons ceroid
lead to improvement (Shapiro et al. 2000). The general and lipofuscin deposits are seen within lysosomes, creating
treatment of dementia is discussed in Section 5.1. Adrenal a typical fingerprint or granular pattern on electron
insufficiency is treated in the usual fashion. microscopy.
Female relatives should be offered testing for very-long-
chain fatty acid levels.
Kufs’ disease is typically suspected in adults with a combi-

8.31 KUFS’ DISEASE nation of myoclonus and dementia, and in such cases one
must consider Creutzfeldt–Jakob disease and Hashimoto’s
Kufs’ disease, also known as the adult form of neuronal encephalopathy. The EEG may be very helpful in making
ceroid lipofuscinosis, is a very rare disorder that typically the differential here in cases with seizures, as the pattern
presents in early adult years with either seizures or dementia. seen in Kufs’ disease is not present in these other disorders.
Clinical features
Treatment
Kufs’ disease typically presents in early adult years in one of
The symptomatic treatment of dementia is discussed in
two fashions (Berkovic et al. 1988; Callagy et al. 2000). In
Section 5.1; divalproex may be considered for seizures.
one, referred to as ‘type A’, patients present with grand mal
and myoclonic seizures and a dementia, which is often
accompanied by ataxia or abnormal movements, such as
athetosis or parkinsonism. In the other, ‘type B’, the pres- 8.32 ESSENTIAL TREMOR
entation is typically with a personality change or dementia,
which may also be accompanied by ataxia and other Essential tremor is a common condition characterized pri-
abnormal movements. marily by a postural tremor of the hands.
p 08.qxd 3/10/08 9:38 AM Page 378
Clinical features would fall. A similar loss of output from the Purkinje cell
layer would also, of course, occur with loss or damage to
Although the range in age of onset is wide, from the first to the Purkinje cells themselves. If these findings are repli-
the ninth decades of life, most patients experience the cated, and if this speculation is correct, then it may well be
onset of tremor during the fifth decade. that essential tremor represents a syndrome composed of
Clinically speaking (Bain et al. 1994; Critchley 1949; two or more inherited disorders causing pathology either
Koller et al. 1994; Lou and Jankovic 1991; Martinelli et al. in brainstem nuclei or in the cerebellum.
1987), in the vast majority of cases, the tremor first
becomes evident in the hand, generally bilaterally; only in a
small minority is the onset unilateral. The tremor, at least Differential diagnosis
initially, is fine, ranging in frequency from 4 to 8cps, and
postural, being most evident when the hands are held out- Essential tremor is a postural tremor and, as discussed
stretched with the fingers spread. In most cases, over time, in Section 3.1, this must be distinguished from rest and
the tremor also becomes apparent elsewhere, including, in intention tremors. Once it is clear that the patient does
decreasing order of frequency, the head, the voice, the have a postural tremor, the differential may be pursued as
chin, and, in a small minority, the feet. Head tremor is gen- outlined in Section 3.1, with special attention given to
erally of the ‘no-no’ type (Bain et al. 1994) with a trembling medication-induced tremors (e.g., sympathomimetics or
oscillation of the head from side to side. Involvement of caffeine), alcohol or sedative/hypnotic withdrawal, and
the voice may impart a quavering quality to the patients’ hyperthyroidism.
speech (Ardran et al. 1966). Recent work (Benito-Leon
et al. 2006) indicates that patients may also display some
cognitive deficits, but these are quite mild and of question-
Treatment
able clinical importance.
A large number of medications are effective in essential
tremor. Primidone (Koller and Royse 1986) and pro-
Course pranolol (Winkler and Young 1974) are the mainstays;
propranolol may be given in doses from 80 to 240 mg/day,
In most cases the course is characterized by progressive and primidone from 25 to 750 mg/day. Alternatives
worsening to a certain plateau, which may persist for years include gabapentin (Gironell et al. 1999; Ondo et al. 2000),
or decades, after which there may be further progression. in doses from 1200 to 3600 mg/day, and topiramate
As the tremor worsens, it characteristically becomes of (Connor 2002; Ondo et al. 2006), from 100 to 400 mg/day.
greater amplitude and slower frequency. Alprazolam is also effective (Gunal et al. 2000), but given
the high risk of physiologic dependence, this should prob-
ably be held in reserve. Regardless of which medication is
Etiology used, one should start at a low dose and increase gradually,
looking for the lowest effective dose. Another ‘medication’,
Although sporadic cases do occur, both family and twin which many patients will already have discovered on their
studies (Bain et al. 1994; Lorenz et al. 2004; Tanner et al. own, is alcohol (Growdon et al. 1975), which, for obvious
2001) indicate that essential tremor is, in most cases, inher- reasons, cannot be recommended. In severe, treatment-
ited, most likely on an autosomal dominant basis. resistant cases, consideration may be given to deep brain
Although the genetic basis remains obscure, in some fami- stimulation of the thalamus (Sydow et al. 2003).
lies linkage has been found to sites on chromosomes 2, 3,
and 6 (Shatunov et al. 2006).
Although routine pathologic studies have been 8.33 HYPEREKPLEXIA
unremarkable (Rajput et al. 2004), recent work has
demonstrated some interesting findings (Louis et al. 2005, Hyperekplexia, also known as hyperexplexia or ‘startle dis-
2006a,b). Lewy bodies have been found in brainstem ease’, is a rare disorder characterized by a pathologic startle
nuclei, most especially the locus ceruleus; furthermore, response.
within the cerebellum, Purkinje cell loss has been noted,
with, in surviving Purkinje cells, torpedoes, or massive col-
lections of disoriented neurofilaments. Although specula- Clinical features
tive, these seemingly disparate findings may be reconciled
as contributing to a final common pathway of reduced Hyperekplexia occurs in two varieties, namely the major
inhibitory output of the Purkinje cell layer. The locus form and the minor form, and these differ both in age of
ceruleus has massive stimulatory projections to the onset and in clinical symptomatology (Andermann et al.
Purkinje cell layer, and with dysfunction of the locus 1980; Kirsten and Silfverskiold 1958; Ryan et al. 1992;
ceruleus, and loss of this stimulation, Purkinje cell output Suhren et al. 1966; Tijssen et al. 1995).
p 08.qxd 3/10/08 9:38 AM Page 379
References 379
The major form of hyperekplexia becomes apparent in REFERENCES

earliest infancy with episodes of hypertonus. By the time
that the child is able to walk, or shortly thereafter, the Aarsland D, Tandberg E, Larsen JP et al. Frequency of dementia in
response typical of hyperekplexia becomes apparent: to an Parkinson disease. Arch Neurol 1996; 53:538–42.
appropriate stimulus, often a loud, unexpected noise, Aarsland D, Laake K, Larsen JP et al. Donepezil for cognitive
patients experience an exaggerated startle response (Brown impairment in Parkinson’s disease: a randomized controlled
et al. 1991) characterized by grimacing, flexion of the neck, study. J Neurol Neurosurg Psychiatry 2002; 72:708–12.
arms and trunk, abduction of the arms, and generalized Aarsland D, Andersen K, Larson JP et al. Prevalence and
stiffness; many fall ‘like a log’ and injuries are common. characteristics of dementia in Parkinson disease: an 8-year
Consciousness is maintained throughout and the stiffness prospective study. Arch Neurol 2003; 60:387–92.
resolves immediately, allowing the patient to stand again. Aarsland D, Perry R, Brown A et al. Neuropathology of dementia in
The minor form of hyperexplexia typically does not Parkinson’s disease: a prospective, community-based study.
become apparent until childhood or later and consists sim- Ann Neurol 2005; 58:773–6.
ply of the exaggerated startle response without any associ- Adachi N, Arima K, Asada T et al. Dentatorubral-pallidoluysia
ated stiffness. atrophy (DRPLA) presenting with psychosis. J Neuropsychiatry
Clin Neurosci 2001; 13:258–60.
Adams C, Starkman S, Pulst S-M. Clinical and molecular analysis
Course of a pedigree of southern Italian ancestry with spinocerebellar
ataxia type 2. Neurology 1997; 49:1163–6.
Although some partial reduction in severity of the startle Adie WJ, Greenfield JG. Dystrophia myotonica (myotonia
response may occur in the adult years, the course is overall atrophica). Brain 1924; 47:73–127.
chronic and unremitting. Symptoms are typically worse Adler CH, Sethi KD, Hauser RA et al. Ropinirole for the treatment
during fatigue or stress. of early Parkinson’s disease. Neurology 1997; 49:393–9.
Adler CH, Singer C, O’Brien C et al. Randomized placebo-
controlled study of tolcapone in patients with fluctuating
Etiology
Parkinson’s disease treated with levodopa–carbidopa. Arch
Neurol 1998; 55:1089–95.
The etiology of the two forms of hyperekplexia probably
del Aguila MA, Longstreth WT, McGuire V et al. Prognosis in
differ.
amyotrophic lateral sclerosis. A population-based study.
Regarding the major form, although sporadic cases do
Neurology 2003; 60:813–19.
occur (Saenz-Lope et al. 1984), most cases are inherited,
Aisen PS, Davis KL. Inflammatory mechanisms in Alzheimer’s disease:
and most are due to mutations in the gene for the alpha-1
implications for therapy. Am J Psychiatry 1994; 151:1105–13.
subunit of the inhibitory glycine receptor (GLRA1) on
Ala TA, Yang KH, Sung JH et al. Hallucinations and signs of
chromosome 5; depending on the mutation, both autoso-
parkinsonism help distinguish patients with dementia and
mal dominant (Andrew and Owen 1997; Shiang et al.
cortical Lewy bodies from patients with Alzheimer’s disease at
1993) and recessive (Rees et al. 1994; Siren et al. 2006; Tsai
presentation: a clinicopathological study. J Neurol Neurosurg
et al. 2004) patterns of inheritance may occur.
Psychiatry 1997; 62:16–21.
The etiology of the minor form is not clear. The fact that
Alberca RA, Chinchon I, Vadillo J et al. Late onset parkinsonian
both major and minor forms may occur in the same family
syndrome in Hallervorden–Spatz disease. J Neurol Neurosurg
(Andermann et al. 1980; Suhren et al. 1966) suggests that
Psychiatry 1987; 50:1665–8.
the minor form may merely be a forme fruste of the major
Almasy L, Bressman SB, Raymond D et al. Idiopathic torsion
form; however, genetic analysis of these cases, although
dystonia linked to chromosome 8 in two Mennonite families.
revealing a mutation in the alpha subunit in those with the
Ann Neurol 1997; 42:670–3.
major form, failed to find mutations in those with the
Altrocchi PH, Forno LS. Spontaneous oral-facial dyskinesia:
minor form (Tijssen et al. 1995).
neuropathology of a case. Neurology 1983; 33:802–5.
Alves D, Pires MM, Guimaraes A et al. Four cases of late onset
Differential diagnosis metachromatic leukodystrophy in a family: clinical,
biochemical and neuropathological studies. J Neurol Neurosurg
The reader is directed to Section 3.14, where the differen- Psychiatry 1986; 49:1417–22.
tial for pathologic startle is discussed. Alzheimer A. Ubr eine eigenartige erkrankung der hirnrinde.
Allermeine Zeitschrift fur Psychiatrie 1907; 64:146–8.
Amaducci LA, Rocca WA, Schoenberg BS. Origin of the distinction
Treatment between Alzheimer’s disease and senile dementia: how history
can clarify nosology. Neurology 1986; 36:1497–9.
Clonazepam is generally effective in reducing the severity of Amatniek JC, Hauser WA, DelCastillo-Castenada C et al. Incidence
the startle response (Ryan et al. 1992); divalproex has also and predictors of seizures in patients with Alzheimer’s disease.
been successfully used (Dooley and Andermann 1989). Epilepsia 2006; 47:867–72.
p 08.qxd 3/10/08 9:38 AM Page 380
American Psychiatric Association. Diagnostic and statistical Baas H, Beiske AG, Ghika J et al. Catechol-O-methyltransferase
manual of mental disorders, 3rd edn. Washington, DC: inhibition with tolcapone reduces the ‘wearing off’
American Psychiatric Press, 1980. phenomenon and levodopa requirements in fluctuating
Aminoff MJ, Dedo HH, Idebski K. Clinical aspects of spasmodic parkinsonian patients. J Neurol Neurosurg Psychiatry 1997;
dysphonia. J Neurol Neurosurg Psychiatry 1978; 41:361–5. 63:421–8.
Andersen J, Asbo E, Gulmann N et al. Anti-depressive treatment in Bacalman S, Farzin F, Bourgeois JA et al. Psychiatric phenotype of
Parkinson’s disease. A controlled trial of the effect of the Fragile X-associated tremor/ataxia syndrome (FXTAS) in
nortriptyline in patients with Parkinson’s disease treated with males: newly described fronto-subcortical dementia. J Clin
L-DOPA. Acta Neurol Scand 1980; 62:210–19. Psychiatry 2006; 67:87–94.
Andersen K, Baldin J, Gottfries CG et al. A double-blind evaluation Bain PG, Findley LJ, Thompson PD et al. A study of hereditary
of electroconvulsive therapy in Parkinson’s disease with ‘on- essential tremor. Brain 1994; 117:805–24.
off’ phenomenon. Acta Neurol Scand 1987; 76:191–9. Bak TH, O’Donovan DG, Xuereb JH et al. Selective impairment of
Andermann F, Keene DL, Andermann E et al. Startle disease or verb processing associated with pathological changes in
hyperekplexia: further delineation of the syndrome. Brain Brodmann areas 44 and 45 in the motor neurone disease-
1980; 103:985–97. dementia-aphasia syndrome. Brain 2001; 124:103–20.
Andreasen N, Minthon L, Davidsson P et al. Evaluation of CSF-tau Ballard C, McKeith I, Harrison R et al. A detailed
and CSF-Abeta42 as diagnostic markers for Alzheimer disease phenomenological comparison of complex visual
in clinical practice. Arch Neurol 2001; 58:349–50. hallucinations in dementia with Lewy bodies and Alzheimer’s
Andrew M, Owen MJ. Hyperekplexia: abnormal startle response disease. Int Psychogeriatr 1997; 9:381–8.
due to glycine receptor mutations. Br J Psychiatry 1997; Ballard C, Holmes C, McKeith I et al. Psychiatric morbidity in
170:106–8. dementia with Lewy bodies: a prospective clinical and
Angelini L, Nardocci N, Rumi V et al. Hallervorden–Spatz disease: neuropathological comparative study with Alzheimer’s disease.
clinical and MRI study of 11 cases diagnosed in life. J Neurol Am J Psychiatry 1999; 156:1039–45.
1992; 239:417–25. Ballard C, O’Brien J, Gray A et al. Attention and fluctuating
Antonini A, Mainero C, Romano A et al. Cerebral atrophy in attention in patients with dementia with Lewy bodies and
myotonic dystrophy: a voxel-based morphometric study. Alzheimer disease. Arch Neurol 2001; 58:977–82.
J Neurol Neurosurg Psychiatry 2004; 75:1611–13. Bandmann O, Valente EM, Holmans P et al. Dopa-responsive
Antonini A, Tesel S, Zechinelli A et al. Randomized study of dystonia: a clinical and molecular genetic study. Ann Neurol
sertraline and low-dose amitriptyline in patients with 1998; 44:649–56.
Parkinson’s disease and depression: effect on quality of life. Barker WW, Luis CA, Kashuba A et al. Relative frequencies of
Mov Disord 2006; 21:1119–22. Alzheimer disease, Lewy body, vascular and frontotemporal
Apaydin H, Ahlskog JE, Parisi JE et al. Parkinson disease dementia, and hippocampal sclerosis in the State of Florida
neuropathology. Arch Neurol 2002; 59:102–12. Brain Bank. Alzheimer Dis Assoc Disord 2002; 16:203–12.
April RS. Observations on parkinsonian tremor in all-night sleep. Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a
Neurology 1966; 16:720–4. review and phenomenological survey. J Neurol Neurosurg
Ardran G, Kinsburne M, Rushworth G. Dysphonia due to tremor. Psychiatry 2001; 70:727–33.
J Neurol Neurosurg Psychiatry 1966; 29:219–23. Barnes S, Hurst W. A further note on hepatolenticular
Arpa J, Cuesta A, Cruz-Martinez A et al. Clinical features and degeneration. Brain 1926; 49:36–60.
genetic analysis of a Spanish family with spinocerebellar Barone P, Scarzella L, Marconi R et al. Pramipexole versus
ataxia 6. Acta Neurol Scand 1999; 99:44–7. sertaline in the treatment of depression in Parkinson’s disease:
Arriagada PV, Growdon JH, Hedley-Whyte ET et al. Neurofibrillary a national multicenter parallel-group randomized study.
tangles but not senile plaques parallel duration and severity of J Neurol 2006; 253:601–7.
Alzheimer’s disease. Neurology 1992; 42:631–9. Barr AN, Fischer JH, Koller WC et al. Serum haloperidol
Ascherio A, Chen C, Weisskopf MG et al. Pesticide exposure and concentrations and choreiform movements in Huntington’s
risk for Parkinson’s disease. Ann Neurol 2006; 60:197–203. disease. Neurology 1988; 38:84–8.
Asmus F, Horber V, Pohlenz J et al. A novel TITF-1 mutation Barth ML, Fensom A, Harris A. Prevalence of common mutations
causes benign hereditary chorea with response to levodopa. in the arylsulfatase A gene in metachromatic leukodystrophy
Neurology 2005; 64:1952–4. patients diagnosed in Britain. Hum Genet 1993; 91:73–7.
Austin J, Armstrong D, Fouch S et al. Metachromatic Batten FE, Gibb HP. Myotonia atrophica. Brain 1909; 32:187–96.
leukodystrophy (MLD). VIII. MLD in adults: diagnosis and Bax RT, Hassler A, Luck W et al. Cerebral manifestation of
pathogenesis. Arch Neurol 1968; 18:225–40. Wilson’s disease successfully treated with liver
Avorn J, Scneeweis S, Sudarksy LR et al. Sudden uncontrollable transplantation. Neurology 1998; 51:863–5.
somnolence and medication use in Parkinson disease. Arch Beatty WW, Winn P, Adams RL et al. Preserved cognitive skills in
Neurol 2005; 62:1242–8. dementia of the Alzheimer type. Arch Neurol 1994;
Avrahami E, Katz A, Bornstein N et al. Computed tomographic 51:1040–6.
findings of brain and skull in myotonic dystrophy. J Neurol Becher MW, Rubinsztein DC, Leggo J et al. Dentatorubral and
Neurosurg Psychiatry 1987; 50:435–8. pallidoluysian atrophy (DRPLA): clinical and neuropathological
p 08.qxd 3/10/08 9:38 AM Page 381
References 381
findings in genetically conformed North American and Binetti G, Bianchetti A, Padovani A et al. Delusions in Alzheimer’s
European pedigrees. Mov Disord 1997; 12:519–30. disease and multi-infarct dementia. Acta Neurol Scand 1993;
Becker T, Becker G, Seufert J et al. Parkinson’s disease and 88:5–9.
depression: evidence for an alteration of the basal limbic Biousse V, Skibell BC, Watts RL et al. Ophthalmologic features of
system detected by transcranial sonography. J Neurol Parkinson’s disease. Neurology 2004; 62:177–80.
Neurosurg Psychiatry 1997; 63:590–6. Bird MT, Paulson GW. The rigid form of Huntington’s chorea.
Behan PO, Bone I. Hereditary chorea without dementia. J Neurol Neurology 1971; 21:271–6.
Neurosurg Psychiatry 1977; 40:687–91. Bird TD, Levy-Lahad E, Poorkaj P et al. Wide range in age of onset
Benarroch EE, Smithson IL, Low PA et al. Depletion of for chromosome 1-related familial Alzheimer’s disease. Ann
catecholaminergic neurons of the rostral ventrolateral medulla Neurol 1996; 40:932–6.
in multiple systems atrophy with autonomic failure. Ann Birdi S, Rajput AH, Fenton M et al. Progressive supranuclear palsy
Neurol 1998; 43:156–63. diagnosis and confounding features: report on 16 autopsied
Bencze KS, Vande Polder DR, Prockop LD. Magnetic resonance cases. Mov Disord 2002; 17:1255–64.
imaging of the brain and spinal cord in cerebrotendinous Bloch MH, Leckman JF, Zhu HS et al. Caudate volumes in
xanthomatosis. J Neurol Neurosurg Psychiatry 1990; childhood predict symptom severity in adults with Tourette
53:166–7. syndrome. Neurology 2005; 65:1253–8.
Benesch CG, McDaniel KD, Cox C et al. End-stage Alzheimer’s Boeve BF, Silber MH, Ferman TJ et al. REM sleep behavior disorder
disease: Glasgow coma scale and neurologic examination. and degenerative dementia: an association likely reflecting
Arch Neurol 1993; 50:1309–15. Lewy body disease. Neurology 1998; 51:363–70.
Benito-Leon J, Louis ED, Bermejo-Pareja F et al. Population-based Bonelli RM, Niederwieser G, Tribl GG et al. High-dose olanzapine
case-control study of cognitive function in essential tremor. in Huntington’s disease. Int Clin Psychopharmacol 2002;
Neurology 2006; 66:69–74. 17:91–3.
Bentivoglio AR, DelGrosso N, Albenese A et al. Non-DYT1 dystonia Bosch EP, Hart MN. Late adult-onset metachromatic
in a large Italian family. J Neurol Neurosurg Psychiatry 1997; leukodystrophy: dementia and polyneuropathy in a 63-year-
62:357–60. old man. Arch Neurol 1978; 35:475–7.
Benton CS, de Silva R, Rutledge SL et al. Molecular and clinical Botez MI, Botez-Marquard T, Elie R et al. Amantadine hydrochloride
studies in SCA-7 define a broad clinical spectrum and the treatment in heredodegenerative ataxia: a double blind study.
infantile phenotype. Neurology 1998; 51:1081–6. J Neurol Neurosurg Psychiatry 1996; 61:259–64.
Bergem AL, Engedal K, Kringlen E. The role of heredity in late- Bourgeois JA, Cogswell JB, Hessl D et al. Cognitive, anxiety and
onset Alzheimer disease and vascular dementia. A twin study. mood disorders in the fragile X-associated tremor/ataxia
Arch Gen Psychiatry 1997; 54:264–70. syndrome. Gen Hosp Psychiatry 2007; 29:349–56.
Bergeron C, Pollanen MS, Weyer L et al. Unusual clinical Bouton SM. Pick’s disease. J Nerv Ment Dis 1940; 91:9–30.
presentation of cortical-basal ganglionic degeneration. Ann Bowler JV, Eliaszaw M, Steenhuis R et al. Comparative evolution
Neurol 1996; 40:893–900. of Alzheimer disease, vascular dementia, and mixed dementia.
Berginer VM, Salen G, Shefer S. Long-term treatment of Arch Neurol 1997; 54:697–703.
cerebrotendinous xanthomatosis with chenodeoxycholic acid. Braak H, Braak E. Neuropathological staging of Alzheimer-related
N Engl J Med 1984; 311:1649–54. changes. Acta Neuropathol 1991; 82:239–59.
Berkovic SF, Carpenter S, Andermann F et al. Kufs’ disease: a Braak H, Rub U, Jansen Steur ENH et al. Cognitive status
critical reappraisal. Brain 1988; 111:27–62. correlates with neuropathologic stage in Parkinson disease.
Besson JAO. A diagnostic pointer to adult metachromatic Neurology 2005; 64:1404–10.
leukodystrophy. Br J Psychiatry 1980; 137:186–7. Bracco L, Gallato R, Grigoletto F et al. Factors affecting course
Betts TA, Smith WT, Kelly RE. Adult metachromatic leukodystrophy and survival in Alzheimer’s disease. Arch Neurol 1994;
(subacute lipidosis) simulating acute schizophrenia: report of a 51:1213–19.
case. Neurology 1968; 18:1140–2. Bradshaw J, Saling M, Hopwood M et al. Fluctuating cognition in
Bhidayasiri R, Jen JC, Baloh RW. Three brothers with a very-late- dementia with Lewy bodies and Alzheimer’s disease is
onset writer’s cramp. Mov Disord 2005; 20:1375–7. qualitatively distinct. J Neurol Neurosurg Psychiatry 2004;
Bicknell JM, Greenhouse AH, Pesch RN. Spastic dysphonia. 75:382–7.
J Neurol Neurosurg Psychiatry 1968; 31:158–61. Brain WR, Greenfield JG. Late infantile metachromatic
Bierer L, Hof P, Purohit D et al. Neocortical neurofibrillary tangles leukodystrophy with primary degeneration of the
correlate with dementia severity in Alzheimer’s disease. Arch interfascicular oligodendroglia. Brain 1950; 73:291–317.
Neurol 1995; 52:81–8. Brans JWM, Lindeboom R, Snoek JW et al. Botulinum toxin versus
Biggins CA, Boyd JL, Harrop FM et al. A controlled, longitudinal trihexyphenidyl in cervical dystonia: a prospective,
study of dementia in Parkinson’s disease. J Neurol Neurosurg randomized, double-blind controlled trial. Neurology 1996;
Psychiatry 1992; 55:566–71. 46:1066–72.
Billings EG, Ravin A. A psychiatric study of patients manifesting Brassat D, Camuzat A, Vidailhet M et al. Frequency of the DYT1
dystrophica myotonica. Am J Psychiatry 1941; 97: mutation in primary torsion dystonia without family history.
1116–34. Arch Neurol 2000; 57:333–5.
p 08.qxd 3/10/08 9:38 AM Page 382
Breedveld GJ, Percy AK, MacDonald ME et al. Clinical and genetic Brouwers N, Sleegers K, Engelborghs S et al. Genetic risk and
heterogeneity in benign hereditary chorea. Neurology 2002; transcriptional variability of amyloid precursor protein in
59:579–84. Alzheimer’s disease. Brain 2006; 129:2984–91.
Breier A, Sutton VK, Feldman PD et al. Olanzapine in the Brown J, Lantos P, Stratton M et al. Familial progressive
treatment of dopamimetic-induced psychosis in patients with supranuclear palsy. J Neurol Neurosurg Psychiatry 1993;
Parkinson’s disease. Biol Psychiatry 2002; 52:438–45. 56:473–6.
Breitner JCS, Walsh KA, Gau BA et al. Alzheimer’s disease in the Brown P, Rothwell JC, Thompson PD et al. The hyperekplexias and
National Academy of Sciences – National Research Council of their relationship to the normal startle reflex. Brain 1991;
Aging Twin Veterans. III: Detection of cases, longitudinal 114:1903–28.
results, and observations on twin concordance. Arch Neurol Brownell B, Oppenheimer DR, Hughes JT. The central nervous
1995; 52:763–71. system in motor neuron disease. J Neurol Neurosurg Psychiatry
Bressman SB, de Leon D, Brin MF et al. Idiopathic torsion dystonia 1970; 33:338–57.
among Ashkenazi Jews: evidence for autosomal dominant Bruggeman R, van der Linden C, Butelaar JK et al. Risperidone
inheritance. Ann Neurol 1989; 26:612–20. versus pimozide in Tourette’s disorder: a comparative double-
Bressman SB, de Leon D, Kramer PL et al. Dystonia in Ashkenazi blind parallel-group study. J Clin Psychiatry 2001; 62:50–6.
Jews: clinical characterization of a founder mutation. Ann Brunberg JA, Jacquemont S, Hagerman RJ et al. Fragile X
Neurol 1994; 36:771–7. premutation carriers: characteristic MR imaging findings of
Bressman SB, Warner TT, Almasy L et al. Exclusion of the DYT1 adult male patients with progressive cerebellar and cognitive
locus in familial torticollis. Ann Neurol 1996; 40:681–4. dysfunction. AJNR 2002; 23:1757–66.
Bressman SB, Sabatti C, Raymond D et al. The DYT1 phenotype Bruni AC, Momeni P, Bernardi L et al. Heterogeneity within a large
and guidelines for diagnostic testing. Neurology 2000; kindred with frontotemporal dementia. Neurology 2007;
54:1746–52. 69:140–7.
Brewer GJ, Turkay A, Yuzbasiyan-Gurkan V. Development of Bruun RD. Subtle and unrecognized side effects of neuroleptic
neurologic symptoms in a patient with asymptomatic Wilson’s treatment in children with Tourette’s disorder. Am J Psychiatry
disease treated with penicillamine. Arch Neurol 1994; 1988; 145:621–4.
51:304–5. Buerger K, Ewers M, Pirtilla T et al. CSF phosphorylated tau
Brewer GJ, Johnson V, Dick RD et al. Treatment of Wilson’s disease protein correlates with neocortical neurofibrillary pathology in
with ammonium tetrathiomolybdate. II. Initial therapy in 33 Alzheimer’s disease. Brain 2006; 129:3035–41.
neurologically affected patients and follow-up with zinc Bull PC, Thomas GR, Rommens JM et al. The Wilson disease gene
therapy. Arch Neurol 1996; 53:1017–26. is a putative copper transporting P-type ATPase similar to
Brewer GJ, Askari F, Lorincz MT et al. Treatment of Wilson disease Menkes gene. Nature Gen 1993; 5:327–37.
with ammonium tetrathiomolybdate. IV. Comparison of Bungener C, Jouvent R, Delaporte C. Psychopathological and
tetrathiomolybdate and trientene in a double blind study of emotional deficits in myotonic dystrophy. J Neurol Neurosurg
treatment of the neurologic presentation of Wilson disease. Psychiatry 1998; 65:353–6.
Arch Neurol 2006; 63:521–7. Burk K, Globas C, Bosch S et al. Cognitive deficits in
Bridgman O, Smyth FS. Progressive lenticular degeneration. J Nerv spinocerebellar ataxia 2. Brain 1999; 122:769–77.
Ment Dis 1944; 99:534–43. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind,
Briel RC, McKeith IG, Barker WA et al. EEG findings in dementia prospective trial of high-dosage trihexyphenidyl. Neurology
with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg 1986; 36:160–4.
Psychiatry 1999; 66:401–3. Burke WJ, Pfeiffer RF, McComb RD. Neuroleptic sensitivity to
Britton JW, Uitti RJ, Ahlskog JE et al. Hereditary late-onset chorea clozapine in dementia with Lewy bodies. J Neuropsychiatry
without significant dementia: genetic evidence for substantial Clin Neurosci 1998; 10:227–9.
phenotypic variation in Huntington’s disease. Neurology 1995; Burkhardt CR, Filley CM, Kleineschmidt-DeMasters BK et al.
45:443–7. Diffuse Lewy body disease and progressive dementia.
Brody IA, Wilkins RH. Huntington’s chorea. Arch Neurol 1967; Neurology 1988; 38:1520–8.
17:331–3. Burneo JG, Arnold T, Palmer CA et al. Adult-onset neuronal ceroid
Bronner IF, ter Meulen BC, Azmani A et al. Hereditary Pick’s lipofuscinosis (Kufs’ disease) with autosomal dominant
disease with the G272V tau mutation showing predominant inheritance in Alabama. Epilepsia 2003; 44:841–6.
three-repeat tau pathology. Brain 2005; 128:2645–53. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s
Brook JD, McCurrach ME, Harley HG et al. Molecular basis of disease. III. Disorders of mood. Br J Psychiatry 1990a;
myotonic dystrophy: expansion of a trinucleotide (CTG) repeat 157:81–6.
at the 3⬘ end of a transcript encoding a protein kinase family Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s
member. Cell 1992; 68:799–808. disease. II. Disorders of perception. Br J Psychiatry 1990b;
Brooks DJ, Sagar H. Entacapone is beneficial in both fluctuating 157:76–81.
and non-fluctuating patients with Parkinson’s disease: a Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s
randomized, placebo controlled, double blind, six month study. disease. I. Disorders of thought content. Br J Psychiatry 1990c;
J Neurol Neurosurg Psychiatry 2003; 74:1071–9. 157:72–6.
p 08.qxd 3/10/08 9:38 AM Page 383
References 383
Byrne EJ, Lennox G, Lowe J et al. Diffuse Lewy body disease: Clark DG, Mendez MF, Farag E et al. Clinicopathologic report:
clinical features in 15 cases. J Neurol Neurosurg Psychiatry progressive aphasia in a 77-year old man. J Neuropsychiatry
1989; 57:709–17. Clin Neurosci 2003; 15:231–8.
Caine ED, Shoulson I. Psychiatric symptoms in Huntington’s Cohen AJ, Leckman JF. Sensory phenomena associated with
disease. Am J Psychiatry 1983; 140:728–33. Gilles de la Tourette’s syndrome. J Clin Psychiatry 1992; 23:
Callagy C, O’Neill G, Murphy SF et al. Adult neuronal ceroid 319–23.
lipofuscinosis (Kufs’ disease) in two siblings in an Irish family. Cohen DJ, Detlor RN, Young G et al. Clonidine ameliorates Gilles
Clin Neuropathol 2000; 19:109–18. de la Tourette’s syndrome. Arch Gen Psychiatry 1980;
Calzetti S, Bortone E, Negrotti A et al. Frontal intermittent 37:1350–7.
rhythmic delta activity (FIRDA) in patients with dementia with Cohen LG, Hallett M. Hand cramps: clinical features and
Lewy bodies: a diagnostic tool? Neurol Sci 2002; electromyographic patterns in a focal dystonia. Neurology
23(suppl. 2):S65–6. 1988; 38:1005–12.
Campbell AMG, Corner B, Norman RM et al. The rigid form of Coleman LW, Digre KB, Stephenson GM et al. Autopsy-proven,
Huntington’s disease. J Neurol Neurosurg Psychiatry 1965; sporadic Pick disease with onset at age 25 years. Arch Neurol
24:71–7. 2002; 59:856–9.
Canelas HM, Quintao ECR, Scaff M et al. Cerebrotendinous Collins SJ, Ahlskog JE, Parisi JE et al. Progressive supranuclear
xanthomatosis: clinical and laboratory study of 2 cases. Acta palsy: neuropathologically based diagnostic clinical criteria.
Neurol Scand 1983; 67:305–11. J Neurol Neurosurg Psychiatry 1995; 58:167–73.
Cardoso F, Veado CCM, de Oliveira JT. A Brazilian cohort of Colosimo C, Albanese A, Hughes AJ et al. Some specific clinical
patients with Tourette’s syndrome. J Neurol Neurosurg features differentiate multiple system atrophy (striatonigral
Psychiatry 1996; 60:209–12. variety) from Parkinson’s disease. Arch Neurol 1995;
Castelbuono A, Miller NR. Spontaneous remission in patients with 52:294–8.
essential blepharospasm and Meige syndrome. Am J Comella CL, Goetz CG. Akathisia in Parkinson’s disease. Mov
Ophthalmol 1998; 126:432–5. Disord 1994; 9:545–9.
Castelnau P, Cif L, Valente EM et al. Pallidal stimulation improves Connor GS. A double-blind placebo-controlled trial of topiramate
pantothenate kinase-associated neurodegeneration. Ann treatment of essential tremor. Neurology 2002; 59:132–4.
Neurol 2005; 57:738–41. Cook RH, Schenck SA, Clark DB. Twins with Alzheimer’s disease.
Celesia GG, Barr AN. Psychosis and other psychiatric manifestations Arch Neurol 1981; 38:300–1.
of levodopa therapy. Arch Neurol 1970; 23:193–200. Cooper GE, Rizzo M, Jones RD. Adult-onset Hallervorden-Spatz
Chan DB, Lang MF, Fahn S. Idiopathic cervical dystonia. Mov syndrome presenting as cortical dementia. Alzheimer Dis Assoc
Disord 1991; 6:119–26. Disord 2000; 14:120–6.
Chan-Palay V, Asan E. Alterations in catecholamine neurons of Corder EH, Saunders EM, Strittmatter WJ et al. Gene dose of
the locus coeruleus in senile dementia of the Alzheimer type apolipoprotein II type 4 allele and the risk of Alzheimer’s
and in Parkinson’s disease with and without dementia and disease in late onset families. Science 1993; 261:921–3.
depression. Comp Neurol 1989; 287:373–92. Critchley EMR, Clark DB, Wikler A. Acanthocytosis and
Chartier-Harlin M, Crawford F, Houlden H et al. Early-onset neurological disorder without abetalipoproteinemia. Arch
Alzheimer’s disease caused by mutations at codon 717 of the Neurol 1968; 18:134–40.
beta-amyloid precursor protein gene. Nature 1991; Critchley M. Observation on essential (heredofamilial) tremor.
353:844–6. Brain 1949; 72:113–39.
Chee KY, Sachdev P. A controlled study of sensory tics in Gilles de Critchley M, Greenfield JG. Olivo-ponto-cerebellar atrophy. Brain
la Tourette syndrome and obsessive-compulsive disorder using 1948; 71:343–64.
a structured interview. J Neurol Neurosurg Psychiatry 1997; Crystal HA, Grober E, Masur D. Preservation of musical memory in
62:188–92. Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1989;
Chelly J, Monaco AP. Cloning the Wilson disease gene. Nature 52:1415–16.
Gen 1993; 5:317–18. Crystal HA, Dixon DW, Lizardi JE et al. Antemortem diagnosis of
Chen J-Y, Stern Y, Sano M et al. Cumulative risk of developing diffuse Lewy body disease. Neurology 1990; 40:1523–8.
extrapyramidal signs, psychosis or myoclonus in the course of Cummings JL, Duchen LW. Kluver–Bucy syndrome in Pick disease:
Alzheimer’s disease. Arch Neurol 1991; 48:1141–3. Clinical and pathologic correlations. Neurology 1981;
Chouinard S, Ford B. Adult onset tic disorder. J Neurol Neurosurg 31:1415–22.
Psychiatry 2000; 68:738–43. Cummings JL, Street J, Masterman D et al. Efficacy of olanzapine
Church AJ, Dale RC, Lees AJ et al. Tourette’s syndrome: a cross- in the treatment of psychosis in dementia with Lewy bodies.
sectional study to examine the PANDAS hypothesis. J Neurol Dement Geriatr Cogn Disord 2002; 13:67–73.
Neurosurg Psychiatry 2003; 74:602–7. Cummings JL, Schneider E, Tariot PN et al. Behavioral effects of
Clark CM, Ewbank D, Lerner A et al. The relationship between memantine in Alzheimer disease patients receiving donepezil
extrapyramidal signs and cognitive performance in patients treatment. Neurology 2006; 67:57–63.
with Alzheimer’s disease enrolled in the CERAD study. Cunningham MA, Darby DG, Donnan GA. Controlled-release
Neurology 1997; 49:70–5. delivery of L-dopa associated with nonfatal hyperthermia,
p 08.qxd 3/15/08 4:37 PM Page 384
rigidity and autonomic dysfunction. Neurology 1991; Dermaut B, Kumar-Singh S, Engelborghs S et al. A novel presenilin
41:942–3. 1 mutation associated with Pick’s disease but not beta-
Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological amyloid plaques. Ann Neurol 2004; 55:617–26.
spectrum of Steele–Richardson–Olszewski syndrome De Stefano N, Dotti MT, Mortilla M et al. Magnetic resonance
(progressive supranuclear palsy): a reappraisal. Brain 1995; imaging and spectroscopic changes in brains of patients with
118:759–70. cerebrotendinous xanthomatosis. Brain 2001; 124:121–3.
Dauer WT, Burke RE, Greene P et al. Current concepts on the Devanand DP, Jacobs DM, Tang M-X et al. The course of
clinical features, aetiology and management of idiopathic psychopathologic features in mild to moderate Alzheimer’s
cervical dystonia. Brain 1998; 121:547–60. disease. Arch Gen Psychiatry 1997; 54:257–63.
Davies RR, Hodges JR, Kril JJ et al. The pathological basis of Deymeer F, Smith TW, DeGirolami U et al. Thalamic dementia and
semantic dementia. Brain 2005; 128:1984–95. motor neuron disease. Neurology 1989; 39:58–61.
Davis EJB, Borde M. Wilson’s disease and catatonia. Br J Di Costanzo A, De Salle F, Santoro L et al. Pattern and significance
Psychiatry 1993; 162:256–9. of white matter abnormalities in myotonic dystrophy type 1:
Davis PH, Bergeron C, McLachlan DR. Atypical presentation of an MRI study. J Neurol 2002; 249:1175–82.
progressive supranuclear palsy. Ann Neurol 1985; 17: Didic M, Cherif AA, Gambarelli D et al. A permanent pure
337–43. amnestic syndrome of insidious onset related to Alzheimer’s
Day JW, Ricker K, Jacobsen JF et al. Myotonic dystrophy type 2. disease. Ann Neurol 1998; 43:526–30.
Molecular diagnostic and clinical spectrum. Neurology 2003; van Diggelen OP, Thobois S, Tilikete C et al. Adult neuronal ceroid
60:657–64. lipofuscinosis with palmitoyl-protein thioesterase deficiency:
Deakin JB, Rahman S, Nestor PJ et al. Paroxetine does not improve first adult-onset patients of a childhood disease. Ann Neurol
symptoms and impairs cognition in frontotemporal dementia: 2001; 50:269–72.
a double-blind randomized controlled trial. Psychopharma- Dion Y, Annable L, Stat D et al. Risperidone in the treatment of
cology 2004; 172:400–8. Tourette syndrome: a double-blind, placebo-controlled trial.
Deep Brain Stimulation for Parkinson’s Disease Study Group. Deep J Clin Psychopharmacol 2002; 22:31–9.
brain stimulation of the subthalamic nucleus or the pars Dipple HC. The use of olanzapine for movement disorder in
interna of the globus pallidus in Parkinson’s disease. N Engl J Huntington’s disease: a first case report. J Neurol Neurosurg
Med 2001; 345:956–63. Psychiatry 1999; 67:123–4.
Defazio G, Berardelli A, Abbruzzese G et al. Risk factors for spread Dodd CM, Klos KS, Bower JH et al. Pathological gambling caused
of primary adult onset blepharospasm: a multicentre by drugs used to treat Parkinson disease. Arch Neurol 2005;
investigation of the Italian movement disorders study group. 62:1377–81.
J Neurol Neurosurg Psychiatry 1999; 67:613–19. Dooley JM, Andermann F. Startle disease or hyperekplexia:
Defazio G, Martino D, Aniello MS et al. A family study on primary adolescent onset and response to valproate. Ped Neurology
blepharospasm. J Neurol Neurosurg Psychiatry 2006; 1989; 5:126–7.
77:252–4. Dooling EC, Schoene WC, Richardson EP. Hallervorden–Spatz
Delacourte A, David JP, Sergeant N et al. The biochemical syndrome. Arch Neurol 1974; 30:70–83.
pathway of neurofibrillary degeneration in aging and Dooling EC, Richardson EP, Davis KR. Computed tomography
Alzheimer’s disease. Neurology 1999; 52:1158–65. in Hallervorden–Spatz disease. Neurology 1980; 30:
Delaporte C. Personality patterns in patients with myotonic 1128–30.
dystrophy. Arch Neurol 1998; 55:635–40. Doran M, Larner AJ. EEG findings in dementia with Lewy bodies
Delwaide PJ, Desseilles M. Spontaneous buccolinguofacial causing diagnostic confusion with sporadic Creutzfeldt-Jakob
dyskinesia in the elderly. Acta Neurol Scand 1977; 56:256–62. disease. Eur J Neurol 2004; 11:838–41.
Demirkiran M, Jankovic J, Lewis RA et al. Neurologic presentation Douyon R, Serby M, Klutchbo B et al. ECT and Parkinson’s disease
of Wilson disease without Kayser–Fleischer rings. Neurology revisited: a ‘naturalistic’ study Am J Psychiatry 1989;
1996; 46:1040–3. 146:1451–5.
Denckla MB, Bemporad JR, MacKay MC. Tics following Duenas AM, Goold R, Giunti P. Molecular pathogenesis of
methylphenidate administration: a report of 20 cases. JAMA spinocerebellar ataxias. Brain 2006; 129:1357–70.
1976; 235:1349–51. Durif F, Debilly B, Galitzky M et al. Clozapine improves dyskinesias
Dening TR, Berrios GE, Walshe JM. Wilson’s disease and epilepsy. in Parkinson disease. A double-blind, placebo-controlled study.
Brain 1988; 111:1139–55. Neurology 2004; 62:381–8.
Dening TR, Berrios GE. Wilson’s disease: psychiatric symptoms in Durr A, Stevanin G, Cancel G et al. Spinocerebellar ataxia 3 and
195 cases. Arch Gen Psychiatry 1989; 46:1126–34. Machado–Joseph disease: clinical, molecular, and
Deonna T. DOPA-sensitive progressive dystonia of childhood with neuropathological features. Ann Neurol 1996; 39:490–9.
fluctuations of symptoms – Segawa’s syndrome and possible Eapen V, Pauls DL, Robertson MM. Evidence for autosomal
variants. Neuropediatrics 1986; 17:81–6. dominant transmission in Tourette’s syndrome – United
Deonna T, Roulet E, Ghika J et al. Dopa-responsive childhood Kingdom cohort study. Br J Psychiatry 1993; 162:593–6.
dystonia: a forme fruste with writer’s cramp, triggered by Edwards KR, Hershel L, Wray L et al. Efficacy and safety of
exercise. Dev Med Child Neurol 1997; 39:49–53. galantamine in patients with dementia with Lewy bodies: a
p 08.qxd 3/10/08 9:38 AM Page 385
References 385
12-week interim analysis. Dement Geriatr Cogn Disord 2004; Finelli PF. Metachromatic leukodystrophy manifesting as a
17(suppl. 1):40–8. schizophrenic disorder: computed tomographic correlation.
Edwards-Lee T, Miller BL, Benson DF et al. The temporal variant of Ann Neurol 1985; 18:94–5.
frontotemporal dementia. Brain 1997; 120:1027–40. Fletcher NA, Harding AE, Marsden CD. A genetic study of
Ellis T, Cudkowicz ME, Sexton PM et al. Clozapine and risperidone idiopathic torsion dystonia in the United Kingdom. Brain 1990;
treatment of psychosis in Parkinson’s disease. J Neuro- 113:379–95.
psychiatry Clin Neurosci 2000; 12:364–9. Folstein SE, Abbott MH, Chase GA et al. The association of
Emre M, Aarsland D, Albanese A et al. Rivastigmine for dementia affective disorder with Huntington’s disease in a case series
associated with Parkinson’s disease. N Engl J Med 2004; and in families. Psychol Med 1983; 13:537–42.
351:2509–18. Forstl H, Besthorn C, Geiger-Kabisch C et al. Psychotic features
Erlington GM, Bateman DE, Jeffrey MJ et al. Adrenoleuko- and the course of Alzheimer’s disease: relationship to
dystrophy: heterogeneity in two brothers. J Neurol Neurosurg cognitive, electroencephalographic and computerized
Psychiatry 1989; 52:310–14. tomography findings. Acta Psychiatr Scand 1993; 87:
Evans AH, Katzenshlager R, Paviour D et al. Punding in Parkinson’s 395–9.
disease: its relation to the dopamine dysregulation syndrome. Frankel M, Cummings JL, Robertson MM et al. Obsessions and
Mov Disord 2004; 19:367–70. compulsions in Gilles de la Tourette’s syndrome. Neurology
Evenhuius HM. The natural history of dementia in Down’s 1986; 36:378–82.
syndrome. Arch Neurol 1990; 47:263–7. Fregni F, Santos CM, Myczkowski ML et al. Repetitive transcranial
Faber-Langendoen K, Morris JC, Knesvich JW et al. Aphasia in magnetic stimulation is as effective as fluoxetine in the
senile dementia of the Alzheimer type. Ann Neurol 1988; treatment of depression in patients with Parkinson’s disease.
23:365–70. J Neurol Neurosurg Psychiatry 2004; 75:1171–4.
Faden AI, Townsend JJ. Myoclonus in Alzheimer’s disease: a Friedman A, Fahn S. Spontaneous remissions in spasmodic
confusing sign. Arch Neurol 1976; 33:278–80. torticollis. Neurology 1986; 36:398–400.
Farpour H, Mahloudji M. Familial cerebrotendinous Friedman A, Sienkiewicz J. Psychotic complications of long-term
xanthomatosis: report of a new family and review of the levodopa treatment of Parkinson’s disease. Acta Neurol Scand
literature. Arch Neurol 1975; 32:223–5. 1991; 84:111–13.
Farrer M, Chan P, Chen R et al. Lewy bodies and parkinsonism in Freiss E, Kuempfel T, Modell S et al. Paroxetine treatment
families with parkin mutation. Ann Neurol 2001; 50:293–300. improves motor symptoms in patients with multiple system
Feany MB. New genetic insights in Parkinson’s disease. N Engl J atrophy. Parkinsonism Relat Disord 2006; 12:432–7.
Med 2004; 351:1937–40. Frucht S, Rogers JD, Greene PE et al. Falling asleep at the wheel:
Feigin A, Kieburtz K, Bordwell K et al. Functional decline in motor vehicle mishaps in persons taking pramipexole and
Huntington’s disease. Mov Disord 1995; 10:211–14. ropinirole. Neurology 1999; 52:1908–10.
Feinberg TE, Cianci CD, Morrow JS et al. Diagnostic tests for Frucht SJ, Fahn S, Greene PE et al. The natural history of
choreoacanthocytosis. Neurology 1991; 41:1000–6. embouchure dystonia. Mov Disord 2001; 16:899–906.
Feldman H, Gauthier S, Heker J et al. A 24-week, randomized, Fukui T, Sugita K, Kawamura M et al. Primary progressive apraxia
double-blind study of donepezil in moderate to severe in Pick’s disease: a clinicopathologic report. Neurology 1996;
Alzheimer’s disease. Neurology 2001; 57:613–20. 47:467–73.
Fenelon G, Mahieux F, Huon R et al. Hallucinations in Parkinson’s Funayama M, Hasegawa K, Kowa H et al. A new locus for
disease: prevalence, phenomenology and risk factors. Brain Parkinson’s disease (PARK8) maps to chromosome 12p11.2-
2000; 123:733–45. q13.1. Ann Neurol 2002; 51:296–301.
Fernandez HH, Friedman JH, Jacques C et al. Quetiapine for the Furukawa Y, Graf WD, Wong H et al. Dopa-responsive dystonia
treatment of drug-induced psychosis in Parkinson’s disease. simulating spastic paraplegia due to tyrosine hydroxylase (TH)
Mov Disord 1999; 14:484–7. gene mutation Neurology 2001; 56:260–3.
Fernandez HH, Trieschmann ME, Burke MA et al. Quetiapine for Gadow KD, Nolan EE, Sverd J. Methylphenidate in hyperactive
psychosis in Parkinson’s disease versus dementia with Lewy boys with comorbid tic disorder. II: Short-term behavioral
bodies. J Clin Psychiatry 2002; 63:513–15. effects in school settings. J Am Acad Child Adolesc Psychiatry
Fernandez M, Raskind W, Matsushita M et al. Hereditary benign 1992; 31:462–71.
chorea: clinical and genetic features of a distinct disease. Gadow KD, Sverd J, Sprafkin J et al. Long-term methylphenidate
Neurology 2001; 57:106–10. therapy in children with comorbid attention-deficit
Ferraro A, Jervis GA. Pick’s disease: clinicopathologic study with hyperactivity disorder and chronic multiple tic disorder. Arch
report of two cases. Arch Neurol Psychiatry 1936; 36:738–67. Gen Psychiatry 1999; 56:330–6.
Ferreira JJ, Galitzky M, Montrastruc JL et al. Sleep attacks and Gagnon J-F, Bedard M-A, Fantini MC et al. REM sleep behavior
Parkinson’s disease treatment. Lancet 2000; 355:1333–4. disorder and REM sleep without atonia in Parkinson’s disease.
Figa-Talamanca L, Gualandi C, Di Meo L et al. Hyperthermia after Neurology 2002; 59:585–9.
discontinuance of levodopa and bromocriptine therapy: Gaig C, Marti MJ, Ezquerra M et al. G2019S LRRK2 mutation
impaired dopamine receptors a possible cause. Neurology causing Parkinson’s disease without Lewy bodies. J Neurol
1985; 35:258–61. Neurosurg Psychiatry 2007; 78:626–8.
p 08.qxd 3/10/08 9:38 AM Page 386
Galasko D, Chang I, Motter I et al. High cerebrospinal fluid tau Gironell A, Kulisevsky J, Barbanoj M et al. A randomized, placebo-
and low amyloid beta-42 levels in the clinical diagnosis of controlled comparative trial of gabapentin and propranolol in
Alzheimer disease and relation to apolipoprotein E genotype. essential tremor. Arch Neurol 1999; 56:475–80.
Arch Neurol 1998; 55:937–45. Giunti P, Sabbadini G, Sweeney MG et al. The role of the SCA2
Gallagher JP. Pathologic laughter and crying in ALS: a search for trinucleotide repeat expansion in 89 autosomal dominant
their origin. Acta Neurol Scand 1989; 80:114–17. cerebellar ataxia families: frequency, clinical and genetic
Galton CJ, Patterson K, Xuereb JH et al. Atypical and typical correlates. Brain 1998; 121:459–67.
presentations of Alzheimer’s disease: a clinical, Glass JD, Reich SG, DeLong MR. Wilson’s disease: development of
neuropsychological, neuroimaging and pathological study of neurological disease after beginning penicillamine therapy.
13 cases. Brain 2000; 123:484–98. Arch Neurol 1990; 47:595–6.
Galvin JE, Lee SL, Perry A et al. Familial dementia with Lewy Goetz CG, Blasucci LM, Leurgans S et al. Olanzapine and
bodies: clinicopathologic analysis of two kindreds. Neurology clozapine. Comparative effects on motor function in
2002; 59:1079–82. hallucinating PD patients. Neurology 2000; 55:789–94.
Garcia Ruiz PJ, Gomez-Tortosa E, del Barrio A et al. Senile chorea: Goetz CG, Wuu J, Curgian LM et al. Hallucinations and sleep
a multicenter prospective study. Acta Neurol Scand 1997; disorders in PD. Six-year prospective longitudinal study.
95:180–3. Neurology 2005; 64:81–6.
Garruto RM, Gajdusek DC, Chen KM. Amyotrophic lateral sclerosis Goetz CG, Fan W, Leurgans S et al. The malignant course of
and parkinsonism-dementia among Filipino immigrants to ‘benign hallucinations’ in Parkinson disease. Arch Neurol 2006;
Guam. Ann Neurol 1981; 10:341–50. 63:713–6.
Gasser T, Windgassen K, Bereznai B et al. Phenotypic expression of Golbe L, Davis P, Schoenberg B et al. Prevalence and natural
the DYT1 mutation: a family with writer’s cramp of juvenile history of progressive supranuclear palsy. Neurology 1988;
onset. Ann Neurol 1998; 44:126–8. 38:1031–4.
Gatz M, Pedersen NL, Berg S et al. Heritability for Alzheimer’s Golden GS. Tics and Tourette’s: a continuum of symptoms? Ann
disease: the study of dementia in Swedish twins. J Gerontol A Neurol 1978; 4:145–8.
Biol Sci Med Sci 1997; 52:17–25. Goldfarb LG, Chumakov MP, Petrov PA et al. Olivopontocerebellar
Geda YE, Boeve BF, Negash S et al. Neuropsychiatric features in atrophy in a large Iakut kinship in Eastern Siberia. Neurology
36 pathologically confirmed cases of corticobasal degeneration. 1989; 39:1527–30.
J Neuropsychiatry Clin Neurosci 2007; 19:77–80. Goldfarb LG, Vasconcelos O, Platonov FA et al. Unstable triplet
van Geel BM, Assies J, Haverkort EB et al. Progression of repeat and phenotypic variability of spinocerebellar ataxia
abnormalities in adrenomyeloneuropathy and neurologically type I. Ann Neurol 1996; 39:500–16.
asymptomatic X-linked adrenoleukodystrophy despite Gomez-Tortosa E, Newell K, Irizarry MC et al. Clinical and
treatment with ‘Lorenzo’s oil’. J Neurol Neurosurg Psychiatry quantitative pathologic correlates of dementia with Lewy
1999; 67:290–9. bodies. Neurology 1999; 53:1284–91.
van Geel BM, Bezman L, Loes DJ et al. Evolution of phenotypes in Goodman L. Alzheimer’s disease: a clinico-pathologic analysis of
adult male patients with X-linked adrenoleukodystrophy. Ann twenty-three cases with a theory on pathogenesis. J Nerv
Neurol 2001; 49:186–94. Ment Dis 1953; 118:97–130.
Gibb WRG, Esiri MM, Lees AJ. Clinical and pathological features of Goto I, Tobimatsu S, Ohta M et al. Dentatorubropallidoluysian
diffuse cortical Lewy body disease (Lewy body dementia). degeneration: clinical, neuro-ophthalmologic, biochemical and
Brain 1987; 110:1131–53. pathologic studies on autosomal dominant form. Neurology
Gibb WR, Lees AJ, Marsden CD. Pathological report of four 1982; 32:1395–9.
patients presenting with cranial dystonia. Mov Disord 1988; Graff-Radford NR, Damasio AR, Hyman BT et al. Progressive
3:211–21. aphasia in a patient with Pick’s disease: a neuropsychological,
Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. A radiologic, and anatomic study. Neurology 1990; 40:620–6.
clinical study of 36 cases. Brain 1994; 117:1183–96. Graham A, Davies R, Xuereb J et al. Pathologically proven
Giladi N, McMahon D, Przedborski S et al. Motor blocks in frontotemporal dementia presenting with severe amnesia.
Parkinson’s disease. Neurology 1992; 42:333–9. Brain 2005; 128:597–605.
Gilbert DL, Dure L, Sethuraman G et al. Tic reduction with Graham DI, Lantos PL. Greenfield’s neuropathology, 6th edn.
pergolide in a randomized controlled trial in children. London: Arnold, 1996.
Neurology 2003; 60:606–11. Graham JM, Grunewald RA, Sagar HJ. Hallucinosis in idiopathic
Gilbert GJ. Brueghel syndrome: its distinction from Meige Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997;
syndrome. Neurology 1996; 46:1767–9. 63:434–40.
Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold, Grandas F, Elston J, Quinn N et al. Blepharospasm: a review of
2000. 264 patients. J Neurol Neurosurg Psychiatry 1988; 51:
Giovannoni G, O’Sullivan JD, Turner K et al. Hedonistic 767–72.
homeostatic dysregulation in patients with Parkinson’s disease Greco CM, Hagerman RJ, Tassone F et al. Neuronal intranuclear
on dopamine replacement therapies. J Neurol Neurosurg inclusions in a new cerebellar tremor/ataxia syndrome among
Psychiatry 2000; 68:423–8. fragile X carriers. Brain 2002; 125:1760–71.
p 08.qxd 3/10/08 9:38 AM Page 387
References 387
Greco CM, Berman RF, Martin RM et al. Neuropathology of fragile Hahn H, Trant MR, Brownstein MJ et al. Neurologic and
X-associated tremor/ataxia syndrome. Brain 2006; psychiatric manifestations in a family with a mutation in exon
129:243–55. 2 of the guanosine triphosphate-cyclohydrolase gene. Arch
Green J, Morris JC, Sandson J et al. Progressive aphasia: a Neurol 2001; 58:749–55.
precursor of global dementia? Neurology 1990; 48:423–9. Hall DA, Berry-Kravis E, Jacquemont S et al. Initial diagnosis given
Greenberg SM, Tennis MK, Brown LB et al. Donepezil therapy in to persons with the fragile X associated tremor/ataxia
clinical practice. A randomized crossover study. Arch Neurol syndrome (FXTAS). Neurology 2005; 65:294–301.
2000; 57:94–9. Haltia T, Palo J, Haltia M et al. Juvenile metachromatic
Greene JDW, Patterson K, Xuereb J et al. Alzheimer disease leukodystrophy: clinical, biochemical, and neuropathologic
and nonfluent progressive aphasia. Arch Neurol 1996; 53: studies in nine new cases. Arch Neurol 1980; 37:42–6.
1072–8. Hampel H, Buerger K, Zinkowski R et al. Measurement of
Greene P, Kang U, Fahn S et al. Double-blind, placebo controlled phosphorylated tau epitopes in the differential diagnosis of
trial of botulinum toxin injection for the treatment of Alzheimer disease: a comparative cerebrospinal fluid study.
spasmodic torticollis. Neurology 1990; 40:1213–18. Arch Gen Psychiatry 2004; 61:95–102.
Grewal RP, Achari M, Matsura T et al. Clinical features and ATTCT Hansen L, Salmon D, Galasko D et al. The Lewy body variant of
repeat expansion in spinocerebellar ataxia type 10. Arch Alzheimer’s disease: a clinical and pathologic entity.
Neurol 2002; 59:1285–90. Neurology 1990; 40:1–8.
Griffin JW, Goren E, Schaumburg H et al. Hansotia P, Frens D. Hypersomnia associated with alveolar hypo-
Adrenomyeloneuropathy: a probable variant of ventilation in myotonic dystrophy. Neurology 1981; 31:1336–7.
adrenoleukodystrophy. Neurology 1977; 27:1107–10. Hansotia P, Cleeland CS, Chun RWM. Juvenile Huntington’s
Grimes DA, Lang AE, Bergeron CB. Dementia as the most common chorea. Neurology 1968; 18:217–24.
presentation of cortical-basal ganglionic degeneration. Hantz P, Caradoc-Davies G, Caradoc-Davies T et al. Depression in
Neurology 1999; 53:1969–74. Parkinson’s disease. Am J Psychiatry 1994; 151:1010–14.
Groen JJ, Endtz LJ. Hereditary Pick’s disease: second re- Hardie RJ, Pullon HWH, Harding AE et al. Neuroacanthocytosis: a
examination of a large family and discussion of other clinical, haematological and pathological study of 19 cases.
hereditary cases with particular reference to Brain 1991; 114:13–49.
electroencephalography and computerized tomography. Brain Harding A. The clinical features and classification of the late
1982; 105:443–59. onset autosomal dominant cerebellar ataxias: a study of
Grotzch H, Pizzolato G-P, Ghika J et al. Neuropathology of a case eleven families including descendants of the ‘Drew family of
of dopa-responsive dystonia associated with a new genetic Walworth’. Brain 1982; 105:1–28.
locus, DYT14. Neurology 2002; 58:1839–42. Harding AE. The hereditary ataxias and related disorders. London:
Growdon JH, Shahani BT, Young RR. The effect of alcohol on Churchill Livingstone, 1984.
essential tremor. Neurology 1975; 25:259–62. Harding AE, Thomas PK, Baraitser M et al. X-linked recessive
Gunal DI, Afsar N, Bekiroglu N et al. New alternative agents in bulbo-spinal neuropathy: a report of ten cases. J Neurol
essential tremor therapy: double-blind placebo-controlled Neurosurg Psychiatry 1982; 45:1012–19.
study of alprazolam and acetazolamide. Neurol Sci 2000; Harding AJ, Stimson E, Hernderson JM et al. Clinical correlates of
21:315–17. selective pathology in the amygdala of patients with
Guttman M, International Pramipexole–Bromocriptine Study Parkinson’s disease. Brain 2002a; 125:2431–45.
Group. Double-blind comparison of pramipexole and Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy
bromocriptine treatment with placebo in advanced Parkinson’s body disease related to Lewy bodies in the temporal lobe.
disease. Neurology 1997; 49:1060–5. Brain 2002b; 125:391–403.
Gysin WM, Cooke ET. Unusual mental symptoms in a case of Harper PS, Harley HG, Reardon W et al. Anticipation in myotonic
hepatolenticular degeneration. Dis Nerv Syst 1950; 11: dystrophy: new light on an old problem. Am J Human Genet
305–9. 1992; 51:10–16.
Haber SN, Kowall NW, Vonsattel JP et al. Gilles de la Tourette’s Harsch HH. Neuroleptic malignant syndrome: physiological and
syndrome. A postmortem neuropathological and laboratory findings in a series of nine cases. J Clin Psychiatry
immunohistochemical study. J Neurol Sci 1986; 75:225–41. 1987; 48:328–33.
Hageman ATM, Gabreels FJM, de Jong JGN et al. Clinical Hartig MB, Hortnagel K, Garavaglia B et al. Genotypic and
symptoms of adult metachromatic leukodystrophy and phenotypic spectrum of PANK2 mutations in patients with
arylsulfatase A pseudodeficiency. Arch Neurol 1995; neurodegeneration with brain iron accumulation. Ann Neurol
52:408–13. 2006; 59:248–56.
Hagerman RJ, Leehey M, Heinrichs W et al. Intention tremor, Harwood G, Hierons R, Fletcher NA et al. Lessons from a
parkinsonism, and generalized brain atrophy in male carriers remarkable family with dopa-responsive dystonia. J Neurol
of fragile X. Neurology 2001; 57:127–30. Neurosurg Psychiatry 1994; 57:460–3.
Hagerman RJ, Leavitt BR, Farzin F et al. Fragile X-associated Hauser RA, Gauger L, McDowell Anderson W et al. Pramipexole-
tremor/ataxia syndrome (FXTAS) in females with the FMR1 induced somnolence and episodes of daytime sleep. Mov
premutation. Am J Hum Genet 2004; 74:1051–6. Disord 2000; 15:658–63.
p 08.qxd 3/10/08 9:38 AM Page 388
Hayflick SJ, Penzien JM, Michl W et al. Cranial MRI changes may Hsieh M, Li S-Y, Tsai C-J et al. Identification of five
preceded symptoms in Hallervorden-Spatz syndrome. Pediatr spinocerebellar ataxia type 2 pedigrees in patients with
Neurol 2001; 25:166–9. autosomal dominant cerebellar ataxia in Taiwan. Acta Neurol
Hayflick SJ, Westaway SK, Levinson B et al. Genetic, clinical, and Scand 1999; 100:189–98.
radiographic delineation of Hallervorden-Spatz syndrome. Huber SJ, Kissel JT, Shuttleworth EC et al. Magnetic resonance
N Engl J Med 2003; 348:33–40. imaging and clinical correlates of intellectual impairment in
Hely MA, Reid WGJ, Halliday GM et al. Diffuse Lewy body disease: myotonic dystrophy. Arch Neurol 1989; 46:536–40.
clinical features in nine cases without coexistent Alzheimer’s Huff FJ, Boller J, Luchelli F et al. The neurologic examination in
disease. J Neurol Neurosurg Psychiatry 1996; 60:531–8. patients with probable Alzheimer’s disease. Arch Neurol 1987;
Henderson JM, Carpenter K, Cartwright H et al. Loss of thalamic 44:929–32.
and intralaminar nuclei in progressive supranuclear palsy and Hughes AJ, Daniel SE, Blankson S et al. A clinicopathologic study
Parkinson’s disease: clinical and therapeutic implications. of 100 cases of Parkinson’s disease. Arch Neurol 1993;
Brain 2000; 123:1410–21. 50:140–8.
Heston LL, White JA, Mastri AR. Pick’s disease. Clinical genetics Hung SW, Hamani C, Lozano AM et al. Long-term outcome of
and natural history. Arch Gen Psychiatry 1987; 44:409–11. bilateral pallidal deep brain stimulation for primary cervical
Heutink P, Stevens M, Rizzu P et al. Hereditary frontotemporal dystonia. Neurology 2007; 68:4579–9.
dementia is linked to chromosome 17q21–q22: a genetic and Huntington G. On chorea. Med Surg Reporter Philadelphia 1872;
clinicopathological study of three Dutch families. Ann Neurol 26:317–21.
1997; 41:150–9. Huntington Study Group. Tetrabenazine as antichorea therapy in
Higgins JJ, Adler RI, Loveless JM. Mutational analysis of the tau Huntington disease: a randomized controlled trial. Neurology
gene in progressive supranuclear palsy. Neurology 1999; 2006; 66:366–72.
53:1421–4. Hurtig HI, Trojanowski JQ, Galvin J et al. Alpha-synuclein cortical
Hillen ME, Sage JI. Nonmotor fluctuations in patients with Lewy bodies correlate with dementia in Parkinson’s disease.
Parkinson’s disease. Neurology 1996; 47:1180–3. Neurology 2000; 54:1916–21.
Hipola D, Mateo D, Gimenez-Roldan S. Meige’s syndrome: acute Hussain IF, Brady CM, Swinn MJ et al. Treatment of erectile
and chronic responses to clonazepam and anticholinergics. Eur dysfunction with sildenafil citrate (Viagra) in parkinsonism due
Neurol 1984; 23:474–8. to Parkinson’s disease or multiple system atrophy. J Neurol
Hirano A, Arumugasamy N, Zimmerman HM. Amyotrophic lateral Neurosurg Psychiatry 2001; 71:371–4.
sclerosis: a comparison of Guam and classical cases. Arch Hutton JT, Koller WC, Ahlskog JE et al. Multicenter, placebo-
Neurol 1967; 16:357–63. controlled trial of cabergoline taken once daily in the
Hirono N, Mori E, Yasuda M et al. Factors associated with treatment of Parkinson’s disease. Neurology 1996; 46:1062–5.
psychotic symptoms in Alzheimer’s disease. J Neurol Neurosurg Hyde TM, Ziegler JC, Weinberger DR. Psychiatric disturbances in
Psychiatry 1998; 64:648–52. metachromatic leukodystrophy: insights into the neurobiology
Hirose G, Bass NH. Metachromatic leukodystrophy in the adult: a of psychosis. Arch Neurol 1992; 49:401–6.
biochemical study. Neurology 1972; 22:312–20. Hyde TM, Stacey ME, Coppoa R et al. Cerebral morphometric
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and abnormalities in Tourette’s syndrome: a quantitative MRI
mortality. Neurology 1967; 17:427–42. study of monozygotic twins. Neurology 1995; 45:1176–82.
Holroyd S, Currie L, Wooten GF. Prospective study of Iizuka R, Hirayama K, Maehara KA. Dentato-rubro-pallido-luysian
hallucinations and delusions in Parkinson’s disease. J Neurol atrophy: a clinico-pathological study. J Neurol Neurosurg
Hoogendijk WJG, Sommer IEC, Pool C et al. Lack of association Ikeda K, Akiyama H, Iritani S et al. Corticobasal degeneration with
between depression and loss of neurons in the locus primary progressive aphasia and accentuated cortical lesion in
coeruleus in Alzheimer disease. Arch Gen Psychiatry 1999; superior temporal gyrus: case report and review. Acta
56:45–51. Neuropath 1996; 92:534–9.
Hoogenraad TU, Van Hattum J, Van den Hamer CJA. Management Ikeda Y, Shizuka M, Watanabe M et al. Molecular and clinical
of Wilson’s disease with zinc sulphate: experience in a series analysis of spinocerebellar ataxia type 8 in Japan. Neurology
of 27 patients. J Neurol Sci 1987; 77:137–46. 2000; 54:950–5.
Horimoto Y, Matsumoto M, Akatsu H et al. Autonomic Ikeuchi T, Takano H, Koide R et al. Spinocerebellar ataxia type 6:
dysfunction in dementia with Lewy bodies. J Neurol 2003; CAG repeat expansion in alpha1a voltage-dependent calcium
250:530–3. channel gene and clinical variations in Japanese population.
Houser M, Waltz T. Meige syndrome and pallidal deep brain Ann Neurol 1997; 42:879–84.
stimulation. Mov Disord 2005; 20:1203–5. Illarioshkin SN, Markova ED, Slominsky PA et al. The GTP
Howard CP, Royce CE. Progressive lenticular degeneration cyclohydrolase I gene in Russian families with dopa-
associated with cirrhosis of the liver (Wilson’s disease). Arch responsive dystonia. Arch Neurol 1998; 55:789–92.
Int Med 1919; 24:497–508. in t’ Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal
Howeler CJ, Busch HF, Geraedts JP et al. Anticipation in myotonic antiinflammatory drugs and the risk of Alzheimer’s disease.
dystrophy: fact or fiction? Brain 1989; 112:779–97. N Engl J Med 2001; 345:1515–21.
p 08.qxd 3/10/08 9:38 AM Page 389
References 389
International Huntington Association, World Federation of Jedynak PC, Trenchant C, de Beyl DZ. Prospective clinical study of
Neurology Research Group on Huntington’s Chorea. Guidelines writer’s cramp. Mov Disord 2001; 16:494–9.
for the molecular genetics predictive test in Huntington’s Jervis GA. Early senile dementia in mongoloid idiocy. Am J
disease. Neurology 1994; 44:1533–6. Psychiatry 1948; 105:102–6.
International Myotonic Dystrophy Consortium. New nomenclature Jervis GA. Huntington’s chorea in childhood. Arch Neurol 1979;
and DNA testing guidelines for myotonic dystrophy type 1 23:83–93.
(DM1). Neurology 2000; 54:1218–21. Jobsis GJ, Weber JW, Barth PG et al. Autosomal dominant
Inzelberg R, Nisipeanu P, Rabey JM et al. Double-blind cerebellar ataxia with retinal degeneration (ADCA II): clinical
comparison of cabergoline and bromocriptine in Parkinson’s and neuropathological findings in two pedigrees and genetic
disease patients with motor fluctuations. Neurology 1996; linkage to 3p12–p21.1. J Neurol Neurosurg Psychiatry 1997;
47:785–8. 62:367–71.
Inzelberg R, Kipervasser S, Korczyn AD. Auditory hallucinations in Johnson W, Schwartz G, Barbeau A. Studies on dystonia
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998; musculorum deformans. Arch Neurol 1962; 7:301–13.
64:533–5. Josephs KA, Parisi JE, Knopman DS et al. Clinically undetected
Iranzo A, Santamaria J, Rye DB et al. Characteristics of idiopathic motor neuron disease in pathologically proven frontotemporal
REM sleep behavior disorder and that associated with MSA lobar degeneration with motor neuron disease. Arch Neurol
and PD. Neurology 2005; 65:247–52. 2006; 63:506–12.
Ironside R. Disorders of laughter due to brain lesions. Brain 1956; Karbe H, Kertesz A, Polk M. Profiles of language impairment in
79:589–609. primary progressive aphasia. Arch Neurol 1993; 50:192–201.
Ishikawa K, Watanabe M, Yoshizawa K et al. Clinical, Karp BI, Hallett M. Extracorporeal ‘phantom’ tics in Tourette’s
neuropathological, and molecular study in two families with syndrome. Neurology 1996; 46:38–40.
spinocerebellar ataxia type 6 (SCA6). J Neurol Neurosurg Kartsounis LD, Hardie RJ. The pattern of cognitive impairments in
Psychiatry 1999; 67:86–9. neuroacanthocytosis: a frontosubcortical dementia. Arch
Jabusch HC, Zschucke D, Schmidt A et al. Focal dystonia in Neurol 1996; 53:77–80.
musicians: treatment strategies and long-term outcome in Kaseda Y, Kawakami H, Matsuyama Z et al. Spinocerebellar ataxia
144 patients. Mov Disord 2005; 20:1623–6. type 6 in relation to CAG repeat length. Acta Neurol Scand
Jacquemont S, Hagerman RJ, Leehey MA et al. Penetrance of 1999; 99:209–12.
fragile X-associated tremor/ataxia syndrome in a premutation Kato K, Wada T, Kawakatsu S et al. Improvement of both
carrier population. JAMA 2004; 291:460–9. psychotic symptoms and parkinsonism in a case of dementia
Jagust WJ, Davies P, Tiller-Borcich JK et al. Focal Alzheimer’s with Lewy bodies by the combination therapy of risperidone
disease. Neurology 1990; 90:14–19. and L-dopa. Prog Neuropsychopharmacol Biol Psychiatry 2002;
Jahanshahi M. Factors that ameliorate or aggravate spasmodic 26:201–3.
torticollis. J Neurol Neurosurg Psychiatry 2000; 68:227–9. Kawanami T, Kato T, Daimon M et al. Hereditary ceruloplasmin
Jankovic J. Blepharospasm with basal ganglia lesions. Arch Neurol deficiency: clinicopathological study of a patient. J Neurol
1986; 43:866–8. Neurosurg Psychiatry 1996; 61:506–9.
Jankovic J, Patel S. Blepharospasm associated with brainstem Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and
lesions. Neurology 1983; 33:1237–40. bulbar muscular atrophy of late onset: a sex-linked recessive
Jankovic J, Kirkpatrick JB, Blomquist KA et al. Late-onset trait. Neurology 1968; 18:671–80.
Hallervorden–Spatz disease presenting as familial Kertesz A, Hudson L, Mackenzie IRA et al. The pathology and
parkinsonism. Neurology 1985; 35:227–34. nosology of primary progressive aphasia. Neurology 1994;
Jankovic J, Leder S, Warner D et al. Cervical dystonia: clinical 44:2065–72.
findings and associated movement disorders. Neurology 1991; Khan NL, Graham E, Critchley P et al. Parkin disease: a phenotypic
41:1088–91. study of a large case series. Brain 2003; 126:1279–92.
Jankovic J, Watts RL, Martin W et al. Transdermal rotigotine. Kidd D, Nelson J, Jones F et al. Long-term stabilization after bone
Double-blind, placebo-controlled trial in Parkinson’s disease. marrow transplantation in juvenile metachromatic
Arch Neurol 2007; 64:676–82. leukodystrophy. Arch Neurol 1998; 51:98–9.
Janssen JC, Lantos PL, Al-Sarraj S et al. Thalamic degeneration Kidd M. Alzheimer’s disease: an electron microscopic study. Brain
with negative prion protein immunostaining. J Neurol 2000; 1964; 87:307–20.
247:48–51. Kirsten L, Silfverskiold B. A family with emotionally precipitated
Janssen JC, Warrington EK, Morris HR et al. Clinical features of drop seizures. Lancet 1958; 2:471–6.
frontotemporal dementia due to the intronic tau 10 ⫹ 16 Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse
mutation. Neurology 2002; 58:1161–8. Lewy body disease: a clinicopathologic study using Alzheimer’s
Janssen JC, Beck JA, Campbell TA et al. Early onset familial disease and Parkinson’s disease comparison groups. Neurology
Alzheimer’s disease. Mutation frequency in 31 families. 1996; 47:1148–52.
Neurology 2003; 60:235–9. Klawans HL, Barr A. Prevalence of spontaneous lingual-facial-
Jayne D, Lees AJ, Stern GM. Remission in spasmodic torticollis. buccal dyskinesias in the elderly. Neurology 1981;
J Neurol Neurosurg Psychiatry 1984; 47:1236–7. 31:558–9.
p 08.qxd 3/10/08 9:38 AM Page 390
Klawans HL, Barr A. Recurrence of childhood multiple tics in late Kurlan R, Behr J, Medved L et al. Transient tic disorder and the
adult life. Arch Neurol 1985; 42:1079–80. spectrum of Tourette’s syndrome. Arch Neurol 1988;
Klein C. Implications of genetics on the diagnosis and care of 45:1200–1.
patients with Parkinson disease. Arch Neurol 2006; Kurth MC, Adler CH, St Hilaire M et al. Tolcapone improves motor
63:328–34. function and reduces levodopa requirement in patients with
Kleiner-Fisman G, Rogaeva E, Halliday W et al. Benign hereditary Parkinson’s disease experiencing motor fluctuations: a
chorea: clinical, genetic, and pathological findings. Neurology multicenter, double-blind, randomized, placebo-controlled
2003; 54:244–7. trial. Neurology 1997; 48:81–7.
Kleiner-Fisman G, Calingasan NY, Putt M et al. Alterations of Kuzis G, Sabe L, Tiberti C et al. Cognitive functions in major
striatal neurons in benign hereditary chorea. Mov Disord 2005; depression and Parkinson disease. Arch Neurol 1997;
20:1353–7. 54:982–6.
Knibb J, Xuereb JH, Patterson K et al. Clinical and pathological Kvale JN. Amitriptyline in the management of progressive
characteristics of progressive aphasia. Ann Neurol 2006; supranuclear palsy. Arch Neurol 1982; 39:387–8.
59:156–65. La Forestier N, Maisonobe T, Piquard A et al. Does primary lateral
Knopman DS, Christensen KJ, Schut LJ et al. The spectrum of sclerosis exist? A study of 20 patients and a review of the
imaging and neuropsychological findings in Pick’s disease. literature. Brain 2001; 124:1989–99.
Neurology 1989; 39:362–8. Lai F, Williams RS. A prospective study of Alzheimer’s disease in
Koch MC, Grimm T, Harley HG et al. Genetic risks for children of Down syndrome. Arch Neurol 1989; 46:849–53.
women with myotonic dystrophy. Am J Human Genet 1991; Lang AE. Patient perception of tics and other movement disorders.
48:1084–91. Neurology 1991; 41:223–8.
Koller WC. Edentulous orodyskinesia. Neurology 1983; 13:97–9. Lang AE, Johnson K. Akathisia in idiopathic Parkinson’s disease.
Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology 1987; 37:477–81.
Neurology 1986; 36:121–4. Lang AE, Consky E, Sandor P. ‘Signing tics’ – insights into the
Koller WC, Busenbark K, Miner K et al. The relationship of pathophysiology of symptoms in Tourette’s syndrome. Ann
essential tremor to other movement disorders: report on 678 Neurol 1993; 33:212–15.
patients. Ann Neurol 1994; 35:717–23. Lantos PL, Cairns NJ, Khan MN et al. Neuropathologic variations
Korczyn AD, Brunt ER, Larsen JP et al. A 3-year randomized trial in frontotemporal dementia due to the intronic tau 10 ⫹ 16
of ropinirole and bromocriptine in early Parkinson’s disease. mutation. Neurology 2002; 58:1169–75.
Neurology 1999; 53:364–70. Lasek K, Lencer R, Gaser C et al. Morphological basis for the
Korenke GC, Fuchs S, Kraseman E et al. Cerebral adreno- spectrum of clinical deficits in spinocerebellar ataxia 17
leukodystrophy in only one of monozygotic twins with an (SCA17). Brain 2006; 129:2341–52.
identical ALD genotype. Ann Neurol 1996; 40:254–7. Lawyer T, Netsky MG. Amyotrophic lateral sclerosis: clinico-
Koss E, Edland S, Fillenbaum G et al. Clinical and anatomic study of 53 cases. Arch Neurol Psychiatry 1953;
neuropsychological differences between patients with earlier 69:171–92.
and later onset of Alzheimer’s disease: a CERAD analysis, Part Le Bars PL, Katz MM, Berman N et al. A placebo-controlled,
XII. Neurology 1996; 46:136–41. double-blind, randomized trial of Ginkgo biloba for dementia:
Kramer PL, de Leon D, Oselius L et al. Dystonia gene in Ashkenazi North American EGb Study Group. JAMA 1997; 278:
Jewish population is located on chromosome 9q32–34. Ann 1327–32.
Neurol 1990; 27:114–20. Le Ber I, Martinez M, Campion D et al. A non-DM1, non DM2
Kremer B, Goldberg P, Andrew SE et al. A world-wide study of the multisystem myotonic disorder with frontotemporal dementia:
Huntington’s disease mutation: the sensitivity and specificity phenotype and suggestive mapping of the DM3 locus to
of measuring CAG repeats. N Engl J Med 1994; 330:1401–6. chromosome 15q21-24. Brain 2004; 127:1979–92.
Krivit W, Lipton ME, Tsai M et al. Prevention of deterioration in Lebert F, Stekke W, Hasenbroek C et al. Frontotemporal dementia:
metachromatic leukodystrophy by bone marrow a randomized, controlled trial with trazodone. Geriatr Cogn
transplantation. Am J Med Sci 1987; 249:80–5. Disord 2004; 17:355–9.
Kruisdijk JJM, Koelman JHTM, Ongerboer BW et al. Botulinum Leckman JF, Ort S, Caruso KA et al. Rebound phenomena in
toxin for writer’s cramp: a randomized, placebo-controlled Tourette’s syndrome after abrupt withdrawal of clonidine.
trial and 1-year follow-up. J Neurol Neurosurg Psychiatry Behavioral, cardiovascular, and neurochemical effects. Arch
2007; 7 8:264–70. Gen Psychiatry 1986; 43:1168–76.
Kugelberg E, Welander L. Heredofamilial juvenile muscular Leckman JF, Hardin MT, Riddle MA et al. Clonidine treatment of
atrophy simulating muscular dystrophy. Arch Neurol Psychiatry Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1991;
1956; 75:500–9. 48:324–8.
Kuipers-Upmeijer J, de Jager AEJ, Hew JM et al. Primary lateral Leckman JF, Walker DE, Cohen DJ. Premonitory urges in Tourette’s
sclerosis: clinical, neurophysiological, and magnetic resonance syndrome. Am J Psychiatry 1993; 150:98–102.
findings. J Neurol Neurosurg Psychiatry 2001; 71:615–20. Leckman JF, Walker DE, Goodman WK et al. ‘Just right’
Kulisevsky J, Marti MJ, Ferrer I et al. Meige syndrome: perceptions associated with compulsive behavior in Tourette’s
neuropathology of a case. Mov Disord 1988; 3:170–5. syndrome. Am J Psychiatry 1994; 151:675–80.
p 08.qxd 3/10/08 9:38 AM Page 391
References 391
Leckman JF, Zhang H, Vitale A et al. Course of tic severity in Litvan I, Agid Y, Jankovic J et al. Accuracy of clinical criteria for
Tourette syndrome: the first two decades. Pediatrics 1998; the diagnosis of progressive supranuclear palsy
102:14–19. (Steele–Richardson Olszewski syndrome). Neurology 1996c;
Lee MS, Lee SB, Kim WC. Spasmodic dysphonia associated with a 46:922–30.
left ventrolateral putaminal lesion. Neurology 1996; Litvan I, Agid Y, Sastrj N et al. What are the obstacles for
47:827–8. accurate clinical diagnosis of Pick’s disease? Neurology
Lee MS, Kim YD, Lyoo CH. Oculogyric crisis as an initial 1997a; 49:62–9.
manifestation of Wilson’s disease. Neurology 1999; Litvan I, Campbell G, Mangone CA et al. Which clinical features
52:1714–15. differentiate progressive supranuclear palsy
Lees AJ, Robertson M, Trimble MR et al. A clinical study of Gilles (Steele–Richardson–Olszewski syndrome) from related
de la Tourette syndrome in the United Kingdom. J Neurol disorders? A clinicopathological study. Brain 1997b;
Lennox G, Lowe J, Landon M et al. Diffuse Lewy body disease: Litvan I, Agid Y, Goetz C et al. Accuracy of the clinical diagnosis
correlative neuropathology using anti-ubiquitin of corticobasal degeneration: a clinicopathologic study.
immunocytochemistry. J Neurol Neurosurg Psychiatry 1989; Neurology 1997c; 48:119–25.
52:1236–47. Litvan I, Cummings JL, Mega M. Neuropsychiatric features of
Leopold NA, Kagel MC. Dysphagia in Huntington’s disease. Arch corticobasal degeneration. J Neurol Neurosurg Psychiatry
Neurol 1985; 42:57–60. 1998; 65:717–21.
Lesse SM. Huntington’s chorea: report of a case. J Nerv Ment Dis Litvan I, Phipps M, Pharr VL et al. Randomized placebo-controlled
1946; 104:84–7. trial of donepezil in patients with progressive supranuclear
Leube B, Hendgen J, Kessler KR et al. Sporadic focal dystonia in palsy. Neurology 2001; 57:467–73.
Northwest Germany: molecular basis on chromosome 18p. Livingston G, Walker AE, Katona CLE et al. Antipsychotics and
Ann Neurol 1997; 42:111–14. cognitive decline in Alzheimer’s disease: the LASER-
Levy-Lahad E, Wasco W, Poorkaj P et al. Candidate gene for the Alzheimer’s disease longitudinal study. J Neurol Neurosurg
chromosome 1 familial Alzheimer’s disease locus. Science Psychiatry 2007; 78:25–9.
1995; 269:973–7. Lopes-Cendes I, Silveira I, Maciel P et al. Limits of clinical
Lieberman A, Ranhosky A, Korts D. Clinical evaluation of assessment as the accurate diagnosis of Machado–Joseph
pramipexole in advanced Parkinson’s disease: results of a disease. Arch Neurol 1996; 53:1168–74.
double-blind, placebo-controlled, parallel-group study. Lopez OL, Becker JT, Sweet RA et al. Psychiatric symptoms vary
Neurology 1997; 49:162–8. with the severity of dementia in probable Alzheimer’s disease.
Lieberman A, Olanow CW, Sethi K et al. A multicenter trial of J Neuropsychiatry Clin Neurosci 2003; 15:346–53.
ropinirole as adjunct treatment for Parkinson’s disease. Lorenz D, Frederiksen H, Moises H et al. High concordance for
Neurology 1998; 51:1057–62. essential tremor in monozygotic twins of old age. Neurology
Lieberman JA, Reife R. Spastic dysphonia and denervation signs in 2004; 62:208–11.
a young man with tardive dyskinesia. Br J Psychiatry 1989; Lossos A, Dobson-Stone C, Monaco AP et al. Early clinical
154:105–9. heterogeneity in choreoacanthocytosis. Ann Neurol 2005;
Lilly R, Cummings JL, Benson DF et al. The human Kluver–Bucy 62:611–14.
syndrome. Neurology 1983; 33:1141–5. Lou J-S, Jankovic J. Essential tremor: clinical correlates in 350
Linet LS. Tourette syndrome, pimozide, and school phobia: the patients. Neurology 1991; 41:234–8.
neuroleptic separation anxiety syndrome. Am J Psychiatry Louis ED, Goldman JE, Powers JM et al. Parkinsonian features of
1985; 12:613–15. eight pathologically diagnosed cases of diffuse Lewy body
Linn RT, Wolf PA, Bachman DL et al. The ‘preclinical phase’ of disease. Mov Disord 1995; 10:188–94.
probable Alzheimer’s disease. Arch Neurol 1995; 52:485–90. Louis ED, Klatka LA, Liu Y et al. Comparison of extrapyramidal
Lippa CF, Smith TW, Swearer JM. Alzheimer’s disease and Lewy features in 31 pathologically confirmed cases of diffuse Lewy
body disease: a comparative clinicopathological study. Ann body disease and 34 pathologically confirmed cases of
Neurol 1994; 35:81–8. Parkinson’s disease. Neurology 1997; 48:376–80.
Little BW, Brown PW, Rodgers-Johnson P et al. Familial myoclonic Louis ED, Honig LS, Vonsattel JPG et al. Essential tremor
dementia masquerading as Creutzfeldt–Jakob disease. Ann associated with focal nonnigral Lewy bodies. Arch Neurol
Neurol 1986; 20:231. 2005; 62:1004–7.
Litvan I, Mega MS, Cummings JL et al. Neuropsychiatric aspects Louis ED, Vonsattel JPG, Honig LS et al. Neuropathologic findings
of progressive supranuclear palsy. Neurology 1996a; 47: in essential tremor. Neurology 2006a; 66:1756–9.
1184–9. Louis ED, Vonsattel JPG, Honig LS et al. Essential tremor
Litvan I, Mangone CA, McKee A et al. Natural history of associated with pathologic change in the cerebellum. Arch
progressive supranuclear palsy (Steele–Richardson– Neurol 2006b; 63:1189–93.
Olszewski syndrome) and clinical predictors of survival: a Lowenberg K, Boyd DA, Salon DD. Occurrence of Pick’s
clinicopathologic study. J Neurol Neurosurg Psychiatry 1996b; disease in early adult years. Arch Neurol Psychiatry 1939;
61:615–20. 41:1004–20.
p 08.qxd 3/10/08 9:38 AM Page 392
Lucking CB, Durr A, Bonifati V et al. Association between early- Mark MH, Sage JI, Dickson DW et al. Meige syndrome in the
onset Parkinson’s disease and mutations in the Parkin gene. spectrum of Lewy body disease. Neurology 1994;
N Engl J Med 2000; 342:1560–7. 44:1432–6.
Maas O, Paterson AS. Myotonia congenita, dystrophia myotonica, Marneros A. Adult onset of Tourette’s syndrome. Am J Psychiatry
and paramyotonia. Brain 1950; 73:318–32. 1983; 140:924–5.
MacDonald JR, Hill JD, Tarnopolsky MA. Modafinil reduces Marsden CD, Harrison MJG. Idiopathic torsion dystonia (dystonia
excessive somnolence and enhances mood in patients with musculorum deformans): a review of forty-two patients. Brain
myotonic dystrophy. Neurology 2002; 59:1876–80. 1974; 97:793–810.
Machado A, Chien HF, Deguti MM et al. Neurological Martin JJ, Yap M, Nei LP et al. Selective thalamic degeneration –
manifestations of Wilson’s disease: report of 119 cases. Mov report of a case with memory and mental disturbances. Clin
Disord 2006; 21:2192–6. Neuropathol 1983; 2:156–62.
MacKenzie IR, Munoz DG. Nonsteroidal anti-inflammatory drug Martin WE, Loewenson RB, Resch JA et al. Parkinson’s disease:
use and Alzheimer-type pathology in aging. Neurology 1998; clinical analysis of 100 patients. Neurology 1973; 23:783–90.
50:986–90. Martinelli P, Gabellini AS, Gulli MR et al. Different clinical
Mackenzie IRA, Baker M, Pickering-Brown S et al. The features of essential tremor: a 200-patient study. Acta Neurol
neuropathology of frontotemporal lobar degeneration caused Scand 1987; 75:106–11.
by mutations in the progranulin gene. Brain 2006; Marttila RJ, Rinne UK. Dementia in Parkinson’s disease. Acta
129:3081–90. Neurol Scand 1976; 54:431–44.
Maher ER, Lees AJ. The clinical features of the Massironi G, Galuzzi S, Frisoni GB. Drug treatment of REM sleep
Steele–Richardson–Olszewski syndrome (progressive behavior disorders in dementia with Lewy bodies. Int
supranuclear palsy). Neurology 1986; 36:1005–8. Psychogeriatr 2003; 15:377–83.
Malamud N, Waggoner RW. Genealogic and clinicopathologic Matsumara R, Futamura N, Fujimoto Y et al. Spinocerebellar
study of Pick’s disease. Arch Neurol Psychiatry 1943; ataxia type 6. Molecular and genetic features of 35 Japanese
50:288–303. patients including one homozygous for the CAG repeat
Malamud N, Hirano A, Kurland LT. Pathoanatomic changes in expansion. Neurology 1997; 49:1238–43.
amyotrophic lateral sclerosis on Guam. Neurology 1961; Matsuura T, Achari M, Khajavi M et al. Mapping of the gene for a
5:401–14. novel spinocerebellar ataxia with pure cerebellar signs and
Maltecca F, Filla A, Castaldo I et al. Intergenerational instability epilepsy. Ann Neurol 1999; 45:407–11.
and marked anticipation in SCA-17. Neurology 2003; Maurage CA, Udd B, Ruchoux MM et al. Similar brain tau
61:1441–3. pathology in DM2/PROMM and DM1/Steinert disease.
Mann D, Yates P, Marcyniuk B. A comparison of changes in the Neurology 2005; 65:1636–8.
nucleus basalis and the locus coeruleus in Alzheimer’s disease. Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer’s disease.
J Neurol Neurosurg Psychiatry 1984; 47:201–3. Lancet 1997; 349:1546–9.
Mann D, South PW, Snowden JS et al. Dementia of frontal lobe Mayeux R, Stern Y, Cote L et al. Altered serotonin metabolism in
type: neuropathology and immunohistochemistry. J Neurol depressed patients with Parkinson’s disease. Neurology 1984;
Neurosurg Psychiatry 1993a; 56:605–14. 34:642–6.
Mann D, Oliver R, Snowden JS. The topographic distribution of Mayeux R, Stern Y, Williams JBW et al. Clinical and biochemical
brain atrophy in Huntington’s disease and progressive features of depression in Parkinson’s disease. Am J Psychiatry
supranuclear palsy. Acta Neuropathol 1993b; 85:553–9. 1986; 143:756–9.
Manni R, Zucca C, Martinetti M et al. Hypersomnia in dystrophica Mayeux R, Stern Y, Rosenstein R et al. An estimate of the
myotonica: a neurophysiological and immunogenetic study. prevalence of dementia in idiopathic Parkinson’s disease. Arch
Acta Neurol Scand 1991; 84:498–502. Neurol 1988; 45:260–2.
Manowitz P, Kling A, Kohn H. Clinical course of adult Mayeux R, Denaro J, Hemenegildo N et al. A population-based
metachromatic leukodystrophy presenting as schizophrenia: a investigation of Parkinson’s disease with and without
report of two living cases in siblings. J Nerv Ment Dis 1978; dementia: relationship to age and gender. Arch Neurol 1992;
166:500–6. 49:492–7.
Marantz AG, Verghese J. Capgras’ syndrome in dementia with Mazza M, Capuano A, Bria P et al. Ginkgo biloba and donepezil: a
Lewy bodies. J Geriatr Psychiatry Neurol 2002; 15:239–41. comparison in the treatment of Alzheimer’s disease in a
Marder K, Ming-Xin T, Cote L et al. The frequency and associated randomized placebo-controlled double-blind study. Eur J
risk factors for dementia in patients with Parkinson’s disease. Neurol 2006; 13:981–5.
Arch Neurol 1995; 52:695–701. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-
Marder K, Sandler S, Lechich A et al. Relationship between CAG inflammatory agents as possible protective factors for
repeat length and late-stage outcomes in Huntington’s Alzheimer’s disease: a review of 17 epidemiologic studies.
disease. Neurology 2002; 59:1622–4. Neurology 1996; 47:425–32.
Margolese HC, Annable L, Dion Y. Depression and dysphoria in McKeith I, Fairbarin A, Perry R et al. Neuroleptic sensitivity in
adult and adolescent patients with Tourette’s disorder treated patients with senile dementia of Lewy body type. BMJ 1992a;
with risperidone. J Clin Psychiatry 2002; 63:1040–4. 305:1158–9.
p 08.qxd 3/10/08 9:38 AM Page 393
References 393
McKeith IG, Perry RH, Fairbarin AF et al. Operational criteria for Mesulam M, Johnson N, Kreftt TA et al. Progranulin mutations in
senile dementia of Lewy body type (SDLT). Psychol Med 1992b; primary progressive aphasia. The PPA1 and PPA3 families. Arch
22:911–22. Neurol 2007; 64:43–7.
McKeith IG, Fairbairn A, Perry RH et al. Neuroleptic sensitivity in Migliorelli R, Teson A, Sabe L et al. Prevalence and correlates of
patients with senile dementia of Lewy body type. BMJ 1992c; dysthymia and major depression among patients with
305:673–8. Alzheimer’s disease. Am J Psychiatry 1995; 152:37–44.
McKeith I, Fairbairn AF, Perry RH et al. The clinical diagnosis and a Mikkelsen EJ, Detlor J, Cohen DJ. School avoidance and social
misdiagnosis of senile dementia of Lewy body type (SDLT). Br J phobia triggered by haloperidol in patients with Tourette’s
Psychiatry 1994a; 165:324–32. disorder. Am J Psychiatry 1981; 138:1572–6.
McKeith IG, Fairbairn AF, Bothwell RA et al. An evaluation of the Modi G, Modi M, Martinus I et al. The clinical and genetic
predictive validity and inter-rater reliability of clinical characteristics of spinocerebellar ataxia type 7 (SCA7) in three
diagnostic criteria for senile dementia of Lewy body type. black South African families. Acta Neurol Scand 2000;
Neurology 1994b; 44:872–7. 101:177–82.
McKeith I, Del Ser T, Spano P et al. Efficacy of rivastigmine in Modoni A, Silvestri G, Pomponi MG et al. Characterization of the
dementia with Lewy bodies: a randomized, double-blind, pattern of cognitive impairment in myotonic dystrophy type 1.
placebo-controlled international study. Lancet 2000; Arch Neurol 2004; 61:1943–7.
356:2031–6. Mohs RC, Breitner JCS, Silverman JM et al. Alzheimer’s disease:
McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management morbid risk among first-degree relatives approximates 50%
of dementia with Lewy bodies: third report of the DLB by 90 years of age. Arch Gen Psychiatry 1987; 44:
consortium. Neurology 2005; 65:1863–72. 405–8.
McNaught KSP, Kaspussin A, Jackson T et al. Brainstem pathology Molloy S, McKeith IG, O’Brien JT et al. The role of levodopa in the
in DYT1 primary torsion dystonia. Ann Neurol 2004; 56:540–7. management of dementia with Lewy bodies. J Neurol
McNeill R, Sare GM, Manoharan M et al. Accuracy of single- Neurosurg Psychiatry 2005; 76:1200–3.
photon emission computed tomography in differentiating Moosey J, Martinez AJ, Hanin I et al. Thalamic and subcortical
frontotemporal dementia from Alzheimer’s disease. J Neurol gliosis with dementia. Arch Neurol 1987; 44:510–13.
Neurosurg Psychiatry 2007; 78:350–5. Moretti R, Torre P, Antonello RM et al. Rivastigmine in
van der Meche FGA, Bogaard JM, van der Sluys JCM et al. Daytime frontotemporal dementia: an open-label study. Drugs Aging
sleep in myotonic dystrophy is not caused by sleep apnoea. 2004; 21:931–7.
J Neurol Neurosurg Psychiatry 1994; 57:626–8. Mori H, Kondo T, Yokochi M et al. Pathologic and biochemical
Medalia A, Merriam A, Sandberg M et al. Neuropsychological studies of juvenile parkinsonism linked to chromosome 6q.
deficits in choreoacanthocytosis. Arch Neurol 1989; Neurology 1998; 51:890–2.
46:573–83. Morris HR, Gibb G, Katzenschlager R et al. Pathological, clinical
Mega MS, Cummings JL, Fiorello T et al. The spectrum of and genetic heterogeneity in progressive supranuclear palsy.
behavioral changes in Alzheimer’s disease. Neurology 1996; Brain 2002; 125:969–75.
46:130–5. Morris ME, Iansek R, Matyas TA et al. Stride length regulation in
Meiner V, Meiner Z, Reshef A et al. Cerebrotendinous Parkinson’s disease: normalization strategies and underlying
xanthomatosis: molecular diagnosis enables presymptomatic mechanisms. Brain 1996; 119:551–68.
detection of a treatable disease. Neurology 1994; 44: Moser HW, Moser AE, Singh I et al. Adrenoleukodystrophy: survey
288–90. of 303 cases: biochemistry, diagnosis and therapy. Ann Neurol
Mendez MF, Selwood A, Mastr AR et al. Pick’s disease versus 1984; 16:628–41.
Alzheimer’s disease: a comparison of clinical characteristics. Moser HW, Raymond GV, Lu S-E et al. Follow-up of 89
Neurology 1993; 43:289–92. asymptomatic patients with adrenoleukodystrophy treated
Mendez MF, Shapira JS, McMurtay A et al. Preliminary findings: with Lorenzo’s oil. Arch Neurol 2005; 62:1073–80.
behavioral worsening on donepezil in patients with Mosser J, Lutz Y, Stoeckel ME et al. The gene responsible for
frontotemporal dementia. Am J Geriatr Psychiatry 2007; adrenoleukodystrophy encodes a peroxisomal membrane
15:84–7. protein. Hum Mol Genet 1994; 3:265–71.
Menkes JH, Schimschock JR, Swanson PD. Cerebrotendinous Muller J, Wissel J, Masuhr F et al. Clinical characteristics of the
xanthomatosis: the storage of cholestanol within the nervous geste antagoniste in cervical dystonia. J Neurol 2001a;
system. Arch Neurol 1968; 19:47–53. 248:478–82.
Menza MA, Cocchiola J, Golbe LI. Psychiatric symptoms in Muller N, Kroll B, Schwarz MJ et al. Increased titers of antibodies
progressive supranuclear palsy. Psychosomatics 1995; 36:550–4. against streptococcal M12 and M19 proteins in patients with
Merims D, Balas M, Peretz C et al. Rater-blinded, prospective Tourette’s syndrome. Psychiatry Res 2001b; 101:187–93.
comparison: quetiapine versus clozapine for Parkinson’s Munoz MF, Selwood A, Mastri AR et al. Pick’s disease versus
disease psychosis. Clin Neuropharmacol 2006; 29:331–7. Alzheimer’s disease: a comparison of clinical abnormalities.
Messert B, Van Nuis C. A syndrome of paralysis of downward Neurology 1993; 43:289–95.
gaze, dysarthria, pseudobulbar palsy, axial rigidity of neck and Munoz-Garcia D, Ludwin SK. Classic and generalized variants of
trunk and dementia. J Nerv Ment Dis 1966; 143:47–54. Pick’s disease: a clinico-pathological, ultrastructural, and
p 08.qxd 3/10/08 9:38 AM Page 394
immunocytochemical comparative study. Ann Neurol 1984; both striatal and nigral dysfunction. Mov Disord 2002;
16:467–80. 17:482–7.
Murayama S, Mori H, Ihara Y et al. Immunocytochemical and Nygaard TG, Duvoisin RC. Hereditary dystonia–parkinsonism
ultrastructural studies of Pick’s disease. Ann Neurol 1990; syndrome of juvenile onset. Neurology 1986; 36:1424–8.
27:394–405. Nygaard TG, Duvoisin RC, Manocha M et al. Seizures in
Murphy MA, Feldman JA, Kilburn G. Hallervorden–Spatz disease in progressive supranuclear palsy. Neurology 1989; 39:138–40.
a psychiatric setting. J Clin Psychiatry 1989; 50:100–3. Nygaard TG, Trugman JM, de Yebenes JG et al. Dopa-responsive
Murray R, Neumann M, Forman MS et al. Cognitive and motor dystonia: the spectrum of clinical manifestations in a large
assessment in autopsy-proven corticobasal degeneration. North American family. Neurology 1990; 40:66–9.
Neurology 2007; 68:1274–83. Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia:
Myers RH, Vonsattel JP, Stevens TJ et al. Clinical and long-term treatment response and prognosis. Neurology 1991;
neuropathologic assessment of severity in Huntington’s 41:174–81.
disease. Neurology 1988; 38:341–7. O’Brien CP, DiGiacomo JN, Fahn S et al. Mental effects of high-
Myers RH, Mac DM, Koroshetz WJ et al. De novo expansion of a dosage levodopa. Arch Gen Psychiatry 1971; 24:61–4.
(CAG) repeat in sporadic Huntington’s disease. Nat Genet Oh J, Park KD, Cho HJ. Spasmodic dysphonia induced by valproic
1993; 5:174–9. acid. Epilepsia 2004; 45:880–1.
Myllyla VV, Sotaniemi KA, Hakulinen P et al. Selegeline as the O’Hearn E, Holmes SE, Calvert PC et al. SCA-12: tremor with
primary treatment of Parkinson’s disease – a long-term cerebellar and cortical trophy is associated with a CAG repeat
double-blind study. Acta Neurol Scand 1997; 95:211–18. expansion. Neurology 2001; 56:299–303.
Nagafuchi S, Yanagisawa H, Sato K et al. Dentatorubral and Ohnishi A, Sato Y, Nagara H et al. Neurogenic muscular atrophy
pallidoluysian atrophy expansion of an unstable CAG repeat and low density of large myelinated fibres of sural nerve in
on chromosome 12p. Nat Genet 1994; 6:14–18. chorea–acanthocytosis. J Neurol Neurosurg Psychiatry 1981;
Nagaoka U, Takashima M, Ishikawa K et al. A gene on SCA4 locus 44:645–8.
causes dominantly inherited pure cerebellar ataxia. Neurology Ohye T, Takahashi E, Seki N et al. Hereditary progressive dystonia
2000; 54:1971–5. with marked diurnal fluctuation caused by mutations in the
Nakagawa M, Yamada H, Higucki I et al. A case of paternally GTP cyclohydrolase I gene. Nat Genet 1994; 8:236–42.
inherited congenital myotonic dystrophy. J Med Genet 1994; Okazaki H, Lipkin LE, Aronson SM. Diffuse intracytoplasmic
31:397–400. ganglionic inclusions (Lewy type) associated with progressive
Navarro C, Fernandez JM, Dominguez C et al. Late juvenile dementia and quadriparesis in flexion. J Neuropathol Exp
metachromatic leukodystrophy treated with bone marrow Neurol 1961; 20:237–44.
transplantation: a 4-year follow-up study. Neurology 1996; Oken BS, Storzbach DM, Kaye JA. The efficacy of Gingko biloba on
46:254–6. cognitive function in Alzheimer’s disease. Arch Neurol 1998;
Neary D, Snowden J, Mann D et al. Alzheimer’s disease – a 55:1409–15.
correlative study. J Neurol Neurosurg Psychiatry 1986; Olanow CW, Tasmar Advisory Panel. Tolcapone and hepatotoxic
49:229–34. effects. Arch Neurol 2000; 57:263–7.
Neary D, Snowden JS, Mann DMA. Familial progressive atrophy: Olson MI, Shaw CM. Presenile dementia and Alzheimer’s disease
its relationship to other forms of lobar atrophy. J Neurol in mongolism. Brain 1969; 92:147–56.
Neurosurg Psychiatry 1993; 56:1122–5. Ondo W, Hunter C, Dat Vuong K et al. Gabapentin for essential
Neary D, Snowden JS, Gustafson L et al. Frontotemporal lobar tremor: a multiple-dose, double-blind, placebo-controlled
degeneration: a consensus on clinical diagnostic criteria. trial. Mov Disord 2000; 15:678–82.
Neurology 1998; 51:1546–54. Ondo W, Jankovic J, Connor GS et al. Topiramate in essential
Nee LE, Caine ED, Polinsky RJ et al. Gilles de la Tourette’s tremor. A double-blind, placebo-controlled trial. Neurology
syndrome: clinical and family study of 50 cases. Ann Neurol 2006; 66:672–7.
1980; 7:41–9. O’Neill BP, Moser HW, Saxena KM. Familial X-linked Addison
Neumann M, Schulz-Schaeffer W, Crowther A et al. Pick’s disease disease as an expression of adrenoleukodystrophy (ALD):
associated with the novel tau gene mutation K369I. Ann elevated C26 fatty acids in cultured skin fibroblasts. Neurology
Neurol 2001; 50:503–13. 1982; 32:543–9.
Newman GC. Treatment of progressive supranuclear palsy Ono S, Kanda F, Takahashi K et al. Neuronal loss in the medullary
with tricyclic antidepressants. Neurology 1985; 35: reticular formation in myotonic dystrophy: a
1189–93. clinicopathological study. Neurology 1996; 46:228–31.
Nichols IC, Weigner WC. Pick’s disease – a specific type of Ono S, Takahashi K, Jinnai K et al. Loss of serotonin-containing
dementia. Brain 1938; 61:237–49. neurons in the raphe of patients with myotonic dystrophy: a
Nielsen JE, Sorensen SA, Hasholt L et al. Dentatorubral- quantitative immunohistochemical study and relation to
pallidoluysian atrophy. Clinical features of a five-generation hypersomnia. Neurology 1998; 50:535–8.
Danish family. Mov Disord 1996; 11:533–41. Onofrj M, Paci C, D’Andreamatteo G et al. Olanzapine in severe
Nijssen PC, Brusse E, Leyten AC et al. Autosomal dominant adult Gilles de la Tourette syndrome: a 5-week double-blind cross-
cerebral neuronal ceroid lipofuscinosis: parkinsonism due to over study vs. low-dose pimozide. J Neurol 2000; 247:443–6.
p 08.qxd 3/10/08 9:38 AM Page 395
References 395
Onofrj M, Luciano AL, Thomas A et al. Mirtazapine induces REM Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette’s
sleep behavior disorder in parkinsonism. Neurology 2003; syndrome and associated behaviors. N Engl J Med 1986;
60:113–15. 315:993–7.
Ostheimer AJ. An essay on the shaking palsy, by James Parkinson, Pauls DL, Pakstis AJ, Kurlan R et al. Segregation and linkage
M.D., member of the Royal College of Surgeons. Arch Neurol analysis of Tourette’s syndrome and related disorders. J Am
Psychiatry 1922; 7:681–710. Acad Child Adolesc Psychiatry 1990; 29:195–203.
O’Suilleabhain P, Dewey RB. A randomized trial of amantadine in Paulson GW. Meige’s syndrome. Dyskinesia of the eyelids and
Huntington disease. Arch Neurol 2003; 60:996–8. facial muscles. Geriatrics 1972; 27:69–73.
Ozawa T, Pavious D, Quinn NP et al. The spectrum of pathological Paulsen JS, Ready RE, Hamilton JN et al. Neuropsychiatric aspects
involvement of the striatonigral and olivopontocerebellar of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001;
system in multiple system atrophy: clinicopathological 71:31–4.
correlations. Brain 2004; 127:2657–71. Paulsen JS, Hoth KF, Nehl C et al. Critical periods of suicide risk in
Ozelius L, Kramer PL, MosKowitz CB et al. Human gene for torsion Huntington’s disease. Am J Psychiatry 2005; 162:725–31.
dystonia located on chromosome 9q32–q34. Neuron 1989; Pellecchia MT, Valente EM, Cif L et al. The diverse phenotype and
2:1427–34. genotype of pantothenate kinase-associated
Ozelius LJ, Kramer PL, de Leon D et al. Strong allelic association neurodegeneration. Neurology 2005; 64:1810–12.
between the torsion dystonia gene (DYT 1) and loci on Perini GI, Colombo G, Armani M et al. Intellectual impairment and
chromosome 9q34 in Ashkenazi Jews. Am J Hum Genet 1992; cognitive evoked potentials in myotonic dystrophy. J Nerv
50:619–28. Ment Dis 1989; 177:750–4.
Ozelius LJ, Hewett JW, Page CE et al. The early-onset torsion Perlmutter SJ, Leitman SF, Garvey MA et al. Therapeutic plasma
dystonia gene (DYT1) encodes an ATP-binding protein. Nat exchange and intravenous immunoglobulin for obsessive-
Genet 1997; 17:40–8. compulsive disorder and tic disorders in childhood. Lancet
Pahwa R, Lyons K, McGuire D et al. Early morning akinesia in 1999; 354:1153–8.
Parkinson’s disease: effect of standard levodopa/carbidopa and Peterson B, Riddle MA, Cohen DJ et al. Reduced basal ganglia
sustained-release levodopa/carbidopa. Neurology 1996; volumes in Tourette’s syndrome using 3-dimensional
46:1059–62. reconstruction techniques from magnetic resonance images.
Paleacu D, Anca M, Giladi N. Olanzapine in Huntington’s disease. Neurology 1993; 43:941–9.
Acta Neurol Scand 2002; 105:441–4. Petry S, Cummings JL, Hill MA et al. Personality alterations in
Palhagen S, Heinonen EH, Hagglund J et al. Selegeline delays the dementia of the Alzheimer type. Arch Neurol 1988;
onset of disability in de novo parkinsonian patients. Neurology 45:1187–90.
1998; 51:520–5. Pflanz S, Besson JAO, Ebmeier KP et al. The clinical manifestation
Palhagen S, Heinonen E, Hagglund J et al. Selegeline slows the of mental disorder in Huntington’s disease: a retrospective
progression of the symptoms of Parkinson’s disease. Neurology case record study of disease progression. Acta Psychiatr Scand
2006; 66:1200–6. 1991; 83:53–60.
Papapetropoulos S, Singer C, Ross OA et al. Clinical heterogeneity Phemister JC, Small JM. Hypersomnia in dystrophia myotonica.
of the LRRK2 G2019S mutation. Arch Neurol 2006; 63:1242–6. J Neurol Neurosurg Psychiatry 1961; 24:173–5.
Papp MI, Lantos PI. The distribution of oligodendroglial inclusions Piccini P, Burn DJ, Ceravolo R et al. The role of inheritance in
in multiple system atrophy and its relevance to clinical sporadic Parkinson’s disease: evidence from a longitudinal
symptomatology. Brain 1994; 117:235–43. study of dopaminergic function in twins. Ann Neurol 1999;
Pappert EJ, Goetz CG, Louis ED et al. Objective assessment of 45:577–82.
longitudinal outcome in Gilles de la Tourette’s syndrome. Pick A. Uber die beziehungen der senilin hirnatrophie zur aphasie.
Neurology 2003; 61:936–40. Prager Med Wochenschur 1892; 17:165–7.
Parkinson Study Group. Safety and efficacy of pramipexole in Pickering-Brown S, Baker M, Yen SH et al. Pick’s disease is
early Parkinson’s disease: a randomized dose-ranging study. associated with mutations in the tau gene. Ann Neurol 2000;
JAMA 1997; 278:125–30. 48:859–67.
Parkinson Study Group. Low-dose clozapine for the treatment of Pierantozzi M, Pietrousti A, Brusa L et al. Helicobacter pylori
drug-induced psychosis in Parkinson’s disease. N Engl J Med eradication and L-dopa absorption in patients with PD and
1999; 340:757–63. motor fluctuations. Neurology 2006; 66:1824–9.
Parkinson Study Group. A controlled, randomized, delayed-start Pineda DA, Buritica O, Sanchez JL et al. Parkinsonian syndromes in
study of rasagaline in early Parkinson disease. Arch Neurol Medellin (Colombia). Rev Neurol 2000; 31:936–43.
2004; 61:561–6. Pinter MM, Pogarell O, Oertel WH. Efficacy, safety, and tolerance
Parkinson Study Group. A randomized placebo-controlled trial of of the non-ergoline dopamine agonist pramipexole in the
rasagaline in levodopa-treated patients with Parkinson disease treatment of advanced Parkinson’s disease: a double blind,
and motor fluctuations. Arch Neurol 2005; 62:241–8. placebo controlled, randomized, multicentre study. J Neurol
Parvizi J, Joseph J, Press DZ et al. Pathological laughter and crying Neurosurg Psychiatry 1999; 66:436–41.
in patients with multiple system atrophy – cerebellar type. Plazzi G, Corsini R, Provini F et al. REM sleep behavior disorder in
Mov Disord 2007; 22:798–803. multiple system atrophy. Neurology 1997; 48:1094–7.
p 08.qxd 3/10/08 9:38 AM Page 396
Pollak P, Tison F, Rascol O et al. Clozapine in drug-induced disease who were treated with ropinirole or levodopa. N Engl J
psychosis in Parkinson’s disease. A randomized, placebo Med 2000; 342:1484–91.
controlled study with open follow up. J Neurol Neurosurg Rasool C, Svendsen CN, Selkoe DJ. Neurofibrillary degeneration of
Psychiatry 2004; 75:689–95. cholinergic and noncholinergic neurons of the basal forebrain
Pontone G, Williams JR, Bassett SS et al. Clinical features in Alzheimer’s disease. Ann Neurol 1986; 20:482–8.
associated with impulse control disorders in Parkinson disease. Rasmussen KG, Russell JC, Kung S et al. Electroconvulsive therapy
Neurology 2006; 67:1258–61. for patients with major depression and probably Lewy body
Pool KD, Freeman FJ, Finitzo T et al. Heterogeneity in spasmodic dementia. J ECT 2003; 19:103–9.
dysphonia. Neurologic and voice findings. Arch Neurol 1991; Raudino F. Non motor off in Parkinson’s disease. Acta Neurol
48:305–9. Scand 2001; 104:312–15.
Potter NT, Meyer MA, Zimmerman AW et al. Molecular and Rauschka H, Colsch B, Bamann N et al. Late-onset metachromatic
clinical findings in a family with dentatorubral-pallidoluysian leukodystrophy. Genotype strongly influences phenotype.
atrophy. Ann Neurol 1995; 37:273–7. Neurology 2006; 67:859–63.
Powers JM, Schaumburg HH, Gaffney CL et al. Kluver–Bucy Ravina B, Pott M, Siderowf A et al. Donepezil for dementia in
syndrome caused by adreno-leukodystrophy. Neurology 1980; Parkinson’s disease: a randomized double-blind, placebo
30:1131–2. controlled crossover study. J Neurol Neurosurg Psychiatry
Pramstaller PP, Schlossmacher MG, Jacques TS et al. Lewy body 2005; 76:934–9.
Parkinson’s disease in a large pedigree with 77 Parkin Rebeiz J, Kolodney E, Richardson EJ. Corticodentatonigral
mutation carriers. Ann Neurol 2005; 58:411–22. degeneration with neuronal achromasia. Arch Neurol 1968;
Price BH, Gurvit H, Weintraud S et al. Neuropsychological patterns 18:20–33.
and language deficits in 20 consecutive cases of autopsy- Rees L, Lipsedge M, Ball C. Textbook of psychiatry. London: Arnold,
confirmed Alzheimer’s disease. Arch Neurol 1993; 50:931–7. 1996.
Price RA, Kidd KK, Cohen DJ et al. A twin study of Tourette Rees MI Andrew M, Jawad S et al. Evidence for recessive as well
syndrome. Arch Gen Psychiatry 1985; 42:815–20. as dominant forms of startle disease (hyperekplexia) caused by
Pringle CE, Hudson AJ, Munoz DJ et al. Primary lateral sclerosis. mutations in the alpha 1 subunit of the inhibitory glycine
Clinical features, neuropathology and diagnostic criteria. Brain receptor. Hum Mol Genet 1994; 3:2175–9.
1992; 115:495–520. Reeves AL, So EL, Sharbrough FW et al. Movement disorders
Priori A, Pesenti A, Cappellari A et al. Limb immobilization for the associated with the use of gabapentin. Epilepsia 1996;
treatment of focal occupational dystonia. Neurology 2001; 37:988–90.
57:405–9. Reeves RR, Liberto V. Treatment of essential blepharospasm with
Pryse-Phillips W, Johnson GJ, Larsen B. Incomplete manifestations quetiapine. Mov Disord 2003; 18:1072–3.
of myotonic dystrophy in a large kinship in Labrador. Ann Regeur L, Pakkenberg B, Fog R et al. Clinical features and long-
Neurol 1982; 11:582–4. term treatment with pimozide in 65 patients with Gilles de la
Quinn N. Multiple system atrophy – the nature of the beast. J Tourette’s syndrome. J Neurol Neurosurg Psychiatry 1986;
Rabey JM, Prokhorov T, Minlovitz A et al. Effect of quetiapine in Reider-Grosswasser I, Bornstein N. CT and MRI in late-onset
psychotic Parkinson’s disease patients: a double-blind labeled metachromatic leukodystrophy. Acta Neurol Scand 1987;
study of 3 month’s duration. Mov Disord 2007; 22:313–8. 75:64–9.
Rajput AH, Gibb WRG, Zhong XH et al. Dopa-responsive dystonia: Rewcastle NB, Ball MJ. Electron microscopic structure of the
pathological and biochemical observations in a case. Ann ‘inclusion bodies’ in Pick’s disease. Neurology 1968;
Neurol 1994; 35:396–402. 18:1205–13.
Rajput AH, Martin W, Saint-Hilaire M-H et al. Tolcapone improves Ribai P, Nguyen K, Hanhn-Barma V et al. Psychiatric and cognitive
motor function in Parkinsonian patients with the ‘wearing-off’ difficulties as indicators of juvenile Huntington’s disease onset
phenomenon: a double-blind, placebo-controlled, multicenter in 29 patients. Arch Neurol 2007; 64:813–19.
trial. Neurology 1997; 49:1066–71. Ricker K, Koch MC, Lehmann-Horn F et al. Proximal myotonic
Rajput A, Robinson CA, Rajput AH. Essential tremor course and myopathy: a new dominant disorder with myotonia, muscle
disability. Neurology 2004; 62:932–6. weakness and cataracts. Neurology 1994; 4:1448–52.
Rahkonen T, Eloniemi-Sulkava U, Rissanen S et al. Dementia with Ricker K, Koch MC, Lehmann-Horn F et al. Proximal myotonic
Lewy bodies according to the consensus criteria in a general myopathy: clinical features of a multisystem disorder similar
population aged 75 or older. J Neurol Neurosurg Psychiatry to myotonic dystrophy. Arch Neurol 1995; 52:25–31.
2003; 74:720–4. Ricker K, Grimm T, Koch MC et al. Linkage of proximal myotonic
Ramos-Arroyo MA, Moreno S, Valiente A. Incidence and mutation myopathy to chromosome 3q. Neurology 1999; 52:170–1.
rates of Huntington’s disease in Spain: experience of 9 years Ridha BH, Josephs KA, Rossor MN. Delusions and hallucinations in
of direct genetic testing. J Neurol Neurosurg Psychiatry 2005; dementia with Lewy bodies: worsening with memantine.
76:337–42. Neurology 2005; 65:481–2.
Rascol O, Brooks DJ, Corczyn AD et al. A five-year study of the Riley DE, Lang AE, Lewis A et al. Cortical-basal ganglionic
incidence of dyskinesia in patients with early Parkinson’s degeneration. Neurology 1990; 40:1203–12.
p 08.qxd 3/10/08 9:38 AM Page 397
References 397
Rinne J, Lee MS, Thompson PD et al. Corticobasal degeneration: a Ros R, Garre P, Hirano M et al. Genetic linkage of autosomal
clinical study of 36 cases. Brain 1994a; 117:1183–96. dominant progressive supranuclear palsy to 1q31.1. Ann
Rinne J, Daniel SE, Scaravilli F et al. The neuropathological Neurol 2005a; 57:634–1.
features of acanthocytosis. Mov Disord 1994b; 9:297–304. Ros R, Thobois S, Streichenberger N et al. A new mutation in the
Rinne UK, Bracco F, Chouza C et al. Cabergoline in the treatment tau gene, G303V, in early-onset familial progressive
of early Parkinson’s disease: results of the first year of supranuclear palsy. Arch Neurol 2005b; 62:1444–50.
treatment in a double-blind comparison of cabergoline and Rosen DR, Siddique T, Patterson D et al. Mutations in Cu/Zn
levodopa. Neurology 1997; 48:363–8. superoxide dismutase gene are associated with familial
Rippon GA, Scarmeas N, Gordon PH et al. An observational study amyotrophic lateral sclerosis. Nature 1993; 362:59–62.
of cognitive impairment in amyotrophic lateral sclerosis. Arch Rosler M, Anand R, Cicin-Sain A et al. Efficacy and safety of
Neurol 2006; 63:345–52. rivastigmine in patients with Alzheimer’s disease:
Rivest L, Lees AJ, Marsden CED. Writer’s cramp: treatment with international randomized controlled trial. BMJ 1999;
botulinum toxin injections. Mov Disord 1991; 6:55–9. 318:633–40.
Rizzo R, Gulisano M, Pavone P et al. Increased antistreptococcal Rosman NP, Kakulas BA. Mental deficiency associated with
antibody titers and anti-basal ganglia antibodies in patients muscular dystrophy: a neuropathological study. Brain 1966;
with Tourette’s syndrome: controlled cross-sectional study. 89:769–87.
J Child Neurol 2006; 21:747–53. Ross SJM, Graham N, Stuart-Green L et al. Progressive biparietal
Robbins TW, James M, Lange KW et al. Cognitive performance in atrophy: an atypical presentation of Alzheimer’s disease.
multiple system atrophy. Brain 1992; 115:271–91. J Neurol Neurosurg Psychiatry 1996; 61:388–95.
Roberts RO, Cha RH, Knopman DS et al. Postmenopausal estrogen Rozdilsky B, Cummings JN, Huston AF. Hallervorden–Spatz
therapy and Alzheimer disease: overall negative findings. disease: late infantile and adult types: report of two cases.
Alzheimer Dis Assoc Disord 2006; 20:141–6. Acta Neuropatholog 1968; 10:1–16.
Robertson EE, Le Roux A, Brown JH. The clinical differentiation of Rubinsztein JS, Rubinsztein DC, Goodburn S et al. Apathy and
Pick’s disease. J Ment Sci 1958; 104:1000–24. hypersomnia are common features of myotonic dystrophy.
Robertson MM, Trimble MR, Lees AJ. The psychopathology of J Neurol Neurosurg Psychiatry 1998; 64:510–15.
Gilles de la Tourette’s syndrome: a phenomenological analysis. Ryan SG, Sherman SL, Terry JC et al. Startle disease, or
Br J Psychiatry 1988; 152:388–90. hyperekplexia: response to clonazepam and assignment of the
Rockwood K, Mintzer J, Truyen L et al. Effects of a flexible gene (STHE) to chromosome 5q by linkage analysis. Ann
galantamine dose in Alzheimer’s disease: a randomized, Neurol 1992; 31:663–8.
controlled trial. J Neurol Neurosurg Psychiatry 2001; Sabbagh MN, Hake AM, Ahmed S et al. The use of memantine in
71:589–95. dementia with Lewy bodies. J Alzheimer’s Dis 2005; 7:285–9.
Rodriguez ME, Artieda O, Zubieta JL et al. Reflex myoclonus in Saenz-Lope E, Herranz-Tanarro FJ, Masdeu JC et al.
olivopontocerebellar atrophy. J Neurol Neurosurg Psychiatry Hyperekplexia: a syndrome of pathological startle responses.
1994; 57:316–19. Ann Neurol 1984; 15:36–41.
Rodriguez-Oroz MC, Zamarbide I, Guridi J et al. Efficacy of deep Sakai T, Mawatari S, Hiroshi I et al. Choreoacanthocytosis: clues
brain stimulation of the subthalamic nucleus in Parkinson’s to the clinical diagnosis. Arch Neurol 1981; 38:333–8.
disease 4 years after surgery: double-blind and open label Salen G. Cholesterol deposition in cerebrotendinous
evaluation. J Neurol Neurosurg Psychiatry 2004; 75:1382–5. xanthomatosis. Ann Intern Med 1971; 75:843–51.
Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in Sallee FR, Nesbitt L, Jackson C et al. Relative efficacy of
patients with Alzheimer’s disease: results of a US multicentre haloperidol and pimozide in children and adolescents with
randomized, double-blind, placebo-controlled study. Dementia Tourette’s disorder. Am J Psychiatry 1997; 154:1057–62.
1996; 7:293–303. Sallee FR, Kurlan R, Goetz CG et al. Ziprasidone treatment of
Rogers SL, Farlow MR, Doody RS et al. A 24-week, double-blind, children and adolescents with Tourette’s syndrome: a pilot
placebo-controlled trial of donepezil in patients with study. J Am Acad Child Adolesc Psychiatry 2000; 39:292–9.
Alzheimer’s disease. Neurology 1998; 50:136–45. Sasaki H, Fukazawa T, Yanagihara T et al. Clinical features and
Rojo A, Pernaute RS, Fontan A et al. Clinical genetics of natural history of spinocerebellar ataxia type 1. Acta Neurol
familial progressive supranuclear palsy. Brain 1999; Scand 1996; 93:64–71.
122:1233–45. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of
Romanelli MF, Morris JC, Ashkin K et al. Advanced Alzheimer’s apolipoprotein E allele epsilon 4 with late-onset and sporadic
disease is a risk factor for late-onset seizures. Arch Neurol Alzheimer’s disease. Neurology 1993; 43:1467–72.
1990; 47:847–50. Sawle GV, Leenders KL, Brooks DJ et al. Dopa-responsive dystonia:
Rondot P, Marchand MP, Dellatolas G. Spasmodic torticollis – [18F]dopa positron emission tomography. Ann Neurol 1991;
review of 220 patients. Can J Neurol Sci 1991; 18:143–51. 30:24–30.
Ropacki SA, Jeste DV. Epidemiology of and risk factors for Scahill L, Chappell PB, Kim YS et al. A placebo-controlled study of
psychosis of Alzheimer’s disease: a review of 55 studies guanfacine in the treatment of children with tic disorders and
published from 1990 to 2003. Am J Psychiatry 2005; attention deficit hyperactivity disorder. Am J Psychiatry 2001;
162:2022–30. 158:1067–74.
p 08.qxd 3/10/08 9:38 AM Page 398
Scahill L, Leckman JF, Schultz RT et al. A placebo-controlled trial Seltzer WK, Boss MA, Vieria-Saecker A-M et al. Expansion of a
of risperidone in Tourette’s syndrome. Neurology 2003; novel CAG trinucleotide repeat in the 5⬘ region of PPP2R2B is
60:1130–5. associated with SCA 12. Nat Genet 1999; 23:391–2.
Scarmeas N, Hadjigeorgiou GM, Papadimitrou A et al. Motor signs Serby M, Angrist B, Lieberman A. Mental disturbances during
during the course of Alzheimer disease. Neurology 2004; bromocriptine and lergotrile treatment of Parkinson’s disease.
63:95–82. Am J Psychiatry 1978; 135:1227–9.
Schaumburg HH, Powers JM, Raine CS et al. Seshadri S, Zornberg GL, Derby LE et al. Postmenopausal estrogen
Adrenoleukodystrophy. A clinical and pathological study of 17 replacement therapy and the risk of Alzheimer disease. Arch
cases. Arch Neurol 1975; 32:577–91. Neurol 2001; 58:435–40.
Schiller A, Wevers RA, Steenbergen GCH et al. Long-term course Shahed J, Poysky J, Kenney C et al. GPi deep brain stimulation for
of L-dopa responsive dystonia caused by tyrosine hydroxylase Tourette syndrome improves tics and psychiatric
deficiency. Neurology 2004; 63:1524–6. comorbidities. Neuroelogy 2007; 68:159–60.
Schimschock JR, Alvord EC, Swanson PD. Cerebrotendinous Shannon KM, Bennett JP, Friedman JH et al. Efficacy of
xanthomatosis: clinical and pathological studies. Arch Neurol pramipexole, a novel dopamine agonist, as monotherapy in
1968; 18:688–98. mild to moderate Parkinson’s disease. Neurology 1997;
Schlote W, Harzer K, Christomanou H et al. Sphingolipid activator 49:724–8.
protein 1 deficiency in metachromatic leukodystrophy with Shapiro E, Shapiro A, Fulop G et al. Controlled study of
normal arylsulfatase A activity. A clinical, morphological, haloperidol, pimozide, and placebo for the treatment of Gilles
biochemical and immunological study. Eur J Pediatr 1991; de la Tourette’s syndrome. Arch Gen Psychiatry 1989;
150:584–91. 46:722–30.
Schmidt A, Jabusch H-C, Altenmuller E et al. Dominantly Shapiro EG, Lockman LA, Knopman D et al. Characteristics of the
transmitted focal dystonia in families of patients with dementia in late-onset metachromatic leukodystrophy.
musician’s cramp. Neurology 2006; 67:691–3. Neurology 1994; 44:662–5.
Schneider JA, Watts RL, Gearing M et al. Corticobasal Shapiro E, Krivit W, Lockman L et al. Long-term effect of bone-
degeneration: neuropathologic and clinical heterogeneity. marrow transplant for childhood-onset X-linked
Neurology 1997; 48:959–69. adrenoleukodystrophy. Lancet 2000; 356:713–18.
Schneider LS, DeKosky ST, Farlow MR et al. A randomized, double- Shatunov A, Sambuughin N, Jankovic J et al. Genomewide scans
blind, placebo-controlled trial of two doses of Ginkgo biloba in North American families reveal genetic linkage of essential
extract in dementia of the Alzheimer’s type. Curr Alzheimer tremor to a region on chromosome 6p23. Brain 2006;
Res 2005; 2:541–51. 129:2318–31.
Schoenfeld M, Myers RH, Cupples LA et al. Increased rate of Sheehy MP, Marsden CD. Writer’s cramp – a focal dystonia. Brain
suicide among patients with Huntington’s disease. J Neurol 1982; 105:461–80.
Neurosurg Psychiatry 1984; 47:1283–7. Shevell M. Hallervorden and history. N Engl J Med 2003; 348:3–4.
Schofield PW, Tang M, Marder K et al. Alzheimer’s disease after Shiang R, Ryan SG, Zhu YZ et al. Mutations in the alpha-1 subunit
remote head injury: an incidence study. J Neurol Neurosurg of the glycine receptor cause the dominant neurologic
Psychiatry 1997; 62:119–24. disorder, hyperekplexia. Nat Genet 1993; 5:351–8.
Schols L, Amoiridis G, Epplen JT et al. Relations between genotype Shinotoh H, Calne DB, Snow B et al. Normal CAG repeat length in
and phenotype in German patients with the Machado–Joseph the Huntington’s disease gene in senile chorea. Neurology
disease mutation. J Neurol Neurosurg Psychiatry 1996; 1994; 44:2183–4.
61:466–70. Shy GM, Drager GA. A neurological syndrome associated with
Schols L, Amoiridis G, Buttner T et al. Autosomal dominant orthostatic hypotension: a clinico-pathologic study. Arch
cerebellar ataxia: phenotypic differences in genetically defined Neurol 1960; 2:511–27.
subtypes? Ann Neurol 1997a; 42:924–32. Siddique T, Figlewicz DA, Pericak-Vance MA et al. Linkage of a
Schols L, Gispert S, Vorgero M et al. Spinocerebellar ataxia type 2. gene causing familial amyotrophic lateral sclerosis to
Genotype and phenotype in German kindreds. Arch Neurol chromosome 21 and evidence of genetic-locus heterogeneity.
1997b; 54:1073–80. N Engl J Med 1991; 324:1381–4.
Schols L, Kruger R, Amoiridis G et al. Spinocerebellar ataxia type Siesling S, Vegter-van der Vlis M, Roos RAC. Juvenile Huntington’s
6: genotype and phenotype in German kindreds. J Neurol disease in the Netherlands. Pediatr Neurol 1997; 17:34–43.
Neurosurg Psychiatry 1998; 54:67–73. Singer HS, Hahn L-S, Moran TH. Abnormal dopamine uptake sites
Schwartz BL, Hashtroudi S, Herting RL et al. d-Cycloserine in postmortem striatum from patients with Tourette’s
enhances implicit memory in Alzheimer patients. Neurology syndrome. Ann Neurol 1991; 30:558–62.
1996; 46:420–4. Singer HS, Reiss AL, Brown JE et al. Volumetric MRI changes in
Scooter AJC, Bronzoua J, Witteman JCM et al. Estrogen use and basal ganglia of children with Tourette’s syndrome. Neurology
early onset Alzheimer’s disease: a population-based study. 1993; 43:950–6.
J Neurol Neurosurg Psychiatry 1999; 67:779–81. Singer HS, Giuliano JD, Hansen BH et al. Antibodies against
Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal human putamen in children with Tourette syndrome.
of levodopa. Neurology 1984; 34:249–51. Neurology 1998; 50:1618–24.
p 08.qxd 3/10/08 9:38 AM Page 399
References 399
Singer HS, Hong JJ, Yoo DY et al. Serum autoantibodies do not basal ganglia and cerebellum, with vertical gaze and
differentiate PANDAS and Tourette syndrome from controls. pseudobulbar palsy, vertical dystonia and dementia. Arch
Neurology 2005; 65:1701–7. Neurol 1964; 10:333–59.
Sinha S, Taly AB, Ravishankar S et al. Wilson’s disease: cranial Steinberger D, Korinthenberg R, Topka H et al. Dopa-responsive
MRI observations and clinical correlation. Neuroradiology dystonia: mutation analysis of GCH1 and analysis of
2006; 48:613–21. therapeutic doses of L-dopa. Neurology 2000; 55:1735–7.
Siren A, Legros B, Crahine L et al. Hyperekplexia in Kurdish Stern G. Parkinson’s disease. London: Arnold, 1990.
families: a possible GLRA1 founder mutation. Neurology 2006; Stern K. Severe dementia associated with bilateral symmetric
67:137–9. degeneration of the thalamus. Brain 1939; 62:157–71.
Sjorgen T, Sjorgen H, Lindgren AGH. Morbus Alzheimer and Stern M, Roffwarg H, Duvoisin R. The parkinsonian tremor in
Morbus Pick. Acta Psychiatr Neurol Scand 1952; sleep. J Nerv Ment Dis 1968; 147:202–10.
82(suppl.):1–152. Stevanin G, Durr A, David G et al. Clinical and molecular features
Snowden JS, Neary D, Mann DMA et al. Progressive language of spinocerebellar ataxia type 6. Neurology 1997; 49:1243–6.
disorder due to lobar atrophy. Ann Neurol 1992; 31:174–83. Stevanin G, Herman A, Brice A et al. Clinical and MRI findings in
Snowden JS, Pickering-Brown SM, Mackenzie IR et al. Progranulin spinocerebellar ataxia type 5. Neurology 1999; 53:1355–7.
gene mutations associated with frontotemporal dementia and Stewart WF, Kawas C, Corrada A et al. Risk of Alzheimer’s disease
progressive non-fluent aphasia. Brain 2006; 129:3091–102. and duration of NSAID use. Neurology 1997; 48:626–32.
Sobue G, Ueno-Natsukari I, Okamoto H et al. Phenotypic Stone LA, Jankovic J. The coexistence of tics and dystonia. Arch
heterogeneity of an adult form of adrenoleukodystrophy in Neurol 1991; 48:862–5.
monozygotic twins. Ann Neurol 1994; 36:912–15. Stracciari A, Tempestini A, Borghi A et al. Effect of liver
Soffer D, Benharroch D, Berginer V. The neuropathology of transplantation on neurological manifestations in Wilson’s
cerebrotendinous xanthomatosis: a case report and a review disease. Arch Neurol 2000; 57:384–6.
of the literature. Acta Neuropathol 1995; 90:213–20. Suhren AL, Bruyn GW, Tuyman JA. Hyperekplexia: a hereditary
Sorensen BF, Hamby WB. Spasmodic torticollis: results in 71 startle syndrome. J Neurol Sci 1966; 3:577–86.
surgically treated patients. Neurology 1966; 16:867–78. Sveinbjornsdottir S, Hicks AA, Jonsson T et al. Familial
Spencer T, Biederman J, Coffey B et al. A double-blind comparison aggregation of Parkinson’s disease in Iceland. N Engl J Med
or desipramine and placebo in children and adolescents with 2000; 343:1765–70.
chronic tic disorder and comorbid attention-deficit/ Swaiman KF. Hallervorden–Spatz syndrome and brain iron
hyperactivity disorder. Arch Gen Psychiatry 2002; 59: metabolism. Arch Neurol 1991; 48:1285–93.
649–56. Swanson PD, Cromwell LD. Magnetic resonance imaging in
Stanford PM, Halliday GM, Brooks WS et al. Progressive cerebrotendinous xanthomatosis. Neurology 1986; 36:124–6.
supranuclear palsy pathology caused by a novel silent Swedo SE, Leonhard HL, Garvey M et al. Pediatric autoimmune
mutation in exon 10 of the tau gene: expansion of the disease neuropsychiatric disorders associated with streptococcal
phenotype caused by tau gene mutations. Brain 2000; infections: clinical description of the first 50 cases. Am J
123:880–93. Psychiatry 1998; 154:264–71.
Starkstein SE, Preziosi TJ, Bolduc PL et al. Depression in Sydow O, Thobois S, Alesch F et al. Multicentre European study of
Parkinson’s disease. J Nerv Ment Dis 1990; 178:27–31. thalamic stimulation in essential tremor: a six year follow up.
Starkstein SE, Migliorelli R, Teson A et al. Prevalence and clinical J Neurol Neurosurg Psychiatry 2003; 74:1387–91.
correlates of pathological affective display in Alzheimer’s Takahashi H, Oyanagi K, Takeda S et al. Occurrence of 15-nm wide
disease. J Neurol Neurosurg Psychiatry 1995; 59:55–60. straight tubules in neocortical neurons in progressive
Starkstein SE, Chemerinski E, Sabe L et al. Prospective longitudinal supranuclear palsy. Acta Neuropathol 1989; 79:233–9.
study of depression and anosognosia in Alzheimer’s disease. Br Takahashi H, Ohama E, Suzuki S et al. Familial juvenile
J Psychiatry 1997; 171:47–52. parkinsonism: clinical and pathologic study in a family.
Starkstein SE, Jorge R, Mizrahi R et al. The construct of minor and Neurology 1994; 44:437–41.
major depression in Alzheimer’s disease. Am J Psychiatry 2005; Takahashi H, Yoshida K, Sugita T et al. Quetiapine treatment of
162:2086–93. psychotic symptoms and aggressive behavior in patients with
Starkstein WE, Jorge R, Mizrahi R et al. A prospective longitudinal dementia with Lewy bodies: a case series. Prog
study of apathy in Alzheimer’s disease. J Neurol Neurosurg Neuropsychopharmacol Biol Psychiatry 2003; 27:549–53.
Psychiatry 2006; 77:8–11. Takiyama T, Oyanagi S, Kawashima S et al. A clinical and
Starosta-Rubinstein S, Young AB, Kluin K et al. Clinical pathologic study of a large Japanese family with
assessment of 31 patients with Wilson’s disease: correlations Machado–Joseph disease tightly linked to the DNA markers on
with structural changes on magnetic resonance imaging. Arch chromosome 14q. Neurology 1994; 44:1302–8.
Neurol 1987; 44:365–70. Taly AB, Meenakshi-Sundaram S, Sinha S et al. Wilson disease:
Steele JC. Progressive supranuclear palsy. Brain 1972; description of 282 patients evaluated over 3 decades.
95:693–704. Medicine 2007; 86:112–21.
Steele JC, Richardson JC, Olszewski J. Progressive supranuclear Tam CW, Burton EJ, McKeith IG et al. Temporal lobe atrophy on
palsy: a heterogenous degeneration involving the brain stem, MRI in Parkinson disease with dementia: a comparison with
p 08.qxd 3/10/08 9:38 AM Page 400
Alzheimer disease and dementia with Lewy bodies. Neurology Tolosa ES, Klawans HC. Meige’s disease: a clinical form of facial
2005; 64:861–5. convulsion, bilateral and medial. Arch Neurol 1979; 36:635–7.
Tan E-K, Jankovic J. Genetic testing in Parkinson’s disease. Arch Toru M, Matsuda O, Makiguchi K et al. Single case study:
Neurol 2006; 63:1232–7. neuroleptic malignant syndrome-like state following a
Tandberg E, Larsen JP, Aarsland D et al. The occurrence of withdrawal of antiparkinsonian drugs. J Nerv Ment Dis 1981;
depression in Parkinson’s disease: a community-based study. 169:324–7.
Arch Neurol 1996; 53:175–9. de la Tourette G. Etude sur une affection nerveuse, characterisee
Tang B, Liu C, Shen L et al. Frequency of SCA1, SCA2, SCA3/MJD, par de ‘incoordination motrice, accompagne d’cholalie et de
SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in coprolalie. Arch Neurol (Paris) 1885; 9:158–200.
patients with hereditary spinocerebellar ataxia from Chinese Tourette’s Syndrome Study Group. Treatment of ADHD in children
kindreds. Arch Neurol 2000; 57:540–4. with tics: a randomized controlled trial. Neurology 2002;
Tang MX, Jacobs D, Stern Y et al. Effect of oestrogen during 58:527–36.
menopause on risk and age at onset of Alzheimer’s disease. Tsai CH, Chang FC, Su YC et al. Two novel mutations of the
Lancet 1996; 348:429–32. glycine receptor gene in a Taiwanese hyperekplexia family.
Tanner CM, Glantz RH, Klawans HL. Meige disease: acute and Neurology 2004; 63:893–6.
chronic anticholinergic effects. Neurology 1982; 32:783–5. Tsai G, Falk W, Gunther J et al. Improved cognition in Alzheimer’s
Tanner CM, Goldman SM, Lyons KE et al. Essential tremor in disease with short-term D-cycloserine treatment. Am J
twins: an assessment of genetic vs environmental Psychiatry 1999; 1567:467–9.
determinants of etiology. Neurology 2001; 57:1389–91. Tsuang D, Almquist EW, Lipe H et al. Familial aggregation of
Terry RD, Peck A, DeTeresa R et al. Some morphometric aspects of psychotic symptoms in Huntington’s disease. Am J Psychiatry
the brain in senile dementia of the Alzheimer type. Ann Neurol 2000; 157:1955–9.
1981; 10:184–92. Turner RS, Kenyon LC, Trojanowski JQ et al. Clinical,
Thacker EL, O’Reilly EJ, Weisskopf MG et al. Temporal relationship neuroimaging, and pathologic features of progressive
between cigarette smoking and risk of Parkinson disease. nonfluent aphasia. Ann Neurol 1996; 39:166–73.
Neurology 2007; 68:764–8. Ueyama H, Kumanoto T, Nagao S et al. Clinical and genetic
Thomas A, Iacono D, Luciano AL et al. Duration of amantadine studies of spinocerebellar ataxia type 2 in Japanese kindreds.
benefit on dyskinesia of severe Parkinson’s disease. J Neurol Acta Neurol Scand 1998; 98:427–32.
Neurosurg Psychiatry 2004; 75:141–3. Vadlamudi L, Westmoreland BF, Klass DW et al.
Thomas AJ, Burn DJ, Rowan EN et al. A comparison of the efficacy Electroencephalographic findings in Kufs disease. Clin
of donepezil in Parkinson’s disease with dementia and Neurophysiol 2003; 114:1738–43.
dementia with Lewy bodies. Int J Geriatr Psychiatry 2005; Valente EM, Bentivoglio AR, Cassetta E et al. DYT13, a novel
20:938–44. primary torsion dystonia locus, maps to chromosome
Thomas GR, Forbes JR, Roberts EA et al. The Wilson disease gene: 1p36.13–36.32 in an Italian family with cranial-cervical or
spectrum of mutations and their consequences. Nat Genet upper limb onset. Ann Neurol 2001; 49:362–6.
1995; 9:210–17. Van Bogaert L, Dewulf A. Diffuse progressive leukodystrophy in
Tijssen MA, Shiang R, van Deutekom J et al. Molecular genetic the adult with production of metachromatic degenerative
reevaluation of the Dutch hyperekplexia family. Arch Neurol products. Arch Neurol Psychiatry 1939; 42:1083–97.
1995; 52:578–82. Vance C, Al-Chalabi A, Ruddy D et al. Familial amyotrophic lateral
Timberlake WH, Vance MA. Four-year treatment of patients with sclerosis with frontotemporal dementia is linked to a locus on
parkinsonism using amantadine alone or with levodopa. Ann chromosome 9p13.2–21.3. Brain 2006; 129:868–76.
Neurol 1978; 3:119–28. Vanek Z, Jankovic J. Dystonia in corticobasal degeneration. Mov
Tinazzi M, Farina S, Bhatia K et al. TENS for the treatment of Disord 2001; 16:252–7.
writer’s cramp dystonia: a randomized, placebo-controlled Van Hove JLK, Steyaert J, Matthijs G et al. Expanded motor and
study. Neurology 2005; 64:1946–8. psychiatric phenotype in autosomal dominant Segawa
Tiraboschi P, Hansen LA, Alford M et al. Early and widespread syndrome due to GTP cyclohydrolase deficiency. J Neurol
cholinergic losses differentiate dementia with Lewy bodies Neurosurg Psychiatry 2006; 77:18–23.
from Alzheimer disease. Arch Gen Psychiatry 2002; Varga E, Sugerman AA, Varga V et al. Prevalence of spontaneous
59:946–51. oral dyskinesia in the elderly. Am J Psychiatry 1982;
Tiraboschi P, Salmon DP, Hansen LA et al. What best differentiates 139:329–31.
Lewy body from Alzheimer’s disease in early-stage dementia? Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P et al. ‘Panic
Brain 2006; 129:729–35. attacks’ in Parkinson’s disease. A long-term complication of
Tison F, Dartigues JF, Auriacombe S et al. Dementia in Parkinson’s levodopa therapy. Acta Neurol Scand 1993; 87:14–18.
disease: population-based study in ambulatory and Verbaan D, Marinus J, Visser M et al. Patient-reported autonomic
institutionalized individuals. Neurology 1995; 45:705–8. symptoms in Parkinson disease. Neurology 2007; 69:
Tolosa ES. Clinical features of Meige’s disease (idiopathic 333–41.
orofacial dystonia): a report of 17 cases. Arch Neurol 1981; Verhagen Metman L, Del Dotto P, van den Munckhof P et al.
38:147–51. Amantadine as treatment for dyskinesias and motor
p 08.qxd 3/10/08 9:38 AM Page 401
References 401
fluctuations in Parkinson’s disease. Neurology 1998; Watanabe H, Saito Y, Terao S et al. Progression and prognosis in
50:1323–6. multiple system atrophy. An analysis of 230 Japanese patients.
Verhagen Metman L, Morris MJ, Farmer C et al. Huntington’s Brain 2002; 125:1070–83.
disease: a randomized, controlled trial using the NMDA- Waters CH, Kurth M, Bailey P et al. Tolcapone in stable
antagonist amantadine. Neurology 2002; 59:694–9. Parkinson’s disease: efficacy and safety of long-term
Verny M, Jellinger KA, Hauw J-J et al. Progressive supranuclear treatment. Neurology 1997; 49:665–71.
palsy: a clinicopathological study of 21 cases. Acta Watts GF, Mitchell WD, Bending JJ et al. Cerebrotendinous
Neuropathol 1996; 91:427–31. xanthomatosis: a family study and pharmacotherapy. Q J Med
Verrips A, Hofsloot LH, Steenbergen GCH et al. Clinical and 1996; 89:55–63.
molecular genetic characteristics of patients with Wechsler AF, Verity A, Rosenschein S et al. Pick’s disease: a
cerebrotendinous xanthomatosis. Brain 2000a; 123: clinical computed tomographic and histologic study with
908–19. Golgi impregnation observation. Arch Neurol 1982;
Verrips A, van Engelen BGM, Wevers RA et al. Presence of diarrhea 39:287–90.
and absence of tendon xanthomas in patients with Weiden P, Bruun R. Worsening of Tourette’s syndrome due to
cerebrotendinous xanthomatosis. Arch Neurol 2000b; neuroleptic-induced akathisia. Am J Psychiatry 1987;
57:520–4. 144:504–5.
Vessie PR. On the transmission of Huntington’s chorea for 300 Weiner MF, Risser RC, Cullum CM et al. Alzheimer’s disease and
years – the Bures family group. J Nerv Ment Dis 1932; its Lewy body variant: a clinical analysis of postmortem
76:553–73. verified cases. Am J Psychiatry 1996; 153:1269–73.
Vidhailet M, Vercueil L, Houeto J-L et al. Bilateral deep-brain Weiner WJ, Nora LM. ‘Trick’ movements in facial dystonia. J Clin
stimulation of the globus pallidus in primary generalized Psychiatry 1984; 45:519–21.
dystonia. N Engl J Med 2005; 352:459–67. Weiner WJ, Nausieda PA, Glantz RH. Meige syndrome
Villani F, Gellera C, Spreafilo R et al. Clinical and molecular (blepharospasm-oromandibulardysonia) after long-term
findings in the first identified Italian family with neuroleptic therapy. Neurology 1981; 31:1555–6.
dentatorubral-pallidoluysian atrophy. Acta Neurol Scand 1998; Weiner WJ, Minagar A, Shulman LM. Quetiapine for L-dopa-
98:324–7. induced psychosis in PD. Neurology 2000; 54:1538.
Voon V, Hassan K, Zurowski M et al. Prevalence of repetitive and Weller M, Liedtke W, Petersen D et al. Very-late-onset
reward-seeking behaviors in Parkinson disease. Neurology adrenoleukodystrophy: possible precipitation of demyelination
2006a; 67:1254–7. by cerebral contusion. Neurology 1992; 42:367–70.
Voon V, Hassan K, Zurowski M et al. Prospective prevalence of Wenning GK, Shlomo YB, Megalhaes M et al. Clinical features and
pathologic gambling and medication association in Parkinson natural history of multiple system atrophy: an analysis of 100
disease. Neurology 2006b; 66:1750–2. cases. Brain 1994; 117:835–45.
Walker RH, Rasmussen A, Rudnicki D et al. Huntington’s disease- Wenning GK, Ben-Shlomo Y, Magalhaes M et al.
like 2 can present as chorea-acanthocytosis. Neurology 2002; Clinicopathological study of 35 cases of multiple system
61:1002–4. atrophy. J Neurol Neurosurg Psychiatry 1995; 58:160–6.
Walker Z, Grace J, Overshot N et al. Olanzapine in dementia with Wenning GK, Tison F, Elliott L et al. Olivopontocerebellar
Lewy bodies: a clinical study. Int J Geriatr Psychiatry 1999; pathology in multiple system atrophy. Mov Disord 1996;
14:459–66. 11:157–62.
Walsh PJ. Adrenoleukodystrophy: report of two cases with Wenning GK, Litvan I, Jankovic J et al. Natural history and survival
relapsing and remitting courses. Arch Neurol 1980; of 14 patients with corticobasal degeneration confirmed at
37:448–50. postmortem examination. J Neurol Neurosurg Psychiatry 1998;
Walshe JM, Yealland M. Wilson’s disease: the problem of delayed 64:184–9.
diagnosis. J Neurol Neurosurg Psychiatry 1992; 55:692–6. Wesnes KA, McKeith IG, Ferrara R et al. Effects of rivastigmine on
Waltz G, Harik SI, Kaufman B. Adult metachromatic cognitive function in dementia with Lewy bodies: a
leukodystrophy: value of computed tomographic scanning and randomized, placebo-controlled international study using the
magnetic resonance imaging of the brain. Arch Neurol 1987; cognitive drug research computerized assessment system.
44:225–7. Dement Geriatr Cogn Disord 2002; 13:183–92.
Warner TT, Lennox GG, Janota I et al. Autosomal-dominant Whitehouse P, Price D, Clark A et al. Alzheimer’s disease: evidence
dentatorubropallidoluysian atrophy. Mov Disord 1994; for a selective loss of cholinergic cells in the nucleus basalis.
9:289–96. Ann Neurol 1981; 10:122–6.
Warner TT, Williams LD, Walker RWH et al. A clinical and Whitehouse PJ, Price DL, Struble RG et al. Alzheimer’s disease and
molecular genetic study of dentatorubropallidoluysian atrophy senile dementia: loss of neurons in the basal forebrain.
in four European families. Ann Neurol 1995; 37:452–9. Science 1982; 215:1237–9.
Warren JD, Firgaira F, Thompson EM et al. The causes of sporadic Wilkins RH, Brody IA. Alzheimer’s disease. Arch Neurol 1969a;
and ‘senile’ chorea. Aust N Z J Med 1998; 28:429–31. 21:109–10.
Wasco W, Pettingell WP, Jondro PD et al. Familial Alzheimer’s Wilkins RH, Brody IA. Parkinson’s syndrome. Arch Neurol 1969b;
chromosome 14 mutations. Nat Med 1995; 1:848. 20:440–5.
p 08.qxd 3/10/08 9:38 AM Page 402
Wilson CM, Grace GM, Munoz DG et al. Cognitive impairment in de Yebenes JG, Sarasa JL, Daniel SE et al. Familial progressive
sporadic ALS. A pathologic continuum underlying a supranuclear palsy: description of a pedigree and review of the
multisystem disorder. Neurology 2001; 57:651–7. literature. Brain 1995; 118:1095–103.
Wilson SAK. Progressive lenticular degeneration: a familial Yoshii F, Tomiyasu H, Shinohara Y. Fluid attenuation inversion
nervous disease associated with cirrhosis of the liver. Brain recovery (FLAIR) images of dentatorubropallidoluysian
1912; 34:295–509. atrophy: case report. J Neurol Neurosurg Psychiatry 1998;
Winblad S, Lindberg C, Hansen S. Temperament and character in 65:396–9.
patients with classical myotonic dystrophy type 1 (DM-1). Younger DS, Rowland LP, Latov N et al. Lymphoma, motor neuron
Neuromuscul Disord 2005; 15:287–92. disease, and amyotrophic lateral sclerosis. Ann Neurol 1991;
Winkler GF, Young RR. Efficacy of chronic propranolol therapy in 29:78–86.
action tremors of the familial, senile or essential varieties. N Zandi PP, Carlson MC, Plassman BL et al. Hormone replacement
Engl J Med 1974; 290:984–8. therapy and incidence of Alzheimer disease in older women:
Wintzen AR, Lammers GJ, van Dijk JG. Does modafinil enhance the Cache County study. JAMA 2002; 288:2123–9.
activity of patients with myotonic dystrophy? A double-blind Zanettini R, Antonini A, Gatto G et al. Valvular heart disease and
placebo-controlled crossover study. J Neurol 2007; 254: the use of dopamine agonists for Parkinson’s disease. N Engl J
26–8. Med 2007; 356:39–46.
Wisniewski HM, Coblentz JM, Terry RD. Pick’s disease: a clinical Zappacosta B, Monza D, Meoni C et al. Psychiatric symptoms do
and ultrastructural study. Arch Neurol 1972; 26:97–108. not correlate with cognitive decline, motor symptoms, or CAG
Wojcieszek JM, Lang AE. Gestes antagonistes in the suppression repeat length in Huntington’s disease. Arch Neurol 1996;
of tics: ‘tricks for tics’. Mov Disord 1995; 10:226–8. 53:493–7.
Worth PF, Giunti P, Gardner-Thorpe C et al. Autosomal dominant Zhou B, Westaway SK, Levinson B et al. A novel pantothenate
cerebellar ataxia type III: linkage in a large British family to a kinase gene (PANK2) is defective in Hallervorden-Sptaz
7.6cM region on chromosome 15q14–21.3. Am J Hum Genet syndrome. Nat Genet 2001; 28:345–9.
1999; 65:420–6. Zhou YX, Takiyama Y, Igarashi S et al. Machado–Joseph disease in
Wright RB, Glantz RH, Butcher J. Hearing loss in myotonic four Chinese pedigrees: molecular analysis of 15 patients
dystrophy. Ann Neurol 1988; 23:202–3. including two juvenile cases and clinical correlations.
Wulff CH, Trojaborg W. Adult metachromatic leukodystrophy: Neurology 1997; 48:482–5.
neurophysiologic findings. Neurology 1985; 35:1776–8. Zhou Y-X, Wang G-X, Tang B-S et al. Spinocerebellar ataxia type
Yamamoto T, Hirano A. Nucleus raphe dorsalis in Alzheimer’s 2 in China: molecular analysis and genotype–phenotype
disease: neurofibrillary tangles and loss of large neurons. Ann correlation in nine families. Neurology 1998; 51:595–8.
Neurol 1985; 17:573–7. Zhukareva V, Mann D, Pickering-Brown S et al. Sporadic Pick’s
Yamashita I, Sasaki H, Yabe I et al. A novel locus for dominant disease: a tauopathy characterized by a spectrum of
cerebellar ataxia (SCA 14) maps to a 10.2–cM interval flanked pathological tau isoforms in gray and white matter. Ann
by D19S206 and D19S605 on chromosome 19q13.4–qter. Ann Neurol 2002; 51:730–9.
Neurol 2000; 48:156–63. Zubenko GS, Moosy J. Major depression in primary dementia:
Yardimci N, Karatas M, Kilinc M et al. Levetiracetam in Meige’s clinical and neuropathologic correlates. Arch Neurol 1998;
syndrome. Acta Neurol Scand 2006; 114:63–6. 45:1182–6.
Yasuda M, Nakamura Y, Kawamata T et al. Phenotypic Zweig RM, Ross CA, Hedreen JC et al. The neuropathology of
heterogeneity within a new family with the MAPT P301S aminergic nuclei in Alzheimer’s disease. Ann Neurol 1988;
mutation. Ann Neurol 2005; 58:920–8. 24:233–42.
p 09.qxd 3/10/08 9:39 AM Page 403
9
Congenital , developmental, and other
childhood-onset disorders
9.1 Sturge–Weber syndrome 403 9.11 Congenital rubella syndrome 413

9.2 Tuberous sclerosis 404 9.12 Fetal alcohol syndrome 414
9.3 Von recklinghausen’s disease (neurofibromatosis 9.13 Rett’s syndrome 414
type 1) 405 9.14 Autism 416
9.4 Down’s syndrome 407 9.15 Attention-deficit/hyperactivity disorder 418
9.5 Klinefelter’s syndrome 408 9.16 Developmental dysphasia 420
9.6 Fragile X syndrome 409 9.17 Developmental dyslexia 421
9.7 Velocardiofacial syndrome 410 9.18 Developmental dysgraphia 422
9.8 Lesch–Nyhan syndrome 411 9.19 Developmental dyscalculia 423
9.9 Bardet–Biedl syndrome 412 9.20 Developmental stuttering 423
9.10 Prader–Willi syndrome 412 References 424
9.1 STURGE–WEBER SYNDROME early adult years, the vast majority of patients will begin
having seizures in the first year of life. Simple partial motor
The Sturge–Weber syndrome, also known as the seizures are classic, and when these do occur the motor
Sturge–Weber–Dimitri syndrome or encephalotrigeminal activity is seen contralateral to the hemisphere affected by
angiomatosis, first described by William Sturge in 1879 calcification. Complex partial seizures may also occur, and
(Sturge 1879), is a rare disorder, characterized, classically, secondary generalization to grand mal seizures is common.
by a unilateral facial port-wine stain, epilepsy, hemiplegia, Mental retardation occurs in the majority of patients,
and mental retardation, and, on appropriate imaging, cere- and, in those with frequent seizures, there may be a decre-
bral cortical calcification in the hemisphere ipsilateral to the ment in cognitive abilities (Lichtenstein 1954; Petermann
port-wine stain (Chao 1959; Lichtenstein 1954; Pascual- et al. 1958).
Castroviejo et al. 1993; Petermann et al. 1958; Sujansky and Other symptoms that may occur include the following:
Conradi 1995a,b). hemiplegia and hemiatrophy, contralateral to the hemi-
sphere with calcification; an enlarged eye, present in
infancy, known as bupthalmos (‘ox-eye’); and glaucoma,
Clinical features which may occur at any age. It is also becoming apparent
that the majority of patients will also have stroke-like
The port-wine stain, also known as a nevus flammeus, is episodes (Maria et al. 1998).
present at birth, and, at a minimum, covers the area of dis- Cortical calcification may not become evident on imaging
tribution of the first division of the trigeminal nerve, until after the age of 2 years but becomes progressively more
including the upper eyelid; in some cases the stain may common with the passage of time, eventually appearing in
extend down the face to the second or even third division, approximately 90 percent of patients over the age of 20 years.
and may even reach the side of the neck. Although in most On skull films, the calcification appears in a classic curvilinear
cases the stain is unilateral, bilateral involvement may ‘trolly-track’ pattern, and on computed tomography (CT)
occur in a small minority; rarely there may be no port-wine scanning, as illustrated in Figure 9.1, there is a ‘serpiginous’
stain (Aydin et al. 2000; Taly et al. 1987). pattern. Magnetic resonance (MR) scanning, in addition to
Seizures occur in the great majority of patients and, revealing calcification, may also demonstrate leptomeningeal
although they can first appear at any time from infancy to vascular malformations (Benedikt et al. 1993).
p 09.qxd 3/10/08 9:39 AM Page 404
404 Congenital, developmental, and other childhood-onset disorders
uncommon, and that the diagnosis of Sturge–Weber

syndrome should never be made on the basis of a port-
wine stain alone.
Treatment
Given the association of seizures with intellectual decre-

ment, vigorous treatment with anti-epilepsy drugs (AEDs)
is imperative. In treatment-resistant cases, considera-
tion should be given to neurosurgical intervention
(Arzimanoglou et al. 2000). Given the possibility of stroke-
like episodes, many physicians will also treat patients pro-
phylactically with aspirin. The port-wine stain may be
treated with laser surgery; glaucoma is treated in the usual
way, and, in cases in which glaucoma is absent, yearly
monitoring of intraocular pressure is indicated. The treat-
ment of mental retardation is discussed in Section 5.5.
9.2 TUBEROUS SCLEROSIS
Figure 9.1 This unenhanced computed tomography scan Tuberous sclerosis, also known as Bourneville’s disease or
demonstrates the serpiginous calcification seen in the Sturge–Weber epiloia, is a rare genetic disorder presenting, classically, with
syndrome. (Reproduced from Gillespie and Jackson 2000.) the triad of seizures, mental retardation, and a particular
skin lesion known as adenoma sebaceum (Alsen et al. 1994;
Critchley and Earl 1932; Devlin et al. 2006; Lagos and Gomez
1967; Monaghan et al. 1981; Pampiglione and Moynahan
Course 1976; Ross and Dickerson 1943; Webb and Osborne 1995).
Although brain lesions, known as tubers, figure most
With the exception of intellectual decrement seen in some prominently in this disorder, it must be borne in mind that
patients with frequent seizures, and of any decrements seen tuberous sclerosis is a systemic disease, with additional
secondary to stroke-like episodes, the overall course is for lesions in the skin, eye, kidneys, heart, and lungs.
the most part static.
Neuropathologically (Roizen et al. 1972; Weber 1929; In most cases, the first sign of tuberous sclerosis is the pres-
Wohlwill and Yakovlev 1957), the hallmark of the disorder ence of hypomelanotic macules, evident in 90 percent or
is a unilateral leptomeningeal angiomatosis, primarily more of affected infants. These macules, which are best seen
venular in type, which, though often confined to the occi- with Wood’s light, range in size from a few millimeters to
pitoparietal area, may extend forward to the frontal area 2 or 3 cm, and are sometimes oval shaped, giving rise to the
and, in some cases, may be bilateral (Bebin and Gomez name ‘ash leaf’ spots. Additional skin lesions include ade-
1988). In the subjacent cortex there is calcification in the noma sebaceum and what are known as ‘shagreen patches’.
walls of small arteries, free calcium deposits within the Adenoma sebaceum typically appears gradually in early
brain parenchyma, and neuronal loss and gliosis. childhood and is present in over 90 percent of those over
The vast majority of cases are sporadic. the age of 4 years; it consists of multiple minute facial nod-
ules, generally arranged in a symmetrical butterfly shape
over the nose, cheeks, and chin, with, typically, sparing of
Differential diagnosis the upper lip. Shagreen patches are leathery-appearing
areas, most frequently seen in the lumbar region.
The combination of a facial port-wine stain, seizures, and Seizures may first appear at any point in childhood, ado-
cortical calcification is pathognomonic for Sturge–Weber lescence, or even late adult years (Gutowski and Murphy
syndrome. In those rare cases in which the port-wine stain 1992). Seizures appearing in the first 2 years of life are gen-
is absent, consideration is given to celiac disease, character- erally of the ‘salaam’ or infantile spasm type (Roth and
ized by occipital calcification and seizures. It must also be Epstein 1971). Other seizure types, especially complex par-
borne in mind that isolated port-wine stains are not at all tial and grand mal seizures, may also appear, not only, as it
p 09.qxd 3/10/08 9:39 AM Page 405
9.3 Von Recklinghausen’s disease (neurofibromatosis type 1) 405
were, to replace infantile spasms but also as the first seizure matter: in some cases subependymal tubers may protrude
type in those patients whose seizures begin at a later age. into the ventricle and may be so numerous that they
Mental retardation is seen in approximately two-thirds impart a ‘candle guttering’ appearance to the surface of the
of patients. Furthermore, and especially in those with fre- ventricle (Richardson 1991). Tubers, as noted, typically
quent seizures, there may be a progressive cognitive decline, undergo calcification, and the calcification may be so pro-
thus constituting a dementia. Autism may occur in up to nounced as to produce ‘brain stones’ (Yakovlev and
one-quarter of all patients (Alsen et al. 1994; Gutierrez et al. Corwin 1939). Some tubers may undergo malignant trans-
1998; Lawlor and Maurer 1987), and is more likely in those formation into astrocytomas (Goh et al. 2004; Morimoto
both with tubers in the temporal lobe and frequent seizures and Mogami 1986), and tubers (or astrocytomas) adjacent
of temporal lobe onset (Bolton and Griffiths 1997; Bolton to the foramen of Monro may cause occlusion and non-
et al. 2002). In a very small minority of patients, hydro- communicating hydrocephalus.
cephalus may occur secondary to occlusion of the foramen
of Monro by a tuber or astrocytoma, with the development
of further cognitive decline accompanied by headache and Differential diagnosis
gait disturbance.
Other lesions include subungual fibromas, retinal The classic triad of seizures, mental retardation, and ade-
phakomas, renal angiomyolipomas and cysts, cardiac rhab- noma sebaceum is pathognomonic. As noted earlier, how-
dolipomas, and pulmonary cysts. ever, about one-third of patients will have normal
Neuroimaging reveals the distinctive tubers. Tubers typ- intelligence, and such cases may present with seizures
ically undergo calcification and, when this occurs, they are alone in adult years (Kofman and Hyland 1959). In these
immediately apparent on skull radiographs or CT scanning. cases, diagnostic suspicion may be aroused by skin lesions,
Magnetic resonance scanning also reveals calcified tubers such as ash leaf spots or adenoma sebaceum, or by finding
and may also identify uncalcified ones, which may be tubers on imaging.
missed on CT scanning. The electroencephalogram (EEG)
is marked by slowing and interictal epileptiform activity,
which is often multifocal. Genetic testing is available. Treatment
Seizure control is imperative. Infantile spasms may

Course respond to adrenocorticotropic hormone (ACTH) or viga-
batrin. Partial or grand mal seizures may be treated with
Tuberous sclerosis is a gradually progressive disease. Those the usual AEDs, with, however, some caveats. In some
with an early childhood onset, especially those with severe cases renal failure may occur, making the use of AEDs that
epilepsy, rarely survive for more than 15 years, eventually undergo primary renal excretion problematic. Other
succumbing to status epilepticus or cardiac or renal com- AEDs, such as carbamazepine (Weig and Pollack 1993),
plications. In adult-onset cases, the progression tends to be may precipitate cardiac block in patients with cardiac
much slower, and the disease may be compatible with a lesions. In treatment-resistant cases in which there is a sin-
normal lifespan. gle, well-localized epileptogenic zone, surgical resection
may be considered (Jarrar et al. 2004).
Obstructive hydrocephalus may respond to neurosur-
Etiology gical intervention. Tubers that have undergone transfor-
mation into astrocytomas may also respond to treatment
Tuberous sclerosis occurs secondary to mutations in either with rapamycin (Franz et al. 2006).
one of two genes: TSC1 is located on chromosome 9 and Mental retardation and autism are treated in the usual
codes for a protein known as hamartin; TSC2 is on chromo- fashion, as discussed in Sections 5.5 and 9.14 respectively.
some 16 and codes for tuberin (European Chromosome 16 When severe, adenoma sebaceum may be surgically
Tuberous Sclerosis Consortium 1993; Fryer et al. 1987; treated, but recurrences are the rule. Genetic counselling
Hyman and Whittemore 2000). Hamartin and tuberin should be offered, not only to patients but also, given that
function as tumor suppressor proteins, and it is presumably some cases (perhaps manifest only by subtle skin lesions)
a lack of this normal ‘suppression’ that allows for the devel- may go undetected, to relatives.
opment of the tubers and other manifestations of the
disease. Approximately two-thirds of cases represent spon-
taneous mutations, whereas in the remaining one-third the 9.3 VON RECKLINGHAUSEN’S DISEASE
disease is inherited on an autosomal dominant basis. (NEUROFIBROMATOSIS TYPE 1)
Tubers are nodules of varying size, ranging from millime-
ters to 2 cm or more, and are composed of glia and enlarged, Von Recklinghausen’s disease, also known as neurofibro-
‘ballooned’, neuronal elements. They are typically found matosis type 1 or ‘peripheral’ neurofibromatosis, is a not
both in the cerebral cortex and in the subependymal white uncommon genetic disorder characterized by skin lesions
p 09.qxd 3/10/08 9:39 AM Page 406
(such as café au lait spots), peripheral neurofibromas, and, Course

in a minority, central nervous system tumors, such as optic
nerve gliomas. Attention-deficit/hyperactivity disorder Neurofibromas typically show a period of progression in
(ADHD), developmental disabilities, and, in a small minor- early adolescence, whereas in adult years, although pro-
ity, mental retardation may also occur. gression may still occur, there are typically long periods of
quiescence. Pregnancy and the use of oral contraceptives
may prompt renewed growth. Most patients live a normal
Clinical features lifespan; exceptions may occur in those who develop any of
the various tumors noted earlier.
The cardinal features of von Recklinghausen’s disease are
café au lait spots and neurofibromas (Huson et al. 1988).
Café au lait spots are generally present in infancy and grow Etiology
in number and size throughout adolescence. Neurofibromas
appear around puberty, are generally either pedunculated or Von Recklinghausen’s disease occurs secondary to any of a
sessile, and may be as large as a walnut or no bigger than a large number of different mutations in a gene on chromo-
grain of sand; they typically appear on the trunk or the some 17 (Wallace et al. 1990) that codes for a protein known
extremities, generally sparing the face, and range in num- as neurofibromin (von Deimling et al. 1995). About half of
ber from a few up to literally hundreds. Large plexiform cases represent spontaneous mutations, whereas the other
neurofibromas may occasionally occur, and these may be half are inherited on an autosomal dominant basis. Of note,
extremely disfiguring. Neurofibromas may be painful to although penetrance is near 100 percent, expressivity is quite
strong touch and at times spontaneous neuralgic pains may variable, and there is considerable inter- and intrafamilial
occur. In a small minority, neurofibromas may appear on phenotypic variability. Neurofibromin acts as a tumor sup-
the central portion of peripheral nerves, and in such cases pressor protein, and it is apparently a deficiency of such sup-
compression of adjacent structures may occur. pression by the abnormal protein that allows for the clinical
Other features found in adults include Lisch nodules and manifestations of the disease.
axillary freckling. Lisch nodules (Lubs et al. 1991) are small, Neurofibromas constitute the neuropathologic hallmark
yellow-brown spots on the iris that are at times visible only of the disease, and these may occur peripherally, where they
by slit-lamp examination. Axillary freckling, although are composed of fibroblasts and Schwann cells, or centrally,
found only in a minority, is virtually pathognomonic of in which case one finds fibroblasts and astrocytes. Within
von Recklinghausen’s disease. Seizures may occur in a very the central nervous system one also finds scattered glial
small minority (Kulkantrakorn and Geller 1998). nodules, neuronal heterotopias, and areas of cortical dys-
Central nervous system tumors, such as astrocytomas, plasia (Rosman and Pearce 1967), and, in the white matter,
meningiomas, and, most commonly, optic nerve gliomas, areas of spongiosus (DiPaolo et al. 1995). Presumably these
may occur (Creange et al. 1999; Guillamo et al. 2003; abnormalities account for the T2 hyperintensities seen on
Listernick et al. 1989; Rodriguez and Barthrong 1966). MR scanning and for the ADHD, developmental disabilities,
Peripheral neurofibromas may undergo sarcomatous change, and mental retardation. As noted earlier, various tumors,
an event heralded both by an increase in size and by the such as optic nerve gliomas, astrocytomas, and meningiomas,
occurrence or exacerbation of pain. Other malignancies may also occur.
seen in von Recklinghausen’s disease include pheochromo-
cytoma, Wilm’s tumor, and various leukemias. Differential diagnosis
Attention-deficit/hyperactivity disorder occurs in roughly
one-third of patients; various developmental disabilities, The diagnosis is self-evident when numerous neurofibro-
such as developmental dyslexia, also occur in about one- mas are present. When these are lacking, the diagnosis may
third of patients and appear more likely in males; and mental depend on dermatologic findings, such as café au lait spots
retardation is seen in a little over 5 percent (Hyman et al. or axillary freckling. Importantly, isolated café au lait spots
2005). Precocious puberty may occur in a small minority. are not uncommon and, hence, to make the diagnosis it is
Magnetic resonance scanning will reveal central nervous necessary to find six or more of these measuring at least
system tumors. Of note, in children and adolescents there 0.5 cm in diameter in children and 1.5 cm in adults.
may also, on T2-weighted scans, be multiple areas of Von Recklinghausen’s disease must be differentiated
increased signal intensity in the brainstem, basal ganglia, from neurofibromatosis type 2, also known as ‘central’
thalamus, and cerebral and cerebellar white matter neurofibromatosis. Neurofibromatosis type 2 is a very rare
(Guillamo et al. 2003), which, in some (Feldmann et al. disorder that is clinically and genetically distinct: clinically,
2003; Hyman et al. 2003; North et al. 1994), but not all it presents with intracranial tumors, classically bilateral
(Legius et al. 1995), studies, have been correlated with the acoustic neuromas, and genetically, it results from muta-
occurrence of cognitive deficits. Of interest, the number of tions in a gene on chromosome 22 (Rouleau et al. 1987);
these areas within the gray matter structures actually cutaneous manifestations in neurofibromatosis type 2 are
decreases with age (DiMario et al. 1998; Hyman et al. 2003). either absent or very scant.
p 09.qxd 3/10/08 9:39 AM Page 407
9.4 Down’s syndrome 407
Treatment memory, disorientation to time, and reduced verbal out-

put (Lai and Williams 1989)
Given that surgery to neurofibromas may predispose to sar- Seizures are common in Down’s syndrome and occur in
comatous change, excision should be reserved for disfigur- a bimodal pattern: among infants and children, infantile
ing peripheral neurofibromas or for central neurofibromas spasms and grand mal seizures may be seen, whereas in
that are causing compression injury. Other tumors are adults, simple or complex partial seizures are more com-
treated in the usual fashion; bilateral optic gliomas may also mon, with a somewhat smaller percentage also having grand
be subjected to radiation treatment. Attention-deficit/hyper- mal seizures (Prasher 1995; Pueschel et al. 1991). During
activity disorder, developmental disabilities, and mental the adult years, the prevalence of seizures increases dra-
retardation are treated in the usual fashion. Genetic coun- matically with increasing age, and close to 50 percent of all
selling should be offered, and it should be stressed to patients patients over 50 years will experience them (McVicker et al.
with mild symptoms that, given the considerable intrafamil- 1994): indeed, among those with dementia, the figure
ial phenotypic heterogeneity, should they have children then approaches 80 percent (Lai and Williams 1989).
those children may be severely affected by the disease. Hypothyroidism may occur in both children and adults
with Down’s syndrome, and in adults this is often associ-
ated with the presence of anti-thyroid antibodies (Chinta
9.4 DOWN’S SYNDROME 1988; Karlsson et al. 1998).
Depression may occur in a minority (Collacott et al.
Down’s syndrome, first described by John Langdon Down 1992), and in some cases this may be so severe as to cause a
in 1866 (Down 1866), is one of the most common causes of dementia (Warren et al. 1989).
mental retardation in the United States. It is also known as Congenital heart disease, such as ventriculoseptal defect
trisomy 21; however, this synonym may not be appropriate or patent ductus arteriosus, is found in up to 40 percent of
because, although about 95 percent of cases are due to tri- patients. Emboli, some of which may be septic, may arise
somy 21, the remainder, which are clinically indistinguish- from the heart, and stroke may occur (Pearson et al. 1985);
able, occur as a result of translocations. in cases with multiple strokes, a dementia may be seen
(Collacott et al. 1994). Other abnormalities seen in Down’s
Clinical features syndrome include duodenal obstruction, intestinal steno-
sis, megacolon, leukemia, and atlanto-axial instability. This
The appearance of patients is so characteristic as to allow a last abnormality is very important to keep in mind, as it
diagnosis in infancy. The head is small with a flattened may lead to cord compression. Obstructive sleep apnea may
occiput. The palpebral fissures show a distinctive oblique also occur, and may cause daytime fatigue and irritability.
slant, and epicanthal folds are present. The bridge of the Although the diagnosis can usually be reliably made on
nose is broad, the mouth is generally small, and the tongue, clinical grounds alone, karyotyping is indicated, not only
which is typically enlarged, often protrudes. The patients to confirm the diagnosis but also to identify the small pro-
tend to be of short stature. The hands are broad and fore- portion of cases that occur secondary to a translocation.
shortened, and the fifth finger is often curved inward; fur-
ther, the palms often display a transverse or ‘Simian’ crease.
The first and second toes are often separated by a wide gap.
Course
The external genitalia are often small; puberty may be
The average age of death is 12 years, with most of those
delayed and fertility in males is often reduced.
who die in childhood or adolescence succumbing to car-
Mental retardation ranges from mild to severe, but, in
diac complications (Baird and Sadovnik 1987). Among
many cases, social skills are more advanced than cognitive
those who survive into adult years, roughly half will live to
ones, and patients with Down’s syndrome tend to be affable,
the seventh decade (Baird and Sadovnik 1988) whereas the
outgoing, and pleasant. A small minority will suffer from
other half will succumb to Alzheimer’s disease, usually
autism (Lund and Munk-Jorgensen 1988).
within 5 years of its onset (Evenhuius 1990).
Dementia due to Alzheimer’s disease occurs in adults
with Down’s syndrome (Collacott et al. 1992; Jervis 1948;
Lai and Williams 1989; Lund and Munk-Jorgensen 1988), Etiology
with an ever-increasing prevalence as patients pass the age
of 20 years, rising to close to 50 percent in those who live to Approximately 95 percent of cases of Down’s syndrome
the fifth decade and beyond. In contrast to the stable level are secondary to trisomy 21 due to non-disjunction during
of reduced cognitive performance characteristic of the meiosis (Petersen and Luzzatti 1965; Stoll et al. 1998). In
mental retardation, there is a gradual deterioration in almost all cases this non-disjunction occurs in the mother,
functioning (Wisniewski et al. 1985a): those with severe and the risk for this rises dramatically with age, from about
retardation may become more apathetic and less sociable, 1 in 1000 in the early twenties to almost 1 in 100 at the age
whereas in those with only a mild or moderate degree of of 40 years and 1 in 50 at the age of 45 years. In a very small
retardation, the dementia may present with decreased minority, mosaicism may occur, and cases secondary to
p 09.qxd 3/10/08 9:39 AM Page 408
Down’s syndrome due to trisomy 21 should be informed

of the high risk of Down’s syndrome in future children.
The treatment of mental retardation, seizures, dementia,
and depression is discussed in Sections 5.5, 7.3, 5.1, and 6.1
respectively. When Alzheimer’s disease occurs, a trial of
donepezil is reasonable (Prasher et al. 2002). Given the
frequency with which hypothyroidism occurs, it is appro-
priate to screen patients with a thyroid profile on a yearly
basis. All patients should have a CT scan of the
atlanto-axial junction, and if there is evidence of instability
appropriate restrictions on contact and similar sports
should be instituted.
9.5 KLINEFELTER’S SYNDROME
Klinefelter’s syndrome, found only in males, occurs second-

ary to the presence of one or more extra X chromosomes and,
Figure 9.2 Note the marked hypoplasia of the superior temporal when fully expressed, is characterized by a tall stature,
gyrus in this case of Down’s syndrome. (Reproduced from Graham hypogonadism, and infertility. Developmental disabilities
and Lantos 1996.) may occur, and a very small minority may have mental
retardation.
this tend to be characterized by mild symptomatology. In
the remaining 5 percent of cases not due to trisomy 21, there
is a translocation, generally from chromosome 21 to 14: such
Clinical features
translocations may occur sporadically or may be inherited
The classic clinical picture (Ratcliffe et al. 1982) of
from either parent.
Klinefelter’s syndrome becomes apparent in post-pubertal
The brain is small and rounded, with a flattened occiput.
males and is characterized, as noted, by tall stature, hypo-
The overall sulcal pattern is often simple and undeveloped,
gonadism, and infertility. Excessive height is primarily
and the superior temporal gyrus is often quite hypoplastic,
caused by a late closure of the epiphyseal plates and results
as illustrated in Figure 9.2. The number of neurons in the
from increased leg length. Hypogonadism manifests with
cerebral cortex is reduced (Ross et al. 1984), and on the
gynecomastia, a female escutcheon, and a small penis and
remaining neurons there is typically a reduced number of
testes; although most patients have a heterosexual orienta-
dendritic spines (Suetsugu and Mehraein 1980). As noted
tion, libido is often low and erectile dysfunction may occur
earlier, Alzheimer’s disease is common in Down’s syndrome
(Pasqualini et al. 1957). Moderate to severe azoospermia is
and, among patients over 40 years, senile plaques and neu-
present, which accounts for the infertility. Importantly, in
rofibrillary tangles (Hyman et al. 1995; Schochet et al. 1973)
an unclear but probably significant proportion of patients,
are almost universal (Wisniewski et al. 1985b). Presumably,
this classic picture is not present, and some patients may
the appearance of Alzheimer’s disease in this population is
come to clinical attention only during a work-up for infer-
due to the fact that the gene for the amyloid precursor pro-
tility or erectile dysfunction.
tein is on chromosome 21, and the extra gene leads to an
Although the vast majority of patients have an IQ
overproduction of amyloid.
within the normal range (Ratcliffe et al. 1982), mental
retardation may be seen in a minority, and developmental
Differential diagnosis disabilities, such as developmental dysphasia or develop-
mental dyslexia, have been noted; rarely, seizures may
The diagnosis of Down’s syndrome is evident on inspection occur (Graham et al. 1988; Khalifa and Struthers 2002;
and difficult to confuse with other causes of mental retarda- Pasqualini et al. 1957; Swanson and Stipes 1969; Tatum
tion. In cases in which dementia supervenes in adult years, et al. 1998; Wakeling 1972). The presence of more than two
although the most common cause is Alzheimer’s disease, X chromosomes is associated with more severe retardation
consideration must also be given to dementia secondary to (Forsman 1970). In those who are retarded, the personality
hypothyroidism, depression, and, rarely, a multi-infarct may be characterized by a sullen sort of withdrawal, with a
dementia. liability to hostile outbursts (Hunter 1969).
There is an uncertain association between Klinefelter’s
Treatment syndrome and various other disorders, such as alcoholism
(Nielsen 1969), bipolar disorder (Everman and Stoudemire
If karyotyping reveals a translocation, all first-degree rela- 1994), and schizophrenia (Nielsen 1969; Pomeroy 1980;
tives should be offered testing. Mothers of patients with Roy 1981).
p 09.qxd 3/10/08 9:39 AM Page 409
9.6 Fragile X syndrome 409
Other associated disorders include Hashimoto’s thy- classic picture of mental retardation with a characteristic
roiditis, acute myeloid leukemia, diabetes mellitus, chronic facial dysmorphism is far more common and severe in
obstructive pulmonary disease, and breast cancer. males, females may also be affected.
Pre-pubertally, hormone levels are generally within
normal limits, but after puberty, abnormalities become
apparent with a low testosterone level and an elevated Clinical features
follicle-stimulating hormone level.
Karyotyping will reveal one or more extra X chromo- The classic syndrome (Baumgardner et al. 1995; Finelli et al.
somes. 1985; Wisniewski et al. 1985c), as noted, is most evident in
males and is characterized by mental retardation, a charac-
teristic dysmorphic facies, and macro-orchidism. Mental
Course retardation ranges from mild to severe. Autistic features,
such as gaze avoidance, are present in most cases, and a
The evolution of the clinical picture is usually complete by
minority will have the full syndrome of autism; ADHD is also
adult years.
seen in a minority. Dysmorphic features include a long, nar-
row face, prognathism, a high forehead, and large ears (De
Etiology Arce and Kearns 1984). Macro-orchidism is a constant
feature in post-pubertal males and may also be seen in a
Klinefelter’s syndrome occurs secondary to non-disjunction minority during childhood (Chudley and Hagerman 1987;
during either spermatogenesis or oogenesis, resulting in the De Arce and Kearns 1984). Seizures, either complex partial
presence of one or more extra X chromosomes. The most or grand mal, occur in a significant minority (Finelli et al.
common karyotype is 47,XXY; in about 10 percent of 1985; Musumeci et al. 1999; Sabaratnam et al. 2001;
cases, mosaicism is present, with a 46,XY/47,XXY karyo- Wisniewski et al. 1985c). Other features include hyperexten-
type. Rarely, more severe abnormalities may occur, yield- sible joints and mitral valve prolapse (Chudley and
ing karyotypes such as 48,XXXY or 49,XXXXY. Hagerman 1987), and in a minority there may also be hyper-
Although much of the symptomatology of Klinefelter’s reflexia and Babinski signs (Finelli et al. 1985). Incomplete
syndrome can be explained on the basis of primary hypo- penetrance may occur in males, and some may be of normal
gonadism secondary to a progressive fibrosis of the testes, intelligence; in these cases, however, elements of develop-
it is clear that hypogonadism alone is not sufficient to mental dysphasia, with both receptive and expressive deficits,
explain all of the neuropsychiatric features of the disorder, are common, and most post-pubertal males will also have
such as mental retardation (Pasqualini et al. 1957; macro-orchidism.
Wakeling 1972). Recent MRI studies have indicated a mild Females with the fragile X syndrome tend to have much
global cerebral atrophy (Giedd et al. 2007; Itti et al. 2006); milder cases. Mental retardation is seen in only about 50
however, the mechanism underlying this is not certain. percent and tends to be of mild degree; facial dysmorphism
is seen in only a small minority.
Genetic testing is available.
Course
When fully expressed, the clinical picture in adults is dis-
tinctive. Diagnostic difficulties may arise in partial cases, Although there is some evidence that, in males, intellectual
and the correct diagnosis may be revealed only incidentally functioning may undergo a decline in late childhood or
during a work-up for infertility or erectile dysfunction. early adolescence (Dykens et al. 1989), it appears that, for
the most part, the clinical picture becomes set in adoles-
Treatment cence and generally remains stable thereafter.
Testosterone treatment improves libido and erectile function,

and tends to help with energy and overall outlook (Nielsen Etiology
et al. 1988); infertility, however, persists. Gynecomastia may
require surgical correction. Developmental disabilities and The fragile X syndrome occurs secondary to mutations in the
mental retardation are treated in the usual fashion. FMR1 gene on the long arm of the X chromosome (Verkerk
et al. 1991), which codes for a protein known as the fragile X
mental retardation-1 protein (FMRP). This gene normally
9.6 FRAGILE X SYNDROME contains a sequence of CGG trinucleotide repeats containing
anywhere from 5 to 55 triplets. An expansion of this
The fragile X syndrome is one of the most common causes sequence to include from 55 to 200 repeats is known as a pre-
of mental retardation in developed countries. Although the mutation, whereas expansions to over 200 triplets constitute
p 09.qxd 3/10/08 9:39 AM Page 410
full mutations. Patients with pre-mutations do not develop the most common of the microdeletion syndromes, being
the fragile X syndrome; however, those with full mutations found in up to 1 in 4000 live births.
do. In those with full mutations, transcription of the gene
fails and levels of functional FMRP are low or undetectable.
The relatively minor symptomatology seen in females is due Clinical features
to random inactivation of the X chromosome, which allows
for some production of FMRP. The fragile X syndrome The facial dysmorphism is characterized by hypertelorism,
derives its name from the fact that when the cells of patients a large, bulbous nose with a squared-off nasal root, and
are cultivated in a medium deficient in thymidine and folic micrognathia. Most patients have a degree of velopharyn-
acid, a fragile site will be found on the long arm of the X chro- geal insufficiency, leading to a hypernasal voice.
mosome (Sutherland 1977), which, as might be expected, About 50 percent of patients suffer from either borderline
corresponds to the location of the expanded CGG repeat. intellectual functioning or mental retardation, which is gen-
Interestingly, although both female and male parents with erally of mild degree (Swillen et al. 1997); perhaps one-fifth
a premutation may pass a full mutation to their children, this of all patients will also have symptomatology similar to that
is far more commonly the case with female parents. The rea- seen in ADHD, with varying mixtures of hyperactivity,
son for this is that expansion of a pre-mutation to a full impulsiveness, and inattentiveness. Autism has been noted
mutation occurs readily during oogenesis but only rarely in a small minority (Fine et al. 2005).
during spermatogenesis. As these patients pass through adolescence into adult
Magnetic resonance imaging studies have revealed years, up to one-third will develop a psychosis phenotypi-
hypertrophy of the hippocampus with atrophy of the supe- cally similar to that seen in schizophrenia (Bassett et al.
rior temporal gyrus (Reiss et al. 1994) and atrophy of the 2003; Gothelf et al. 2007; Murphy et al. 1999), with delu-
cerebellar vermis (Mostofsky et al. 1998). Autopsy studies sions and hallucinations. Mood disturbances may also
have demonstrated that, although neuronal cell counts are occur and may be more frequent than psychosis: both
normal in the cortex, dendritic spines are long and tortu- manic or hypomanic episodes (Papolos et al. 1996) and
ous in shape (Hinton et al. 1991; Rudelli et al. 1985). depressive episodes (Murphy et al. 1999) may occur.
Obsessions and compulsions have also been noted in
roughly one-third of teenagers (Gothelf et al. 2004).
Differential diagnosis Other clinical features include cardiac defects, hypocal-
cemia secondary to hypoparathyroidism, and, in a small
The full clinical syndrome of mental retardation, with or minority, seizures (Kao et al. 2004).
without autism, and the characteristic facial dysmorphism
(with, in males, macro-orchidism) is distinctive.
Course
Mention should also be made of a condition known as
FXTAS, or fragile X-associated tremor/ataxia syndrome. As
The course is chronic; although some die of cardiac com-
noted earlier, patients with pre-mutations do not develop the
plications, most live a normal lifespan.
fragile X syndrome. This is not to say, however, that the pre-
mutation is benign, given that those who carry this premuta-
tion are at high risk for developing FXTAS in middle or later Etiology
years, with tremor, ataxia, and, in a minority, dementia.
This syndrome occurs secondary to a microdeletion at
22q11.2 and is inherited in an autosomal dominant fashion
Treatment with variable penetrance (McDonald-McGinn et al. 2001).
Magnetic resonance imaging studies (van Amelsvoort et al.
The general treatment of mental retardation, autism, and 2004; Bish et al. 2004, Campbell et al. 2006, Eliez et al. 2000,
ADHD is discussed in Sections 5.5, 9.14, and 9.15 respec- Kates et al. 2006; Schaer et al. 2006) have revealed atrophy
tively. Importantly, fragile X patients with ADHD respond of the cerebral cortex and white matter, with reduced gyri-
well to methylphenidate (Hagerman et al. 1988). fication of the cortex; enlargement of the right caudate;
enlargement of the amygdalae; and atrophy of the thala-
mus. In the cerebellum, atrophy of the cortex and white
9.7 VELOCARDIOFACIAL SYNDROME matter is also seen.
The velocardiofacial syndrome, also known as the 22q11.2

deletion syndrome, is an inherited disorder characterized Differential diagnosis
by facial dysmorphism, intellectual deficits, and a number
of neuropsychiatric syndromes, most notably a psychosis In adults, velocardiofacial syndrome must be distin-
phenotypically similar to schizophrenia. First described in guished from schizophrenia, bipolar disorder, major
1978 by Shprintzen et al., this disorder is now recognized as depression, obsessive–compulsive disorder, and ADHD.
p 09.qxd 3/10/08 9:39 AM Page 411
9.8 Lesch-Nyhan syndrome 411
The distinctive facial dysmorphism, nasal voice, mental Genetic testing is available. As noted below, hypoxanthine-
retardation, hypocalcemia, and cardiac defects may all sug- guanine phosphoribosyl transferase (HPRT) activity is grossly
gest the correct diagnosis; however, at times these abnor- reduced or absent, and diagnosis may also be established by
malities may be absent or subclinical, and the diagnostic measuring this enzymatic activity in erythrocytes, hair roots
possibility may only be raised when the family history sug- or cultured skin fibroblasts.
gests the syndrome in a relative, thus prompting genetic
testing.
Course
Treatment Self-mutilation may decrease, or even remit, in early adoles-

cence (Mizuno 1986); most patients, however, die of infec-
There are no blinded treatment studies for this disorder; the tion or renal failure in their teenage or early adult years.
neuropsychiatric syndromes seen here are treated as
described in the sections on mental retardation (Chapter 5),
ADHD and autism (Chapter 9), psychosis (Chapter 7),
Etiology
mania and depression (Chapter 6), and obsessions and
The Lesch–Nyhan syndrome occurs secondary to any one of
compulsions (Chapter 4).
a large number of different mutations in the gene for HPRT,
found on the X chromosome (Davidson et al. 1989; Edwards
et al. 1990; Gibbs and Caskey 1987; Yang et al. 1984).
9.8 LESCH–NYHAN SYNDROME Although cases in females have been reported (van Bogaert
et al. 1992; Ogasawara et al. 1989), this disorder, as noted
The Lesch–Nyhan syndrome, first described in 1964 (Lesch
above, is seen almost exclusively in males. Hyperuricemia is a
and Nyhan 1964), is a rare X-linked recessively inherited dis-
constant feature of this syndrome, and this occurs secondary
order, occurring almost exclusively in males, which is
to disturbances in purine metabolism due to the mutation in
characterized, classically, by mental retardation, a move-
HPRT. The hyperuricemia, however, does not explain the
ment disorder with both dystonic and choreoathetotic
mental retardation, movement disorder or self-mutilation.
components, and, most notably, a striking degree of
Although routine neuropathologic examinations are
self-mutilative lip biting.
unrevealing, MR scanning has demonstrated mild atrophy of
both the cerebral cortex and of the caudate nucleus (Harris
et al. 1998). Several studies have strongly suggested distur-
Clinical features
bances in dopaminergic functioning. Post-mortem work has
The overall clinical picture has been described in several demonstrated reduced dopamine content in the caudate
studies (Christie et al. 1982; Jankovic et al. 1988; Jinnah et al. (Saito et al. 1999), and cerebrospinal fluid (CSF) studies have
2006; Lesch and Nyhan 1964; Nyhan 1972). Toward the demonstrated a reduction in the level of homovanillic acid
end of the first year of life, dystonia and choreoathetosis (HVA), a metabolite of dopamine (Jankovic et al. 1988).
gradually appear, and with time spasticity may also occur. Positron emission tomography (PET) studies have indicated
Mental retardation eventually becomes apparent in early a reduction in pre-synaptic dopamine stores (Ernst et al.
childhood, and may range from mild to severe; notably, in 1996; Wong et al.1996), and post-mortem work has
a very small minority the IQ may be in the normal range demonstrated an increase in post-synaptic dopamine recep-
(Mathews et al. 1995). tors (Saito et al. 1999). Taken together, these results are con-
The characteristic self-mutilation typically begins in early sistent with a reduction of dopamine in pre-synaptic
childhood, after teeth come in; later onsets, up to the age of 8 neurons and an expected compensatory up-regulation of
years, however, have been reported (Hatanaka et al. 1990). post-synaptic dopamine receptors.
Despite being normally sensitive to pain, patients repeatedly
bite at their lips, tongue, buccal mucosa, and fingers, to the Differential diagnosis
point where the lips and fingers are literally bitten off in some
cases. It must clearly be kept in mind that there is no anesthe- Although patients with other forms of mental retardation
sia here and that the biting is involuntary: Lesch and Nyhan may bite themselves, the degree of self-biting rarely ever
(1964) commented that one of their patients ‘appeared terri- approaches that seen in the Lesch–Nyhan syndrome.
fied and screamed as if in pain during the process (of biting)
and appeared happy only when restrained securely’.
A minority of patients may also have seizures. Treatment
Hyperuricemia is a constant feature of this disease, and
tophaceous gout and gouty nephropathy may appear in Allopurinol, by forestalling gouty nephropathy, may pro-
adolescence. A megaloblastic anemia may also occur in long life; it has, however, no effect on the central nervous
some patients. system manifestations.
p 09.qxd 3/10/08 9:39 AM Page 412
Lip biting may be curtailed by lip or mouth guards or by Differential diagnosis

face masks; however, in severe cases, teeth extraction may be
required. In cases with finger biting, restraints may be help- Both the Prader–Willi and Alstrom–Hallgren syndromes
ful. Various medications have been reported in non-blind are characterized by obesity; however, neither of these dis-
case reports or studies to be helpful in reducing the biting, orders is associated with polydactyly or syndactyly. Further
including risperidone (Allen and Rice 1996), levodopa differentiating features include a ravenous hunger in the
(Jankovic et al. 1988), gabapentin (McManaman and Tam Prader–Willi syndrome and sensorineuronal deafness in
1999), and carbamazepine (Roach et al. 1996). In one case the Alstron–Hallgren syndrome.
report, a patient with a severe movement disorder underwent
deep brain stimulation of the globus pallidus that not only
relieved the movement disorder but was also followed by a Treatment
remission of the self-biting (Taira et al. 2003).
The treatment of mental retardation is discussed in Section
5.5.
9.9 BARDET–BIEDL SYNDROME
The Bardet–Biedl syndrome is a rare autosomal recessively 9.10 PRADER–WILLI SYNDROME

inherited disorder, characterized in its fully expressed form
by obesity, polydactyly or syndactyly, retinal dystrophy, The Prader–Willi syndrome is a congenital disorder charac-
and mental retardation. Although this syndrome is well- terized by extreme hyperphagia, obesity, various dysmorphic
characterized, there is some inconsistency in the literature features, and, in a majority, mild mental retardation; other
regarding its name: in the past it was often referred to as neuropsychiatric features, as described below, may also be
the Laurence–Moon–Biedl syndrome; however, the cur- present. This is a not uncommon disorder, and is found
rently preferred name is Bardet–Biedl syndrome. with equal frequency in males and females.

Clinical features have been discussed in a number of papers The overall clinical features have been described in several
(Beales et al. 1997; Green et al. 1989; Klein and Ammann papers (Bray et al. 1983; Burke et al. 1987; Butler et al. 1986;
1969; Rathmell and Burns 1938; Roth 1947). Obesity is Dunn 1968; Greenswag 1987; Hall and Smith 1972;
almost universal and tends to be of the central type. Robinson et al. 1992). This disorder presents in infancy with
Syndactyly or polydactyly is also almost universal; when somnolence, hypotonia, and decreased oral intake. By the
polydactyly is present, it typically manifests with an extra age of 2 years, however, a remarkable transformation occurs,
finger or toe, which may range from rudimentary to fully in that these patients become alert and begin to display a
formed. Retinal dystrophy is also almost universal, but may remarkable hyperphagia.
not become symptomatic until later childhood or adoles- The hyperphagia of the Prader–Willi syndrome is severe
cence; by early adult years, however, a majority of patients and leads to extreme obesity. It stems from a ravenous
will become blind. Mental retardation ranges from mild to hunger: one patient literally ‘took off running’ and ‘as soon as
severe, and is seen in the majority of cases. Other features she could walk, she was constantly near the refrigerator, beg-
include hypogenitalism in males, with a small penis and ging for food’ (Zellweger and Schneider 1968). Patients often
testes, menstrual irregularities in females, renal dysplasia go to any lengths to satisfy this hunger and, if refrigerators
(which may progress to renal failure in a minority), con- and food cabinets are locked, may turn to other sources: one
genital heart disease, hypertension, and diabetes mellitus. patient ‘ate catfood, begged food from neighbors, and ate
rotting chicken carcasses and other items removed from
Course dustbins’ (Clarke 1993).
Characteristic dysmorphic features include a narrow
Apart from retinal dystrophy and renal abnormalities, head, almond-shaped eyes, and a narrowed or tented upper
both of which are progressive, the overall clinical course lip. Micromelia is also often present, with slender arms and
remains static through adult life. legs and small hands and feet. Hypogonadism is present,
manifesting in males with micropenis and cryptorchidism,
and in females with hypoplastic labia, a lack of breast
Etiology development, and varying degrees of amenorrhea.
Mental retardation is present in the majority of patients,
As noted, this disorder is inherited on an autosomal but is generally mild. Behavioral abnormalities include skin
recessive basis: 12 loci (BBS1 through BBS12) have been picking, which may be quite severe, temper tantrums, and
identified. The neuropathology is not known. stubbornness; ritualistic behaviors may also be present.
p 09.qxd 3/10/08 9:39 AM Page 413
9.11 Congenital Rubella syndrome 413
(Clarke et al. 2002). Depression occurs in a minority, and (Selikowitz et al. 1990); however, this agent is no longer
may be quite severe (Boer et al. 2002); psychosis has also available in the United States. An open study also sug-
been reported (Clarke 1993). Seizures may occur in a gested effectiveness of risperidone in this regard (Durst et
minority. al. 2000). Obstructive sleep apnea and the Pickwickian syn-
Hypersomnolence is common and appears to be multi- drome are treated as discussed in Sections 18.8 and 18.9
factorial. With the extreme obesity, obstructive sleep apnea respectively.
(Clift et al. 1994) and the Pickwickian syndrome (Bye et al. Mental retardation is treated as outlined in Section 5.5.
1983) may occur; however, in some cases the degree of Of note, open work has found that topiramate, although
hypersomnolence seems more severe than can be ineffective for weight loss in this population, did reduce skin
accounted for by these disorders. picking (Smathers et al. 2003); in cases with seizures, this
The diagnosis may be confirmed by DNA methylation would be a logical choice. Case reports also suggest that
analysis, as discussed below. selective serotonin reuptake inhibitors (SSRIs) may reduce
skin picking (Hellings and Warnock 1994).
Course
9.11 CONGENITAL RUBELLA SYNDROME
The disorder is chronic and many die prematurely of the
complications of obesity. The congenital rubella syndrome occurs secondary to fetal
infection during the first trimester. In the past, this was an
important cause of mental retardation; however, in devel-
Etiology oped countries, vaccination of females has made this a very
rare disorder.
The Prader–Willi syndrome occurs secondary to a lack of a
critical portion of the paternally-derived chromosome 15,
and this deficit may occur via any one of three mechanisms. Clinical features
The most common mechanism involves a microdeletion on
the paternally derived chromosome 15; the next most com- In its fully developed form (Forrest and Menser 1970;
mon is uniparental disomy, with both chromosome 15s Forrest et al. 2002; Hardy 1973; Miller et al. 1982; Tartakow
being derived maternally; finally, and rarely, mutations may 1965), the syndrome is characterized by mental retardation,
occur on the paternally derived chromosome 15. The diag- cataracts, deafness, and various cardiac abnormalities, such
nosis, as indicated earlier, may be made via methylation as patent ductus arteriosus and ventricular septal defect. A
analysis. The methylation pattern on chromosome 15 differs minority of patients may also have autism (Chess et al.
for paternally and maternally derived chromosomes, and 1978; Fombonne et al. 1997).
hence analysis allows one to determine whether the patient
has a normal, paternally-derived chromosome 15.
The neuropathology of the Prader–Willi syndrome is Course
not clear. Magnetic resonance imaging (Miller et al. 2007)
has indicated cortical atrophy and, in some cases, polymi- In those who survive into late childhood or beyond, the
crogyria. The remarkable hunger has suggested hypothala- course is static, except in the small minority who go on to
mic involvement, and one study found a reduction in the develop the dementia of progressive rubella panencephalitis,
size and neuronal count of the hypothalamic paraventricu- as discussed in Section 14.14.
lar nucleus (Swaab et al. 1995).
Etiology
Maternal rubella infection leads to fetal infection via
The Bardet–Biedl syndrome is distinguished by the pres- transplacental spread and, if this occurs in the first trimester,
ence of polydactyly or syndactyly. various abnormalities may occur, including areas of focal
necrosis, primarily in the basal ganglia, mesencephalon, and
cord (Desmond et al. 1967; Plotkin et al. 1965; Rorke 1973;
Treatment Rorke and Spiro 1967); microcephaly and spina bifida may
also be present (Tartakow 1965).
Growth hormone, given early in life, may improve both
overall height and lean body mass (Myers et al. 2006).
Early dietary management is essential and in some cases Differential diagnosis
institutionalization may be required to forestall the develop-
ment of a lethal degree of obesity. In one double-blind Fetal infection with toxoplasma, cytomegalovirus or herpes
study, fenfluramine was effective in reducing weight simplex virus can cause a similar syndrome.
p 09.qxd 3/10/08 9:39 AM Page 414
Treatment Furthermore, it is also unclear whether it is the total amount

of alcohol consumed that is important or whether relatively
The treatment of mental retardation is discussed in Section brief exposures to high levels, as may occur with binge drink-
5.5, and of autism in Section 9.14. Hearing aids are generally ing, are more toxic. Finally, there is also debate as to whether
required. it is alcohol itself that is toxic, or its metabolite, acetaldehyde.
Prevention is critical, and females of child-bearing age Neuropathologic studies (Clarren et al. 1978; Ferrer and
should be vaccinated if they have not already had rubella. Galofre 1987; Konovalov et al. 1997; Pfeiffer et al. 1979;
Contraception for the 3 months post-vaccination is criti- Wisniewski et al. 1983) have revealed numerous abnormali-
cal, as, albeit rarely, congenital rubella has occurred in ties (which may be present in various combinations), includ-
fetuses conceived during this time period. ing microcephaly, agenesis of the corpus callosum, and
hypoplasia of the cerebellar vermis; microscopically, cortical
dyslamination may be present, and glial and glial-neuronal
9.12 FETAL ALCOHOL SYNDROME nodules may be found in the white matter and also in the
leptomeninges.
The fetal alcohol syndrome, caused by in utero exposure to
alcohol, consists, classically, of a characteristic facial dys-
morphism, mental retardation, and behavioral problems, Differential diagnosis
most notably hyperactivity (Clarren and Smith 1978; Jones
and Smith 1973; Jones et al. 1974). This is a not uncom- The characteristic facial dysmorphism, coupled with a his-
mon disorder, being present in roughly 1 in 1000 live tory of maternal alcohol use, strongly suggest the diagnosis.
births, and represents one of the most common causes of Difficulties may arise on two counts. First, it may not be
mental retardation in the United States. Partial syndromes possible to establish the degree of alcohol use during preg-
also occur, and such patients are often said to have ‘fetal nancy. Second, as noted earlier, the facial dysmorphism
alcohol effect’. tends to fade and hence may be very subtle, or even absent,
in teenagers or adults: when the diagnosis is strongly sus-
Clinical features pected but the facial dysmorphism is absent, examining
childhood photographs may be very helpful.
The characteristic dysmorphism includes microcephaly, A similar syndrome may occur in cases of in utero
shortened palpebral fissures, epicanthal folds, maxillary exposure to various anti-epileptic drugs, most notably
hypoplasia, a thin upper lip, a flattened philtrum, and phenytoin and valproic acid.
micrognathia. Mental retardation ranges from severe to
mild, and some may be of normal intelligence: those with an Treatment
IQ within the normal range, however, may have develop-
mental disorders, such as developmental dyscalculia or The treatment of mental retardation is discussed in Section
developmental dysphasia (Larsson et al. 1985; Shaywitz et al. 5.5; hyperactivity and distractability may be treated as
1981). Behavioral problems are common, and patients may described for ADHD in Section 9.15. Prevention, of course,
not only be irritable but also display hyperactivity and dis- is critical, and females of child-bearing age should be
tractability reminiscent of ADHD. Cardiac abnormalities informed that binge drinking may be as dangerous as daily
may also occur, such as atrial or ventricular septal defects. drinking and that there may indeed be no minimal ‘thresh-
Magnetic resonance scanning may be normal or, in severe old’ of alcohol consumption below which a pregnant
cases, may disclose cortical atrophy, ventricular enlargement, woman can drink without endangering the fetus.
and hypoplasia or agenesis of the corpus callosum.
Course 9.13 RETT’S SYNDROME
Although some improvement may occur during adoles- Rett’s syndrome, first described by Andreas Rett in 1966
cence, especially with regard to the severity of the facial (Rett 1966), is a rare disorder characterized by mental
dysmorphism (Spohr et al. 1993; Streissguth et al. 1991), retardation, microcephaly, autistic features, and peculiar
the overall course is one of a stable chronicity. stereotypic hand movements. This is a rare disorder that
occurs almost exclusively in females.
Etiology
Clinical features
Although the syndrome is clearly related to maternal alcohol
ingestion, multiple uncertainties remain as to the details. For As described in a number of papers (Coleman et al. 1988;
example, it is not clear whether it is the first or, rather, later Hagberg 1989; Hagberg and Witt-Engerstrom 1986;
trimesters that constitute the greatest period of risk. Hagberg et al. 1983; Witt-Engerstrom 1990), the clinical
p 09.qxd 3/10/08 9:39 AM Page 415
9.13 Rett’s syndrome 415
features of Rett’s syndrome in females may be roughly and may occur secondary to infections or post-operative
divided into four stages. It must be emphasized that the complications.
delineations between various stages are not precise, and that
various features may overlap from one stage to another.
Stage I becomes apparent at around the age of 10 months Etiology
and is characterized by a general stagnation of normal devel-
opment. There may be a failure of normal weight gain, and, Rett’s syndrome is an X-linked dominant disorder due to
rather than beginning to crawl, patients may display a per- any one of a large number of different mutations in the gene
sistent ‘bottom shuffling’. This stage persists for anywhere for methyl-CpG-binding protein 2 (MECP2) (Amir et al.
from a month up to a year and a half. 1999; Auranen et al. 2001). Phenotypic variation reflects
Stage II generally occurs around the age of 18 months and not only the effects of different mutations (Dotti et al.
is characterized by a regression. Interestingly, although the 2002) but also non-random inactivation of the X chromo-
onset of this stage is generally gradual, spanning weeks or some (Amir et al. 2000). Almost all cases represent de novo
months, it may at times occur relatively acutely, with an mutations; in the few familial cases identified, it appears
onset spanning days. The regression itself presents with that the mother was a ‘carrier’ who was either unaffected
autistic features, including a general withdrawal of contact (Dayer et al. 2007) or had a very mild phenotype (Huppke
with surroundings, and the appearance of characteristic et al. 2006). The extreme rarity of this disorder in males
stereotypies. Initially patients may suck their hands or grasp probably reflects the lethal nature of most mutations when
their tongues; however, with time, the classic hand stereo- not ‘balanced’, as in females, by a normal X chromosome.
typies emerge, with hand-wringing, hand-clasping or wash- Neuropathologic studies have revealed microcephaly
ing movements. There may also be attacks of violent and hypopigmentation of the pars compacta of the
screaming, teeth gnashing, and nocturnal awakenings substantia nigra (Jellinger and Seitelberger 1986; Jellinger
accompanied by peculiar laughter. Most patients also display et al. 1988). Microscopically, there is a loss of cortical
episodes of irregular respiration while awake, with periods of pyramidal cells (Belichenko et al. 1997); remaining
hyperventilation followed by apneas. During this stage, head neurons are generally small and closely packed (Bauman
growth decelerates, and patients gradually develop micro- et al. 1995), and dendrites show decreased branching
cephaly. Stage II generally lasts about a year and a half. (Armstrong et al. 1998). Cerebellar pathology is also pres-
Stage III typically begins around the age of 3 years and is ent (Oldfors et al. 1990), with cerebellar cortical atrophy
often referred to as the ‘pseudostationary’ stage, reflecting the and a loss of Purkinje cells; of note, although gliosis may be
fact that, for the most part, the regression seen in stage II ends present in those dying in adult years, it appears absent or
and there is a period of relative stability. Patients are left with scant in childhood.
mental retardation, which is generally severe, and ambulation
may or may not be possible. Seizures, if not already evident in
stage II, now appear in most patients, and may be complex
partial or grand mal. This stage lasts for many years, occa-
sionally persisting into early adult years or even middle age.
The overall differential diagnosis of mental retardation is
Stage IV, also known as the stage of late motor deteriora-
discussed in Section 5.5; the combination of mental retar-
tion, may appear at any point from late childhood to adult
dation, autistic features, and hand stereotypies in a female,
years, and is characterized by dystonia and lower motor neu-
although not specific for Rett’s syndrome (Temudo et al.
ron muscular atrophy, both most prominent in the lower
2007), is very suggestive.
extremities, and by scoliosis, which at times may be quite
severe.
Although these clinical stages are the rule in females,
exceptions do occur, and at times there may be mild or Treatment
‘variant’ cases in which speech is preserved.
As noted earlier, the vast majority of cases are seen in The general treatment of mental retardation is discussed in
females. In those very rare instances in which Rett’s syn- Section 5.5. In one blind study, in a minority, bromocrip-
drome occurs in males, it tends to be more severe (Dotti et al. tine was followed by some improvement in cognition and
2002), with most patients dying in infancy (Kankirawatana overall behavior (Zappella 1990). Non-blind work suggests
et al. 2006) that in some patients folinic acid treatment may be fol-
Genetic testing is available. lowed by overall improvement (Ramaekers et al. 2003).
Naltrexone should not be used, as it may cause a distinct
worsening of symptoms (Percy et al. 1994). With regard to
Course seizures, although there are no blind studies, case series
support the use of carbamazepine (Huppke et al. 2007),
Stage IV may persist for decades and some patients may lamotrigine (Stenbom et al. 1998), or topiramate (Goyal
live into their 60s. Early death, however, is not uncommon et al. 2004).
p 09.qxd 3/10/08 9:39 AM Page 416
9.14 AUTISM jars by the hour . . . He would watch them and get severely
excited and jump up and down in ecstasy’. Stereotypies
Autism, first described by Leo Kanner in 1943 (Kanner such as repetitive hand flapping or finger flicking may
1943), is a chronic, lifelong disorder that is characterized by occur, and some patients may engage in posturing or, clas-
an inability on the patient’s part to form normal relation- sically, toe walking. The persistence of stereotypies can be
ships with others. The relationships that are formed exhibit astonishing: one child (Ornitz and Ritvo 1968) sustained
a peculiar disturbance, in that patients act toward others as ‘oscillatory hand-flapping throughout the entire day’. Some
if those others were inanimate objects: there is a machine- patients seem insensitive to pain, whereas others display an
like quality to the patient’s overall behavior with others, as inordinate, often terrifying, sensitivity to innocuous stim-
if the patient fails to sense the difference between the ani- uli: one of Kanner’s (1943) patients ‘was so afraid of the
mate and inanimate. In severe cases patients may be almost vacuum cleaner that she would not even go near the closet
totally inaccessible, whereas in milder ones an observer where it was kept, and when it was used, ran out into the
might note only a peculiar awkwardness and stiltedness in garage, covering her ears with her hands’. Head banging
the patient’s social behavior. Most, but certainly not all, and other self-injurious behaviors, such as self-biting, may
patients also have mental retardation. also occur. An overall hyperactivity may also occur.
Autism is a relatively rare disorder, with a lifetime Another classic symptom of autism is an ‘anxiously obses-
prevalence of about 0.05 percent; it is far more common in sive desire for the maintenance of sameness’ (Kanner 1943;
males than females, by a ratio of 3–4:1. Although some italics in original). As noted further by Kanner (1951):
recent studies have indicated an increase in the rate with
which the diagnosis of autism is made, it is unclear whether the autistic child desires to live in a static world, a
this represents an actual increase in prevalence or rather world in which no change is tolerated. The status
better case finding. quo must be maintained at all cost. Only the child
himself may sometimes take it upon himself to
modify existing combinations. But no one else may
Clinical features do so without arousing unhappiness and anger . . .
The slightest change of arrangement, sometimes so
Autism has an insidious onset in infancy. Parents may minute that it is hardly perceived by others, may
recall that the child cried infrequently and seemed indiffer- evoke a violent outburst of rage.
ent to being held or cuddled; some parents, as noted by
Kanner (1943), were ‘astonished at the children’s failure to Not only arrangements but also routines and sequences
assume at any time an anticipatory posture to being picked must be maintained inviolate: the aisles in the grocery store
up’ (italics in original). Although symptoms are typically must be traversed in exactly the same order and direction
obvious by the age of 3 years, in mild cases they may escape every time, and the exact same route must be taken to
notice, and children may not come to attention until they school every day.
enter elementary school and their behavior is compared to Speech and language are also disturbed. Some patients
that of their normal peers. are mute, and those who do speak often display a curious
The full picture of autism is typically best seen in middle aprosody, wherein they not only seem insensitive to the
childhood. Autistic children prefer solitary play and, rather emotional inflections of those speaking to them but also
than playing with other children, occupy themselves with display a monotonous or ‘sing-song’ quality in their own
objects such as toys or machines of some sort. They seem, as speech. There may also be echolalia and, classically, prono-
noted by Kanner (1943), to be unable ‘to relate themselves in mial reversals, wherein the patients refer to themselves in
the ordinary way to people and situations’ (italics in origi- the third person.
nal); indeed, other people, whether adults or children, are Some patients (Kanner 1944) may display ‘an astound-
often treated as if they were machines or perhaps mere props ing vocabulary . . . excellent memory for events of several
to be used during play. Attempts to make contact with such years before . . . [and] phenomenal rote memory for poems
children generally fail. If one tries to catch their eyes, they and names’. Kanner (1944) was impressed with their ‘strik-
will often exhibit ‘gaze avoidance’ (Richer and Coss 1976), ingly intelligent physiognomies’, believing that most, if not
staring fixedly at something else, perhaps something just to all, of his patients were of normal intelligence. It is now
the side of the examiner’s head. One gets the impression that clear, however, that Kanner’s original sample of 20 patients
a mannequin would be more satisfactory to the autistic child was not representative and that, in fact, about three-quar-
than an actual playmate. ters of autistic patients have mental retardation, ranging in
The behavior of autistic children may, at times, seem severity from mild to severe.
bizarre. There are often what are known as ‘fascinations’, in The mental retardation seen in autism is, however, pecu-
which the child becomes intently interested in and fasci- liar in that, unlike most examples of mental retardation, the
nated with certain objects, such as a piece of cloth, jewelry, decrement in abilities is not even: indeed, in some cases one
or, classically, spinning things such as tops. One of Kanner’s may find ‘islets’ of normal, or even superior, functioning in
patients (Kanner 1944) spun ‘toys and lids of bottles and an otherwise retarded patient. For example, one autistic man
p 09.qxd 3/10/08 9:39 AM Page 417
9.14 Autism 417
with an IQ of 71, although unable to abstract on proverbs Although MRI studies overall have not been conclusive,
testing or do simple arithmetic, was nevertheless able to ‘cor- with numerous contradictory results and failures of
rectly give the day of the week of any day this century’ (Hurst replication, two findings appear fairly solid, namely
and Mulhall 1988). In the past, such patients have been vermal hypoplasia and a degree of macroencephaly.
referred to as ‘idiots savants’ (Treffert 1988), and although Neuropathologic studies (as recently reviewed by Palmen
this terminology is unfortunate, it does forcefully convey the et al. in 2004), although likewise not conclusive, do suggest
sometimes astounding contrast between the ‘islets’ of supe- cerebral cortical dysgenesis, abnormalities of neuronal cell
rior functioning and the overall intellectual decrement. packing and size within the limbic cortex, and a loss of
Seizures occur in roughly one-third of patients and, Purkinje cells within the cerebellum.
although these are most common in those with mental retar- It is unclear what role environmental factors play in the
dation, they may also occur in those of normal intelligence. etiology of autism. Recent concerns regarding an etiologic
Infantile spasms may occur in younger children, whereas in role of the measles/mumps/rubella vaccine appear
older children and in adults, simple partial, complex unfounded (Madsen et al. 2002).
partial, and grand mal seizures may be seen (Danielsson Although the etiology of the vast majority of cases of
et al. 2005; Olsson et al. 1988). autism thus remains unclear, it does appear that in a small
Before leaving this discussion of the clinical features of minority, perhaps 10 percent, autism occurs secondary to
autism, it is appropriate to comment on the putative entity certain other well-described disorders (Kielinen et al. 2004;
known as Asperger’s syndrome. As noted earlier, in some mild Ritvo et al. 1990), including tuberous sclerosis (Alsen et al.
cases of autism, symptoms may not come to light until the 1994; Lawlor and Maurer 1987), the fragile X syndrome
child enters elementary school and, in very mild cases, recog- (Wisniewski et al. 1985c), Rett’s syndrome (Percy et al.
nition may be delayed until much later. Some authors believe 1990), Down’s syndrome (Lund and Munk-Jorgensen
that these cases represent a separate disorder, called Asperger’s 1988), velocardiofacial syndrome (Fine et al. 2005), and
syndrome; myself and others, however, conceive of such the congenital rubella syndrome (Chess et al. 1978).
patients as merely constituting the very ‘high-functioning’
end of the spectrum of clinical severity of autism.
Course As noted, mental retardation is seen in association with
autism in about three-quarters of cases, and hence autism
The overall outcome is strongly influenced by whether or not with mental retardation must be distinguished from
there is an associated mental retardation and, if so, its sever- mental retardation of other causes. At times this may be
ity. With regard to autistic symptoms, there is typically some difficult, given that many patients with mental retardation
gradual improvement by adult years, and, from a prognostic of other causes will display repetitive, stereotyped behav-
point of view, the course during middle childhood is particu- iors, which at times may be similar to the ‘fascinations’ and
larly important: those who attain some language and some stereotypies seen in autism. A cardinal differential feature,
social skills around this time have a much more favorable however, is the patient’s social relatedness: upon
outcome than those who do not. No matter how great the approaching a child with mental retardation of other
spontaneous recovery, however, residual symptoms, such as causes, one may be greeted by a smile and an expectant
aprosodia, social awkwardness, and a reduced awareness of posture; by contrast, the child with autism may show no
social conventions, remain in adult years (Rumsey et al. more interest in the approaching physician than might be
1985). evinced for a machine.
Developmental dysphasia, especially when both expres-
sive and receptive components are present, may be con-
Etiology fused with autism; however, here again the quality of the
patient’s social relatedness enables a differentiation. The
Etiologic theories regarding autism have changed radically child with developmental dysphasia, although unable to
over the past few decades. This disorder was once believed to communicate verbally, will still, by gesture, tone of voice,
result from faulty child rearing by cold and distant parents. and facial expression, clearly desire social contact, in stark
This theory has now been soundly discredited, and current contrast to the child with autism.
research focuses primarily on genetics and neuropathology. Schizophrenia may enter the differential, especially in
Family studies strongly support a genetic basis. As cases characterized by significant inaccessibility and bizarre
noted earlier, the lifetime prevalence is about 0.05 percent; stereotypies. Here the age of onset is helpful. As noted
however, the concordance among monozygotic twins is earlier, most cases of autism become obvious by the age of
over 60 percent (Bailey et al. 1995; Folstein and Rutter 3 years; by contrast, schizophrenia only very rarely has an
1977). Genetic heterogeneity is almost assured, and linkage onset before the age of 8 years. Furthermore, in schizo-
studies have identified loci on various chromosomes, phrenia one finds hallucinations and delusions, symptoms
including chromosomes 2, 3, 7, 11, 15, 19, and X. that are absent in autism.
p 09.qxd 3/10/08 9:39 AM Page 418
Treatment atomoxetine or naltrexone may occasionally constitute first-

line treatment in cases in which hyperactivity far overshad-
Treatment of autism involves behavior modification, family ows other symptoms; however, in most cases these are
counselling, special education, and medication. All compo- reserved as ‘add-on’ treatments in cases in which hyperactiv-
nents are important, and most patients generally receive a ity persists despite treatment with an antipsychotic or an
combination of these. antidepressant.
Behavior modification programs that target specific In planning the pharmacologic treatment of autism, it is
behaviors, such as head banging or aggressive behavior, are important to adopt a methodical approach, using one agent
often quite effective. Unfortunately, however, there is often at a time and giving each agent a ‘good’ trial before moving
very little generalization: the learning of autistic patients is on to another: ‘good’ trials must involve not only adequate
often quite state specific and, hence, although a program dosage but also adequate duration, keeping in mind that
might eliminate, for example, head banging at school, the weeks or months may be required to see the effect of any
patient might continue to engage in this behavior at home, given dose.
until a similar program is implemented at home.
Family counselling is aimed at helping parents adjust to
their ill child, and to implementing and continuing behav- 9.15 ATTENTION-DEFICIT/HYPERACTIVITY
ior programs at home. In all cases it is also important to DISORDER
forcefully convey to the parents that they are in no way
responsible for their child’s illness. Attention-deficit/hyperactivity disorder (Biederman and
Special education classes are generally appropriate. A class Faraone 2005), often referred to simply as ADHD, is charac-
that is highly structured is more effective in fostering terized by a variable mixture of hyperactivity, impulsivity, and
appropriate classroom behavior and learning than is a more inattentiveness. This is a common disorder, found in any-
permissive or ‘open’ classroom. where from 3 to 7 percent of school-age children, and occurs
A variety of medications have been found useful in the in males far more frequently than in females, with reported
treatment of autism. Stereotypies, repetitive behaviors, sex ratios varying from 2:1 to 10:1 depending on the
aggressiveness, hyperactivity, and, to a degree, overall diagnostic criteria utilized. Synonyms for ADHD include
social relatedness all improve with antipsychotics minimal brain dysfunction, hyperkinetic syndrome, or,
(risperidone [McCracken et al. 2002; McDougle et al. 1998, simply, hyperactivity.
2005; Research Units on Pediatric Psychopharmacology
Autism Network 2002], olanzapine [Hollander et al.
2006a], and haloperidol [Anderson et al. 1984]), antide- Clinical features
pressants (clomipramine [Gordon et al. 1993], fluovoxam-
ine [McDougle et al. 1996], and fluoxetine [Hollander et al. Although the onset of symptoms may occur as early as
2005]), and divalproex (Hollander et al. 2006b). infancy, most patients do not come to clinical attention until
Hyperactivity also responds to clonidine (Frankhauser kindergarten or early elementary school years. In infancy,
et al. 1992), methylphenidate (Research Units on Pediatric one may see an unusual degree of fussiness and irritability,
Psychopharmacology [RUPP] Autism Network 2005), and during toddler years affected children may be constantly
atomoxetine (Arnold et al. 2006), and naltrexone (Felman ‘on the go’ and forever ‘into things’, as if the ‘motor’ is never
et al. 1999). turned off. Preschoolers may be impulsive, and parents may
Risperidone, in doses from 0.5 to 3 mg/day, is probably find it almost impossible to impose discipline.
the best pharmacologic treatment overall, with haloperidol, As these children enter kindergarten or elementary school,
in similar doses, coming a close second; olanzapine is associ- their behavior in the classroom generally brings them to
ated with significant and problematic weight gain. Concerns attention. The clinical picture may be dominated by hyperac-
regarding long-term side-effects of these antipsychotics often tivity and impulsivity (in which case one speaks of ADHD
prompt clinicians to try an antidepressant first; however, at ‘predominantly hyperactive–impulsive type’), or inattentive-
least in the case of clomipramine, haloperidol had fewer ness (wherein the term ADHD ‘predominantly inattentive
side-effects and was better tolerated in the short term type’ is used), or a combination of all three symptoms (in
(Remington et al. 2001); consequently fluvoxamine or flu- which case one speaks of ADHD ‘combined type’).
oxetine might represent a better choice. The experience with Hyperactivity may first come to attention in the
divalproex is relatively limited. classroom as the children appear incapable of remaining
Clonidine tends to cause sedation, and methylphenidate seated. They may squirm in their seats, fidget constantly,
(and, to a lesser degree, atomoxetine) and naltrexone may get up abruptly, or walk to another desk or over to a shelf.
cause irritability and increased social withdrawal. Teachers may be able to get them seated again, but the
All things being otherwise equal, it may be appropriate to success is generally only short-lived. These children may
begin with an antidepressant (or perhaps divalproex) and to also be incessant talkers, and other students may be both-
hold an antipsychotic in reserve; of the antipsychotics, ered by this. At home the hyperactivity persists, and chil-
risperidone is preferable. Clonidine, methylphenidate, dren may restlessly go from room to room. Even favorite
p 09.qxd 3/10/08 9:39 AM Page 419
9.15 Attention-deficit/hyperactivity disorder 419
television shows may not be able to keep these children in adolescence into adulthood such that, by adult years,
one place, and asking about this point is often helpful in roughly two-thirds of patients, although perhaps not
the attempt to make the diagnosis. symptom free, have improved to the point where symp-
Impulsivity leads to multiple forms of ‘thoughtless’ toms are no longer disabling.
behavior and may prompt teachers and parents to comment
on an absence of any self-restraint. In the classroom, these
Etiology
children may blurt out answers even before the teacher has
finished asking a question; in the lunch line, they may barge
Attention deficit/hyperactivity disorder is clearly familial,
ahead to get a favorite dessert; and in the playground they may
however, genetic studies, although offering some promis-
rush uninvited into the middle of other children’s games. At
ing leads regarding genes for dopamine receptors and
home they may be in constant conflict with siblings and
dopamine transporters, have not as yet provided any con-
neighborhood children, commandeering their toys and
clusive results (Faraone et al. 2005). Magnetic resonance
generally bursting into otherwise quiet activities.
imaging studies have, however, demonstrated thinning of
Inattentiveness is typically most apparent in the classroom.
the cerebral cortex and atrophy of the cerebellar vermis
These children seem incapable of paying attention to their
(Berquin et al. 1998, Castellanos et al. 2002; Mackie et al.
schoolwork, and this is particularly the case whenever atten-
2007; Shaw et al. 2006).
tion to detail is required. At times, it may appear as if it’s not
Attention deficit/hyperactivity disorder may also occur
so much a matter of inattentiveness as easy distractibility. A
secondary to lead encephalopathy, a rare condition of inher-
noise in the hallway, a car passing by outside, or simply
ited resistance to thyroid hormones (Hauser et al. 1993), or
something on another child’s desk may pull their attention
as a sequela of traumatic brain injury (Max et al. 2005).
away from the task at hand, as if everything has the same
degree of importance as the schoolwork in front of them.
Thus, incapable of giving their work the required attention, Differential diagnosis
these children predictably get very poor grades. At home,
parents may complain about difficulties in getting the Autistic children may be quite hyperactive, impulsive, and
attention of these children: sometimes it may have been distractible; however, here, in contrast with ADHD, one
necessary for parents to literally hold a child’s head still in also sees the typical peculiar lack of relatedness with others,
order to ‘get the message through’, and even with this tactic as if others were mere machines. This is an important differ-
the effort may fail. ential to make, as a misdiagnosis here may lead to stimulant
As noted below, in the natural course of events there is treatment, which may make some features of autism worse.
a gradual and spontaneous diminution of symptoms as Childhood schizophrenia may also be characterized by
these young patients enter adolescence and then adult hyperactivity and impulsivity; however, these children
years, with a consequent change in the overall clinical have additional symptoms not seen in ADHD, such as
presentation. delusions, hallucinations, and loosened associations.
In adolescence, although the grosser manifestations of If accompanied by agitation, depression may make it
hyperactivity tend to diminish and patients may be able to impossible for a child to remain seated in class or attend to
stay seated in the classroom, there may still be an undue schoolwork; however, here one sees depressed mood, fatigue,
amount of fidgetiness. Impulsivity may result in merely a and sleep disturbance, symptoms not typical of ADHD.
few too many ‘larks’, such as ‘joyrides’ or unplanned drink- Mania is typified by hyperactivity, impulsivity, and dis-
ing bouts; in more severe cases, an otherwise easily resolved tractibility, and, especially when mild, may be difficult to
confrontation with another teenager, or with an authority distinguish from ADHD. The age of onset here may help,
figure, may rapidly escalate into violence. Inattentiveness, as it is extremely rare for bipolar disorder to present at 10
abetted by normal teenage restlessness, may lead to poor years or earlier: in contrast, in most cases of ADHD the ill-
grades, despite normal intelligence. ness is well-established by this time. Symptomatology is
Among adults, hyperactivity tends to fade into the clini- also different: in mania the hyperactivity stems from an
cal background, being manifest in these years merely by excess of energy, whereas in ADHD energy levels are gen-
restlessness; impulsivity likewise recedes and may fade into erally not elevated.
a mere flightiness. Inattentiveness, however, tends to persist Fetal alcohol syndrome may be characterized by the typi-
to a significant degree, and patients may find themselves cal ADHD triad; however, here, one also sees a typical facial
unable to advance in work situations that require sustained dysmorphism, with shortened palpebral fissures, epicanthal
attention. folds, a thin upper lip, and a smooth philtrum. Furthermore,
most patients with the fetal alcohol syndrome also have
either mental retardation or borderline intellectual function-
Course ing, in contrast to ADHD in which intelligence is normal.
Phenobarbital may cause hyperactivity as a side-effect.
As just described, there is a gradual and spontaneous par- Diagnosing ADHD in adults is a difficult task. First, one
tial remission of symptoms as patients pass through must rule out a host of other disorders that may be
p 09.qxd 3/10/08 9:39 AM Page 420
characterized by one or more of the ADHD triad. These depression is present, it also makes sense to use bupropion,
include schizophrenia, agitated depression, mania, border- in hopes of clearing both ADHD and depression with one
line personality disorder, antisocial personality disorder, medication. Tic disorders were once thought to constitute a
and various substance use disorders, in particular depend- relative contraindication to stimulants given the possibility
ence on alcohol or stimulants. In some cases, the differential that tics may be exacerbated by these agents. Recent research,
task is relatively easy, as for example with cases of schizo- however, suggests that, in fact, patients with tic disorders
phrenia, depression or mania, in which other typical symp- generally do well with stimulants. In those cases, however, in
toms immediately suggest the correct diagnosis. In others, which tics are exacerbated by stimulants, consideration may
the only truly reliable way to make the differential involves be given to an alpha-2 autoreceptor agonist or, in adults, to
documenting the onset of symptoms in early childhood desipramine, as both of these are effective not only for
(Mannuzza et al. 2002), an admittedly difficult task, involv- ADHD but also may ameliorate tics. Of the alpha-2 autore-
ing, as it may, interviewing parents, siblings, and others. ceptor agonists, guanfacine is probably better tolerated;
desipramine should be limited to adults, given the risk of
arrhythmia in children. Schizophrenia does constitute a con-
Treatment traindication to stimulant use as these agents exacerbate psy-
chotic symptoms: here, either bupropion or lithium may be
A large number of medications are useful in ADHD, includ- considered. Bipolar disorder likewise constitutes a con-
ing stimulants (and stimulant-like medications), certain traindication to stimulants given their propensity to precipi-
antidepressants, lithium, and alpha-2 autoreceptor agonists. tate mania, and here the obvious alternative is lithium.
Stimulant and stimulant-like medications include Regardless of which medication is chosen for children
methylphenidate, mixed amphetamine salts, atomoxetine, or adolescents, it is also appropriate to offer psychosocial
modafinil, and dextroamphetamine. Methylphenidate and treatments, such as parent training classes and behavior
mixed amphetamine salts are roughly equivalent in efficacy modification programs for the classroom. It must be borne
(Pelham et al. 1999); methylphenidate appears superior to in mind, however, that medication, in particular stimu-
dextroamphetamine, and mixed amphetamine salts appear lants, is more effective, sometimes far more effective, than
superior to atomoxetine (Wigal et al. 2005); modafinil psychosocial treatment.
appears roughly equivalent to dextroamphetamine (Taylor
and Russo 2000). Methylphenidate is available in both
immediate and time-release preparations; in general, the 9.16 DEVELOPMENTAL DYSPHASIA
time-release preparation, given its convenience, should be
used. Developmental dysphasia, also known as ‘language disor-
Antidepressants effective in ADHD include the tricyclic der’ or ‘specific language impairment’, is characterized by
desipramine (Spencer et al. 2002), the monoamine oxidase an incomplete acquisition of linguistic skills in children
inhibitors tranylcypromine (Zametkin et al. 1985) and selegi- (Webster and Shevell 2004). In some cases, this results pri-
line (Mohammadi et al. 2004), and bupropion (Kuperman marily in an expressive dysphasia, in which children,
et al. 2001). although capable of understanding what is said to them,
In adults, lithium appeared as effective as methylphenidate have great difficulty in expressing their thoughts in speech.
(Dorrego et al. 2002). In other cases, in addition to this expressive deficit, there is
Alpha-2 autoreceptor agonists effective in ADHD also difficulty in understanding what others say, producing
include clonidine and guanfacine (Scahill et al. 2001, a clinical picture referred to as ‘mixed receptive–expressive
Taylor and Russo 2001). language disorder’.
Barring certain complicating factors, discussed below, it Developmental dysphasia is seen in 2–4 percent of school
appears reasonable to start with a stimulant or stimulant-like age children, and is more common in boys than girls.
medication and, of these, either methylphenidate or mixed
amphetamine salts may be utilized. In cases in which these Clinical features
medications are either ineffective or poorly tolerated, con-
sideration may be given to an antidepressant and, among the Depending on its severity, developmental dysphasia may
antidepressants, bupropion is a reasonable choice. Lithium come to clinical attention anywhere from the age of 2 years
may also be considered but the data supporting its effective- up to early school years.
ness are not as robust as for the other agents. Alpha-2 autore- In the expressive form of developmental dysphasia,
ceptor agonists are less well-tolerated than the other agents children, although able generally to understand what is
and are generally held in reserve. said to them, have a greater or lesser degree of difficulty in
Certain complicating conditions may dictate a change in expressing their thoughts in speech (Sato and Dreifuss
strategy, and these include substance abuse, depression, tic 1973). In severe cases vocabulary is restricted to simple
disorders, schizophrenia, and bipolar disorder. Substance words, and patients may be unable to speak in sentences.
abusers, in general, should not be given stimulants, and in In milder cases, sentences may be possible, but are short,
this group it is reasonable to begin with bupropion. When incomplete, and often telegraphic in form.
p 09.qxd 3/10/08 9:39 AM Page 421
9.17 Developmental dyslexia 421
The mixed receptive–expressive form, when severe, Both autism and childhood-onset schizophrenia may
may be characterized by muteness. In less severe cases, be characterized by linguistic disturbances similar to those
patients may be able to understand simple words, such as seen in the mixed form of developmental dysphasia; how-
‘cat’, or even simple sentences, such as ‘sit down’, but more ever, in these disorders other symptoms also occur (e.g., a
complex vocabulary or sentences leave them baffled lack of social relatedness in autism, or hallucinations and
(Bartak et al. 1975; Cohen et al. 1989; Paul et al. 1983). delusions in schizophrenia) that are not seen in dysphasia.
In addition to these linguistic problems, these children Acquired dysphasia is distinguished from developmental
often have other difficulties, including anxiety, emotional dysphasia by the course. In acquired dysphasia one sees a
lability, and, especially in boys, aggressiveness and hyper- more or less normal acquisition of language followed by a
activity. ‘regression’ or loss of linguistic competence. By contrast, in
developmental dysphasia, the gradual acquisition of lan-
guage appears simply to ‘stall out’ and plateau at a level well
Course below that expected for the child’s age. Acquired dysphasia
may be seen with head trauma, encephalitis, tumors, and the
Although some degree of improvement may gradually Landau–Kleffner syndrome, and has also been reported as a
occur during adolescence, for the most part this is a side-effect of topiramate (Gross-Tsur and Shalev 2004).
chronic disorder. Finally, there is the question of the ‘late talkers’, that is
children whose language development, although delayed,
eventually results in normal linguistic competence. At
Etiology present, there is no method whereby these children can be
confidently distinguished from those whose development
Developmental dysphasia is familial and linkage has been will eventually plateau at a lower than normal level, and
found to loci on chromosomes 13, 16, and 19 (Bartlett et al. consequently long-term clinical follow-up is required.
2002, SLI Consortium 2004). In one well-studied family
(‘KE’), in which developmental dysphasia is inherited in a
fully penetrant autosomal dominant fashion, a specific Treatment
mutation was found on chromosome 7 (Lai et al. 2001).
Magnetic resonance imaging has demonstrated both a Remedial education is critical and often helpful. Some prac-
reversed asymmetry of linguistic cortex (De Fosse et al. titioners recommend treatment with anti-epileptic drugs in
2004) and, in a substantial minority of cases, polymicro- cases with interictal epileptiform discharges; however, this
gyria in the peri-sylvian region (Guerreiro et al. 2002). is controversial and there are no controlled studies to
Electroencephalogram studies have revealed an support this practice.
increased incidence of interictal epileptiform discharges
(Nasr et al. 2001), especially evident in sleep studies
(Picard et al. 1998). 9.17 DEVELOPMENTAL DYSLEXIA
One autopsy study demonstrated a dysplastic gyrus on the
inferior surface of the left frontal cortex (Cohen et al. 1989). In developmental dyslexia (Demonet et al. 2004), children,
Overall, it appears probable that developmental dysphasia despite normal intelligence and adequate educational
occurs secondary to a genetically mediated disruption of nor- opportunity, have great difficulty in learning how to read.
mal neuronal migration to the peri-sylvian cortex, resulting First described by Hinshelwood in 1896, this is a common
in gyriform or dysplastic abnormalities. It is not clear disorder, seen in up to 4 percent of school age children.
whether the interictal epileptiform discharges are merely Although once thought to be far more common in boys,
epiphenomenal, reflecting an unexpressed epileptogenic recent epidemiologic work suggests that the prevalence is
potential of dysplastic cortex, or are perhaps indicative of an roughly equal in boys and girls. Synonyms include reading
epileptic process that, at least theoretically, could disturb disorder, specific reading disability, and congenital word
normal development or function of the linguistic cortex. blindness (Orton 1925).

Deafness may simulate developmental dysphasia, and all Depending on its severity, developmental dyslexia may
children in whom this diagnosis is considered should have first come to light anywhere between the ages of 6 and 9
audiometry. years as the child falls behind his or her peers in the acqui-
Severe deprivation may stunt language development; sition of reading skills.
however, these children, in contrast to those with dyspha- In attempting to read out loud, these young patients seem
sia, typically show rapid gains when placed in a linguisti- to stumble over certain words: they may skip words and go
cally stimulating environment. on to the next, or they may misread a word and say one that
p 09.qxd 3/10/08 9:39 AM Page 422
is different from that on the page. The errors in reading often Mental retardation is characterized by deficient reading,
involve omitting certain letters or supplying a different letter but here, in contrast to developmental dyslexia, one finds
than the one printed; letter reversals often occur, such as ‘d’ deficits in other academic skills.
for ‘b’. In some cases, entire words are reversed, with the
child saying ‘pat’ for the written word ‘tap’, for example.
Reading comprehension is impaired and, after finally, and Treatment
haltingly, reading a paragraph, the child may be unable to
paraphrase it in his or her own words. In striking contrast, if Remedial education is often strikingly effective. Piracetam,
the same paragraph is read out loud to the child, he or she not available in the United States, may be helpful (Wilsher
may then be able to paraphrase it with little difficulty. et al. 1987); however, not all studies agree on this (Ackerman
Writing is also impaired, and similar reversals may be et al. 1991).
seen. Thus, intending to write ‘top’, the child may write
‘pot’. In some cases entire sentences may be reversed, with
the written words reading from right to left on the page. Of 9.18 DEVELOPMENTAL DYSGRAPHIA
note, if the child is asked to take a look at what he or she
has written and then asked if there are any errors, the Developmental dysgraphia (Deuel 1995; Gubbay and de
answer is often ‘no’. Klerk 1995; Roeltgen and Tucker 1988), also known as
developmental agraphia or ‘disorder of written express-
ion’, is characterized by an impaired acquisition of the
Course ability to write, despite normal intelligence and adequate
educational opportunity. This is probably an uncommon
Although there may be some spontaneous improvement disorder, and is probably more common in boys than girls.
over long periods of time, the overall natural course is
marked by a chronic difficulty in reading.
Clinical features
Etiology Children with this disorder often misspell words; their sen-
tences tend to be short and deficient in terms of grammar
Developmental dyslexia is clearly familial; concordance and syntax, and at times whole words may be missing,
among dizygotic twins is about 25 percent, and among giving sentences a ‘telegraphic’ quality. Penmanship may
monozygotic twins it rises to about 50 percent. Genetic hete- or may not be poor; at times the penmanship far outshines
rogeneity exists (Williams and O’Donovan 2006), with loci what is actually written. Importantly, and in stark contrast
identified on chromosomes 1, 3, 6, and 7. Autopsy studies in to what they write, these children are often able to express
males reveal cortical dysgenesis, which, although widespread, themselves quite well when speaking.
is concentrated in the left peri-sylvian areas (Galaburda et al.
1985). In females, although similar findings were noted,
Course
there was, in addition, widespread glial scarring (Humphreys
et al. 1990). Of note, and again in males, dysplastic changes
In the natural course of events, developmental dysgraphia
have also been identified in the medial geniculate body and
appears to be chronic.
the posterior lateral nucleus of the thalamus (Galaburda and
Eidelberg 1982). Magnetic resonance scanning has also sug-
gested a lack of normal cerebral asymmetry of the planum Etiology
temporale (Hynd et al. 1990); however, not all studies agree
on this (Rumsey et al. 1997). Of interest, recent work has Apart from the fact that dysgraphia tends to run in families
demonstrated that specific evoked potential abnormalities in (Schulte-Korne 2001), little is known about its etiology.
infants predict the appearance of dyslexia (Molfese 2000).
Overall, it appears likely that developmental dyslexia
occurs secondary to an inherited disturbance of neuronal Differential diagnosis
migration, resulting in cortical microdysgenesis of the
temporal cortex. Developmental dyslexia is distinguished by a concurrent
difficulty with reading, and mental retardation by associated
deficits in other academic abilities.
Decreased visual acuity, severe anxiety, or a less than ade- Treatment

quate educational setting may all impair a child’s ability to
learn to read. Remedial education is effective.
p 09.qxd 3/10/08 9:39 AM Page 423
9.20 Developmental stuttering 423
9.19 DEVELOPMENTAL DYSCALCULIA 9.20 DEVELOPMENTAL STUTTERING

Developmental dyscalculia (Shalev 2004) is characterized Developmental stuttering occurs in roughly 1 percent of
by a more or less complete inability, despite otherwise nor- school-age children, and is about four times as common in
mal intelligence and adequate educational opportunity, to boys than girls.
acquire arithmetic skills. This is a relatively common disor-
der, occurring in 5–6 percent of school age children, and is
seen with roughly equal frequency in boys and girls. Clinical features
Synonyms for this disorder include mathematics disorder
and developmental arithmetic disorder. Stuttering typically first appears between the ages of 2 and 10
years. The stuttering itself may occur with any word or, alter-
natively, only with certain syllables or letters. Typically, when
Clinical features stuttering occurs over syllables or letters, it is the first syllable
or letter in a word that usually blocks speech; in this regard,
In severe cases, patients are unable to perform the simplest of ‘b’s, ‘d’s, ‘k’s, ‘p’s, and ‘t’s are common precipitants. In
numerical operations, such as counting to 10. In other cases, attempting to speak, the patient feels ‘blocked’ and may
children, although able to count, are unable to perform sim- appear to stumble over the word or sound, attempting to
ple addition; those who progress to the mastery of simple say it again and again, sometimes with increasingly explosive
addition may be unable to subtract, multiply, or divide. force. Often these attempts are accompanied by repetitive
grimacing, blinking, hissing, or forceful thrusting of the head,
arms, or even the trunk. After the sound or word is eventu-
Course ally spoken, there may be a veritable cascade of words, all
correctly pronounced, until the next verbal stumbling
Roughly one-half of patients will experience considerable block is encountered.
improvement by the early teenage years (Shalev et al. 2005). Stuttering is generally worse when patients are anxious,
pressed for time, or speaking in front of a group.
Interestingly, fluency may be improved or even restored if
Etiology
the patient reads a text, speaks in unison with others, or sings.
Although developmental dyscalculia is clearly familial
(Shalev et al. 2001), the genetic basis for this is not clear. Course
Autopsy studies are lacking; however, both magnetic reso-
nance spectroscopy (Levy et al. 1999) and voxel-based Spontaneous remission occurs in about three-quarters of
morphometry (Issacs et al. 2001) indicate a lesion in the patients by early teenage years, and is more likely to occur
left parietal cortex. in girls than boys.
Differential diagnosis Etiology

An inability to learn arithmetic has also been noted in chil- Developmental stuttering is clearly familial, and linkage
dren who were born prematurely with very low birth weight studies suggest loci on chromosomes 7 and 12 (Suresh et al.
(Issacs et al. 2001) and in association with the fragile X syn- 2006). Magnetic resonance imaging has indicated both
drome or petit mal epilepsy (Shalev and Gross-Tsur 1993). reduced cerebral asymmetry of the plana temporalia and dis-
Inability to learn arithmetic may also, of course, be seen in ruption of gyral architecture along the left peri-sylvian cortex
mental retardation of any cause; however, here it is associa- (Foundas et al. 2001). PET scanning (Fox et al. 1996, Wu
ted with other cognitive disabilities, thus distinguishing it et al. 1995) has demonstrated reduced metabolic activity in
from developmental dyscalculia, in which the inability to the left frontal peri-sylvian cortex and increased activity in
learn arithmetic occurs in isolation. the homologous area on the right, which may, however,
New-onset dyscalculia in a child who has previously merely represent a compensatory change. Taken together,
learned to do arithmetic is, of course, inconsistent with a these findings are consistent with an inherited disorder of
diagnosis of developmental dyscalculia; such a scenario has neuronal migration to the left superior perisylvian cortex.
been reported in a child with a left temporoparietal tumor
(Martins et al. 1999).
Treatment Acquired stuttering differs clinically from developmental

stuttering in that acquired stuttering is likely to occur on
Remedial education is effective. any syllable, regardless of where it falls in a word, rather
p 09.qxd 3/10/08 9:39 AM Page 424
than on the first one, as is the case in developmental stutter- Armstrong DD, Dunn K, Antalffy B. Decreased dendritic branching
ing. Furthermore, those with acquired stuttering rarely in frontal, motor and limbic cortex in Rett syndrome compared
demonstrate the kind of forceful effort to overcome a block with trisomy 21. J Neuropathol Exp Neurol 1998; 57:1013–17.
as is seen with developmental stuttering. Acquired stuttering Arnold LE, Aan MG, Cook AM et al. Atomoxetine for hyperactivity
may be seen with lesions of the left frontal or parietal in autism spectrum disorders: placebo-controlled crossover
cortices or basal ganglia, and may also occur as a side-effect pilot trial. J Am Acad Child Adolesc Psychiatry 2006;
of various drugs, including methylphenidate, tricyclic anti- 45:1196–205.
depressants, monoamine oxidase inhibitors, SSRIs, certain Arzimanoglou AA, Andermann F, Aicardi J et al. Sturge–Weber
antipsychotics, theophylline, and phenytoin. syndrome. Indications and results of surgery in 20 patients.
Neurology 2000; 55:1472–9.
Auranen M, Vanhala R, Vosman M et al. MECP2 gene analysis in
Treatment classical Rett syndrome and in patients with Rett-like
features. Neurology 2001; 56:611–17.
Speech therapy appears to be effective. In cases in which Aydin A, Cakmakci H, Kovanlikaya A et al. Sturge–Weber
stuttering persists despite adequate speech therapy, consid- syndrome without facial nevus. Pediatr Neurol 2000;
eration may be given to pharmacologic treatment. Various 22:400–2.
medications have been demonstrated to be effective in dou- Bailey A, le Couteur A, Gottesmann I et al. Autism as a strongly
ble-blind trials, including clomipramine (mean dose genetic disorder: evidence from a British twin study. Psychol
⬃150 mg) (Gordon et al. 1995), haloperidol (mean dose Med 1995; 25:63–77.
⬃3 mg) (Murray et al. 1977), olanzapine (2.5–5 mg/day) Baird PA, Sadovnik AD. Life expectancy in Down syndrome.
(Maguire et al. 2004), and risperidone (best results seen at J Pediatr 1987; 110:849–54.
0.5 mg/day; in some cases, higher doses were associated Baird PA, Sadovnik AD. Life expectancy in Down syndrome adults.
with a loss of effect) (Maguire et al. 2000). As there have Lancet 1988; 2:1354–6.
been no head-to-head comparative studies of these agents, Bartak L, Rutter M, Cox A. A comparative study of infantile autism
choosing among them requires clinical judgment. In this and specific developmental receptive language disorder. I. The
regard, it should be borne in mind that haloperidol, children. Br J Psychiatry 1975; 126:127–45.
although effective, was poorly tolerated. In addition to Bartlett CW, Flax JF, Logue MW et al. A major susceptibility locus
these blind studies, there is also a very intriguing case report for specific language impairment is located on 13q21. Am J
of complete remission of developmental stuttering with Hum Genet 2002; 71:45–55.
chronic treatment with levetiracetam (Canevini et al. 2002). Bassett AS, Chow EWC, Abdelmalik P et al. The schizophrenia
phenotype in 22q11 deletion syndrome. Am J Psychiatry 2003;
160:1580–6.
REFERENCES Bauman ML, Kemper TL, Arin DM. Pervasive neuroanatomic
abnormalities of the brain in three cases of Rett’s syndrome.
Ackerman PT, Dykman RA, Hooloway C et al. A trial of piracetam Neurology 1995; 45:1581–6.
in two subgroups of students with dyslexia enrolled in summer Baumgardner TL, Reiss AL, Freund LS et al. Specification of the
tutoring. J Learn Disabil 1991; 24:542–9. neurobehavioral phenotype in males with fragile X syndrome.
Allen SM, Rice SN. Risperidone antagonism of self-mutilation in a Pediatrics 1995; 95:744–52.
Lesch–Nyhan patient. Prog Neuropsychopharmacol Biol Beales PL, Warner AM, Hitman GA et al. Bardet-Biedl syndrome: a
Psychiatry 1996; 20:793–800. molecular and phenotypic study of 18 families. J Med Genet
Alsen G, Gillberg IC, Lindblom R et al. Tuberous sclerosis in 1997; 34:92–8.
Western Sweden: a population study of cases with early Bebin EM, Gomez MR. Prognosis in Sturge–Weber disease:
childhood onset. Arch Neurol 1994; 51:76–81. comparison of unihemispheric and bihemispheric involvement.
van Amelsvoort T, Daly E, Henry J et al. Brain anatomy in adults J Child Neurology 1988; 3:181–4.
with velocardiofacial syndrome with and without Belichenko PV, Hagberg B, Dahlstrom A. Morphological study of
schizophrenia: preliminary results of a structural magnetic neocortical areas in Rett syndrome. Acta Neuropathol 1997;
resonance imaging study. Arch Gen Psychiatry 2004; 93:50–61.
61:1085–96. Benedikt RA, Brown DC, Walker R et al. Sturge–Weber syndrome;
Amir RE, Van den Veyver IB, Wan M et al. Rett syndrome is caused cranial MR with Gd-DTPA. AJNR 1993; 14:409–15.
by mutations in X-linked MECP2, encoding methyl-CpG- Berquin PC, Gledd JN, Jacobsen LK et al. Cerebellum in attention-
binding protein 2. Nat Genet 1999; 23:185–8. deficit hyperactivity disorder: a morphometric MRI study.
Amir RE, Van den Veyver IB, Schultz R et al. Influence of mutation Neurology 1998; 50:1087–93.
type and X chromosome inactivation on Rett syndrome Biederman J, Faraone SV. Attention-deficit hyperactivity disorder.
phenotypes. Ann Neurol 2000; 47:670–9. Lancet 2005; 366:237–48.
Anderson LT, Campbell M, Grega DM et al. Haloperidol in the Bish JP, Nguyen V, Ding L et al. Thalamic reductions in children
treatment of infantile autism: effects on learning and with chromosome 22q11.2 deletion syndrome. Neuroreport
behavioral symptoms. Am J Psychiatry 1984; 141:195–202. 2004; 15:1413–15.
p 09.qxd 3/10/08 9:39 AM Page 425
References 425
Boer H, Holland A, Whittington J et al. Psychotic illness in people with other mentally handicapped adults. Br J Psychiatry 1992;
with Prader Willi syndrome due to chromosome 15 maternal 161:671–4.
uniparental disomy. Lancet 2002; 359:135–6. Collacott RA, Cooper SA, Ismail IA. Multi-infarct dementia in
van Bogaert P, Ceballos I, Desguerre I et al. Lesch–Nyhan in a girl. Down’s syndrome. J Intellect Disabil Res 1994; 38:203–8.
J Inherit Metabol Dis 1992; 15:790–1. Creange A, Zeller J, Rostaing-Rigattieri et al. Neurological
Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal complications of neurofibromatosis type 1 in adulthood. Brain
lobes with autism and atypical autism. Lancet 1997; 349:392–5. 1999; 122:473–81.
Bolton PF, Park RJ, Higgins JN et al. Neuro-epileptic determinants Critchley M, Earl CJ. Tuberous sclerosis and allied conditions.
of autism spectrum disorders in tuberous sclerosis complex. Brain 1932; 55:311–46.
Brain 2002; 125:1247–55. Danielsson S, Gillberg C, Billstedt E et al. Epilepsy in young adults
Bray GA, Dahms WT, Swerdloff RS et al. The Prader–Willi with autism: a prospective population based follow-up study
syndrome: a study of 40 patients and a review of the of 100 individuals diagnosed in childhood. Epilepsia 2005;
literature. Medicine 1983; 62:59–88. 46:918–23.
Burke CM, Kousseff BG, Gleeson M et al. Familial Prader–Willi Davidson BL, Tarle SA, Patella TD et al. Molecular basis of
syndrome. Arch Int Med 1987; 147:673–5. hypoxanthine-guanine phosphoribosyltransferase deficiency in
Butler MG, Meany FJ, Palmer CG. Clinical and cytogenetic survey ten subjects determined by direct sequencing of amplified
of 39 individuals with Prader–Labhart–Willi syndrome. Am J transcripts. J Clin Invest 1989; 84:342–6.
Med Genet 1986; 23:793–809. Dayer AG, Bottani A, Bouchardy I et al. MECP2 mutant allele in a
Bye AM, Vines R, Fronsek K. The obesity hypoventilation syndrome boy with Rett syndrome and his unaffected hemizygous
and the Prader–Willi syndrome. Aust Paediatr J 1983; 19:251–5. mother. Brain Dev 2007; 29:47–50.
Campbell LE, Daly E, Toal F et al. Brain and behavior in children De Arce MA, Kearns A. The fragile X syndrome: the patients and
with 22q11.2 deletion syndrome: a volumetric and voxel-based their chromosomes. J Med Genet 1984; 21:84–91.
morphometry MRI study. Brain 2006; 129:1218–28. De Fosse L, Hodge SM, Makris N et al. Language-association
Canevini MP, Chifari R, Piazzini A. Improvement of a patient with cortex asymmetry in autism and specific language impairment.
stuttering on levetiracetam. Neurology 2002; 59:1288. Ann Neurol 2004; 56:757–66.
Castellanos FS, Lee PP, Sharp W et al. Developmental trajectories of von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1:
brain volume abnormalities in children and adolescents with pathology, clinical features and molecular genetics. Brain
attention-deficit/hyperactivity disorder. JAMA 2002; 288:1740–8. Pathol 1995; 5:153–62.
Chao DHC. Congenital neurocutaneous syndromes of childhood. Demonet JF, Taylor MJ, Chaix Y. Developmental dyslexia. Lancet
III. Sturge–Weber disease. J Pediatr 1959; 55:635–49. 2004; 364:247–8.
Chess S, Fernandez P, Korn S. Behavioral consequences of Desmond M, Wilson G, Melnick J et al. Congenital rubella
congenital rubella. J Pediatr 1978; 93:699–703. encephalitis. J Pediatrics 1967; 71:311–31.
Chinta M. Hypothyroidism in Down’s syndrome. Br J Psychiatry Deuel RK. Developmental dysgraphia and motor skills disorders.
1988; 153:102–4. J Child Neurol 1995; 10 (suppl. 1):6–8.
Christie R, Bay C, Kaufman IA et al. Lesch–Nyhan disease: clinical Devlin LA, Shepherd CH, Crawford H et al. Tuberous sclerosis
experience with nineteen patients. Dev Med Child Neurol complex: clinical features, diagnosis, and prevalence within
1982; 24:293–306. Northern Ireland. Dev Med Child Neurol 2006; 48:495–9.
Chudley AE, Hagerman RJ. Fragile X syndrome. J Pediatrics 1987; DiMario FJ, Ramsby G. Magnetic resonance imaging lesion analysis
110:821–31. in neurofibromatosis type 1. Arch Neurol 1998; 55:500–5.
Clarke DJ. Prader–Willi syndrome and psychoses. Br J Psychiatry DiPaolo DP, Zimmerman RA, Rorke LB et al. Neurofibromatosis
1993; 163:680–4. type 1: pathologic substrate of high-signal intensity in the
Clarke DJ, Baer H, Whittington J et al. Prader-Willi syndrome, brain. Radiology 1995; 195:721–4.
compulsive and ritualistic behaviors: the first population- Dorrego MF, Canevaro L, Kuzia G et al. A randomized, double-blind,
based survey. Br J Psychiatry 2002; 180:358–62. crossover study of methylphenidate and lithium in adults with
Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med attention-deficit/hyperactivity disorder: preliminary findings.
1978; 298:1063–7. J Neuropsychiatry Clin Neurosci 2002; 14:289–95.
Clarren SK, Alvord EC, Sumi SM et al. Brain malformations related Dotti MT, Orrico A, De Stefano N et al. A Rett syndrome MECP2
to prenatal exposure to alcohol. J Pediatrics 1978; 92:64–7. mutation that causes mental retardation in men. Neurology
Clift S, Dahlitz M, Parkes JD. Sleep apnoea in the Prader-Willi 2002; 58:226–30.
syndrome. J Sleep Res 1994; 3:121–6. Down JLH. Observation on an ethnic classification of idiots. Clin
Cohen M, Campbell R, Yaghmai F. Neuropathological Lect Rep Lond Hosp 1866; 3:259–62.
abnormalities in developmental dysphasia. Ann Neurol 1989; Dunn HG. The Prader–Labhart–Willi syndrome: a review of the
25:546–70. literature and report of nine cases. Acta Paediatr Scand Suppl
Coleman M, Brubaker J, Hunter K et al. Rett syndrome: a survey of 1968; 186:1–38.
North American patients. J Ment Def Res 1988; 32:117–24. Durst R, Rubin-Jabotinsky K, Raskin S et al. Risperidone in
Collacott RA, Cooper S-A, McGrother C. Differential rates of treating behavioral disturbances of Prader-Willi syndrome.
psychiatric disorder in adults with Down’s syndrome compared Acta Psychiatr Scand 2000; 102:461–5.
p 09.qxd 3/10/08 9:39 AM Page 426
Dykens EM, Hodapp RM, Ort S et al. The trajectory of cognitive Franz DN, Leonard J, Tudor C et al. Rapamycin causes regression
development in males with fragile X syndrome. J Am Acad of astrocytomas in tuberous sclerosis complex. Ann Neurol
Child Adolesc Psychiatry 1989; 28:422–6. 2006; 59:490–8.
Edwards A, Voss H, Rice P et al. Automated DNA sequencing of Fryer AE, Chalmers A, Connor JM et al. Evidence that the gene for
the human HPRT locus. Genomics 1990; 6:593–608. tuberous sclerosis is on chromosome 9. Lancet 1987; 1:659–61.
Eliez S, Schmitt JE, White CD et al. Children and adolescents with Galaburda AM, Eidelberg D. Symmetry and asymmetry in the
velocardiofacial syndrome: a volumetric MRI study. Am J human posterior thalamus. II. Thalamic lesions in a case of
Psychiatry 2000; 157:409–15. developmental dyslexia. Arch Neurol 1982; 39:333–6.
Ernst M, Zametkin AJ, Matochil JA et al. Presynaptic dopaminergic Galaburda AM, Sherman GF, Rosen GS et al. Developmental
deficits in Lesch–Nyhan disease. N Engl J Med 1996; dyslexia: four consecutive patients with cortical abnormalities.
334:1568–72. Ann Neurol 1985; 18:222–33.
European Chromosome 16 Tuberous Sclerosis Consortium. Gibbs RA, Caskey CT. Identification and localization of mutations
Identification and characterization of the tuberous sclerosis at the Lesch–Nyhan locus by ribonuclease A cleavage. Science
gene on chromosome 16. Cell 1993; 75:1305–15. 1987; 236:303–5.
Evenhuius HM. The natural history in Down’s syndrome. Arch Giedd JN, Clasen LS, Wallace GL et al. XXY (Klinefelter syndrome):
Neurol 1990; 47:263–7. a pediatric quantitative brain magnetic resonance imaging
Everman DB, Stoudemire A. Bipolar disorder associated with case-control study. Pediatrics 2007; 119:232–40.
Klinefelter’s syndrome and other chromosomal abnormalities. Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold,
Psychosomatics 1994; 35:35–40. 2000.
Faraone SV, Perlis RH, Doyle AE et al. Molecular genetics of Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in
attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; tuberous sclerosis complex. Neurology 2004; 63:1457–61.
57:1313–23. Gordon CT, State RC, Nelson JE et al. A double-blind comparison
Feldmann R, Denecke J, Grenzebach M et al. Neurofibromatosis of clomipramine, desipramine and placebo in the treatment of
type 1. Motor and cognitive function and T2-weighted MRI autistic disorder. Arch Gen Psychiatry 1993; 50:441–7.
hyperintensities. Neurology 2003; 61:1725–8. Gordon CT, Cotelingam GM, Stager S et al. A double-blind
Felman HM, Kolmen BK, Gonzaga AM. Naltrexone and comparison of clomipramine and desipramine in the treatment
communication skills in young children with autism. J Am of developmental stuttering. J Clin Psychiatry 1995;
Acad Child Adolesc Psychiatry 1999; 38:587–93. 56:238–42.
Ferrer I, Galofre E. Dendritic spine abnormalities in fetal alcohol Gothelf D, Presburger G, Zohar AH et al. Obsessive-compulsive
syndrome. Neuropediatrics 1987; 18:161–3. disorder in patients with velocardiofacial (22q11 deletion)
Fine SE, Weissman A, Gerdes M et al. Autism spectrum disorders syndrome. Am J Med Genet B Neuropsychiatr Genet 2004;
and symptoms in children with molecularly confirmed 126:99–105.
22q11.2 deletion syndrome. Autism Dev Disord 2005; Gothelf D, Feinstein C, Thompson T et al. Risk factors for the
35:461–70. emergence of psychotic disorders in adolescents with 22q11.2
Finelli PF, Pueschel SM, Padre-Mendoza T et al. Neurological deletion syndrome. Am J Psychiatry 2007; 164:663–9.
findings in patients with the fragile-X syndrome. J Neurol Goyal M, O’Riordan MA, Wiznetzer M. Effect of topiramate on
Neurosurg Psychiatry 1985; 48:150–3. seizures and respiratory dysrhythmia in Rett syndrome. J Child
Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin Neurol 2004; 19:588–91.
pairs. J Child Psychol Psychiatry 1977; 18:297–321. Graham DI, Lantos PL. Greenfield’s neurology, 6th edn. London:
Fombonne E, Du Mazuabrun C, Cans C et al. Autism and Arnold, 1996.
associated medical disorders in a French epidemiological Graham JM, Bashir AS, Stark RE et al. Oral and written language
study. J Am Acad Child Adolesc Psychiatry 1997; 36:1561–9. abilities of XXY boys: implications for anticipatory guidance.
Foundas AL, Bollich AM, Corey DM et al. Anomalous anatomy of Pediatrics 1988; 81:795–806.
speech-language areas in adults with persistent Green JS, Parfrey PS, Harnett JD et al. The cardinal features of
developmental stuttering. Neurology 2001; 57:207–15. Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl
Forrest JM, Menser MA. Congenital rubella in school children and syndrome. N Engl J Med 1989; 321:1002–9.
adolescents. Arch Dis Child 1970; 45:63–9. Greenswag LR. Adults with Prader-Willi syndrome: a survey of
Forrest JM, Turnbull FM, Sholler GF et al. Gregg’s congenital 232 cases. Dev Med Child Neurol 1987; 29:145–52.
rubella patients 60 years later. Med J Aust 2002; 177:664–7. Gross-Tsur V, Shalev RS. Reversible language regression as an
Forsman H. The mental implications of sex chromosome adverse effect of topiramate treatment in children. Neurology
aberrations. The Blake Marsh lecture for 1970. Br J Psychiatry 2004; 62:299–300.
1970; 117:353–63. Gubbay SS, de Klerk NH. A study and review of developmental
Fox PT, Ingham RJ, Ingham JC et al. A PET study of the neural dysgraphia in relation to acquired dysgraphia. Brain Dev 1995;
systems of stuttering. Nature 1996; 382:158–61. 17:1–8.
Frankhauser MP, Karumanchi VC, German ML et al. A double-blind Guerreiro MM, Hage SR, Guimaraes CA et al. Developmental
placebo-controlled study of the efficacy of transdermal language disorder associated with polymicrogyria. Neurology
clonidine in autism. J Clin Psychiatry 1992; 53:77–82. 2002; 59:245–50.
p 09.qxd 3/10/08 9:39 AM Page 427
References 427
Guillamo J-S, Creange A, Kalifa C et al. Prognostic features of CNS Hunter H. A controlled study of the psychopathology and physical
tumors in neurofibromatosis 1 (NF1): a retrospective study of measurements of Klinefelter’s syndrome. Br J Psychiatry 1969;
104 patients. Brain 2003; 126:152–60. 115:443–8.
Gutierrez GC, Smalley SL, Tanguey PE. Autism in tuberous Huppke P, Maier EM, Warnke A et al. Very mild cases of Rett
sclerosis complex. J Autism Dev Disord 1998; 28:97–103. syndrome with skewed X inactivation. J Med Genet 2006;
Gutowski NJ, Murphy RP. Late onset epilepsy in undiagnosed 43:814–16.
tuberous sclerosis. Postgrad Med J 1992; 68:970–1. Huppke P, Kohler K, Brockmann K et al. Treatment of epilepsy in
Hagberg BA. Rett syndrome: clinical peculiarities, diagnostic Rett syndrome. Eur J Paediatr Neurol 2007; 11:10–16.
approach, and possible cause. Pediatr Neurol 1989; 5:75–83. Hurst LC, Mulhall DJ. Another calendar savant. Br J Psychiatry
Hagberg BA, Witt-Engerstrom I. Rett’s syndrome: a suggested 1988; 152:274–7.
staging system for describing the impairment profile with Huson SM, Harper PS, Compston DAS. Von Recklinghausen
increasing age toward adolescence. Am J Med Genet 1986; neurofibromatosis: a clinical and population study in south-
24(suppl. 1):47–59. east Wales. Brain 1988; 111:1355–81.
Hagberg B, Aicardi J, Ramos O. A progressive syndrome of autism, Hyman BT, West HL, Rebeck GW et al. Neuropathological changes
ataxia and loss of purposeful hand use in girls: Rett’s in Down’s syndrome hippocampal formation. Effect of age and
syndrome: report of 35 cases. Ann Neurol 1983; apolipoprotein E genotype. Arch Neurol 1995; 52:373–8.
14:471–9. Hyman MH, Whittemore VH. National Institutes of Health
Hagerman RJ, Murphy MA, Wittenberger MD. A controlled trial of consensus conference: tuberous sclerosis complex. Arch Neurol
stimulant medication in children with fragile X syndrome. Am 2000; 57:662–5.
J Med Genet 1988; 30:377–92. Hyman SL, Gill DS, Shees EA et al. Natural history of cognitive
Hall BD, Smith DW. Prader–Willi syndrome. J Pediatrics 1972; deficits and their relationship to MRI T2-hyperintensities in
81:286–93. NF1. Neurology 2003; 60:1139–45.
Hardy JB. Clinical and developmental aspects of congenital Hyman SL, Shores A, North KN. The nature and frequency of
rubella. Arch Otolaryngol 1973; 98:230–6. cognitive deficits in children with neurofibromatosis type 1.
Harris JC, Less RR, Jinnah HA et al. Craniocerebral magnetic Neurology 2005; 65:1037–44.
resonance imaging measurement and findings in Lesch–Nyhan Hynd GW, Semrud-Clikeman M, Lorys AR et al. Brain morphology
syndrome. Arch Neurol 1998; 55:547–53. in developmental dyslexia and attention deficit
Hatanaka T, Higashino H, Woo M et al. Lesch–Nyhan syndrome disorder/hyperactivity. Arch Neurol 1990; 47:919–26.
with delayed onset of self-mutilation: hyperactivity of Issacs EB, Edmonds CJ, Lucas A et al. Calculation difficulties in
interneurons at the brainstem and blink reflex. Acta Neurol children of very low birthweight: a neural correlate. Brain
Scand 1990; 81:184–7. 2001; 124:1681–2.
Hauser P, Zametkin AJ, Martinez P et al. Attention deficit- Itti E, Gaw Gonsalo IT, Pawlikowska-Haddel A et al. The structural
hyperactivity disorder in people with generalized resistance to brain correlates of cognitive deficits in adults with Klinefelter’s
thyroid hormone. N Engl J Med 1993; 328:997–1001. syndrome. J Endocrinol Metabol 2006; 91:1423–7.
Hellings JA, Warnock JK. Self-injurious behavior and serotonin in Jankovic J, Caskey TC, Stout T et al. Lesch–Nyhan syndrome: a
Prader-Willi syndrome. Psychopharmacol Bull 1994; study of motor behavior and cerebrospinal fluid
30:245–50. neurotransmitters. Ann Neurol 1988; 33:466–9.
Hinshelwood J. A case of dyslexia – a peculiar form of word Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy
blindness. Lancet 1896; 2:1454. surgery in patients with tuberous sclerosis. Neurology 2004;
Hinton VJ, Brown WT, Wisniewski K et al. Analysis of neocortex in 62:479-81.
three males with the fragile X syndrome. Am J Med Genet Jellinger K, Seitelberger F. Neuropathology of Rett syndrome. Am J
1991; 41:289–94. Med Genet 1986; 1(suppl.):259–88.
Hollander E, Phillips A, Chaplin W et al. A placebo controlled Jellinger K, Armstrong D, Zoghbi HY et al. Neuropathology of Rett
crossover trial of liquid fluoxetine on repetitive behaviors in syndrome. Acta Neuropath 1988; 76:142–58.
childhood and adolescent autism. Neuropsychopharmacology Jervis GA. Early senile dementia in mongoloid idiocy. Am J
2005; 30:582–9. Psychiatry 1948; 105:102–6.
Hollander E, Wasserman S, Swanson EN et al. A double-blind Jinnah HA, Visser JE, Harris JC et al. Delineation of the motor
placebo-controlled pilot study of olanzapine in disorder of Lesch–Nyhan disease. Brain 2006; 129:1210–17.
childhood/adolescent pervasive developmental disorder. J Child Jones KL, Smith DW. Recognition of fetal alcohol syndrome in
Adolesc Psychopharamcol 2006a; 16:541–8. early infancy. Lancet 1973; 2:999–1001.
Hollander E, Soorya L, Wasserman S et al. Divalproex sodium vs. Jones KL, Smith DW, Streissguth AP et al. Outcome in offspring of
placebo in the treatment of repetitive behaviors in autism chronic alcoholic women. Lancet 1974; 1:1076–8.
spectrum disorders. Int J Neuropsychopharmacol 2006b; Kankirawatana P, Leonard H, Ellaway C et al. Early progressive
9:209–13. encephalopathy in boys and MECP2 mutation. Neurology
Humphreys P, Kaufmann WE, Galaburda AM. Developmental 2006; 67:164–6.
dyslexia in women: neuropathological findings in three Kanner L. Autistic disturbances of affective contact. Nervous Child
patients. Ann Neurol 1990; 28:727–38. 1943; 2:217–50.
p 09.qxd 3/10/08 9:39 AM Page 428
Kanner L. Early infantile autism. J Pediatrics 1944; 25:211–17. Listernick R, Charrow J, Greenwald MJ et al. Optic gliomas in
Kanner L. The conception of wholes and parts in early infantile children with neurofibromatosis type 1. J Pediatr 1989;
autism. Am J Psychiatry 1951; 108:23–6. 114:788–92.
Kao A, Mariani J, McDonald-McGinn DM et al. Increased Lubs M-LE, Bauer MS, Formas ME et al. Lisch nodules in
prevalence of seizures in patients with a 22q11.2 deletion. Am neurofibromatosis type 1. N Engl J Med 1991; 324:1264–6.
J Med Genet A 2004; 129:29–34. Lund J, Munk-Jorgensen P. Psychiatric aspects of Down’s
Karlsson B, Gustafsson J, Hedov G et al. Thyroid dysfunction in syndrome. Acta Psychiatr Scand 1988; 78:369–74.
Down’s syndrome: relation to age and thyroid autoimmunity. Mackie S, Shaw P, Lenroot R et al. Cerebellar development and
Arch Dis Child 1998; 79:242–5. clinical outcome in attention deficit hyperactivity disorder. Am
Kates WR, Miller AM, Abdulsabur N et al. Temporal lobe anatomy J Psychiatry 2007; 164:645–55.
and psychiatric symptoms in velocardiofacial syndrome Madsen KM, Huiid A, Vestergaard M et al. A population-based
(22q11.2 deletion syndrome). J Am Acad Child Adolesc study of measles, mumps, and rubella vaccination and autism.
Psychiatry 2006; 45:587–95. N Engl J Med 2002; 347:1477–82.
Khalifa MM, Struthers JL. Klinefelter syndrome is a common cause Maguire GA, Riley GD, Franklin DL et al. Risperidone for the
for mental retardation of unknown etiology among treatment of stuttering. J Clin Psychopharmacol 2000;
prepubertal males. Clin Genet 2002; 61:49–53. 20:479–82.
Kielinen M, Rantala H, Timonen E et al. Associated medical Maguire GA, Riley GD, Franklin DL et al. Olanzapine in the
disorders and disabilities in children with autistic disorder: a treatment of developmental stuttering: a double-blind,
population-based study. Autism 2004; 8:49–60. placebo-controlled trial. Ann Clin Psychiatry 2004;
Klein D, Ammann F. The syndrome of 16:63–7.
Laurence–Moon–Biedl–Bardet and allied diseases in Mannuzza S, Klein RG, Klein DF et al. Accuracy of adult recall of
Switzerland. J Neurol Sci 1969; 9:479–513. childhood attention deficit hyperactivity disorder. Am J
Kofman O, Hyland HH. Tuberous sclerosis in adults with normal Psychiatry 2002; 159:1882–8.
intelligence. Arch Neurol Psychiatry 1959; 81:557–90. Maria BL, Neufeld JA, Rosainz LC et al. Central nervous system
Konovalov HV, Kovetsky NS, Bobryshev YV et al. Disorders of structure and function in Sturge–Weber syndrome: evidence
brain development in the progeny of mothers who used of neurologic and radiologic progression. J Child Neurol 1998;
alcohol during pregnancy. Early Hum Dev 1997; 13:606–18.
25:153–66. Martins IP, Ferreira J, Borges L. Acquired procedural dyscalculia
Kulkantrakorn K, Geller TJ. Seizures in neurofibromatosis 1. associated to a left parietal lesion in a child. Child
Pediatr Neurology 1998; 19:347–50. Neuropsychol 1999; 5:265–73.
Kuperman S, Perry PJ, Gaffney GR et al. Bupropion SR vs. Mathews WS, Solan A, Barabas G. Cognitive functioning in
methylphenidate vs. placebo for attention deficit hyperactivity Lesch–Nyhan syndrome. Dev Med Child Neurol 1995;
disorder in adults. Ann Clin Psychiatry 2001; 13:129–34. 37:715–22.
Lagos JC, Gomez MR. Tuberos sclerosis: reappraisal of a clinical Max JE, Schacher RJ, Levin HS et al. Predictors of secondary
entity. Mayo Clin Proc 1967; 42:26–49. attention-deficit/hyperactivity disorder in children and
Lai CS, Fisher SE, Hurst JA et al. A forkhead-domain gene is adolescents 6 to 24 months after traumatic brain injury. J Am
mutated in severe speech and language disorder. Nature 2001; Acad Child Adolesc Psychiatry 2005; 44:1041–9.
413:519–23. McCracken JT, McGough J, Shah H et al. Risperidone in children
Lai F, Williams RS. A prospective study of Alzheimer’s disease in with autism and serious behavioral problems. N Engl J Med
Down syndrome. Arch Neurol 1989; 46:849–53. 2002; 347:314–21.
Larsson G, Bohlin A-B, Tunell R. Prospective study of children McDonald-McGinn DM, Tonnesen MK, Laufer-Cahana A et al.
exposed to variable amounts of alcohol in utero. Arch Dis Child Phenotype of the 22q11.2 deletion in individuals identified
1985; 60:316–21. through an affected relative: cast a wide FISHing net! Genet
Lawlor BA, Maurer RG. Tuberous sclerosis and the autistic Med 2001; 3:23–9.
syndrome. Br J Psychiatry 1987; 150:396–7. McDougle CJ, Naylor ST, Cohen DJ et al. A double-blind, placebo-
Legius E, Descheemaeker MJ, Steyaert J et al. Neurofibromatosis controlled study of fluvoxamine in adults with autistic
type 1 in childhood: correlation of MRI findings with disorder. Arch Gen Psychiatry 1996; 53:1001–8.
intelligence. J Neurol Neurosurg Psychiatry 1995; 59:638–40. McDougle CJ, Holmes JP, Carlson DC et al. A double-blind,
Lesch M, Nyhan WL. A familial disorder of uric acid metabolism placebo-controlled study of risperidone in adults with autistic
and central nervous system function. Am J Med 1964; disorder and other pervasive developmental disorders. Arch
36:561–70. Gen Psychiatry 1998; 55:633–41.
Levy AM, Reiss IL, Grafman J. Metabolic abnormalities detected by McDougle CJ, Scahill L, Aman MG et al. Risperidone for the core
1H-MRS in dyscalculia and dysgraphia. Neurology 1999; symptom domains of autism: results from the study by the
53:639–41. Autism Network of the Research Units on Pediatric
Lichtenstein BW. Sturge–Weber–Dimitri syndrome: cephalic form Psychopharmacology. Am J Psychiatry 2005; 162:1142–8.
of neurocutaneous hemangiomatosis. Arch Neurol Psychiatry McManaman J, Tam DA. Gabapentin for self-injurious behavior in
1954; 71:291–301. Lesch–Nyhan syndrome. Pediatr Neurology 1999; 20:381–2.
p 09.qxd 3/10/08 9:39 AM Page 429
References 429
McVicker RW, Shanks OEP, McClelland RJ. Prevalence and including certain cases of childhood schizophrenia. Arch Gen
associated features of epilepsy in adults with Down’s Psychiatry 1968; 18:76–8.
syndrome. Br J Psychiatry 1994; 164:528–32. Orton ST. Word blindness in school children. Arch Neurol
Miller E, Craddock-Watson JE, Pollock TM. Consequences of Psychiatry 1925; 14:581–615.
confirmed maternal rubella at successive stages of pregnancy. Palmen SJ, von Engeland H, Hof PR et al. Neuropathological
Lancet 1982; 2:781–4. findings in autism. Brain 2004; 127:2572–83.
Miller JL, Couch JA, Schmalfuss et al. Intracranial abnormalities Pampiglione G, Moynahan EJ. The tuberous sclerosis syndrome:
detected by three-dimensional magnetic resonance imaging in clinical and EEG studies in 100 children. J Neurol Neurosurg
Prader-Willi syndrome. Am J Med Genet A 2007; 143:476–83. Psychiatry 1976; 39:666–73.
Mizuno T. Long-term follow-up of ten patients with Lesch–Nyhan Papolos DF, Faedda GL, Veit S et al. Bipolar spectrum disorders in
syndrome. Neuropediatrics 1986; 17:158–61. patients diagnosed with velo-cardio-facial syndrome: does a
Mohammadi MR, Ghanizadeh A, Alaghband-Rad J et al. Selegeline hemizygous deletion of chromosome 22q11 result in bipolar
in comparison with methylphenidate in attention deficit affective disorder? Am J Psychiatry 1996; 153:1541–7.
hyperactivity disorder children and adolescents in a double- Pascual-Castroviejo I, Diaz-Gonzales C, Garcia-Melian RM et al.
blind, randomized trial. J Child Adolesc Psychopharamcol Sturge–Weber syndrome: study of 40 patients. Pediatr
2004; 14:418–25. Neurology 1993; 9:283–8.
Molfese DL. Predicting dyslexia at 8 years of age using neonatal Pasqualini RQ, Vidal G, Bur GE. Psychopathology of Klinefelter’s
brain responses. Brain Lang 2000; 72:238–45. syndrome. Review of thirty-one cases. Lancet 1957; 2:164–7.
Monaghan HP, Krafchik BR, Macgregor DL et al. Tuberous sclerosis Paul R, Cohen DJ, Caparulo BK. A longitudinal study of patients
complex in children. Am J Dis Child 1981; 135:912–17. with severe developmental disorders of language learning.
Morimoto K, Mogami H. Sequential CT study of subependymal J Am Acad Child Psychiatry 1983; 22:525–34.
giant-cell astrocytoma associated with tuberous sclerosis. Pearson E, Lenn NJ, Cail WS. Moymoya and other causes of stroke
J Neurosurg 1986; 65:874–7. in patients with Down syndrome. Pediatr Neurol 1985;
Mostofsky SH, Mazzocco MM, Aakalu G et al. Decreased cerebellar 1:174–9.
posterior vermis size in fragile X syndrome: correlation with Pelham WE, Gnagy EM, Chronis AM et al. A comparison of
neurocognitive performance. Neurology 1998; 50:121–30. morning-only and morning/late afternoon Adderall to
Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in morning-only, twice-daily, and three times-daily
adults with velo-cardio-facial syndrome. Arch Gen Psychiatry methylphenidate in children with attention-
1999; 56:940–5. deficit/hyperactivity disorder. Pediatrics 1999; 104:1300–11.
Murray TJ, Kelly P, Campbell L et al. Haloperidol in the treatment Percy AK, Gillberg C, Hagberg B et al. Rett syndrome and the
of stuttering. Br J Psychiatry 1977; 130:370–3. autistic disorders. Neurol Clinics 1990; 8:659–76.
Musumeci SA, Hagerman RJ, Ferri R et al. Epilepsy and EEG findings Percy AK, Glaze DG, Schultz RJ et al. Rett syndrome: controlled
in males with fragile X syndrome. Epilepsia 1999; 40:1092–9. study of oral opiate antagonist naltrexone. Ann Neurol 1994;
Myers SE, Whitman BY, Carrel AL et al. Two years of growth 35:464–70.
hormone therapy in young children with Prader-Willi Petermann AF, Hayles AB, Dockerty MB et al. Encephalotrigeminal
syndrome: physical and neurodevelopmental benefits. Am J angiomatosis (Sturge–Weber disease). Clinical study of 35
Med Genet A 2006; 143:443–8. cases. J Am Med Assoc 1958; 167:2169–76.
Nasr JT, Gabis L, Savatic M et al. The electroencephalogram in Petersen CD, Luzzatti K. The role of chromosome translocation in
children with developmental dysphasia. Epilepsy Beh 2001; the recurrence risk of Down’s syndrome. Pediatrics 1965;
2:115–18. 35:463–9.
Nielsen J. Klinefelter’s syndrome and the XYY syndrome. Acta Pfeiffer J, Majewski F, Fischbach H et al. Alcohol embryopathy and
Psychiatr Scand Suppl 1969; 209:1–353. fetopathy: neuropathology of three children and three fetuses.
Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males J Neurol Sci 1979; 41:125–37.
treated with testosterone. Clin Genet 1988; 33:262–9. Picard A, Cheliout Heraut F, Bouskaoui M et al. Sleep EEG and
North K, Joy P, Yuille D et al. Specific learning disability in developmental dysphasia. Dev Med Child Neurol 1998;
children with neurofibromatosis type 1: significance of MRI 40:595–9.
abnormalities. Neurology 1994; 44:878–83. Plotkin SA, Oski SA, Hartnett EM et al. Some recently recognized
Nyhan WL. Clinical features of the Lesch–Nyhan syndrome. Arch manifestations of the rubella syndrome. J Pediatrics 1965;
Int Med 1972; 130:186–92. 67:182–91.
Ogasawara N, Stout JT, Goto H et al. Molecular analysis of a Pomeroy JC. Klinefelter’s syndrome and schizophrenia. Br J
female Lesch–Nyhan patient. J Clin Invest 1989; 84:1024–7. Psychiatry 1980; 136:597–9.
Oldfors A, Sourander P, Armstrong DL et al. Rett syndrome: Prasher VP. Epilepsy and associated effects on adaptive behavior
cerebellar pathology. Pediatr Neurol 1990; 6:310–14. in adults with Down syndrome. Seizure 1995; 4:53–6.
Olsson I, Steffenberg S, Billberg C. Epilepsy in autism and autistic- Prasher VP, Huxley A, Haque MS et al. A 24-week, double-blind,
like conditions. Arch Neurol 1988; 45:666–8. placebo-controlled trial of donepezil in patients with Down
Ornitz EM, Ritvo ER. Perceptual inconstancy in early infantile syndrome and Alzheimer’s disease – pilot study. Int J Geriatr
autism: the syndrome of early infant autism and its variants, Psychiatry 2002; 17:270–8.
p 09.qxd 3/10/08 9:39 AM Page 430
Pueschel SM, Louis S, McKnight P. Seizure disorders in Down Ross MH, Galaburda AM, Kemper TL. Down’s syndrome: is there a
syndrome. Arch Neurol 1991; 48:318–20. decreased population of neurons? Neurology 1984;
Ramaekers VT, Hansen SI, Holm J et al. Reduced folate transport 34:909–16.
to the CNS in female Rett patients. Neurology 2003; Roth AA. Familial eunuchoidism: the Laurence–Moon–Biedl
61:506–15. syndrome. J Urology 1947; 57:427–42.
Ratcliffe SG, Bancroft J, Axworthy D et al. Klinefelter’s syndrome Roth JC, Epstein CJ. Infantile spasms and hypopigmented
in adolescents. Arch Dis Child 1982; 57:6–12. macules: early manifestations of tuberous sclerosis. Arch
Rathmell TK, Burns MA. The Laurence–Moon–Biedl syndrome Neurol 1971; 25:547–51.
occurring in a brother and a sister. Arch Neurol Psychiatry Rouleau GA, Wertelecki BR, Martuza RI et al. Genetic linkage of
1938; 39:1022–42. bilateral acoustic neurofibromatosis to a DNA marker on
Reiss AL, Lee J, Freunc L. Neuroanatomy of fragile X syndrome: chromosome 22. Nature 1987; 329:246–8.
the temporal lobe. Neurology 1994; 44:1317–24. Roy A. Schizophrenia and Klinefelter’s syndrome. Can J Psychiatry
Remington G, Sloman L, Konstantareas M et al. Clomipramine 1981; 26:262–4.
versus haloperidol in the treatment of autistic disorder: a Rudelli RD, Brown WT, Wisniewski K et al. Adult fragile X
double-blind, placebo-controlled, crossover study. J Clin syndrome: clinico-neuropathologic findings. Acta Neuropathol
Psychopharmacol 2001; 21:440–4. 1985; 67:289–95.
Research Units on Pediatric Psychopharmacology Autism Rumsey JM, Rapoport JL, Sceery WR. Autistic children as adults:
Network. Risperidone in children with autism and serious psychiatric, social, and behavioral outcomes. J Am Acad Child
behavioral problems. N Engl J Med 2002; 347:314–21. Psychiatry 1985; 24:465–73.
Research Units on Pediatric Psychopharmacology (RUPP) Autism Rumsey JM, Donohue BC, Brady DR et al. A magnetic resonance
Network. Randomized, controlled, crossover trial of imaging study of planum temporale asymmetry in men with
methylphenidate in pervasive developmental disorder with developmental dyslexia. Arch Neurol 1997; 54:1481–9.
hyperactivity. Arch Gen Psychiatry 2005; 62:1266–74. Sabaratnam M, Vroegop PG, Gangadhran SK. Epilepsy and EEG
Rett A. Uber ein eigenartiges hirnatrophisches syndrom bei findings in 18 males with fragile X syndrome. Seizure 2001;
hyperammonamie im kindersalter. Wien Med Wochenschr 10:60–3.
1966; 116:723–6. Saito Y, Ito M, Hanaoka S et al. Dopamine receptor upregulation
Richardson EP. Pathology of tuberous sclerosis. Neuropathologic in Lesch-Nyhan syndrome: a postmortem study.
aspects. Ann NY Acad Sci 1991; 615:128–39. Neuropediatrics 1999; 30:66–71.
Richer JM, Coss RG. Gaze aversion in autistic and normal children. Sato S, Dreifuss FE. Electroencephalographic findings in a patient
Acta Psychiatr Scand 1976; 53:193–210. with developmental expressive aphasia. Neurology 1973;
Ritvo ER, Mason-Brothers A, Freeman BJ et al. The 23:181–5.
UCLA–University of Utah epidemiologic survey of autism: the Scahill L, Chappell PB, Kim YS et al. A placebo-controlled study of
etiological role of rare diseases. Am J Psychiatry 1990; guanfacine in the treatment of children with tic disorders and
147:1614–21. attention deficit hyperactivity disorder. Am J Psychiatry 2001;
Roach ES, Delgado M, Anderson L et al. Carbamazepine trial for 158:1067–74.
Lesch-Nyhan self-mutilation. J Child Neurol 1996; 11:476–8. Schaer M, Schmitt JE, Glaser B et al. Abnormal patterns of cortical
Robinson WP, Bottani A, Yagang X. Molecular, cytogenetic and gyrification in velo-cardio-facial syndrome (deletion 22q11.2):
clinical investigations of Prader–Willi syndrome patients. Am J an MRI study. Psychiatry Res 2006; 146:1–11.
Hum Genet 1992; 49:1219–34. Schochet SS, Lampert PW, McCormick WF. Neurofibrillary tangles
Rodriguez HA, Barthrong M. Multiple primary intracranial tumors in patients with Down’s syndrome: a light and electron-
in von Recklinghausen’s neurofibromatosis. Arch Neurol 1966; microscopic study. Acta Neuropathol 1973; 23:342–6.
14:467–75. Schulte-Korne G. Annotation: genetics of reading and spelling
Roeltgen DP, Tucker DM. Developmental phonological and lexical disorder. J Child Psychol Psychiatry 2001; 42:985–97.
agraphia in adults. Brain Lang 1988; 35:287–300. Selikowitz M, Sunman J, Pendergast A et al. Fenfluramine in
Roizen L, Gold G, Berman HH et al. Congenital vascular anomalies Prader-Willi syndrome: a double blind, placebo controlled trial.
and their histopathology in Sturge–Weber–Dimitri syndrome Arch Dis Child 1990; 65:112–14.
(nevus flammeus with angiomatosis and encephalosis Shalev RS. Developmental dyscalculia. J Child Neurol 2004;
calcificans). J Neuropathol Exp Neurol 1972; 14:173–88. 19:765–71.
Rorke LB. Nervous system lesions in the congenital rubella Shalev RS, Gross-Tsur V. Developmental dyscalculia and medical
syndrome. Arch Otolaryngol 1973; 98:249–51. assessment. J Learn Disabil 1993; 26:134–7.
Rorke LB, Spiro AJ. Cerebral lesions in congenital rubella Shalev RS, Manor O, Kerem B et al. Developmental dyscalculia is a
syndrome. J Pediatrics 1967; 70:243–55. familial learning disability. J Learn Disabil 2001; 34:59–65.
Rosman NP, Pearce J. The brain in multiple neurofibromatosis Shalev RS, Manor O, Gross-Tsur V. Developmental dyscalculia: a
(von Recklinghausen’s disease): a suggested basis for the prospective six-year follow-up. Dev Med Child Neurol 2005;
associated mental defect. Brain 1967; 90:829–37. 47:121–5.
Ross AT, Dickerson WW. Tuberous sclerosis. Arch Neurol Psychiatry Shaw J, Lerch J, Greenstein D et al. Longitudinal mapping of
1943; 50:233–57. cortical thickness and clinical outcome in children and
p 09.qxd 3/10/08 9:39 AM Page 431
References 431
adolescents with attention-deficit/hyperactivity disorder. Arch bilateral chronic stimulation of the globus pallidus internus. J
Gen Psychiatry 2006; 63:540–9. Neurosurg 2003; 98:414–16.
Shaywitz SE, Caparulo B, Hodgson ES. Developmental language Taly AB, Nagaraja D, Das S et al. Sturge–Weber–Dimitri disease
disability as a result of prenatal exposure to ethanol. without facial nevus. Neurology 1987; 37:1063–4.
Pediatrics 1981; 68:850–5. Tartakow IJ. The teratogenicity of maternal rubella. J Pediatrics
Shprintzen RJ, Goldberg RB, Lewin ML et al. A new syndrome 1965; 66:380–91.
involving cleft palate, cardiac anomalies, typical facies, and Tatum WO, Passaro EA, Elia M et al. Seizure in Klinefelter’s
learning disabilities: velo-cardio-facial syndrome. Cleft Palate syndrome. Pediatr Neurology 1998; 19:275–82.
J 1978; 15:56–62. Taylor FB, Russo J. Efficacy of modafinil compared to
SLI Consortium (SLIC). Highly significant linkage to the SLI1 locus dextroamphetamine for the treatment of attention deficit
in an expanded sample of individuals affected by specific hyperactivity disorder in adults. J Child Adolesc
language impairment. Am J Hum Genet 2004; 74:1225–38. Psychopharmacol 2000; 10:311–20.
Smathers SA, Wilson JG, Nigro MA. Topiramate effectiveness in Taylor FB, Russo J. Comparing guanfacine and destroamphetamine
Prader-Willi syndrome. Pediatr Neurol 2003; 28:130–3. for the treatment of adult attention-deficit/hyperactivity
Spencer T, Biederaman J, Coffey B et al. A double-blind comparison disorder. J Clin Psychopharmacol 2001; 21:223–8.
of desipramine and placebo in children and adolescents with Temudo T, Oliveira P, Santos M et al. Stereotypies in Rett
chronic tic disorder and comorbid attention-deficit/hyperactivity syndrome. Analysis of 83 patients with and without detected
disorder. Arch Gen Psychiatry 2002; 59:649–56. MECP2 mutation. Neurology 2007; 68:1183–7.
Spohr HL, Willms J, Steinhausen HC. Prenatal alcohol exposure Treffert D. The idiot savant: a review of the syndrome. Am J
and long-term developmental consequences. Lancet 1993; Psychiatry 1988; 145:563–72.
341:907–10. Verkerk AJ, Pieretti M, Sutcliffe JS et al. Identification of a gene
Stenbom Y, Tonnby B, Hagberg B. Lamotrigine in Rett syndrome: (FMR1) containing a CGG repeat coincident with a breakage
treatment experience from a pilot study. Eur Child Adolesc point cluster region exhibiting length variation in fragile X
Psychiatry 1998; 7:49–52. syndrome. Cell 1991; 65:905–14.
Stoll C, Alembik Y, Dott B et al. Study of Down syndrome in Wakeling A. Comparative study of psychiatric patients with
238,942 consecutive births. Ann Genet 1998; 41:44–51. Klinefelter’s syndrome and hypogonadism. Psychol Med 1972;
Streissguth AP, Aase JM, Clarren SK et al. Fetal alcohol syndrome 2:139–54.
in adolescents and adults. J Am Med Assoc 1991; 265:1961–7. Wallace MR, Marchuk DA, Andersen LB et al. Type 1
Sturge WA. A case of partial epilepsy, apparently due to a lesion neurofibromatosis gene: identification of a large transcript
of one of the vaso-motor centres of the brain. Trans Clin Soc disrupted in three NF1 patients. Science 1990; 249:181–6.
London 1879; 12:162–7. Warren AC, Holroyd S, Folstein MF. Major depression in Down’s
Suetsugu M, Mehraein P. Spine distribution along the apical syndrome. Br J Psychiatry 1989; 155:202–5.
dendrites of the pyramidal neurons in Down’s syndrome. A Webb DW, Osborne JP. Tuberous sclerosis. Arch Dis Child 1995;
quantitative Golgi study. Acta Neuropathol 1980; 50:207–10. 72:471–4.
Sujansky E, Conradi S. Sturge–Weber syndrome: age of onset of Weber FP. A note on the association of extensive
seizures and glaucoma and the prognosis for affected children. haemangiomatous naevus of the skin with cerebral (meningeal)
J Child Neurol 1995a; 10:49–58. haemangioma especially cases of facial vascular naevus with
Sujansky E, Conradi S. Outcome of Sturge–Weber syndrome in 52 contralateral hemiplegia. Proc R Soc Med 1929; 22:431–42.
adults. Am J Med Genet 1995b; 57:35–45. Webster RI, Shevell MI. Neurobiology of specific language
Suresh R, Ambrose N, Roe C et al. New complexities in the impairment. J Child Neurol 2004; 19:471–81.
genetics of stuttering: significant sex-specific linkage signals. Weig SG, Pollack P. Carbamazepine-induced heart block in a child
Am J Hum Genet 2006; 78:554–63. with tuberous sclerosis and cardiac rhabdomyoma:
Sutherland GR. Heritable fragile sites on human chromosomes. implications for evaluation and follow-up. Ann Neurol 1993;
Demonstration of their dependence on the type of tissue 34:617–19.
culture medium. Science 1977; 197:265. Wigal SB, McGough JJ, McCracken JT et al. A laboratory school
Swaab DJ, Purba JS, Hofman MA. Alterations in the hypothalamic comparison of mixed amphetamine salts extended release
paraventricular nucleus and its xytocin neurons (putative (Adderall XR) and atomoxatine (Strattera) in school-aged
satiety cells) in Prader-Willi syndrome: a study of five cases. children with attention deficit/hyperactivity disorder. J Attent
J Clin Endocrinol Metab 1995; 80:573–9. Disord 2005; 9:275–89.
Swanson DW, Stipes AH. Psychiatric aspects of Klinefelter’s Williams J, O’Donovan MC. The genetics of developmental
syndrome. Am J Psychiatry 1969; 126:814–22. dyslexia. Eur J Hum Genet 2006; 14:681–9.
Swillen A, Devriendt K, Legius E et al. Intelligence and Wilsher CR, Bennett D, Chase CH et al. Piracetam and dyslexia:
psychosocial adjustment in velocardiofacial syndrome: a study effects on reading tests. J Clin Psychopharmacol 1987;
of 37 children and adolescents with VCFS. J Med Genet 1997; 7:230–7.
34:453–8. Wisniewski K, Dambska M, Sher JH et al. A clinical
Taira T, Kobayashi T, Hori T. Disappearance of self-mutilating neuropathological study of the fetal alcohol syndrome.
behavior in a patient with Lesch-Nyhan syndrome after Neuropediatrics 1983; 14:197–201.
p 09.qxd 3/10/08 9:39 AM Page 432
Wisniewski KE, Dalton AJ, McLachlan DRC et al. Alzheimer’s Wu JC, Maguire G, Riley G et al. A positron emission tomography
disease in Down’s syndrome: clinicopathologic studies. (18F) deoxyglucose study of developmental stuttering.
Neurology 1985a; 35:957–61. Neuroreport 1995; 15:501–5.
Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of Yakovlev PI, Corwin W. Roentgenographic sign in cases of
neuropathological changes and dementia of Alzheimer’s tuberous sclerosis of the brain (multiple ‘brain stones’). Arch
disease in Down’s syndrome. Ann Neurol 1985b; 17:278–82. Neurol Psychiatry 1939; 40:1030–7.
Wisniewski KE, Frency JH, Fernando S et al. Fragile X syndrome: Yang TP, Patel PI, Stout JT et al. Molecular evidence for new
associated neurological abnormalities and developmental mutations in the HPRT locus in Lesch–Nyhan patients. Nature
disabilities. Ann Neurol 1985c; 18:665–9. 1984; 310:412–14.
Witt-Engerstrom I. Rett syndrome in Sweden. Neurodevelopment – Zametkin A, Rapoport JL, Murphy DL et al. Treatment of hyperactive
disability – pathophysiology. Acta Pediatr Scand Suppl 1990; children with monoamine oxidase inhibitors. I. Clinical efficacy.
Wohlwill FS, Yakovlev PI. Histopathology of meningo-facial Zappella M. A double blind trial of bromocriptine in the Rett
angiomatosis (Sturge–Weber’s disease). J Neuropathol Exp syndrome. Brain Dev 1990; 12:148–50.
Neurol 1957; 16:341–64. Zellweger H, Schneider HJ. Syndrome of hypotonia–hypomentia–
Wong DF, Harris JC, Naidu S et al. Dopamine transporters are hypogonadism–obesity (HHHO) or Prader–Willi syndrome.
markedly reduced in Lesch-Nyhan disease in vivo. Proc Natl Am J Dis Child 1968; 115:588–98.
Acad Sci 1996; 93:5539–43.
p 10.qxd 3/10/08 5:52 PM Page 433
10
Vascular disorders
10.1 Multi-infarct dementia 433 10.10 Wegener’s granulomatosis 442

10.2 Lacunar dementia 434 10.11 Behçet’s disease 442
10.3 Vascular parkinsonism 435 10.12 Hypertensive encephalopathy 443
10.4 Binswanger’s disease 436 10.13 Reversible posterior leukoencephalopathy syndrome 444
10.5 Cranial arteritis 437 10.14 MELAS 445
10.6 Cerebral amyloid angiopathy 438 10.15 Thrombotic thrombocytopenic purpura 446
10.7 CADASIL 439 10.16 Fat embolism syndrome 446
10.8 Granulomatous angiitis of the central 10.17 Multiple cholesterol emboli syndrome 447
nervous system 440 10.18 Transient global amnesia 447
10.9 Polyarteritis nodosa 441 References 449
10.1 MULTI-INFARCT DEMENTIA multiple strokes preceding the onset of cognitive decline.
Although in some cases the dementia may be rather non-
Multi-infarct dementia is the traditional name given to specific, with mere difficulties in memory, calculations, and
dementia occurring secondary to multiple, generally large, abstractions, etc., in many cases multi-infarct dementia is
cortical infarctions; classically, in addition to the dementia, marked by depression, agitation, and hallucinations or delu-
such patients also have focal signs, such as aphasia, and their sions (Cummings et al. 1987). Depression may be heavily
history is characterized by a ‘stepwise’ course, with succes- tinged with irritability, and agitation may be extreme.
sive steps further down the cognitive ladder corresponding Hallucinations are generally visual, and delusions tend to be
to successive large-vessel, territorial infarctions. As will be either of persecution or misidentification. Focal signs, as
noted below, however, variations on this classic picture do noted, are common and may include aphasia, apraxia,
occur. Thus conceived, multi-infarct dementia is, in all like- neglect, and hemiparesis etc.; late in the course a pseudobul-
lihood, a common cause of dementia in the elderly. bar palsy may also appear, with, as discussed in Section 4.7,
Before proceeding, some comments are in order regard- emotional incontinence. Seizures may also occur.
ing the term ‘vascular dementia’. Vascular dementia is an Neuroimaging, either with computed tomography (CT)
umbrella term that includes not only multi-infarct dementia or, preferably, magnetic resonance imaging (MRI), will
but also lacunar dementia (Section 10.2) and Binswanger’s reveal evidence of multiple old infarctions in, as discussed
disease (Section 10.4). Lacunar dementia occurs secondary below, appropriately ‘strategic’ locations.
to multiple subcortical lacunar infarctions, whereas
Binswanger’s disease appears on the basis of a gradually pro-
gressive ischemic leukoencephalopathy. Unfortunately for Course
those diagnosticians who yearn for precision, although
‘pure’ cases of each of these three types of vascular dementia As noted, the classic course of multi-infarct dementia is
do occur, it is common to find elements of two or even all stepwise, with successive strokes bringing the patient down
three of these at the same time in any given patient. yet another step into further cognitive deterioration.
Importantly, many of these steps are characterized by a
delirium, which gradually resolves concurrent with the res-
Clinical features olution of peri-lesional edema. Exceptions to this rule,
however, do occur. In some cases, the course may be
The onset of multi-infarct dementia corresponds to the age marked by one giant step down, as in cases of multiple
of greatest risk for stroke, and hence most patients are in simultaneous infarcts or with one infarct occurring in an
their sixties or older. In most cases, one finds a history of exquisitely strategic location.
p 10.qxd 3/10/08 5:52 PM Page 434
434 Vascular disorders
Etiology symptoms, and antipsychotics, such as risperidone, for hal-

lucinations, delusions, and agitation. There is also evidence
In most cases, the dementia occurs secondary to bilateral, that both the cholinesterase inhibitors donepezil (Black et al.
multiple, territorial large vessel infarctions involving the 2003; Wilkinson et al. 2003) and galantamine (Auchus et al.
frontal, parietal, and temporal cortices (Erkinjunti et al. 1988; 2007), and memantine (Orgogozo et al. 2002; Wilcock
Jayakumar et al. 1989; Ladurna et al. 1982; Liu et al. 1992; et al. 2002) may improve overall cognitive function.
Tomlinson et al. 1970); rarely, single infarctions, for example Concurrent with symptomatic treatment, steps should
in the temporal or frontal lobes, may be responsible (Auchus be taken to prevent future strokes if possible, as discussed
et al. 2002; Yoshitake et al. 1995). Although most cases are in Section 7.4.
due to infarction, as the name ‘multi-infarct’ suggests, a very
similar clinical picture can emerge with multiple intracerebral
hemorrhages, and it is probably appropriate to lump these 10.2 LACUNAR DEMENTIA
cases under the rubric of multi-infarct dementia. A better
name might be ‘multi-stroke’ dementia, but the term multi- As discussed in Section 7.4, lacunes are small cavities that
infarct has great currency and probably will not change. may be found in the thalamus, basal ganglia, and internal and
The multiple causes of these infarctions (and hemor- external capsules, among other locations, and which occur as
rhages) are discussed in Section 7.4. sequelae to infarctions in the areas of distribution of central
or perforating arteries. Single lacunes may be clinically ‘silent’
or present with one of the classic lacunar syndromes, such as
Differential diagnosis pure motor stroke. When multiple lacunes are present, one
speaks of the ‘lacunar state’; when significant cognitive
The diagnosis of multi-infarct dementia should be consid- impairment occurs on the basis of multiple lacunes (or, albeit
ered in any patient with dementia and a history of stroke. uncommonly, on the basis of a single ‘strategically’ located
In weighing this history, however, one must take into lacune) it is customary to speak of subcortical vascular
account the location of the lesion: whereas infarcts in such dementia or, more simply, lacunar dementia. Lacunar demen-
cognitively strategic locations as the frontal, parietal, or tia, along with multi-infarct dementia and Binswanger’s dis-
temporal cortices might be expected to cause dementia, ease, is a vascular dementia, and although it may occur in a
one would be hard-pressed to attribute a dementia to ‘pure’ state, it is not uncommonly accompanied by other evi-
infarctions occurring in the occipital lobes. dence of vascular pathology, such as the large territorial
Lacunar dementia may also present with a history of infarcts seen in multi-infarct dementia or the ischemic
stroke; however, here the strokes tend to be of the lacunar leukoencephalopathy of Binswanger’s disease.
variety, such as pure motor stroke. Furthermore, and in Although the prevalence of lacunar dementia is not
contrast to multi-infarct dementia, lacunar dementia tends known with any precision, the clinical impression is that it
to be characterized by a frontal lobe syndrome. is not uncommon.
As noted earlier, it is not uncommon to find patients
with more than one vascular process underlying a demen-
tia, and in such cases MR scanning is generally necessary to Clinical features
determine the various contributions of cortical infarctions,
lacunar infarctions, and diffuse white matter disease. In In addition to cognitive deficits such as decreased short-
some instances, it may not be possible to disentangle the term memory, slowed thinking, and disorientation (Mok
effects of each of these separate processes, and in such et al. 2004), etc., one also classically sees elements of the
cases, one may have to be content with merely making a frontal lobe syndrome such as disinhibition, affective
diagnosis of vascular dementia. change, perseveration or apathy (Ishii et al. 1986; Wolfe et al.
Given the prevalence of Alzheimer’s disease, it must 1990). In some cases, parkinsonism may occur, as discussed
also be borne in mind that it is not at all uncommon to find in Section 10.3. As might be expected, there is typically also
patients with a ‘mixed’ dementia, that is with a combina- a history of lacunar syndromes, such as pure motor stroke,
tion of multi-infarct dementia and Alzheimer’s disease ataxic hemiparesis, dysarthria–clumsy hand or pure sensory
(Tomlinson et al. 1970). Such a diagnosis should be con- stroke. Furthermore, and in advanced cases of the lacunar
sidered in cases in which the course is mixed, being com- state, it is common to see a psuedobulbar palsy with, as
posed of sequential downward steps occurring on a described in Section 4.7, emotional incontinence.
background of a steady, gradual decline. Although CT scanning may reveal some lacunes, MRI is
far more sensitive and is strongly recommended.
Treatment
Course
The general treatment of dementia is discussed in Section
5.1. Antidepressants, for example a selective serotonin In most cases, lacunar dementia is a progressive condition,
reuptake inhibitor (SSRI), may be needed for depressive and the progression itself may be either ‘stepwise’ or more
p 10.qxd 3/10/08 5:52 PM Page 435
10.3 Vascular parkinsonism 435
or less gradual (Ishii et al. 1986; Swartz and Black 2006; 10.3 VASCULAR PARKINSONISM
Yoshitake et al. 1995), depending on the size and location
of subsequent lacunar infarctions. Larger or strategically Vascular parkinsonism, formerly known as arteriosclerotic
placed lacunes may cause an obvious step down the cogni- parkinsonism, first described by Critchley in 1929, is char-
tive ladder; conversely, small lacunes, although individu- acterized by an atypical parkinsonism occurring on the
ally clinically ‘silent’, may, upon accumulation, cause a basis of lacunar infarctions either in the mesencephalon or
clinically noticeable, and more or less gradually appearing, basal ganglia. It is probably an uncommon disorder.
cognitive deficit.
Clinical features
Etiology
The onset is generally in the seventh or eighth decade.
In all likelihood, lacunes cause cognitive deficits by inter- Clinically (Bruetsch and Williams 1954; Keschner and Sloane
rupting the circuit that runs from the frontal cortex to 1931; Murrow et al. 1990; Tolosa and Santamaria 1984;
the basal ganglia, then to the thalamus and finally back to Winikates and Jankovic 1999; Zijlmans et al. 2004a), the
the frontal lobe, and this may account for the frequency parkinsonism is characterized by bradykinesia, lead-pipe
with which the frontal lobe syndrome accompanies rigidity, instability, and a tendency to fall. The posture of
this dementia. A discussion of the mechanisms underlying these patients may or may not be in flexion; the gait is either
the infarctions that create these lacunes is provided in shuffling or ‘magnetic’ in that the feet seem ‘stuck’ to the
Section 7.4. floor. Overall, these parkinsonian features may be either
Although in most cases multiple lacunes (generally a symmetric or asymmetric. Notably, both tremor and cog-
dozen or more [Ishii et al. 1986]) are found, in some wheeling are generally absent, and, as discussed below, the
instances single lacunes, if strategically located, for exam- response to levodopa is generally poor. A lacunar dementia,
ple in the anteromedial thalamus (Auchus et al. 2002; Katz as described in Section 10.2, may occur (Bruetsch and
et al. 1987; Mori et al. 1986; Sandson et al. 1991; Swartz and Williams 1954; Keschner and Sloane 1931), and typically one
Black 2006), may cause a dementia. finds evidence of damage to corticospinal tracts (e.g., spastic-
ity) and corticobulbar tracts, with pseudobulbar palsy.
Magnetic resonance scanning reveals multiple lacunes,
Differential diagnosis with at least some of them involving either the basal gan-
glia or the mesencephalon (Zijlmans et al. 1995).
Lacunar dementia should be suspected in any demented
patient with a history of lacunar syndromes or with multi-
ple (or strategically placed) lacunes found on MR scan- Course
ning. As noted earlier, it is not uncommon to find evidence
of other vascular pathology and, in cases in which there are The overall course is generally one of progression, and may
also large, territorial cortical infarcts or extensive white be either ‘stepwise’ or more or less gradual.
matter disease in addition to lacunes, clinical judgment
must come into play in deciding how important the Etiology
lacunes are in the development of the dementia. In this
regard, one looks not only to the number of lacunes but Case reports have clearly demonstrated that parkinsonism
also, as noted, to their location: whereas lacunes in the pos- can occur secondary to solitary lacunar infarctions in such
terior limb of the internal capsule may not be that impor- strategic locations as the basal ganglia (Lazzarino et al.
tant, those situated in the thalamus, genu or anterior limb 1990) or the substantia nigra (Akyol et al. 2006; Hunter
of the internal capsule or the head of the caudate are more et al. 1978). In most patients, however, vascular parkinson-
likely to cause cognitive deficits. ism occurs in the setting of multiple lacunes (Bruetsch and
Williams 1954; Keschner and Sloane 1931; Murrow et al.
1990; Zijlmans et al. 2004a) that affect not only the basal
Treatment ganglia or substantia nigra but also the corticospinal and
corticobulbar tracts as they course through the internal
The overall treatment of dementia, the frontal lobe syn- capsule, thus giving rise to the other symptoms described
drome, and pseudobulbar palsy is discussed in Sections above.
5.1, 7.2, and 4.7 respectively. There is some evidence that
donepezil (Black et al. 2003; Wilkinson et al. 2003), galant-
amine (Auchus et al. 2007), and memantine (Orgogozo et al. Differential diagnosis
2002; Wilcock et al. 2002) are helpful. Treatment aimed at
preventing future lacunar infarctions is discussed in The full differential for parkinsonism is described in Section
Section 7.4. 3.8. Of the disorders considered there, the neurodegenerative
p 10.qxd 3/10/08 5:52 PM Page 436
causes of parkinsonism are most likely to be confused with

vascular parkinsonism. Parkinson’s disease is distinguished
by the presence of tremor, cogwheel rigidity, and a good
response to levodopa. Diffuse Lewy body disease is suggested
by the early occurrence of a dementia marked by confusion
and visual hallucinations, and multiple system atrophy by
associated ataxia and autonomic failure. Progressive
supranuclear palsy may appear very similar to vascular
parkinsonism, and, in cases in which supranuclear ophthal-
moplegia has not as yet appeared, the differential may rest on
MR scanning, which reveals midbrain atrophy in progressive
supranuclear palsy, in contrast to the multiple lacunes of vas-
cular parkinsonism.
Treatment
Although the response to levodopa is generally not good

(Winikates and Jankovic 1999), some patients may respond
(Zijlmans et al. 2004b) and, hence, it is worth a try. Dementia
may be treated as described for lacunar dementia in Section
10.2, and the treatment of pseudobulbar palsy is discussed in
Section 4.7. Efforts should be undertaken to prevent further
lacunar infarctions, as discussed in Section 7.4. Figure 10.1 A T2-weighted magnetic resonance (MR) scan in a
case of Binswanger’s disease, with large confluent areas of
increased signal intensity in the centrum semiovale. (Reproduced
from Gillespie and Jackson 2000.)
10.4 BINSWANGER’S DISEASE
Binswanger’s disease, first described by Otto Binswanger in Computed tomography scanning reveals widespread
1894 (Binswanger 1894), is characterized by a slowly pro- areas of radiolucency in the periventricular white matter
gressive dementia occurring in the elderly on the basis of a and centrum semiovale. Magnetic resonance scanning is far
diffuse microangiopathic ischemic leukoencephalopathy more sensitive and on fluid-attenuated inversion recovery
or leukoaraiosis. Thus conceived, Binswanger’s disease is (FLAIR) or T2-weighted images one finds, as illustrated in
considered to be one of the vascular dementias, along with Figure 10.1, multiple patchy and confluent areas of
multi-infarct dementia and lacunar dementia. Traditional increased signal intensity in the periventricular region and
synonyms for this disease include subcortical arterioscle- the centrum semiovale, extending close to the cortex but
rotic encephalopathy, chronic progressive subcortical sparing the U-fibers. In advanced cases, these patchy areas
encephalopathy, and encephalitis subcorticalis chronica may coalesce to the point of creating a virtual ‘white-out’.
progressiva. Although precise figures regarding prevalence
are not available, the clinical impression is that it is not
uncommon. Course
Although the course of Binswanger’s disease has not been

Clinical features well-studied, it appears that the dementia undergoes a
gradual progression over many years.
The onset is generally gradual, occurring in the sixth or
later decades. Clinically (Bogucki et al. 1991; Caplan and
Schoene 1978), as described by Binswanger himself (Blass Etiology
et al. 1991), there is a ‘slow development of the deteriora-
tion of the intellectual capacities’, and patients present The neuropathologic changes have been described in sev-
with a non-specific dementia, with slowness of thought, eral reports (Akiguchi et al. 1997; Caplan and Schoene
decreased short-term memory, disorientation, and con- 1978; Lin et al. 2000; Revesz et al. 1989; Yamanouchi 1991).
creteness. In advanced cases, a pseudobulbar palsy may At autopsy, the small penetrating medullary vessels display
occur. Minor focal signs, such as asymmetric deep tendon lipohyalinosis and, in some cases, the lumens are obliter-
reflexes or a Babinski sign, may be seen, but, in uncompli- ated. There is widespread demyelinization with some asso-
cated Binswanger’s disease, major, clear-cut syndromes, ciated axonal loss and, in severe cases, cystic changes may
such as aphasia or apraxia, do not occur. occur. Although it is suspected that these microangiopathic
p 10.qxd 3/10/08 5:52 PM Page 437
10.5 Cranial arteritis 437
changes occur on the basis of longstanding hypertension, non-confluent, small patchy areas in the centrum semio-
other factors are probably also at work, as Binswanger’s dis- vale or periventricular areas, which are, in fact, asymptom-
ease may occur in normotensive individuals. atic. The diagnosis of Binswanger’s disease should not be
made unless the white matter disease is severe and exten-
sive, approaching, ideally, a ‘white-out’.
Binswanger’s disease is one of the dementias of gradual Treatment

onset that often lack distinctive features and, as discussed in
Section 5.1, it must therefore be distinguished from several The general treatment of dementia is discussed in Section
other disorders, including Alzheimer’s disease, diffuse Lewy 5.1; there is some evidence that donepezil (Black et al. 2003;
body disease, and normal pressure hydrocephalus. These Wilkinson et al. 2003), galantamine (Auchus et al. 2007), and
disorders are immediately made doubtful by MR scanning, memantine (Orgogozo et al. 2002; Wilcock et al. 2002) may
which fails to demonstrate the white matter pathology also be helpful. Control of blood pressure is important;
characteristic of Binswanger’s disease. Clinical features may however, one must not be overzealous here as given that
also help. Alzheimer’s disease classically presents first with a other vascular pathology is common, creating hypotension
slowly progressive short-term memory loss, in contrast to runs the risk of watershed infarctions.
Binswanger’s disease in which the memory loss occurs hand
in hand with other cognitive changes. Diffuse Lewy body
disease may present with a dementia, but here one finds 10.5 CRANIAL ARTERITIS
visual hallucinations and spontaneous episodes of confu-
sion early on, findings not seen in Binswanger’s disease. Cranial arteritis, also known as giant cell arteritis or tem-
Finally, in normal pressure hydrocephalus, one sees both a poral arteritis, is characterized pathologically by a segmen-
‘magnetic’ gait and urinary urge incontinence, which are tal inflammation of various, primarily cranial, arteries, and
generally not seen in Binswanger’s disease. clinically by symptoms related to ischemia in the areas of
There are two disorders that present with dementia in the distribution of those arteries. Classically, this disorder
context of diffuse white matter changes, namely cerebral presents with headache (due to inflammation of one of the
amyloid angiopathy and CADASIL (cerebral autosomal branches of the external carotid artery, typically the super-
dominant arteriopathy with subcortical infarcts and ficial temporal artery) and either amaurosis fugax or blind-
leukoencephalopathy), and these may cause some diagnos- ness due to involvement of the ophthalmic artery.
tic difficulty. In cerebral amyloid angiopathy, gradient echo In those over 50 years, this is a not uncommon disorder;
recall MRI may reveal evidence of ‘microbleeds’; further- it is seen primarily in Caucasians, especially those of
more, in most cases there will eventually also be lobar intra- Nordic descent.
cerebral hemorrhages, which clinch the diagnosis. CADASIL
is suggested by a history of migraine headaches and also by
the distinctive finding of a leukoencephalopathy that Clinical features
extends into the anterior temporal lobe.
As noted earlier, Binswanger’s disease is one of the vas- The symptomatology of cranial arteritis varies according to
cular dementias, and, given that patients may develop not which arteries are inflamed (Wilkinson and Russell 1972).
only the microangiopathic changes of Binswanger’s disease Branches of the external carotid artery are commonly
but also disease of the large pial vessels and the smaller involved, and, as noted above, inflammation of the tempo-
penetrating central perforating vessels, it is not uncommon ral artery is classic, causing a severe headache in the tempo-
to find a mixture of vascular pathology; in such cases ral region, which, although generally unilateral, can be
Binswanger’s disease may be complicated by territorial bilateral. In some cases the occipital artery is involved and in
infarctions and lacunar infarctions. There is often a history these instances the headache may be localized to the neck.
of multiple strokes in addition to the gradually progressive Involvement of the facial artery may lead to ‘jaw claudica-
dementia, and clinical judgment is required in deciding tion’ with facial pain upon chewing, and involvement of the
what weight to give to each of the vascular pathologies with lingual artery may cause tongue necrosis. Of the branches of
regard to the dementia. In cases characterized by a promi- the internal carotid artery, the ophthalmic artery, as noted, is
nent amount of all three vascular pathologies, one may classically involved, and in such cases unilateral blindness
have to content oneself with an ‘umbrella’ diagnosis of may occur (Caselli et al. 1988), which may or may not be
‘vascular dementia’. preceded by episodes of amaurosis fugax.
Finally, in evaluating a patient with a slowly progressive In about 10 percent of cases, strokes or transient ischemic
non-specific dementia, care must be taken not to place too attacks may occur (Caselli et al. 1988), and this may be seen
much diagnostic weight on minor changes seen on MR with involvement of either the vertebral artery or the inter-
scanning. Periventricular ‘caps’ and ‘rims’ are of no signif- nal carotid artery. With vertebral artery involvement, clots
icance, and it is not at all uncommon to find multiple, may form that may then embolize further downstream, for
p 10.qxd 3/10/08 5:52 PM Page 438
example to the posterior cerebral artery. It also appears that also be suspected; however, here, renal or gastrointestinal
small branches of the vertebral arteries may also be involvement will indicate the correct diagnosis.
occluded, leading to medullary infarction. With involve-
ment of the internal carotid artery, clots may also form, with
embolization downstream to cause occlusion of the middle Treatment
or anterior cerebral arteries or their branches. It is debated
whether (or with what frequency) smaller arteries in the Urgent treatment with steroids is essential to prevent stroke
anterior circulation become inflamed; however, one report or blindness. Traditionally, prednisone is used, starting at
suggested that small penetrating arteries may be involved, doses of approximately 60 mg/day and, once symptoms are
causing multiple lacunes. In some cases, if the number and controlled and the ESR has dropped, tapering the dose
location of infarctions is appropriate, either a multi-infarct gradually to the minimum required to keep the patient
dementia (Caselli 1990) or a lacunar dementia (Nightingale asymptomatic and the ESR down. Recent work suggests
et al. 1982) may ensue. that aggressive treatment with methylprednisolone at
Most cases of cranial arteritis are further characterized 15 mg/kg (of ideal body weight) daily for the first 3 days,
by constitutional symptoms, such as malaise, fatigue, followed by prednisone, induces a more rapid remission
anorexia, and a low-grade fever, and most patients will also and ensures a more favorable course (Mazlumzadeh et al.
have an associated polymyalgia rheumatica, with muscle 2006). Uncontrolled work further suggests that use of low-
aching and stiffness, which, although diffuse, is most dose aspirin concurrent with prednisone may also reduce
prominent in the neck and shoulders. the risk of stroke (Nesher et al. 2004).
With rare exceptions (Kansu et al. 1977) the erythrocyte
sedimentation rate (ESR) is elevated, generally above
50 mm/min (Westergen) and often above 100 mm/min. 10.6 CEREBRAL AMYLOID ANGIOPATHY
Mild anemia is common and the alkaline phosphatase may
also be elevated. The diagnosis is confirmed by biopsy of an Cerebral amyloid angiopathy, also known as congophilic
involved artery, such as the temporal artery; given the seg- amyloid angiopathy, is a not uncommon disorder charac-
mental nature of the inflammation, however, false nega- terized by an amyloid angiopathy that may lead to sponta-
tives are possible and multiple biopsies may be required. neous lobar intracerebral hemorrhages, a gradually
progressive dementia secondary to a widespread leuko-
encephalopathy, or a combination of these findings; cerebral
Course ‘microhemorrhages’ commonly accompany these findings.
The inflammatory process generally undergoes a gradual,

spontaneous remission in anywhere from several months Clinical findings
to several years.
Cerebral amyloid angiopathy typically has an onset in the
seventh or later decades, and may present with either spon-
Etiology taneous lobar intracerebral hemorrhages or with a gradu-
ally progressive dementia (Cosgrove et al. 1985; Gilles et al.
Involved arteries show a graulomatous inflammation char- 1984; Haan et al. 1990a; Nobuyoshi et al. 1984; Yoshimura
acterized by the presence of giant cells. As noted, the et al. 1992).
inflammation is segmental, and between the involved seg- The lobar intracerebral hemorrhages present with a
ments the artery may be normal. Thrombi may form over gradual evolution, over perhaps a half-hour, of headache,
the inflamed areas and, as noted earlier, emboli may be nausea and vomiting, and a focal deficit appropriate to the
generated (Wilkinson and Russell 1972); in some cases the location of the hemorrhage. Classically, the hemorrhage
artery may become occluded. Although the mechanism occurs spontaneously and recurrences are the rule. With
underlying the inflammation is not known, an autoim- multiple recurrences, a ‘stepwise’ accrual of cognitive
mune process is suspected. deficits may occur, eventually leading to a picture of multi-
infarct dementia.
Dementia, as noted, may also be of gradual onset and
Differential diagnosis progression, and in this instance it is non-specific in char-
acter, with decreased short-term memory, variable dis-
The diagnosis should be suspected in cases of amaurosis orientation, and deficits in abstracting and calculating ability.
fugax, blindness, or stroke, occurring in the setting of Cerebral microhemorrhages may occur, and these may
headache, constitutional symptoms, polymyalgia rheumat- be silent or may present with relatively minor focal find-
ica, or an elevated ESR. Systemic lupus erythematosus may ings that, in most cases, resolve over time (Greenberg et al.
be considered in the differential, but here the anti-nuclear 1993). Residual deposits of hemosiderin may serve as
antibody (ANA) test is positive. Polyarteritis nodosa may seizure foci, and partial seizures may also occur.
p 10.qxd 3/10/08 5:52 PM Page 439
10.7 CADASIL 439
Magnetic resonance scanning will reveal evidence of or rupture of a vascular malformation when these are lobar
any old intracerebral hemorrhages; in cases with a are more difficult to distinguish and, in such cases, follow-
leukoencephalopathy, T2-weighted or FLAIR images up MRI scans, obtained after the hemorrhage has resolved,
reveal bilateral, more or less symmetric, patchy or conflu- are often required. A helpful rule is that the occurrence of
ent areas of increased signal intensity that spare the two or more spontaneous intracerebral hemorrhages that
U-fibers. Gradient echo images may reveal punctate areas are lobar in location reliably indicates a diagnosis of cere-
of decreased signal intensity, corresponding to old micro- bral amyloid angiopathy (Knudson et al. 2001).
hemorrhages (Greenberg et al. 1999). Recent work has also Cerebral amyloid angiopathy may be very difficult to
demonstrated that, in some cases, one will find large asym- distinguish from Binswanger’s disease, as both of these dis-
metric areas of increased signal intensity on T2-weighted orders present with a gradually progressive dementia asso-
or FLAIR imaging in the subcortical white matter, which ciated with a diffuse, bilateral leukoencephalopathy.
fail to enhance and which may represent vasogenic edema Certainly if there are spontaneous lobar intracerebral hem-
(Kinnecom et al. 2007). orrhages, this would point to a diagnosis of cerebral amy-
loid angiopathy. In their absence, one should perform
gradient recall MRI to look for evidence of old microhem-
Course orrhages: although these are not always present in cerebral
amyloid angiopathy, they are never present on the basis of
The course of cerebral amyloid angiopathy depends on the Binswanger’s disease, and hence they represent a signif-
preponderance of the underlying pathology. With repeated icant pertinent positive finding.
intracerebral hemorrhages, a ‘stepwise’ course, as noted,
may occur, whereas cases with leukoencephalopathy are
characterized by a gradual progression of cognitive deficits. Treatment
The combination of these two courses may also occur, and
is quite distinctive for this disease (Nobuyoshi et al. 1984). At present, there is no specific treatment; the general treat-
ment of dementia is outlined in Section 5.1. Given that
aspirin, warfarin (Rosand et al. 2000), and tissue plasmino-
Etiology gen activator (Pendlebury et al. 1991) may all increase the
risk of hemorrhage, these should be avoided. In cases in
Amyloid deposition occurs in the walls of small and which MR scanning reveals large areas of vasogenic edema,
medium-sized cortical arterioles, resulting in fibrinoid consideration may be given to treatment with steroids
degeneration and the formation of microaneurysms (Kinnecom et al. 2007).
(Okazaki et al. 1979). Affected vessels are ‘congophilic’,
staining well with Congo red dye, thus accounting for the
alternative name for this disorder, ‘congophilic amyloid 10.7 CADASIL
angiopathy’. The aneurysmal dilations of these vessels are
quite fragile, and account for both spontaneous lobar CADASIL is a rare autosomal dominantly inherited arteri-
intracerebral hemorrhages and microhemorrhages. Within opathy characterized by migraine, stroke, and dementia.
the areas of distribution of the affected arteries, rarefaction The name CADASIL is an acronym for cerebral autosomal
of the white matter occurs (Gray et al. 1985), probably on dominant arteriopathy with subcortical infarcts and
an ischemic basis. leukoencephalopathy.
Although the vast majority of cases are sporadic, cere-
bral amyloid angiopathy may also occur on an autosomal
dominant basis as ‘hereditary cerebral hemorrhage with Clinical features
amyloidosis’, either of the ‘Dutch’ (Haan et al. 1990a,b;
Levy et al. 1990; Wattendorff et al. 1995) or ‘Icelandic’ In general, the overall clinical picture of CADASIL
(Gudmundsson et al. 1972; Palsdottir et al. 1988) type. (Bergmann et al. 1996; Dichgans et al. 1998; Jung et al. 1995;
Kim et al. 2006; Malandrini et al. 1996; Markus et al. 2002;
Sourander and Walinder 1977) is characterized by the onset
Differential diagnosis of recurrent migraine headaches, typically with aura, in the
third or fourth decade, followed by recurrent strokes or
Intracerebral hemorrhages of cerebral amyloid angiopathy transient ischemic attacks (TIAs) in the fourth or fifth
must be distinguished from intracerebral hemorrhages of decade, and a dementia in the sixth and seventh decade; a
other causes. Hypertensive intracerebral hemorrhage is pseudobulbar palsy may occur and, in a small minority,
suggested by location: hypertensive hemorrhages tend to seizures may appear. The strokes are typically of the lacunar
involve deep subcortical structures, such as the putamen, in type, reflecting infarcts that occur primarily in the basal
contrast to the hemorrhages of cerebral amyloid angiopa- ganglia. The dementia, although generally reflecting the
thy, which are lobar in location. Hemorrhage into tumors effects of multiple lacunar infarctions (Liem et al. 2007), at
p 10.qxd 3/10/08 5:52 PM Page 440
times may also be due to a progressive leukoencephalopa- occurring in CADASIL must be distinguished from the
thy, and in rare instances CADASIL may present with a dementia occurring in lacunar dementia and in Binswanger’s
dementia secondary to the leukoencephalopathy in the disease. In all these instances, a positive family history is most
absence of stroke (Filley et al. 1999; Mellies et al. 1998). helpful as it points to CADASIL; however, in some cases such
Two unusual manifestations of CADASIL must also be a history may be unavailable. Other features suggesting
kept in mind, namely intracerebral hemorrhage and a CADASIL are migraine with aura and, most importantly, the
reversible delirium. Intracerebral hemorrhage, primarily early appearance of leukoencephalopathy in the anterior
of the thalamus or basal ganglia, may occur but is uncom- portion of the temporal lobe, which, although common in
mon (Choi et al. 2006). Delirium has also been reported CADASIL, is most unlikely in other disorders.
but appears rare. Patients present with a subacute delir- Cerebral amyloid angiopathy may cause some diagnos-
ium, often accompanied by seizures and fever, which may tic difficulty, as it can present with a dementia in the setting
progress to coma; recovery is spontaneous and occurs after of a diffuse leukoencephalopathy with old microhemor-
1–2 weeks (Schon et al. 2003). rhages. Here, MRI evidence of lacunar infarctions or ante-
Magnetic resonance scanning will reveal any prior lacu- rior temporal leukoencephalopathy point to CADASIL,
nar infarctions. Furthermore, most patients will also have a and the appearance of lobar intracerebral hemorrhages at
diffuse leukoencephalopathy and, indeed, this may be any time generally indicates cerebral amyloid angiopathy.
present early on, even before the first stroke. The leukoen- MELAS (mitochondrial encephalomyopathy, lactic aci-
cephalopathy is evident on either T2-weighted or FLAIR dosis, and stroke-like episodes) may present in a fashion
imaging: patchy, confluent areas of increased signal inten- similar to CADASIL, but is distinguished by deafness.
sity are seen in the centrum semiovale and the periventric-
ular white matter, and also, classically, in the external
capsule and, most notably, in the white matter of the ante- Treatment
rior temporal lobe (O’Sullivan et al. 2001). Recent work
using gradient echo imaging has also identified evidence At present, there is no specific treatment for CADASIL.
for old microhemorrhages in the thalamus and basal gan- The general treatment of dementia is discussed in Section
glia (Choi et al. 2006; Lesnik Oberstein et al. 2001). 5.1; genetic counselling should be offered.
Diagnosis may be made by genetic testing. Skin biopsy
may also be performed, but false negatives are common
(Malandrini et al. 2007). 10.8 GRANULOMATOUS ANGIITIS OF THE
CENTRAL NERVOUS SYSTEM
Course Granulomatous angiitis of the central nervous system is a
rare disorder characterized pathologically by a granuloma-
The overall course is as described above; death occurs in tous angiitis confined to the central nervous system, and
the seventh through ninth decades, often from pneumonia clinically by headache and delirium. An often used syn-
(Opherk et al. 2004). onym is primary angiitis of the central nervous system;
however, at times this term has also been used to refer to
other vasculitic processes and hence the reader should
Etiology examine any literature carefully, to ensure that, indeed,
granulomatous angiitis is the disorder in question.
As noted, CADASIL is an autosomal dominant disorder:
mutations are found in the Notch3 gene on chromosome
19 (Joutel et al. 1997; Tournier-Lasserve et al. 1993). Clinical features
Pathologically, there is concentric fibrous thickening of
small penetrating arteries (Sourander and Walinder 1977), Although the disease may present at any age, from child-
leading to both the subcortical infarcts and the widespread hood to senescence, most patients are in their 30s or 40s.
leukoencephalopathy (Baudrimont et al. 1993). Although The onset itself is generally subacute, spanning a few
peripheral nerves (Schroder et al. 1995) and skin (Ruchoux weeks. Clinically (Abu-Shakara et al. 1994; Calabrese and
et al. 1994) may also be involved, symptoms referable to Mallek 1988; Case Records 1989; Hughes and Brownell
them are generally absent. 1966; Kolodny et al. 1968; Koo and Massey 1988; Lie 1992;
Moore 1989; Vollmer et al. 1993), patients typically have
severe, generalized headache, and in this setting they
Differential diagnosis develop a delirium that may be accompanied by focal
deficits or, uncommonly, seizures. Although focal deficits,
Lacunar strokes occurring in CADASIL must be distin- such as hemiparesis, may have a stroke-like onset, in most
guished from lacunar infarctions occurring on the basis of cases they appear gradually. In some cases, the spinal cord
lipohyalinosis or atherosclerosis. Similarly, the dementia may be involved.
p 10.qxd 3/10/08 5:52 PM Page 441
10.9 Polyarteritis nodosa 441
The ESR is generally either normal or only mildly ele- Clinical features
vated (Lie 1992; Moore 1989). Magnetic resonance scan-
ning may initially be normal; however, over time areas of The onset is generally subacute or gradual in middle years
increased signal intensity on FLAIR or T2-weighted imag- with constitutional symptoms and evidence of involve-
ing appear in the cerebrum or cerebellum (Alhalabi and ment of the kidneys, gastrointestinal tract or muscles; renal
Moore 1994; Ehsan et al. 1995). Angiography may be nor- disease may lead to hypertension or renal failure.
mal or may disclose typical beading (Alrawi et al. 1999). Importantly, the respiratory tract is not involved.
Lumbar puncture should be performed in all suspected Nervous system involvement generally occurs only after
cases: there is typically a lymphocytic pleocytosis, an ele- other evidence of the disease is well-established (Sigal
vated protein, and a normal glucose (Vollmer et al. 1993). 1987). Peripheral nervous system involvement, which is
Brain biopsy, sampling both the leptomeninges and the most common, typically involves a mononeuritis multi-
cerebrum, is the ‘gold standard’ (Alrawi et al. 1999); how- plex (Lovelace 1964). In a minority of cases, central ner-
ever, even this may be falsely negative, missing affected tis- vous system involvement may occur, most commonly
sue (Alhalabi and Moore 1994; Lie 1992). presenting with lacunar strokes (Reichart et al. 2000);
larger territorial infarctions or intracerebral hemorrhages
are rare. In a very small minority delirium (Ford and
Course Siekert 1965) or dementia (MacKay et al. 1950) may occur,
and seizures have also been noted.
Untreated, progressive deterioration occurs in almost all Both the peripheral white blood cell count and the ESR
cases and perhaps half of all patients will die within months, are elevated. Anti-neutrophil cytoplasmic antibodies
with the remainder surviving for up to two or more years. (ANCA) (especially perinuclear ANCA [pANCA]) are
found in the majority of cases and the Venereal Disease
Research Laboratories (VDRL) test may be falsely positive.
Etiology Magnetic resonance scanning will reveal infarctions.
Definitive diagnosis is made by biopsy of an affected
A granulomatous angiitis affects both small lep-
muscle or peripheral nerve.
tomeningeal vessels and small- or medium-sized parenchy-
mal vessels (Cravioto and Feigin 1959). The cerebrum is
most commonly affected, although the cerebellum, brain- Course
stem, and even the cord may also be involved. Although
the cause is unknown, an autoimmune process, confined Although spontaneous remissions do occur they are rare,
to the central nervous system, is suspected. and most cases are characterized by relentless progression,
with only about 10 percent of patients surviving past 5 years.
Other vasculidities, such as polyarteritis nodosa or zoster

Etiology
arteritis, must be considered, along with subacute menin-
There is a systemic, segmental panarteritis affecting
gitides, as may be seen with fungal infections or syphilis.
medium and small arteries, with, at times, extension into
arterioles. With intimal proliferation, thrombosis and
Treatment occlusion of arteries may occur, and with involvement of
the muscular layer, microaneurysms may form. These
The general treatment of delirium is discussed in Section microaneurysms may occasionally rupture; however, they
5.3. Most patients are treated with a combination of pred- typically undergo fibrosis, thus creating nodules along the
nisone and cyclophosphamide. course of the artery, thereby providing the characteristic
that gives the disease its name.
Involvement of the peripheral vasa nervorum leads to
10.9 POLYARTERITIS NODOSA the mononeuritis multiplex. Within the central nervous
system, involvement of small perforating arteries leads to
Polyarteritis nodosa, also known as periarteritis nodosa, is lacunar infarctions; in those uncommon cases involving
a rare systemic vasculitis characterized pathologically by a larger arteries, territorial infarctions may occur and, with
segmental necrotizing panarteritis. Most patients present rupture of an aneurysm, an intracerebral hemorrhage may
with constitutional symptoms and involvement of the kid- be seen.
neys, gastrointestinal tract or muscles; in a minority there Although the mechanism underlying the arteritis is not
may be a peripheral neuropathy, and in a smaller minority, known with certainty, deposition of immune complexes
central nervous system involvement, with stroke, delirium, probably plays a role, and in this regard there is an associa-
or dementia. tion with hepatitis B antigenemia.
p 10.qxd 3/10/08 5:52 PM Page 442
Differential diagnosis Course

In addition to suggesting polyarteritis nodosa, the occur- The disease is progressive and, once renal involvement
rence of nervous system involvement in the context of a occurs, death may follow within months.
systemic illness also raises the possibility of systemic lupus
erythematosus, indicated by a positive ANA, and Wegener’s
granulomatosis, which, unlike polyarteritis nodosa, also Etiology
involves the respiratory tract.
Within the central nervous system, several different patholo-
gies may be found (Drachman 1963, Nishino et al. 1993a;
Treatment Seror et al. 2006; Weinberger et al. 1993). Small, or rarely
large, vessels may undergo a vasculitis and, with occlusion,
Treatment with corticosteroids and cyclophosphamide is infarction occurs. Granulomas may be found, and these
recommended; consideration may also be given to may appear by extension from an extracranial source (e.g.,
antiplatelet agents (Reichart et al. 2000). a sinus or the orbit) or they may occur independently.
Granulomatous involvement of the meninges, primarily the
pachymeninges, may also occur, and cranial nerves may be
10.10 WEGENER’S GRANULOMATOSIS entrapped and compressed; cranial neuropathies may also
occur due to compression of the cranial nerves in their
Wegener’s granulomatosis is an uncommon disease charac- extracranial portions by extracranial granulomas. In some
terized pathologically by a systemic necrotizing granuloma- cases granulomas may appear in the hypothalamus.
tous vasculitis, most commonly affecting the respiratory Although the etiology of Wegener’s granulomatosis is
tract and kidneys. The nervous system is involved in a not known, an autoimmune response, perhaps to an
minority of cases: peripheral neuropathy is the most com- inhaled substance, is suspected.
mon manifestation; within the central nervous system there
may be a vasculitis, intracerebral granulomas, and, rarely, a
pachymeningitis. Differential diagnosis
Central or peripheral nervous system involvement in the

Clinical features setting of respiratory tract or renal disease should raise the
possibility of Wegener’s granulomatosis. Sarcoidosis may
Over 90 percent of patients have symptoms referable to gran- be considered, but this disease has features not seen in
ulomas within the respiratory tract. Upper respiratory tract Wegener’s granulomatosis, such as erythema nodosum,
involvement is most common, with sinusitis, epistaxis, or rhi- lupus pernio, hypercalcemia, etc. Polyarteritis nodosa may
norrhea; involvement of the nasal septum may lead to its col- also be considered, although in polyarteritis nodosa one
lapse, and extension of granulomatous disease to the orbit does not find the respiratory tract involvement typical of
may cause proptosis. Pulmonary involvement may be asymp- Wegener’s granulomatosis.
tomatic or lead to cough or hemoptysis. Some three-quarters
of patients will have renal involvement, which may manifest
initially with proteinuria and microscopic hematuria. Treatment
Nervous system involvement generally occurs in the con-
text of respiratory or renal symptomatology (Hoffman et al. In most cases, treatment with a combination of prednisone
1992). Clinical evidence of a mononeuritis multiplex or and cyclophosphamide is required. The symptomatic
polyneuropathy is seen in about one-third of patients (de treatment of delirium and dementia is discussed in
Groot et al. 2001). With central nervous system involvement Sections 5.3 and 5.1 respectively.
(Nishino et al. 1993a,b; Weinberger et al. 1993) there may be
delirium, dementia, stroke, seizures, and, with meningeal
involvement, headache and cranial neuropathies; diabetes 10.11 BEHÇET’S DISEASE
insipidus has also been reported (Rosete et al. 1991).
Magnetic resonance scanning will reveal intracerebral Behçet’s disease, first described in 1937 by the Turkish der-
granulomatous lesions, infarcts, and meningitis. The cere- matologist Hulusi Behçet, is characterized pathologically by
brospinal fluid may be normal or may show a lymphocytic a systemic, primarily venular, vasculitis, and clinically by
pleocytosis and an elevated total protein. oral aphthous ulcers, genital ulcers, uveitis, and, in any-
The ESR is elevated, and over 90 percent of patients will where from one-tenth to one-third of patients, by evidence
have elevated levels of ANCA of either the pANCA or of central nervous system involvement. Although not
cANCA (circulating) type. Definitive diagnosis is made by uncommon in Japan and the Eastern Mediterranean region,
biopsy of the lung or kidney. Behçet’s disease is rare in Europe and the United States.
p 10.qxd 3/10/08 5:52 PM Page 443
10.12 Hypertensive encephalopathy 443

Behçet’s disease typically presents in the twenties or thirties, A perivenular vasculitis occurs and, although this may be
and almost all patients will have oral aphthous ulcers and seen in any part of the central nervous system, there is a
some form of uveitis; genital ulcers are somewhat less com- predilection for the pons, mesencephalon and dien-
mon. Another distinctive sign, not seen in all, is pathergy: cephalon, the cerebellum, and, to a lesser degree, the frontal
here, within 1–2 days of minor skin trauma, for example lobes. Meningeal inflammation may also occur, which may
phlebotomy, a large pustule forms at the site of the trauma. be accompanied by dural sinus thrombosis.
Other symptoms include furuncles, erythema nodosum, Although the etiology is not known, an autoimmune
migratory thrombophlebitis, and a non-deforming poly- process is suspected; the vast majority of cases are sporadic.
arthritis. Within the context of these symptoms evidence
of central nervous system involvement may appear.
When the central nervous system is involved, a wide Differential diagnosis
variety of symptoms may appear (Akman-Demir et al.
1993, 1999; Al-Araji et al. 2003; Altinors et al. 1987; Chajek The relapsing and remitting course of Behçet’s syndrome
and Fainaru 1975; Farah et al. 1998; Iragui and Miravi immediately suggests multiple sclerosis; however, in multi-
1986; Joseph and Scolding 2007; Kidd et al. 1999; ple sclerosis one does not find the characteristic apthous
Motomura et al. 1980; Serdaroglu et al. 1989; Wadia and and genital ulcers, uveitis or pathergy.
Williams 1957; Wolf et al. 1965). These include delirium,
dementia, pseudobulbar palsy with emotional inconti-
nence (Pallis and Fudge 1956; Motomura et al. 1980; Treatment
Rubinstein and Urich 1963; Wechsler et al. 1990), hemi-
plegia, ataxia, cranial nerve palsies, abnormal movements During attacks patients should be treated with prednisone
(e.g., chorea), a personality change of the frontal lobe type, and an immunosuppressant. The general management of
and, rarely, seizures (Aykutlu et al. 2002). As noted below, delirium and dementia are discussed in Sections 5.3 and
in addition to vasculitis, both meningitis and dural sinus 5.1 respectively.
thrombosis may occur, and in such cases one may see
headache; in cases of dural sinus thrombosis, one may also
see signs of increased intracranial pressure, with nausea, 10.12 HYPERTENSIVE ENCEPHALOPATHY
vomiting, and papilledema.
T2-weighted or FLAIR MR scanning may reveal areas Hypertensive encephalopathy, a relatively common dis-
of increased signal intensity in the brainstem, cerebellum order, is characterized by the occurrence of delirium and
or, less commonly, cerebrum; these areas may demonstrate headache in the setting of severe diastolic hypertension.
enhancement with gadolinium. Magnetic resonance Before proceeding, some words are in order regarding
venography may be required to demonstrate dural sinus the syndrome known as reversible posterior leukoen-
thrombosis. The CSF may be abnormal, with an elevated cephalopathy. Some authors use this as an ‘umbrella’ term,
total protein and/or a pleocytosis, which is generally subsuming not only hypertensive encephalopathy but also
lymphocytic (Akman-Demir et al. 1999; Farah et al. cases that are clinically similar but which do not occur on
1998). The ESR and peripheral white blood cell count may the basis of hypertension. To this author, such a nosologic
be elevated. practice seems to represent inappropriate ‘lumping’ and,
in this text, these disorders are treated separately.
Course
Clinical features
Most cases of Behçet’s disease demonstrate an episodic
course. The first attack, as noted, tends to occur in the 20s In the setting of sustained diastolic pressure elevations,
or 30s, and most attacks last in the order of weeks or a often 130 mmHg or higher, delirium and headache evolve
month or more, after which there is a spontaneous remis- over a matter of 1–3 days; most patients also experience
sion. These remissions, however, are generally not com- nausea and vomiting, and a majority will experience bilat-
plete, and most patients are left with residual symptoms. eral visual blurring, which may progress to cortical blind-
Recurrent attacks are the rule, and after each attack the ness; seizures may also occur and, in a minority, focal signs
overall burden of residual symptoms increases. In some such as aphasia or hemiplegia may occur (Chester et al.
cases, this typical episodic course may evolve into one of 1978; Healton et al. 1982; Oppenheimer and Fishberg
steady, waxing and waning progression; rarely Behçet’s 1928). Untreated, patients may become comatose.
disease may pursue a chronic, non-episodic course from Funduscopic examination may reveal papilledema or reti-
the outset, as was seen in a case of progressive dementia nal hemorrhages. Acute cardiac and renal failure may
with apthous and genital ulcers (Borson 1982). accompany the cerebral symptomatology.
p 10.qxd 3/10/08 5:52 PM Page 444
Computed tomography scanning may reveal bilaterally autoregulatory capacity, a systemic pressure within normal
symmetric areas of hypodensity in the occipitoparietal limits may be followed by cerebral hypoperfusion and water-
white matter. Magnetic resonance scanning is far more shed infarctions. Consequently, during acute treatment the
sensitive and, on T2-weighted or FLAIR imaging, diastolic pressure should be lowered to between 110 and
increased signal intensity will be seen in the same areas 120 mmHg; once this has been accomplished, further treat-
(Hauser et al. 1988); gradient echo imaging may reveal evi- ment may be aimed at bringing the pressure down further in
dence of petechial hemorrhages (Weingarten et al. 1994). a more leisurely manner over the next few days. Acute treat-
Diffusion-weighted imaging is generally normal unless ment may be accomplished with intravenous sodium nitro-
infarction has occurred. Rarely, these MRI findings may be prusside, labetalol or diazoxide. In cases in which
found in the brainstem and cerebellum (Cruz-Flores et al. intravenous access is not immediately available or when the
2004; Kanazawa et al. 2005). clinical situation is not as urgent, intramuscular hydralazine
may be utilized. Seizures may be treated with intravenous
lorazepam and fosphenytoin, as described in Section 7.3. The
Course general treatment of delirium is discussed in Section 5.3.
Untreated hypertensive encephalopathy may be fatal. In

cases in which blood pressure is corrected, symptoms grad- 10.13 REVERSIBLE POSTERIOR
ually resolve over a matter of days and white matter abnor- LEUKOENCEPHALOPATHY SYNDROME
malities seen on CT or MR scanning typically clear within
a week or so. In those cases in which focal findings were The reversible posterior leukoencephalopathy syndrome is
noted, these may persist, and MR scanning will show per- a recently described disorder marked by delirium, cortical
sistent abnormalities consistent with infarction. With a blindness, and seizures, occurring secondary to treatment
sufficient number of strategically placed infarctions, with various chemotherapeutic agents. As noted in the pre-
patients may be left with a multi-infarct dementia. ceding section, this disorder is clinically identical to hyper-
tensive encephalopathy and differs only in mechanism.
Etiology
Clinical features
As blood pressure rises above a critical level, autoregulation of
small- and medium-sized cerebral arteries fails and there is The syndrome (Hinchey et al. 1996) presents acutely, over
extravasation of proteinaceous fluid into the surrounding hours, and manifests with delirium or lethargy, accompa-
white matter; some vessels may also rupture, causing petechial nied typically by headache, nausea or vomiting, and grand
hemorrhages, and others may undergo fibrinoid necrosis and mal seizures, which may have a focal onset. Cortical blind-
occlusion, causing infarction (Chester et al. 1978). ness is common and other symptoms may also occur, such
as hemianopia, hemiparesis, abulia, or asterixis.
Differential diagnosis T2-weighted or FLAIR MR scanning (Lamy et al. 2004)
reveals areas of increased signal intensity bilaterally in the
Not all deliria occurring in the setting of grossly elevated dias- white matter of the occipital and parietal lobes, with simi-
tolic pressures occur due to hypertensive encephalopathy. lar findings, in many cases, noted in the posterior aspects
Indeed, in patients with chronic and gradually increasing of the temporal lobes.
blood pressure, such very high pressures, being very gradually
reached, may be well tolerated without any immediate seque-
lae. As noted earlier, renal failure is not uncommon, and ure- Course
mic encephalopathy must also be considered. Intracerebral
hemorrhage may also be considered in the differential, but With prompt and adequate treatment, clinical findings
is generally of more acute onset and is easily recognized on resolve within days to weeks.
neuroimaging. Reversible posterior leukoencephalopathy
should be considered in cases that are clinically identical to
hypertensive encephalopathy in all respects except for the fact Pathology and etiology
that hypertension is either lacking or only mild.
Vasogenic edema is seen within the white matter, as indi-
cated by both brain biopsy (Lavigne et al. 2004) and MRI
Treatment findings. In cases with an unfavorable outcome, infarction
of the white matter occurs.
Hypertensive encephalopathy is a medical emergency and This syndrome has been noted secondary to treatment
the pressure must be lowered within an hour. Normotensive with a variety of chemotherapeutic and immunomodula-
levels, however, are not the goal because, with a loss of tory agents, including tacrolimus, cyclosporine, vincristine,
p 10.qxd 3/10/08 5:52 PM Page 445
10.14 MELAS 445
methotrexate, bevacizumab, cyclophosphamide, Hearing loss is common, and there may be an associ-
L-asparaginase, cisplatin, cytarabine, interferon-alpha, and ated clinically apparent myopathy. Diabetes mellitus and
immunoglobulins. Although the mechanism of toxicity is either hypo- or hyperthyroidism may occur.
not clear, it probably involves damage to the vascular Diffusion-weighted MR scanning during stroke-like
endothelium. episodes will reveal areas of increased signal intensity; over
time, these same areas will demonstrate increased signal
intensity on FLAIR imaging. Importantly, these areas gen-
Differential diagnosis erally do not fall within the area of distribution of any
major vessels and are most commonly seen in the occipital
The differential with hypertensive encephalopathy rests on and parietal lobes.
the presence or absence of severe hypertension: although The electroencephalogram (EEG) may reveal periodic
patients with the reversible posterior leukoencephalopathy lateralized epileptiform discharges (PLEDs) in patients with
syndrome may have an elevated pressure, for example a seizures.
diastolic pressure of up to 105 mmHg, pressures simply do Lactic acidosis is found in both the serum and CSF, and
not rise to the levels seen in hypertensive encephalopathy. the CSF total protein is also elevated.
Bilateral occipital infarction, as seen in the ‘top of the Muscle biopsy reveals ragged red fibers, and genetic test-
basilar’ syndrome, is distinguished by the involvement of ing for mutations in mitochondrial DNA may reveal char-
the occipital cortex, which is in contrast to the sparing of acteristic mutations.
the gray matter seen in reversible posterior leuko-
encephalopathy syndrome.
Course
Treatment Although the overall course is characterized by progres-
sion, the rate of progression, and the sequence with which
Potentially offending medications should be discontinued. various symptomatologies occur, is quite varied.
Seizure may be treated with lorazepam and fosphenytoin,
as described in Section 7.3. The general treatment of delir-
ium is discussed in Section 5.3.
Etiology
Mitochondrial dysfunction occurs secondary to mutations

10.14 MELAS in the gene for mitochondrial tRNA, with proliferation of
abnormal mitochondria in vascular endothelial and
MELAS (an acronym derived from mitochondrial
smooth muscle cells. Infarcts, which, as noted earlier, do
encephalomyopathy, lactic acidosis, and stroke-like
not conform to vascular territories, are found to affect
episodes) is a rare inherited disorder characterized by vary-
both gray and white matter, primarily in the parietal and
ing combinations of encephalopathy, stroke-like episodes,
occipital lobes.
migrainous headaches, seizures, and deafness; as with all
mitochondrial disorders, it displays a maternal pattern of
inheritance. Although almost all cases present before the
age of 40 years, with most occurring before the age of 20 Differential diagnosis
years, later onsets have been reported.
MELAS should be suspected in any young person with
recurrent stroke, especially when accompanied by
Clinical features migrainous headache or hearing loss. CADASIL is high on
the differential and is suggested by the MRI finding of
As noted, the clinical presentation is quite varied. Some white matter changes in the anterior portion of the tempo-
may present with stroke-like episodes, with hemiparesis, ral lobes.
hemianopia, cortical blindness or aphasia (Iizuka et al.
2003). Delirium may accompany these episodes and may
persist, only to resolve into a dementia, which, in turn, may Treatment
be gradually progressive (Sharfstein et al. 1999). In some
cases, psychosis has been noted (Apostolova et al. 2005). Symptomatic treatment of delirium and dementia is
Seizures may occur, and may be simple partial (Canafoglia described in Sections 5.3 and 5.1 respectively. Seizures may
et al. 2001), complex partial (including complex partial be treated with anti-epileptic drugs; however, valproic acid
status epilepticus [Leff et al. 1998]) or grand mal in type. should be avoided as it may aggravate seizures (Lin et al.
Migrainous headaches may precede, accompany, or follow 2007). L-arginine, given during stroke-like episodes, may
any of these symptomatologies. be followed by improvement (Koga et al. 2005).
p 10.qxd 3/10/08 5:52 PM Page 446
10.15 THROMBOTIC THROMBOCYTOPENIC 10.16 FAT EMBOLISM SYNDROME

PURPURA
This syndrome represents an uncommon complication of
Thrombotic thrombocytopenic purpura, or TTP, is an fractures or surgery to the long bones, or trauma to fatty
uncommon, devastating disorder, typically occurring in tissues, in which showers of fat globules pass to and
young or middle-aged adults. It is marked by the subacute through the lungs, leaving the patient in respiratory dis-
onset of delirium and thrombocytopenia (Druschky et al. tress and with a delirium.
1998).
Clinical features
Clinical features
Anywhere from 1 to 3 days after relevant trauma or sur-
The delirium is marked by a pronounced fluctuation in the gery, patients develop dyspnea and confusion; there may
severity of symptoms throughout the day. Other sympto- also be seizures and strokes and in severe cases coma may
matology includes focal signs, such as hemiparesis or apha- develop (Dines et al. 1975; Jacobson et al. 1986). In some
sia, which are typically transient, and seizures, with, in a cases a petechial rash may appear on the trunk.
small minority, complex partial status epilepticus (Blum Diffusion-weighted MR scanning reveals multiple punc-
and Drislane 1996). tate areas of increased signal intensity, primarily scattered
The platelet count is generally reduced below throughout the white matter with variable involvement of
30 000/mm3, and there is an accompanying microangio- the cortex or subcortical structures (Marshall et al. 2004).
pathic hemolytic anemia with schistocytes or Burr cells. Chest radiographs will reveal bilateral ‘fluffy’ infiltrates
Renal failure with proteinuria and azotemia is common, as and in a minority of cases fat globules may be observed on
are fever and purpura. urinalysis.
Course
Course
The mortality rate is as high as 10 percent; those who sur-
The disorder may persist for days to months; untreated, it vive experience a variable degree of recovery over the fol-
is typically fatal. lowing days.
Etiology Etiology
Procoagulants are released from vessel endothelial cells With fractures or surgery of the long bones, neutral fat is
with the subsequent appearance of widespread platelet released into the venous circulation and travels to the lungs
microthrombi in arterioles, capillaries, and venules. and then to the brain. A similar scenario may occur with
Presumably, the ongoing aggregation and disaggregation trauma to fatty tissues. Within the brain, multiple microin-
of platelet thrombi account for the classic waxing and farctions occur (von Hochstetter and Friede 1977;
waning nature of the symptomatology of this disorder. In Kamenar and Burger 1980).
some cases, small cortical infarctions may occur (Gruber
et al. 2000).
In cases secondary to trauma, head trauma may also have

occurred; in post-operative cases, other causes of post-
operative delirium, as discussed in Section 5.3, must be
Disseminated intravascular coagulation is distinguished by
considered. When pulmonary involvement is severe, respi-
a decreased fibrinogen level, an increase in fibrin split
ratory failure may occur and global cerebral hypoxia must
products, and a prolonged partial thromboplastin time.
also be considered.
Treatment Treatment
Plasma exchange is generally effective. With timely treat- In addition to any necessary respiratory support, seizures
ment most patients recover, with only a minority being left may be treated with anti-epileptic drugs and symptomatic
with persistent deficits. Anti-epileptic drugs may be treatment of delirium may be provided, as outlined in
required pending the effect of plasma exchange. Section 5.3.
p 10.qxd 3/10/08 5:52 PM Page 447
10.18 Transient global amnesia 447
10.17 MULTIPLE CHOLESTEROL EMBOLI Treatment

SYNDROME
The best treatment is prevention of atherosclerosis.
In patients with severe atheromatous disease of the ascend- Furthermore, extra caution should be exercised regarding
ing aorta or cerebral vessels, multiple crystals of cholesterol instrumentation affecting the ascending aorta or cerebral
may break off from plaques, either spontaneously or with vasculature in any patient with severe atherosclerosis.
instrumentation, and embolize to the brain causing multi- There is a case report suggesting that steroids given acutely
ple, generally small, infarctions. Such microemboli also, of may be beneficial (Andreaux et al. 2007).
course, travel to other structures, most notably the kidneys.
10.18 TRANSIENT GLOBAL AMNESIA

Clinical features
Transient global amnesia, first described in the English lan-
The mode of onset appears related to whether the syn- guage literature by Fisher and Adams in 1958 (Fisher and
drome occurs with instrumentation or spontaneously. Adams 1958), is an uncommon disorder characterized by
Cases occurring secondary to instrumentation (e.g., with infrequent amnestic episodes. Although the etiology of this
coronary artery bypass grafting, cardiac catheterization, or disorder is not known, it is included in this section on vas-
carotid angiography [Hagiwara et al. 2004]) tend to pres- cular disorders because of the strong suspicion that, as
ent acutely with a full syndrome a day or so after the instru- noted below, it may result from either transient ischemia
mentation. By contrast, spontaneously occurring cases or venous congestion of medial temporal structures.
may present subacutely, with the syndrome evolving over
weeks or months.
Acute cases occurring after instrumentation present Clinical features
with delirium (Ezzeddine et al. 2000), which may or may
not be accompanied by focal signs, such as hemiplegia or The overall clinical features have been described in a num-
hemianopia. Evidence of multiple emboli to other organs ber of papers (Bolwig 1968; Fisher and Adams 1958, 1964;
(Colt et al. 1988) includes renal failure, livedo reticularis of Gordon and Marin 1979; Heathfield et al. 1973; Hodges
the lower extremities, ‘blue toes’, petechial hemorrhages of and Ward 1989; Kushner and Hauser 1985; Miller et al.
the skin, a peripheral mononeuritis multiplex, and abdom- 1987a; Quinette et al. 2006; Regard and Landis 1984;
inal pain. Leukocytosis, eosinophilia, and an elevated ESR Shuttleworth and Morris 1966).
may all be present. The first episode of transient global amnesia generally
Subacute cases occurring spontaneously may present occurs in the sixth or seventh decade. Episodes themselves
with TIAs or multiple cerebral infarctions; progressive are generally of abrupt onset, and may be associated with
renal failure is also typically present (Andreaux et al. 2007; various precipitating events, such as strong emotion, sexual
Beal et al. 1981). intercourse, pain, physical exertion, Valsalva maneuvers,
and even immersion in cold water (Fisher 1982; Kushner
and Hauser 1985; Quinette et al. 2006). Whether or not a
Course precipitating event is present, patients suddenly experience
an amnesia that has both retrograde and anterograde com-
In cases of acute onset, fatalities, often secondary to multi- ponents. The retrograde component covers at least the pre-
organ failure, are common. Patients with subacute cases vious few hours and in many cases may stretch much further
typically develop severe renal failure. into the past: typically, this retrograde amnesia displays a
temporal gradient, such that whereas the amnesia may be
quite dense for events of the very recent past, it become
Differential diagnosis ‘patchy’ for events further back (Kritchevsky and Squire
1989). The anterograde component is fairly dense, and
Acute cases must be differentiated from other causes of patients are unable to keep track of any ongoing events dur-
post-operative delirium, as discussed in Section 5.3. ing the episode. Most patients, although not confused, are
Subacute cases must be distinguished from the lacunar more or less alarmed at their state, and many will anxiously
state: here the accompanying renal failure provides a clue. and repeatedly ask where they are and how they got to be
where they are. Formal mental status testing reveals that
patients are coherent, alert, and, as noted, not confused.
Etiology Although digit span is intact, patients are unable to recall
any of three words after 5 minutes; furthermore, they will be
Showers of microemboli composed of cholesterol crystals unable to recall events of the recent past leading up to the
eventually lodge in small arterioles where they provoke an onset of the episode. In essence, cognitive ability, other than
inflammatory response. memory, remains normal, and indeed some patients may
p 10.qxd 3/10/08 5:52 PM Page 448
engage in quite complex activity, such as playing an organ episode of ‘spreading depression of Leão’ confined to medial
piece, during the episode itself (Byer and Crowley 1980). temporal structures could, conceivably, cause amnesia.
The neurologic examination is generally normal. The Migraine, however, would not explain the SPECT and
episode itself generally lasts anywhere from 4 to 18 hours, diffusion-weighted imaging abnormalities described earlier.
averaging about 6 hours, and terminates gradually. The final proposed mechanism, namely venous reflux,
After the episode has cleared, patients are once again able is quite interesting. To understand the theory of venous
to keep track of ongoing events, and their ability to recall reflux one must recall some anatomy. Normally the medial
words after 5 minutes is fully restored. When they try and temporal structures are drained by the deep veins of
recall what happened, however, they often find an ‘island’ of Rosenthal. These veins, in turn, drain to the great vein of
amnesia that covers not only the duration of the event itself Galen, which drains to the straight sinus. The straight
but also any events that occurred anywhere from a few min- sinus, in turn, courses posteriorly to join the superior sagit-
utes to an hour or so just before the onset of the episode. tal sinus at the sinus confluens. The sinus confluens gives
Although clinically patients are thus fully restored, detailed rise to the left and right transverse sinuses, which in turn
testing may reveal some subtle decrements in memory drain to the sigmoid sinuses and eventually into the inter-
(Guillery-Girard et al. 2006; Steinmetz and Vroom 1972). nal jugular veins. Of note, and of particular importance to
the venous reflux theory, in the majority of individuals, the
straight sinus drains not into both transverse sinuses but
Course only into the left transverse sinus. Given this unique
drainage pattern, it is theoretically possible that venous
Long-term follow-up of approximately 5–6 years shows reflux confined to the left internal jugular vein could cause
that only about one-fifth to one-quarter of patients have a venous stasis in the medial aspects of both the left and the
recurrence (Gandolfo et al. 1992; Hinge et al. 1986; Miller right temporal lobes. Recent studies have demonstrated
et al. 1987a). such reflux through incompetent valves (Maalikjy Akkawi
et al. 2003) in the left internal jugular vein in patients with
transient global amnesia, adding weight to this theory
Etiology (Chung et al. 2006; Sander et al. 2000). The reflux itself
could be related to a Valsalva-type maneuver, consistent
It appears that the amnesia seen in transient global amnesia with some of the precipitating events mentioned earlier,
represents the effects of a similarly transient dysfunction of or, as indicated in one study, to intrathoracic compression
medial temporal lobe structures. Single photon emission of the left brachiocephalic vein (Chung et al. 2006).
computed tomography (SPECT) studies have revealed
hypoperfusion of the medial aspects of both temporal lobes
(Lampl et al. 2004), more so the left than the right, and Differential diagnosis
diffusion-weighted imaging has revealed punctate areas of
increased signal intensity in the hippocampus (Bartsch et al. Transient global amnesia, as discussed in Section 5.4, is best
2006; Sedlaczek et al. 2004; Strupp et al. 1998); notably both conceived of as one of the episodic anterograde amnesias
of these abnormal findings clear with time. Structural MRI and, as such, must be distinguished from TIAs, pure epilep-
studies are generally normal (Bartsch et al. 2006); however, tic amnesia, concussion, and substance-induced blackouts.
one high-resolution MRI study found an increased number Transient ischemic attacks affecting the temporal lobes
of microcavities in the CA-1 subfield of the hippocampus, may produce a syndrome quite similar to transient global
suggesting that there may be some subtle permanent dam- amnesia. However, when ischemia occurs in the area of
age (Nakada et al. 2005). Several mechanisms have been distribution of the posterior cerebral arteries, in addition
proposed to account for these changes, including epileptic to amnesia one typically also sees evidence of ischemia of
activity, transient ischemia, migraine, and, recently, venous the occipital lobes, such as hemianopia or cortical blind-
reflux. Epileptic activity appears unlikely: EEGs obtained ness, findings not seen in transient global amnesia.
during episodes of transient global amnesia do not display Pure epileptic amnesia is suggested by a sudden offset of
ictal activity (Miller et al. 1987b), and the attacks themselves, the episode, in contrast to the gradual offset of transient
rather than ending abruptly, as is typical of a seizure, tend to global amnesia, and by the fact that patients in the midst of
clear gradually. Transient ischemia has long been an attrac- an epileptic amnestic episode generally do not engage in
tive hypothesis, but patients with transient global amnesia the anxious questioning typical of transient global amne-
generally have few risk factors for stroke (Hodges and sia. Other distinguishing features include the occurrence of
Warlow 1990; Lauria et al. 1998; Melo et al. 1992) and rarely other seizure types, such as complex partial or grand mal
end up having stroke during follow-up (Zorzon et al. 1995). seizures, and a pattern of frequent recurrence.
Migraine may play a role: there is a definite association Concussion is immediately suggested by a history of
between transient global amnesia and migraine (Crowell head injury, which, of course, must often be gained from
et al. 1984; Hodges and Warlow 1990; Melo et al. 1992; others. Furthermore, during concussion, patients may dis-
Schmidtke and Ehmsen 1998; Zorzon et al. 1995), and an play a degree of confusion.
p 10.qxd 3/10/08 5:52 PM Page 449
References 449
Blackouts, as seen during alcohol intoxication or intox- Aykutlu E, Baykan B, Serdaroglu P et al. Epileptic seizures in
ication with benzodiazepines, are suggested by other evi- Behçet disease. Epilepsia 2002; 43:832–5.
dence of intoxication, such as dysarthria or ataxia, and by a Bartsch T, Alfke K, Stingele R et al. Selective affection of
lack of recognition on the part of the ‘blacked-out’ patient hippocampal CA-1 neurons in patients with transient global
that anything is amiss and a corresponding absence of any amnesia. Brain 2006; 129:2874–84.
anxious questioning. Baudrimont M, Dubas F, Joutel A et al. Autosomal dominant
leukoencephalopathy and subcortical ischemic stroke. A
clinicopathological study. Stroke 1993; 24:122–5.
Treatment Beal MF, Williams RS, Richardson EP et al. Cholesterol embolism
as a cause of transient ischemic attacks and cerebral
Apart from supervision during the episode itself, and reas- infarction. Neurology 1981; 31:860–5.
surance afterwards of its overall benign nature, no treat- Bergmann M, Ebke M, Yuan Y. Cerebral autosomal dominant
ment is generally required. However, in cases in which arteriopathy with subcortical infarcts and
there are obvious precipitating factors, patients should be leukoencephalopathy (CADASIL): a morphological study of a
accordingly instructed to avoid them. German family. Acta Neuropathol 1996; 92:341–50.
Binswanger O. Die abgrenzung des allgemeinen progressiven.
Paralysie Klin Wochenschr 1894; 31:1103–5, 1137–9, 1180–6.
REFERENCES Black S, Roman GC, Geldmacher DS et al. Efficacy and tolerability
of donepezil in vascular dementia; positive results of a 24-
Abu-Shakara M, Khraishi M, Grossman H et al. Primary angiitis of week, multicenter, international, randomized, placebo-
the CNS diagnosed by angiography. QJ Med 1994; 87:351–8. controlled trial. Stroke 2003; 34:2323–30.
Alhalabi M, Moore PM. Serial angiography in isolated angiopathy Blass JP, Hoyer S, Nitsch R. A translation of Otto Binswanger’s
of the central nervous system. Neurology 1994; 44:1221–6. article ‘The delineation of the generalized progressive
Akiguchi I, Tomimoto H, Suenega T et al. Alterations in glia and paralyses’. Arch Neurol 1991; 48:961–72.
axons in the brains of Binswanger’s disease patients. Stroke Blum AS, Drislane FW. Nonconvulsive status epilepticus in
1997; 28:1423–9. thrombotic thrombocytopenic purpura. Neurology 1996;
Akman-Demir G, Baykan-Kurt B, Serdaroglu P et al. Seven year 47:1079–81.
follow-up of neurologic involvement in Behçet syndrome. Arch Bogucki A, Janczewska E, Koszewska I et al. Evaluation of
Neurol 1993; 53:691–4. dementia in subcortical arteriosclerotic encephalopathy
Akman-Demir G, Serdaroglu P, Tasci B et al. Clinical patterns of (Binswanger’s disease). Eur Arch Psychiatry Clin Neurosci 1991;
neurological involvement in Behçet’s disease: evaluation of 241:91–7.
200 patients. Brain 1999; 122:2171–81. Bolwig TG. Transient global amnesia. Acta Neurol Scand 1968;
Akyol A, Akyildiz UO, Tataroglu C. Vascular parkinsonism: a case 44:101–6.
of lacunar infarction localized to mesencephalic substantia Borson S. Behçet’s disease as a psychiatric disorder: a case report.
nigra. Parkinsonism Relat Disord 2006; 12:459–61. Am J Psychiatry 1982; 139:1348–9.
Al-Araji A, Sharquie K, Al-Rawi Z. Prevalence and patterns of Bruetsch WL, Williams CL. Arteriosclerotic muscular rigidity with
neurological involvement in Behçet’s disease: a prospective study special reference to gait disturbances. Am J Psychiatry 1954;
from Iraq. J Neurol Neurosurg Psychiatry 2003; 74:608–13. 111:332–6.
Alrawi A, Trobe JD, Blaivas M et al. Brain biopsy in primary Byer JA, Crowley WJ. Musical performance during transient global
angiitis of the central nervous system. Neurology 1999; amnesia. Neurology 1980; 30:80–2.
53:858–60. Calabrese LH, Mallek JA. Primary angiitis of the central nervous
Altinors N, Senveli E, Arda N et al. Intracerebral hemorrhage and system: report of 8 new cases, review of the literature, and
hematoma in Behçet’s disease: case report. Neurosurgery proposal for diagnostic criteria. Medicine 1988; 67:20–39.
1987; 21:582. Canafoglia L, Franceschetti S, Antozzi C et al. Epileptic
Andreaux R, Marro B, El Khoury N et al. Reversible phenotypes associated with mitochondrial disorders.
encephalopathy associated with cholesterol embolism Neurology 2001; 56:1340–6.
syndrome: magnetic resonance imaging and pathological Caplan LR, Schoene WC. Clinical features of subcortical
findings. J Neurol Neurosurg Psychiatry 2007; 78:180–2. arteriosclerotic encephalopathy (Binswanger disease).
Apostolova LG, White M, Moore SA et al. Deep white matter Neurology 1978; 28:1206–15.
pathologic features in watershed regions: a novel pattern of Caselli RJ. Giant cell (temporal) arteritis: a treatable cause of
central nervous system involvement in MELAS. Arch Neurol multi-infarct dementia. Neurology 1990; 40:753–5.
2005; 62:1154–6. Caselli RJ, Hunder GG, Whisnant JP. Neurologic disease in biopsy-
Auchus AP, Chen CP, Sadagar SN et al. Single stroke dementia: proven giant cell (temporal) arteritis. Neurology 1988; 38:352–9.
insights from 12 cases in Singapore. J Neuro Sci 2002; Case Records of the Massachusetts General Hospital. Case
203–4:85–9. 8–1989. N Engl J Med 1989; 320:514–24.
Auchus AP, Brasher HR, Salloway S et al. Galantamine treatment Chajek T, Fainaru M. Behçet’s disease: report of 41 cases and a
of vascular dementia. Neurology 2007; 69:448–58. review of the literature. Medicine 1975; 54:179–86.
p 10.qxd 3/10/08 5:52 PM Page 450
Chester EM, Agamanolis DP, Banker BQ et al. Hypertensive Gandolfo C, Caponnetto C, Conti M et al. Prognosis of transient
encephalopathy: a clinicopathologic study of 20 cases. global amnesia: a long-term follow-up study. Eur Neurol
Neurology 1978; 28:928–39. 1992; 32:52–7.
Choi JC, Kang S-Y, Kang J-H et al. Intracerebral hemorrhages in Gilles C, Brucher JM, Khoubesserian P et al. Cerebral amyloid
CADASIL. Neurology 2006; 67:2042–4. angiopathy as a cause of multiple intracerebral hemorrhages.
Chung C-P, Hsu H-Y, Chang F-C et al. Detection of intracranial Neurology 1984; 34:730–5.
venous reflux in patients of transient global amnesia. Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold,
Neurology 2006; 66:1873–7. 2000.
Colt HG, Begg RJ, Saporito JJ et al. Cholesterol emboli after Gordon B, Marin OSM. Transient global amnesia: an extensive
cardiac catheterization. Eight cases and a review of the case report. J Neurol Neurosurg Psychiatry 1979; 42:572–5.
literature. Medicine 1988; 67:389–400. Gray F, Dubas F, Roullet E et al. Leukoencephalopathy in diffuse
Cosgrove CR, Leblanc R, Meagher-Villemure K et al. Cerebral hemorrhagic amyloid angiopathy. Ann Neurol 1985; 18:54–9.
amyloid angiopathy. Neurology 1985; 38:625–31. Greenberg SM, Vonsattel JPG, Stakes JW et al. The clinical
Cravioto H, Feigin I. Noninfectious granulomatous angiitis involving spectrum of cerebral amyloid angiopathy: presentations
the central nervous system. Neurology 1959; 9:599–609. without lobar hemorrhage. Neurology 1993; 43:2073–9.
Critchley M. Arteriosclerotic parkinsonism. Brain 1929; 52:23–83. Greenberg SM, O’Donnell HC, Schaefer PW et al. MRI detection of
Crowell GF, Stump DA, Biller J et al. The transient global new hemorrhages: potential marker of progression in cerebral
amnesia–migraine connection. Arch Neurol 1984; 41:75–19. amyloid angiopathy. Neurology 1999; 53:1135–8.
Cruz-Flores S, de Assis Aquino Gondim F, Leira EC. Brainstem de Groot K, Schmidt DK, Arlt AC et al. Standardized neurologic
involvement in hypertensive encephalopathy: clinical and evaluation of 128 patients with Wegener granulomatosis. Arch
radiological findings. Neurology 2004; 62:1417–19. Neurol 2001; 58:1215–21.
Cummings JL, Miller B, Hill MA et al. Neuropsychiatric aspects of Gruber O, Wittig L, Wiggins CJ et al. Thrombotic
multi-infarct dementia and dementia of the Alzheimer type. thrombocytopenic purpura: MRI demonstration of persistent
Arch Neurol 1987; 44:389–93. small cerebral infarcts after clinical recovery. Neuroradiology
Dichgans M, Mayer M, Uttner I et al. The phenotypic spectrum of 2000; 42:616–18.
CADASIL: clinical findings in 102 cases. Ann Neurol 1998; Gudmundsson G, Halgrimsson I, Jonasson TA et al. Hereditary
44:731–9. cerebral haemorrhage with amyloidosis. Brain 1972;
Dines DE, Burgher LW, Okazaki H. The clinical and pathologic 95:387–404.
correlation of fat embolism. Mayo Clin Proc 1975; 50:407–11. Guillery-Girard B, Quinette P, Desgranges B et al. Long-term
Drachman DA. Neurological complications of Wegener’s memory following transient global amnesia: an investigation
granulomatosis. Arch Neurol 1963; 8:145–55. of episodic and semantic memory. Acta Neurol Scand 2006;
Druschky A, Erguth F, Strauss R et al. Central nervous system 114:329–33.
involvement in thrombotic thrombocytopenic purpura. Eur Haan J, Lanser JBK, Zigderveld I et al. Dementia in hereditary
Neurol 1998; 40:220–4. cerebral hemorrhage with amyloidosis – Dutch type. Arch
Ehsan T, Hasan S, Powers JM et al. Serial magnetic resonance Neurol 1990a; 47:965–7.
imaging in isolated angiitis of the central nervous system. Haan J, Algra PR, Roos RAC. Hereditary cerebral hemorrhage with
Neurology 1995; 45:1462–5. amyloidosis – Dutch type. Clinical and computed tomographic
Erkinjunti T, Haltia M, Palo J et al. Accuracy of the clinical analysis of 24 cases. Arch Neurol 1990b; 47:649–53.
diagnosis of vascular dementia: a prospective clinical and Hagiwara N, Toyoda K, Nakayama M et al. Renal cholesterol
post-mortem study. J Neurol Neurosurg Psychiatry 1988; emboli in patients with carotid stenosis: a severe and
51:1037–44. underdiagnosed complication following cerebrovascular
Ezzeddine MA, Primavera JM, Rosand J et al. Clinical procedures. J Neurol Sci 2004; 222:109–12.
characteristics of pathologically proved cholesterol emboli to Hauser RA, Lacey M, Knight R. Hypertensive encephalopathy:
the brain. Neurology 2000; 54:1681–3. magnetic resonance imaging demonstration of reversible
Farah S, Al-Shubaili A, Montasar A et al. Behçet’s syndrome: a cortical and white matter lesions. Arch Neurol 1988;
report of 41 patients with emphasis on neurological 45:1078–83.
manifestations. J Neurol Neurosurg Psychiatry 1998; 64:382–4. Healton EB, Brust JC, Feinfeld DA et al. Hypertensive
Filley CM, Thompson LL, Sze CI et al. White matter dementia in encephalopathy and the neurologic manifestations of
CADASIL. J Neurol Sci 1999; 163:163–7. malignant hypertension. Neurology 1982; 32:127–31.
Fisher CM. Transient global amnesia: precipitating activities and Heathfield K, Croft P, Swash M. The syndrome of transient global
other observations. Arch Neurol 1982; 39:605–8. amnesia. Brain 1973; 96:729–36.
Fisher CM, Adams RD. Transient global amnesia. Trans Am Neurol Hinchey J, Chaves C, Appignani B et al. A reversible posterior
Assoc 1958; 83:143–6. leukoencephalopathy syndrome. N Engl J Med 1996;
Fisher CM, Adams RD. Transient global amnesia. Acta Neurol 334:494–500.
Scand 1964; 40(suppl. 9):1–83. Hinge HH, Jensen TS, Kjaer M et al. The prognosis of transient
Ford RG, Siekert RG. Central nervous system manifestations of global amnesia. Results of a multicenter study. Arch Neurol
periarteritis nodosa. Neurology 1965; 15:114–22. 1986; 43:673–6.
p 10.qxd 3/10/08 5:52 PM Page 451
References 451
Hodges JR, Ward CD. Observations during transient global Knudson KA, Rosand J, Karluk D et al. Clinical diagnosis of
amnesia: a behavioral and neuropsychological study of five cerebral amyloid angiopathy: validation of the Boston criteria.
cases. Brain 1989; 112:595–620. Neurology 2001; 56:537–9.
Hodges JR, Warlow CP. The aetiology of transient global amnesia. Koga Y, Akita Y, Nishioka J et al. L-arginine improves the
A case-control study of 114 patients with prospective follow-up. symptoms of strokelike episodes in MELAS. Neurology 2005;
Brain 1990; 113:639–57. 64:710–12.
von Hochstetter AR, Friede RL. Residual lesions of cerebral fat Kolodny EH, Rebeiz JJ, Caveness VS et al. Granulomatous angiitis
embolism. J Neurol 1977; 216:227–33. of the central nervous system. Arch Neurol 1968; 19:510–24.
Hoffman GS, Kerr GS, Leavitt RY. Wegener’s granulomatosis: an Koo EH, Massey EW. Granulomatous angiitis of the central
analysis of 158 patients. Ann Intern Med 1992; 116:488–98. nervous system: protean manifestations and response to
Hughes JT, Brownell B. Granulomatous giant-celled angiitis of the treatment. J Neurol Neurosurg Psychiatry 1988; 51:1126–33.
central nervous system. Neurology 1966; 16:293–8. Kritchevsky M, Squire LR. Transient global amnesia: evidence for
Hunter R, Smith J, Thompson T et al. Hemiparkinsonism with extensive, temporally graded retrograde amnesia. Neurology
infarction of the ipsilateral substantia nigra. Neuropathol Appl 1989; 39:213–18.
Neurobiol 1978; 4:297–301. Kushner MJ, Hauser WA. Transient global amnesia: a case-control
Iizuka R, Sakai F, Kan S et al. Slowly progressive spread of the study. Ann Neurol 1985; 18:684–95.
stroke-like lesions in MELAS. Neurology 2003; 61:1238–44. Ladurna G, Iliff LD, Lechner H. Clinical factors associated with
Iragui VJ, Miravi E. Behçet syndrome presenting as ischaemic stroke. J Neurol Neurosurg Psychiatry 1982;
cerebrovascular disease. J Neurol Neurosurg Psychiatry 1986; 45:97–101.
49:838–9. Lampl Y, Sadeh M, Loberboym M. Transient global amnesia – not
Ishii N, Nishihara Y, Imamura T. Why do frontal lobe symptoms always a benign process. Acta Neurol Scand 2004; 110:75–9.
predominate in vascular dementia with lacunes? Neurology Lamy C, Oppenheim C, Meder JF et al. Neuroimaging in posterior
1986; 36:340–5. reversible leukoencephalopathy syndrome. J Neuroimaging
Jacobson DM, Terrence CF, Reinmuth OM. The neurologic 2004; 14:89–96.
manifestations of fat embolism. Neurology 1986; 36:847–51. Lauria G, Gentile M, Fassetta G et al. Transient global amnesia and
Jayakumar PN, Taly AB, Shanmugam V et al. Multi-infarct transient ischemic attack: a community-based case-control
dementia: a computed tomographic study. Acta Neurol Scand study. Acta Neurol Scand 1998; 97:381–5.
1989; 73:292–5. Lavigne CM, Shrier DA, Letkar M et al. Tacrolimus
Joseph FG, Scolding NJ. Neuro-Behçet’s disease in Caucasians: a leukoencephalopathy: a neuropathologic confirmation.
study of 22 patients. Eur J Neurol 2007; 14:174–80. Neurology 2004; 63:1132–3.
Joutel A, Vahedi K, Corpechot C et al. Strong clustering and Lazzarino LG, Nicolai A, Toppani D. Subacute parkinsonism from a
stereotyped nature of Notch3 mutations in CADASIL patients. single lacunar infarct in the basal ganglia. Acta Neurol 1990;
Lancet 1997; 350:1511–15. 12:292–5.
Jung HH, Bassetti C, Tournier-Lasserve E et al. Cerebral autosomal Leff AP, McNabb AW, Hanna MG et al. Complex partial status
dominant arteriopathy with subcortical infarcts and epilepticus in late-onset MELAS. Epilepsia 1998; 39:438–41.
leukoencephalopathy: a clinicopathological and genetic study of Lesnik Oberstein SAJ, van den Boom R, van Bucher MA et al.
a Swiss family. J Neurol Neurosurg Psychiatry 1995; 59:138–43. Cerebral microbleeds in CADASIL. Neurology 2001; 57:1066–70.
Kamenar E, Burger PC. Cerebral fat embolism: a neuropathologic Levy E, Carman MD, Fernandez Madrid IJ et al. Mutation of the
study of a microembolic state. Stroke 1980; 11:477–84. Alzheimer’s disease amyloid gene in hereditary cerebral
Kanazawa M, Sanpei K, Kasuga K. Recurrent hypertensive hemorrhage, Dutch type. Science 1990; 248:1124–6.
brainstem encephalopathy. J Neurol Neurosurg Psychiatry Lie JT. Primary (granulomatous) angiitis of the central nervous
2005; 76:888–90. system: a clinicopathologic analysis of 15 new cases and a
Kansu T, Corbett JJ, Savino P et al. Giant cell arteritis with normal review of the literature. Hum Pathol 1992; 23:164–71.
sedimentation rate. Arch Neurol 1977; 34:624–5. Liem MK, van den Grond J, Haan J et al. Lacunar infarcts are the
Katz DI, Alexander MP, Mandell AM. Dementia following strokes main correlate with cognitive dysfunction in CADASIL. Stroke
in the mesencephalon and diencephalon. Arch Neurol 1987; 2007; 38:923–8.
44:1127–33. Lin CM, Thajeb P. Valproic acid aggravates epilepsy due to MELAS
Keschner M, Sloane P. Encephalitic, idiopathic and arteriosclerotic in a patient with an A3243G mutation of mitochondrial DNA.
parkinsonism: a clinicopathologic study. Arch Neurol Metabol Brain Dis 2007; 22:105–9.
Psychiatry 1931; 25:1011–41. Lin JX, Tomimoto H, Akiguchi I et al. Vascular cell components of
Kidd D, Stever A, Denman AM et al. Neurological complications in the medullary arteries in Binswanger’s disease brains: a
Behçet’s syndrome. Brain 1999; 122:2183–94. morphometric and immunoelectron microscopic study. Stroke
Kim Y, Choi EJ, Choi CG et al. Characteristics of CADASIL in Korea. 2000; 31:1838–42.
a novel cysteine-sparing Notch3 mutation. Neurology 2006; Liu CK, Miller BL, Cummings JL et al. A quantitative MRI study of
66:1511–16. vascular dementia. Neurology 1992; 42:138–43.
Kinnecom C, Lev MH, Wendell L et al. Course of cerebral amyloid Lovelace RE. Mononeuritis multiplex in polyarteritis nodosa.
angiopathy-related inflammation. Neurology 2007; 68:1411–16. Neurology 1964; 14:434–42.
p 10.qxd 3/10/08 5:52 PM Page 452
Maalikjy Akkawi N, Agosti C, Anzola GP et al. Transient global Nishino H, Rubino FA, DeRemee RA et al. Neurological involvement
amnesia: a clinical and sonographic study. Eur Neurol 2003; in Wegener’s granulomatosis: an analysis of 324 consecutive
49:67–71. patients at the Mayo Clinic. Ann Neurol 1993a; 33:4–9.
MacKay ME, McLardy T, Harris C. A case of periarteritis nodosa of Nishino H, Rubino FA, Parisi JE. The spectrum of neurologic
the central nervous system. J Ment Sci 1950; 96:470–5. involvement in Wegener’s granulomatosis. Neurology 1993b;
Malandrini A, Carrera P, Palmeri S et al. Clinicopathological and 43:1334–7.
genetic studies of two further families with cerebral Nobuyoshi I, Nishihara Y, Horie A. Amyloid angiopathy and lobar
autosomal dominant arteriopathy. Acta Neuropathol 1996; cerebral haemorrhage. J Neurol Neurosurg Psychiatry 1984;
92:115–22. 47:1203–10.
Malandrini A, Gaudiano C, Gambelli S et al. Diagnostic value of Okazaki H, Reagan TJ, Campbell RJ. Clinicopathologic studies of
ultrastructural skin biopsy in CADASIL. Neurology 2007; primary cerebral amyloid: angiopathy. Mayo Clin Proc 1979;
68:1430–2. 54:22–31.
Markus HS, Martin RJ, Simpson MA et al. Diagnostic strategies in Opherk C, Peters N, Herzog J et al. Long-term prognosis and
CADASIL. Neurology 2002; 59:1134–8. causes of death in CADASIL: a retrospective study of 411
Marshall GB, Heale VR, Herx L et al. Magnetic resonance diffusion patients. Brain 2004; 127:2533–9.
weighted imaging in cerebral fat embolism. Can J Neurol Sci Oppenheimer BS, Fishberg AM. Hypertensive encephalopathy.
2004; 31:417–21. Arch Intern Med 1928; 41:264–78.
Mazlumzadeh M, Hunter GG, Easley KA et al. Treatment of giant Orgogozo JM, Rigaud AS, Stoffer A et al. Efficacy and safety of
cell arteritis using induction therapy with high-dose memantine in patients with mild to moderate vascular
glucocorticoids: a double-blind, placebo-controlled, dementia: a randomized, placebo-controlled trial (MMM
randomized prospective clinical trial. Arthritis Rheum 2006; 3000). Stroke 2002; 33:1834–9.
54:3310–18. O’Sullivan M, Jarosz JM, Martin RJ et al. MRI hyperintensities of
Mellies JK, Baumer T, Muller JA et al. SPECT study of a German the temporal lobe and external capsule in patients with
CADASIL family: a phenotype with migraine and progressive CADASIL. Neurology 2001; 56:628–34.
dementia only. Neurology 1998; 50:1715–21. Pallis CA, Fudge BJ. The neurological complications of Behçet’s
Melo TP, Ferro JM, Ferro H. Transient global amnesia. A case syndrome. Arch Neurol Psychiatry 1956; 75:1–14.
control study. Brain 1992; 115:261–70. Palsdottir A, Abrahamson M, Thorsteinsson L et al. Mutation in
Miller JW, Petersen RC, Metter EJ et al. Transient global amnesia: cystatin C gene causes hereditary brain haemorrhage. Lancet
clinical characteristics and prognosis. Neurology 1987a; 1988; 2:603–4.
37:733–7. Pendlebury WW, Iole ED, Tracy RP et al. Intracerebral hemorrhage
Miller JW, Yanagihara T, Petersen RC et al. Transient global related to cerebral amyloid angiopathy and t-PA treatment.
amnesia and epilepsy. Electroencephalographic distinction. Ann Neurol 1991; 29:210–13.
Arch Neurol 1987b; 44:629–33. Quinette P, Guillery-Girard B, Dayan J et al. What does transient
Mok VCT, Wong A, Lam WWM et al. Cognitive impairment and global amnesia really mean? Review of the literature and
functional outcome after stroke associated with small vessel thorough study of 142 cases. Brain 2006; 129:1640–58.
disease. J Neurol Neurosurg Psychiatry 2004; 75:560–6. Regard M, Landis T. Transient global amnesia: neuropsychological
Moore PM. Diagnosis and management of isolated angiitis of the dysfunction during attack and recovery in two ‘pure’ cases. J
central nervous system. Neurology 1989; 39:167–73. Neurol Neurosurg Psychiatry 1984; 47:668–72.
Mori E, Yamdori A, Mitani Y. Left thalamic infarction and Reichart MD, Bogousslavsky J, Janzer RC. Early lacunar strokes
disturbance of verbal memory: a clinicoanatomical study with complicated polyarteritis nodosa: thrombotic
a new method of computed tomographic stereotaxic lesion microangiopathy. Neurology 2000; 54:883–9.
location. Ann Neurol 1986; 20:671–6. Revesz T, Hawkins CP, du Boulay EPGH et al. Pathological findings
Motomura S, Tabira T, Kuroiwa Y. A clinical comparative study of correlated with magnetic resonance imaging in subcortical
multiple sclerosis and neuro-Behçet’s syndrome. J Neurol arteriosclerotic encephalopathy (Binswanger’s disease). J
Neurosurg Psychiatry 1980; 43:210–13. Neurol Neurosurg Psychiatry 1989; 52:1337–44.
Murrow RW, Schweiger GD, Kepes JJ et al. Parkinsonism due to a Rosand J, Hylek EM, O’Donnell HC et al. Warfarin-associated
basal ganglia lacunar state: clinicopathologic correlation. hemorrhage and cerebral amyloid angiopathy: a genetic and
Neurology 1990; 40:897–900. pathologic study. Neurology 2000; 55:947–51.
Nakada T, Kwee IL, Fujii Y et al. High-field, T2 reversed MRI of Rosete A, Cabral AR, Kraus A et al. Diabetes insipidus secondary to
hippocampus in transient global amnesia. Neurology 2005; Wegener’s granulomatosis: report and review of the literature.
64:1170–4. J Rheumatol 1991; 18:761–5.
Nesher G, Berkun Y, Mates M et al. Low-dose aspirin and Rubinstein LJ, Urich H. Meningo-encephalitis of Behçet’s disease:
prevention of cranial ischemic complications in giant cell Case report with pathological findings. Brain 1963;
arteritis. Arthritis Rheum 2004; 50:1332–7. 86:151–60.
Nightingale S, Venables GS, Bates D. Polymyalgia rheumatica with Ruchoux M-M, Chabriat H, Bousser M-G et al. Presence of
diffuse cerebral disease responding rapidly to steroid therapy. ultrastructural arterial lesions in muscle and skin vessels of
J Neurol Neurosurg Psychiatry 1982; 45:841–3. patients with CADASIL. Stroke 1994; 25:2291–2.
p 10.qxd 3/10/08 5:52 PM Page 453
References 453
Sander D, Winbeck K, Etgen T et al. Disturbances of venous flow Wattendorff AR, Frangione B, Luyendijk W et al. Hereditary
patterns in patients with transient global amnesia. Lancet cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-
2000; 356:1982–4. D); clinicopathological studies. J Neurol Neurosurg Psychiatry
Sandson TA, Daffener KR, Carvalho PA et al. Frontal lobe 1995; 58:699–705.
dysfunction following infarction of the left-sided medial Wechsler B, Dell’Isola B, Vidhaillet M et al. MRI in 31 patient’s
thalamus. Arch Neurol 1991; 48:1300–3. with Behçet’s disease and neurological involvement:
Schmidtke K, Ehmsen L. Transient global amnesia and migraine. A prospective study with clinical correlation. J Neurol Neurosurg
case control study. Eur Neurol 1998; 40:9–14. Psychiatry 1990; 53:793–8.
Schon F, Martin RJ, Prevett M et al. ‘CADASIL coma’: an Weinberger LM, Cohen ML, Remler BF et al. Intracranial
underdiagnosed acute encephalopathy. J Neurol Neurosurg Wegener’s granulomatosis. Neurology 1993; 43:1831–4.
Psychiatry 2003; 74:249–52. Weingarten K, Barbut D, Filippi C et al. Acute hypertensive
Schroder JM, Sellhaus B, Jorg J. Identification of the encephalopathy: findings on spin-echo and gradient-echo MR
characteristic vascular changes in a sural nerve biopsy of a imaging. Am J Roentgenol 1994; 162:665–70.
case with cerebral autosomal dominant arteriopathy with Wilcock G, Mobius HJ, Stoffer A. A double-blind, placebo-
subcortical infarcts and leukoencephalopathy (CADASIL). Acta controlled multicentre study of memantine in mild to
Neuropathol (Berl) 1995; 89:116–21. moderate vascular dementia (MMM500). Int Clin
Sedlaczek O, Hirsch JG, Grips E et al. Detection of delayed focal Psychopharmacol 2002; 17:297–305.
MR changes in the lateral hippocampus in transient global Wilkinson D, Doody R, Helme R et al. Donepezil in vascular
amnesia. Neurology 2004; 62:2165–70. dementia: a randomized, placebo-controlled study. Neurology
Serdaroglu P, Yazici H, Ozdemir C et al. Neurologic involvement in 2003; 61:479–86.
Behçet’s syndrome: a prospective study. Arch Neurol 1989; Wilkinson IMS, Russell RWR. Arteries of the head and neck in
46:265–9. giant cell arteritis. A pathological study to show the pattern of
Seror R, Mahr A, Ramanoelina J et al. Central nervous system arterial involvement. Arch Neurol 1972; 27:378–91.
involvement in Wegener granulomatosis. Medicine 2006; Winikates J, Jankovic J. Clinical correlates of vascular
85:54–65. parkinsonism. Arch Neurol 1999; 56:98–102.
Sharfstein SR, Gordon MF, Libman RB et al. Adult-onset MELAS Wolf SM, Schotland DL, Phillips LL. Involvement of nervous system
presenting as herpes encephalitis. Arch Neurol 1999; in Behçet’s syndrome. Arch Neurol 1965; 12:315–25.
56:241–3. Wolfe N, Linn R, Babikian VL et al. Frontal system impairment
Shuttleworth EC, Morris CE. The transient global amnesia following multiple lacunar infarcts. Arch Neurol 1990;
syndrome. Arch Neurol 1966; 15:515–20. 47:129–32.
Sigal LH. The neurologic presentation of vasculitic and Yamanouchi H. Loss of white matter oligodendrocytes and
rheumatologic syndromes. A review. Medicine 1987; 66:157–80. astrocytes in progressive subcortical vascular encephalopathy
Sourander P, Walinder J. Hereditary multi-infarct dementia. Acta of Binswanger type. Acta Neurol Scand 1991; 83:301–5.
Neuropathol (Berl) 1977; 39:247–54. Yoshimura M, Yamanouchi H, Kazuhara S et al. Dementia in
Steinmetz EF, Vroom FQ. Transient global amnesia. Neurology cerebral amyloid angiopathy: a clinicopathological study. J
1972; 22:1193–200. Neurol 1992; 239:441–50.
Strupp M, Bruning R, Wu RH et al. Diffusion-weighted MRI in Yoshitake T, Kiyohara Y, Kato I et al. Incidence and risk factors of
transient global amnesia: elevated signal intensity in the left vascular dementia and Alzheimer’s disease in a defined elderly
medial temporal lobe in 7 of 10 patients. Ann Neurol 1998; Japanese population: the Hisayama study. Neurology 1995;
43:164–70. 45:1161–8.
Swartz RH, Black SE. Anterior-medial thalamic lesions in Zijlmans JCM, Thijssen HOM, Vogels OJM et al. MRI in patients
dementia: frequent, and volume dependently associated with with suspected vascular parkinsonism. Neurology 1995;
sudden cognitive decline. J Neurol Neurosurg Psychiatry 2006; 45:2183–8.
77:1307–12. Zijlmans JC, Daniel SE, Hughes AJ et al. Clinicopathological
Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts. investigation of vascular parkinsonism, including clinical
Neurology 1984; 34:1515–18. criteria for diagnosis. Mov Disord 2004a; 19:630–40.
Tomlinson BE, Blessed GE, Roth M. Observations on the brains of Zijlmans JC, Katzenschlager R, Daniel SE et al. The L-dopa
demented old people J Neurol Sci 1970; 11:205–42. response in vascular parkinsonism. J Neurol Neurosurg
Tournier-Lasserve E, Joutel A, Melki J et al. Cerebral autosomal Psychiatry 2004b; 75:545–7.
dominant arteriopathy with subcortical infarcts and Zorzon M, Antonutti L, Mase G et al. Transient global amnesia and
leukoencephalopathy maps to chromosome 19q12. Nature transient ischemic attack. Natural history, vascular risk
Genet 1993; 3:256–9. factors, and associated conditions. Stroke 1995; 26:1536–42.
Vollmer TL, Guarnaccia J, Harrington W et al. Idiopathic
granulomatous angiitis of the central nervous system:
diagnostic challenges. Arch Neurol 1993; 50:925–30.
Wadia N, Williams E. Behçet’s syndrome with neurological
complications. Brain 1957; 80:59–71.
p 11.qxd 3/10/08 9:49 AM Page 454
11
Trauma
11.1 Subdural hematoma 454 11.4 Post-concussion syndrome 457

11.2 Diffuse axonal injury 455 11.5 Radiation encephalopathy 458
11.3 Dementia pugilistica 456 References 459
11.1 SUBDURAL HEMATOMA hematoma may present with depression (Black 1984). Focal
signs, such as hemiparesis, may or may not be present, and,
Subdural hematomas, which typically, but not always, when present, may be quite mild. Rarely seizures may occur
occur secondary to head trauma, may present acutely, sub- (Annegers et al. 1998).
acutely, or in a chronic fashion; acute and subacute onsets Computed tomography (CT) or magnetic resonance
may be characterized by delirium, whereas chronic sub- (MR) scanning are diagnostic. In the case of acute and sub-
dural hematomas classically present with dementia. In all acute hematomas, blood may be demonstrated for a week
three varieties, blood accumulates between the dura and or two, after which, with hemolysis, a proteinaceous fluid
arachnoid; in acute subdural hematomas, this is generally remains. In chronic cases the fluid has the same imaging
due to arterial bleeding, whereas subacute and chronic sub- characteristics as the cerebrospinal fluid. Most cases of
dural hematomas generally result from venous bleeding. subdural hematoma occur over the frontal or parietal con-
vexities, and the hematoma itself has a convex shape; in a
minority hematomas may also be found in the inter-
Clinical features hemispheric fissure or layering on top of the tentorium
cerebelli.
Acute subdural hematoma typically occurs in the setting of
a traumatic brain injury, and is often accompanied by
other intracranial injuries, such as diffuse axonal injury,
Course
contusions, intracerebral hemorrhages, and subarachnoid
Acute subdural hematomas tend to rapidly enlarge and
hemorrhage. Patients may develop delirium or may pres-
may become immediately life-threatening. Subacute sub-
ent in stupor or coma.
dural hematomas tend to evolve over a matter of weeks and
Subacute subdural hematoma tends to present with
may either progress to stupor or coma or may stabilize,
drowsiness and delirium (Black 1984), and symptoms may
after which there may be a greater or lesser degree of grad-
fluctuate for days; when the hematoma occurs secondary to
ual improvement. Chronic subdural hematomas tend to
trauma, the latent interval between the trauma and the
undergo a very gradual progression.
onset of symptoms may last from days to a week or so. Focal
signs, such as hemiparesis, may or may not be present. With
progression, uncal herniation may occur with the develop- Etiology
ment of an ipsilateral third nerve palsy and hemiparesis.
Chronic subdural hematoma may be caused by trivial Most cases of subdural hematoma occur secondary to
head injury and, indeed, anywhere from one-quarter to trauma, either due to a blow to the head or to an
one-half of patients may not recall any head trauma acceleration–deceleration injury. This may be quite obvious
(Cameron 1978; Fogelholm and Waltimo 1975). After a and severe, for example in a motor vehicle accident; however,
latent interval of months to years patients gradually develop in the elderly the trauma need not be severe and indeed may
a dementia, which is often accompanied by headache appear trivial. Acute subdural hematomas generally occur
(Arieff and Wetzel 1964; Black 1984; Ishikawa et al. 2002; secondary to arterial bleeding, which explains their rapid
Ramachandran and Hegde 2007); a personality change evolution and grave prognosis. Subacute and chronic sub-
may occur (Cameron 1978) and, rarely, chronic subdural dural hematomas, however, typically appear secondary to
p 11.qxd 3/10/08 9:49 AM Page 455
11.2 Diffuse axonal injury 455
With chronic subdural hematomas, given the long

latency and the fact that the head trauma may have been
forgotten, the diagnosis may remain obscure until, in the
work-up for dementia, neuroimaging reveals the encapsu-
lated fluid collection. Importantly, however, some judg-
ment is required here before ascribing a dementia to a
chronic subdural hematoma: whereas a thick chronic
hematoma that grossly compresses the underlying cortex
may reasonably be held accountable for a dementia, a thin
structure that barely compresses the underlying cortex
might well be incidental and in such cases it is appropriate
to look for other causes of dementia.
Treatment
Figure 11.1 Bilateral encapsulated subdural hematomas seen
over the convexities. (Reproduced from Graham and Lantos 1996.) Symptomatic subdural hematomas generally require surgi-
cal evacuation, either by burr holes or craniotomy.
venous bleeding due to rupture of the delicate bridging veins Importantly, in the case of chronic subdural hematomas,
that span from the surface of the cortex to the overlying dural after evacuation of the clot a considerable amount of
sinuses. Regardless of the source of the bleeding, blood accu- time may be required for the gradual re-expansion of the
mulates in the ‘virtual space’ between the dura and the arach- chronically compressed cortex and, hence, clinical
noid. As noted, hemolysis occurs and, within a week or two improvement may be delayed. The symptomatic treatment
of the initial bleed, a relatively clear fluid remains. At this of dementia and delirium is discussed in Sections 5.1 and
point, the further evolution may take one of two paths. 5.3 respectively.
In cases in which the hematoma is relatively small, the fluid
may simply be resorbed, with little in the way of anatomic
sequelae (Dolinskas et al. 1979). However, in cases of larger 11.2 DIFFUSE AXONAL INJURY
fluid collection, fibroblastic activity may either create a
fibrotic scar that replaces the fluid or one may see the cre- With a sudden and severe acceleration–deceleration injury,
ation of a ‘pseudomembrane’ that encapsulates the remain- axons and arterioles are subjected to substantial shearing
ing fluid, as illustrated in Figure 11.1. The appearance of a and rotational stresses leading to widespread damage.
psuedomembrane sets the stage for the clinical occurrence of Although this condition is referred to as ‘diffuse axonal
a chronic subdural hematoma. These encapsulated fluid col- injury’, given the extensive vascular injury it could also be
lections tend to very gradually enlarge, probably as a result of called ‘diffuse vascular injury’. These injuries are typically
bleeding from fragile capillaries found in the pseudomem- accompanied by other traumatic lesions, such as contu-
brane itself (Markwalder 1981), and it is this gradual enlarge- sions, intracerebral hemorrhages, etc., and the reader is
ment that accounts for the gradual progression of symptoms referred to Section 7.5 for a discussion of the overall syn-
characteristic of chronic subdural hematoma. drome of traumatic brain injury: this section confines itself
Chronic subdural hematomas are more likely in patients to diffuse axonal injury.
who are prone to falls, such as those with alcoholism or
epilepsy, and in those on warfarin or suffering from blood
dyscrasias. Simple old age also increases the risk of a chronic
subdural hematoma, and this may be because the normal
Clinical features
atrophy seen with age leads to a stretching of the bridging
Typically, patients are rendered immediately unconscious
veins, thus making them more vulnerable to rupture.
at the moment of injury. Some may never regain con-
sciousness; those that do may develop a persistent vegeta-
Differential diagnosis tive state (Levin et al. 1991) or may emerge into a delirium,
which, upon clearing, typically leaves patients with signifi-
In the case of acute and subacute subdural hematomas, the cant cognitive deficits, in some cases amounting to demen-
proximity of the delirium or stupor to the head trauma tia (Scheid et al. 2006; Strich 1956). Other sequelae, as
immediately suggests the diagnosis; however, as noted in discussed in Section 7.5, may include agitation and person-
Section 7.5 on traumatic brain injury, multiple other ality change.
intracranial injuries may also be present and at times it is Computed tomography scanning may demonstrate
difficult to discern how much of the patient’s clinical multiple petechial hemorrhages, typically in the centrum
condition is secondary to the subdural hematoma. semiovale or corpus callosum; however, in many cases the
p 11.qxd 3/10/08 9:49 AM Page 456
456 Trauma
CT scan may look unremarkable. Magnetic resonance 11.3 DEMENTIA PUGILISTICA

scanning is far more sensitive in diffuse axonal injury and
typically displays multiple abnormalities (Huisman et al. Dementia pugilistica is a distinct syndrome that occurs
2003) in the centrum semiovale, corpus callosum, internal secondary to repeated blows to the head and is character-
capsules, dorsolateral quadrants of the brainstem, and the ized by dementia, ataxia, and parkinsonism. Synonyms for
superior cerebellar peduncles. Although both fluid- this disorder include ‘punch drunk syndrome’, ‘punch
attenuated inversion recovery (FLAIR) and diffusion- drunkenness’, and chronic traumatic encephalopathy.
weighted imaging are helpful, gradient echo imaging, Although dementia pugilistica is found most com-
which enables identification of microhemorrhages, is the monly in boxers, others may also be at risk, for example
most sensitive imaging modality (Ezaki et al. 2006). professional jockeys.
Clinical features
Course
The onset of symptoms is gradual and occurs anywhere
Most improvement is seen over the first 6 months post- from 5 to 40 years after there has been an accumulation of
injury, with some further, but less substantial, progress a sufficient number of blows to the head, which, in the case
over the following 6 months; after a year, however, little of professional boxers, equates to perhaps a dozen or so
further spontaneous improvement may be expected. knockouts. Thus, although some boxers may develop this
disorder while they are still professionally active, in most
cases symptoms are delayed until long after the boxer has
Etiology left the ring.
Clinically (Corsellis 1989; Critchley 1957; Harvey and
With either a sudden impact or merely a severe ‘whiplash’ Davis 1974; Jordan 1987; McLatchie et al. 1987; Martland
injury the head undergoes an acceleration–deceleration 1928; Mawdsley and Ferguson 1963), when the syndrome
injury and tremendous shearing and rotational forces are is fully developed, patients present with dementia, ataxia,
exerted intracranially, resulting in immediate damage to some dysarthria, and parkinsonism. The presence of ataxia
long axons and penetrating arterioles (Adams et al. 1982, and dysarthria often gives the impression of alcohol intox-
1989; Blumbergs et al. 1989; Ng et al. 1994; Strich 1956). ication, and this accounts for the synonym ‘punch drunk’.
Axons acutely display retraction balls and microglial clus- The dementia itself is non-specific, except perhaps for an
ters and, over time, microglial scars appear. Damage to undue amount of irritability.
arterioles leads to petechial hemorrhages of various sizes. Computed tomography or MR scanning typically dis-
Certain areas of the brain are more susceptible to such plays an enlarged cavum septi pellucidi, cerebral cortical
injuries, including the corpus callosum, the white matter of atrophy, and ventricular dilation.
the centrum semiovale near the gray–white junction, the
internal capsules, dorsolateral quadrants of the brainstem,
and the superior cerebellar peduncles. Etiology
Neuropathologic findings are described in the classic paper

by Corsellis et al. (1973). As illustrated in Figure 11.2, the
cavum septi pellucidi is enlarged. The cerebral cortex is
atrophied and the ventricles are enlarged; cerebellar atro-
As noted earlier, diffuse axonal injury occurs as part of the
phy is also present. Microscopically, there are widespread
syndrome of traumatic brain injury and in many cases it
neurofibrillary tangles, which are identical to those found
may be very difficult to determine how great a part diffuse
in Alzheimer’s disease (Roberts 1988; Schmidt et al. 2001).
axonal injury plays in the overall clinical picture compared
Senile plaques are also present; however, in contrast to the
with other injuries, such as contusions, intracerebral hem-
plaques seen in Alzheimer’s disease, which are discrete, the
orrhages, subarachnoid hemorrhage, subdural hematomas,
plaques seen in dementia pugilistica are diffuse (Roberts
and infarctions. In some cases, however, imaging is either
et al. 1990). Cell loss is found in the substantia nigra and in
normal or displays only findings consistent with diffuse
the locus ceruleus, but Lewy bodies are absent. The mech-
axonal injury, and here one may confidently ascribe the
anism whereby repeated blows to the head induce these
clinical findings to this etiology.
changes is not known.
Treatment Differential diagnosis
The overall treatment of the delirium and dementia of Not all dementias occurring long after repeated head injury
traumatic brain injury is discussed in Section 7.5. are due to dementia pugilistica. Some patients may have
p 11.qxd 3/10/08 9:49 AM Page 457
11.4 Post-concussion syndrome 457
other cases, patients may remain conscious but appear

‘dazed’ and mildly confused, with these symptoms again
resolving quickly. The amnesia seen in concussion extends in
a retrograde fashion for up to hours and in an anterograde
fashion from minutes to, in rare cases, hours (Fisher 1966;
Martland 1928). In a very small minority of cases, concus-
sion may be associated with a grand mal seizure occurring
within seconds of the impact; also known as ‘concussive
convulsions’, these events do not recur and do not portend
the development of epilepsy (McCrory et al. 1997).
Although the grosser aspects of concussion clear immedi-
ately, there may be some subtle and mild difficulty with
memory and concentration that typically resolves gradu-
ally within a week (McCrea et al. 2003); in those with a his-
tory of prior concussion, however, these symptoms may
take longer to resolve (Guskiewicz et al. 2003).
In a minority of cases, concussion may be followed by
the post-concussion syndrome (Lishman 1968; Mapothar
Figure 11.2 Note the wide cavum septi pellucidi in the brain of
1937; Symonds 1962). In these cases, in addition to the
a professional boxer. (Reproduced from Graham and Lantos 1996.)
cognitive difficulties just described, other symptoms
become evident within the first day and then persist.
Headache tends to be severe and may be continuous or
had a traumatic subarachnoid hemorrhage followed by the episodic; it may be dull and continuous, or throbbing, and
gradual development of a communicating hydrocephalus. may be exacerbated by loud noises, coughing or sneezing.
Clinically, although perhaps having a ‘magnetic’ gait, such Fatigue may be constant or may become evident only when
patients do not develop parkinsonism; furthermore, on patients exert themselves. Dizziness may consist of mere
imaging, the ventricular dilation will be out of all proportion light-headedness or there may be a true vertigo; when ver-
to any cortical atrophy. Chronic subdural hematoma must tigo is present, patients may complain that it is exacerbated
also be considered but is readily diagnosed on imaging. or precipitated by changes in position or by any sudden
movements. Depression may occur and may be marked by
severe insomnia. Irritability may be prominent, and
Treatment
patients may complain of great difficulty controlling their
tempers. Anxiety may also be seen but appears less com-
The general treatment of dementia is discussed in Section
mon. Other symptoms may occur, including photophobia,
5.1. In cases in which parkinsonism is prominent, consid-
hyperacusis, and hyperhidrosis, which at times may be
eration may be given to a trial of levodopa.
quite impressive. Many patients report that alcohol exacer-
bates their symptoms.
11.4 POST-CONCUSSION SYNDROME
Concussion is characterized by a brief loss of consciousness Course

or merely a sense of being dazed, occurring immediately
after a blow to the head or, in some cases, a whiplash injury In most cases, a gradual remission of symptoms occurs
(Miller 1982); patients also experience a variable, but anywhere from a few weeks up to 3 years after the concus-
short, period of amnesia, with both retrograde and antero- sion, with the majority of patients recovering in a matter of
grade components. Most recover fairly promptly, however, months. When symptoms persist for more than 3 years, a
in a minority a post-concussion syndrome will develop. chronic, indefinite, course may be anticipated.
Post-concussion syndrome, also known as post-concussional
disorder, is characterized by headache, difficulty with con-
centration and memory, fatigue, dizziness, various admix- Etiology
tures of depression, irritability and anxiety, and other
symptoms, such as photophobia. Although concussion probably occurs secondary to a fully
reversible disruption of axonal function, the post-concussion
syndrome in all likelihood occurs secondary to a mild
Clinical features degree of diffuse axonal injury, as indicated by MR scan-
ning (Hofman et al. 2001) and in one autopsy case of a
As noted, concussion may be associated with a loss of con- patient with the syndrome who died 7 months after the
sciousness and this generally lasts only a minute or so; in concussion of an unrelated cause (Bigler 2004).
p 11.qxd 3/10/08 9:49 AM Page 458
458 Trauma
Differential diagnosis form is fairly common, the delayed forms are seen in only
a very small minority of cases.
As discussed in Section 7.5, traumatic brain injury may be
followed by a dementia, and some would argue that the
difference here is merely one of degree in both the severity Clinical features
of the underlying diffuse axonal injury and the resulting
cognitive deficits, which are, in both cases, far more pro- Acute radiation encephalopathy occurs within hours to
found in the dementia following traumatic brain injury. days of irradiation, and probably reflects a breakdown of
In addition to causing the minor degree of diffuse the blood–brain barrier. Patients may experience delirium,
axonal injury underlying the post-concussion syndrome, drowsiness, ataxia, headache, nausea and vomiting, and, in
head trauma sufficient to cause a concussion may also, a small minority, seizures (Oliff et al. 1978). Symptoms
especially in the elderly, alcoholics, and those on warfarin, undergo a gradual, spontaneous resolution.
cause other injuries, such as contusions, intracerebral Early-delayed radiation encephalopathy appears sub-
hemorrhages or subdural hematoma, which may all cause acutely anywhere from 1 to 6 months post-irradiation, sec-
persistent symptoms. ondary to demyelinization. In patients who received
Post-traumatic stress disorder may follow an assault whole-brain irradiation, there may be delirium, drowsi-
involving a blow to the head, but here one finds evidence of ness, headache, and nausea. By contrast, in those subjected
a re-experiencing of the event, as in dreams or waking to focal irradiation there may be focal signs appropriate to
memories, symptoms not typical of the post-concussion the irradiated area. Symptoms generally resolve sponta-
syndrome. neously within 6–8 weeks.
Malingering may occur after a concussion and this is Late-delayed radiation encephalopathy, which probably
often suspected in cases in which litigation is in play. occurs secondary to a vasculopathy, presents gradually,
Sometimes in these cases, the diagnostic question can be generally within 6–36 months post-irradiation, with most
resolved only on observation after resolution of the lawsuit. cases occurring around 14 months; in some cases, however,
the latency between irradiation and the onset of symptoms
may be much longer, in one case 33 years (Duffy et al.
1996). In patients who received whole-brain irradiation, a
Treatment
dementia occurs, which is often accompanied by ataxia and
urinary incontinence (DeAngelis et al. 1989; Martins et al.
Concussion itself does not generally require specific treat-
1977; Morris et al. 1994). As with the early-delayed type,
ment. Computed tomography scanning may be considered
focal brain irradiation may be followed by focal signs, again
in the elderly, in alcoholics, those on warfarin, and in any
appropriate to the irradiated area (Kaufman et al. 1990;
patients with atypical symptoms, such as severe headache,
Shewmon and Masdeu 1980). Of interest, focal irradiation
focal signs or the subsequent development of delirium,
may be followed by a dementia when the focally irradiated
lethargy or stupor. Athletes should not return to play until
area is ‘strategic’ for cognitive functioning, as may occur
all symptoms, including the mild difficulty with memory
when one or both temporal lobes are damaged during irra-
and concentration, have cleared.
diation of a pituitary tumor (Crompton and Layton 1961)
Treatment of the post-concussion syndrome should
or a nasopharyngeal carcinoma (Woo et al. 1988). In con-
begin with reassurance regarding the typically benign
trast to the other two types of radiation encephalopathy, the
course. Headache is treated with non-opioid analgesics.
late-delayed type does not remit spontaneously, but rather
Dizziness may respond to antihistamines, but caution
displays a progressive course.
should be used here as these agents may exacerbate any
Magnetic resonance scanning shows an increased signal
cognitive deficits. Depression may respond to anti-
intensity on T2-weighted and FLAIR images in both the
depressants: one single-blind study noted that treatment
early- and late-delayed types. In cases secondary to whole-
with sertraline was not only effective in this regard (Fann
brain irradiation, this is seen diffusely in the white matter,
et al. 2000) but was also associated with cognitive improve-
whereas in focal cases the signal abnormalities are local-
ment (Fann et al. 2001). Alcohol should be forbidden until
ized. In addition, in the late-delayed type cortical atrophy
recovery is complete.
and ventricular dilation are often seen.
Before leaving this section, it is also appropriate to com-
ment on endocrinologic changes that may occur in irradi-
11.5 RADIATION ENCEPHALOPATHY ated patients (Agha et al. 2005; Constine et al. 1993; Lam
et al. 1991). With irradiation of the hypothalamus there
Irradiation of the central nervous system may be followed may be hyperprolactinemia or tertiary forms of hypothy-
by a radiation encephalopathy, and this may occur subse- roidism, adrenocortical insufficiency, or growth hormone
quent to either whole-brain or focal irradiation. There are deficiency; with irradiation of the pituitary, one may in
three different forms of radiation encephalopathy, namely turn see the secondary forms of hypothyroidism, adreno-
acute, early-delayed, and late-delayed: whereas the acute cortical insufficiency, or growth hormone deficiency. Such
p 11.qxd 3/10/08 9:49 AM Page 459
References 459
changes tend to occur very gradually, with roughly the Treatment

same time course as the late-delayed radiation encepha-
lopathy; hypothyroidism is especially important to keep Acute radiation encephalopathy may be treated with
in mind as it may present as a dementia. Hypothalamic steroids and, indeed, it is customary to give steroids
damage may also cause other symptomatology, as in one prophylactically.
case of hyperphagia with severe weight gain (Christianson Early-delayed radiation encephalopathy may show some
et al. 1994). response to either dexamethasone or prednisone; the symp-
tomatic treatment of delirium is discussed in Section 5.3.
Treatment of the late-delayed form of radiation
Course encephalopathy is not settled: a large case series suggests
improvement with either heparin or warfarin (Glantz et al.
This is as described above. 1994). The symptomatic treatment of dementia is dis-
cussed in Section 5.1.
Etiology
REFERENCES
As indicated above, the acute form occurs secondary to a
radiation-induced breakdown of the blood–brain barrier. Adams JH, Graham DI, Murray LS et al. Diffuse axonal injury due
The early-delayed type represents demyelinization to non-missile injury in humans: an analysis of 45 cases. Ann
(Lampert and Davies 1964), which probably occurs second- Neurol 1982; 12:557–63.
ary to radiation damage of oligodendroglia. The half-life of Adams JH, Doyle D, Ford I et al. Diffuse axonal injury in head
myelin ranges from 5 to 8 weeks and, with loss or dysfunc- injury: definition, diagnosis and grading. Histopathology 1989;
tion of oligodendroglia, symptoms appear as myelin 15:49–59.
degrades in the absence of ongoing replacement. With a Agha A, Sherlock M, Brennan S et al. Hypothalamic-pituitary
new ‘crop’ of oligodendroglia, replenishment of myelin dysfunction after irradiation of nonpituitary brain tumors in
gradually occurs and symptoms resolve. adults. J Clin Endocrinol Metabol 2005; 90:6355–60.
Late-delayed radiation encephalopathy probably occurs Annegers JF, Hauser WA, Coan SP et al. A population-based study
on the basis of hyalinization of penetrating arterioles with of seizures after traumatic brain injury. N Engl J Med 1998;
fibrinoid necrosis, microthrombosis, and a myriad of 338:20–4.
microinfarctions (De Reuck and vander Eecken 1975; Arieff AJ, Wetzel N. Subdural hematoma following epileptic
Pennybaker and Russell 1948). convulsion. Neurology 1964; 14:731–2.
Bigler Ed. Neuropsychological results and neuropathological
findings at autopsy in a case of mild traumatic brain injury.
Differential diagnosis J Int Neuropsychol Soc 2004; 10:794–806.
Black DW. Mental changes resulting from subdural hematoma.
The history of irradiation makes the diagnosis of the acute Br J Psychiatry 1984; 145:200–3.
form obvious and is highly suggestive when the delayed Blumbergs PC, Jones NR, North JB. Diffuse axonal injury in head
forms present after whole-brain irradiation with delirium trauma. J Neurol Neurosurg Psychiatry 1989; 52;838–41.
(in the case of the early-delayed form) or dementia (with Brada M, Ford D, Ashley S et al. Risk of second brain tumor after
the late-delayed form). Difficulties may arise, however, conservative surgery and radiotherapy for pituitary adenoma.
when the delayed forms occur after focal irradiation for a BMJ 1992; 304:1343–6.
central nervous system tumor, as in these cases the possi- Cameron MM. Chronic subdural hematoma: a review of 114
bility exists that the focal findings could represent not radi- cases. J Neurol Neurosurg Psychiatry 1978; 41:834–9.
ation damage but rather tumor recurrence. In such cases, Christianson SA, Neppe V, Hofman H. Amnesia and vegetative
although MR scanning may not be helpful, positron emis- abnormalities after irradiation treatment: a case study. Acta
sion tomography (PET) scanning reliably distinguishes the Neurol Scand 1994; 90:360–6.
two possibilities, demonstrating decreased glucose utiliza- Constine LS, Woolf PD, Cann D et al. Hypothalamic-pituitary
tion in radiation encephalopathy and increased utilization dysfunction after radiation for brain tumors. N Engl J Med
in cases of tumor recurrence (Glantz et al. 1991). 1993; 328:87–94.
Two other differential possibilities to keep in mind are Corsellis JAN. Boxing and the brain. BMJ 1989; 298:105–9.
the appearance of a new tumor and large-vessel infarction. Corsellis JAN, Bruton CJ, Freeman-Browne D. The aftermath of
Irradiation may cause tumors (Robinson 1978) and, boxing. Psychol Med 1973; 3:270–303.
although this is rare, both meningiomas (Brada et al. 1992; Critchley M. Medical aspects of boxing particularly from a
Soffer et al. 1983) and gliomas (Zampieri et al. 1989) may neurological standpoint. BMJ 1957; 1:357–66.
appear. Further, in cases in which large vessels were exposed Crompton MR, Layton DD. Delayed radionecrosis of the brain
to irradiation, a vasculitis may occur, with thrombosis and following therapeutic X-irradiation of the pituitary. Brain
large, territorial infarctions (Grattan-Smith et al. 1992). 1961; 84:85–101.
p 11.qxd 3/10/08 9:49 AM Page 460
460 Trauma
DeAngelis LM, Delattre J-Y, Posner JB. Radiation-induced Lam KN, Tse VK, Wang C et al. Effects of cranial irradiation on
dementia in patients cured of brain metastases. Neurology hypothalamic-pituitary function – a 5-year longitudinal study
1989; 39:172–7. in patients with nasopharyngeal cancer. Q J Med 1991;
De Reuck J, vander Eecken H. The anatomy of late radiation 78:165–76.
encephalopathy. Eur Neurol 1975; 13:481–94. Lampert PW, Davies RL. Delayed effects of radiation on the
Dolinskas CS, Zimmerman RA, Bilaniuk LT et al. Computed human central nervous system. Neurology 1964; 14:912–17.
tomography of post-traumatic extracerebral hematomas. Levin HS, Saydjari C, Eisenberg HM et al. Vegetative state after
J Trauma 1979; 19:163–9. closed-head injury. A traumatic coma data bank report. Arch
Duffy P, Chari G, Cartlidge NEF et al. Progressive deterioration of Neurol 1991; 48:580–5.
intellect and motor function occurring several decades after Lishman WA. Brain damage in relation to psychiatric disability
cranial irradiation. Arch Neurol 1996; 53:814–18. after head injury. Br J Psychiatry 1968; 114:373–410.
Ezaki Y, Tsutsumi K, Morikawa M et al. Role of diffusion-weighted McCrea M, Guskiewicz KM, Marshall SW et al. Acute effects and
magnetic resonance imaging in diffuse axonal injury. Acta recovery time following concussion in collegiate football
Radiol 2006; 47:733–40. players: the NCAA Concussion Study. JAMA 2003;
Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of 290:2556–63.
major depression following mild traumatic brain injury. McCrory PR, Bladin PF, Berkovic SF. Retrospective study of
J Neuropsychiatry Clin Neurosci 2000; 12:226–32. concussive convulsions in elite Australian rules and rugby
Fann JR, Uomoto JM, Katon WJ. Cognitive improvement with league footballers: phenomenology, aetiology, and outcome.
treatment of depression following mild traumatic brain injury. BMJ 1997; 314:171–4.
Psychosomatics 2001; 42:48–54. McLatchie G, Brooks N, Galbraith S et al. Clinical neurologic
Fisher CM. Concussion amnesia. Neurology 1966; 16:826–30. examination and computed tomographic head scanning in
Fogelholm R, Waltimo O. Epidemiology of chronic subdural active amateur boxers. J Neurol Neurosurg Psychiatry 1987;
haematoma. Acta Neurochirug 1975; 32:247–50. 50:96–9.
Glantz MJ, Hoffman JM, Coleman RE et al. Identification of early Mapothar E. Mental symptoms associated with head injury:
recurrence of primary central nervous system tumors by [18F] the psychiatric aspects. BMJ 1937; 2:1055–61.
fluorodeoxyglucose positron emission tomography. Ann Neurol Markwalder T-M. Chronic subdural hematomas: a review.
1991; 29:347–55. J Neurosurg 1981; 54:637–45.
Glantz MJ, Burger PC, Friedman AH et al. Treatment of radiation- Martins AN, Johnston JS, Henry JM et al. Delayed radiation
induced nervous system injury with heparin and warfarin. necrosis of the brain. J Neurosurg 1977; 47:336–45.
Neurology 1994; 44:2020–7. Martland HS. Punch drunk. JAMA 1928; 91:1103–7.
Graham DL, Lantos PL. Greenfield’s neuropathology, 6th edn. Mawdsley C, Ferguson FR. Neurological disease in boxers. Lancet
London: Arnold, 1996. 1963; 2:795–801.
Grattan-Smith PJ, Morris JG, Langlands AO. Delayed radiation Miller CM. Whiplash amnesia. Neurology 1982; 32:667–8.
necrosis of the central nervous system in patients irradiated Morris JG, Gratten-Smith P, Panegyres PK et al. Delayed cerebral
for pituitary tumor. J Neurol Neurosurg Psychiatry 1992; radiation necrosis. Q J Med 1994; 87:119–29.
55:949–55. Ng HK, Mahaliyana RD, Poon WS. The pathological spectrum of
Guskiewicz KM, McCrea M, Marshall SW et al. Cumulative effects diffuse axonal injury in blunt head trauma: assessment with
associated with recurrent concussion in collegiate football axon and myelin stains. Clin Neurol Neurosurg 1994;
players: the NCAA Concussion Study. JAMA 2003; 96:24–31.
290:2459–55. Oliff A, Bleyer WA, Poplack DG. Acute encephalopathy after
Harvey PKP, Davis JN. Traumatic encephalopathy in a young initiation of cranial irradiation for meningeal leukaemia.
boxer. Lancet 1974; 2:928–9. Lancet 1978; 2:13–15.
Hofman PA, Stapert SZ, von Kroonenburgh MJ et al. MR Pennybaker J, Russell DS. Necrosis of the brain due to radiation
imaging, single-photon emission CT, and neurocognitive therapy: clinical and pathological observations. J Neurol
performance after mild traumatic brain injury. AJNR 2001; Neurosurg Psychiatry 1948; 11:183–98.
22:441–9. Ramachandran R, Hegde T. Chronic subdural hematomas –
Huisman TA, Sorensen AG, Hergan K et al. Diffusion-weighted causes of morbidity and mortality. Surg Neurol 2007;
imaging for the evaluation of diffuse axonal injury in closed 67:367–72.
head injury. J Comput Assist Tomogr 2003; 27:5–11. Roberts GW. Immunocytochemistry of neurofibrillary tangles in
Ishikawa E, Yanaka K, Sugimoto K et al. Reversible dementia in dementia pugilistica and Alzheimer’s disease: evidence for
patients with chronic subdural hematoma. J Neurosurg 2002; common genesis. Lancet 1988; 2:1456–8.
96:680–3. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing.
Jordan BD. Neurologic aspects of boxing. Arch Neurol 1987; J Neurol Neurosurg Psychiatry 1990; 53:373–8.
44:453–9. Robinson RG. A second brain tumor and irradiation. J Neurol
Kaufman M, Swartz BE, Mandelkern M et al. Diagnosis of delayed Neurosurg Psychiatry 1978; 41:1005–12.
cerebral radiation necrosis following proton beam therapy. Scheid R, Walther K, Guthke T et al. Cognitive sequelae of diffuse
Arch Neurol 1990; 47:474–6. axonal injury. Arch Neurol 2006; 63:418–24.
p 11.qxd 3/10/08 9:49 AM Page 461
References 461
Schmidt ML, Zhukareva V, Newell KL et al. Tau isoform profile and Symonds CP. Concussion and its sequelae. Lancet 1962; 1:1–5.
phosphorylation state in dementia pugilistica recapitulate Woo E, Lam K, Yu YL et al. Temporal lobe and hypothalamo-
Alzheimer’s disease. Acta Neuropathol 2001; 101:518–24. pituitary dysfunctions after radiotherapy for nasopharyngeal
Shewmon DA, Masdeu JC. Delayed radiation necrosis of the brain carcinoma: a distinct clinical syndrome. J Neurol Neurosurg
contralateral to original tumor. Arch Neurol 1980; 37:592–4. Psychiatry 1988; 51:1302–7.
Soffer D, Pittaluga S, Feiner M et al. Intracranial meningiomas Zampieri P, Zorat PL, Mingrino S et al. Radiation-associated
following low-dose irradiation to the head. J Neurosurg 1983; cerebral gliomas: a report of two cases and review of the
59:1048–53. literature. J Neurosurg Sci 1989; 33:271–9.
Strich SJ. Diffuse degeneration of the cerebral white matter in
severe dementia following head injury. J Neurol Neurosurg
Psychiatry 1956; 19:163–85.
p 12.qxd 3/10/08 9:50 AM Page 462
12
Hypoxic disorders
12.1 Post-anoxic encephalopathy 462 12.3 Carbon monoxide poisoning 463

12.2 Delayed post-anoxic leukoencephalopathy 463 References 464
12.1 POST-ANOXIC ENCEPHALOPATHY Course
Global cerebral ischemia or anoxia will, if sufficiently Dementia and amnesia may show some improvement over
prolonged, cause coma, and those who survive may be the first 6 months or so, after which these features tend to
left with a dementia, an amnesia, or a movement disorder, remain stably chronic. Parkinsonism and dystonia, by con-
such as myoclonus or parkinsonism. Common causes trast, may show a gradual progression over many years.
include cardiac arrest, hemorrhagic or septic shock, carbon
monoxide poisoning, strangulation, or drowning. In this
text, this disorder is referred to as post-anoxic encephalopa- Etiology
thy; other names include post-hypoxic encephalopathy,
post-ischemic encephalopathy or ischemic–hypoxic After five or more minutes of global ischemia or anoxia, per-
encephalopathy. manent damage occurs. In those who develop post-anoxic
encephalopathy, one finds cortical atrophy, ventricular dila-
tion, and, within the cerebral cortex, either a laminar or a
multifocal pattern of cortical necrosis (Richardson et al.
1959; Weinberger et al. 1940). In cases characterized by iso-
Clinical features
lated amnesia, the temporal lobes, in particular the hip-
pocampi, are heavily involved (Cummings et al. 1984;
Among those who survive the ischemic–hypoxic event and
Muramoto et al. 1979), and in cases of parkinsonism or dys-
emerge from coma, some may be left in a persistent vegeta-
tonia, the basal ganglia show similar changes. In some cases
tive state whereas others will emerge into a delirium of
of global ischemia watershed infarctions may also occur.
variable duration. After the delirium clears, some patients
may recover entirely; however, most will be left with either
a dementia or an amnesia. The dementia may or may not Differential diagnosis
be accompanied by delusions and hallucinations; many
patients will be restless and in some cases there may be a As the name suggests, delayed post-anoxic encephalopathy
significant degree of agitation. In some cases, rather than a is distinguished by the delay between the anoxic/ischemic
dementia, patients will be left with an isolated amnestic event and the onset of the encephalopathy: in post-anoxic
syndrome, which has both anterograde and retrograde encephalopathy, as noted above, there is no delay and
components (Berlyne and Strachan 1968; Bowman et al. patients emerge from coma and delirium directly into the
1997; Broman et al. 1997; Medalia et al. 1991). dementia or amnesia, whereas in delayed post-anoxic
Action (or intention) myoclonus may occur (Lance and encephalopathy there is a latent interval, lasting from days
Adams 1963; Werhahan et al. 1997), and may appear inde- to months, after which clinical deterioration occurs.
pendently or in concert with a dementia or amnesia.
Parkinsonism, dystonia or athestosis (or a combination of
these) may also appear. Treatment
Magnetic resonance (MR) scanning may reveal a variety
of findings, including laminar cortical necrosis, watershed The general treatment of dementia and amnesia is dis-
infarctions, and abnormalities in the basal ganglia. cussed in Sections 5.1 and 5.4 respectively. A case report
p 12.qxd 3/10/08 9:50 AM Page 463
12.3 Carbon monoxide poisoning 463
suggests that agitation may respond to amitriptyline patients experiencing a more or less complete recovery of
(Szlabowicz and Stewart 1990), and the author has seen cognitive abilities over 6–12 months, with only a minority
dramatic results with mirtazapine in such cases. Myoclonus being left with a residual dementia (Choi 1983; Min 1986;
is traditionally treated with clonazepam, eventually in doses Plum et al. 1962; Shillito et al. 1936). The movement disor-
of 6 mg or more daily; other options include valproate der, however, may persist, and in some cases may progres-
(Rollinson and Gilligan 1979) or levetiracetam (Krauss et al. sively worsen.
2001). Parkinsonism may be treated with levodopa.
Etiology
12.2 DELAYED POST-ANOXIC
LEUKOENCEPHALOPATHY At autopsy there is a massive, symmetric, diffuse demyelin-
ization of the white matter (Plum et al. 1962), with variable
After a global hypoxic or ischemic insult, patients typically involvement of the basal ganglia. Although the mechanism
develop a coma or, occasionally, merely a delirium. Upon underlying this is not known, an autoimmune response,
emergence from coma some may develop a post-anoxic triggered by damage sustained during the original
encephalopathy, as described in the preceding section, hypoxic/ischemic insult, is strongly suspected.
whereas others will recover more or less completely. In a
few percent of these patients who do enjoy a more or less Differential diagnosis
complete recovery, however, a delayed post-anoxic
encephalopathy, characterized by delirium or a movement Delayed post-anoxic encephalopathy is distinguished from
disorder, may appear after a lucid interval. post-anoxic encephalopathy by the latent interval between
the hypoxic/ischemic insult and the onset of symptoms.
Clinical features
Treatment
Clinically (Choi 1983, 2002; Courville 1957; Gottfried et al.
1997; Min 1986; Murata et al. 1995; Norris et al. 1982; Although there is no established treatment for this disor-
Plum et al. 1962), the lucid interval averages about 2–3 der, a case may be made, given the suspected mechanism,
weeks, ranging from as little as 2 days to up to 2 months. for acute treatment with methylprednisolone or pred-
The onset of the encephalopathy itself is fairly sudden, nisone. The general treatment of delirium is discussed in
occurring over a matter of a day or two, and patients gen- Section 5.3; in cases characterized by parkinsonism, a trial
erally present with a combination of delirium and a move- of levodopa may be considered.
ment disorder. Confusion, amnesia, apathy, irritability,
and incontinence are prominent, and some patients may
become mute. Parkinsonism is the most common move- 12.3 CARBON MONOXIDE POISONING
ment disorder seen, but some patients may develop dysto-
nia and some may experience a combination of the two Carbon monoxide poisoning may be accidental, as may
syndromes. Spasticity is common, with hyper-reflexia and occur with poorly ventilated gas, wood, or charcoal stoves,
extensor plantar responses. Delirium may occasionally be or by suicidal intent, such as when patients hook a hose to
absent and patients may present only with a movement the car exhaust and then funnel it into the tightly windowed
disorder, such as parkinsonism (Choi et al. 2002; Goto car, or simply leave the car running in an enclosed garage.
et al. 1997; Grinker 1926; Klawans et al. 1982; Rosenberg
et al. 1989), dystonia (Valenzuela et al. 1992), or chorea
(Davous et al. 1986; Schwartz et al. 1985). Clinical features
T2-weighted MR scanning reveals increased signal inten-
sity in the white matter in those with delirium (Chang et al. The onset of intoxication may be gradual or sudden, and,
1992; Gottfried et al. 1997); acutely, diffusion-weighted given that carbon monoxide is colorless and odorless, vic-
imaging will show increased signal intensity in the same area tims may be unaware of their plight. In general (Sayers and
(Kim et al. 2003). In patients with a movement disorder, T1- Davenport 1930), although the correlation between
weighted scanning may reveal decreased signal intensity in carboxyhemoglobin level and clinical symptomatology is
the striatum (Takahashi et al. 1998). only a rough one, headache and delirium appear at a
carboxyhemoglobin level between 10 and 30 percent, wors-
ening and being joined by nausea and vomiting as the level
Course rises to 40 percent. At levels of 40–50 percent, stupor and
ataxia appear, and cyanosis may be seen. When the level rises
In a small minority the course is fulminant, with coma and above 50 percent, coma and convulsions occur, and levels
death. In most, however, the course is favorable, with over 60 percent are often fatal. Although it is traditional to
p 12.qxd 3/10/08 9:50 AM Page 464
464 Hypoxic disorders
The circumstances in which the patient is found usually
leave little doubt as to the diagnosis; in cases of attempted
suicide, however, one must keep in mind that the patient
may also have overdosed.
Treatment
The goal of treatment is to eliminate the carbon monoxide

as rapidly as possible. The half-life of carboxyhemoglobin
ranges from 4 to 6 hours; with inhalation of 100 percent
oxygen, however, this is cut to about 1 hour, and with
hyperbaric oxygen it falls to 30 minutes or less; conse-
quently hyperbaric oxygen is preferred in virtually all cases
(Weaver et al. 2002).
REFERENCES
Figure 12.1 T2-weighted magnetic resonance imaging scan in
a case of carbon monoxide poisoning, demonstrating increased Berlyne N, Strachan M. Neuropsychiatric sequelae of attempted
signal intensity in the globus pallidus. (Reproduced from Graham hanging. Br J Psychiatry 1968; 114:411–22.
and Lantos 2002.) Bowman M, Rose AL, Hotson G et al. Severe anterograde amnesia
with onset in childhood as a result of anoxic encephalopathy.
Brain 1997; 120:417–33.
associate carbon monoxide poisoning with a cherry-red Broman M, Rose AL, Hotson G et al. Severe anterograde amnesia
discoloration of the lips, nails and skin, this is in fact rare: with onset in childhood as a result of anoxic encephalopathy.
if anything, most patients will display a degree of cyanosis. Brain 1997; 120:417–33.
In those who survive, characteristic changes may be Chang KH, Han MH, Kim HS et al. Delayed encephalopathy after
seen in the globus pallidus on MR scanning, as illustrated acute carbon monoxide intoxication: MR imaging features and
in Figure 12.1. distribution of cerebral white matter lesions. Radiology 1992;
184:117–22.
Choi IS. Delayed neurologic sequelae in carbon monoxide
Course
intoxication. Arch Neurol 1983; 40:433–5.
Choi IS. Parkinsonism following carbon monoxide poisoning.
In general, if intoxication ceases before the onset of stupor,
Eur Neurol 2002; 48:30–3.
recovery is typically complete within anywhere from hours
Courville CB. The process of demyelination in the central nervous
to weeks (Smith and Brandon 1970). Should coma occur,
system. IV. Demyelination as a delayed residual of carbon
and even in some cases in which only delirium has
monoxide asphyxiation. J Nerv Ment Dis 1957; 125:534–46.
occurred, a minority of patients may experience significant
Cummings JL, Tomiyasu U, Read S et al. Amnesia with
sequelae, such as a post-anoxic encephalopathy or a
hippocampal lesions after cardiopulmonary arrest. Neurology
delayed post-anoxic encephalopathy.
1984; 24:679–81.
Davous P, Rondot P, Marion MH et al. Severe chorea after acute
Etiology carbon monoxide poisoning. J Neurol Neurosurg Psychiatry
1986; 49:206–8.
The affinity of carbon monoxide for hemoglobin is over Finck PA. Exposure to carbon monoxide: review of the literature
200 times greater than that of oxygen and, when a high and 567 autopsies. Milit Med 1966; 131:1513–39.
fraction of hemoglobin exists as carboxyhemoglobin, tis- Goto S, Kunitoku N, Suyama N et al. Posteroventral pallidotomy in
sue anoxia supervenes. Anoxia may not, however, be the a patient with parkinsonism caused by hypoxic
only mechanism of toxicity. Carbon monoxide also binds encephalopathy. Neurology 1997; 49:707–10.
to mitochondrial cytochrome oxidase and thus impairs Gottfried JA, Mayer SA, Shungu DC et al. Delayed posthypoxic
cellular respiration; furthermore, carbon monoxide also demyelination: association with arylsulfatase A deficiency and
binds to areas of the central nervous system rich in iron, for lactic acidosis on proton MR spectroscopy. Neurology 1997;
example the globus pallidus and the substantia nigra. In 49:1400–4.
fatal cases widespread petechial hemorrhages are found Graham DL, Lantos PL. Greenfield’s neuropathology, 7th edn.
throughout the cerebrum (Finck 1966). London: Arnold, 2002.
p 12.qxd 3/10/08 9:50 AM Page 465
References 465
Grinker RR. Parkinsonism following carbon monoxide poisoning. Rollinson RD, Gilligan BS. Post-anoxic myoclonus (Lance-Adams
J Nerv Ment Dis 1926; 64:18–28. syndrome) responding to valproate. Arch Neurol 1979; 36:44–5.
Kim JH, Chang KH, Song IC et al. Delayed encephalopathy of Rosenberg NL, Myers JA, Martin WRW. Cyanide-induced
acute carbon monoxide intoxication: diffusivity of cerebral parkinsonism: clinical MRI and 6-fluorodopa PET studies.
white matter lesions. AJNR 2003; 24:1592–7. Neurology 1989; 39:142–4.
Klawans HL, Stein RW, Tanner CM et al. A pure parkinsonian Sayers PR, Davenport SJ. Review of carbon monoxide poisoning.
syndrome following acute carbon monoxide intoxication. Arch Public Health Bulletin No. 195. Washington DC: US
Neurol 1982; 39:302–4. Government Printing Office, 1930.
Krauss GL, Bergin A, Kramer RE et al. Suppression of post-hypoxic Schwartz A, Hennerici M, Wegener OH. Delayed choreoathetosis
and post-encephalitic myoclonus with levetiracetam. following acute carbon monoxide poisoning. Neurology 1985;
Neurology 2001; 56:1144–5. 35:98–9.
Lance JW, Adams RD. The syndrome of intention or action Shillito FH, Drinker CK, Shaughnessy TJ. The problem of nervous
myoclonus as a sequel to hypoxic encephalopathy. Brain 1963; and mental sequelae in carbon monoxide poisoning. JAMA
86:111–36. 1936; 106:669–74.
Medalia AA, Merriam AE, Ehrenreich JH. The neuropsychological Smith JS, Brandon S. Acute carbon monoxide poisoning – 3 years
sequelae of attempted hanging. J Neurol Neurosurg Psychiatry experience in a defined population. Postgrad Med J 1970;
1991; 54:546–8. 46:65–70.
Min SK. A brain syndrome associated with delayed Szlabowicz JW, Stewart JT. Amitriptyline treatment of agitation
neuropsychiatric sequelae following acute carbon monoxide associated with anoxic encephalopathy. Arch Phys Med
intoxication. Acta Psychatr Scand 1986; 73:80–6. Rehabil 1990; 71:612–13.
Muramoto O, Kuru Y, Sugishita M et al. Pure memory loss with Takahashi W, Ohnuki Y, Takizawa S et al. Neuroimaging on
hippocampal lesions: a pneumoencephalographic study. Arch delayed postanoxic encephalopathy with lesions localized in
Neurol 1979; 36:54–6. the basal ganglia. Clin Imaging 1998; 22:188–91.
Murata T, Itoh S, Koshino Y et al. Serial proton magnetic Valenzuela R, Court J, Godoy J. Delayed cyanide induced dystonia.
resonance spectroscopy in a patient with the interval form of J Neurol Neurosurg Psychiatry 1992; 55:198–9.
carbon monoxide poisoning. J Neurol Neurosurg Psychiatry Weaver LK, Hopkins RD, Chan KJ et al. Hyperbaric oxygen for
1995; 58:100–3. acute carbon monoxide poisoning. N Engl J Med 2002;
Norris CR, Trench JM, Hook R. Delayed carbon monoxide 347:1057–67.
encephalopathy: clinical and research implications. J Clin Weinberger LM, Gibbon MH, Gibbon JH. Temporary arrest of the
Psychiatry 1982; 43:294–5. circulation to the central nervous system. II. Pathologic
Plum F, Posner JB, Hain RF. Delayed neurological deterioration effects. Arch Neurol Psychiatry 1940; 43:961–86.
after anoxia. Arch Intern Med 1962; 110:56–63. Werhahan KJ, Brown P, Thompson PD et al. The clinical features
Richardson JC, Chambers RA, Heywood PM. Encephalopathies of and prognosis of chronic posthypoxic myoclonus. Mov Disord
anoxia and hypoglycemia. Arch Neurol 1959; 1:178–90. 1997; 12:216–20.
p 13.qxd 3/10/08 9:50 AM Page 466
13
Nutritional, toxic, and metabolic disorders
13.1 Vitamin B12 deficiency 466 13.13 Dialysis dementia 476

13.2 Folic acid deficiency 468 13.14 Dialysis disequilibrium syndrome 477
13.3 Pellagra 468 13.15 Hypoglycemia 478
13.4 Wernicke’s encephalopathy 469 13.16 Hyperviscosity syndrome 479
13.5 Korsakoff’s syndrome 471 13.17 Central pontine myelinolysis 479
13.6 Manganism 472 13.18 Uremic encephalopathy 481
13.7 Thallium intoxicaton 473 13.19 Hepatic encephalopathy 481
13.8 Arsenic intoxication 473 13.20 Acquired hepatocerebral degeneration 482
13.9 Bismuth intoxication 474 13.21 Hepatic porphyria 483
13.10 Tin intoxication 474 13.22 Fahr’s syndrome 484
13.11 Lead encephalopathy 475 References 486
13.12 Mercury intoxication 476
13.1 VITAMIN B12 DEFICIENCY suspicious, heard the voice of God commanding her to
board a spaceship, and prayed fervently, with all symptoms
Vitamin B12 deficiency may lead to demyelinization in the resolving upon B12 administration. There is also a case
cerebrum, with, among other disturbances, dementia, or report of tremor and chorea occurring as a manifestation
in the cord, leading to a syndrome known as subacute of B12 deficiency (Pacchetti et al. 2002).
combined degeneration; a macrocytic anemia is also com- Subacute combined degeneration (Healton et al. 1991;
mon; however, as stressed below, neuropsychiatric symp- Russell et al. 1900) reflects demyelinization of the periph-
tomatology may occur in patients with normal red blood eral nerves, posterior columns, and lateral corticospinal
cell counts and red blood cell indices. Although vitamin tracts. Patients present with acral parasthesiae, followed by
B12 deficiency is most commonly due to pernicious ane- ataxia, a positive Romberg test, and eventually spasticity:
mia, multiple other causes must also be considered. the plantar responses are generally extensor, but the deep
tendon reflexes may be either increased or depressed,
depending on the severity of the peripheral neuropathy.
Clinical features Macrocytosis, with or without anemia, is common;
however, as noted above, it must be stressed that both these
Symptoms referable to the cerebrum or spinal cord tend to findings may be absent. Indeed, in one large study both the
appear subacutely over weeks or months. red blood cell count and the mean corpuscular volume
Cerebral involvement (Healton et al. 1991; Lindenbaum were normal in approximately one-fifth of all patients
et al. 1988) manifests most commonly with a dementia, (Lindenbaum et al. 1988).
which may be marked by hallucinations and delusions Magnetic resonance imaging (MRI) scanning reveals
(Lurie 1919). Personality change may also occur, and, patchy, confluent areas of increased signal intensity in the
rarely, one may also see depression (Fraser 1960) or mania centrum semiovale in patients with cerebral symptomatol-
(Goggans 1984). Another rare manifestation is psychosis, ogy (Chatterjee et al. 1996; Stojsavljevic et al. 1997).
referred to in the past as ‘megaloblastic madness’: in one The electroencephalogram (EEG) may show generalized
case (Smith 1929), a 46-year-old woman developed delu- slowing (Watson et al. 1954).
sions of persecution and jealousy, and was only correctly It is customary to obtain a serum B12 level; although
diagnosed when symptoms of subacute combined degen- this custom should be observed, it is also appropriate to
eration became evident; in another (Evans et al. 1983), a obtain levels of both methylmalonic acid and homocys-
47-year-old woman became withdrawn, guarded, and teine. In B12 deficiency, both methylmalonic acid and
p 13.qxd 3/10/08 9:50 AM Page 467
13.1 Vitamin B12 deficiency 467
homocysteine levels are elevated, and this combination of insufficiency, steatorrhea or malabsorption of any cause,
findings is extremely sensitive and specific for B12 deficiency tapeworms, bacterial overgrowth (as may occur after a
(Lindenbaum et al. 1988); when the serum B12 level is Billroth II operation), ileal diseases (e.g., Crohn’s disease),
‘borderline’, these two findings should be relied on when ileal resection, and chronic treatment with either omepra-
deciding whether intracellular B12 deficiency is present. zole (Marcuard et al. 1994) or metformin (Andres et al.
Before leaving this section, it is appropriate to note that 2002). All of the preceding causes lead to intracellular B12
clinical B12 deficiency can be precipitated by inhalation of deficiency because of a failure of B12 absorption, and all
nitrous oxide, as may occur during dental procedures or in are associated with decreased serum B12 levels. It is impor-
drug abusers. In cases in which there is already a ‘subclini- tant to keep in mind, however, that in addition to these
cal’ B12 deficiency, nitrous oxide inhalation can acutely causes there are also some very rare diseases characterized
precipitate symptoms (Beltramello et al. 1998; Kinsella and by intracellular B12 deficiency or malutilization, and that
Green 1995; Marie et al. 2000); in other cases, for example in these disorders the serum B12 level will be normal, but
in young, well-nourished drug abusers, symptoms may not the serum methylmalonic acid and homocysteine levels
occur until nitrous oxide has been abused for a long time. will be elevated. Examples include inherited abnormalities
in transcobalamin II and abnormalities in the intracellular
metabolism of cobalamin (Bodamar et al. 2001; Boxer et al.
Course 2005; Powers et al. 2001). Finally, there may also be an
association between acquired autoimmune deficiency syn-
Most cases of B12 deficiency are gradually progressive. drome (AIDS) and B12 deficiency (Herzlich and Schiano
1993; Shor-Posner et al. 1995).
When B12 deficiency has been confirmed by elevated
Etiology methylmalonic acid and homocysteine levels, efforts
should be made to determine the cause of this deficiency.
Vitamin B12, or cobalamin, is formed only by certain In the past, the Schilling test was utilized to determine
plant-associated bacteria, and humans generally obtain whether or not B12 absorption could be increased by the
their supply indirectly by eating liver, other organ meats, addition of hog-derived intrinsic factor: if this test was pos-
beef, pork, milk, or eggs. Once ingested, cobalamin is first itive, then one inferred that the deficiency was due to
bound within the stomach to gastric R binder; this com- destruction of parietal cells, as seen in pernicious anemia.
plex is digested by pancreatic enzymes in the duodenum With the availability of assays for anti-parietal cell and
and the liberated cobalamin is then bound to intrinsic fac- anti-intrinsic factor antibodies, however, this test is gener-
tor, a glycoprotein that is secreted by gastric parietal cells. ally no longer required. Given that pernicious anemia is
This cobalamin–intrinsic factor complex then passes to the the most common cause of B12 deficiency, all patients
ileum, where it is bound to a receptor on the cell wall and should be tested for these antibodies. If these are absent,
taken into the cell. Inside the ileal epithelial cell, cobalamin then the other causes noted above should be considered.
is released from intrinsic factor and bound to a carrier Neuropathologically, demyelinization is seen within the
protein known as transcobalamin II. The cobalamin– centrum semiovale (Ferraro et al. 1945; Lurie 1919), and in
transcobalamin II complex is then released into the sys- the posterior columns and the lateral corticospinal tracts
temic circulation. A substantial amount of cobalamin is within the spinal cord (Russell et al. 1900).
stored in the liver and, because of extensive enterohepatic
recirculation, years must pass before hepatic stores are
depleted. Differential diagnosis
As noted earlier, the most common cause of B12 defi-
ciency is pernicious anemia (Healton et al. 1991). In this Vitamin B12 deficiency may be almost perfectly mimicked
disease, anti-parietal cell antibodies lead to the destruction by folic acid deficiency, and the differential rests on the
of gastric parietal cells, with a consequent lack of intrinsic results of testing for homocysteine and methylmalonic acid
factor and a deficient uptake of ingested B12 by the ileal levels: in B12 deficiency both are elevated, whereas in folic
cells. In addition to anti-parietal cell antibodies, the major- acid deficiency the homocysteine level is elevated but the
ity of patients also have anti-intrinsic factor antibodies, methylmalonic acid level is normal.
and it is customary to test for both of these. Other anti- Progressive multiple sclerosis may also mimic B12 defi-
bodies may also be present in patients with pernicious ane- ciency, and the differential again rests on testing for homo-
mia, including antibodies against the thyroid and the adrenal cysteine and methylmalonic acid levels.
gland, and patients may develop Hashimoto’s thyroiditis
with hypothyroidism, or adrenocortical insufficiency.
Other causes of B12 deficiency include strict vegetarian- Treatment
ism, severe malnutrition (as may be seen in chronic alco-
holics), total or partial gastrectomy, inherited abnormalities Traditionally, treatment involves the administration of
of the R binder or intrinsic factor, achlorhydria, pancreatic intramuscular cyanocobalamin at a dose of 1000 μg daily
p 13.qxd 3/10/08 9:50 AM Page 468
468 Nutritional, toxic, and metabolic disorders
for 1 week, then weekly for 4 weeks, then monthly there- Etiology
after until maximum recovery has occurred. In those rare
cases in which the underlying cause has been corrected, Folic acid is a necessary factor in DNA synthesis and is
treatment may then cease; however, given that most of the found in fresh green vegetables, some fruits, yeast, kidney,
underlying causes are not treatable, chronic treatment is and liver. Dietary deficiency, as may be seen in chronic
typically required. After patients have been treated for 2 alcoholics, is the most common cause of folic acid defi-
weeks, folic acid, at a dose of 2 mg daily, should be added; ciency; intestinal malabsorption, for example in sprue,
importantly, folic acid should not be administered earlier may also be a factor. Given the limited hepatic storage
than this as it may lead to an exacerbation of symptoms. of folic acid, symptoms of deficiency may appear within
Potassium levels should be checked periodically, as a few months of poor oral intake or malabsorption.
hypokalemia may develop early in the course of treatment Certain medicines also reduce folate levels, including oral
with cyanocobalamin. contraceptives, phenytoin, primidone, phenobarbital, car-
Although, as noted, traditional treatment involves par- bamazepine, pyrimethamine, trimethoprim, pentamidine,
enteral administration of B12, recent work has indicated sulfasalazine, and methotrexate. Marginal folic acid
that oral treatment with 1 or 2 mg daily may be just as effec- reserves may be rapidly depleted in conditions of increased
tive (Kuzminski et al. 1998; Rajan et al. 2002). Most physi- metabolic demand, for example during pregnancy and lac-
cians, however, continue to use intramuscular B12, at least tation, and during the reticulocytosis seen with treatment
early on, switching to oral treatment only after patients of B12-induced anemia.
have recovered. The underlying neuropathology is not known.
With B12 treatment improvement may not occur for
months, and up to 18 months may be required for full
improvement. If treatment is begun early, before axonal Differential diagnosis
loss has occurred, recovery may be complete; however, if
symptoms have been present for months prior to treat- As noted in the preceding chapter, it may not be possible
ment, irreversible damage may already have occurred and clinically to differentiate folic acid deficiency from B12 defi-
the recovery will only be partial. ciency, and the diagnosis here rests on homocysteine and
methylmalonic acid levels: in folate deficiency only homo-
cysteine levels are increased, whereas in B12 deficiency,
13.2 FOLIC ACID DEFICIENCY both homocysteine and methylmalonic levels are elevated.
Although there has been controversy over whether folic

Treatment
acid deficiency can cause disease of the central nervous sys-
tem, it appears that, albeit rarely, dementia and subacute
Parenteral treatment is almost never required, even in
combined degeneration of the cord do in fact occur on this
cases of intestinal disease, and an oral dose of 1–2 mg daily
basis.
is generally sufficient.
Clinical features 13.3 PELLAGRA

The onset of symptoms appears to be gradual over weeks Niacin, also known as nicotinic acid or vitamin B3, is a
or months. Reynolds et al. (1973) demonstrated an associ- water-soluble B vitamin found in liver, yeast, poultry, fish,
ation of folate deficiency with dementia, and Strachan and and meat. Another source of this vitamin is tryptophan,
Henderson (1967) described two very convincing cases of which is converted endogenously into niacin.
dementia secondary to folate deficiency, one occurring in Niacin deficiency causes pellagra, and this may occur
combination with a peripheral neuropathy and the other clinically in one of two forms: acute pellagra, also known as
without any other symptoms. Furthermore, Pincus et al. ‘encephalopathic’ pellagra, is characterized by delirium,
(1972) reported a convincing case of a folate-induced com- whereas gradually developing, chronic pellagra is charac-
bination of dementia and subacute combined degenera- terized by dementia. In developed countries, pellagra is
tion. Folic acid deficiency, of course, is also a cause of seen most commonly in malnourished alcoholics as the
megaloblastic anemia. encephalopathic form; chronic pellagra, although once
The serum homocysteine level is elevated. endemic in the American South, is now only rarely seen.
It appears that, in the absence of treatment, the course is Encephalopathic pellagra presents fairly acutely, over days
progressive. to a week, and, when fully developed, is characterized by
p 13.qxd 3/10/08 9:50 AM Page 469
13.4 Wernicke’s encephalopathy 469
delirium, dysarthria, cogwheel rigidity, gegenhalten, and form of pyridoxine (vitamin B6); isoniazid impairs the
myoclonus (Ishii and Nishihara 1981; Jolliffe et al. 1940; conversion of the inactive form of B6 to the active form
Serdaru et al. 1988). and by this indirect mechanism reduces the endogenous
Pellagra of gradual onset appears insidiously over many production of niacin (Ishii and Nishihara 1985). Another
months, and, when fully developed, is characterized by the example is in cases of carcinoid tumor, in which the gross
classic ‘three Ds’ of dementia, dermatitis, and diarrhea overutilization of tryptophan by the tumor leaves less
(Spivak and Jackson 1977). The dementia may present available for conversion to niacin.
with apathy, depression, or anxiety; however, over time Within the central nervous system (Hauw et al. 1988;
typical cognitive deficits, such as decreased memory and Ishii and Nishihara 1981; Langworthy 1931), neurons are
poor concentration, eventually appear. The dementia at swollen and display chromatolysis with eccentric nuclei
times may also be marked by delusions or hallucinations and a loss of Nissl substance. These chromatolytic changes
(Pierce 1924). The dermatitis is characterized initially by may be seen in neurons of the cerebral cortex, basal
erythematous lesions in sun-exposed areas. Eventually, the ganglia, dentate nuclei, brainstem motor nuclei, and the
skin becomes hyperpigmented and roughened, and it is anterior horn of the spinal cord.
from the Italian for rough (pelle) skin (agra) that the dis-
ease gains its name. Diarrhea may be severe, and the fluid
may be blood tinged. It must be stressed that most cases of Differential diagnosis
pellagra do not, however, present with the full ‘three Ds’;
some patients with pellagrous dementia may have only one The acute encephalopathic form may be confused with
of the other ‘Ds’, and in some cases there may only be other disorders seen in chronic alcoholics, such as delirium
dementia, without any rash or diarrhea. tremens or Wernicke’s encephalopathy. Prominent
MRI scanning is unremarkable and the EEG shows gen- tremor, of course, favors a diagnosis of delirium tremens.
eralized slowing. Nystagmus, a sixth cranial nerve palsy, or ataxia favors
Although the serum niacin level is low, a more reliable, Wernicke’s encephalopathy. Cogwheel rigidity favors
if rarely ordered, test is a 24-hour urine test for niacin encephalopathic pellagra. In practice, however, it may be
metabolites. difficult to differentiate between these disorders, and
indeed they may appear concurrently (Serdaru et al. 1988).
The chronic form of pellagra is difficult to miss when all
Course three of the ‘Ds’ are present; however, as noted earlier,
many patients have only two of these, and some may have
The encephalopathic form may be rapidly progressive, and only one. Consequently, a high index of suspicion is
coma and death may occur in a matter of weeks. The required, and chronic pellagra should always be suspected
chronic form pursues a slower course, with death in a in any chronically malnourished patient who gradually
matter of years. develops a dementia.
Etiology Treatment
Niacin deficiency occurs most commonly as a result of Niacin may be given orally in doses from 250 to 500 mg
dietary deficiency. As noted earlier, in current practice in daily. In the encephalopathic form, the response is rapid
developed countries this is seen primarily in malnourished and often robust; in the chronic form recovery is slower
alcoholics as the encephalopathic form. The chronic form and may be incomplete. Once full benefit has occurred,
of pellagra was endemic in the American South among patients may be maintained on 50–100 mg of niacin daily.
those individuals who subsisted primarily on corn. As corn In cases due to isoniazid, administration of pyridoxine, in
contains niacin in a bound, biologically less active form, doses of 50 mg daily, is generally sufficient; however, in
and also lacks tryptophan, these individuals very gradually some cases symptoms may persist and in these cases isoni-
became niacin deficient. Since corn flour was ‘enriched’ with azid must be discontinued (Burke and Hiangabeza 1977).
niacin, however, the chronic form of pellagra has almost dis-
appeared in the United States. Other causes of niacin defi-
ciency include bowel resection, Crohn’s disease (Zaki and 13.4 WERNICKE’S ENCEPHALOPATHY
Millard 1995), and anorexia nervosa (Rapaport 1985).
In addition to dietary lack, pellagra has also been noted Wernicke’s encephalopathy, also known as Wernicke’s dis-
in conditions in which the normal endogenous conversion ease, occurs secondary to thiamine (vitamin B1) deficiency
of tryptophan to niacin is, for one reason or another, and, in its fully developed classic form, it presents with the
impaired. Perhaps the most common example of this is in triad of delirium, nystagmus, and ataxia. It occurs most
patients treated with isoniazid. The normal enzymatic con- frequently in malnourished alcoholics and is a common
version of tryptophan to niacin is dependent on the activated cause of delirium in general hospital practice.
p 13.qxd 3/10/08 9:50 AM Page 470
Before proceeding further, a word on nomenclature medial aspects of the thalami, periaqueductal gray, and the
is in order. In the literature, one often sees the term midbrain tectum (Chu et al. 2002; Weidauer et al. 2003);
‘Wernicke–Korsakoff syndrome’; however, this practice with gadolinium, enhancement may be seen in some cases
should be avoided as Wernicke’s encephalopathy and in the mammillary bodies (Zuccoli et al. 2007).
Korsakoff’s syndrome are, from a clinical point of view,
fundamentally different. Wernicke’s encephalopathy, as
just noted, is characterized by delirium. Korsakoff’s syn- Course
drome, although occurring as a sequela to Wernicke’s
encephalopathy, is an amnestic disorder in which there is Untreated, approximately 50 percent of patients die, in
no confusion. Lumping the two together under one name some cases suddenly (Harper 1979). Among those who
serves only to confuse the diagnostic picture. survive, sequelae are common. With resolution of the
delirium, confusion clears and patients may be left with a
Korsakoff’s syndrome (Malamud and Skillicorn 1956),
Clinical features which, as discussed in Section 13.5, is characterized by an
amnesia with both anterograde and retrograde compo-
In general the onset is subacute, spanning several days, and nents. In those with a sixth nerve palsy, residual nystagmus
nystagmus is often one of the earliest signs. Occasionally, is very common, and in those with ataxia, only a partial
however, one may see an acute onset over hours and this clearing is seen in a majority.
may follow a glucose load, either orally or intravenously, in
a thiamine-deficient patient.
Delirium is characterized by confusion and disorienta- Etiology
tion, and is often accompanied by a degree of lethargy or
drowsiness. With progression, stupor or coma may occur Thiamine is found in many foods and 1–2 mg daily is gen-
(Wallis et al. 1978). erally sufficient to meet most daily needs. Total body stores
Nystagmus, although generally horizontal, may at times of thiamine range from 20 to 100 mg, and the half-life of
be vertical. With progression, a bilateral and typically thiamine ranges from 10 to 20 days; thus, with severely
asymmetric sixth cranial nerve palsy may appear and reduced thiamine intake, significant deficiency may appear
patients may complain of diplopia. In extreme cases, a total in 1–3 months.
ophthalmoplegia may occur. Once absorbed, thiamine is converted to its active form,
Ataxia typically follows nystagmus and may be evident thiamine pyrophosphate; this molecule functions as an
as an ataxia of gait or as a truncal ataxia, which, in turn, essential co-factor for transketolase, which plays a critical
may be so severe that patients are unable to sit up in bed. role in the hexose monophosphate shunt pathway. With
It must be emphasized that this classic triad of symp- significant thiamine deficiency, transketolase activity is lost,
toms is the exception rather than the rule. Autopsy studies and the characteristic lesions, described below, develop.
have revealed that the full triad is found in only 14–16 per- Although most cases of Wernicke’s encephalopathy are
cent of cases (Cravioto et al. 1961; Harper et al. 1986). By seen in malnourished alcoholics, cases have also been noted
far the most common presentation is with delirium alone, in a number of other conditions (Ogershok et al. 2002),
or with a combination of delirium and either nystagmus or including hunger strikes (Frantzen 1966), anorexia nervosa
ataxia (Harper et al. 1986). (Handler and Perkin 1982), prolonged parenteral nutri-
In addition to delirium, nystagmus, and ataxia, a tion (Vortmeyer et al. 1992) with inadequate thiamine
minority of patients will have grand mal seizures. The tem- supplementation, bariatric surgery (Abarbanel et al. 1987;
perature is often decreased and there may be tachycardia Paulson et al. 1985; Singh and Kumar 2007) with subsequent
and postural hypotension. prolonged vomiting, peritoneal dialysis or hemodialysis
Various laboratory and imaging findings occur in (Jagadha et al. 1987), hyperemesis gravidarum (Gardian et al.
Wernicke’s encephalopathy but these are rarely required 1999), and prolonged vomiting occurring after liver trans-
for the diagnosis, and, in any case, treatment of suspected plantation (DiMartini 1996) or as a side-effect of digitalis
Wernicke’s encephalopathy should never wait upon test (Richmond 1959). Importantly, two or more of these fac-
results. tors may at times be required to produce the encephalopathy.
The EEG may show generalized slowing, but in many There are, for example, case reports of patients developing
cases it is within normal limits. Although the cerebrospinal Wernicke’s encephalopathy anywhere from 2 to 20 years
fluid (CSF) is generally normal, an elevated total protein, post-gastrectomy, the precipitant being a modestly decreased
rarely more than 100 mg/dL, may be found. Red blood cell thiamine intake, for example secondary to a loss of appetite
transketolase activity may be decreased (Dreyfus 1962), during an upper respiratory infection (Shimomura et al.
and blood pyruvate and lactate levels may be increased. 1998).
MRI scanning may reveal increased signal intensity on Although, generally, at least a month must pass before a
T2-weighted, fluid-attenuated inversion recovery (FLAIR), significant deficiency occurs, there are exceptions to this rule.
and diffusion-weighted images in the mammillary bodies, Glucose loads, either orally or parenterally, may rapidly
p 13.qxd 3/10/08 9:50 AM Page 471
13.5 Korsakoff’s syndrome 471
precipitate symptoms. Furthermore, some individuals have flour was ‘enriched’ with niacin and the plague of endemic
an inherited form of transketolase that displays a decreased pellagra was eradicated.
affinity for thiamine pyrophosphate (Blass and Gibson
1977), and these individuals are at higher risk of develop-
ing Wernicke’s encephalopathy and may do so even if their
13.5 KORSAKOFF’S SYNDROME
thiamine reserves are only marginally depleted.
Korsakoff’s syndrome is a chronic amnestic disorder with
In acute cases petechial hemorrhages are seen in gray
prominent anterograde and variable retrograde compo-
matter adjacent to the third ventricle, aqueduct of Sylvius,
nents that occurs as sequela to Wernicke’s encephalopathy.
and the fourth ventricle, including the dorsomedial and
Some words are in order regarding nomenclature. As
anterior nuclei of the thalamus, the mammillary bodies,
noted in Section 13.4, the term ‘Wernicke–Korsakoff’ syn-
the periaqueductal gray, the oculomotor and abducens
drome is often seen; however, this should probably be
nuclei, and the superior vermis (Cravioto et al. 1961;
abandoned as, from a clinical point of view, Wernicke’s
Harper 1983; Malamud and Skillicorn 1956; Victor et al.
encephalopathy and Korsakoff’s syndrome are fundamen-
1971). In those who survive, neuronal loss and gliosis are
tally different: Wernicke’s encephalopathy is marked by a
seen in the same areas.
delirium, whereas Korsakoff’s syndrome is characterized by
an amnesia that is not accompanied by confusion. There is
an additional difficulty regarding nomenclature and this
has to do with the definition of Korsakoff’s syndrome. In
some texts this term is used to refer to any chronic amnestic
The diagnosis of Wernicke’s encephalopathy should be
disorder, regardless of cause. In this text, however, the term
entertained in any malnourished patient who develops
refers only to the chronic amnestic disorder that occurs as
delirium; although from a diagnostic point of view it is
a sequela to Wernicke’s encephalopathy.
comforting to also see nystagmus and ataxia, it must be
forcefully kept in mind that, as noted above, these are
typically not present. Clinical features
Among alcoholics, consideration must also be given to
delirium tremens, encephalopathic pellagra, and hepatic As noted in Section 13.4, Wernicke’s encephalopathy is
encephalopathy. Prominent tremor suggests delirium characterized by delirium with or without nystagmus and
tremens, cogwheel rigidity points to pellagra, and myoclonus ataxia. In those who survive, the delirium gradually resolves
suggests hepatic encephalopathy. These disorders, however, and patients may then be left with an amnestic disorder.
often appear simultaneously, and it is appropriate to treat all These patients, as pointed out by Korsakoff himself
alcoholics with thiamine, as described below. (Victor and Yakovlev 1955), may not, at least to casual
Rarely, a clinical picture identical to Wernicke’s inspection, appear ill at all. They are typically able to carry
encephalopathy may occur secondary to a cytomegalovirus on a conversation and may be reasonably sociable.
ventriculoencephalitis, for example in patients with AIDS However, formal testing reveals that, although immediate
(Torgovnik et al. 2000). recall, as with a digit span, is intact, short-term memory,
tested by asking the patient to recall three objects after 5
minutes, is severely deficient. Indeed, patients may not be
Treatment able to recall a conversation they had with the physician
just minutes before. A degree of disorientation to time and
Whenever Wernicke’s encephalopathy is suspected, patients place inevitably accompanies this anterograde amnesia.
should emergently be given 100 mg thiamine intravenously The retrograde component of the amnesia becomes appar-
or intramuscularly. Barring a severe degree of hypoglycemia, ent on asking patients about their lives before the
food and glucose-containing fluids should be withheld for at Wernicke’s encephalopathy: answers often display a ‘tem-
least several hours. Thiamine is then continued at a dose of poral gradient’ (Albert et al. 1979; Seltzer and Benson 1974),
100 mg twice daily parenterally until substantial improve- such that patients, although having no recall of the events
ment is seen, after which patients may be continued on the occurring for perhaps months before the Wernicke’s
same dose of oral thiamine for at least a month. encephalopathy, may have a hazy or partial recall of events
The response to treatment is at times spectacular. occurring years earlier and a fairly clear memory of child-
Nystagmus may begin to clear within hours, and delirium hood events. In questioning patients about recent events,
and ataxia improve over a matter of days; maximum one often encounters the phenomenon of confabulation:
improvement generally takes about a month. here, the patient blithely makes up responses, as if to ‘fill in’
On a political note, it is remarkable, given the devasta- the amnestic gap. Thus, if a patient were asked whether he
tion of Wernicke’s encephalopathy and its major sequela or she had ever met the physician before, the patient might
Korsakoff’s syndrome, that governments have not man- respond in the affirmative and go on to talk about meeting
dated the addition of thiamine to alcoholic beverages. The the physician at a local tavern the week before, where they
results could be as spectacular as those that occurred when had a ‘few’ beers, played some pool, etc.
p 13.qxd 3/10/08 9:50 AM Page 472
Course The personality change (Abd El Naby and Hassanein

1965; Cook et al. 1974) typically consists of asthenia, fatigue,
Over the first year, approximately one-quarter of patients irritability, emotional lability, and a peculiar kind of ‘incon-
will show improvement, which in some cases may be gruous’ laughter, reminiscent of the emotional incontinence
substantial; in the remainder a stable chronicity is seen. seen in pseudobulbar palsy: patients may smile without
cause, or burst out in laughter, again for no apparent rea-
son (Charles 1927). Insomnia or hypersomnia may accom-
Etiology pany these changes (Abd El Naby and Hassanein 1965;
Cook et al. 1974).
As stressed above, Korsakoff’s syndrome occurs as a sequela The parkinsonism (Abd El Naby and Hassanein 1965;
to Wernicke’s encephalopathy (Malamud and Skillicorn Calne et al. 1994; Cook et al. 1974; Huang et al. 1989) is
1956). characterized by rigidity, bradykinesia, postural instability,
Neuropathologically, one sees atrophy and fibrosis in the and a tendency to ‘freeze’ and fall upon turning. Cogwheel-
mediodorsal and anterior nuclei of the thalamus (Halliday ing is often seen and, although tremor may also be present,
et al. 1994; Malamud and Skillicorn 1956; Victor et al. 1971). it is generally not of the ‘pill-rolling’ type. The parkinson-
ism may also be accompanied by dystonia, often affecting
the cervical musculature or the face. The most characteris-
Differential diagnosis tic feature of manganese-induced parkinsonism is, how-
ever, a distinctive dystonic gait abnormality known as a
As discussed in detail in Section 5.4, Korsakoff’s syndrome
‘cock-walk’. Here, patients walk on their metatarsopha-
is one of the chronic anterograde amnesias that also have a
langeal joints as if they were wearing high heels; at times,
retrograde component and as such must be distinguished
the elbows may be flexed, creating the overall appearance of
from other disorders capable of producing such an amne-
the walk of a rooster. Such a ‘cock-walk’ has been reported
sia. When the history of an immediately preceding
in anywhere from a small minority (Cook et al. 1974; Huang
Wernicke’s encephalopathy is present, the diagnosis is
et al. 1993) to up to one-third (Abd El Naby and Hassanein
fairly clear; however, in cases in which the patient’s prior
1965) of patients.
history is unknown, consideration must be given to other
Dementia may occur concurrent with the parkinson-
disorders, such as infarctions or tumors.
ism, and may be characterized by a marked degree of
memory loss (Cook et al. 1974).
Treatment Psychosis, known as ‘manganese madness’, may occur,
and is characterized by excitation, hallucinations, and
Some form of supervision is generally required and, in severe delusions (Abd El Naby and Hassanein 1965).
cases, institutionalization may be necessary. Pharmacologic T1-weighted MRI scanning may reveal increased signal
treatment seems of no avail: double-blind studies fail to intensity within the globus pallidus bilaterally. Manganese
support a role for donepezil (Sahin et al. 2002), fluvoxamine levels are increased in the serum, hair or a 24-hour urine
(O’Carroll et al. 1994), or clonidine (O’Carroll et al. 1993). sample.
13.6 MANGANISM Course

Chronic exposure to manganese may be followed by the As one might expect, with ongoing exposure, symptoms
development of a personality change, an atypical parkin- gradually worsen. With cessation of exposure, however,
sonism, and, less commonly, a dementia or psychosis. rather than a gradual reduction of parkinsonian signs and
Although most cases occur as a result of inhalation among symptoms, these actually continue to gradually worsen
manganese miners and those who work in steel or battery over the next 10 years or so (Huang et al. 1993, 1998), after
factories, cases have also been reported secondary to drink- which they persist in a stable chronicity (Huang et al.
ing contaminated well water or, very rarely, to prolonged 2007). A similar progression has been noted for the ‘cock-
intravenous total parenteral nutrition with manganese- walk’ (Huang et al. 1997).
containing solutions (Nagatomo et al. 1999).

The onset of symptoms is typically gradual, occurring after Neuronal loss and gliosis, although most prominent in the
months or years of exposure, and patients may present globus pallidus, are also found in the putamen, the pars
with a personality change, parkinsonism, or both (Abd El reticulata of the substantia nigra, the thalamus, hypothala-
Naby and Hassanein 1965). mus, and the cerebral cortex (Yamada et al. 1986).
p 13.qxd 3/10/08 9:50 AM Page 473
13.8 Arsenic intoxication 473
Differential diagnosis Thallium may be found in the urine and serum, and, in
long-standing cases, the hair.
Lacking a history of manganese exposure, the differential
generally involves a consideration of other causes of
Course
parkinsonism, as discussed in Section 3.8. In this regard,
special attention should be given to those disorders that
Acute intoxications may be fatal in up to one-tenth of
can cause a combination of parkinsonism and dystonia,
cases. In those who survive, there is a gradual, more or less
such as late-onset pantothenate kinase-associated neuro-
complete recovery; in some cases there may be persistent
degeneration, Wilson’s disease, corticobasal ganglionic
cognitive deficits (which may be severe enough to produce
degeneration, and progressive supranuclear palsy.
a dementia [Reed et al. 1963; Thompson et al. 1988]) or a
personality change (McMillan et al. 1997). Gradual intoxi-
Treatment cations likewise show a variable degree of recovery.
The general treatment of personality change, dementia,

and psychosis are outlined in Sections 7.2, 5.1, and 7.1
Etiology
respectively. If antipsychotics are required, consideration
In acute cases there is cerebral edema, often with petechial
should be given to second-generation agents, such as que-
hemorrhages; in more gradual onset cases, and in those
tiapine, in an effort to avoid exacerbating parkinsonism.
who have recovered, there is a variable degree of neuronal
Regarding the parkinsonism, although case reports suggest
loss in the cortex, basal ganglia, and thalamus (Cavanagh
a usefulness for levodopa (Huang et al. 1993) (sometimes
et al. 1974). In the peripheral nerves axonal degeneration
in high doses of up to 3 g or more daily [Mena et al. 1970]),
and demyelinization are seen (Davis et al. 1981).
placebo-controlled studies cast doubt on this (Koller et al.
2004; Lu et al. 1994). In practice, however, it is reasonable
to give it a trial. Differential diagnosis
Manganese is stored in bone and has a long half-life,
extending to 1 month or more. Although the role of chelat- Acute cases may be confused with arsenic intoxication or,
ing agents during the first few months is not established, when symptoms are confined primarily to a polyneuro-
case reports suggest their utility (Discalzi et al. 2000). pathy, with the Guillain–Barré syndrome. The eventual
appearance of severe alopecia, however, indicates the
correct diagnosis.
13.7 THALLIUM INTOXICATON
Although thallium can be absorbed through either the Treatment

lungs or the skin, industrial exposure is rare, and most
cases of thallium intoxication are by ingestion. Since thal- Thallium undergoes enterohepatic recirculation and, con-
lium was banned as a rodenticide, current cases generally sequently, laxatives and activated charcoal should be given.
represent a deliberate, often homicidal, poisoning. Prussian blue binds to thallium in the gut, and this is part
of standard treatment. Both forced diuresis and hemodial-
ysis hasten excretion. Chelation therapy is contraindicated
Clinical features as it may be followed by a deterioration in the patient’s
condition (Wainwright et al. 1988).
The onset of symptoms may be either acute or gradual,
depending on the amount ingested.
Acute intoxication (Bank et al. 1972; Moore et al. 1993;
13.8 ARSENIC INTOXICATION
Reed et al. 1963; Thompson et al. 1988; Wainwright et al.
1988) generally presents with abdominal pain, vomiting,
Although elemental arsenic causes relatively little central
and diarrhea. Within days or a week or so, patients develop
nervous system toxicity, arsenic salts are toxic; with acute
a delirium and a painful peripheral sensorimotor polyneu-
intoxication one may see a delirium, whereas with chronic,
ropathy, which may progress to a quadriplegia. Cranial
low-level exposure a dementia may occur. Arsenic salts are
neuropathies, with facial palsy or ophthalmoplegia, may
found in certain herbicides and rodenticides, and ingestion
also develop, and, rarely, grand mal seizures may occur.
may occur accidentally or with suicidal or homicidal intent.
Within 1–3 weeks patients then develop the most charac-
teristic feature of thallium intoxication, namely a severe,
generalized alopecia. Clinical features
Gradual intoxication presents with dementia, a sensori-
motor polyneuropathy, and alopecia; gastrointestinal symp- Acute ingestion is followed rapidly by delirium (Freeman
tomatology may or may not be present. and Couch 1978), nausea, vomiting, and diarrhea, which
p 13.qxd 3/10/08 9:50 AM Page 474
may be bloody; convulsions may also occur. Classically an acute onset of delirium, accompanied by myoclonus,
there is also an odor of garlic on the breath. Arrhythmias, ataxia, and, in a minority, seizures (Buge et al. 1981; Burns
renal failure, and hypotension may occur. Within 1–3 weeks et al. 1974; Supino-Viterbo et al. 1977).
a painful peripheral sensorimotor polyneuropathy appears. Computed tomography (CT) scanning may reveal patchy
Chronic exposure to small amounts of arsenic salts may areas of radiolucency in the cortex (Gardeur et al. 1978).
cause both a dementia and a polyneuropathy. Hyperkeratosis
of the palms and soles may occur, and Mees’ lines may
appear, which are transverse white discolorations of the Course
nails. Occasionally there may be a mild degree of alopecia.
Arsenic may be found in a 24-hour urine sample, and, Recovery is gradual, occurring over many months.
within weeks of exposure, is also found in the hair and nails.
Etiology
Course
In one autopsied case neuronal loss was noted among the
Purkinje cells of the cerebellum and in the hippocampus
Acute arsenic intoxication is often fatal. In those who sur-
(Liessens et al. 1978).
vive either acute or chronic intoxication, there may be
either cognitive deficits or a peripheral neuropathy, both of
which may show a greater or lesser degree of resolution Differential diagnosis
over long-term follow-up (Fincher et al. 1987).
When the history of bismuth ingestion is lacking, the dif-
ferential includes other deliria associated with myoclonus,
Etiology as discussed in Section 3.2.
In acute cases, widespread petechial hemorrhages within
the white matter are seen (Hurst 1959; Russell 1937). Treatment
Within the peripheral nervous system, axonal degenera-
tion occurs. Supportive care is provided; there is no specific treatment.
Differential diagnosis 13.10 TIN INTOXICATION

Thallium intoxication is suggested by the prominent Exposure to tin compounds may occur in certain indus-
alopecia. tries or by ingestion, and may be followed by delirium.
Treatment Clinical features

Acute intoxication is treated with gastric lavage, osmotic Delirium and seizures have been reported after intoxication
diuresis, and intensive supportive care. Chelation therapy with trimethyltin (Feldman et al. 1993; Fortemps et al. 1978)
is appropriate for both acute and chronic cases. and triethyltin (Alajouanine et al. 1958); with phenyltin
ingestion, delirium and ataxia occur (Wu et al. 1990).
13.9 BISMUTH INTOXICATION
Course
Bismuth is found in a number of preparations and is used
for the control of diarrhea and in the treatment of Although most patients survive trimethyltin intoxication
Helicobacter pylori infection. Although generally quite (Besser et al. 1987; Feldman et al. 1993), the mortality rate
safe, high dosage may be followed by a delirium. after triethyltin intoxication is approximately 50 percent
(Alajouanine et al. 1958). Among patients who do survive
tin intoxication, residual symptoms are common and may
Clinical features be severe.
The onset may be gradual or acute, depending on the

dosage. Gradual onsets (Supino-Viterbo et al. 1977) are Etiology
marked by insomnia and mood changes, with depression,
irritability, or, uncommonly, euphoria; rarely, delusions or With trimethyltin, neuronal loss has been observed in the
hallucinations may occur. With high dosage, there may be temporal cortex, amygdala, basal ganglia, and cerebellum
p 13.qxd 3/10/08 9:50 AM Page 475
13.11 Lead encephalopathy 475
(Besser et al. 1987; Kreyberg et al. 1992). In contrast, with lead exposure in children and the development of a
triethyltin intoxication, the myelin becomes edematous syndrome virtually identical to attention deficit/hyperac-
and vacuolization may be seen in the white matter (Cossa tivity disorder. Occasionally seizures may occur.
et al. 1958). Chronic lead encephalopathy in adults may present
with either a personality change or a dementia of variable
severity; patients also may complain of colicky abdominal
Differential diagnosis pain and a metallic taste. In some cases, depressive symp-
toms may be seen (Schottenfeld and Cullen 1984). A motor
When the history of exposure is lacking the differential peripheral neuropathy may occur, with, classically, wrist
becomes quite wide, as discussed in Section 5.3. and foot drop.
Whole blood lead levels of over 80 μg/dL are associated
with an acute presentation, whereas levels of 10–20 μg/dL,
Treatment if chronically maintained, produce a chronic encephalopa-
thy. The zinc protoporphyrin level is also increased. In
There is no known specific treatment. both children and adults ‘lead lines’ may be seen at the bor-
der of the gingiva and teeth, and in childhood cases lead
lines may also be seen in radiographs of the tibia or other
13.11 LEAD ENCEPHALOPATHY long bones.
Toxic accumulations of lead may occur in a number of ways.

Children may eat lead-based paint chips. Among adults, Course
exposure may occur in certain occupations, for example in
welders or those who work in battery factories or lead Acute lead encephalopathy runs a rapid course, with mor-
smelters; ‘moonshine’ whiskey, made with the help of old tality rates approaching 25 percent. Those who survive
car radiators, may also be a source (Akelaitis 1941; Morris may be left with dementia (Jenkins and Mellins 1957),
et al. 1964; Whitfield et al. 1972). Other less common seizures, or spasticity. Chronic lead encephalopathy shows
sources include lead-glazed pottery (Matte et al. 1994), little improvement over time.
certain ‘alternative’ medications (Fisher and Le Couteur
2000), and retained bullets. Leaded gasoline used to be a
major source, but since lead additives were banned this has Etiology
essentially ceased to be a problem.
A sudden massive exposure in either children or adults In acute encephalopathy there is widespread cerebral edema
may cause an acute lead encephalopathy with, among associated with petechial hemorrhages and microinfarc-
other symptoms, a delirium. Enduring, low-level exposure tions (Pentschew 1965; Smith et al. 1960). In chronic cases
may produce a chronic lead encephalopathy: in children there is cortical atrophy and widespread neuronal loss.
one may see cognitive decline and symptoms similar to
those of attention deficit/hyperactivity disorder, whereas
in adults there may be a dementia, a motor polyneuro- Differential diagnosis
pathy, and colicky abdominal pain.
Colicky abdominal pain and complaints of a metallic taste
in patients with delirium or dementia should always sug-
Clinical features gest lead encephalopathy. When these symptoms are absent,
or go unrecognized, the differential widens, as discussed in
In children, acute lead encephalopathy may be preceded by Sections 5.1 and 5.3.
a prodrome of irritability, abdominal pain, and lethargy
that lasts for weeks. In both children (Jenkins and Mellins
1957; Mellins and Jenkins 1955) and adults (Akelaitis 1941; Treatment
Morris et al. 1964; Whitfield et al. 1972), the full syndrome
is marked by delirium, which may be accompanied by exci- Acute lead encephalopathy is a medical emergency. Steroids
tation, hallucinations and delusions, ataxia, and seizures; and mannitol may be required for cerebral edema, and
classically, patients complain of a metallic taste. Hemolysis patients should undergo chelation treatment with dimer-
and renal failure may occur. captosuccinic acid, calcium sodium diacetate, dimercaprol,
Chronic lead encephalopathy in children (Baghurst et al. or penicillamine. The half-life for lead in blood ranges
1992; Bellinger et al. 1987; Canfield et al. 2003; Needleman from 25 to 35 days, whereas in the brain it is 2 years and in
et al. 1990) may present with a very gradual cognitive bone it is decades. Chelation therapy is of unproven bene-
decline, which may range in severity from a drop of a few fit in chronic lead encephalopathy. Public health measures
IQ points to a dementia. There is also an association between to remove lead paint are imperative.
p 13.qxd 3/10/08 9:50 AM Page 476
13.12 MERCURY INTOXICATION may be quite severe in the case of mercury salts and which
may also be accompanied by renal failure.
Three forms of mercury are potentially toxic to humans, Among patients who survive the acute exposure, and in
namely elemental mercury, salts of mercury, and organic cases of chronic, low-level exposure, various sequelae may
mercury. gradually ensue, including a personality change, a demen-
Elemental mercury at room temperature is a liquid. tia, and various abnormal movements. The personality
Ingestion is generally non-toxic as it is poorly absorbed change, known as erethism, is classically characterized by
through the gastrointestinal tract. Elemental mercury, emotional lability, shyness, and anxiety, all of which may
however, readily volatizes with warming or merely with be accompanied by insomnia. The dementia, occurring
shaking, and may be inhaled. Once inhaled, it readily generally only with greater exposure, does not appear to
passes across the alveoli and into the blood, where it is have any specific distinguishing features. Of the abnormal
taken up into erythrocytes and oxidized to a mercuric salt. movements seen with mercury intoxication, tremor is per-
This mercuric salt, and any unoxidized elemental mercury, haps the most classic, and this may affect the hands, lips,
then cross the blood–brain barrier and are taken up by and tongue. Ataxia is common and may be accompanied
neurons. Exposure to elemental mercury generally occurs by an intention tremor and dysarthria. Choreoathetosis
in gold miners and in certain other industries. may occur, as may parkinsonian features. A sensorimotor
Salts of mercury may be either monovalent (mer- polyneuropathy may also appear, which may be quite
curous) or divalent (mercuric). Salts of mercury may be painful. Visual scotoma or tunnel vision may also occur.
absorbed through the gastrointestinal tract or transder- Whole blood levels of mercury are elevated, but the cor-
mally and, as just noted, once absorbed they may cross the relation between blood levels and clinical symptomatology
blood–brain barrier. Mercury salts were once used medici- is rough at best. In chronic cases, neuroimaging may reveal
nally, as in the case of calomel, also called mercurous chlo- atrophy of the cerebral cortex (most prominently the
ride (Davis et al. 1974). Currently, however, most exposure calcarine cortex) and the cerebellar cortex (Tokuomi et al.
occurs in those employed in the manufacture of plastics, 1982).
fungicides, and electronics. In the nineteenth century,
mercuric nitrate was used in the manufacture of felt, and
chronic exposure among hat makers led to the ‘mad hatter Course
syndrome’, made famous in Lewis Carroll’s Alice’s
Adventures in Wonderland. For the most part the sequelae described are chronic.
Organic mercury is found as methylmercury, ethylmer-
cury (Hay et al. 1963), and phenylmercury (O’Carroll et al.
1995), and, of these, methylmercury is the most toxic. Etiology
Organic mercury, especially methylmercury, is readily
taken up through the gastrointestinal tract and easily Pathologically, there is widespread neuronal loss through-
crosses the blood–brain barrier. Exposure occurs generally out the cerebral and cerebellar cortex, especially involving
by accidental ingestion. Perhaps the most notorious exam- the calcarine cortex and, in the cerebellum, the granule cell
ple of this is the Minamata epidemic, named after the town layer (Davis et al. 1974; Hunter and Russell 1954).
in Japan where it occurred (Kurland et al. 1960). Industrial
waste containing elemental mercury was discharged into
Minamata bay where it was converted by bacteria into Differential diagnosis
methylmercury; fish became contaminated and, when res-
idents ate the fish, the stage was set for disaster. Other inci- The diagnosis rests heavily on a history of exposure.
dents have involved methylmercury used as a fungicide on
seed grain. In one example, treated seed grain was sent to
Iraq (Amin-Zaki et al. 1978; Rustam and Hamri 1974). Treatment
Although civilians had been warned not to eat the grain but
only to plant it, the contaminated grain was nevertheless Acute exposure to salts of mercury or to organic mercury
made into flour and bread, leading to hundreds of deaths. may be treated with gastric lavage and activated charcoal.
In another example, hogs were fed with treated seed grain, Chelation treatment is also indicated.
and those that then ate the hogs became ill (Snyder 1972).
13.13 DIALYSIS DEMENTIA

Clinical features
Dialysis dementia, also known as progressive dialysis
With acute exposure to elemental mercury via inhalation, a encephalopathy, might better be termed ‘aluminum
pneumonitis may occur. Acute exposure to either mercury dementia’ or ‘aluminum intoxication’ given that it is the
salts or to organic mercury may cause vomiting, which accumulation of aluminum in the central nervous system
p 13.qxd 3/10/08 9:50 AM Page 477
13.14 Dialysis disequilibrium syndrome 477
that causes the dementia. This used to be a not uncommon Diazepam may reduce the severity of many of the symp-
cause of dementia and death in patients undergoing toms of dialysis dementia (Nadel and Wilson 1976) but
chronic hemodialysis, and in such cases the aluminum does not alter the course of the disease. Chelation with
intoxication occurred secondary to aluminum in the deferoxamine may be considered; however, in some
dialysate (Davison et al. 1982) and perhaps also to the use patients this may lead to a mobilization of aluminum
of aluminum-containing phosphate binders. With the rou- from bone with a consequent worsening of the cerebral
tine purification of the dialysate, this disorder has almost symptomatology (Sherrard et al. 1988).
disappeared; occasional cases, however, still occur, for
example with the use of aluminum-containing medica-
tions in patients with chronic renal failure who are not on
13.14 DIALYSIS DISEQUILIBRIUM
hemodialysis (Andreoli et al. 1984; Shirabe et al. 2002).
SYNDROME
Clinical features The dialysis disequilibrium syndrome (Mawdsley 1972;

Peterson and Swanson 1964; Raskin and Fishman 1976;
The onset of the dementia is gradual, occurring on average Tyler 1965) is a transient disorder seen in approximately
after 37–40 months of dialysis (Garrett et al. 1988; Lederman 5 percent of patients undergoing hemodialysis, especially
and Henry 1978). Typically (Burks et al. 1976; Chokroverty early on or during rapid dialyses.
et al. 1976; Garrett et al. 1988; Lederman and Henry 1978;
O’Hare et al. 1983), patients present with a peculiar, stut-
tering type of aphasia, followed by myoclonus, seizures, Clinical features
and dementia. In a minority (Garrett et al. 1988), psychotic
symptoms may occur, with delusions, hallucinations, and The syndrome usually appears several hours after the start
bizarre behavior (Chokroverty et al. 1976; Scheiber and of a dialysis run, but may sometimes be delayed for up to a
Ziesat 1976); in one case mania occurred (Jack et al. 1983). day. The most common symptom is headache, which is
The EEG reveals periodic spikes or spike-and-wave generalized and may be severe. Other symptoms, seen in a
complexes on a background of slowing; there may also be minority of cases, include nausea, muscle cramping, delir-
bursts of frontally dominant slow activity (Hughes and ium, and grand mal seizures; rarely one may find papilledema
Schreeder 1980). or exophthalmos. The EEG shows generalized slowing.
Course Course
Untreated, the disease is progressive, with death on average Typically the syndrome resolves spontaneously within a
within 6 months. matter of hours or, at the very most, a few days.
Etiology Etiology
The brain aluminum content is elevated (Alfrey et al. 1976) Normally in hemodialysis an osmotic gradient occurs
and there is widespread neuronal loss in the cerebral cortex, between the blood and CSF (Yoshida et al. 1987) and cere-
with, in some cases, laminar spongiform change (Shirabe bral edema occurs (Walters et al. 2001). In all likelihood
et al. 2002; Winkelman and Ricanti 1986). the syndrome occurs secondary to a pronounced degree of
these changes.
Other disorders that are not uncommon in dialysis patients Differential diagnosis
and which are capable of causing dementia include intra-
cerebral hemorrhage, infarctions, and subdural hematoma. Consideration should be given to subdural hematoma or
Patients on dialysis may also develop thiamine deficiency, intracerebral hemorrhage.
with a resulting Wernicke’s encephalopathy (Hung et al.
2001).
Treatment
Treatment Symptomatic treatment of delirium is discussed in Section

5.3; if necessary seizures may be treated with lorazepam, as
Dialysate purity must be maintained and patients should described in Section 7.3. Future episodes may be prevented
not be given any aluminum-containing medications. by slowing the dialysis run.
p 13.qxd 3/10/08 9:50 AM Page 478
13.15 HYPOGLYCEMIA dementia. In cases characterized by a residual dementia, a

greater or lesser degree of recovery may occur over the
Hypoglycemia may cause autonomic symptoms, such as following year or two.
tremor, and may also cause ‘neuroglycopenic’ symptoms,
such as delirium or seizures; when severe enough, coma
may ensue and patients may be left with dementia. Etiology
Symptomatic hypoglycemia may occur in the fasting state,

Clinical features for example early in the morning before breakfast or in
those who skip meals, or post-prandially, several hours
As the blood glucose level falls below 2.5 mmol/L after a meal. Fasting hypoglycemia is seen most commonly
(45 mg/dL), autonomic symptoms appear fairly promptly. in diabetics on insulin or oral antidiabetic agents; it may
These include anxiety, palpitations, tremulousness, and also occur in patients with insulinomas (Dizon et al. 1999)
diaphoresis; patients may also complain of hunger and or in those who undertake a prolonged fast, for example
nausea, headache, and generalized weakness. during hunger strikes or in patients with anorexia nervosa
Neuroglycopenic symptoms (Hart and Frier 1998; (Rich et al. 1990). Liver disease, by impairing gluconeo-
Malouf and Brust 1985) are associated with blood glucose genesis, may also set the stage for fasting hypoglycemia.
levels of 1.67 mmol/L (30 mg/dL) or lower, but, unlike the Gluconeogenesis is also inhibited by alcohol and, after a
autonomic symptoms, these tend to appear only after this bout of binge drinking when little food is consumed, hypo-
degree of hypoglycemia has been sustained for approxi- glycemia is common. Post-prandial hypoglycemia may be
mately 30 minutes. Initially, patients may experience light- seen in early type II diabetes; after vagotomy, gastrectomy,
headedness or depersonalization. A delirium is common pyloroplasty, or gastrojejeunostomy; and in a rare (Palardy
and this may be associated with unusual behavior: in one et al. 1989) and somewhat controversial condition known
case (Bosboom et al. 1996), the patient ‘was restless, open- as ‘functional’ or ‘essential’ post-prandial hypoglycemia.
ing and closing his eyes, and thrashing about with his arms Hypoglycemia may also be intentionally produced
and legs, occasionally hitting onlookers and spitting in by malingerers who inject themselves with insulin or take
their faces’; in another case (Zivin 1970), the patient, a sol- high doses of oral antidiabetic agents (Price et al. 1986).
dier, ‘walked into the mess hall . . . [dressed] in his under- Whenever this is suspected, as well as checking the glucose
wear’. Seizures may occur, and these may be either partial level one should also determine the insulin and C-peptide
seizures or grand mal in type. A very small minority of levels and obtain a toxicology screen for oral agents. C-
patients will also have focal findings, such as hemiplegia peptide is normally excreted in conjunction with insulin
(Malouf and Brust 1985) or aphasia (Shintani et al. 1993; and, under physiologic conditions, when the insulin is ele-
Wallis et al. 1985). With sustained hypoglycemia, coma vated so too is the C-peptide level. In cases of exogenous
may ensue (Ben-Ami et al. 1999). insulin administration, however, whereas the insulin level is
Of note, although in most cases neuroglycopenic symp- elevated, the C-peptide level will be normal or low (Scarlett
toms are preceded by autonomic symptoms, exceptions to et al. 1977). In cases in which the elevated insulin level is
this rule occur, and some patients may present with neuro- produced by an oral agent, both the insulin and C-peptide
glycopenic symptoms alone (Case Records 1988; Malouf level will be increased, but the toxicology will be positive.
and Brust 1985; Moersch and Kernohan 1938). This may Autonomic symptoms reflect an immediate physiologic
occur in diabetics who have developed a diabetic autonomic sympathetic response to hypoglycemia. Neuroglycopenic
neuropathy or in patients under treatment with beta- symptoms, by contrast, reflect a complex series of events
blockers, which mask autonomic symptoms. Such a sce- triggered by intraneuronal hypoglycemia. The half-hour or
nario may also occur in cases in which the blood glucose so delay in the onset of neuroglycopenic symptoms reflects
level drops very slowly, for example as may occur with the time required for the depletion of intraneuronal glucose
fasting. stored as glycogen. In cases in which coma occurs, neuronal
In cases of coma, diffusion-weighted MRI scanning may death occurs, and, if sufficient, this constitutes the cause of
reveal areas of increased signal intensity in the cerebral cor- any persistent coma or residual dementia. In such cases
tex, white matter, and basal ganglia (Jung et al. 2005). EEGs pathologic studies have revealed (Auer et al. 1989; Kalimo
obtained during neuroglycopenic delirium will display and Olsson 1980; Lawrence et al. 1942; MacKeith and Meyer
generalized slowing. 1939) neuronal loss and gliosis in the cerebral cortex, the
hippocampus (especially the dentate gyrus), and the basal
ganglia; in severe cases laminar cortical necrosis was found.
Course
Whereas autonomic symptoms respond promptly to treat- Differential diagnosis

ment with glucose, delirium may take up to an hour to
subside. Patients who have developed coma may not In cases in which the symptomatology is restricted to auto-
recover consciousness and those that do may be left with a nomic symptoms, the diagnosis is immediately suggested
p 13.qxd 3/10/08 9:50 AM Page 479
13.17 Central pontine myelinolysis 479
by associated hunger and the prompt relief gained by eating vision, dizziness, ataxia, and dysarthria. Stroke may occur
or drinking glucose-rich fluids. Consideration may also be (Pavy et al. 1980), and seizures have been reported.
given to the possibility of an anxiety attack, hyperventilation, Serum viscosity is measured in centipoises, and in
or a simple partial seizure, as discussed in Section 6.5. most symptomatic cases the viscosity is elevated above
In cases characterized by autonomic symptoms fol- 4 centipoises.
lowed by delirium, consideration may be given to other
deliria associated with tremor, such as delirium tremens,
thyroid storm, amphetamine intoxication, and either the Course
serotonin syndrome or the neuroleptic malignant syndrome.
In some cases, however, as noted above, autonomic symp- As might be expected, the course parallels changes in serum
toms may be lacking, and here the differential becomes viscosity. With progression, coma and death may occur.
quite wide, as discussed in Section 5.3; special attention
should be given to complex partial seizures. Etiology
In doubtful cases, consideration may be given to
demonstrating ‘Whipple’s triad’ by performing a glucose The presence of excess or variously deformed proteins,
tolerance test. Whipple’s triad consists of: usually immunoglobulins, increases serum viscosity with,
1. the presence of typical symptoms; as noted, literal sludging of blood flow within capillaries. In
2. the concurrent presence of significant hypoglycemia; some cases, it appears that this sludging is also accompa-
3. the relief of symptoms with glucose administration. nied by microthrombus formation.
As noted, the most common cause of hyperviscosity is
The duration of the glucose tolerance test may range
Waldenstrom’s macroglobulinemia; cases may also be seen
from 5 hours in cases with a post-prandial pattern to up to
in multiple myeloma (Camacho et al. 1985), cryoglobuline-
12 hours in those with a fasting pattern.
mia, and, rarely, in rheumatoid arthritis (Bach et al. 1989).
Treatment
If the patient is able to take fluids, a glass of orange juice or
soda mixed with two or three tablespoonfuls of sugar is often Given the non-specific nature of the syndrome, the index
adequate. Patients unable to take fluids should be given of suspicion must be high.
50 mL of a 50 percent solution of glucose intravenously. In
cases in which intravenous access is lacking, one may stim-
ulate gluconeogenesis by giving glucagon in a dose of 1 mg
Treatment
intramuscularly, keeping in mind, of course, that glucagon
Daily plasmapheresis should be performed until symptoms
is ineffective in patients with significant liver damage.
clear.
Regardless of which therapy is given, patients should be
closely monitored to see if repeat doses are required. An
exception to this approach occurs in alcoholics, in whom a
glucose load may precipitate a Wernicke’s encephalopathy.
13.17 CENTRAL PONTINE MYELINOLYSIS
In such a situation one should given 100 mg of thiamine
Central pontine myelinolysis, originally described by Adams
intravenously and refrain from administering glucose for
and Foley in 1953, is classically characterized clinically by the
several hours or as long as clinically possible; clearly, much
development of a combination of flaccid quadriplegia and
clinical judgment is required in this situation.
delirium, and pathologically by demyelinization in the cen-
tral portion of the pons, all occurring within 2–3 days of
13.16 HYPERVISCOSITY SYNDROME overly rapid correction of chronic hyponatremia. Exceptions
to this classic picture, as described further below, do occur,
Significantly increased viscosity will cause microcircula- with prominent demyelinization in extrapontine sites associ-
tory sludging within the central nervous system leading to, ated with movement disorders or delirium in the absence of
among other symptoms, a dementia. This is a very rare quadriplegia. The existence of these exceptions has led some
syndrome and is generally seen in patients with a parapro- authors to propose alternative names for this syndrome, such
teinemia such as Waldenstrom’s macroglobulinemia as ‘central pontine and extrapontine myelinolysis’ or, more
(Mehta and Singhal 2003). generally, ‘osmotic demyelination syndrome’.
Patients may present with a dementia (Mueller et al. 1983) In classic cases, a flaccid symmetric quadriparesis develops
and lethargy. Other symptoms include headache, blurry within 2–3 days of rapid correction of chronic hyponatremia,
p 13.qxd 3/10/08 9:50 AM Page 480
accompanied by a delirium or lethargy (Karp and Laureno to demyelinization. Although such a scenario is most likely
1993), which in turn may be marked by both visual and in chronic alcoholics given intravenous fluids (Lampl and
auditory hallucinations (Sterns et al. 1986). Symptoms Yazdi 2002), other groups at risk include the recipients of
gradually worsen over about a week and, in severe cases, liver transplants (Estol et al. 1989), those suffering from
patients may be left in a ‘locked in’ state and totally para- severe malnutrition, and patients hyponatremic because of
lyzed except for vertical eye movements. Over time the protracted vomiting (Dickoff et al. 1988) or diarrhea (Price
flaccidity resolves, to be replaced by spasticity with hyper- and Mesulam 1987).
reflexia. Within the first day, diffusion-weighted MRI Although this mechanism appears operative for the vast
scanning may reveal increased signal intensity within the majority of cases, other mechanisms may also be found.
central portion of the pons, and over the following days the For example, central pontine myelinolysis has been noted
same area will reveal increased signal intensity on FLAIR in severe burn patients who were not hyponatremic but
and T2-weighted imaging and decreased signal intensity who had developed a severe hyperosmolar state (McKee et al.
on T1-weighted imaging (Ruzek et al. 2004). Importantly, 1988), leading, presumably, to the same kind of osmotic shift.
CT scanning is very insensitive here and may be normal Pathologically, in classic cases one finds symmetric
despite florid symptomatology. demyelinization within the basis pontis (Adams et al.
Exceptions to this classic picture occur when demyelin- 1959). This is most prominent within the central portion
ization occurs in extrapontine locations. Thus, one may see of the pons and spreads outward but does not involve the
delirium alone (without quadriplegia) (Hadfield and periphery of the pons where a rim of intact white matter
Kubal 1996; Karp and Laureno 1993) or a movement dis- survives. This demyelinization may at times extend to the
order such as dystonia (Maraganore et al. 1992; Yoshida pontine tegmentum and occasionally also into the mesen-
et al. 2000) or parkinsonism (Dickoff et al. 1988; Seiser et al. cephalon, but the medulla is generally spared. In severe
1998; Sullivan et al. 2000; Tomita et al. 1997); importantly, cases, cavitation may occur. Extrapontine myelinolysis, as
in cases characterized by a movement disorder, these noted, may also occur, and has been noted in the centrum
symptoms may be delayed for weeks or months. semiovale, internal capsule, striatum, thalamus, subthala-
mic nucleus, and the lateral geniculate body (Wright et al.
1979). In pathologic material, the most common pattern is
Course myelinolysis confined to the pons, followed by myelinoly-
sis involving both the pons and extrapontine sites; the least
In classic cases, death may occur within a matter of days. In common pattern consists of myelinolysis solely in extrapon-
those who survive, recovery may begin within a week or tine sites (Gocht and Colmant 1987).
two of the syndrome reaching its peak intensity, with max-
imum recovery taking up to a year; enduring deficits may
include a variable degree of quadriparesis or dementia Differential diagnosis
(Menger and Jorg 1999). In cases characterized by a move-
ment disorder, symptoms may either resolve over many Classic cases must be distinguished from stroke secondary
months or be chronic, or, in the case of dystonia, may to infarction in the area of distribution of the basilar artery.
actually gradually worsen. Stroke is suggested by a more rapid onset and by an asym-
metry of signs; furthermore, MRI scanning will reveal a
lesion that, in contrast to central pontine myelinolysis,
Etiology involves the periphery of the pons. In cases characterized
by delirium alone, the clue, of course, would be the history
As noted earlier, the classic precipitant for central pontine of rapid correction of hyponatremia 2 or 3 days earlier.
myelinolysis is the overly rapid correction of a chronic
hyponatremia (Brunner et al. 1990; Karp and Laureno 1993;
Messert et al. 1979; Norenberg et al. 1982; Sterns et al. 1986). Treatment
In cases of chronic hyponatremia, intracellular osmolarity
gradually falls to maintain an osmotic balance with the As there is no specific treatment for acute central pontine
hypo-osmolar extracellular fluid. If the hyponatremia is myelinolysis, prevention is essential. It must be borne in
corrected gradually, there is time for the intracellular mind that, when chronic, hyponatremia is often relatively
osmolarity to ‘catch up’, so that an excessive osmotic gra- well-tolerated and indeed some patients may be asympto-
dient does not appear between the intracellular and extra- matic. Consequently, even in cases in which the serum
cellular fluids. However, when the hyponatremia is rapidly sodium is as low as 115 mEq/L, simple fluid restriction to
corrected, an osmotic gradient does occur, with a substan- perhaps 800–1200 mL/24 hours is adequate. In cases, how-
tial fluid shift from the intracellular to extracellular com- ever, in which significant symptoms of hyponatremia are
partments. Oligodendrocytes appear particularly affected present or anticipated and treatment with normal or
by this osmotic shift, and these cells, in particular those hypertonic saline is required, it is essential to temper one’s
located within the pons, become damaged or die, leading therapeutic enthusiasm and to limit the rise in sodium to
p 13.qxd 3/10/08 9:50 AM Page 481
13.19 Hepatic encephalopathy 481
no more than approximately 0.4 mEq/L/hour (Norenberg is not the cause of the central nervous system dysfunction
et al. 1982; Sterns et al. 1986) and to aim only for a level of and in all likelihood the delirium results from an ‘auto-
120 mEq/L: once that level is reached, further correction may intoxication’ by as yet unidentified substances. In chronic
be made at a much more leisurely pace. Patients left with a cases that come to autopsy, an excess of protoplasmic
dementia may be treated as described in Section 5.1; parkin- astrocytes has been found.
sonism may respond to levodopa (Sullivan et al. 2000).
13.18 UREMIC ENCEPHALOPATHY
Not all deliria occurring in the context of an elevated BUN
In severe renal failure, patients may develop a delirium due represent uremic encephalopathy. Certain disorders, such
to a condition known as uremic encephalopathy. as polyarteritis nodosa and systemic lupus erythematosus,
may not only cause renal failure but also directly affect the
central nervous system. Another example is malignant
Clinical features hypertension, which may cause a concurrent hypertensive
encephalopathy and renal failure.
The mode of onset, as might be expected, reflects the rapid- Renal failure is also associated with subdural hematoma
ity with which the kidneys fail, and hence the onset of (Fraser and Arieff 1988), hypocalcemia, and hypomagne-
uremic encephalopathy may range from acute to gradual. semia, each of which may also cause delirium. Finally,
Patients may initially experience some lassitude or a mild attention must be paid to toxicity from drugs excreted
degree of somnolence; however, eventually a delirium primarily via the kidneys.
appears that is often marked by visual hallucinations.
Asterixis (Raskin and Fishman 1976; Tyler 1968) and multi-
focal myoclonus are common, and in some cases one may Treatment
see diffuse multifocal muscle twitching; dysarthria may also
occur. In a minority seizures, typically grand mal in type, If the underlying cause of the renal failure is untreatable
may appear. In one rare case, uremia presented with mania and spontaneous improvement is not expected, then
alone, without any other symptoms (El-Mallakh et al. 1987). uremic encephalopathy constitutes an indication for dialy-
A sensorimotor polyneuropathy may occur (Ropper sis. With dialysis, the delirium typically resolves in a matter
1993; Thomas et al. 1971) and, as with the encephalopathy, of days.
this may be acute or gradual in onset; the motor component
may be quite severe and patients may become quadriparetic.
In a little under 50 percent of patients with a polyneuro- 13.19 HEPATIC ENCEPHALOPATHY
pathy there may be prominent dysesthesiae and restless-
ness, similar to that seen in the restless legs syndrome. With significant disease or dysfunction of hepatocytes, or
The severity of the encephalopathy correlates not only with significant shunting of blood past the liver and directly
with the level of the blood urea nitrogen (BUN) but also into the systemic circulation, toxins normally removed by
with the rapidity with which the BUN rises. For example, the liver reach the brain and a hepatic encephalopathy may
although in cases of acute renal failure levels of 35.7 mmol/L occur.
(100 mg/dL) are typically associated with delirium, in renal
failure of very gradual onset, levels of 71.4 mmol/L Clinical features
(200 mg/dL) may be tolerated with few if any symptoms.
The EEG typically shows generalized slowing; triphasic The mode of onset of hepatic encephalopathy mirrors the
waves may also be seen. rapidity with which hepatic failure occurs, and thus may
range from acute, as in fulminant hepatic failure in some
Course cases of viral hepatitis, to gradual, as in slowly progressive
alcoholic cirrhosis.
Typically the symptoms of the delirium show marked fluc- Acute-onset hepatic encephalopathy typically presents
tuations throughout the day. The overall course parallels with a delirium; in gradual-onset cases, although a delir-
that of the renal failure, and in some progressive cases ium eventually occurs, this development is often preceded
coma may ensue. by a more or less lengthy prodrome characterized by
impaired judgment, difficulty with abstracting, and mood
changes, which often tend toward euphoria. The delirium
Etiology (Adams and Foley 1953; Fraser and Arieff 1985; Read et al.
1961; Summerskill et al. 1956) is characterized by confu-
Although the level of the BUN serves as a rough guide to sion, drowsiness, sleep reversal, asterixis, and myoclonus; a
the presence and severity of the encephalopathy, urea itself small minority may have seizures, which may be partial or
p 13.qxd 3/10/08 9:50 AM Page 482
grand mal, and a minority may also have focal signs, such differential for delirium accompanied by asterixis is dis-
as hemiparesis (Cadranel et al. 2001). Rarely, catatonic cussed in Section 3.12, and for delirium with myoclonus
symptoms, such as waxy flexibility, may occur (Jaffe 1967). in Section 3.2.
Fetor hepaticus, a sickly-sweet musty odor to the breath, is Rarely, valproic acid may cause an encephalopathy asso-
seen in about half of the cases. With progression of the ciated with an elevated ammonia level (Baver et al. 2005);
hepatic failure, stupor and coma may occur, accompanied however, the relation of this encephalopathy to hepatic
by rigidity and bilateral Babinski signs. encephalopathy is not entirely clear. In any case, treatment
The EEG shows generalized slowing, which is often of valproic acid encephalopathy consists of discontinuing
accompanied by triphasic waves; interictal epileptiform dis- the drug and administering carnitine (Bohan et al. 2001).
charges may be seen in a small minority (Ficker et al. 1997).
Although the blood ammonia level is elevated in the vast
majority of cases, there is only a rough correlation between Treatment
the degree of elevation and the severity of the encephalopa-
thy (Ong et al. 2003); indeed, although rare, in some cases In addition to treating any precipitating events, efforts are
the ammonia level may be normal (Sherlock 1993). made to reduce the nitrogenous load in the gut. This may
be accomplished using three methods, individually or in
combination: a low-protein diet, lactulose, and treatment
Course with rifaximin. Reducing dietary protein to 20–60 g/day is
helpful, but many patients find this unpalatable. In acute
In the absence of treatment, the course of the encephalopa- situations, lactulose may be started at a dose of 20–45 mL
thy mirrors the severity of the underlying hepatic failure. hourly until the patient starts to have bowel movements,
With treatment, provided that coma has not supervened, after which the dose may be decreased to a maintenance
the recovery is generally quite good; in cases that have pro- dose of 30–45 mL q.i.d.; in less urgent situations, one may
gressed to coma, however, the mortality rate is high. simply start with a maintenance dose, with dosage adjust-
With repeated episodes patients may develop acquired ments as required to ensure three to four soft bowel move-
hepatocerebral degeneration, as described in Section 13.20. ments daily. Rifaximin is a non-absorbable intestinal
antibiotic that targets nitrogenous bacteria, and this may
Etiology be given in a dose of 400 mg t.i.d.
The general symptomatic treatment of delirium is dis-
As indicated earlier, hepatic encephalopathy occurs when cussed in Section 5.3. With regard to symptomatic pharma-
the brain is exposed to toxins found in the portal vessels, cologic treatment, benzodiazepines are contraindicated; if
toxins that are normally removed by the liver. Although antipsychotics are required the dose should be low, as all of
ammonia itself is the most likely culprit here, other candi- these agents are metabolized in the liver.
dates have also been considered, including mercaptans, Patients in coma may require treatment with mannitol
various aromatic amino acids, and short-chain fatty acids. and monitoring of intracranial pressure.
In chronic cases, there may be an increased number of
Alzheimer type II astrocytes (Adams and Foley 1953). In
acute cases characterized by coma, cerebral edema occurs, 13.20 ACQUIRED HEPATOCEREBRAL
with, in some instances, transtentorial herniation (Donovan DEGENERATION
et al. 1998).
The most common causes of hepatic failure are viral Acquired hepatocerebral degeneration is a rare disorder
hepatitis and alcoholic cirrhosis. In many cases, the onset that occurs secondary to repeated or prolonged bouts of
of the delirium may be traced to an event that increased the hepatic encephalopathy and is characterized by variable
nitrogenous load in the gut beyond the diminished detoxi- mixtures of cognitive deficits and abnormal movements.
fying capacity of the liver. Examples include high protein
meals, blood (as may occur with bleeding esophageal
varices or peptic ulcer disease), and constipation. Other Clinical features
precipitants include infection, anesthesia, hypokalemia,
uremia, and exposure to alcohol or sedative–hypnotics, Clinical features have been described in a number of reports
especially benzodiazepines. (Finlayson and Superville 1981; Graham et al. 1970; Raskin
et al. 1984; Victor et al. 1965). The onset is typically gradual
and is often punctuated by repeated episodes of hepatic
Differential diagnosis encephalopathy. Cognitive deficits may occur, which may
be quite mild or, in some cases, amount to a dementia. The
In alcoholics, consideration must be given to delirium movement disorder is often complex, with variable admix-
tremens, Wernicke’s encephalopathy, hypoglycemia, tures of chorea, facial grimacing, postural tremor, parkin-
encephalopathic pellagra, and subdural hematoma. The sonism, and ataxia. Chorea, when present, often affects the
p 13.qxd 3/10/08 9:50 AM Page 483
13.21 Hepatic porphyria 483
head and neck, and the resulting movements may be namely acute intermittent porphyria, variegate porphyria,
tic-like in character. and hereditary coproporphyria, whereas the fourth, delta-
T1-weighted MRI scanning (Burkhard et al. 2003; aminolevulinic acid (ALA) dehydratase deficiency, is an auto-
Krieger et al. 1995) typically reveals increased signal inten- somal recessive disorder. Acute intermittent porphyria is
sity in the globus pallidus; similar changes may be seen in found worldwide and may have a prevalence as high as 5–10
the striatum and in the substantia nigra. cases per 100 000 population. Variegate porphyria, although
rare in the United States, may be found in Sweden and among
white people in South Africa. Hereditary coproporphyria
Course is quite rare, and ALA dehydratase deficiency is so extraor-
dinarily rare that it is not considered further in this text.
In general, the overall course is marked by slow progression. From a clinical viewpoint the three autosomal domi-
nantly inherited hepatic porphyrias are essentially the
same, with the exception that both variegate porphyria and
Etiology
hereditary coproporphyria may cause a photosensitive
rash, a symptom not seen in acute intermittent porphyria.
At autopsy (Finlayson and Superville 1981; Victor et al.
Of interest, it appears that the periodic ‘madness’ of
1965), spongiform change or laminar cortical necrosis may
King George III represented attacks of hepatic porphyria
be found in the cerebral and cerebellar cortices; spongiform
(Cox et al. 2005; Macalpine and Hunter 1966; Macalpine
change is also noted in the basal ganglia and this may be
et al. 1968).
accompanied by microcavitation. Alzheimer type II astro-
cytes are present in the cortex and basal ganglia.
The occurrence of these changes in the context of
repeated episodes of hepatic encephalopathy strongly sug-
Clinical features
gests that they are toxic in nature and, of the various candi-
The hepatic porphyrias are episodic disorders and the first
date toxins, manganese stands out. Elevated manganese
episode usually appears in late adolescence or early adult
levels are found in the basal ganglia and cerebral cortex
years. The attacks themselves tend to present fairly acutely
(Klos et al. 2006; Krieger et al. 1995) and also in the CSF
and are often precipitated by one of the factors discussed
and blood (Burkhard et al. 2003); furthermore, one study
below, such as infection, menstruation, or pregnancy.
found a correlation between the elevation in blood man-
The overall symptomatology of the episodes has been
ganese and the increase in signal intensity on T1-weighted
reported in a number of papers (Becker and Kramer 1975;
scanning in the globus pallidus (Krieger et al. 1995).
Goldberg 1959; Rowland 1961; Stein and Tschudy 1970).
Classically, episodes are characterized by abdominal pain
Differential diagnosis with vomiting, constipation, or diarrhea, accompanied, in
about half of the cases, by a delirium. The delirium is often
Hepatic encephalopathy is distinguished by the presence of marked by affective lability, delusions of persecution, and
delirium and asterixis, alcoholic dementia by the absence visual hallucinations, which may be quite compelling (Cross
of abnormal movements, and Wilson’s disease by copper 1956; Paredes and Jones 1959); in some cases, stupor or coma
studies. may supervene. Uncommonly, rather than a delirium there
may be a psychosis with auditory hallucinations, delusions of
persecution, and bizarre behavior, all occurring in a ‘clear
Treatment sensorium’ without confusion or cognitive deficits (Hirsch
and Dunsworth 1955; Mandoki and Sumner 1994). Other
Remarkably, symptoms may remit after liver transplanta- symptoms, seen in a minority, include a primarily motor
tion (Powell et al. 1990; Servin-Abad et al. 2006; Stracciari polyneuropathy (which may progress to a quadriparesis), a
et al. 2001). In cases in which transplantation is not possi- cranial neuropathy (most commonly with ophthalmoplegia
ble, consideration may be given to treatment with or facial palsy), partial or grand mal seizures, hypertension,
branched-chain amino acids, which in case reports led to a tachycardia, and fever. A small minority of patients may also
reduction in abnormal movements and a partial resolution have significant hyponatremia, which in turn may be due
of MRI abnormalities (Ueki et al. 2002); furthermore, in either to a syndrome of inappropriate antidiuretic hormone
cases in which parkinsonism is prominent, case series sug- (ADH) secretion or to intestinal or renal sodium loss.
gest an effectiveness for levodopa (Burkhard et al. 2003). As noted earlier, patients with variegate porphyria and
hereditary coproporphyria may have a rash: this is a photo-
sensitive rash that may or may not coincide with the
13.21 HEPATIC PORPHYRIA episodes just described.
T2-weighted MR scanning may reveal scattered areas
Of the hepatic porphyrias, four can cause delirium. Three of increased signal intensity within the subcortical white
of these are inherited in an autosomal dominant pattern, matter (Bylesjo et al. 2004; King and Bragdon 1991).
p 13.qxd 3/10/08 9:50 AM Page 484
During episodes, a 24-hour urine test will reveal ele- and alcohol. Importantly, the following drugs appear to be
vated levels of both porphobilinogen and ALA in all three safe: phenothiazines (e.g. chlorpromazine or trifluoper-
of these porphyrias, and the diagnosis rests on this finding. azine), opioid analgesics, chloral hydrate, gabapentin, lev-
In addition to these findings, both variegate porphyria and etiracetam, diazepam, diphenhydramine, aspirin, and
hereditary coproporphyria will also display an elevated uri- acetaminophen.
nary coproporphyrin. Distinguishing between variegate
porphyria and hereditary coproporphyria requires a 24-
hour stool collection for protoporphyrin and copro- Differential diagnosis
porphyrin. In variegate porphyria, protoporphyrin levels
are higher than those of coproporphyrin, whereas in hered- Both thallium and arsenic intoxication may produce a sim-
itary coproporphyria the converse holds true. Importantly, ilar clinical picture.
in between episodes all of these measurements may be
normal.
Treatment
Course Acute episodes may respond to a high carbohydrate diet

or, if patients cannot take food or fluid (as is often the
The duration of episodes usually ranges from days to weeks, case), to intravenous glucose in a dose of 400 g/day. In cases
although sometimes they can be much longer. Although resistant to this, consideration should be given to intra-
most patients recover completely, death may occur as a venous hemin (formerly known as hematin), which sup-
result of respiratory failure due to the motor neuropathy, presses the heme biosynthetic pathway and provides relief
or an arrhythmia. Repeat episodes are common and typi- generally within 3 days. Pending resolution of the episode,
cally occur in response to a specific precipitating factor. symptomatic treatment, in addition to general supportive
care, may include chlorpromazine or propranolol. Chlor-
promazine, in doses of 25–50 mg intramuscularly or intra-
Etiology venously every 4–6 hours, may not only control symptoms
of the delirium but also reduce abdominal pain (Calvy et al.
All of these hepatic porphyrias occur secondary to muta- 1957). Propranolol, in doses ranging from 20 to 200 mg
tions in genes that code for various enzymes involved in the total daily, will control both blood pressure and tachycar-
heme biosynthetic pathway: acute intermittent porphyria dia (Menawat et al. 1979). If seizures occur and require
occurs secondary to mutations in the gene for porphobilino- treatment, consideration may be given to either gabapentin
gen deaminase on chromosome 11; variegate porphyria to (Hahn et al. 1997; Tatum and Zachariah 1995) or levetirac-
mutations in the gene for protoporphyrinogen oxidase on etam (Paul and Meencke 2004); in emergent situations,
chromosome 1; and hereditary coproporphyria to muta- diazepam may be given intravenously.
tions in the gene for coproporphyrinogen oxidase on chro- Prevention is critical and this may generally be accom-
mosome 3. When the heme biosynthetic pathway becomes plished by maintaining a high carbohydrate diet and, when
stressed in the presence of these mutated proteins, ‘upstream’ possible, avoiding precipitating factors. In cases of men-
proteins, such as porphobilinogen and ALA, accumulate strually induced attacks, consideration may be given to
and an episode occurs. Although the mechanism by which leuteinizing hormone-releasing hormone to suppress
central nervous system dysfunction occurs is not clear, one menstruation. In instances in which episodes recur despite
theory suggests that ALA acts as an agonist at GABAergic these measures, consideration may be given to prophylac-
sites. Although most autopsy studies of the brain (reviewed tic use of hemin.
by Suarez et al. [1997]) have been negative, some have
found diffuse neuronal loss and diffuse perivascular
demyelinization within the central nervous system. Within 13.22 FAHR’S SYNDROME
the peripheral nervous system, axonal damage (Cavanagh
and Mellick 1965; Sweeney et al. 1970) with associated Fahr’s syndrome is characterized by a movement disorder,
chromatolysis of the spinal motor neurons (Hierons 1957) generally parkinsonism, or a neuropsychiatric syndrome,
has been noted. most commonly dementia, or both, occurring secondary
As noted earlier, most episodes are precipitated by vari- to brain calcification, which, although most common in
ous factors including infection, menstruation, pregnancy, the basal ganglia, may also be found in the dentate nuclei,
fasting (or merely a low-carbohydrate diet), surgery, and a thalamus, and at the gray–white junction of the cerebral
host of drugs including barbiturates, phenytoin, valproic and cerebellar cortices. This calcification may be either sec-
acid, carbamazepine, nortriptyline, sulfonamides, griseo- ondary to some other disorder, such as hypoparathyroidism,
fulvin, meprobamate, glutethimide, methyprylon, or may occur on a primary basis as either an idiopathic or
ethchlorvynol, ergot derivatives, synthetic estrogens and inherited disorder, in which case one speaks of Fahr’s
progestins, danazol, alpha-methyldopa, chlorpropamide, disease. Synonyms for Fahr’s disease include idiopathic
p 13.qxd 3/10/08 9:50 AM Page 485
13.22 Fahr’s syndrome 485
striopallidodentate calcinosis and idiopathic calcification

of the basal ganglia (ICBG).
Although, as noted below, asymptomatic basal ganglia
calcification is a not uncommon incidental finding, espe-
cially in the elderly, Fahr’s syndrome, by contrast, is rare.
Clinical features
The presentation is generally gradual and may be charac-

terized by either a movement disorder or a neuropsychi-
atric syndrome. Regardless of the presentation, over
long-term follow-up most patients will display a combina-
tion of these symptoms.
Of the movement disorders seen in Fahr’s syndrome,
the most common is parkinsonism (Klawans et al. 1976;
Margolin et al. 1980; Tambyah et al. 1993); choreathetosis
or dystonia (Larsen et al. 1985; Saiki et al. 2007) may also
occur and in a small minority there may be ataxia or
dysarthria.
Neuropsychiatric syndromes most commonly include
dementia (Kobari et al. 1997; Slyter 1979; Wszolek et al.
2006). Personality change, which may be of the frontal lobe
type (Lam et al. 2007; Weisman et al. 2007), may also Figure 13.1 Computed tomography (CT) scan showing
occur. A psychosis, similar to that seen in schizophrenia extensive calcium deposition in a case of Fahr’s syndrome.
(Chabot et al. 2001; Francis and Freeman 1984), has also (Reproduced from Gillespie and Jackson 2000.)
been reported, especially in the elderly (Ostling et al. 2003).
Other presentations include depression or mania (Trautner
et al. 1988) and obsessions and compulsions (Lopez-Villegas
Secondary cases may occur on the basis of hypoparathy-
et al. 1996). Seizures have also been noted, and in cases
roidism (either surgical [Berger and Ross 1981; Klawans
occurring secondary to hypoparathyroidism these may
et al. 1976; Tambyah et al. 1993] or idiopathic [Kazis 1985;
occur on the basis of hypocalcemia.
Slyter 1979]), pseudohypoparathyroidism (Mathews
Computed tomography scanning is superior to both
1957), pseudo-pseudohypoparathyroidism (Nyland and
MRI and skull radiography and in all cases displays bilat-
Skre 1977), or, rarely, hyperparathyroidism (Margolin et al.
eral calcification in the basal ganglia; in most cases, as illus-
1980). Fahr’s syndrome may also occur in concert with
trated in Figure 13.1, one also sees bilateral calcification in
bone cysts of the hands and feet in the very rare autosomal
other structures, such as the dentate nuclei, the thalamus,
recessive Nasu–Hakola disease (Kluneman et al. 2005;
and the gray–white junction of the cerebral and cerebellar
Kondo et al. 2002).
cortices.
Course Differential diagnosis
Fahr’s syndrome is generally gradually progressive. In practice, the question of this diagnosis arises when, in
the evaluation of patients with one of the clinical syn-
dromes described above, neuroimaging reveals calcifica-
Etiology tion. Care must be taken at this point, however, given that
a degree of calcification of the basal ganglia, primarily in
The majority of cases occur on a primary basis. These may the globus pallidus, is not uncommon in asymptomatic
be either idiopathic (Trautner et al. 1988) or inherited individuals, being found in approximately 0.5 percent of
(Boller et al. 1977; Kobari et al. 1997); of the inherited the general population (Harrington et al. 1981; Koller et al.
cases, although most occur on an autosomal dominant 1979) and up to 19 percent of 85 year olds (Ostling et al.
basis (Manyam et al. 2001), a recessive pattern has also 2003). In general, the diagnosis should therefore be
been noted (Smits et al. 1983). At present, the genetic basis reserved either for cases in which there is massive calcifica-
of the autosomal dominant cases is not known; although tion involving not only the basal ganglia but also the other
linkage has been demonstrated to the IBGC1 locus on structures noted above (Manyam et al. 2001) or for cases in
chromosome 14 in some cases (Geschwind et al. 1999), which no other cause may be found for the patients’ symp-
such linkage was not found in others (Oliveira et al. 2004). tomatology despite an exhaustive evaluation.
p 13.qxd 3/10/08 9:50 AM Page 486
Treatment Baver MS. Fatal hepatic failure and valproate. Am J Psychiatry

2005; 162:192.
If present hypoparathyroidism should be treated as this Becker DM, Kramer S. The neurological manifestations of
may prompt a partial remission of symptoms (Berger and porphyria: a review. Medicine 1975; 56:411–23.
Ross 1981; Slyter 1979). Parkinsonism may respond to Bellinger D, Leviton A, Waternaux C et al. Longitudinal analysis of
levodopa. The general treatment of dementia is described prenatal and postnatal lead exposure and early cognitive
in Section 5.1. In cases characterized by depression, mania, development. N Engl J Med 1987; 316:1037–43.
or obsessions or compulsions, treatment may be attempted Beltramello A, Puppini G, Cerini R et al. Subacute combined
as described in Sections 6.1, 6.3, and 4.17 respectively. degeneration of the spinal cord after nitrous oxide
anaesthesia: role of magnetic resonance imaging. J Neurol
Neurosurg Psychiatry 1998; 64:563–4.
REFERENCES Ben-Ami H, Nagachandran P, Mendelson A et al. Drug-induced
hypoglycemic coma in 102 diabetic patients. Arch Intern Med
Abarbanel JM, Berginer VM, Osimani A et al. Neurologic 1999; 159:281–4.
complications after gastric restriction surgery for morbid Berger JR, Ross DB. Reversible Parkinson syndrome complicating
obesity. Neurology 1987; 37:196–200. postoperative hypoparathyroidism. Neurology 1981;
Abd El Naby S, Hassanein M. Neuropsychiatric manifestations of 31:881–2.
chronic manganese poisoning. J Neurol Neurosurg Psychiatry Besser R, Kramer G, Thumler R et al. Acute trimethyltin
1965; 28:282–8. limbic–cerebellar syndrome. Neurology 1987; 37:945–50.
Adams RD, Foley JM. The neurological disorder associated with Blass JP, Gibson GE. Abnormality of a thiamine-requiring enzyme
liver disease. Assoc Res Nerv Ment Dis Proc 1953; 32:198–237. in patients with the Wernicke–Korsakoff syndrome. N Engl J
Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a Med 1977; 297:1367.
hitherto undescribed disease occurring in alcoholic and Bodamar OAF, Rosenblatt DS, Appel SH et al. Adult-onset
malnourished patients. Arch Neurol Psychiatry 1959; combined methylmalonic aciduria and homocystinuria.
81:154–72. Neurology 2001; 56:1113.
Akelaitis AJ. Lead encephalopathy in children and adults. J Nerv Bohan TP, Helton E, McDonald I et al. Effect of l-carnitine
Ment Dis 1941; 93:313–32. treatment for valproate-induced hepatotoxicity. Neurology
Alajouanine T, DeRobert L, Thieffry S. Etude clinique d’ensemble 2001; 56:1405–9.
de 210 cas d’intoxication par les sels organiques d’etain. Boller F, Boller M, Gilbert J. Familial idiopathic cerebral
Rev Neurol 1958; 98:85–96. calcifications. J Neurol Neurosurg Psychiatry 1977; 40:280–5.
Albert MS, Butters N, Levin J. Temporal gradients in the Bosboom WMJ, Frijns CJM, Gijn J. Yelling attacks and wasted
retrograde amnesia of patients with alcoholic Korsakoff’s hands. Lancet 1996; 348:238.
disease. Arch Neurol 1979; 36:211–16. Boxer AL, Kramer JH, Johnston N et al. Executive dysfunction in
Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy hyperhomocystinemia responds to homocysteine-lowering
syndrome. Possible aluminium intoxication. N Engl J Med treatment. Neurology 2005; 64:1431–4.
1976; 294:184–8. Brunner JE, Redmond JM, Haggar AM et al. Central pontine
Amin-Zaki L, Majeed MA, Traxon TW et al. Methyl mercury myelinolysis and pontine lesions after rapid correction of
poisoning in Iraqi children: clinical observations of two years. hyponatremia: a prospective magnetic resonance imaging
BMJ 1978; 1:613–16. study. Ann Neurol 1990; 27:61–6.
Andreoli SP, Bergstein JM, Sherrard DJ. Aluminum intoxication Buge A, Supino-Viterbo V, Rancurel G et al. Epileptic phenomena
from aluminum-containing phosphate binders in children with in bismuth toxic encephalopathy. J Neurol Neurosurg
azotemia not undergoing dialysis. N Engl J Med 1984; Psychiatry 1981; 44:62–7.
310:1079–84. Burke GJ, Hiangabeza T. Isoniazid-induced pellagra in a patient on
Andres E, Noel e, Goichot B. Metformin-associated vitamin B12 vitamin B supplement. S Afr Med J 1977; 51:719.
deficiency. Arch Int Med 2002; 162:2251–2. Burkhard PR, Delavelle J, Du Pasquier R et al. Chronic
Auer RN, Hugh J, Cosgrove E et al. Neuropathologic findings in parkinsonism associated with cirrhosis: a distinct subset of
three cases of profound hypoglycemia. Clin Neuropathol 1989; acquired hepatocerebral degeneration. Arch Neurol 2003;
8:63–8. 60:521–8.
Bach LA, Buchanan RR, Scarlett JD et al. Hyperviscosity syndrome Burks JS, Alfrey AC, Huddlestone J et al. A fatal encephalopathy in
secondary to rheumatoid arthritis. Aust NZ J Med 1989; chronic hemodialysis patients. Lancet 1976; 1:764–8.
19:710–12. Burns R, Thomas DQ, Barron VJ. Reversible encephalopathy
Baghurst PA, McMichael AJ, Wigg NR et al. Environmental possibly associated with bismuth subgallate ingestion. BMJ
exposure to lead and children’s intelligence at the age of 1974; 1:220–3.
seven years – the Port Pirie Cohort Study. N Engl J Med 1992; Bylesjo I, Brekke OL, Prytz J et al. Brain magnetic resonance
327:1279–84. imaging white-matter lesions an cerebrospinal fluid findings
Bank WJ, Pleasure DE, Suzuki K et al. Thallium poisoning. Arch in patients with acute intermittent porphyria. Eur Neurol
Neurol 1972; 26:456–64. 2004; 51:1–5.
p 13.qxd 3/10/08 9:50 AM Page 487
References 487
Cadranel JF, Lebiz E, Di Martino V et al. Focal neurologic signs in Davison AM, Walker GS, Oh H et al. Water supply aluminum
hepatic encephalopathy in cirrhotic patients: an concentration dialysis dementia, and effect of reverse-osmosis
underestimated entity? Am J Gastroenterol 2001; 96:515–18. water treatment. Lancet 1982; 2:785–7.
Calne DB, Chu NS, Huang CC et al. Manganese and idiopathic Dickoff DJ, Raps M, Yahr MD. Striatal syndrome following
parkinsonism: similarities and differences. Neurology 1994; hyponatremia and its rapid correction: a manifestation of
44:1583–6. extrapontine myelinolysis confirmed by magnetic resonance
Calvy GL, Leeper RD, Monaco RN et al. Intermittent acute imaging. Arch Neurol 1988; 45:112–14.
porphyria treated with chlorpromazine. N Engl J Med 1957; DiMartini A. Wernicke–Korsakoff syndrome in a liver transplant
256:309–11. recipient. Psychosomatics 1996; 37:564–7.
Camacho J, Arnalich F, Anciones B et al. The spectrum of Discalzi G, Pira E, Herrero Hernandez E et al. Occupational Mn
neurological abnormalities in myeloma. J Med 1985; parkinsonism: magnetic resonance imaging and clinical
16:597–611. patterns following CaNa2-EDTA chelation. Neurotoxicology
Canfield RL, Henderson CP, Cory-Slechta DA et al. Intellectual 2000; 21:863–6.
impairment in children with blood lead concentrations Dizon AM, Kowaly S, Hoogwerf BJ. Neuroglycopenic and other
below 10 microgr per deciliter. N Engl J Med 2003; symptoms in patients with insulinomas. Am J Med 1999;
348:1517–26. 106:307–10.
Case Records of the Massachusetts General Hospital. N Engl J Donovan JP, Schaefer DF, Shaw BW et al. Cerebral oedema and
Med 1988; 318:1523–8. increased intracranial pressure in chronic liver disease. Lancet
Cavanagh JB, Mellick RS. On the nature of the peripheral nerve 1998; 351:719–21.
lesions with acute intermittent porphyria. J Neurol Neurosurg Dreyfus PM. The clinical applications of blood transketolase
Psychiatry 1965; 28:320–72. determinations. N Engl J Med 1962; 267:596–8.
Cavanagh JB, Fuller NH, Johnson HRM et al. The effects of El-Mallakh RS, Shrader SA, Widger E. Single case study: mania as
thallium salts, with particular reference to the nervous system a manifestation of end-stage renal disease. J Nerv Ment Dis
changes. Q J Med 1974; 43:293–319. 1987; 175:243–5.
Chabot B, Roulland C, Dollfus S. Schizophrenia and familial Estol CJ, Faris AA, Martinez J et al. Central pontine myelinolysis
idiopathic basal ganglia calcification: a case report. Psychol after liver transplantation. Neurology 1989; 39:493–8.
Med 2001; 31:741–7. Evans DL, Edelsohn GA, Golden RN. Organic psychosis without
Charles JR. Manganese toxaemia, with special reference to the anemia or spinal cord symptoms in patients with B12
effects of liver feeding. Brain 1927; 50:30–43. deficiency. Am J Psychiatry 1983; 140:218–21.
Chatterjee A, Yapundich R, Palmer CA et al. Leukoencephalopathy Feldman RG, White RF, Eriator II. Trimethyltin encephalopathy.
associated with cobalamin deficiency. Neurology 1996; Arch Neurol 1993; 50:1320–4.
46:832–4. Ferraro A, Arieti S, English WH. Cerebral changes in the course of
Chokroverty S, Bruetman ME, Berger V et al. Progressive dialytic pernicious anemia and their relationship to psychic changes.
encephalopathy. J Neurol Neurosurg Psychiatry 1976; J Neuropathol Exp Neurol 1945; 4:217–39.
39:411–19. Ficker DM, Westmoreland BF, Sharbrough FW. Epileptiform
Chu K, Kang DW, Kim HJ et al. Diffusion-weighted imaging abnormalities in hepatic encephalopathy. J Clin Neurophysiol
abnormalities in Wernicke encephalopathy: reversible 1997; 14:230–4.
cytotoxic edema? Arch Neurol 2002; 59:123–7. Fincher RM, Koerker RM. Long-term survival in acute arsenic
Cook DG, Fahn S, Brairt KA. Chronic manganese intoxication. Arch encephalopathy. Follow-up using newer measures of
Neurol 1974; 30:59–64. electrophysiologic parameters. Am J Med 1987; 82:549–52.
Cossa P, Duplay J, Fischgold A et al. Encephalopathies toxiques au Finlayson MH, Superville B. Distribution of cerebral lesions in
Stalinon. Aspects anatomo-cliniques et acquired hepatocerebral degeneration. Brain 1981;
electroencephalographiques. Rev Neurol 1958; 98:97–108. 104:79–85.
Cox TN, Jack N, Lofthouse S et al. King George III and porphyria: Fisher AA, Le Couteur DG. Lead poisoning from complementary
an elemental hypothesis and investigation. Lancet 2005; and alternative medicine in multiple sclerosis. J Neurol
366:332–5. Neurosur Psychiatry 2000; 69:687–9.
Cravioto H, Korein J, Silberman J. Wernicke’s encephalopathy: a Fortemps E, Amand G, Bomboir A et al. Trimethyltin poisoning.
clinical and pathological study of 28 autopsied cases. Arch Report of two cases. Int Arch Occup Environ Health 1978;
Neurol 1961; 4:510–19. 41:1–6.
Cross TN. Porphyria – a deceptive syndrome. Am J Psychiatry Francis A, Freeman H. Psychiatric abnormality and brain
1956; 112:1010–14. calcification over four generations. J Nerv Ment Dis 1984;
Davis LE, Wands JR, Weiss SA et al. Central nervous system 172:166–70.
intoxication from mercurous chloride laxative. Arch Neurol Frantzen E. Wernicke’s encephalopathy: 3 cases occurring in
1974; 30:428–31. connection with severe malnutrition. Acta Neurol Scand 1966;
Davis LE, Standefer JC, Kornfeld M et al. Acute thallium poisoning: 42:426–41.
toxicological and morphological studies of the nervous system. Fraser CL, Arieff AI. Hepatic encephalopathy. N Engl J Med 1985;
Ann Neurol 1981; 10:38–44. 313:865–73.
p 13.qxd 3/10/08 9:50 AM Page 488
Fraser CL, Arieff AI. Nervous system complications in uremia. Ann Hauw J-J, De Baecque C, Hausser-Hauw C et al. Chromatolysis in
Intern Med 1988; 109:143–9. alcoholic encephalopathies. Brain 1988; 111:843–57.
Fraser TN. Cerebral manifestations of addisonian pernicious Hay WJ, Rickards AG, McMenemey WH et al. Organic mercurial
anemia. Lancet 1960; 2:458–9. encephalopathy. J Neurol Neurosurg Psychiatry 1963;
Freeman JW, Couch JR. Prolonged encephalopathy with arsenic 26:199–202.
poisoning. Neurology 1978; 28:853–5. Healton EH, Savage DG, Brust JCM et al. Neurologic aspects of
Gardeur D, Buge A, Rancurel G et al. Bismuth encephalopathy and cobalamin deficiency. Medicine 1991; 70:228–45.
cerebral computed tomography. J Comput Assist Tomogr 1978; Herzlich BC, Schiano TD. Reversal of apparent AIDS dementia
2:436–8. complex following treatment with vitamin B12. J Intern Med
Gardian G, Voros E, Jardanhazy T et al. Wernicke’s encephalopathy 1993; 233:495–7.
induced by hyperemesis gravidarum. Acta Neurol Scand 1999; Hierons R. Changes in the nervous system in acute porphyria.
95:196–8. Brain 1957; 80:176–92.
Garrett PJ, Mulcahey D, Carmody M et al. Aluminum Hirsch S, Dunsworth FA. An interesting case of porphyria. Am J
encephalopathy: clinical and immunologic features. Q J Med Psychiatry 1955; 111:703.
1988; 69:775–83. Huang C-C, Chu N-S, Lu C-S et al. Chronic manganese
Geschwind DH, Loginov M, Stern JM. Identification of a locus on intoxication. Arch Neurol 1989; 46:1104–6.
chromosome 14q for idiopathic basal ganglia calcification Huang C-C, Lu C-S, Chu N-S et al. Progression after chronic
(Fahr disease). Am J Hun Genet 1999; 65:764–72. manganese exposure. Neurology 1993; 43:1479–83.
Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold, 2000. Huang C-C, Chus N-S, Lu C-S et al. Cock gait in manganese
Gocht A, Colmant HJ. Central pontine and extrapontine myelinolysis: intoxication. Mov Disord 1997; 12:807–8.
a report of 58 cases. Clin Neuropathol 1987; 6:262–70. Huang C-C, Chu N-S, Lu C-S et al. Long-term progression in chronic
Goggans FC. A case of mania secondary to vitamin B12 manganism: ten years of follow-up. Neurology 1998; 50:698–700.
deficiency. Am J Psychiatry 1984; 141:300–1. Huang C-C, Chu N-S, Lu C-S et al. The natural history of
Goldberg A. Acute intermittent porphyria. Q J Med 1959; 28:183–209. neurological manganism over 18 years. Parkinsonism Relat
Graham DI, Adams JH, Caird FI et al. Acquired hepatocerebral Disord 2007; 13:143–5.
degeneration: report of an atypical case. J Neurol Neurosurg Hughes JR, Schreeder MT. EEG in dialysis encephalopathy.
Psychiatry 1970; 23:656–62. Neurology 1980; 30:1148–54.
Hadfield MG, Kubal WS. Extrapontine myelinolysis of the basal Hung SC, Hung SH, Tarug DC et al. Thiamine deficiency and
ganglia without central pontine myelinolysis. Clin Neuropathol unexplained neuropathology in hemodialysis and peritoneal
1996; 15:96–100. dialysis patients. Am J Kidney Dis 2001; 38:941–7.
Hahn M, Gildemeister OS, Krauss GL et al. Effects of new Hunter D, Russell DS. Focal cerebral and cerebellar atrophy in a
anticonvulsant medications on porphyrin synthesis in cultured human subject due to organic mercury compounds. J Neurol
liver cells: potential implications for patients with acute Neurosurg Psychiatry 1954; 17:235–41.
porphyria. Neurology 1997; 49:97–106. Hurst EW. The lesions produced in the central nervous system by
Halliday G, Cullen K, Harding A. Neuropathological correlates of certain organic arsenical compounds. J Pathol Bacteriol 1959;
memory dysfunction in the Wernicke–Korsakoff syndrome. 77:523–34.
Alcohol Alcoholism Suppl 1994; 2:247–53. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical
Handler CE, Perkin GD. Anorexia nervosa and Wernicke’s and pathological study of 20 necropsy cases. J Neurol
encephalopathy: an underdiagnosed association. Lancet 1982; Neurosurg Psychiatry 1981; 44:209–15.
2:771–2. Ishii N, Nishihara Y. Pellagra encephalopathy among tuberculous
Harper C. Wernicke’s encephalopathy: a more common disease patients: its relation to isoniazid therapy. J Neurol Neurosurg
than realized: a neuropathological study of 51 cases. J Neurol Psychiatry 1985; 48:628–34.
Neurosurg Psychiatry 1979; 42:226–31. Jack RA, Rivers-Bulkeley NT, Rabin PL. Single case study:
Harper C. The incidence of Wernicke’s encephalopathy in secondary mania as a presentation of progressive dialysis
Australia – a neuropathological study of 131 cases. J Neurol encephalopathy. J Nerv Ment Dis 1983; 171:193–5.
Neurosurg Psychiatry 1983; 46:593–8. Jaffe N. Catatonia and hepatic dysfunction. Dis Nerv Syst 1967;
Harper CG, Giles M, Finlay-Jones R. Clinical signs in the 28:606–8.
Wernicke–Korsakoff complex: a retrospective analysis of 131 Jagadha V, Deck JHN, Halliday WL et al. Wernicke’s
cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry encephalopathy in patients on peritoneal dialysis or
1986; 49:341–5. hemodialysis. Ann Neurol 1987; 21:78–84.
Harrington MG, MacPherson P, McIntosh WB et al. The Jenkins CD, Mellins RB. Lead poisoning in children. Arch Neurol
significance of the incidental finding of basal ganglia Psychiatry 1957; 77:70–8.
calcification on computed tomography. J Neurol Neurosurg Jolliffe N, Bowman K, Rosenblum L et al. Nicotinic acid deficiency
Psychiatry 1981; 44:1168–70. encephalopathy. J Am Med Assoc 1940; 114:307–9.
Hart SP, Frier BM. Causes, management and morbidity of acute Jung SL, Kim BS, Lee KS et al. Magnetic resonance imaging and
hypoglycaemia in adults requiring hospital admission. Q J Med diffusion-weighted imaging changes after hypoglycemic
1998; 91:505–10. coma. J Neuroimaging 2005; 15:193–6.
p 13.qxd 3/10/08 9:50 AM Page 489
References 489
Kalimo H, Olsson Y. Effect of severe hypoglycemia on the human Lindenbaum J, Healton EB, Savage DG et al. Neuropsychiatric
brain. Acta Neurol Scand 1980; 62:345–56. disorders caused by cobalamin deficiency in the absence of
Karp BI, Laureno R. Pontine and extrapontine myelinolysis: a anemia or macrocytosis. N Engl J Med 1988; 318:1720–8.
neurologic disorder following rapid correction of Lopez-Villegas D, Kulisevsky J, Deus J et al. Neuropsychological
hyponatremia. Medicine 1993; 72:359–73. alterations in patients with computed tomography-detected
Kazis AD. Contribution of CT scan to the diagnosis of Fahr’s basal ganglia calcification. Arch Neurol 1996; 53:251–6.
syndrome. Acta Neurol Scand 1985; 71:206–11. Lu C-S, Huang C-C, Chu N-S et al. Levodopa failure in chronic
King PH, Bragdon AC. MRI reveals multiple reversible cerebral manganism. Neurology 1994; 44:1600–2.
lesions in an attack of acute intermittent porphyria. Neurology Lurie LA. Pernicious anemia with mental symptoms: observations
1991; 41:1300–2. on the variable extent and probable duration of central
Kinsella LJ, Green R. ‘Anesthesia paresthetica’ nitrous oxide- nervous system lesions in four autopsied cases. Arch Neurol
induced cobalamin deficiency. Neurology 1995; 45:1608–10. Psychiatry 1919; 2:67–109.
Klawans HL, Lipton M, Simon L. Calcification of the basal ganglia Macalpine I, Hunter R. The ‘insanity’ of King George III: a classic
as a cause of levodopa-resistant parkinsonism. Neurology case of porphyria. BMJ 1966; 1:65–71.
1976; 26:221–5. Macalpine I, Hunter R, Rimington C. Porphyria in the royal houses
Klunemann HH, Ridha BH, Magy L et al. The genetic causes of of Stuart, Hanover and Prussia: a follow-up study of George
basal ganglia calcification, dementia, and bone cysts. DAP12 III’s illness. BMJ 1968; 1:7–8.
and TREM2. Neurology 2005; 64:1502–7. MacKeith SA, Meyer A. A death during insulin treatment of
Klos KJ, Ahlskog JE, Kumar N et al. Brain metal concentrations in schizophrenia; with pathological report. J Ment Sci 1939;
chronic liver failure patients with pallidal T1 MRI 85:96–105.
hyperintensity. Neurology 2006; 67:1984–9. Malamud N, Skillicorn SA. Relationship between the Wernicke
Kobari M, Nogawa S, Sugimoto Y et al. Familial idiopathic brain and the Korsakoff syndrome. Arch Neurol Psychiatry 1956;
calcification with autosomal dominant inheritance. Neurology 76:585–96.
1997; 48:645–9. Malouf R, Brust JCM. Hypoglycemia: causes, neurological
Koller WC, Cochran JW, Klawans HL. Calcification of the basal manifestations, and outcome. Ann Neurol 1985; 17:421–30.
ganglia: computerized tomography and clinical correlation. Mandoki MW, Sumner GS. Psychiatric manifestations of
Neurology 1979; 29:328–33. hereditary coproporphyria in a child. J Nerv Ment Dis 1994;
Koller WC, Lyons KE, Truly W. Effect of levodopa treatment for 182:117–18.
parkinsonism in welders. Neurology 2004; 62:730–3. Manyam BV, Walters AS, Narla KR. Bilateral striopallidodentate
Kondo T, Takahashi K, Kohara N et al. Heterogeneity of presenile calcinosis: clinical characteristics of patients seen in a
dementia with bone cysts (Nasu-Hakola disease). Neurology registry. Mov Disord 2001; 16:258–64.
2002; 59:1105–7. Maraganore DM, Folger WN, Swanson JW et al. Movement
Kreyberg S, Torvik A, Bjorneboe A et al. Trimethyltin poisoning: disorders as sequelae of central pontine myelinolysis: report of
report of a case with postmortem examination. Clin three cases. Mov Disord 1992; 7:142–8.
Neuopathol 1992; 11:256–9. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy
Krieger D, Krieger S, Jansen O et al. Manganese and chronic causes malabsorption of cyanocobalamin (vitamin B12). Ann
hepatic encephalopathy. Lancet 1995; 346:270–4. Intern Med 1994; 120:211–15.
Kurland LT, Faro SN, Siedler H. Minamata disease. World Neurol Margolin D, Hammerstad J, Orwoll E et al. Intracranial
1960; 1:370–95. calcification in hyperparathyroidism associated with gait
Kuzminski AM, Del Giacco EJ, Allen RH et al. Effective treatment apraxia and parkinsonism. Neurology 1980; 30:1005–7.
of cobalamin deficiency with oral cobalamin. Blood 1998; Marie R-M, Le Biez E, Busson P et al. Nitrous oxide anesthesia-
92:1191–8. associated myelopathy. Arch Neurol 2000; 57:380–2.
Lam JS, Fong SY, Yiu GC et al. Fahr’s disease: a differential diagnosis Mathews WB. Familial calcification of the basal ganglia with
of frontal lobe syndrome. Hong Kong Med J 2007; 13:75–7. response to parathormone. J Neurol Neurosurg Psychiatry
Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002; 1957; 20:172–7.
47:3–10. Matte TD, Proops D, Palazuelos E et al. Acute high-dose lead
Langworthy OR. Lesions of the central nervous system exposure from beverage contaminated by traditional Mexican
characteristic of pellagra. Brain 1931; 54:291–302. pottery. Lancet 1994; 344:1064.
Larsen TA, Dunn HG, Jae JE et al. Dystonia and calcification of the Mawdsley C. Neurological complications of haemodialysis. Proc R
basal ganglia. Neurology 1985; 35:533–7. Soc Med 1972; 65:871–3.
Lawrence RD, Meyer R, Nevin S. The pathological changes in fatal McKee AC, Winkleman MD, Banker BQ. Central pontine
hypoglycemia. Q J Med 1942; 11:181–201. myelinolysis in severely burned patients: relationship to serum
Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann hyperosmolality. Neurology 1988; 38:1211–17.
Neurol 1978; 4:199–204. McMillan TM, Jacobson RR, Gross M. Neuropsychology of thallium
Liessens JL, Monstrui J, Vanden Eeckhout E et al. Bismuth poisoning. J Neurol Neurosurg Psychiatry 1997; 63:247–50.
encephalopathy. A clinical case and anatomicopathological Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell
report of one case. Acta Neurol 1978; 78:301–9. dyscrasias. Semin Thromb Hemost 2003; 29:467–471.
p 13.qxd 3/10/08 9:50 AM Page 490
Mellins RB, Jenkins CD. Epidemiologic and psychological study Pacchetti C, Cristina S, Nappi G. Reversible chorea and focal
of lead poisoning in children. J Am Med Assoc 1955; dystonia in vitamin B12 deficiency. N Engl J Med 2002;
158:15–20. 347:295.
Mena I, court J, Fuenzalida S et al. Modification of chronic Palardy J, Havrankova J, Lepage R et al. Blood glucose
manganese poisoning. Treatment with L-dopa or 5-OH measurements during symptomatic episodes in patients with
tryptophan. N Engl J Med 1970; 282:5–10. suspected postprandial hypoglycemia. N Engl J Med 1989;
Menawat AS, Panwar RB, Kochar DK et al. Propranolol in acute 321:1421–5.
intermittent porphyria. Postgrad Med J 1979; 55:546–7. Paredes A, Jones H. Psychopathology of acute intermittent
Menger H, Jorg J. Outcome of central pontine and extrapontine porphyria: case report. J Nerv Ment Dis 1959; 129:291–301.
myelinolysis (n⫽ 44). J Neurol 1999; 246:700–5. Paul F, Meencke H-J. Levetiracetam in focal epilepsy and hepatic
Messert B, Orrison WM, Quaglieri CE. Central pontine porphyria: a case report. Epilepsia 2004; 45:559–60.
myelinolysis. Neurology 1979; 29:147–60. Paulson GW, Martin EW, Mojzisik C et al. Neurologic
Moersch FP, Kernohan JW. Hypoglycemia: neurologic and complications of gastric partitioning. Arch Neurol 1985;
neuropathologic studies. Arch Neurol Psychiatry 1938; 42:675–7.
39:242–57. Pavy MD, Murphy PL, Virella G. Paraprotein-induced
Moore D, House I, Dixon A. Thallium poisoning. Diagnosis may be hyperviscosity. A reversible cause of stroke. Postgrad Med
elusive but alopecia is the clue. BMJ 1993; 306:1527–9. 1980; 68:109–12.
Morris CE, Heyman A, Pozersky T. Lead encephalopathy caused by Pentschew A. Morphology and morphogenesis of lead
ingestion of illicitly distilled whiskey. Neurology 1964; encephalopathy. Acta Neuropathol 1965; 5:133–60.
14:493–9. Peterson H, Swanson AG. Acute encephalopathy occurring during
Mueller J, Hotson JR, Langston JW. Hyperviscosity-induced hemodialysis. Arch Int Med 1964; 113:877–80.
dementia. Neurology 1983; 33:101–3. Pierce LB. Pellagra: report of a case. Am J Psychiatry 1924;
Nadel AM, Wilson WP. Dialysis encephalopathy: a possible seizure 81:237–43.
disorder. Neurology 1976; 26:1130–2. Pincus JH, Reynolds EH, Glaser GH. Subacute combined system
Nagatomo S, Umehara F, Hanada K et al. Manganese intoxication degeneration with folate deficiency. J Am Med Assoc 1972;
during total parenteral nutrition: report of two cases and 221:496–7.
review of the literature. J Neurol Sci 1999; 162:102–5. Powell EE, Pender MP, Chalk JB et al. Improvement in chronic
Needleman HL, Shell A, Ballinger D et al. The long-term effects of hepatocerebral degeneration following liver transplantation.
exposure to low doses of lead in childhood: an 11-year follow Gastroenterology 1990; 98:1079–82.
up report. N Engl J Med 1990; 322:83–8. Powers JM, Rosenblatt DS, Schmidt RE et al. Neurological and
Norenberg MD, Leslie KO, Robertson AS. Association between rise neuropathologic heterogeneity in two brothers with
in serum sodium and central pontine myelinolysis. Ann Neurol cobalamin C deficiency. Ann Neurol 2001; 49:396–400.
1982; 11:128–35. Price BH, Mesulam M-M. Behavioral manifestation of central
Nyland H, Skre H. Cerebral calcinosis with late onset pontine myelinolysis. Arch Neurol 1987; 44:671–3.
encephalopathy. Acta Neurol Scand 1977; 56:309–25. Price WA, Zimmer B, Conway R et al. Insulin-induced factitious
O’Carroll RE, Moffoot A, Ebmeir KP et al. Korsakoff’s syndrome, hypoglycemic coma. Gen Hosp Psychiatry 1986; 8:291–3.
cognition and clonidine. Psychol Med 1993; 23:341–7. Rajan S, Wallache JI, Brodkin KI et al. Response of elevated
O’Carroll RE, Moffoot APR, Ebmeier KP et al. Effects of methylmalonic acid to three dose levels of oral cobalamin in
fluvoxamine on cognitive functioning in the alcoholic older adults. J Am Geriatr Soc 2002; 50:1789–95.
Korsakoff syndrome. Psychopharmacology 1994; 116:85–8. Rapaport MJ. Pellagra in a patient with anorexia nervosa.
O’Carroll RE, Masterton G, Dougall N et al. The neuropsychiatric Arch Dermatol 1985; 121:255–7.
sequelae of mercury poisoning: the Mad Hatter’s disease Raskin NH, Fishman RA. Neurologic disorders in renal failure.
revisited. Br J Psychiatry 1995; 167:95–8. N Engl J Med 1976; 294:143–8, 204–10.
Ogershok PR, Rahman A, Nestor S et al. Wernicke encephalopathy Raskin NH, Bredesen D, Ehrenfeld WK et al. Periodic confusion
in nonalcoholic patients. Am J Med Sci 2002; 323:107–11. caused by congenital extrahepatic portocaval shunt.
O’Hare JA, Callaghan NM, Murnaghan DJ. Dialysis Neurology 1984; 34:666–9.
encephalopathy. Clinical, electroencephalographic, and Read AE, Laidlaw J, Sherlock S. Neuropsychiatric complications of
interventional aspects. Medicine 1983; 62:129–41. portocaval anastamosis. Lancet 1961; 1:961–4.
Oliveira JR, Spiteri E, Sobrio MJ et al. Genetic heterogeneity in Reed D, Crawley J, Faro SN et al. Thallotoxicosis. J Am Med Assoc
familial idiopathic basal ganglia calcification (Fahr disease). 1963; 183:516–22.
Neurology 2004; 63:2165–7. Reynolds EH, Rothfeld P, Pincus JH. Neurological disease
Ong JP, Aggarwal A, Krieger D et al. Correlation between associated with folate deficiency. BMJ 1973; 2:398–400.
ammonia levels and the severity of hepatic encephalopathy. Rich LM, Caine MR, Findling JW et al. Hypoglycemic coma in
Am J Med 2003; 114:188–93. anorexia nervosa. Case report and review of the literature.
Ostling S, Andreasson LA, Skoog I. Basal ganglia calcification and Arch Int Med 1990; 150:894–5.
psychotic symptoms in the very old. Int J Geriatr Psychiatry Richmond J. Wernicke’s encephalopathy associated with digitalis
2003; 18:983–7. poisoning. Lancet 1959; 1:344–5.
p 13.qxd 3/10/08 9:50 AM Page 491
References 491
Ropper AH. Accelerated neuropathy of renal failure. Arch Neurol Shor-Posner G, Morgan R, Wilkie F et al. Plasma cobalamin levels
1993; 50:536–9. affect information processing speed in a longitudinal study of
Rowland LP. Acute intermittent porphyria: search for an HIV-1 disease. Arch Neurol 1995; 52:195–8.
enzymatic defect with implications for neurology and Singh S, Kumar A. Wernicke encephalopathy after obesity surgery.
psychiatry. Dis Nerv Syst 1961; 22(suppl.):1–12. A systematic review. Neurology 2007; 68:807–11.
Russell DS. Changes in the central nervous system following Slyter H. Idiopathic hypoparathyroidism presenting as dementia.
arsphenamine medication. J Pathol 1937; 45:357–66. Neurology 1979; 29:393–4.
Russell JSR, Batten FE, Collier J. Subacute combined degeneration Smith JF, McLaurin RL, Nichols JP et al. Studies in cerebral
of the spinal cord. Brain 1900; 23:39–110. oedema and cerebral swelling. 1. The changes in lead
Rustam H, Hamri T. Methyl mercury poisoning in Iraq. Brain 1974; encephalopathy in children compared with those in alkyl tin
97:499–510. poisoning in animals. Brain 1960; 83:411–24.
Ruzek KA, Campeau NG, Miller GM. Early diagnosis of central Smith LH. Mental and neurologic changes in pernicious anemia.
pontine myelinolysis with diffusion-weighted imaging. AJNR Arch Neurol Psychiatry 1929; 22:551–7.
2004; 25:210–13. Smits MG, Gabreels FJ, Thijssen HO et al. Progressive idiopathic
Sahin HA, Gurvit IH, Bilgic B et al. Therapeutic effects of an strio-pallido-dentate calcinosis (Fahr’s disease) with
acetylcholinesterase inhibitor (donepezil) on memory in autosomal recessive inheritance. Report of three siblings.
Wernicke-Korsakoff’s disease. Clin Neuropharmacol 2002; Eur Neurol 1983; 22:58–64.
25:16–20. Snyder RD. The involuntary movements of chronic mercury
Saiki M, Saiki S, Saiki K et al. Neurological deficits are associated poisoning. Arch Neurol 1972; 26:379–81.
with increased brain calcinosis, hypoperfusion and Spivak JL, Jackson DL. Pellagra: an analysis of 18 patients and a
hypometabolism in idiopathic basal ganglia calcification. review of the literature. Johns Hopkins Med J 1977;
Mov Disord 2007; 22:1027–30. 140:295–309.
Scarlett JA, Mako ME, Rubenstein AH et al. Factitious Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical
hypoglycemia: diagnosis by measurement of serum C-peptide and biochemical study of 46 patients. Medicine 1970;
immunoreactivity and insulin-binding antibodies. N Engl J Med 49:1–16.
1977; 297:1029–32. Sterns RH, Riggs JE, Schochet SS. Osmotic demyelination
Scheiber SC, Ziesat H. Brief communication: clinical and syndrome following correction of hyponatremia. N Engl J Med
psychological test findings in cerebral dyspraxia associated 1986; 314:1535–42.
with hemodialysis. J Nerv Ment Dis 1976; 162:212–14. Stojsavljevic N, Levic Z, Drulovic J et al. A 44-month clinical-brain
Schottenfeld RS, Cullen MR. Organic affective illness associated MRI follow-up in a patient with B12 deficiency. Neurology
with lead intoxication. Am J Psychiatry 1984; 141:1425–6. 1997; 49:878–81.
Seiser A, Schwarz S, Aichinger-Steiner MM et al. Parkinsonism Stracciari A, Guarino M, Pazzaglia P et al. Acquired
and dystonia in central pontine and extrapontine myelinolysis. hepatocerebral degeneration: full recovery after liver
J Neurol Neurosurg Psychiatry 1998; 65:119–21. transplantation. J Neurol Neurosurg Psychiatry 2001;
Seltzer B, Benson DF. The temporal pattern of retrograde amnesia 70:136–70.
in Korsakoff’s disease. Neurology 1974; 24:527–30. Strachan RW, Henderson JG. Dementia and folate deficiency.
Serdaru M, Hausser-Hauw C, Laplane D et al. The clinical Q J Med 1967; 36:189–204.
spectrum of alcoholic pellagra encephalopathy. A Suarez JI, Cohen ML, Larkin J et al. Acute intermittent porphyria:
retrospective analysis of 22 cases studied pathologically. Brain clinicopathologic correlation. Report of a case and review of
1988; 111:829–42. the literature. Neurology 1997; 48:1678–83.
Servin-Abad L, Tzakis A, Schiff ER et al. Acquired hepatocerebral Sullivan AA, Chervin RD, Albin RL. Parkinsonism after correction
degeneration in a patient with HCV cirrhosis: complete of hyponatremia with radiological central pontine myelinolysis
resolution with subsequent recurrence after liver and changes in the basal ganglia. J Clin Neurosci 2000;
transplantation. Liver Transpl 2006; 12:1161–5. 7:256–9.
Sherlock S. Fulminant hepatic failure. Adv Intern Med 1993; Summerskill WHJ, Davidson EA, Sherlock S et al. The
38:245–67. neuropsychiatric syndrome associated with hepatic cirrhosis
Sherrard DJ, Walker JV, Boykin JL. Precipitation of dialysis and extensive portal collateral circulation. Q J Med 1956;
dementia by deferoxamine treatment of aluminum-related 25:245–66.
bone disease. Am J Kidney Dis 1988; 12:12–30. Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic
Shimomura T, Mori E, Hirono N et al. Development of encephalopathy due to ingestion of bismuth salts: clinical and
Wernicke–Korsakoff syndrome after long intervals following EEG studies of 45 patients. J Neurol Neurosurg Psychiatry
gastrectomy. Arch Neurol 1998; 55:1242–5. 1977; 40:748–52.
Shintani S, Tsuruoka S, Shiigai T. Hypoglycemic hemiplegia: a Sweeney VP, Pathak MA, Asbury AK et al. Acute intermittent
repeat SPECT study. J Neurol Neurosurg Psychiatry 1993; porphyria. Increased ALA-synthetase activity during an acute
56:700–1. attack. Brain 1970; 93:369–80.
Shirabe T, Irie K, Uchida M. Autopsy cases of aluminum Tambyah PA, Ong BKC, Lee KO. Reversible parkinsonism and
encephalopathy. Neuropathology 2002; 22:206–10. asymptomatic hypocalcemia with basal ganglia calcification
p 13.qxd 3/10/08 9:50 AM Page 492
from hypoparathyroidism 26 years after thyroid surgery. Am J Wallis WE, Willoughby E, Baker P. Coma in the
Med 1993; 94:444–5. Wernicke–Korsakoff syndrome. Lancet 1978; 2:400–1.
Tatum WO, Zachariah SB. Gabapentin treatment of seizures Wallis WE, Donaldson I, Scott RS et al. Hypoglycemia
in acute intermittent porphyria. Neurology 1995; masquerading as cerebrovascular disease (hypoglycemic
45:1216–17. hemiplegia). Ann Neurol 1985; 18:510–12.
Thomas PK, Hollinrake K, Lascelles RG et al. The polyneuropathy of Walters RJ, Fox NC, Crum WR et al. Hemodialysis and cerebral
chronic renal failure. Brain 1971; 94:761–80. oedema. Nephron 2001; 87:143–7.
Thompson C, Dent J, Saxby P. Effect of thallium poisoning on Watson JN, Kiloh LG, Osselton JW et al. The electroencephalogram
intellectual function. Br J Psychiatry 1988; 153:396–9. in pernicious anemia and subacute combined degeneration of
Tokuomi H, Uchino M, Imamura S et al. Minamata disease the spinal cord. Electroencephalogr Clin Neurophysiol 1954;
(organic mercury poisoning): neuroradiologic and 6:45–64.
electrophysiologic studies. Neurology 1982; 32:1369–75. Weidauer S, Nichtweiss M, Lanfermann H et al. Wernicke
Torgovnik J, Arsura EL, Lala D. Cytomegalovirus encephalopathy: MR findings and clinical presentation.
ventriculoencephalitis presenting as Wernicke’s Eur Radiol 2003; 13:1001–9.
encephaloathy-like syndrome. Neurology 2000; 55:1910–13. Weisman DC, Yaari R, Hansn LA et al. Density of the brain, decline
Tomita I, Satoh H, Satoh A et al. Extrapontine myelinolysis of the mind. An atypical case of Fahr disease. Arch Neurol
presenting with parkinsonism as a sequel of rapid correction 2007; 64:756–7.
of hyponatremia. J Neurol Neurosurg Psychiatry 1997; Whitfield CL, Ch’ien LT, Whitehead JD. Lead encephalopathy in
62:422–3. adults. Am J Med 1972; 52:289–98.
Trautner RJ, Cummings JL, Read SL et al. Idiopathic basal ganglia Winkelman MD, Ricanti ES. Dialysis encephalopathy:
calcification and organic mood disorders. Am J Psychiatry neuropathologic aspects. Hum Pathol 1986; 17:82–33.
1988; 145:350–3. Wright DG, Laureno R, Victor M. Pontine and extrapontine
Tyler RH. Neurological complications of dialysis, transplantation myelinolysis. Brain 1979; 102:361–85.
and other forms of treatment in chronic uremia. Neurology Wszolek ZK, Baba Y, Mackenzie IR et al. Autosomal dominant
1965; 15:1081–8. dystonia-plus with cerebral calcifications. Neurology 2006;
Tyler RH. Neurologic disorders in renal failure. Am J Med 1968; 67:620–5.
44:734–48. Wu R-M, Chang Y-C, Chiu H-C. Acute triphenyltin intoxication: a
Ueki Y, Isozaki E, Miyazaki Y et al. Clinical and neuroradiological case report. J Neurol Neurosurg Psychiatry 1990; 53:356–7.
improvement in chronic acquired hepatocerebral degeneration Yamada M, Ohno S, Okayasu I et al. Chronic manganese
after branched-chain amino acid therapy. Acta Neurol Scand poisoning: a neuropathological study with determination of
2002; 106:113–16. managanese distribution in the brain. Acta Neuropathol 1986;
Victor M, Yakovlev PI. Korsakoff’s psychic disorder in conjunction 70:273–8.
with peripheral neuritis: a translation of Korsakoff’s original Yoshida S, Tajika T, Yamasaki N et al. Dialysis disequilibrium
article with brief comments on the author and his syndrome in neurosurgical patients. Neurosurgery 1987;
contribution to clinical medicine. Neurology 1955; 5:394–406. 20:716–21.
Victor M, Adams RD, Cole M. The acquired ‘non-Wilsonian’ type of Yoshida Y, Akanuma J, Tochikubo S et al. Slowly progressive
chronic hepatocerebral degeneration. Medicine 1965; dystonia following central pontine and extrapontine
44:345–96. myelinolysis. Intern Med 2000; 39:956–60.
Victor M, Adams RD, Collins GH. The Wernicke–Korsakoff Zaki I, Millard L. Pellagra complicated Crohn’s disease. Postgrad
syndrome. Oxford: Blackwell, 1971. Med J 1995; 71:496–7.
Vortmeyer AO, Hagel C, Laas R. Haemorrhagic thiamine deficient Zivin I. The neurological and psychiatric aspects of hypoglycemia.
encephalopathy following prolonged parenteral nutrition. Dis Nerv Syst 1970; 31:604–7.
J Neurol Neurosurg Psychiatry 1992; 55:826–9. Zuccoli G, Gallucci M, Capellades J et al. Wernicke
Wainwright AP, Kox WJ, House IM et al. Clinical features and encephalopathy: MR findings at clinical presentation in
therapy of acute thallium poisoning. Q J Med 1988; twenty-six alcoholic and non-alcoholic patients. AJNR 2007;
69:939–44. 28:1328–31.
14
Infectious and related disorders
14.1 Acquired immunodeficiency syndrome (AIDS) 493 14.13 Subacute measles encephalitis 506
14.2 Cytomegalovirus encephalitis 495 14.14 Progressive rubella panencephalitis 507
14.3 Progressive multifocal leukoencephalopathy 496 14.15 Neurosyphilis 508
14.4 Arbovirus meningoencephalitis 497 14.16 Lyme disease 510
14.5 Herpes simplex encephalitis 498 14.17 Tuberculosis 512
14.6 Encephalitis lethargica 499 14.18 Whipple’s disease 513
14.7 Infectious mononucleosis 500 14.19 Rocky mountain spotted fever 514
14.8 Mumps 501 14.20 Malaria 514
14.9 Varicella-zoster 502 14.21 Toxoplasmosis 515
14.10 Rabies 503 14.22 Fungal infections 516
14.11 Acute disseminated encephalomyelitis 504 References 516
14.12 Subacute sclerosing panencephalitis 506
14.1 ACQUIRED IMMUNODEFICIENCY et al. 1986a; Price et al. 1988), the dementia is of subacute
SYNDROME (AIDS) or gradual onset and is characterized by apathy, poor con-
centration, and forgetfulness; in some cases there may be
AIDS may affect the nervous system in a variety of ways. agitation, delusions, and visual hallucinations. Accompany-
Cerebral involvement may manifest with an early mononu- ing the dementia one often sees dysarthria, ataxia, and long-
cleosis-like syndrome, and, later, with dementia or seizures; tract signs, such as hyper-reflexia and Babinski signs; in
there may also be a myelopathy with paraparesis and one case, the dementia was accompanied by chorea (Pardo
a peripheral sensorimotor polyneuropathy. Fatigue and et al. 1998). With progression, there may be muteness, con-
depression are also common, and, rarely, mania may be seen. fusion, seizures, and myoclonus (Maher et al. 1997).
Seizures occur in a small minority of patients (Pascual-
Sedano et al. 1999; Wong et al. 1990), and these may be
Clinical features due to human immunodeficiency virus (HIV) infection
itself or to opportunistic infections (e.g., toxoplasmosis) or
Although nervous system involvement, such as AIDS metabolic abnormalities (e.g., hypomagnesemia or hypocal-
dementia, may rarely be the presenting symptom of AIDS cemia). Although grand mal seizures are most common, both
(Navia and Price 1987), in most cases patients already have simple partial and complex partial seizures may also occur.
other evidence of the illness, such as generalized lymph- The spinal cord may be affected by a vacuolar myelopa-
adenopathy, constitutional symptoms, thrush, diarrhea, thy (Navia et al. 1986b; Sharer et al. 1986), with paraparesis
shingles, cytopenia (including thrombocytopenia) Kaposi’s and sensory ataxia; within the peripheral nervous system
sarcoma, and Pneumocystis pneumonia. there may be a sensorimotor polyneuropathy (de la Monte
Early on in the infection, often concurrent with sero- et al. 1988; Morgello et al. 2004), which may be quite painful.
conversion, patients may develop a mononucleosis-like Fatigue is common in AIDS and may be debilitating.
syndrome, which may be accompanied by an aseptic menin- Depression is likewise common; however, it is unclear
gitis. Cranial nerve palsies, particularly affecting the fifth, whether this syndrome occurs as a direct effect of central
seventh, and eighth nerves, may accompany the meningi- nervous system involvement or rather reflects other fac-
tis, and there may rarely also be an encephalitis with delir- tors. Mania, although rare in AIDS, may, by contrast, occur
ium (McArthur 1987; Malouf et al. 1990). directly as a result of the infection (Kieburtz et al. 1991).
AIDS dementia typically appears about 10 years after Serologic testing generally becomes positive within
the initial infection, generally only when the CD4⫹ count 2–12 weeks of the initial infection and is inevitably positive
has fallen below 200 cells/mm3 Clinically speaking (Navia by 6 months; thus, in patients with AIDS dementia, the
p 14.qxd 3/10/08 9:50 AM Page 494
494 Infectious and related disorders
transfusion-related transmission is now becoming quite

rare, but blood-borne transmission remains a significant
problem among intravenous drug users who fail to sterilize
their needles. Although the virus is also found in saliva,
urine, and tears, there is as yet no convincing evidence that
it can be spread by these.
HIV gains attachment to cells such as lymphocytes,
monocytes, and macrophages by virtue of the CD4 mole-
cule found on the cell membrane (Pantaleo et al. 1993).
Once inside the cell, the enzyme reverse transcriptase cat-
alyzes the reverse transcription of genomic viral RNA into
DNA, which eventually becomes inserted into the chromo-
somes of the host cell. With cell activation, this inserted
DNA is copied, which is eventually followed by the pro-
duction of mature HIV virus particles.
Subsequent to infection there is an intense viremia
followed by a vigorous cellular and humoral immune
response, such that, in most cases, the viremia is substan-
tially contained within about 3 months. The virus, how-
ever, is not eradicated but rather continues to reproduce
within lymphoid tissue. Tragically, the cell most likely to be
Figure 14.1 This T2-weighted magnetic resonance imaging
infected is the CD4⫹ T-lymphocyte, with the result that,
scan shows both patchy and confluent areas of increased signal
over many years, there is a gradual loss of these ‘helper’
intensity in the centrum semiovale of a patient with AIDS
lymphocytes and the body’s defenses are subverted to the
dementia. (Reproduced from Gillespie and Jackson 2000.)
point at which a significant viremia again occurs. In addi-
tion, with the loss of these CD4⫹ helper lymphocytes,
enzyme-linked immunosorbent assay (ELISA) test will be opportunistic infections begin to appear.
positive, as will the confirmatory Western blot test. It is not entirely clear how HIV gains entry into the cen-
Magnetic resonance imaging (MRI) in AIDS dementia tral nervous system. One theory holds that free viruses pass
generally reveals a degree of cortical atrophy and ventricu- directly through a disrupted blood–brain barrier; another,
lar dilation, and there may also be multiple areas, some con- known as the ‘Trojan horse’ theory, suggests that infected
fluent, of increased signal intensity in the centrum semiovale peripheral monocytes carry the virus with them as they
on T2-weighted scans (Dooneief et al. 1992; Navia et al. cross the blood–brain barrier. Although at autopsy approx-
1986a), as illustrated in Figure 14.1. imately 90 percent of patients have evidence of HIV within
The cerebrospinal fluid (CSF) in AIDS dementia gener- the central nervous system, the frequency of AIDS demen-
ally displays a mild mononuclear pleocytosis, a mildly tia is not as high, ranging from 15 percent (McArthur et al.
elevated total protein level, an increased IgG index, and 1993) to 65 percent (Navia et al. 1986a). Once inside the
oligoclonal bands. central nervous system HIV is found primarily in mono-
cytes, macrophages, and microglia: although astrocytes
and neurons may also be infected, this is far less promi-
Course nent. In cases of AIDS dementia, the primary pathologic
changes include diffuse myelin pallor (in some cases with
In the natural course of events, AIDS dementia is relent-
vacuolization), scattered microglial nodules, and multinu-
lessly progressive, and death usually occurs within 3–6
cleated giant cells (Glass et al. 1993; Gray et al. 1988; Navia
months (Bouwman et al. 1998).
et al. 1986b); there may also be a relatively minor degree of
neuronal loss within the cerebral cortex (Wiley et al. 1991).
Etiology Of note, in patients with AIDS dementia, definite micro-
scopic pathology may be lacking, and it is hypothesized
AIDS is caused by infection with HIV. This RNA virus that the dementia in these cases, and perhaps also in those
is found in blood, semen, vaginal fluid, breast milk, and with definite pathology, results from the toxic effects of
colostrum, and may be spread via all these fluids. In cytokines released by inflammatory cells (Glass et al. 1993).
the United States, spread occurs most commonly with
homosexual contact, in particular anal intercourse; how-
ever, as the virus spreads among females, it is likely that the Differential diagnosis
most common mode of transmission in the United States
will eventually become heterosexual contact, as is the case Opportunistic central nervous system infections are very
in Africa. With improved screening of blood products, common and may cause dementia, delirium, focal signs, or
p 14.qxd 3/10/08 9:50 AM Page 495
14.2 Cytomegalovirus encephalitis 495
seizures. These include toxoplasmosis, cytomegalovirus intravenous drug users, if unable to stop, should
(CMV) encephalitis, progressive multifocal leukoen- be instructed to sterilize their needles with household
cephalopathy, mycoses (e.g., candidiasis), tuberculosis, bleach. Blood and organ donation are prohibited, as is
varicella-zoster encephalitis or vasculopathy, herpes sim- breastfeeding.
plex encephalitis, and neurosyphilis. With regard to the
possibility of neurosyphilis, it must be kept in mind that,
in patients with AIDS, treatment of primary syphilis with 14.2 CYTOMEGALOVIRUS ENCEPHALITIS
benzathine penicillin may not prevent the development of
neurosyphilis. Primary central nervous system lymphoma The great majority of adults show evidence of prior infec-
(Hochberg and Miller 1988) and, rarely, Kaposi’s sarcoma tion with cytomegalovirus (CMV), and in immunocom-
may also appear as space-occupying lesions. promised patients, for example those with AIDS or those
For unclear reasons, vitamin B12 deficiency is not uncom- undergoing transplantation, the virus may reactivate and,
mon in patients with AIDS (Herzlich and Schiano 1993), among other syndromes, produce a delirium. Autopsy
and as it may produce a dementia or a spinal cord syn- studies have demonstrated evidence of CMV infection of
drome similar to that of vacuolar myelopathy it should the central nervous system in approximately one-third of
always be checked for (Beach et al. 1992). patients with AIDS, making it one of the most common
Concurrent drug addiction (e.g., to cocaine) and alco- opportunistic infections seen in this condition (Vintners
holism are also common, and these must be attended to. et al. 1989).
With regard to alcoholism, special attention must be paid
to such alcohol-related disorders as Wernicke’s encephalopa-
thy and alcoholic dementia.
Clinical features
Treatment The delirium typically presents subacutely and is of vari-

able severity (Berman and Kim 1994; Holland et al. 1994);
The advent of highly active antiretroviral treatment in some cases, however, the onset may be fulminant
(HAART) has revolutionized the treatment of AIDS, and and the delirium quite severe, and in such cases there are
may lead to stabilization or improvement of its central often signs of brainstem involvement, such as nystagmus,
nervous system manifestations. Given the complex and ophthalmoplegia, and ataxia (Kalayjian et al. 1993;
rapidly evolving nature of antiretroviral treatment, referral Torgovnik et al. 2000). Some patients may also have cord
to a specialist is always essential. involvement or a peripheral neuropathy.
The general treatment of dementia is discussed in In most cases, immunocompromised patients with CMV
Section 5.1 In addition to the measures noted there, there encephalitis will also have evidence of systemic infection,
is some evidence that selegiline may improve cognitive such as retinitis, esophagitis, gastritis, colitis, hepatitis,
performance (Dana Consortium 1998); a dose no higher and, importantly, adrenalitis, which may cause adrenocor-
than 10 mg should be used to avoid the risk of a hyperten- tical insufficiency.
sive crisis. If antipsychotics are required, either for the In most cases the CD4⫹ count is below 100 cells/mm3.
dementia or for delirium, low doses are used as patients T2-weighted or fluid-attenuated inversion recovery
with AIDS seem particularly likely to develop extrapyrami- (FLAIR) MR scanning may reveal patchy, confluent areas
dal side-effects (Hriso et al. 1991); in this regard, second- of increased signal intensity both in the centrum semiovale
generation agents, such as quetiapine or risperidone, are and in a periventricular distribution.
preferable to the first-generation agents such as haloperi- The CSF may be normal or may display a mild lym-
dol. Anti-epileptic drugs may be used for seizures; although phocytic pleocytosis and a mildly elevated total protein.
phenytoin is often used, side-effects may dictate one of the Polymerase chain reaction (PCR) assay for CMV will gen-
other agents discussed in Section 7.3. Painful peripheral erally be positive.
neuropathy may respond to gabapentin (Hahn et al. 2004), Before leaving this section on clinical features, it is
lamotrigine (Simpson et al. 2003), or smoked cannabis appropriate to note that CMV infection of the central nerv-
(Abrams et al. 2007), but amitriptyline does not appear to ous system may rarely occur in immunocompetent adults.
be effective (Kieburtz et al. 1998). Fatigue may respond to In such cases there may be either a meningitis (Causey
treatment with methylphenidate (Breitbart et al. 2001); 1976) or an encephalitis (Studahl et al. 1994), occurring in
however, this should not be given to patients who might the context of a mononucleosis-like syndrome.
abuse it. Depression may be treated with antidepressants
such as fluoxetine (Rabkin et al. 1999).
All patients should be reminded to practice ‘safe sex’, Course
with an emphasis on latex condoms and the use of
nonoxynol-9 spermicide. Patients should also be reminded In severe cases of fulminant onset, death may occur within
that AIDS may be spread via fellatio and cunnilingus. All weeks or months.
p 14.qxd 3/10/08 9:50 AM Page 496
Etiology secondary to brainstem involvement (Kastrup et al. 2002),

and dystonia (Factor et al. 2003), chorea (Piccolo et al. 1999),
In most cases there are widespread microglial nodules and or parkinsonism (Bhatia et al. 1996).
inclusion-positive cytomegalic cells (Morgello et al. 1987); The electroencephalogram (EEG) may show diffuse or
in those cases characterized by a fulminant delirium there focal slowing.
is marked periventricular inflammation, with, in some Magnetic resonance scanning (Guilleux et al. 1986; Kuker
cases, necrotic changes (Berman and Kim 1994; Kalayjian et al. 2006) will reveal one or more focal lesions, generally
et al. 1993). in the subcortical white matter. On T1-weighted imaging
these display decreased signal intensity, and on FLAIR
or T2-weighted imaging, increased signal intensity is
Differential diagnosis seen. Diffusion-weighted imaging may demonstrate mild
increased signal intensity in some cases and, again, in some
Both AIDS dementia and other opportunistic infections cases there may be enhancement with gadolinium (Huang
must be considered; fulminant cases with brainstem signs et al. 2007).
may mimic Wernicke’s encephalopathy. The CSF, although characteristically normal, may occa-
sionally reveal a mild lymphocytic pleocytosis. The PCR
assay for JC virus is generally, but not always, positive
Treatment (Hensen et al. 1991; Koralnik et al. 1999). Serum testing for
antibodies to JC virus is not helpful, given, as noted below,
The general treatment of dementia and delirium are dis- that most adults will be positive. In doubtful cases brain
cussed in Sections 5.1 and 5.3 respectively. Ganciclovir and biospy may be required.
foscarnet are typically prescribed; however, in some cases
CMV encephalitis has occurred despite ongoing treatment
with these agents (Berman and Kim 1994). Course
In the natural course of events the disease is generally

14.3 PROGRESSIVE MULTIFOCAL relentlessly progressive, with death occurring after about 4
LEUKOENCEPHALOPATHY months on average. Rarely the course may stretch out for
years, and even more rarely there may be spontaneous
Progressive multifocal leukoencephalopathy occurs sec- remissions (Price et al. 1983).
ondary to an opportunistic infection of the central nervous
system by the JC virus (Padgett et al. 1971). Multifocal areas
of demyelinization occur, producing various focal signs Etiology
and, in some, a dementia. In almost all cases patients have
depressed cell-mediated immunity, most commonly due Approximately 80 percent of the adult population of
to AIDS, in which 2–5 percent of patients are afflicted. the United States has latent infection with the JC virus.
In a very small minority of patients with depressed cell-
mediated immunity, this virus reactivates and spreads to
Clinical features the brain. Although by far the most common cause of
immunoincompetence in these patients is AIDS, progres-
The onset is typically subacute, generally over approxi- sive multifocal leukoencephalopathy has also been noted
mately 2 weeks. In most cases, patients present with a slowly in patients with Hodgkin’s disease, other lymphomas,
progressive focal sign, such as hemianopia, aphasia, apraxia, leukemia, other cancers, tuberculosis, sarcoidosis, systemic
hemisensory loss, or hemiplegia (Astrom et al. 1958; Krupp lupus erythematosus (Krupp et al. 1985), and in patients
et al. 1985; Richardson 1961); rarer focal findings such undergoing therapeutic immunosuppression after trans-
as Balint’s syndrome (Ayuso-Peralta et al. 1994) have plantation (Sponzilli et al. 1975). Progressive multifocal
also been reported. Over time, these initially unilateral leukoencephalopathy may also, albeit rarely, occur in
deficits become bilateral, and many patients then go on patients treated with natalizumab (Yousry et al. 2006).
to develop a personality change, a dementia or, rarely, a Finally, it also appears that, very rarely, progressive multi-
delirium. Seizures may occur in up to 20 percent of patients focal leukoencephalopathy may occur in otherwise healthy
and may be simple partial, complex partial, or grand mal individuals (Fermaglich et al. 1970; Guillaume et al. 2000).
(Lima et al. 2006; Moulignier et al. 1995). Rarely, progres- Within the central nervous system, oligodendrocytes
sive multifocal leukoencephalopathy may present with a and, to a lesser degree, astrocytes are infected by the JC
dementia (Sellal et al. 1996; Zunt et al. 1997), delirium virus. With destruction of oligodendrocytes, demyeliniza-
(Davies et al. 1973), or personality change (Astrom et al. tion with only relative axonal sparing occurs, and foci of
1958). Cerebellar signs may occur but are not common demyelinization begin to appear. Within and surrounding
(Parr et al. 1979). Other rare signs include quadriparesis these foci there is a variable, and typically quite slight,
p 14.qxd 3/10/08 9:50 AM Page 497
14.4 Arbovirus meningoencephalitis 497
degree of inflammation. At least initially, these foci are The peripheral white blood cell count is typically
generally few in number and confined to one hemisphere; elevated.
most commonly they are seen in the subcortical white mat- Magnetic resonance scanning may be normal early on;
ter and the centrum semiovale; however, rarely they may however, eventually both T2-weighted and FLAIR imaging
be prominent in the cerebellar white matter or the brain- will reveal areas of increased signal intensity, which may be
stem. Over time, the foci increase in size and number, and seen in the thalami, basal ganglia, and the cortex.
bilateral involvement occurs. The CSF may be under increased pressure. The white
blood cell count is typically increased. Early on, polymor-
phonuclear cells may predominate; however, over time the
Differential diagnosis pleocytosis becomes lymphocytic. The total protein is
increased but the glucose is normal. Both PCR assay and
In patients with AIDS, consideration must be given to assays for specific IgM antibodies are available for all of the
AIDS dementia and to other opportunistic infections, such arboviruses.
as CMV or toxoplasmosis, and to primary central nervous The EEG typically shows generalized slowing, at times
system lymphoma. with focal predominances; in some cases interictal epilepti-
form discharges may be present.
Treatment
No specific treatment is available. In patients with AIDS it Course

is clear that treatment with HAART slows the progression
of the disease. The general treatment of dementia is dis- The mortality rate varies from as little as 1 percent for La
cussed in Section 5.1. Crosse virus to close to 50 percent for eastern equine
encephalitis. For those who survive, the encephalitis tends
to run its course within a matter of a few weeks, sometimes
14.4 ARBOVIRUS MENINGOENCEPHALITIS longer. A minority of patients will be left with sequelae,
such as dementia, personality change, or a persistence of
Viruses transmitted by arthropods are known as arboviruses, any focal signs or abnormal movements seen during the
a term derived from the fact that they are all arthropod borne. acute illness (Herzon et al. 1957; Przelomski et al. 1988;
In North America, there are seven arboviruses known to Smardel et al. 1958); in this regard, post-encephalitic parkin-
cause meningoencephalitis, including six mosquito-borne sonism has been noted after western equine encephalitis
viruses (eastern equine, western equine, Venezualan, (Mulder et al. 1951; Schultz et al. 1977) and dementia after
St. Louis, La Crosse, and the newest member, West Nile) Japanese encephalitis (Solomon et al. 2002), which, in some
and one tick-borne virus (Powassan virus). Most cases cases, may have prominent psychotic symptoms (Richter
occur in the late summer and early fall, when mosquitoes and Shimojyo 1961).
are most active. Mention should also be made of Japanese
encephalitis, which, although not endemic in North
America, is a very common cause of meningoencephalitis Etiology
in the Far East (Lewis et al. 1947; Solomon et al. 2000,
2002) and may be contracted by travellers there. After the mosquito or tick bite, hematogenous spread car-
ries the virus to the brain. Although the severity of the
Clinical features pathologic changes varies widely depending on the respon-
sible virus, in general one finds widespread perivascular
The onset is typically acute, over a matter of days or, excep- inflammation and areas of focal cerebritis in the lep-
tionally, merely hours. Patients present with delirium, tomeninges, cortical gray matter, cerebral white matter,
fever, and, typically, meningeal signs such as headache, stiff subcortical gray structures, and, in some cases, brainstem.
neck, and photophobia. Seizures, focal signs, and abnor- At times, thrombus formation may occur in the vessels
mal movements may or may not occur, and some patients involved, with infarction (Leech and Harris 1977; Reyes
may develop a syndrome of inappropriate antidiuretic et al. 1981).
hormone (ADH) secretion. Patients may progress to stu-
por or coma. Although distinguishing among the various
pathogens on clinical grounds is difficult, some features Differential diagnosis
may be helpful: St. Louis encephalitis may be marked by a
coarse tremor (Wasay et al. 2000); West Nile encephalitis As discussed in Section 7.6, arboviral meningoencephalitis
by a rash, flaccid paralysis, and cranial nerve palsies (Davis represents just one cause of acute encephalitis, and the
et al. 2006); and Japanese virus by parkinsonism (Pradhan reader is directed to that section for a discussion of the dif-
et al. 1999) or dystonia (Kalita and Misra 2000). ferential possibilities.
p 14.qxd 3/10/08 9:50 AM Page 498
Treatment
There is no specific treatment. In many cases, aggressive
supportive care is required and osmotic agents may be
indicated to lower intracranial pressure. Some authors rec-
ommend prophylactic use of anti-epileptic drugs such as
phenytoin or fosphenytoin. The routine treatment of delir-
ium is discussed in Section 5.3.
A vaccine is available for Japanese encephalitis, and
travellers may wish to consider this.
14.5 HERPES SIMPLEX ENCEPHALITIS
Although herpes simplex infection accounts for only about

one-tenth of all cases of acute encephalitis, it is by far the
most common cause of sporadic encephalitis and, given its
treatability, it should be strongly considered in the differ-
ential of any adult suspected of having acute encephalitis.
Clinical features Figure 14.2 This T2-weighted magnetic resonance imaging

scan shows increased signal intensity in the left temporal lobe
Herpes simplex encephalitis can occur at any age but most (especially its medial aspect) of a patient with herpes simplex
patients are middle-aged or older (Koskiniemi et al. 1996). encephalitis. (Reproduced from Gillespie and Jackson 2000.)
The onset itself generally spans several days; however,
the range is wide, from explosive onsets over several hours
to gradual ones lasting weeks or more. In some cases the periodic complexes; with progression of the disease, bilat-
onset may be preceded be a prodrome, lasting several days, eral involvement may be seen.
of malaise, headache, irritability, and mild fever. Polymerase chain reaction assay of the CSF (Aurelius
Typically (Kennedy 1988; Marton et al. 1996; McGrath et al. 1991) is almost 100 percent sensitive for herpes sim-
et al. 1997; Whitley et al. 1986; Williams and Lerner 1978), plex DNA and is the diagnostic procedure of choice. The
patients present with fever, headache, and delirium. In this CSF itself may be normal during the first few days but will
setting a majority of patients will also develop focal signs, in most cases show an elevated total protein with a lymph-
such as hemiparesis or aphasia, and approximately two- ocytic and polymorphonuclear pleocytosis; red cells may
thirds will have seizures, which may be either complex par- also be present, reflecting the hemorrhagic nature of the
tial or grand mal in type. Although meningeal signs, such as inflammatory process. Although the glucose level is typi-
a stiff neck or photophobia, are common, they are generally cally normal, it may rarely be reduced.
not at all severe. Notably, bizarre behavior is common and, If lumbar puncture is not possible, brain biopsy may be
although this usually occurs in the context of the delirium, necessary to make a definitive diagnosis; however, as noted
there are rare reports of the encephalitis presenting with below, treatment rarely waits upon such a procedure.
either mania (Fisher 1996) or a psychosis (Wilson 1976).
Untreated, coma develops in about one-third of patients.
Computed tomographic (CT) scanning may show radi- Course
olucent areas in the medial aspects of one or both temporal
lobes, but it may be normal for up to a week. Magnetic res- Untreated, over 50 percent of patients will die in days or a
onance scanning is much more sensitive, showing increased few weeks. In those who survive, the clinical picture usually
signal intensity on FLAIR or T2-weighted scans in the stabilizes in a matter of weeks; exceptionally the acute ill-
medial temporal lobe (Figure 14.2), although this too may ness may be prolonged for months (Sage et al. 1985) or
be normal for the first few days. Diffusion-weighted imag- even longer (Yamada et al. 2003).
ing may show increased signal intensity in the same areas, Although most patients have only one episode, recur-
and this abnormality may be evident earlier than that seen rences may appear in a small minority.
on T2-weighted or FLAIR imaging. Gadolinium enhance- Among those who do survive, the vast majority will be
ment may also occur. left with significant sequelae, most commonly a chronic
The EEG (Upton and Gumpert 1970) is usually normal amnestic syndrome (Hokkanen et al. 1996; Kapur et al. 1994;
for the first few days but will eventually show delta slowing Young et al. 1992), dementia (Hokkanen et al. 1996; McGrath
in one temporal area, which may be accompanied by et al. 1997), or a personality change (Caparros-Lefebvre
p 14.qxd 3/10/08 9:50 AM Page 499
14.6 Encephalitis lethargica 499
et al. 1996). Other sequelae include focal signs (e.g., aphasia on. Polymerase chain reaction assay of the CSF for herpes
or hemiplegia) (McGrath et al. 1997) or epilepsy (McGrath simplex DNA is critical and should be promptly performed.
et al. 1997); rarely there may be a Kluver–Bucy syndrome In instances in which a reliable differential between herpes
(Greenwood et al. 1983; Lilly et al. 1983; Marlowe et al. simplex encephalitis and other encephalitides cannot be
1975). There is also a case report in which complex motor made, either because MRI findings are equivocal or lumbar
and vocal tics occurred as a sequela (Northam and Singer puncture cannot be performed, most clinicians will make a
1991). presumptive diagnosis of herpes simplex encephalitis and
treat the patient accordingly. Given that herpes simplex
encephalitis is treatable whereas the other viral encephali-
Etiology tides are not, and given the generally benign side-effect pro-
file of acyclovir, such a course is justifiable.
There are two types of herpes simplex virus: type 1 and In those rare cases in which the presentation is with
type 2. Type 1 virus usually causes orolabial infections and mania or a psychosis, the differential is wide, as discussed
type 2 virus generally causes genital infections. Although in Sections 6.3 and 7.1 respectively; however, the eventual
the vast majority of cases of herpes simplex encephalitis are development of fever, headache, and delirium will settle
caused by type 1 virus, type 2 virus may be at fault in a the issue.
small minority (Koskiniemi et al. 1996). The majority of
the adult population has at some time been infected with
herpes simplex type 1, and the virus may remain in a latent Treatment
state in various sites, including the trigeminal ganglion
(Baringer and Swoveland 1973). In addition to aggressive supportive care, patients should
Although it is known that the virus can undergo retro- be treated with acyclovir using a dose of 10 mg/kg intra-
grade axonal transport, it is not clear precisely how the venously every 8 hours for a course of 2–3 weeks. It also
virus gains entry into the central nervous system. One the- appears that concurrent treatment with dexamethasone or
ory suggests that, after the reactivation of a latent infection methylprednisolone will enhance recovery (Kamei et al.
in the trigeminal ganglion, the virus undergoes transport 2005). Seizures may be treated with a standard anti-epileptic
through the ophthalmic division of the trigeminal nerve to drug, such as phenytoin or fosphenytoin, and it is prudent
the olfactory mucosa, where it gains access to the olfactory to continue treatment with an anti-epileptic until the
filia and undergoes retrograde transport through the olfac- patient has been seizure free for at least a year. The general
tory nerve and then to the temporal lobes; another holds treatment of delirium is further discussed in Section 5.3.
that, after reactivation in the trigeminal ganglion, the virus
spreads along sensory fibers to the meninges of the middle
and anterior fossae where it then gains entry. 14.6 ENCEPHALITIS LETHARGICA
Pathologically (Adams and Miller 1973; Esiri 1982) there
is intense inflammation (which may progress to hemor- Encephalitis lethargica, also known as von Economo’s dis-
rhagic necrosis) affecting initially the medial portions of ease or European sleeping sickness, was first described by
the temporal lobe, with, in most cases, eventual spread to Baron Constantin von Economo at a meeting of the
other areas, including the lateral aspects of the temporal Vienna Psychiatric Society in April 1917 (Dickman 2001;
lobe, the insula, inferior portions of the frontal lobes, and Wilkins and Brody 1968). This disease swept the world in
the cingulate cortex. Although involvement is typically an epidemic that lasted from 1917 to 1928 and, although
unilateral early on, with time both temporal lobes become there have been no further epidemics, sporadic cases
involved. There may be substantial edema, and both uncal still occur (Dale et al. 2004; Howard and Lees 1987), mak-
and subfalcine herniation may occur. In those who survive, ing a familiarity with this disease of more than academic
scarring, cavitation, and cystic change is seen in the interest.
involved areas.
Clinical features
Acute encephalitis lethargica (Hohman 1921; Kirby and
A delirium accompanied by headache and fever immedi- Davis 1921) is characterized by headache, fever, sleep rever-
ately suggests the diagnosis of an acute encephalitis, and, as sal (nocturnal wakefulness and diurnal somnolence), delir-
discussed in Section 7.6, consideration must be given not ium, various oculomotor pareses, and, classically, oculogyric
only to herpes simplex encephalitis but also to various other crises; some patients also displayed euphoria or psychosis
encephalitides, for example arboviral infections. Magnetic (Kirby and Davis 1921; Meninger 1926; Sands 1928), or stu-
resonance scanning is helpful here as medial temporal lobe porous catatonia (Bond 1920; Shill and Stacy 2000).
involvement strongly suggests herpes simplex encephalitis; The CSF may be normal or may reveal a lymphocytic
however, as noted above, MR findings may be normal early pleocytosis and an elevated total protein; oligoclonal
p 14.qxd 3/10/08 9:50 AM Page 500
bands may also be present (Dale et al. 2004; Howard and assault having been triggered by a preceding viral or bacte-
Lees 1987). rial pharyngitis (Dale et al. 2004).
Course Differential diagnosis
The mortality rate for acute encephalitis was about 25 per- Encephalitis lethargica must be distinguished from other
cent; among those who survived, the encephalitis gradually acute encephalitides, as discussed in Section 7.6. One clue
cleared over about a month. Of great importance, neu- here is the presence of sleep reversal and, especially, oculo-
ropsychiatric sequelae, most notably post-encephalitic gyric crises, which are very rare in other cases of acute viral
parkinsonism, occurred in the majority of cases. encephalitis.
Post-encephalitic parkinsonism occurred in over 50 With regard to sequelae, the diagnosis is fairly straight-
percent of survivors after a latent interval of from 1 to over forward when they are present immediately after resolu-
20 years (Duvoisin and Yahr 1965). Patients gradually tion of the acute syndrome. Difficulty, however, may arise
developed a syndrome similar to that seen in idiopathic when, as in the case of post-encephalitic parkinsonism,
Parkinson’s disease (Rail et al. 1981). In addition, other there is a prolonged latent interval between the encephalitis
motor abnormalities, including dystonia, blepharospasm and the onset of the parkinsonism. In such cases, the pres-
(Alpers and Patten 1927), and, most importantly, oculo- ence of oculogyric crises is again an important clue.
gyric crises (Taylor and McDonald 1928), were often pres-
ent. Interestingly, these transient oculogyric crises could
also be accompanied by classic obsessions or compulsions Treatment
(Jelliffee 1929); in some cases, palilalia (Van Bogaert 1934)
or agitation and excitation (McCowan et al. 1928) were In addition to routine supportive care, consideration may
noted to accompany the oculogyric crises. Oculogyric be given to corticosteroids.
crises, although most commonly seen in conjunction with
post-encephalitic parkinsonism, at times occurred inde-
pendently (McCowan et al. 1928). 14.7 INFECTIOUS MONONUCLEOSIS
Other sequelae, seen in a minority, included dementia,
narcoleptic and cataplectic attacks (Adie 1926; Fournier In up to a little over 5 percent of cases of infectious mono-
and Helguera 1934), and, in children, restlessness and inat- nucleosis (Gautier-Smith 1965), the central or peripheral
tentiveness (Hohman 1922). nervous system may be involved, producing, variously,
delirium, seizures, meningismus, ataxia, a cord syndrome,
or a cranial or peripheral neuropathy.
Etiology
Autopsies of those dying in the acute stage revealed inflam- Clinical features
mation with a perivascular accumulation of lymphocytes
and plasma cells in the midbrain, basal ganglia, and cortex Although mononucleosis may occur in adults (Fujimoto
(Buzzard and Greenfield 1919; Howard and Lees 1987). In et al. 2003), it is most commonly seen in children or ado-
those with sequelae, autopsy studies (Geddes et al. 1993; lescents. Typically there is a prodrome, lasting for 1–2
Ishii and Nakamura 1981; Rail et al. 1981) have revealed weeks, of fatigue, malaise, and headache, after which one
neuronal loss, gliosis, and, in the remaining neurons, neuro- sees the classic development of sore throat, fever, and cer-
fibrillary tangles similar to those seen in Alzheimer’s dis- vical adenopathy; splenomegaly and hepatomegaly may
ease, in the substantia nigra, locus ceruleus, hippocampus, also occur.
basal ganglia, thalamus, and cerebral cortex. Macroscopi- Although nervous system involvement generally occurs
cally, there was cortical atrophy and depigmentation of the in the context of this typical clinical picture, at times it may
substantia nigra and locus ceruleus. be the presenting feature of the disease. Meningism with stiff
Given that the pandemic of encephalitis lethargica coin- neck is the most common manifestation, followed by delir-
cided with the Spanish influenza epidemic, it was long sus- ium (Bergin 1960; Schlesinger and Crelinsten 1977; Schnell
pected that encephalitis lethargica was secondary to et al. 1966; Tselis et al. 1997). Seizures may occur (Doja et al.
influenza. Recent work on archived specimens, however, 2006; Freedman et al. 1953; Silverstein et al. 1972) and status
failed to find any evidence of influenza RNA (McCall et al. epilepticus has been reported (Russell et al. 1985). Other fea-
2001), and consideration is now being given to the possi- tures include acute cerebellar ataxia (Gautier-Smith 1965;
bility that encephalitis lethargica, rather than resulting Leavell et al. 1986), a transverse myelitis, a cranial neuro-
directly from a viral infection, may represent an autoim- pathy (with either a unilateral or bilateral Bell’s palsy), and a
mune disease with antibodies directed at the midbrain, primarily motor peripheral polyneuropathy that may
basal ganglia, and other structures, with the autoimmune resemble the Guillan–Barré syndrome.
p 14.qxd 3/10/08 9:50 AM Page 501
14.8 Mumps 501
In most cases there is a lymphocytosis with atypical quite rare in developed countries; although overall mumps
lymphocytes, and the ‘monospot’ test will be positive in is equally common in males and females, males are far
over 90 percent of cases. When the diagnosis remains in more likely to develop symptomatology reflecting infec-
doubt, one may also test for IgM anti-viral capsid antigen tion of the central nervous system.
(anti-VCA) and anti-early antigen (anti-EA). In cases of
central nervous system involvement, PCR assay of the CSF
for Epstein–Barr virus DNA may be positive (Tselis et al. Clinical features
1997). The anti-nuclear antibody (ANA) test and Venereal
Disease Research Laboratories (VDRL) test may tran- Mumps typically occurs in children or adolescents, gener-
siently be falsely positive. ally during the winter or spring, and presents with a pro-
In delirious patients the EEG may show generalized drome of fever, myalgia, and malaise, followed within 1–7
slowing (Doja et al. 2006), with, rarely, periodic complexes days by the typical parotitis; males may also develop a uni-
(Greenberg et al. 1982). lateral or bilateral orchitis.
Meningitis manifests with headache, drowsiness, and a
stiff neck, and typically follows the parotitis after a latency
Course of from 2 to 20 days; occasionally the meningitis will pre-
cede the parotitis (Levitt et al. 1970) and rarely parotitis
Symptoms typically resolve after about a month. Although may be absent.
most patients recover completely, a minority will be left Encephalitis presents with an increasing fever and either
with persistent fatigue (Petersen et al. 2006) or sleepiness delirium or stupor; seizures, ataxia, and various focal signs
(Guilleminault and Mondini 1986). may also occur (Azimi et al. 1969; Bistrian et al. 1972;
Finklestein 1938; Koskiniemi et al. 1983; Levitt et al. 1970).
Serum anti-mumps IgM antibody is present acutely,
Etiology and acute and convalescent serum IgG antibody displays a
fourfold or greater rise. The CSF usually shows a lympho-
Infectious mononucleosis is caused by the Epstein–Barr cytic pleocytosis and an elevated protein, and the mumps-
virus (Epstein and Achong 1977) and is transmitted prima- specific IgG index is generally increased; mumps virus
rily via oral secretions passed during intimate contact such RNA may also be detected via PCR assay.
as kissing. The virus gains access to the bloodstream and
infects lymphocytes, spreading later to various other
organs, including the brain. Scarce autopsy reports have
Course
revealed a widespread lymphocytic or monocytic inflam-
Overall, mumps usually runs its course in 3–4 weeks, and
mation of the cerebrum (Roulet Perez et al. 1993; Sworn
meningitis or encephalitis typically resolve after a week or
and Urich 1970).
two. Rarely, it appears that the encephalitis may remain
chronic (Vaheri et al. 1982).
Although most recover from meningitis or encephalitis
Differential diagnosis without sequelae, some post-encephalitic patients may be
left with chronic cognitive deficits, ataxia, seizures or deaf-
A similar syndrome may occur during seroconversion in
ness; rarely hydrocephalus, secondary to aqueductal steno-
HIV infection.
sis (Thompson 1979), may occur.
Treatment Etiology
At present, treatment is supportive; there is no good evi- The mumps virus is spread via the respiratory route and is
dence for the effectiveness of antiviral medications or trophic for salivary glands, gonads, and the nervous sys-
corticosteroids. tem. Within the meninges and cerebrum there may be a
widespread perivascular lymphocytic and mononuclear
inflammation.
14.8 MUMPS
Although over 50 percent of patients with mumps will have Differential diagnosis
a CSF pleocytosis (Russell and Donald 1958), only a
minority will have clinical evidence of central nervous sys- Mumps encephalitis must be distinguished from other acute
tem involvement, with 15 percent developing a meningitis viral encephalitides, as discussed in Section 7.6; the
and less than 1 percent with evidence of an encephalitis. occurrence of parotitis or orchitis constitute obvious
Currently, thanks to widespread vaccination, mumps is clues. Importantly, either a history of mumps or mumps
p 14.qxd 3/10/08 9:50 AM Page 502
vaccination effectively rules out the diagnosis, given that there may be a transverse myelitis or, rarely, a
both of these generally confer lifelong immunity. Brown–Sequard syndrome.
When virus latent within the gasserian ganglion of the
trigeminal nerve undergoes reactivation, anterograde
Treatment spread leads to a zosteriform rash within the area of distri-
bution of one of the divisions of the trigeminal nerve,
There is no specific treatment for mumps; the general almost always the first or ophthalmic division. The result-
treatment of delirium is discussed in Section 5.3. ing herpes zoster ophthalmicus may disastrously also
involve the eye. Patients who have suffered a herpes zoster
ophthalmicus are also at risk for a rare complication,
14.9 VARICELLA-ZOSTER namely a zoster vasculopathy (Doyle et al. 1982;
Linnemann and Alvira 1980). In these cases, the virus
Infection with the varicella-zoster virus may cause two dif- spreads anterogradely along sensory fibers to the
ferent illnesses (Strauss et al. 1984). Acute infection causes meninges, resulting in infection of either the middle or
chickenpox, also known as varicella. After resolution of anterior cerebral arteries: after a latency of from weeks to
chickenpox, the virus undergoes latency in the sensory months, thrombus formation in these arteries may lead to
ganglia of the cord and also in the gasserian ganglion of the ischemic infarction of subserved areas, with the develop-
trigeminal nerve and the geniculate ganglion of the facial ment of focal syndromes, such as hemiparesis contralateral
nerve (Mahalingam et al. 1990). In the aged or immuno- to the side where the zoster rash occurred (Hilt et al. 1983).
compromised, the virus may reactivate to cause shingles In cases in which the geniculate ganglion is the site of
(also known as herpes zoster) or one of the other forms of reactivation, the Ramsey Hunt syndrome (also known as
zoster noted below. zoster oticus) may occur, with a rash in the external audi-
tory canal or the pinna, and a peripheral seventh cranial
nerve palsy (Sweeney and Gliden 2001).
Clinical features Rarely, and generally only in debilitated patients, there
may be a hematogenous dissemination of the reactivated
Chickenpox is a disease of childhood or adolescence that is virus with the development of a severe, generalized vesicu-
spread via respiratory droplets. The pharynx is the initial lar rash, and in such cases hematogenous spread of the
seat of the infection; subsequently, a viremia occurs, result- virus may also occur to the brain, causing an encephalitis
ing in a characteristic rash. Rarely, the central nervous sys- (Applebaum et al. 1962; Jemsek et al. 1983; Krumholz and
tem may be affected during the viremia, producing either an Luhan 1945). Typically in such cases, within days to weeks
encephalitis (with various symptoms, including delirium (or exceptionally months [Weaver et al. 1999]) of the onset
[Applebaum et al. 1953] or ataxia [Johnson and Milbourn of the generalized rash, a delirium develops that may be
1970]) or a meningitis. accompanied by seizures, focal signs, ataxia, or mening-
Reactivation of the latent varicella-zoster virus may occur ismus. In such cases the EEG shows generalized slowing, and
during the immune ‘senescence’ that occurs with aging FLAIR or T2-weighted MR scanning will reveal multifocal
(Miller 1980), during certain illnesses, such as AIDS (Gilden areas of increased signal intensity within both the white
et al. 1988), Hodgkin’s disease (McCormick et al. 1969) or matter and the cortex. The CSF is typically, but not always,
other cancers, or during treatment with corticosteroids or abnormal, with a lymphocytic pleocytosis and an elevated
various immunosuppressants, and the form of the result- total protein; anti-varicella-zoster IgG antibodies are com-
ing zoster is determined by the site of the reactivation. monly found and, although somewhat less sensitive, PCR
With reactivation of virus latent within the sensory gan- assay may reveal varicella-zoster DNA (Nagel et al. 2007).
glia of the cord, anterograde spread of the virus down the Although the encephalitis usually resolves in a matter of
sensory nerve results in a classic dermatomal rash. weeks, chronic courses may be seen, especially in severely
Typically there is a prodrome of malaise, lasting several immunocompromised patients, such as those with AIDS.
days, followed by the occurrence of dermatomal pain; over Before leaving this section on clinical features, note must
the next 3 or 4 days, a typical vesicular rash follows. In also be made of a variant of zoster known as zoster sine her-
almost all cases the rash is unilateral and typically occurs in pete (Gilden et al. 1994). In such cases the rash does not
one of the thoracic dermatomes. Resolution occurs gradu- appear, and hence one may have dermatomal pain, spinal
ally after a matter of weeks. In a very small minority of cord symptoms, vasculopathy or encephalitis without this
cases, the virus may spread retrogradely to the cord with all-important diagnostic clue (Mayo and Booss 1989).
the delayed and gradual appearance of myelitic symptoms
(Devinsky et al. 1991; Hogan and Krigman 1973); involve-
ment of the ventral horn may lead to a segmental sensory Course
loss whereas involvement of the anterior horn may lead to
segmental weakness and amyotrophy. Occasionally the The course of zoster is dependent on the immunological
white matter of the cord may be involved and in such cases competence of the patient. In immunocompetent patients,
p 14.qxd 3/10/08 9:50 AM Page 503
14.10 Rabies 503
symptoms generally resolve within a matter of weeks; in and amitriptyline, patients get relief regardless of whether
the immunocompromised, however, protracted, and at they are depressed or not. Nortriptyline and amitriptyline
times fatal, courses may be seen. are equally effective, but nortriptyline is better tolerated
One complication of a zoster rash, whether dermatomal (Watson et al. 1998); nortriptyline may be given in doses
or cranial, is post-herpetic neuralgia, in which the pain ranging from 10 to 75 mg, and amitriptyline in doses rang-
persists beyond resolution of the rash. This neuralgic pain ing from 10 to 100 mg. Gabapentin is roughly equivalent in
may be lancinating or burning in quality and may cause effectiveness to nortriptyline but better tolerated (Chandra
considerable disability; although in some cases a gradual et al. 2006); it may be given in doses ranging from 1200 to
remission may occur after many months, in others the pain 3600 mg. Pregabalin is the most recently introduced agent
proves to be chronic. and it is unclear how effective it is compared with the others;
it may be given in doses ranging from 150 to 600 mg
(Dworkin et al. 2003). Regardless of which agent is used, a
Etiology week or more may be required before some relief is seen.
As indicated above, zoster may be complicated by a
myelitis, a cerebral vasculopathy or an encephalitis. The
14.10 RABIES
myelitis results from retrograde spread from the sensory
ganglia. In all likelihood, the cerebral vasculopathy occurs
Rabies typically occurs after being bitten by a rabid animal,
secondary to seeding of such large pial vessels as the middle
for example a dog, cat, wolf, fox, skunk, raccoon, or vampire
or anterior cerebral arteries by virus that spreads from the
bat; cases have also been reported secondary to respiratory
gasserian ganglion up along sensory nerves destined for the
transmission in spelunkers within bat-infested caves and in
meninges; in such cases, there is often segmental narrow-
a veterinarian who was working with the homogenized
ing of the involved vessels (MacKenzie et al. 1981) and
brain of a rabid animal (Conomy et al. 1977); recently
virus has been found within the vessel walls (Linnemann
rabies was also reported secondary to solid organ transplan-
and Alvira 1980; Melanson et al. 1996); in some cases
tation from a donor with an unsuspected case (Srinivasan
thrombotic occlusion has been noted with little or no asso-
et al. 2005). Although very rare in developed countries, rabies
ciated inflammation (Eidelberg et al. 1986). As noted ear-
remains a significant problem in India and parts of Asia.
lier, the encephalitis occurs secondary to hematogenous
seeding of the cerebrum, generally occurring only during a
disseminated rash. In such cases one may find multifocal Clinical features
areas of cerebritis (Weaver et al. 1999), primarily affecting
the white matter, with, at times, multiple areas of micro- After being bitten by an infected animal there is a latent,
infarction occurring secondary to small vessel vasculitis asymptomatic period, generally of 1–3 months, with a
(Kleinschmidt-DeMasters et al. 1996). range of weeks to a year or more; the duration of the
latency appears related not only to the severity of the bite
Differential diagnosis but also to the distance from the bitten area to the brain,
with bites on the feet having the longest latency and facial
The occurrence of a myelopathy, stroke or encephalitic bites the shortest.
symptoms (e.g., delirium, seizures, etc.) in the setting of a With resolution of the latent interval, there is usually a
recent rash should immediately suggest a varicella-zoster prodrome, lasting days, characterized by headache and
infection. As noted earlier, some of these manifestations may malaise; pain or parasthesiae may also develop at the site of
occur in the absence of a rash, and in such cases one would the original bite. Subsequently, the illness may evolve in
have to closely question the patient and family regarding any one of two forms, namely ‘furious’ rabies or ‘dumb’ (also
complaints of pain, either in a dermatomal pattern or in the known as ‘paralytic’) rabies.
ophthalmic division of the fifth cranial nerve. Furious rabies (Adle-Biassette et al. 1996; Blatt et al. 1938;
Dupont and Earle 1965) is seen in perhaps 80 percent of cases
and is characterized by restlessness, agitation, excitability,
Treatment excessive startability, and convulsions; delirium is typical and
patients may engage in bizarre behavior, including biting.
Treatment with an antiviral agent, such as acyclovir, valacy- The combination of excessive salivation and dysphagia
clovir, famciclovir, or brivudin, should be immediately insti- caused by pharyngeal spasm may literally cause the patient to
tuted for all forms of zoster, and, in the case of large-vessel ‘foam at the mouth’. Pharyngeal spasm may also be pro-
vasculopathy, antiplatelet agents should also be started. voked by swallowing water or even by the sight of water, giv-
With regard to post-herpetic neuralgia, a number of ing rise to the classic symptom of hydrophobia.
agents have been shown to be effective in double-blind Dumb rabies (Chopra et al. 1980) is characterized by a
studies, including nortriptyline, amitriptyline, gabapentin, flaccid paralysis that typically begins in one limb and rap-
and pregabalin. Importantly, with regard to nortriptyline idly becomes generalized and symmetric.
p 14.qxd 3/10/08 9:50 AM Page 504
The CSF shows a lymphocytic pleocytosis, elevated pro- assault on the cerebrum, primarily the white matter, trig-
tein level, and anti-rabies antibodies. Rabies virus RNA gered by a preceding infectious illness or vaccination. It is
may also be detected by PCR assay. T2-weighted magnetic characterized clinically by multifocal lesions within the
resonance scanning may reveal multiple foci of increased cerebrum. This disease was formerly called post-infectious
signal intensity in both the gray and white matter of the encephalomyelitis (PIE) or, if it occurred after a vaccina-
cerebrum and cerebellum (Laothamatas et al. 2003). tion, post-vaccinial encephalomyelitis, and these names,
although no longer current, have much to recommend
them, as they not only refer to the clinical picture, namely
Course an encephalomyelitis, but also to the etiology, namely a
reaction to a preceding infection or vaccination. By con-
Although survival has been reported (Porras et al. 1976; trast, the term acute disseminated encephalomyelitis
Willoughby et al. 2005), this is exceptional and the over- encompasses only the clinical picture and, as such, it may,
whelming majority of patients die within days to a couple in the minds of some authors, perhaps inappropriately
of weeks. broaden the concept to include encephalomyelitides that
occur on the basis of other causes.
Responsible infections include measles, mumps,
Etiology rubella, pertussis, chickenpox, infectious mononucleosis,
influenza, arboviruses, herpes simplex virus, HIV, hepati-
In the typical case of rabies secondary to a bite by a rabid tis, non-specific viral infections, scarlet fever, mycoplasma,
animal, the virus slowly travels up a peripheral nerve to Borrelia, and typhoid (Fisher et al. 1983; Hart and Earle
finally gain access to the central nervous system. Within 1975; Moscovich et al. 1995; Paskavitz et al. 1995). Vaccina-
the brain and spinal cord there is a widespread inflamma- tions associated with ADEM include those for measles,
tory response, with a predilection for the limbic system and mumps, rubella, chickenpox, influenza, rabies, hepatitis,
the cerebellum. Within neurons, one finds cytoplasmic typhoid, and tetanus. Both smallpox and smallpox vacci-
eosinophilic inclusions, known as Negri bodies (Chopra nation (Dolgopol et al. 1955) were once very common
et al. 1980; Dupont and Earle 1965). causes, but with this disease now apparently eradicated
they are no longer of immediate concern.
Clinical features
Lacking the history of exposure, the differential in the case of
furious rabies includes other causes of acute encephalitis, as Although ADEM is most common in children and adoles-
discussed in Section 7.6; the presence of excessive salivation cents, it also occurs in adults and the elderly.
and dysphagia, and certainly hydrophobia, however, would In general, between the preceding infection or vaccina-
suggest the correct diagnosis. In cases of dumb rabies, con- tion and the onset of ADEM there is a latent interval lasting
sideration must be given to Guillan–Barré syndrome. about a week or two, with a range of from 2 to 30 days.
Clinically (Hollinger et al. 2002; Marchioni et al. 2005;
Miller et al. 1956; Tenembaum et al. 2002), the onset is
Treatment generally acute, with the full picture evolving over a day or
so. The symptomatology may be quite varied, depending
There is no specific treatment for either furious or dumb on which part of the central nervous system bears the
rabies; intensive supportive care, as described in a recent brunt of the autoimmune assault. Thus, with cerebral
case (Willoughby et al. 2005), may rarely enable a patient involvement there may be headache, delirium, seizures,
to survive. and various focal signs, such as hemiparesis; meningismus
Given this lack of treatment, the focus must be on pre- may be present, but is usually mild, and there may be fever,
vention. In cases of animal bites, the wound should be thor- but again this too is generally mild; rarely, mania may
oughly cleansed and consideration should be given to the occur (Moscovich et al. 1995; Paskavitz et al. 1995).
injection of rabies immune globulin followed by vaccination Cerebellar involvement may cause an ataxia, and with
with human diploid cell anti-rabies vaccine. Those caring spinal involvement there may be a transverse myelitis with
for patients with rabies must avoid any contact with saliva. paraplegia. The cranial nerves (most commonly the optic
nerve) may be affected, and patients may develop visual
obscurations or blindness. Rarely the basal ganglia are
14.11 ACUTE DISSEMINATED involved with chorea or dystonia.
ENCEPHALOMYELITIS MRI scanning may be normal for the first day or two
although, eventually, T2-weighted imaging will reveal mul-
Acute disseminated encephalomyelitis (ADEM) is a tiple areas of increased signal intensity (Kesserling et al.
monophasic illness that occurs as a result of an autoimmune 1990); these are typically found in the cerebral white matter
p 14.qxd 3/10/08 9:50 AM Page 505
14.11 Acute disseminated encephalomyelitis 505
Etiology
As noted earlier, ADEM occurs secondary to an autoimmune
attack on the cerebrum. Pathologically (Greenfield 1929;
Hart and Earle 1975), there are multiple foci of perivenous
mononuclear inflammation with associated demyeliniza-
tion and relative axonal sparing: although these are most
common in the white matter of the cerebrum, cerebellum,
and cord, the gray matter, as noted earlier, may also be
involved. In severe cases, known as acute hemorrhagic
leukoencephalitis (Hart and Earle 1975; Russell 1955),
widespread petechial hemorrhages are also seen.
Differential consideration must be given to acute

viral encephalitides and to a first episode of multiple
sclerosis (MS).
Most of the viral illnesses capable of causing ADEM can
also directly cause an encephalitis in their own right, and
the differential in such cases rests primarily on the existence
Figure 14.3 Multiple bilateral areas of increased signal of a clear latent interval. In cases presumably triggered by
intensity on a T2-weighted magnetic resonance imaging scan of a measles, consideration must also be given to subacute
patient with acute disseminated encephalomyelitis. (Reproduced measles encephalitis, as discussed in Section 14.13.
from Marsden and Fowler 1998.) Multiple sclerosis often enters into the differential;
however, in most cases a clinical distinction between
ADEM and MS is possible on several counts. First,
although MS may present with multiple acute areas of
(as illustrated in Figure 14.3) but may also appear in the demyelinization, more commonly one finds only one or a
gray matter of the cerebral cortex, the basal ganglia, and few, in marked contrast to the common picture in ADEM,
the thalamus; other potentially affected areas include the which is characterized by multiple lesions (Schwarz et al.
cerebellar white matter, the brainstem, and the cord. A 2001). Second, consideration should be given to whether
minority of these lesions will also demonstrate gadolinium or not the patient may have had prior lesions that perhaps
enhancement. Of note, T2-weighted signal abnormalities were clinically ‘silent’, as may often occur in MS. Here, MR
may persist far beyond clinical resolution of ADEM, often imaging is quite helpful, as T1-weighted scanning may dis-
for many months (O’Riordan et al. 1999). close old ‘burnt-out’ lesions known as ‘black holes’;
The EEG typically displays generalized slowing with or although these may occur in MS they are classically absent
without more focal areas of accentuated slowing. in ADEM, which, as noted earlier, is typically a monophasic
The CSF is generally, but not always, abnormal. illness. Finally, in cases in which there is still doubt, the
Findings include a lymphocytic pleocytosis, an elevated diagnosis may rest on long-term follow-up: MS is typically
total protein, an elevated myelin basic protein, and oligo- a relapsing illness and thus one expects to see future clini-
clonal bands. In severe cases there may be both polymor- cal episodes or MRI evidence of new lesions, whereas in
phonuclear and red blood cells. ADEM no new lesions, either clinical or ‘silent’, occur,
unless of course the patient is again exposed to a precipitat-
ing illness or vaccination.
Course
The outcome is fatal in roughly 20 percent of cases; those Treatment

who survive tend to recover gradually over a week or two.
Although most appear to recover completely, sequelae, Methylprednisolone should be immediately started using a
reflecting the initial clinical picture, may occur, including dose for adults of 250 mg intravenously every 6 hours; this is
dementia, epilepsy, and various focal signs. continued for approximately 2 weeks after which the patient
As noted earlier, ADEM is a ‘monophasic’ illness that, may be switched to prednisone, which may then be tapered
in the natural course of events, does not recur unless the over a month or so. Although the response to steroids is often
patient is again exposed to one of the precipitating infec- prompt (and at times dramatic), some patients fail to
tions or vaccinations. respond and in such cases consideration may be given to
p 14.qxd 3/10/08 9:50 AM Page 506
intravenous immune globulins, plasmapheresis or immuno- Course

suppression with, for example, cyclophosphamide.
Although the course is variable, most patients pass through
the three stages and die within 1–3 years; in fulminant
14.12 SUBACUTE SCLEROSING cases, however, a fatal outcome may occur within several
PANENCEPHALITIS months. Occasionally the course is prolonged, up to a
decade or more, and there may at times be periods of rela-
Subacute sclerosing panencephalitis (SSPE), also known as tive stability (Risk et al. 1978), lasting many years (Cobb et al.
Dawson’s disease, results from a reactivation of a defective 1984; Donner et al. 1972; Landau and Luse 1958); however,
measles virus and is typically characterized by dementia, these inevitably give way to further progression.
myoclonus, and ataxia. This is a very rare disorder, occur-
ring in 5–10 out of 1 000 000 with a history of measles and
in approximately 1 out of 1 000 000 who receive the
Etiology
measles vaccine; it is three to four times more common in
SSPE occurs secondary to a reactivation of a ‘dormant’
males than females.
measles virus that has the peculiarity of lacking a normal M
protein; rather than undergoing ‘budding’, these defective
Clinical features viruses spread by means of cell fusion within the central
nervous system. Pathologically there is widespread perivas-
The vast majority of cases occur in children; in these cases cular inflammation accompanied by patchy demyeliniza-
the average latency between the preceding infection or vac- tion and neuronal loss (Ohya et al. 1974). Within surviving
cination is about 8 years, and the average age of onset neurons inclusions are found within nuclei, which, by elec-
is about 13 years. In adults, the latency ranges from 8 to tron microscopy, appear similar to measles nucleocapsids.
33 years and the average age of onset is in the early 20s.
The onset itself is generally gradual, even insidious, and Differential diagnosis
typically the disease evolves through three stages (Dawson
1934; Ozturk et al. 2002; Prashanth et al. 2006). In the first Subacute measles encephalitis, like subacute sclerosing
stage, the patient may become restless, distractable, and panencephalitis, also occurs as a sequela to measles; how-
forgetful, and irritability and moodiness may be noted. In ever, in subacute measles encephalitis the latent interval
some cases, particularly in those with adult onset, this first between the preceding measles and the onset of the illness is
stage may be characterized by a psychosis (Cape et al. 1973; much shorter than in subacute sclerosing panencephalitis,
Salib 1988) that may faithfully mimic schizophrenia, with being measured in months and not years. In adult-onset
delusions (including Schneiderian first-rank symptoms cases, consideration may be given to other dementias asso-
[Duncalf et al. 1989]) and stuporous catatonia (Koehler ciated with myoclonus, such as Creutzfeldt–Jakob disease
and Jakumeit 1976). In the second stage a dementia evolves, or possibly AIDS dementia.
which is accompanied by myoclonus, ataxia, and seizures,
which may be partial or grand mal in type; abnormal invol-
untary movements, such as chorea, athetosis, or dystonia, are Treatment
occasionally seen at this point. In the third and final stage
there is stupor and generalized rigidity, and eventually coma. Various treatments have been advocated. However, in the
It must be borne in mind that there are many exceptions to only randomized study to date it appears that oral inosi-
this typical picture (Risk and Haddad 1979). In some cases plex was equivalent to a combination of oral inosiplex and
the onset may be relatively fulminant, with severe sympto- intraventricular interferon-alpha (Gascon et al. 2003); the
matology seen in a matter of months, and, furthermore, benefit, however, was not great. The general treatment of
there may be considerable overlap among the various stages. dementia is discussed in Section 5.1; in cases with marked
Magnetic resonance scanning may reveal cortical atrophy myoclonus, consideration may be given to either clonaz-
and, on T2-weighted imaging, multiple areas of increased epam or carbamazepine.
signal intensity in the gray and white matter of the cere-
brum, with a predilection for the periventricular area
(Anlar et al. 1996). 14.13 SUBACUTE MEASLES ENCEPHALITIS
The EEG in the second and third stages will display a
classic burst-suppression pattern in the majority of cases Subacute measles encephalitis, also known as measles inclu-
(Wulf 1982). sion body encephalitis, is a rare disorder occurring gener-
The CSF is generally acellular with a mildly elevated ally, but not always, in immunocompromised patients who
total protein. The IgG level is increased, sometimes greatly have recently recovered from the measles. Although, given
so, oligoclonal bands may be found, and, most impor- the epidemiology of measles, most cases occur in children,
tantly, anti-measles antibodies are present. adult-onset cases have been reported (Croxson et al. 2002).
p 14.qxd 3/10/08 9:50 AM Page 507
14.14 Progressive rubella panencephalitis 507
Clinical features 14.14 PROGRESSIVE RUBELLA

PANENCEPHALITIS
Clinically (Agamanolis et al. 1979; Aicardi et al. 1977), after
an asymptomatic latent interval ranging from 1 to 6 Progressive rubella panencephalitis is a vanishingly rare
months after a measles infection, there is a subacute onset disorder occurring as a result of a reactivation of rubella
of delirium over days or a week or so, accompanied, vari- infection, generally in a patient with the congenital rubella
ously, by myoclonus, focal signs, and seizures, which may syndrome.
be either grand mal or partial; in some cases simple partial
motor status epilepticus has been noted.
Although the CSF is generally normal, in some cases Clinical features
there may be a mild lymphocytic pleocytosis or a mildly
elevated total protein; anti-measles antibodies may or may The congenital rubella syndrome is characterized by men-
not be present. tal retardation, microcephaly, deafness, and cataracts, and
most cases of progressive rubella panencephalitis occur in
this setting in patients aged from 4 to 19 years (Townsend
Course et al. 1975a; Weil et al. 1975). Rarely, progressive rubella
panencephalitis has occurred as a sequela to an uncompli-
The disease is relentlessly progressive to coma and death cated case of German measles in an otherwise healthy indi-
within weeks to months. vidual (Lebon and Lyon 1974; Wolinsky et al. 1976), again
after a long latent interval.
Clinically (Townsend et al. 1975a, 1976) there is a grad-
ual onset of dementia, which is typically accompanied by
Etiology ataxia; seizures are uncommon and myoclonus is generally
absent.
This disease probably occurs secondary to reactivation of a
The EEG shows generalized slowing and, in some cases,
defective measles virus within neurons and oligodendro-
a burst-suppression pattern may eventually appear.
cytes; pathologically, there is very little or no inflamma-
Neuroimaging reveals cortical atrophy and ventricular
tion, and measles-containing inclusion bodies may be
dilation. The CSF is generally abnormal, with a lympho-
found within both the nuclei and cytoplasm of both types
cytic pleocytosis, an elevated total protein, oligoclonal
of cells (Aicardi et al. 1977; Gazzola et al. 1999).
bands, and anti-rubella antibodies.
Although most patients have been children with
leukemia, cases have occurred in adults with Hodgkin’s
disease (Wolinsky et al. 1977), adults undergoing thera-
Course
peutic immunosuppression (Gazzola et al. 1999), patients
with AIDS (Budka et al. 1996), and, rarely, apparently
This is a relentlessly progressive disease; spasticity and
immunocompetent adult patients (Chadwick et al. 1982;
quadriparesis eventually appear and death occurs after
Croxson et al. 2002).
8–10 years.
Differential diagnosis Etiology

Subacute measles encephalitis must be distinguished from Pathologically (Townsend et al. 1975a, 1976, 1982; Weil et al.
other measles-related disorders. Acute measles may be 1975; Wolinsky et al. 1976), there is a widespread perivas-
complicated by an encephalitis; however, in these cases cular inflammatory response, with prominent demyelin-
symptoms occur in the context of a measles rash. Acute ization and gliosis; although rubella virus may be found in
disseminated encephalomyelitis, like subacute measles neurons, there are no inclusion bodies. Furthermore,
encephalitis, also has a latent interval but it is shorter, in immunoglobulin deposits are found on cerebral vessels.
the order of weeks; furthermore, there is no myoclonus in
acute disseminated encephalomyelitis. Subacute sclerosing
panencephalitis also has a latent interval but this is much Differential diagnosis
longer, in the order of years.
When the syndrome occurs in the setting of the congenital
rubella syndrome, there is little doubt as to the diagnosis.
Treatment When, however, it occurs in an otherwise healthy child or
adolescent, consideration may be given to subacute scle-
The general treatment of delirium is discussed in Section rosing panencephalitis, which is distinguished by promi-
5.3; anecdotally, ribavirin was beneficial. nent myoclonus.
p 14.qxd 3/10/08 9:50 AM Page 508
Treatment and has an onset after a latency of about 6 or 7 years, with

a range of 1 to 12 years. Gummas are currently quite rare
The general treatment of dementia is discussed in Section and present with the same latency as meningovascular
5.1; there is no specific treatment for this disease. syphilis. General paresis has a longer latency, ranging from
15 to 20 years, and tabes dorsalis has potentially the longest
latency, ranging from 10 to 30 years. Each of these will be
14.15 NEUROSYPHILIS discussed below, and consideration will also be given to
laboratory findings, to the effect of concurrent AIDS and
Infection by the spirochete Treponema pallidum may cause neurosyphilis, and to congenital neurosyphilis. It must be
primary, secondary, or tertiary syphilis. Primary syphilis borne in mind that, although the various forms of tertiary
typically presents with a painless chancre that remits spon- neurosyphilis may occur in isolation, more commonly
taneously. Secondary syphilis may appear weeks to months patients will have elements of two or more forms.
after resolution of the chancre and is characterized by a
widespread rash, which may or may not be accompanied ACUTE SYPHILITIC MENINGITIS
by an acute syphilitic meningitis. Following resolution of
the rash there is a long latency interval, lasting years, after In close relation to the rash of secondary syphilis, a minor-
which about 10 percent of patients go on to develop terti- ity of patients may develop a meningitis with typical symp-
ary syphilis. Tertiary syphilis may manifest in a variety of toms such as malaise, headache, stiff neck, and, in some, a
organs, including the central nervous system, in which case delirium. Although these symptoms generally undergo a
one speaks of neurosyphilis. gradual spontaneous remission, a small minority of patients
Neurosyphilis may occur in any one of several forms may develop obstructive hydrocephalus.
(Merritt et al. 1946), including meningovascular syphilis,
gummas, general paresis, and tabes dorsalis, each discussed MENINGOVASCULAR SYPHILIS
below. Meningovascular neurosyphilis is characterized by
a chronic, indolent basilar meningitis; both arteries and The symptomatology of meningovascular syphilis depends
cranial nerves that cross the meninges may be affected and on which arteries and which cranial nerves are affected.
there may be infarctions and cranial nerve palsies. Gummas When large arteries, such as the middle or posterior cere-
are granulomatous tumors that are typically found in asso- bral arteries, are involved, one sees a thrombotic stroke
ciation with meningovascular syphilis and which may with the gradual evolution of appropriate focal deficits,
range in size from minute to quite large, in which case they such as hemiparesis or hemianopia (Holmes et al. 1984). In
may present as any other mass lesion. General paresis is cases in which small arteries are involved, there may be
characterized pathologically by a direct invasion of the small lacunar infarctions with appropriate lacunar syn-
brain by the spirochete and clinically by a dementia. Tabes dromes, as discussed in Section 7.4; with an accrual of a
dorsalis is characterized by inflammation of the posterior significant number of these a lacunar dementia, as dis-
spinal roots and softening of the posterior columns with cussed in Section 10.2, may occur. Of the various cranial
ataxia and, in some, severe pain. nerves, the most commonly involved are the third and
Although tertiary syphilis was common in the pre- sixth, with diplopia; the seventh, with unilateral or bilateral
antibiotic era, after World War II, with the widespread use facial palsy; and the first, with unilateral or bilateral blind-
of penicillin, the incidence fell dramatically to the point ness. Rarely, obstructive hydrocephalus may appear. Most
where it appeared to have almost vanished in developed cases of meningovascular syphilis will also be characterized
countries. Over the past couple of decades, however, it has by the Argyll Robertson pupil, in which, although pupillary
been enjoying something of a resurgence, particularly among constriction to direct illumination is lost, constriction
those with AIDS. upon accommodation testing is preserved.
GUMMAS
Clinical features
Gummas tend to occur at the base of the brain or over the
As noted, some patients with secondary syphilis may convexities; occasionally they may be deep-seated. They
develop acute syphilitic meningitis. Whether or not this tend to present similarly to any gradually enlarging mass
condition should be subsumed under the rubric of neu- lesion and, if large enough, may cause dementia (Bianchi
rosyphilis is not clear, although given that it does, of course, and Frera 1957).
involve the nervous system it appears reasonable to do so;
however, many authors reserve the term ‘neurosyphilis’ for GENERAL PARESIS
nervous system manifestations occurring after a long latent
interval as part of tertiary syphilis. Of these traditional General paresis, also known as general paresis of the insane
forms of neurosyphilis, meningovascular neurosyphilis is (GPI), dementia paralytica, or paretic neurosyphilis, is not
currently the most common (Conde-Sendin et al. 2004) necessarily associated with meningovascular syphilis and,
p 14.qxd 3/10/08 9:50 AM Page 509
14.15 Neurosyphilis 509
indeed, it may be the only manifestation of tertiary neu- In practice, demented patients are often screened with a
rosyphilis. General paresis typically manifests with a demen- serum VDRL and, if this is positive, with a serum FTA for
tia of gradual onset and slow progression (Gomez and confirmation. Given, however, the relative insensitivity of
Aviles 1984; Storm-Mathisen 1969). Although the dementia the serum VDRL, it is more appropriate to skip the VDRL
may be non-specific in nature, certain cases may be marked and proceed directly to a serum FTA. If the serum FTA is
by a personality change of the frontal lobe type; by mood negative, then neurosyphilis is effectively ruled out. In
changes, tending either toward mania or toward depression; cases in which the serum FTA is positive and there is clini-
or by delusions and hallucinations. Rarely, general paresis cal evidence of neurosyphilis, then CSF should be
may present with a psychosis (Rothschild 1940; Schube obtained. If the CSF VDRL is positive, then the diagnosis of
1934). Regardless of the typology of the dementia, other signs neurosyphilis is almost certain. If the CSF VDRL is nega-
and symptoms gradually accrue. Seizures, either partial or tive but there is other CSF evidence of infection (e.g., lym-
grand mal, are common. Dysarthria and anomia may occur, phocytic pleocytosis or an elevated total protein), then it
and handwriting becomes very poor. Coarse tremor is com- may be prudent to obtain a CSF FTA, as this is more sensi-
mon and may be present not only in the hands but also in the tive than the CSF VDRL. Obtaining a CSF FTA, however, is
lips and tongue. Very typically the facial musculature loses its controversial, as even minute contamination of the CSF by
tone, giving the patient a vacant, dull facial expression. The blood may create a false-positive FTA (Davis and Sperry
Argyll Robertson pupil, described earlier, is present in most 1979); caution is therefore required when interpreting this
cases. With further progression the gait becomes unsteady result. In the rare cases in which both the CSF VDRL and
and a true ‘general paresis’ occurs, with profound widespread the CSF FTA are negative (Ch’ien et al. 1970) but the clini-
weakness of almost all of the voluntary musculature. The cal picture is highly suggestive of neurosyphilis and there is
plantar responses become extensor and, unless tabes dorsalis evidence of infection in the CSF, then some clinicians will
is present, there is a generalized hyper-reflexia. treat the patient as if neurosyphilis is present; if there is
clinical improvement on follow-up, and if other CSF
TABES DORSALIS abnormalities resolve (e.g., the cell count falls), then it is
reasonable to assume that a correct ‘diagnosis by treatment
Tabes dorsalis is characterized by ataxia, diminished vibra- response’ has been made.
tory sense, a positive Romberg test, urinary incontinence, Given the frequency with which neurosyphilis is seen in
and erectile dysfunction. There may also be ‘tabetic pains’ AIDS, it is prudent to check all patients with neurosyphilis
in the lower extremities that tend to be lightning-like and for HIV infection.
lancinating. ‘Visceral crises’ may also occur with abdomi-
nal pain similar to that seen in the ‘acute abdomen’.
AIDS AND NEUROSYPHILIS
LABORATORY FINDINGS Some 15 percent of patients with AIDS are seropositive
for syphilis and about 1 percent have neurosyphilis.
Magnetic resonance scanning may reveal a basal pachy- Immunoincompetence in AIDS has probably altered the
meningitis in meningovascular syphilis, along with evi- clinical picture of neurosyphilis in these patients: the laten-
dence for any concurrent infarctions. In general paresis cies may be shorter and the evolution of the various forms
both cortical atrophy and ventricular dilation are seen, and may be more rapid (Johns et al. 1987).
if gummas are present they will immediately be apparent as
space-occupying lesions.
Examination of the CSF is critical and must be inter- CONGENITAL NEUROSYPHILIS
preted in light of the results of testing for VDRL and fluo-
rescent treponemal antibody (FTA). The pressure of the Infected mothers may pass the spirochete to the fetus, and
CSF is generally normal. There is usually a mild lympho- congenitally infected children may or may not have the
cytic pleocytosis and the total protein is generally elevated classic ‘Hutchinson’s triad’ of cataracts, sensorineuronal
as is the IgG index; oligoclonal bands may also be seen. The deafness, and ‘Hutchinson’s teeth’, in which the central
serum VDRL is positive in only about 70 percent of cases of incisors are notched, widely spaced, and often tapering.
neurosyphilis (Simon 1985), and the CSF VDRL is less sen- Neurosyphilis may present in these children after the nor-
sitive: one study found a sensitivity of only 27 percent mal latency periods and, in such cases, a dementia second-
(Davis and Schmitt 1989). The serum FTA is positive in ary to general paresis may present in teenage years.
almost 100 percent of cases, whereas the CSF FTA, like the
CSF VDRL, is less sensitive, being positive in about 75 per-
cent of patients. False-positive serum VDRLs may occur in Course
collagen vascular diseases, such as lupus, and also in heroin
addicts; generally these false-positive VDRLs are low titer All forms of neurosyphilis are gradually progressive;
(e.g., less than 1:8). False-positive serum FTAs may occur untreated, both meningovascular neurosyphilis and gen-
under the same circumstances but are much less common. eral paresis are fatal within 3–5 years.
p 14.qxd 3/10/08 9:50 AM Page 510
Etiology should be given to desensitization. In a minority of

patients, institution of antibiotic treatment will immediately
The spirochete T. pallidum first gains access to the central be followed by what is known as the Jarisch–Herxheimer
nervous system during the course of secondary syphilis. reaction, with malaise and fever and, in some, a transient
Indeed, CSF studies indicate infection in up to one-third of exacerbation of the clinical symptomatology (Hahn et al.
patients at this stage (Lukehart et al. 1988). In most cases, 1959), which in one extraordinary case characterized by a
however, host defenses are adequate to eradicate T. pallidum large gumma was fatal (Zifko et al. 1994); this Jarisch–
before tissue damage occurs. However, in about one-tenth Herxheimer reaction probably represents an inflammatory
of cases, host defenses fail and the stage is set for the reaction to dying spirochetes, and may be treated by a
appearance of one or more forms of neurosyphilis after the short course of steroids. Because a course of penicillin G is
latent intervals noted earlier. not universally effective (especially in patients with AIDS
In meningovascular neurosyphilis, a granulomatous [Gordon et al. 1994]), it is necessary to follow patients with
basilar meningitis is present. Cranial nerves traversing these serial examinations of the CSF every 3–6 months until
meninges may become inflamed and undergo degenerative there has been a satisfactory response. In general, the first
changes. Traversing arteries develop an endarteritis that evidence of improvement is a fall in the cell count, the total
may be followed by thrombotic occlusion and infarction of protein level falling later. The VDRL titer is the last to fall,
subserved tissues. Obstruction of the outflow foramina of a fourfold fall being seen as significant. As treatment failure
the fourth ventricle may lead to hydrocephalus. is most common in patients with AIDS, serial CSF exami-
Gummas are granulomatous tumors that probably rep- nations are particularly important in this group.
resent ‘localized’ forms of meningovascular neurosyphilis. Treatment with penicillin halts the progression of the
In general paresis, cortical atrophy is prominent, more symptoms of neurosyphilis, and in the case of general pare-
so in the frontal and temporal areas than elsewhere. The sis there may be a partial remission. Gummas may or may
ventricles are dilated and generally display a granular not respond. In treatment-resistant cases the addition of
ependymitis. Spirochetes are found throughout the cortex, steroids may be beneficial (Fleet et al. 1986); however, in
and neurons are lost with a disruption of the normal corti- some cases surgical resection is required.
cal architecture. Microglia and astrocytes are present in With regard to the dementia that may occur with a lacu-
abundance, and there may be some perivascular cuffing by nar state in meningovascular syphilis or with general pare-
lymphocytes of small penetrating vessels. sis, symptomatic treatment is discussed in Section 5.1.
In tabes dorsalis, inflammation is present in the ventral Tabetic pains may respond to carbamazepine (Gimenez-
spinal roots, and the posterior columns display atrophy Roldan and Martin 1981).
and softening.
14.16 LYME DISEASE

Lyme disease is caused by the spirochete Borrelia burgdor-
Importantly, a history of treatment of primary or second- feri and is transmitted to humans via the bite of an ixodid
ary syphilis with benzathine penicillin does not rule out a tick (Burgdorfer et al. 1982). The disease itself may be
diagnosis of neurosyphilis, given that benzathine penicillin loosely divided into three stages. Stage I is characterized by
is not capable of consistently inducing treponemocidal lev- a rash, known as erythema chronicum migrans. Stage II is
els of penicillin within the CSF (Holmes et al. 1984). characterized by cardiac conduction defects, polyarthral-
Meningovascular syphilis may be mimicked by other gia, and, in a minority, nervous system involvement with,
disorders capable of causing an indolent basilar meningitis, variously, meningitis, cranial neuritis, and radiculitis; a
such as sarcoidosis, tuberculosis, and mycotic infections. small percentage may also develop an encephalitis. Stage
Gummas may be difficult to distinguish on clinical grounds III may present with an oligoarthritis, a mild dementia, or
from other granulomatous mass lesions. General paresis may both. When Lyme disease is characterized by nervous sys-
mimic other dementias of gradual or subacute onset, as dis- tem involvement, the term ‘neuroborreliosis’ is often used.
cussed in Section 5.1; in this regard, particular attention must Although Borrelia is endemic in certain parts of North
be paid to the possibility of concurrent AIDS dementia. America, particularly the Northeast and the Midwest,
One clinical finding may be very helpful in the differen- Lyme disease itself is uncommon.
tial diagnosis, namely the Argyll Robertson pupil, which is
very rare in other disorders.
Clinical features
Treatment In considering the various stages of Lyme disease it must
be borne in mind that there may be some overlap between
A 2-week course of intravenous penicillin G is the treatment them and that not all patients will experience all three
of choice, and in patients allergic to penicillin consideration stages: stage I is seen in about 75 percent and stage II
p 14.qxd 3/10/08 9:50 AM Page 511
14.16 Lyme disease 511
nervous system involvement occurs in about 15 percent; the with neurologic involvement, and IgM antibodies may be
percentage of patients who develop stage III disease is not found in those with stage I and stage II disease.
clear, but is probably low. Each of these stages is discussed in The CSF may display a lymphocytic pleocytosis, an ele-
turn, followed by a consideration of laboratory testing. vated protein, and oligoclonal bands; anti-Borrelia anti-
bodies may or may not be present. PCR assay is generally
STAGE I less sensitive than testing for antibodies. Although the CSF
is typically clearly abnormal in stage II disease, findings
Erythema chronicum migrans appears anywhere from may be equivocal in stage III.
3 days to a month after the tick bite. The rash is characterized Magnetic resonance scanning in stage III may reveal
by a gradually enlarging, ring-like erythematous lesion, multifocal areas of demyelinization in the subcortical
which as it enlarges leaves a pale, indurated central por- and periventricular white matter, or multifocal areas of
tion, thus creating an overall ‘bull’s-eye’ effect. Smaller, cerebritis.
‘satellite’ lesions may also occur. In general, the rash resolves
spontaneously in a matter of weeks.
Course
STAGE II
This is as noted above.
Stage II typically follows stage I within weeks to months.
Cardiac involvement most frequently manifests with an
atrioventricular block; evidence of pericarditis or even Etiology
myocarditis may also be found. As noted earlier, polyarthral-
gia may also occur. Nervous system involvement classically Erythema chronicum migrans represents a local reaction
manifests with the triad of meningitis, cranial neuritis, and to the infection; hematogenous spread then occurs to the
radiculoneuritis (Hansen and Lebech 1992; Pachner and heart, joints, and nervous system. Various findings have
Steere 1985). The meningitis presents with headache, neck been reported in the nervous system, including a lympho-
stiffness, and malaise. Although cranial neuritis may affect cytic vasculitis in stage II (Meurers et al. 1990), and, in
virtually any of the cranial nerves, by far the most common addition to a small-vessel vasculitis, multifocal areas of
manifestation is a unilateral or bilateral peripheral facial either demyelinization or cerebritis in stage III (Kobayashi
palsy. When radiculitis occurs it is often accompanied by et al. 1997; Oksi et al. 1996).
significant pain. The occurrence of encephalitis is heralded
by somnolence and delirium, and, in a small minority,
seizures or chorea. In addition to this classic triad, one may Differential diagnosis
also find evidence of a mononeuritis multiplex, a primarily
sensory polyneuropathy, or, rarely, a myelitis. In general, In classic cases with a well-documented progression from
symptoms gradually remit over 3–18 months. stage I to stage II and beyond, the diagnosis is fairly
straightforward. Unfortunately, however, as noted earlier,
STAGE III up to one-quarter of patients do not have erythema chron-
icum migrans, and those who do may not recall having it.
Stage III Lyme disease may appear anywhere from months Consequently, diagnosis may rest on a high index of suspi-
to up to a decade after stage I, and may be characterized by cion. In this regard, however, prudence must be exercised
a large-joint oligoarthritis or, in a minority, by a dementia. in evaluating the results of serum testing for anti-Borrelia
The dementia tends to be quite mild and manifests with poor antibodies. Although the absence of IgG antibodies argues
short-term memory, poor concentration, mild somnolence, strongly against the diagnosis, their presence cannot be
fatigue, and either depression or irritability (Halperin et al. seen as strongly confirmatory: in some parts of North
1989; Logigian et al. 1990; Shadick et al. 1994); a peripheral America, 5 percent or more of inhabitants will be seropos-
polyneuropathy may also be present and in a minority there itive, with absolutely no evidence of active disease.
may also be focal signs such as ataxia, aphasia, or hemiplegia;
seizures have also been noted. In one very rare case, stage III
Lyme disease presented with a psychosis characterized by Treatment
delusions of persecution, auditory hallucinations, and stu-
porous catatonia (Pfister et al. 1993). Although some For stage II, intravenous ceftriaxone is recommended; in a
patients may show gradual progression, it appears that in small minority, a Jarisch–Herxheimer-like reaction may
most cases the course is characterized by a stable chronicity. develop soon after the initiation of treatment, with
malaise, fever, and, in some, an exacerbation of the pre-
LABORATORY TESTING senting symptomatology. Treatment of stage III is a matter
of debate. Although some patients with marked dementia
Serum should be tested for both IgG and IgM anti-Borrelia and clearly positive CSF findings definitely respond to cef-
antibodies: IgG antibodies are found in almost all patients triaxone (Steinbach et al. 2005), it appears that patients
p 14.qxd 3/10/08 9:50 AM Page 512
with only mild cognitive complaints do no better with cef- may be either lymphocytic from the start or characterized
triaxone than with placebo (Klempner et al. 2001; Krupp initially by polymorphonuclear cells, which eventually give
et al. 2003). In my opinion, when the diagnosis of stage III way to lymphocytes. The total protein is increased and the
disease is clinically suspected, antibiotic treatment should glucose is decreased. All specimens should be stained for
probably be offered only to patients with positive CSF or acid-fast rods, but the search may be fruitless. Culture
MRI findings. results, although positive in perhaps one-half of cases, may
take weeks, and treatment decisions should never wait
upon them. PCR assay is generally positive (Lin et al. 1995)
14.17 TUBERCULOSIS and results are available promptly.
The PPD skin test may be falsely negative, and this is
Mycobacterium tuberculosis is an acid-fast intracellular particularly likely in those with AIDS (Sanchez-Portocarrero
bacillus that in most cases is spread by droplets from et al. 1996).
patients with pulmonary tuberculosis. In many patients a
focus of infection may be held in check by adequate host
defenses for many years or even decades until some loss of Course
immunocompetence, for example in AIDS or after treat-
ment with steroids or immunosuppressants, is followed by Untreated, tubercular meningitis is generally fatal within
reactivation. Hematogenous spread may carry the bacillus weeks to months, and those who survive may be left with
to various organs, including the brain, where it may cause dementia, cranial nerve palsies, or focal signs (Kalita et al.
a meningitis or present with one or more tuberculomas. 2007). Tuberculomas generally show some progression
In North America the incidence of tuberculosis has but may eventually stabilize, in some cases undergoing
increased dramatically over the past decades, in large part calcification.
because of its occurrence in patients with AIDS; indeed in
some cases tubercular meningitis has constituted the pres- Etiology
entation of AIDS (Barnes et al. 1979).
With hematogenous spread, bacilli may infect the meninges
with the formation of minute tuberculomas; these may
Clinical features subsequently rupture with spread of the bacilli throughout
the subarachnoid space, prompting the development of a
The meningitis seen in tuberculosis is generally basilar in
thick, almost gelatinous exudate that, as noted earlier, is
location and typically presents subacutely, over a matter of
typically basilar in location (Rich and McCordock 1933).
weeks. When fully developed (Davis et al. 1993; Kennedy
Cranial nerves and arteries traversing the exudate may
and Fallon 1979; Sanchez-Portocarrero et al. 1996; Traub
become inflamed with cranial nerve palsies or infarctions.
et al. 1984; Williams and Smith 1954), patients have delir-
In some cases the parenchyma directly subjacent to the
ium or stupor, headache, stiff neck, and fever. Cranial nerves
inflamed meninges may also become infiltrated.
may be entrapped and palsies of cranial nerves III, IV, VI,
Hematogenous spread may also carry bacilli to the brain
and VII are common (McKendrick and Grose 1957). Arteries
parenchyma, with the subsequent development of tubercu-
traversing the inflamed meninges may undergo an arteritis
lomas, which, like tuberculomas anywhere, may undergo
with thrombus formation and infarction of subserved tissue:
caseation necrosis. As noted earlier, these tuberculomas
the basal ganglia are most vulnerable in this regard and there
tend to be multiple and exhibit a broad range in size, from
may be focal signs or abnormal movements, such as tremor,
minute to so large that they destroy an entire lobe.
chorea, or dystonia (Alacon et al. 2000). Involvement of the
hypothalamus or pituitary may lead to either the syndrome
of inappropriate ADH secretion or diabetes insipidus. Differential diagnosis
Obstruction of the outflow foramina of the fourth ventricle is
common and produces obstructive hydrocephalus, with a Tubercular meningitis may be confused with basilar menin-
dramatic worsening of the clinical picture. gitides seen with fungal infections, tertiary neurosyphilis,
Tuberculomas may be single or, more commonly, mul- sarcoidosis, and meningeal carcinomatosis. Tuberculomas
tiple, may occur either in the cerebellum or cerebrum, and may be mimicked by gliomas or other mass lesions.
present as would any mass lesion, with focal signs or
seizures (Damergis et al. 1978).
The spinal cord may also be involved. Spinal meningitis Treatment
may lead to entrapment of nerve roots, and arteritis of
spinal arteries may lead to infarction of the cord. Tuberculous meningitis requires urgent treatment and a
In cases of meningitis, MR scanning typically reveals multiple-drug regimen is typically utilized, often consisting
enhancement of the basilar meninges. In addition, the CSF of isoniazid, rifampin, pyrazinamide, and ethambutol. Given
is often under increased pressure. There is a pleocytosis that the recent emergence of drug-resistant strains (Frieden et al.
p 14.qxd 3/10/08 9:50 AM Page 513
14.18 Whipple’s disease 513
1993), sensitivity testing should be undertaken. If isoniazid but also a positive PCR assay; in this regard, however, it
is used, consideration should be given to supplementation must be kept in mind that, albeit rarely, central nervous
with vitamin B6 to prevent the development of pellagra system Whipple’s disease can occur with a negative small
(Ishii and Nishihara 1985), as discussed in Section 13.3. bowel biopsy (Pollock et al. 1981).
Tuberculomas may be treated with the same drug regi-
men. In some cases, excision is required.
Course
14.18 WHIPPLE’S DISEASE Central nervous system involvement is a grave sign in

Whipple’s disease; in most cases there is a steady progres-
Whipple’s disease, first described by George Hoyt Whipple sion, with death occurring within 6–12 months.
in 1907 (Whipple 1907), is a rare disorder found mostly in
white males, which occurs secondary to infection with a
bacillus known as Tropheryma whippelii. Although Whipple’s Etiology
disease most commonly causes arthralgia and abdominal
complaints, the nervous system may be involved with, as Whipple’s disease, as noted, occurs secondary to infection
described below, a wide variety of signs and symptoms. by T. whippelii (Raoult et al. 2000; Relman et al. 1992).
Within the central nervous system (Powers and Rawe
1979; Smith et al. 1965), focal areas of inflammation and
Clinical features necrosis, along with glial scars, are found in the cerebral
cortex, basal ganglia, hypothalamus, brainstem (especially
Whipple’s disease typically presents in middle years. the periaqueductal gray), and cerebellar cortex. PAS-
Migratory large-joint polyarthralgia is common and patients positive macrophages are found in these areas, and elec-
also typically have abdominal pain, diarrhea, weight loss, tron microscopy may reveal the bacillus within the
and mild fever. In a minority of cases the central nervous macrophage.
system is involved and, although such involvement gener-
ally occurs within the context of long-standing arthralgia
or abdominal symptomatology, there are definite cases in Differential diagnosis
which Whipple’s disease has presented with central nerv-
ous system involvement alone (Adams et al. 1987; Lampert The appearance of dementia, delirium, or personality
et al. 1962; Pruss et al. 2007; Romanul et al. 1977). change in the context of long-standing polyarthralgia or
When the central nervous system is involved (Gerard abdominal complaints is highly suggestive; in these cases,
et al. 2002; Louis et al. 1996; Manzel et al. 2000; Matthews consideration might also be given to Lyme disease or to
et al. 2005), patients typically present with a gradually pro- cerebrotendinous xanthomatosis. The differential for
gressive dementia, delirium or personality change. In most dementia or delirium occurring with myoclonus is discussed
cases other symptoms are also present, including upper in Sections 5.1 and 5.3 respectively. Oculomasticatory
motor neuron signs, ataxia, nystagmus, myoclonus, seizures, myorhythmia, although present in only a minority of cases,
supranuclear ophthalmoplegia, and various manifestations is a particularly valuable sign as it is virtually pathogno-
of hypothalamic dysfunction including sleep disturbance monic for this disease.
(with either hypersomnolence or, less commonly, insomnia), Vitamin B12 deficiency may occur in cases character-
hyperphagia, decreased libido or diabetes insipidus. A small ized by severe diarrhea, making an independent contribu-
minority of patients may also display a very distinctive tion to central nervous system symptomatology.
abnormal movement known as oculomasticatory myorhyth-
mia, in which pendular eye movements occur in concert with
rhythmic jaw movements (Schwartz et al. 1986). Treatment
T2-weighted MRI may reveal multifocal areas of
increased signal intensity within the cerebral cortex, the The general treatment of dementia, delirium, and person-
basal ganglia, thalamus, midbrain, and cerebellar cortex; in ality change is discussed in Sections 5.1, 5.3, and 7.2
some cases these lesions may show enhancement with respectively. Although there are no controlled trials of
gadolinium. antibiotic treatment, most clinicians will begin with a
The CSF may show either a lymphocytic pleocytosis or 2-week course of ceftriaxone, followed by treatment with
an elevated total protein, or both, with a normal glucose. trimethoprim–sulfamethoxazole. The CSF should be mon-
In rare instances some of the white cells may be periodic itored and treatment continued until the patient is clini-
acid–Schiff (PAS) positive. PCR assay is typically, but not cally stable and the CSF has normalized; in many cases this
always, positive for T. whippelii DNA. may take up to 2 years. If antibiotics are discontinued the
The diagnosis may also be established by small bowel patient should be closely monitored as relapses may occur;
biopsy, which may reveal not only PAS-positive macrophages in some cases indefinite treatment is required.
p 14.qxd 3/10/08 9:50 AM Page 514
14.19 ROCKY MOUNTAIN SPOTTED FEVER Treatment

Rocky Mountain spotted fever is a rare disorder secondary In adults, treatment is with tetracycline or doxycycline.
to infection by a tick-borne obligate intracellular parasite,
Rickettsia rickettsii, which manifests classically with fever,
rash, and delirium. Rocky Mountain spotted fever is gener- 14.20 MALARIA
ally found in the Rocky Mountain area and the Appalachians,
and is most common in the spring or early summer. Malaria occurs secondary to infection with any one of four
species of the protozoon Plasmodium, including P. malar-
iae, P. vivax, P. ovale, and P. falciparum. Of these four
Clinical features species, only one, P. falciparum, invades the central nerv-
ous system, thereby causing cerebral malaria.
After the tick bite, which is recalled by only about three- Malaria is endemic in Haiti, much of Asia and Oceania,
quarters of patients, there is a latent interval of from days and in tropical and subtropical areas of Africa and South
to a couple of weeks, after which there is a fairly abrupt America; although it has been eradicated from most of
onset of fever, headache, malaise, and myalgia. After a few North America and Europe, cases may still be seen in those
days, a characteristic maculopapular rash appears: this is returning from travel in endemic areas who did not take
initially present at the ankles and wrists but then spreads to adequate prophylactic medication.
involve the extremities and, in over 50 percent of cases, the
soles and palms. In this setting, most patients become
delirious or lethargic, and this may be accompanied by Clinical features
seizures and various focal signs; coma may supervene (Bell
and Lascari 1970; Horney and Walker 1988; Kirk et al. 1990). Anywhere from 1 to 4 weeks after infection via the bite of an
Pulmonary and hepatic involvement may also occur. Anopheles mosquito, patients fall ill with fever, headache,
The CSF typically shows a mild lymphocytic pleocytosis malaise, and myalgia. A small minority of those patients
and an elevated total protein; the glucose is generally whose malaria has occurred secondary to P. falciparum may
normal. then develop cerebral malaria (Blocker et al. 1968; Idro et al.
Serologic testing may reveal anti-rickettsial IgM or, with 2005), with delirium, stupor or coma, and seizures. Focal
serial testing, a fourfold or greater rise in IgG antibodies. signs, such as hemiparesis, may occur, but are uncommon.
Prompter diagnosis may be obtained via a punch biopsy of The CSF may be normal or may show a mild pleocyto-
affected skin. sis and a mildly elevated total protein.
Diagnosis is made by examination of peripheral blood
smears.
Course
Course
Untreated, the mortality rate is as high as 20 percent.
Among those who survive, recovery occurs gradually in Cerebral malaria is fatal in perhaps one-third of all cases;
a matter of weeks; various sequelae may be found, includ- among those who survive, sequelae may occur in 10–20 per-
ing dementia or any focal signs present during the acute cent of children, including dementia, hemiparesis, aphasia,
illness. ataxia, and blindness (Brewster et al. 1990). Sequelae are
less common in adults, but may include dementia (Roze et al.
2001) and epilepsy (Ngoungou et al. 2006).
Etiology Recently, a ‘post-malaria neurological syndrome’ has
been described (Schnorf et al. 1998; Zambito Marsala et al.
Rickettsia rickettsii undergoes hematogenous spread to the 2006). Here, after recovering from malaria there is an
brain. Within the cortex and the subcortical gray matter asymptomatic latent interval of several weeks, after which
there are multiple petechial hemorrhages and areas of patients fall ill with various symptoms, including delirium,
perivascular inflammation; small arteries may become myoclonus, tremor, aphasia, ataxia, and seizures. The syn-
occluded, resulting in multiple mini-infarcts (Green et al. drome responds promptly to treatment with corticos-
1978; Miller and Price 1972). teroids, and it is suspected that it represents an example of
acute disseminated encephalomyelitis.
Etiology
Typhus may be virtually indistinguishable from Rocky
Mountain spotted fever; however, this disease is virtually Erythrocytes infected with P. falciparum develop ‘knobs’ on
extinct in North America. their cell membranes, which promote the adhesion of the
p 14.qxd 3/10/08 9:50 AM Page 515
14.21 Toxoplasmosis 515
erythrocyte to the vascular endothelium; within the brain, Clinical features

capillaries and post-capillary venules are packed with
infected red cells (Oo et al. 1987). Petechial and ring hem- Although fulminant onsets have been noted, in most cases
orrhages are found scattered throughout the parenchyma central nervous system toxoplasmosis presents subacutely,
and in chronic cases there may be widespread gliotic areas, over a matter of weeks. The presentation is variable (Navia
known as Durck’s granulomas (Oo et al. 1987; Toro and et al. 1986c; Porter and Sande 1992), depending on the
Roman 1978). Cerebral edema is common, and in some number and location of toxoplasma abscesses, and may
cases there may be herniation. include headache, fever, delirium, dementia, seizures
(Pascual-Sedano et al. 1999), and various focal signs, includ-
ing hemianopia, hemiparesis, aphasia, or, uncommonly,
abnormal movements such as dystonia (Factor et al. 2003)
or chorea (Piccolo et al. 1999).
The differential diagnosis of acute encephalitis is discussed
Magnetic resonance scanning reveals toxoplasma
in Section 7.6. In North America and Europe, the diagno-
abscesses as areas of increased signal intensity on T2-
sis should be suspected in travellers who have returned
weighted or FLAIR imaging, which typically show ring
from an endemic area; in this regard it must be kept in
enhancement with gadolinium. Typically, multiple lesions
mind that mosquitoes can gain access to airplanes during
are present in the cortex, white matter, and subcortical
stopovers, and hence it is not necessary for travellers to
structures, but the number varies from a solitary lesion to
actually disembark in endemic areas to become infected.
such a high number as to constitute a miliary presentation.
The CSF may be normal or may display a mild lymphocytic
Treatment pleocytosis and a mildly elevated total protein. Polymerase
chain reaction assay for toxoplasma DNA is generally pos-
Although chloroquine was once considered adequate treat- itive, and occasionally the organism may be detected in the
ment, drug-resistant strains of malaria are emerging, and CSF by staining with Wright’s or Giesma’s stain.
various combination treatments are now recommended. Serologic testing may or may not be helpful. Finding a
Steroids are not recommended (Warrell et al. 1982) and, positive IgG, of course, proves little, given the high preva-
although anti-epileptic drugs may be required, they should lence of past infection among adults; in addition, although
not be given prophylactically. a negative serum IgG anti-toxoplasma antibody would
argue against the diagnosis, in immunocompromised
patients toxoplasmosis may not be accompanied by either
14.21 TOXOPLASMOSIS the appearance of IgM antibodies or a fourfold rise in the
IgG titer. In one large study (Porter and Sande 1992) about
Infection by Toxoplasma gondii is common in birds and one-fifth of patients with AIDS and central nervous system
mammals; cats serve as the definitive hosts and oocysts toxoplasmosis were negative for IgG.
found in cat feces may remain viable for up to a year.
Primary infection in humans occurs secondary to eating Course
contaminated food or undercooked lamb, pork or beef
from infected animals, and is very common: serologic Untreated, central nervous system toxoplasmosis is gener-
studies indicate that about one-third of adults in North ally fatal in a matter of months.
America and Europe have been infected. In the vast major-
ity of cases, host defenses are capable of rapidly controlling
the infection and, during primary infection, patients are Etiology
either asymptomatic or suffer a self-limited mononucleo-
sis-like syndrome. Toxoplasma, however, may not be erad- Although toxoplasma abscesses may occur anywhere in the
icated but remain latent in cysts, often in muscle. brain, favored sites include the junction of the cerebral cor-
Infection of the central nervous system is very rare in tex and subcortical white matter, and the basal ganglia
immunocompetent adults. In immunocompromised (Navia et al. 1986c). These abscesses, as noted earlier, vary
patients, however, central nervous system toxoplasmosis widely both in number and size; in some cases they may
does occur, either during a primary infection or, more com- become quite large. Rarely, an abscess may obstruct CSF
monly, with reactivation of a latent infection. In the pre- outflow, causing obstructive hydrocephalus, and, also rarely,
AIDS era this was noted in patients with cancer or those the pituitary may be involved with subsequent endocrino-
undergoing therapeutic immunosuppression, but was rare logic disturbances.
(Townsend et al. 1975b); with the advent of AIDS, how-
ever, central nervous system toxoplasmosis has become Differential diagnosis
common and indeed is the most common opportunistic
infection in AIDS patients, where it typically appears only Although toxoplasmosis is the most common opportunis-
when the CD4⫹ count falls below 200/mm3. tic central nervous system infection in AIDS, it must
p 14.qxd 3/10/08 9:50 AM Page 516
nevertheless be distinguished from other opportunistic lacunar syndromes, discussed in Section 7.4. With obstruc-
infections, such as tuberculosis, fungal infections, and pro- tion of the outflow foramina of the fourth ventricle, an
gressive multifocal leukoencephalopathy. A solitary toxo- obstructive hydrocephalus may occur, with a dramatic
plasma must also be distinguished from primary central worsening of the overall clinical picture.
nervous system lymphoma. In practice, the differential Magnetic resonance scanning reveals both abscesses
here is often based on a ‘diagnosis by treatment response’ and granulomas and evidence of a basilar meningitis.
strategy: when lesions fail to regress with adequate anti- The CSF may be normal when pathology is confined to
toxoplasma therapy then one or more of the other possibil- abscesses or granulomas. When basilar meningitis is pres-
ities is strenuously investigated. ent, the fluid may be under increased pressure and there is
a pleocytosis, which may be lymphocytic, polymorphonu-
clear, or mixed; the total protein is increased, sometimes
Treatment greatly so, and the glucose is decreased. India ink staining
may reveal cryptococci. Assays for cryptococcal or coccid-
A 2-week course of combination treatment with ioidomycoccal antigen may be positive, and pan-fungal
pyrimethamine and sulfadiazine is generally sufficient to PCR assay appears to hold great promise.
prompt a regression of the lesions; chronic treatment,
however, is typically required to prevent relapses.
Course
14.22 FUNGAL INFECTIONS In the natural course of events, symptoms progress gradu-
ally, typically over months, with a fatal outcome in roughly
Fungal, or mycotic, infection of the central nervous sys- one-half of all cases.
tem (Mori et al. 1992; Walsh et al. 1985a) generally occurs
only in immunocompromised patients, such as those with
AIDS, and includes candidiasis, histoplasmosis, cryptococ- Etiology
cosis, coccidioidomycosis, aspergillosis, and, much less com-
monly, mucormycosis, nocardiosis, or blastomycosis. In Abscesses or granulomas may be single or multiple and
general, the primary site of infection is the respiratory may occur in any part of the cerebrum. Basilar meningitis
tract, most often the lung, and this may represent either an is characterized by a thick exudate at the base of the brain,
initial infection or a reactivation of a latent one. In either which, as noted earlier, may entrap arteries or cranial
case, the brain is typically reached via hematogenous spread; nerves.
aspergillosis at times, however, may spread directly from a
sinus infection.
Clinical features Fungal abscesses and granulomas must be distinguished

from other opportunistic infections, such as toxoplasmosis
Typically, the onset is subacute, over days or weeks, and or tuberculosis. A fungal basilar meningitis may be mim-
patients may or may not be febrile. As noted below, the icked by tuberculosis, tertiary neurosyphilis, and sarcoidosis.
pathology seen in these fungal infections may include
either a basilar meningitis or multiple abscesses or granu-
lomas, or both. In candidiasis, granulomas and abscesses Treatment
predominate (Parker et al. 1981; Roessman and Friede
1967), whereas in histoplasmosis (Cooper and Goldstein Treatment involves amphotericin B, either singly or in
1963), cryptococcosis (Chuck and Sande 1989; Edwards et al. combination with other anti-fungals.
1970) and coccidiomycosis (Caudill et al. 1970), the clinical
picture is often dominated by a basilar meningitis. In
aspergillosis (Walsh et al. 1985b), abscesses and granulomas REFERENCES
are dominant, but here one may also see mycotic aneurysms.
Abscesses and granulomas may either present as mass Abrams DI, Jay CA, Shade SB et al. Cannabis in painful HIV-
lesions, with focal signs determined by their location, or, if associated sensory neuropathy: a randomized placebo-
there are a large number of lesions, a delirium may occur. controlled trial. Neurology 2007; 68:515–21.
Basilar meningitis typically presents with headache and Adams JH, Miller D. Herpes simplex encephalitis: a clinical and
delirium. With entrapment of cranial nerves and arteries pathological analysis of twenty-two cases. Postgrad Med J
that traverse the inflamed meninges, there may be cranial 1973; 49:393–7.
nerve palsies or infarctions; when infarctions do occur they Adams M, Rhyner PA, Day J et al. Whipple’s disease confined to
preferentially involve the penetrating arteries and produce the central nervous system. Ann Neurol 1987; 21:104–8.
p 14.qxd 3/10/08 9:50 AM Page 517
References 517
Adie WJ. Idiopathic narcolepsy: a disease sui generis with remarks Bistrian B, Phillips CA, Kaye IS. Fatal mumps meningoencephalitis.
on the mechanism of sleep. Brain 1926; 49:257–306. JAMA 1972; 222:478–9.
Adle-Biassette H, Bourhy H, Gisselbrecht M et al. Rabies Blatt ML, Hoffman SJ, Schneider M. Rabies: report of twelve
encephalitis in a patient with AIDS: a clinicopathological cases, with a discussion of prophylaxis. JAMA 1938;
study. Acta Neuropathol 1996; 92:415–20. 111:688–91.
Agamanolis DP, Tan JS, Parker DL. Immunosuppressive measles Blocker WW, Kasil AJ, Daroff RB. The psychiatric manifestations
encephalitis in a patient with a renal transplant. Arch Neurol of cerebral malaria. Am J Psychiatry 1968; 125:192–6.
1979; 36:686–90. Bond ED. Epidemic encephalitis and katatonic symptoms. Am J
Aicardi J, Goutieres F, Arsenio-Nunes HL et al. Acute measles Insanity 1920; 76:261–4.
encephalitis in children with immunosuppression. Pediatrics Bouwman FH, Skolasky RL, Hes D et al. Variable progression of
1977; 55:232–5. HIV-associated dementia. Neurology 1998; 50:1814–20.
Alacon F, Duenas G, Cevallos N et al. Movement disorders in 30 Breitbart W, Rosenfeld B, Kaim M et al. A randomized, double-blind,
patients with tuberculous meningitis. Mov Disord 2000; placebo-controlled trial of psychostimulants for the treatment
15:561–9. of fatigue in ambulatory patients with human immunodeficiency
Alpers BJ, Patten CA. Paroxysmal spasm of the eyelids as a virus disease. Arch Int Med 2001; 161:411–20.
postencephalitic manifestation. Arch Neurol Psychiatry 1927; Brewster DR, Kwiatkowski D, White NJ. Neurological sequelae of
18:427–32. cerebral malaria in children. Lancet 1990; 336:1039–43.
Anlar B, Saatci I, Kose G et al. MRI findings in subacute sclerosing Budka H, Urbanits S, Liberski PP et al. Subacute measles virus
panencephalitis. Neurology 1996; 47:1278–83. encephalitis: a new and fatal opportunistic infection in a
Applebaum E, Rachelson MH, Dolgopol VB. Varicella encephalitis. patient with AIDS. Neurology 1996; 46:586–7.
Am J Med 1953; 15:233–6. Burgdorfer W, Barbour AF, Hayes SF et al. Lyme disease – a
Applebaum E, Krebs SI, Sunshine A. Herpes zoster encephalitis. tick-borne spirochetosis. Science 1982; 216:1317–19.
Am J Med 1962; 32:25–31. Buzzard EF, Greenfield JG. Lethargic encephalitis: its sequelae and
Astrom KE, Mancall EL, Richardson EP. Progressive multifocal morbid anatomy. Brain 1919; 42:305–38.
leuko-encephalopathy: a hitherto unrecognized complication Caparros-Lefebvre D, Girard-Buttaz I, Rebout S et al. Cognitive
of chronic lymphatic leukaemia and Hodgkin’s disease. Brain and psychiatric impairment in herpes simplex virus
1958; 81:93–111. encephalitis suggest involvement of the amygdalo-frontal
Aurelius E, Johansson G, Skoldenberg B et al. Rapid diagnosis of pathways. J Neurol 1996; 243:248–56.
herpes simplex encephalitis by nested polymerase chain Cape CA, Martinez AJ, Robertson JJ et al. Adult onset of subacute
reaction assay of cerebrospinal fluid. Lancet 1991; sclerosing panencephalitis. Arch Neurol 1973; 28:124–7.
337:189–92. Caudill RG, Smith CE, Reinharz JA. Coccidioidal meningitis. A
Ayuso-Peralta L, Jimenez-Jimenez FJ, Tejeiro J et al. Progressive diagnostic challenge. Am J Med 1970; 49:360–5.
multifocal leukoencephalopathy in HIV infection presenting as Causey JQ. Spontaneous cytomegalovirus mononucleosis-like
Balint’s syndrome. Neurology 1994; 44:1339–40. syndrome and aseptic meningitis. South Med J 1976;
Azimi PH, Cramblett HG, Haynes RE. Mumps meningoencephalitis 69:1384–7.
in children. JAMA 1969; 207:509–12. Chadwick DW, Martin S, Buxton PH et al. Measles virus and
Baringer JR, Swoveland P. Recovery of herpes simplex virus from subacute neurological disease: an unusual presentation of
human trigeminal ganglions. N Engl J Med 1973; 228:648–50. measles inclusion body encephalitis. J Neurol Neurosurg
Barnes PF, Bloch AB, Davidson PT et al. Tuberculosis in patients Psychiatry 1982; 45:680–4.
with human immunodeficiency virus. N Engl J Med 1979; Chandra K, Shafiq N, Pandhi P et al. Gabapentin versus
301:126–30. nortriptyline in post-herpetic neuralgia patients: a
Beach RS, Morgan R, Wilkie F et al. Plasma vitamin B12 level as a randomized, double-blind clinical trial – the GONIP Trial.
potential cofactor in studies of human immunodeficiency virus Int J Clin Pharmacol Ther 2006; 44:358–63.
type 1-related cognitive changes. Arch Neurol 1992; Ch’ien L, Hathaway BM, Israel CW. Seronegative dementia
49:501–6. paralytica: report of a case. J Neurol Neurosurg Psychiatry
Bell WE, Lascari AD. Rocky Mountain spotted fever. Neurologic 1970; 33:376–80.
manifestations in the acute phase. Neurology 1970; 20:841–7. Chopra JS, Banerjee AK, Murthy JMK et al. Paralytic rabies: a
Bergin JD. Fatal encephalopathy in glandular fever. J Neurol clinicopathological study. Brain 1980; 103:789–802.
Neurosurg Psychiatry 1960; 23:69–73. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in
Berman SM, Kim RC. The development of cytomegalovirus the acquired immunodeficiency syndrome. N Engl J Med 1989;
encephalitis in AIDS patients receiving ganciclovir. Am J Med 321:580–4.
1994; 96:415–19. Cobb WA, Marshall J, Scaravilli F. Long survival in subacute
Bhatia KP, Morris JH, Frackowiak RS. Primary progressive sclerosing panencephalitis. J Neurol Neurosurg Psychiatry
multifocal leukoencephalopathy presenting as an 1984; 47:176–83.
extrapyramidal syndrome. J Neurol 1996; 243:91–5. Conde-Sendin MA, Amela-Paris R, Aladro-Benito Y et al. Current
Bianchi M, Frera C. A case of brain gumma. J Neurol Neurosurg clinical spectrum of neurosyphilis in immunocompetent
Psychiatry 1957; 20:133–5. patients. Eur Neurol 2004; 52:29–35.
p 14.qxd 3/10/08 9:50 AM Page 518
Conomy JP, Leibovitz A, McCombs W et al. Airborne rabies Dupont JR, Earle KM. Human rabies encephalitis: a study of forty-
encephalitis: demonstration of rabies virus in the human nine fatal cases with a review of the literature. Neurology
central nervous system. Neurology 1977; 27:67–9. 1965; 15:1023–34.
Cooper RA, Goldstein E. Histoplasmosis of the central nervous Duvoisin RC, Yahr MD. Encephalitis and parkinsonism. Arch Neurol
system. Report of two cases and review of the literature. Am J 1965; 12:227–39.
Med 1963; 35:45–57. Dworkin RH, Corbin AE, Young JP et al. Pregabalin for the
Croxson MC, Anderson NE, Vaughn AA et al. Subacute measles treatment of postherpetic neuralgia: a randomized, placebo-
encephalitis in an immunocompetent adult. J Clin Neurosci controlled trial. Neurology 2003; 60:1274–83.
2002; 9:600–4. Edwards VE, Sutherland JM, Tyrer JH. Cryptococcosis of the
Dale RC, Church AJ, Surtees RA et al. Encephalitis lethargica central nervous system. J Neurol Neurosurg Psychiatry 1970;
syndrome: 20 new cases and evidence of basal ganglia 33:415–25.
autoimmunity. Brain 2004; 127:21–33. Eidelberg D, Sotrel A, Hooupian DS et al. Thrombotic cerebral
Damergis JA, Leftwich EI, Curtin JA et al. Tuberculoma of the vasculopathy associated with herpes zoster. Ann Neurol 1986;
brain. JAMA 1978; 239:413–15. 19:7–14.
Dana Consortium on the Therapy of HIV Dementia and Related Epstein MA, Achong BG. Pathogenesis of infectious
Cognitive Disorders. A randomized, double-blind, placebo- mononucleosis. Lancet 1977; 2:1270–3.
controlled trial of deprynel and thioctic acid in human Esiri MM. Herpes simplex encephalitis. An immunohistological
immunodeficiency virus-associated cognitive impairment. study of the distribution of viral antigen within the brain.
Neurology 1998; 50:645–51. J Neurol Sci 1982; 54:209–26.
Davies JA, Hughes JT, Oppenheimer DR. Richardson’s disease Factor SA, Troche-Panetto M, Weaver SA. Dystonia in AIDS: report
(progressive multifocal leukoencephalopathy). Q J Med 1973; of four cases. Mov Disord 2003; 18:1492–8.
42:481–93. Fermaglich J, Hardman JM, Earle KM. Spontaneous progressive
Davis LE, Schmitt JW. Clinical significance of cerebrospinal fluid multifocal leukoencephalopathy. Neurology 1970; 20:479–85.
tests for neurosyphilis. Ann Neurol 1989; 25:50–5. Finklestein H. Meningoencephalitis in mumps. JAMA 1938;
Davis LE, Sperry S. The CSF-FTA test and the significance of blood 111:17–19.
contamination. Ann Neurol 1979; 6:68–9. Fisher CM. Hypomanic symptoms caused by herpes simplex
Davis LE, Rastogi KR, Lambert LC et al. Tuberculous meningitis in encephalitis. Neurology 1996; 47:1374–8.
the southwest United States: a community-based study. Fisher RS, Clark AW, Wolinsky JS et al. Post-infectious
Neurology 1993; 43:1775–8. leukoencephalitis complicating Mycoplasma pneumoniae
Davis LE, DeBiasi R, Goade DE et al. West Nile virus neuroinvasive infection. Arch Neurol 1983; 40:109–13.
disease. Ann Neurol 2006; 60:286–300. Fleet WS, Watson RT, Ballinger WE. Resolution of gumma with
Dawson JR. Cellular inclusions in cerebral lesions of epidemic steroid therapy. Neurology 1986; 36:1104–7.
encephalitis. Arch Neurol Psychiatry 1934; 31:685–700. Fournier JCM, Helguera RAL. Postencephalitic narcolepsy and
Devinsky O, Cho E-S, Petito CK et al. Herpes zoster myelitis. Brain cataplexy: muscles and motor nerves inexcitability during the
1991; 114:1991–9. attack of cataplexy. J Nerv Ment Dis 1934; 80:159–62.
Dickman MS. von Economo encephalitis. Arch Neurol 2001; Freedman MJ, Odland LT, Cleve EA. Infectious mononucleosis with
58:1696–8. diffuse involvement of nervous system: report of a case. Arch
Doja A, Bitnun A, Ford Jones EL et al. Pediatric Epstein–Barr virus- Neurol Psychiatry 1953; 69:49–54.
associated encephalitis: 10-year review. J Child Neurol 2006; Frieden TR, Sterling T, Pables-Mendes A et al. The emergence of
21:384–91. drug-resistant tuberculosis in New York City. N Engl J Med
Dolgopol VB, Greenberg M, Aronoff R. Encephalitis following 1993; 328:521–6.
smallpox vaccination. Arch Neurol Psychiatry 1955; Fujimoto H, Asaoka K, Imaizumi T et al. Epstein-Barr infections of
73:216–23. the central nervous system. Intern Med 2003; 42:33–40.
Donner M, Waltimo O, Poros J et al. Subacute sclerosing Gascon GG, International Consortium on Subacute Sclerosing
panencephalitis as a cause of chronic dementia and Panencephalitis. Randomized treatment study of inosiplex
relapsing brain disorder. J Neurol Neurosurg Psychiatry 1972; versus combined inosiplex and intraventricular inteferon-alfa
35:180–5. in subacute sclerosing panencephalitis (SSPE): international
Dooneief G, Bello J, Todak G et al. A prospective controlled study multicenter study. J Child Neurol 2003; 18:819–27.
of magnetic resonance imaging of the brain in gay men and Gautier-Smith PC. Neurological complications of glandular fever.
parenteral drug users with human immunodeficiency virus Brain 1965; 88:323–34.
infection. Arch Neurol 1992; 49:38–43. Gazzola P, Cocito L, Capello E et al. Subacute measles encephalitis
Doyle P, Gibson GM, Dolman CL. Proved herpes zoster arteritis in a young man immunocompromised for ankylosing
with cerebral infarct. J Neuropathol Exp Neurol 1982; spondylitis. Neurology 1999; 52:1074–7.
41:351. Geddes JF, Hughes AJ, Lees AJ et al. Pathological overlap in cases
Duncalf CM, Kent JNG, Harbord M et al. Subacute sclerosing of parkinsonism associated with neurofibrillary tangles. A
panencephalitis presenting as schizophreniform psychosis. study of recent cases of postencephalitic parkinsonism and
Br J Psychiatry 1989; 155:557–9. comparison with progressive supranuclear palsy and
p 14.qxd 3/10/08 9:50 AM Page 519
References 519
Guamanian parkinsonism–dementia complex. Brain 1993; study of 187 patients with Borrelia burgdorferi specific
116:281–302. intrathecal antibody production. Brain 1992; 115:399–423.
Gerard A, Sarrot-Reynauld F, Liozon E et al. Neurologic Hart MN, Earle KM. Haemorrhagic and perivenous encephalitis: a
presentation of Whipple disease: report of 12 cases and review clinical–pathological review of 38 cases. J Neurol Neurosurg
of the literature. Medicine 2002; 81:443–57. Psychiatry 1975; 38:585–91.
Gilden DH, Murray RS, Wellish M et al. Chronic progressive Hensen J, Rosenblum M, Armstrong D et al. Amplification of JC
varicella-zoster virus encephalitis in an AIDS patient. virus DNA from brain and cerebrospinal fluid of patients with
Neurology 1988; 38:1150–3. progressive multifocal leukoencephalopathy. Neurology 1991;
Gilden DH, Wright RR, Schneck SA et al. Zoster sine herpete, a 41:1967–71.
clinical variant. Ann Neurol 1994; 35:530–3. Herzlich BC, Schiano TD. Reversal of apparent AIDS dementia
Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold, complex following treatment with vitamin B12. J Intern Med
2000. 1993; 233:495–7.
Gimenez-Roldan S, Martin M. Tabetic lightning pains: high- Herzon H, Shelton JT, Bruyn HG. Sequelae of western equine and
dosage intravenous penicillin versus carbamazepine therapy. other arthropod-borne encephalitides. Neurology 1957;
Eur Neurol 1981; 20:424–8. 7:535–48.
Glass JD, Wesselingh SL, Selnes OA et al. Clinical-neuropathologic Hilt DC, Bucholz D, Krumholz A et al. Herpes zoster ophthalmicus
correlation in HIV-associated dementia. Neurology 1993; and delayed contralateral hemiparesis caused by cerebral
43:2230–7. angiitis: diagnosis and management approaches. Ann Neurol
Gomez EA, Aviles M. Neurosyphilis in community mental health 1983; 14:543–53.
clinics: a case series. J Clin Psychiatry 1984; 45:127–9. Hochberg FH, Miller DC. Primary central nervous system
Gordon SM, Eaton ME, George R et al. The response of lymphoma. J Neurosurg 1988; 68:835–53.
symptomatic neurosyphilis to high-dose intravenous penicillin Hogan EL, Krigman MR. Herpes zoster myelitis: evidence for viral
G in patients with human immunodeficiency virus infection. invasion of spinal cord. Arch Neurol 1973; 29:309–13.
N Engl J Med 1994; 331:1469–73. Hohman LB. Epidemic encephalitis (lethargic encephalitis): its
Gray F, Gherardi R, Scaravilli F. The neuropathology of the psychotic manifestations with a report of twenty-three cases.
acquired immune deficiency syndrome (AIDS): a review. Brain Arch Neurol Psychiatry 1921; 6:295–333.
1988; 11:245–66. Hohman LB. Post-encephalitic behavior disorders in children. Bull
Green WR, Walker DH, Cain BG. Fatal viscerotropic Rocky Johns Hopkins Hosp 1922; 33:372–5.
Mountain spotted fever. Report of a case diagnosed by Hokkanen L, Salonen O, Launes J. Amnesia in acute herpetic and
immunofluorescence. Am J Med 1978; 64:523–8. nonherpetic encephalitis. Arch Neurol 1996; 53:972–8.
Greenberg DA, Weinkle DJ, Aminoff MJ. Periodic EEG complexes Holland NR, Power C, Mathews VP et al. Cytomegalovirus
in infectious mononucleosis encephalitis. J Neurol Neurosurg encephalitis in acquired immunodeficiency syndrome (AIDS).
Psychiatry 1982; 45:648–51. Neurology 1994; 44:507–14.
Greenfield JG. The pathology of measles encephalomyelitis. Brain Hollinger P, Sturzenegger M, Mathis J et al. Acute disseminated
1929; 52:171–95. encephalomyelitis in adults: a reappraisal of clinical, CSF, EEG
Greenwood R, Bhalla A, Gordon A et al. Behavior disturbances and MRI findings. J Neurol 2002; 249:320–9.
during recovery from herpes simplex encephalitis. J Neurol Holmes MD, Brant-Zawadzki MM, Simon RP. Clinical features of
Neurosurg Psychiatry 1983; 46:809–17. meningovascular syphilis. Neurology 1984; 34:553–6.
Guillaume B. Sindic CJ, Weber T. Progressive multifocal Horney LF, Walker DH. Meningoencephalitis as a major manifestation
leukoencephalopathy: simultaneous detection of JCV DNA and of Rocky Mountain spotted fever. South Med J 1988; 81:915–18.
anti-JCV antibodies in cerebrospinal fluid. Eur J Neurol 2000; Howard RS, Lees AJ. Encephalitis lethargica: a report of four
7:101–6. recent cases. Brain 1987; 110:19–33.
Guilleminault C, Mondini S. Mononucleosis and chronic daytime Hriso E, Kuhn T, Masdeu JC et al. Extrapyramidal symptoms
sleepiness. A long-term follow-up study. Arch Int Med 1986; due to dopamine-blocking agents in patients with AIDS
146:1333–5. encephalopathy. Am J Psychiatry 1991; 148:1558–61.
Guilleux MH, Steneir RE, Young IR. MR imaging in progressive Huang D, Cossoy M, Li M et al. Inflammatory progressive
multifocal leukoencephalopathy. AJNR 1986; 7:1033–5. multifocal leukoencephalopathy in human immunodeficiency
Hahn K, Arendt G, Braun JS et al. A placebo-controlled trial of virus-negative patients. Ann Neurol 2007; 62:34–9.
gabapentin for painful HIV-associated sensory neuropathies. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features,
J Neurol 2004; 251:1260–6. and neurological outcome of cerebral malaria. Lancet Neurol
Hahn RD, Webster B, Weickhardt G et al. Penicillin treatment of 2005; 4:827–40.
general paresis (dementia paralytica). Arch Neurol Psychiatry Ishii N, Nishihara Y. Pellagra encephalopathy among tuberculosis
1959; 81:557–90. patients: its relation to isoniazid therapy. J Neurol Neurosurg
Halperin JJ, Luft BJ, Anand AK et al. Lyme neuroborreliosis: central Psychiatry 1985; 48:628–34.
nervous system manifestations. Neurology 1989; 39:753–9. Ishii T, Nakamura Y. Distribution and ultrastructure of Alzheimer’s
Hansen K, Lebech AM. The clinical and epidemiological profile of neurofibrillary tangles in postencephalitic parkinsonism of
Lyme neuroborreliosis in Denmark 1985–1990. A prospective Economo type. Acta Neuropathol 1981; 55:59–62.
p 14.qxd 3/10/08 9:50 AM Page 520
Jelliffee SE. Oculogyric crises as compulsion phenomena in Kobayashi K, Mizukoshi C, Aoki T et al. Borrelia-burgdorferi-
postencephalitis: their occurrence, phenomenology and seropositive encephalomyelopathy: Lyme neuroborreliosis?
meaning. J Nerv Ment Dis 1929; 69:59–68, 165–84, 278–97, An autopsied report. Dement Geriatr Cogn Disord 1997;
415–26, 531–51, 666–9. 8:384–90.
Jemsek J, Greenberg SB, Tabor L et al. Herpes zoster-associated Koehler K, Jakumeit U. Subacute sclerosing panencephalitis
encephalitis: clinicopathologic report of twelve cases and presenting as Leonhard’s speech-prompt catatonia. Br J
review of the literature. Medicine 1983; 62:81–97. Psychiatry 1976; 129:29–31.
Johns DR, Tierney M, Felsenstein D. Alteration in the natural Koralnik IJ, Boden O, Mai VX et al. JC virus DNA load in patients
history of neurosyphilis by concurrent infection with the with and without progressive multifocal leukoencephalopathy.
human immunodeficiency virus. N Engl J Med 1987; Neurology 1999; 52:253–60.
316:1569–72. Koskiniemi M, Donner M, Pettay O. Clinical appearance and
Johnson RT, Milbourn PE. Central nervous system manifestations outcome in mumps encephalitis in children. Acta Paediatr
of chickenpox. Can Med Assoc J 1970; 102:831–6. Scand 1983; 72:603–9.
Kalayjian RC, Cohen ML, Bonomo RA et al. Cytomegalovirus Koskiniemi M, Piiparinen H, Mannonen L et al. Herpes encephalitis
ventriculoencephalitis in AIDS. A syndrome with distinct is a disease of middle aged and elderly people: polymerase
clinical and pathologic features. Medicine 1993; 72:67–77. chain reaction for detection of herpes simplex virus in the CSF
Kalita J, Misra UK. Markedly severe dystonia in Japanese of 516 patients with encephalitis. J Neurol Neurosurg
encephalitis. Mov Disord 2000; 15:1168–72. Psychiatry 1996; 60:174–8.
Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological Krumholz S, Luhan JA. Encephalitis associated with herpes zoster.
sequelae of tuberculous meningitis: a multivariate analysis. Arch Neurol Psychiatry 1945; 53:59–67.
Eur J Neurol 2007; 14:33–7. Krupp LB, Lipton RB, Swerdlow ML et al. Progressive multifocal
Kamei S, Sekizawa T, Shiota H et al. Evaluation of combination leukoencephalopathy: clinical and demographic features.
therapy using aciclovir and corticosteroid in adult patients Ann Neurol 1985; 17:344–9.
with herpes simplex virus encephalitis. J Neurol Neurosurg Krupp LB, Hyman LG, Grimson R et al. Study and treatment of
Psychiatry 2005; 76:1544–9. post Lyme disease (STOP-LD). A randomized double masked
Kapur N, Barker S, Burrows EH et al. Herpes simplex encephalitis: clinical trial. Neurology 2003; 60:1923–30.
long term magnetic resonance imaging and Kuker W, Mader I, Nagele T et al. Progressive multifocal
neuropsychological profile. J Neurol Neurosurg Psychiatry leukoencephalopathy; value of diffusion-weighted and
1994; 57:1334–42. contrast-enhanced magnetic resonance imaging for diagnosis
Kastrup O, Maschke M, Diener HC et al. Progressive multifocal and treatment control. Eur J Neurol 2006; 13:819–26.
leukoencephalopathy limited to the brainstem. Neuroradiology Lampert P, Tom MI, Cumings JN. Encephalopathy in Whipple’s
2002; 44:227–9. disease: a histochemical study. Neurology 1962; 12:65–71.
Kennedy DH, Fallon RJ. Tuberculous meningitis. J Am Med Assoc Landau WM, Luse SA. Relapsing inclusion encephalitis (Dawson
1979; 241:264–8. type) of eight years’ duration. Neurology 1958; 8:669–76.
Kennedy PGE. A retrospective study of forty-six cases of herpes Laothamatas J, Hemachudha T, Mitrabhakdi E et al. MR imaging
simplex encephalitis seen in Glasgow between 1962 and 1985. in human rabies. AJNR 2003; 24:1102–9.
Q J Med 1988; 68:533–40. Leavell R, Ray CG, Ferry PC et al. Unusual acute neurologic
Kesserling J, Miller DH, Robb SA et al. Acute disseminated presentations with Epstein–Barr virus infection. Arch Neurol
encephalomyelitis. MRI findings and the distinction from 1986; 43:186–8.
multiple sclerosis. Brain 1990; 113:291–302. Lebon P, Lyon G. Non-congenital rubella encephalitis. Lancet
Kieburtz K, Zettelmaier AE, Ketonen L et al. Manic syndrome in 1974; 2:468.
AIDS. Am J Psychiatry 1991; 148:1068–70. Leech RW, Harris JC. The neuropathology of Western equine and
Kieburtz K, Simpson D, Yiannoutsos C et al. A randomized trial of St Louis encephalitis: a review of the 1975 North Dakota
amitriptyline and mexiletine for painful neuropathy in HIV epidemic. J Neuropathol Exp Neurol 1977; 36:611.
infection. AIDS Clinical Trial Group 242 Protocol Team. Levitt LP, Rich TA, Kinde SW et al. Central nervous system mumps:
Neurology 1998; 51:1682–8. a review of 64 cases. Neurology 1970; 20:829–34.
Kirby GH, Davis TK. Psychiatric aspects of epidemic encephalitis. Lewis L, Taylor HG, Sorem MB. Japanese B encephalitis: clinical
Arch Neurol Psychiatry 1921; 5:491–551. observations in an outbreak on Okinawa Shima. Arch Neurol
Kirk JL, Fine DP, Sexton DJ et al. Rocky Mountain spotted fever. Psychiatry 1947; 57:430–63.
A clinical review based on 48 confirmed cases, 1943–1986. Lilly R, Cummings JL, Benson DF et al. The human Kluver–Bucy
Medicine 1990; 69:35–45. syndrome. Neurology 1983; 33:1141–5.
Kleinschmidt-DeMasters BK, Amlie-Lefond C, Gilden DH. The Lima MA, Drislane FW, Koralink IJ. Seizures and their outcome in
patterns of varicella zoster encephalitis. Hum Pathol 1996; progressive multifocal leukoencephalopathy. Neurology 2006;
27:927–38. 66:262–4.
Klempner MS, Hu LT, Evans J et al. Two controlled trials of Lin JJ, Harn HJ, Hsue YD et al. Rapid diagnosis of tuberculous
antibiotic treatment in patients with persistent symptoms and meningitis by polymerase chain reaction assay of
a history of Lyme disease. N Engl J Med 2001; 345:85–92. cerebrospinal fluid. J Neurol 1995; 242:147–52.
p 14.qxd 3/10/08 9:50 AM Page 521
References 521
Linnemann CC, Alvira MM. Pathogenesis of varicella-zoster Melanson M, Chalk C, Georgevich L et al. Varicella-zoster virus
angiitis in the CNS. Arch Neurol 1980; 37:239–40. DNA in CSF and arteries in delayed contralateral hemiplegia:
Logigian EL, Kaplan RF, Steere AC. Chronic neurologic evidence for viral invasion of cerebral arteries. Neurology
manifestations of Lyme disease. N Engl J Med 1990; 1996; 47:569–70.
323:1438–44. Meninger KA. Influenza and schizophrenia. Am J Psychiatry 1926;
Louis ED, Lynch T, Kaufman P et al. Diagnostic guidelines in 82:469–529.
central nervous system Whipple’s disease. Ann Neurol 1996; Merritt HH, Adams RD, Solomon HC. Neurosyphilis. New York:
40:561–8. Oxford University Press, 1946.
Lukehart SA, Hook EW, Baker-Zander SA et al. Invasion of the Meurers B, Kohlepp WRG, Rohrbach E et al. Histopathological
central nervous system by Treponema pallidum: implications findings in the central and peripheral nervous system in
for diagnosis and treatment. Ann Int Med 1988; 109:855–62. neuroborreliosis. A report of three cases. J Neurol 1990;
Mahalingam R, Wellis M, Wolf W et al. Latent varicella-zoster 327:113–16.
viral DNA in human trigeminal and thoracic ganglia. N Engl J Miller AE. Selective decline in cellular immune response
Med 1990; 323:627–9. to varicella-zoster in the elderly. Neurology 1980;
Maher J, Choudri S, Halliday W et al. AIDS dementia complex with 30:582–7.
generalized myoclonus. Mov Disord 1997; 12:593–7. Miller HG, Stanton JB, Gibbons JL. Para-infectious
Malouf R, Jacquette G, Dobkin J et al. Neurologic disease in encephalomyelitis and related syndromes. Q J Med 1956;
human immunodeficiency virus-infected drug abusers. Arch 25:427–505.
Neurol 1990; 47:1002. Miller JQ, Price TR. The nervous system in Rocky Mountain
Manzel K, Tranel D, Cooper G. Cognitive and behavioral spotted fever. Neurology 1972; 22:561–70.
abnormalities in a case of central nervous system Whipple de la Monte SM, de la Gabuzda DH, Ho DD et al. Peripheral
disease. Arch Neurol 2000; 57:399–403. neuropathy in the acquired immunodeficiency syndrome.
Marchioni E, Ravaglia S, Piccolo G et al. Postinfectious Ann Neurol 1988; 23:485–92.
inflammatory disorders. Subgroups based on prospective Morgello S, Cho ES, Nielsen S et al. Cytomegalovirus encephalitis
follow-up. Neurology 2005; 65:1057–65. in patients with acquired immunodeficiency syndrome: an
Marlowe WB, Mancall EL, Thomas TJ. Complete Kluver–Bucy autopsy study of 30 cases and a review of the literature. Hum
syndrome in man. Cortex 1975; 11:53–9. Pathol 1987; 18:289–97.
Marsden CD, Fowler TJ. Clinical neurology, 2nd edn. London: Morgello S, Estanislao L, Simpson D et al. HIV-associated distal
Arnold, 1998. sensory polyneuropathy in the era of highly active
Marton R, Gotlieb-Steimatsky T, Klein C et al. Acute herpes antiretroviral therapy: the Manhattan HIV Brain Bank. Arch
simplex encephalitis: clinical assessment and prognostic data. Neurol 2004; 61:546–51.
Acta Neurol Scand 1996; 93:149–55. Mori T, Ebe T. Analysis of cases of central nervous system fungal
Matthews BR, Jones LK, Saad DA et al. Cerebellar ataxia and infections reported in Japan between January 1979 and June
central nervous system Whipple disease. Arch Neurol 2005; 1989. Intern Med 1992; 31:174–9.
62:618–20. Moscovich DG, Singh MB, Eva FJ et al. Acute disseminated
Mayo DR, Booss J. Varicella zoster-associated neurologic disease encephalomyelitis presenting as an acute psychotic state.
without skin lesions. Arch Neurol 1989; 46:313–15. J Nerv Ment Dis 1995; 183:116–17.
McArthur JC. Neurologic manifestations of AIDS. Medicine 1987; Moulignier A, Mikol J, Pialoux G et al. AIDS-associated progressive
66:407–11. multifocal leukoencephalopathy revealed by new-onset
McArthur JC, Hoover DR, Bacellar H et al. Dementia in AIDS seizure. Am J Med 1995; 99:64–8.
patients: incidence and risk factors. Neurology 1993; Mulder DW, Parrott M, Thaler M. Sequelae of Western equine
43:2245–52. encephalitis. Neurology 1951; 1:318–27.
McCall S, Henry JM, Reid AH et al. Influenza RNA not detected in Nagel MA, Forghani B, Mahalingam R et al. The value of detecting
archival brain tissues from acute encephalitis lethargica cases anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy.
or in postencephalitic Parkinson cases. J Neuropathol Exp Neurology 2007; 68:1069–73.
Neurol 2001; 60:696–704. Navia BA, Price RW. The acquired immunodeficiency syndrome
McCormick WF, Rodnitzky RL, Schochet SS et al. Varicella-zoster dementia complex as the presenting or sole manifestation of
encephalomyelitis. Arch Neurol 1969; 21:559–70. human immunodeficiency virus infection. Ann Neurol 1987;
McCowan PK, Cook LC, Cantab BA. Oculogyric crises in chronic 44:656–9.
epidemic encephalitis. Brain 1928; 51:285–309. Navia BA, Jordan BD, Price RW. The AIDS dementia complex. I.
McGrath N, Anderson NE, Croxson MC et al. Herpes simplex Clinical features. Ann Neurol 1986a; 19:517–24.
encephalitis treated with acyclovir: diagnosis and long term Navia BA, Jordan BD, Price RW. The AIDS dementia complex. II.
outcome. J Neurol Neurosurg Psychiatry 1997; 63:321–6. Neuropathology. Ann Neurol 1986b; 19:525–35.
McKendrick GDW, Grose RJ. Tuberculous meningitis. J Neurol Navia BA, Petito CK, Gold JWM et al. Cerebral toxoplasmosis
Neurosurg Psychiatry 1957; 20:198–201. complicating the acquired immune deficiency syndrome:
MacKenzie RA, Forbes GS, Karnes WE. Angiographic findings in clinical and neuropathological findings in 27 patients. Ann
herpes zoster arteritis. Ann Neurol 1981; 10:458–64. Neurol 1986c; 19:224–38.
p 14.qxd 3/10/08 9:50 AM Page 522
Ngoungou EB, Koko J, Druet-Cabanac M et al. Cerebral malaria Porter SB, Sande MA. Toxoplasmosis of the central nervous
and sequelar epilepsy: first matched case-control study in system in the acquired immunodeficiency syndrome. N Engl J
Gabon. Epilepsia 2006; 47:2147–53. Med 1992; 327:1643–8.
Northam RS, Singer HS. Postencephalitic acquired Tourette-like Powers JM, Rawe SE. A neuropathological study of Whipple’s
syndrome in a child. Neurology 1991; 41:592–3. disease. Acta Neuropathol 1979; 48:223–6.
Ohya T, Martinez AJ, Jabbour JT et al. Subacute sclerosing Pradhan S, Pandey N, Shashank S et al. Parkinsonism due to
panencephalitis. Neurology 1974; 24:211–18. predominant involvement of substantia nigra in Japanese
Oksi J, Kalimo H, Marttila RJ et al. Inflammatory brain changes in encephalitis. Neurology 1999; 53:1781–6.
Lyme borreliosis. A report on three patients and review of the Prashanth LK, Taly AB, Ravi V et al. Adult subacute sclerosing
literature. Brain 1996; 119:2143–54. panencephalitis: clinical profile of 39 patients from a tertiary
Oo MM, Aikawa M, Than T et al. Human cerebral malaria: care center. J Neurol Neurosurg Psychiatry 2006; 77:630–3.
pathological study. J Neuropathol Exp Neurol 1987; Price RW, Nielsen S, Horten B et al. Progressive multifocal
46:223–31. leukoencephalopathy: a burnt-out case. Ann Neurol 1983;
O’Riordan JI, Gomez-Anson B, Moseley IF et al. Long term MRI 13:485–9.
follow-up of patients with post infectious encephalomyelitis: Price RW, Berew B, Sidtis J et al. The brain in AIDS: central
evidence for a monophasic disease. J Neurol Sci 1999; nervous system HIV-1 infection and AIDS dementia complex.
167:132–6. Science 1988; 239:586–91.
Ozturk A, Gurses C, Baykan B et al. Subacute sclerosing Pruss H, Katchanov J, Zschederlein R et al. A patient with cerebral
panencephalitis: clinical and magnetic resonance imaging Whipple disease with gastric involvement but not
evaluation of 36 patients. J Child Neurol 2002; 17:25–9. gastrointestinal symptoms: a consequence of local protective
Pachner AR, Steere AC. The triad of neurologic manifestations of immunity? J Neurol Neurosurg Psychiatry 2007; 78:896–8.
Lyme disease: meningitis, cranial neuritis and radiculoneuritis. Przelomski MM, O’Rourke E, Grady GF et al. Eastern equine
Neurology 1985; 35:47–53. encephalitis in Massachusetts. Neurology 1988; 38:736–9.
Padgett BL, Walker DL, Zurheim GM et al. Cultivation of papova- Rabkin JG, Wagner GJ, Rabkin R. Fluoxetine treatment for
like virus from human brain with progressive multifocal depression in patients with HIV and AIDS: a randomized,
leukoencephalopathy. Lancet 1971; 1:1257–60. placebo-controlled trial. Am J Psychiatry 1999; 156:101–7.
Pantaleo G, Graziosi C, Fauci AS. The immunopathogenesis of Rail D, Scholtz C, Swash M. Post-encephalitic parkinsonism: current
human immunodeficiency virus infection. N Engl J Med 1993; experience. J Neurol Neurosurg Psychiatry 1981; 44:670–6.
328:327–35. Raoult D, Birg ML, La Scola B et al. Cultivation of the bacillus of
Pardo J, Marcos A, Bhathal H et al. Chorea as a form of Whipple’s disease. N Engl J Med 2000; 342:620–5.
presentation of human immunodeficiency virus-associated Relman DA. Schmidt TM, MacDermott RP et al. Identification of
dementia complex. Neurology 1998; 50:568–9. the uncultured bacillus of Whipple’s disease. N Engl J Med
Parker JC, McCloskey JJ, Lee RS. Human cerebral candidosis. A 1992; 327:293–301.
post mortem evaluation of 19 patients. Hum Pathol 1981; Reyes MG, Gardner JJ, Poland JD et al. St Louis encephalitis:
12:23–8. quantitative, histologic and immunofluorescent studies. Arch
Parr J, Horoupian DS, Winkelman AC. Cerebellar form of Neurol 1981; 38:329–34.
progressive multifocal leukoencephalopathy (PML). Can J Rich AR, McCordock HA. The pathogenesis of tuberculous
Neurol Sci 1979; 6:123–8. meningitis. Bull Johns Hopkins Hosp 1933; 52:5–37.
Pascual-Sedano B, Iranzo A, Marti-Fabregas J et al. Prospective Richardson EP. Progressive multifocal leukoencephalopathy.
study of new-onset seizures in patients with human N Engl J Med 1961; 265:815–23.
immunodeficiency virus infection. Arch Neurol 1999; 56:609–12. Richter RW, Shimojyo S. Neurologic sequelae of Japanese B
Paskavitz JF, Anderson CA, Filley CM et al. Acute arcuate fiber encephalitis. Neurology 1961; 11:553–9.
demyelination encephalopathy following Epstein–Barr virus Risk WS, Haddad FS. The variable natural history of subacute
infection. Ann Neurol 1995; 38:127–31. sclerosing panencephalitis: a study of 118 cases from the
Petersen I, Thomas JM, Hamilton WT et al. Risk and predictors of middle east. Arch Neurol 1979; 36:610–14.
fatigue after infectious mononucleosis in a large primary-care Risk WS, Haddad FS, Chemali R. Substantial spontaneous long-
cohort. Q J Med 2006; 99:49–55. term improvement in subacute sclerosing panencephalitis: six
Pfister H-W, Preac-Mursic V, Wilske B et al. Catatonic syndrome cases from the middle east and overview of the literature.
in acute severe encephalitis due to Borrelia burgdorferi Arch Neurol 1978; 35:495–502.
infection. Neurology 1993; 43:433–5. Roessman U, Friede RL. Candidal infection of the brain. Arch
Piccolo I, Causarano R, Sterzi R et al. Chorea in patients with Pathol 1967; 48:495–8.
AIDS. Acta Neurol Scand 1999; 100:332–6. Romanul FCA, Radvany J, Rosales RK. Whipple’s disease confined
Pollock S, Lewis PD, Kendall B. Whipple’s disease confined to the to the brain: a case confirmed clinically and pathologically.
central nervous system. J Neurol Neurosurg Psychiatry 1981; J Neurol Neurosurg Psychiatry 1977; 40:901–9.
44:1104–9. Rothschild D. Dementia paralytica accompanied by manic-
Porras C, Barboza JJ, Fuenzalida E et al. Recovery from rabies in depressive and schizophrenic psychoses. Am J Psychiatry 1940;
man. Ann Intern Med 1976; 85:44–8. 96:1043–60.
p 14.qxd 3/10/08 9:50 AM Page 523
References 523
Roulet Perez E, Mader P, Cotting J et al. Acute fatal parainfectious Simon RP. Neurosyphilis. Arch Neurol 1985; 42:606–13.
cerebellar swelling in two children. A rare or an overlooked Simpson DM, McArthur JC, Olney R et al. Lamotrigine for HIV-
situation? Neuropediatrics 1993; 24:346–51. associated painful sensory neuropathies: a placebo-controlled
Roze E, Thiebault MM, Mazevet D et al. Neurologic sequelae after trial. Neurology 2003; 60:1508–14.
severe falciparum malaria in adult travelers. Eur Neurol 2001; Smardel JE, Bailey P, Baker AB. Sequelae of the arthropod-borne
46:192–7. encephalitides. Neurology 1958; 8:873–96.
Russel J, Fisher M, Zivin JA et al. Status epilepticus and Epstein- Smith WT, Frency JM, Guttsmann M et al. Cerebral complications
Barr virus encephalopathy. Diagnosis by modern serologic of Whipple’s disease. Brain 1965; 88:137–50.
techniques. Arch Neurol 1985; 42:789–92. Solomon T, Dung NM, Kneen R et al. Japanese encephalitis.
Russell DS. The nosological unity of acute haemorrhagic J Neurol Neurosurg Psychiatry 2000; 68:405–15.
leucoencephalitis and acute disseminated encephalomyelitis. Solomon T, Dung NM, Kneen R et al. Seizures and raised
Brain 1955; 78:369–76. intracranial pressure in Vietnamese patients with Japanese
Russell RR, Donald JC. The neurological complications of mumps. encephalitis. Brain 2002; 125:1084–93.
BMJ 1958; 2:27–30. Sponzilli EE, Smith JK, Malamud N et al. Progressive multifocal
Sage JI, Weinstein MP, Miller DC. Chronic encephalitis possibly leukoencephalopathy: a complication of immunosuppressive
due to herpes simplex virus: two cases. Neurology 1985; treatment. Neurology 1975; 25:664–8.
35:1470–2. Srinivasan A, Burton EC, Kuehnert MJ et al. Transmission of rabies
Salib EA. Subacute sclerosing panencephalitis (SSPE) presenting virus from an organ donor to four transplant recipients. N Engl
at the age of 21 as a schizophrenia-like state with bizarre J Med 2005; 352:1103–11.
dysmorphophobic features. Br J Psychiatry 1988; 152:709–10. Steinbach JP, Melms A, Skalej M et al. Delayed resolution of white
Sanchez-Portocarrero J, Perez-Cecilia E, Jimenez-Escrig A et al. matter changes following therapy of B burgdorferi
Tuberculous meningitis: clinical characteristics and comparison encephalitis. Neurology 2005; 64:758–9.
with cryptococcal meningitis in patients with human Storm-Mathisen A. General paresis: a follow-up study of 203
immunodeficiency virus infection. Arch Neurol 1996; 53:671–6. patients. Acta Psychiatr Scand 1969; 45:118–32.
Sands IJ. The acute psychiatric type of epidemic encephalitis. Strauss SE, Reinhold W, Smith HA et al. Endonuclease analysis of
Am J Psychiatry 1928; 84:975–87. viral DNA from varicella and subsequent zoster infections in
Schlesinger RD, Crelinsten GL. Infectious mononucleosis the same patients. N Engl J Med 1984; 311:1362–4.
dominated by neurologic symptoms and signs. Can Med Assoc Studahl M, Rickstein A, Sandberg T et al. Cytomegalovirus
J 1977; 117:652–3. infection of the CNS in non-compromised patients. Acta
Schnell RG, Dyck PJ, Bowie EJW et al. Infectious mononucleosis: Neurol Scand 1994; 89:451–7.
neurologic and EEG findings. Medicine 1966; 45:51–63. Sweeney CJ, Gilden DG. Ramsey Hunt syndrome. J Neurol
Schnorf H, Diserens K, Schnyder H et al. Corticosteroid-responsive Neurosurg Psychiatry 2001; 71:149–54.
postmalaria encephalopathy characterized by motor aphasia, Sworn MJ, Urich H. Acute encephalitis in infectious
myoclonus, and postural tremor. Arch Neurol 1998; mononucleosis. J Pathol 1970; 100:201–5.
55:417–20. Taylor EW, McDonald CA. Forced conjugate upward movement of
Schube PG. Emotional states of general paresis. Am J Psychiatry the eyes following epidemic encephalitis. Arch Neurol
1934; 91:625–38. Psychiatry 1928; 19:95–103.
Schultz DR, Barthal JS, Garrett C. Western equine encephalitis Tenembaum S, Chamoles N, Fejerman N. Acute disseminated
with rapid onset parkinsonism. Neurology 1977; 27:1095–6. encephalomyelitis. A long-term follow-up of 84 pediatric
Schwartz MA, Selhorst JB, Ochs AI et al. Oculomasticatory patients. Neurology 2002; 59:1224–31.
myorhythmia: a unique movement disorder occurring in Thompson JA. Mumps: a cause of acquired aqueductal stenosis.
Whipple’s disease. Ann Neurol 1986; 20:677–83. J Pediatr 1979; 94:923–4.
Schwarz S, Mohr A, Knauth M et al. Acute disseminated Torgovnik J, Arsura EL, Lala D. Cytomegalovirus
encephalomyelitis. A follow-up study of 40 adult patients. ventriculoencephalitis presenting as a Wernicke’s
Neurology 2001; 56:1313–18. encephalopathy-like syndrome. Neurology 2000;
Sellal F, Mohr M, Collard M. Dementia in a 58-year-old woman. 55:1910–13.
Lancet 1996; 347:236. Toro G, Roman G. Cerebral malaria. A disseminated
Shadick NA, Phillis CB, Logigian EL et al. The long-term clinical vasculomyelopathy. Arch Neurol 1978; 35:271–5.
outcomes of Lyme disease. Ann Intern Med 1994; 121:560–7. Townsend JJ, Baringer JR, Wolinsky JS et al. Progressive rubella
Sharer LR, Epstein LG, Cho ES et al. HTLV-III and vacuolar panencephalitis: late onset after congenital rubella. N Engl J
myelopathy in AIDS. N Engl J Med 1986; 315:62–3. Med 1975a; 292:990–3.
Shill HA, Stacy MA. Malignant catatonia secondary to sporadic Townsend JJ, Wolinsky JS, Baringer JR et al. Acquired
encephalitis lethargica. J Neurol Neurosurg Psychiatry 2000; toxoplasmosis: a neglected cause of treatable central nervous
69:402–3. system disease. Arch Neurol 1975b; 32:335–43.
Silverstein A, Steinberg G, Nathanson M. Nervous system Townsend JJ, Wolinsky JS, Baringer JR. The neuropathology of
involvement in infectious mononucleosis. Arch Neurol 1972; progressive rubella panencephalitis of late onset. Brain 1976;
26:353–8. 99:81–90.
p 14.qxd 3/10/08 9:50 AM Page 524
Townsend JJ, Stroop WG, Baringer JR et al. Neuropathology of Whitley RJ, Alford CA, Hirsch MS et al. Vadarabine versus
progressive rubella panencephalitis after childhood rubella. acyclovir therapy in herpes simplex encephalitis. N Engl J Med
Neurology 1982; 32:185–90. 1986; 314:144–9.
Traub M, Colchester ACF, Kingsley DPE et al. Tuberculosis of the Wiley CA, Masliah E, Morey M et al. Neocortical damage during
central nervous system. Q J Med 1984; 53:81–100. HIV infection. Ann Neurol 1991; 29:651–7.
Tselis A, Duman R, Storch GA et al. Epstein–Barr virus Wilkins RH, Brody IA. Encephalitis lethargica. Arch Neurol 1968;
encephalomyelitis diagnosed by polymerase chain reaction: 18:324–8.
detection of the genome in the CSF. Neurology 1997; Williams BB, Lerner AM. Some previously unrecognized features
48:1351–5. of herpes simplex encephalitis. Neurology 1978; 28:1193–6.
Upton A, Gumpert J. Electroencephalography in diagnosis of Williams M, Smith HV. Mental disturbances in tuberculous
herpes-simplex encephalitis. Lancet 1970; 1:650–2. meningitis. J Neurol Neurosurg Psychiatry 1954; 17:173–82.
Vaheri A, Julkunen I, Koskiniemi M. Chronic encephalomyelitis Willoughby RE, Tieves KS, Hoffman GM et al. Survival after
with specific increase in intrathecal mumps antibodies. Lancet treatment of rabies with induction of coma. N Engl J Med
1982; 2:685–8. 2005; 352:2508–14.
Van Bogaert L. Ocular paroxysms and palilalia. J Nerv Ment Dis Wilson LG. Viral encephalopathy mimicking functional psychosis.
1934; 80:48–61. Am J Psychiatry 1976; 133:165–70.
Vintners HV, Kwok MK, Ho HW et al. Cytomegalovirus in the Wolinsky JS, Berg BO, Maitland CJ. Progressive rubella
nervous system of patients with the acquired panencephalitis. Arch Neurol 1976; 33:722–3.
immunodeficiency syndrome. Brain 1989; 112:245–68. Wolinsky JS, Swoveland P, Johnson KP et al. Subacute measles
Walsh TJ, Hier DB, Caplan LR. Fungal infections of the encephalitis complicating Hodgkin’s disease in an adult.
central nervous system: comparative analysis of risk factors Ann Neurol 1977; 1:452–4.
and clinical signs in 57 patients. Neurology 1985a; Wong MC, Suite ND, Labar DR. Seizures in human
35:1654–7. immunodeficiency virus infection. Arch Neurol 1990; 47:640–2.
Walsh TJ, Hier DB, Caplan LR. Aspergillosis of the central nervous Wulf CH. Subacute sclerosing panencephalitis: serial
system: clinicopathological analysis of 17 patients. Ann Neurol electroencephalographic studies. J Neurol Neurosurg
1985b; 18:574–82. Psychiatry 1982; 45:418–21.
Warrell DA, Loorareesuwan S, Warrell MJ et al. Dexamethasone Yamada S, Kaneyama T, Nagaya S et al. Relapsing herpes simplex
proves deleterious in cerebral malaria. A double-blind trial in encephalitis: pathological confirmation of viral reactivation.
100 comatose patients. N Engl J Med 1982; 306:313–19. J Neurol Neurosurg Psychiatry 2003; 74:262–4.
Wasay M, Diaz-Arrastia R, Suss RA et al. St Louis encephalitis. Young CA, Humphrey DM, Ghadiali EJ et al. Short-term memory
A review of 11 cases in a 1995 Dallas, Tex, epidemic. Arch impairment in an alert patient as a presentation of herpes
Neurol 2000; 57:114–18. simplex encephalitis. Neurology 1992; 42:260–1.
Watson CP, Vernich L, Chipman M et al. Nortriptyline versus Yousry TA, Major EO, Ryschkewitsch C et al. Evaluation of patients
amitriptyline in postherpetic neuralgia: a randomized trial. treated with natalizumab for progressive multifocal
Neurology 1998; 51:1166–71. leukoencephalopathy. N Engl J Med 2006; 354:924–33.
Weaver S, Rosenblum MK, DeAngelis LM. Herpes varicella zoster Zambito Marsala S, Ferracci F, Cecotti L et al. Post-malaria
encephalitis in immunocompromised patients. Neurology neurological syndrome: clinical and laboratory findings in one
1999; 52:193–5. patient. Neurol Sci 2006; 27:442–4.
Weil ML, Itibashi HH, Cremer NE et al. Chronic progressive Zifko U, Linder K, Wimberger D et al. Jarisch–Herxheimer reaction
panencephalitis due to rubella virus simulating subacute in a patient with neurosyphilis. J Neurol Neurosurg Psychiatry
sclerosing panencephalitis. N Engl J Med 1975; 292:994–8. 1994; 57:865–7.
Whipple GH. A hitherto undescribed disease characterized Zunt JR, Tu RK, Anderson DM et al. Progressive multifocal
anatomically by deposits of fat and fatty acids in the leukoencephalopathy presenting as human immunodeficiency
intestinal and mesenteric lymphatic tissues. Johns Hopkins virus type 1 (HIV)-associated dementia. Neurology 1997;
Hosp Bull 1907; 18:382–91. 49:263–5.
p 15.qxd 3/10/08 9:51 AM Page 525
15
Prion diseases
15.1 Creutzfeldt–Jakob disease 525 15.4 Fatal familial insomnia 528

15.2 New-variant Creutzfeldt–Jakob disease 527 15.5 Kuru 529
15.3 Gerstmann–Sträussler–Scheinker disease 528 References 530
15.1 CREUTZFELDT–JAKOB DISEASE akinetic variety may occur, as may upper motor neuron
signs, and, in a small minority, evidence of lower motor
Creutzfeldt–Jakob disease, also known as transmissible neuron dysfunction, such as fasciculations, may be seen.
spongiform encephalopathy, is characterized by a fairly Seizures occur in a small minority.
rapidly progressive dementia accompanied, in most cases, Magnetic resonance imaging (MRI) generally discloses
by myoclonus. In the past, this disease was also termed a cortical atrophy, the progression of which may be moni-
‘slow virus’ infection; however, it is now known that it is tored with serial scans. T2-weighted and fluid-attenuated
caused not by a virus but by a unique agent known as a inversion recovery (FLAIR) imaging, and, with greater sen-
prion. This is a rare disorder, occurring at a yearly rate of sitivity, diffusion-weighted imaging, may display increased
1–2 cases per 1 000 000, and is equally common in males signal intensity in the striatum and in the cerebral and
and females. About 85 percent of cases occur on a sporadic cerebellar cortices; within the cortex the increased signal
basis, 10 percent are inherited on an autosomal dominant intensity follows the cortical ribbon, displaying a ‘gyri-
basis, and the remainder represent iatrogenic infections, as form’ pattern (Shiga et al. 2004; Tschampa et al. 2005).
has occurred with dura mater grafts for example. The electroencephalogram (EEG) may show generalized
slowing (Burger et al. 1972) and in some cases frontal inter-
mittent rhythmic delta activity (FIRDA) has been noted
Clinical features (Wieser et al. 2004). The most characteristic EEG findings,
however, are periodic spike-and-slow-wave complexes
On average, sporadic cases appear in the early sixties, but (Collins et al. 2006; Levy et al. 1986; May 1986; Steinhoff
the range is wide, from late teenage years to the tenth et al. 2004), which are eventually seen in anywhere from
decade. Inherited cases tend to appear a bit earlier, mostly one-half to three-quarters of all cases. Importantly, the EEG
in the early fifties. Iatrogenic cases appear anywhere from may become abnormal only as the disease progresses, and
1 to 30 years after the infectious event. Although most cases consequently, when the initial EEG fails to reveal this finding,
appear subacutely, over weeks to months, fulminant onsets it may be appropriate to perform serial EEGs.
spanning only a few days have been reported. The cerebrospinal fluid (CSF) is acellular with a normal
The overall symptomatology of Creutzfeldt–Jakob dis- glucose; in a very small minority the total protein level
ease has been described in several studies (Brown et al. may show a mild elevation. Most importantly, the 14-3-3
1986, 1994; Collins et al. 2006; Cooper et al. 2006; Glatzel et protein is found in anywhere from 50 to 95 percent of cases
al. 2005; Roos et al. 1973). The presentation may be with (Collins et al. 2006; Geschwind et al. 2003; Hsich et al.
dementia, personality change, psychosis (Dervaux et al. 1996; Lemstra et al. 2000; Rosenmann et al. 1997; Van
2004; Zeng et al. 2001), cerebellar ataxia, or visual sympto- Everbroeck et al. 2005; Zerr et al. 1998a).
matology, such as hemianopia or cortical blindness; rare Although, at present, a definitive ante-mortem diagnosis
presentations include aphasia (Mandell et al. 1989), the may be made only by brain biopsy, this is rarely performed.
alien hand sign (MacGowan et al. 1997), or mania
(Lendvai et al. 1999). With progression almost all patients Course
become profoundly demented, and the dementia is accom-
panied by myoclonus (which may be stimulus responsive) This disease progresses rapidly, with death occurring within
in almost 90 percent of cases. Parkinsonism of the rigid, about 6 months on average. The overall range, however,
p 15.qxd 3/10/08 9:51 AM Page 526
526 Prion diseases
is wide, with some dying in as little as a month and others et al. 1980). The finding of prions within the olfactory neu-
surviving for up to 3 years (Masters and Richardson 1978; roepithelium is intriguing in this regard, as their presence
Pocchiara et al. 2004; Will and Mathews 1984). The rapid could be accounted for either by spread from the brain
progression is one of the hallmarks of Creutzfeldt–Jakob dis- down the olfactory tracts and filia, in which case they
ease, and often one may seen a decline from week to week. might merely be seen as epiphenomenal, or by contact with
airborne prions from an infected person, in which case
they could represent the bridgehead of an infection. Recent
Etiology work has further subdivided sporadic cases according to
the type of pathologic prion protein present and to a poly-
Microscopically there is widespread spongiform change morphism at codon 129 of PRNP (Parchi et al. 1999a). The
within the gray matter of the cerebral cortex, basal ganglia, pathologic prion protein actually exists in two isoforms,
thalamus, and cerebellar cortex (Masters and Richardson type 1 and type 2, and in each patient it appears that only
1978), which in turn is accounted for by grossly swollen one type is present. At codon 129 of PRNP there is a nor-
dendrites and axons (Beck et al. 1982; Chou et al. 1980). mal isomorphism with either a methionine or a valine
In a small minority, perhaps 5–10 percent of cases, plaques allele, thus there are potentially three genotypes, namely
resembling the amyloid plaques seen in Alzheimer’s disease MM, MV, and VV. Combining both the type of pathologic
may be found. In contrast to the plaques of Alzheimer’s prion protein and the genotype gives six potential variants
disease, however, these plaques are not composed of beta- of sporadic Creutzfeldt–Jakob disease, namely MM1,
amyloid but appear to be, at least in part, composed of pri- MM2, MV1, MV2, VV1, and VV2. At present, it is not clear
ons (Kitamoto et al. 1986). There is also neuronal loss and how useful this classification scheme is for clinical work.
astrogliosis, but very little, if any, inflammation. It must be Inherited cases occur secondary to any one of a large
emphasized that prions are found not only in the central number of mutations in the PRNP gene (Goldfarb et al.
nervous system but also in peripheral nerves (Favereaux et 1990; Hsiao et al. 1991a; Owen et al. 1989). Importantly, in
al. 2004), olfactory neuroepithelium (Tabaton et al. 2004; many cases mutations may occur spontaneously, and here,
Zanusso et al. 2003), spleen, and muscle (Glatzel et al. of course, the family history will be negative (Ladogana et al.
2003). 2005).
The prion protein is a normally occurring cellular pro- Iatrogenic cases have occurred upon inadvertent expo-
tein that is coded for by the PRNP gene on chromosome sure to tissue from patients with Creutzfeldt–Jakob disease
20. It is a constituent of the neuronal cell membrane and via the following procedures: corneal transplants (Duffy et al.
undergoes recycling from the exterior surface of the cell 1974; Heckmann et al. 1997); dura mater grafts (Brown
membrane into the cytoplasm, where it is digested by et al. 2000; Hannah et al. 2001; Heath et al. 2006; Miyashita
lysozymes. The agent responsible for Creutzfeldt–Jakob et al. 1991); the use of contaminated electrodes during neu-
disease is a pathologic form of the prion protein The nor- rosurgical procedures (Bernouilli et al. 1977); injections of
mal prion protein exists in an alpha-helical conformation, human growth hormone (Billette de Villemeur et al. 1991,
whereas the pathologic prion protein exists for the most 1996; Brown et al. 2000); and the injection of human pitu-
part in a beta-sheet conformation (Pan et al. 1993). This itary gonadotrophins (Cochius et al. 1992; Healy and Evans
beta-sheet conformation allows for aggregation of these 1993); it is of especial interest that a case also occurred sec-
pathologic prion proteins once they recycle into the cyto- ondary to the use of lyophilized dura mater in the treat-
plasm and, as they aggregate and coalesce, a particle known ment of a nasopharyngeal angiofibroma, a procedure in
as a prion is formed. Eventually, with an accumulation of which the dura mater remained extracranial (Antoine et al.
prions, spongiform change occurs. 1997). The persistence of prions cannot be overemphasized:
As an aside, in the literature the normal form of the in one case (Gibbs et al. 1994), electrodes that had been used
prion protein is often referred to as PrPc, with the ‘c’ during neurosurgery on a patient with Creutzfeldt–Jakob
derived from the fact that these are normal ‘cellular’ com- disease 2 years earlier were cleaned three times and repeat-
ponents. The pathologic form, however, is often referred to edly sterilized in ethanol and formaldehyde vapor yet were
as PrPsc, with the ‘sc’ derived from ‘scrapie’, which is the still able to transmit the disease to a chimpanzee.
name given to a disease similar to Creutzfeldt–Jakob dis- Presumably, in these iatrogenic cases, the pathogenic prion
ease that is found in sheep. protein acts as a template that alters the conformation of
As noted earlier, Creutzfeldt–Jakob disease may occur the patient’s normal prion protein into the pathologic
sporadically, as an autosomal dominantly inherited dis- beta-sheet protein.
ease, or iatrogenically, and each of these is now discussed
in turn.
The etiology of the sporadic cases is not clear. Some Differential diagnosis
believe that they represent spontaneous, age-related trans-
formations of normal cellular prion proteins into patho- The diagnosis of Creutzfeldt–Jakob disease is often sus-
genic prion proteins, whereas others suspect that they may pected in cases of a fairly rapidly progressive dementia when
represent infections with a long incubation period (Galvez accompanied by myoclonus. As discussed in Section 5.1,
p 15.qxd 3/10/08 9:51 AM Page 527
15.2 New-variant Creutzfeldt-Jakob disease 527
however, the combination of dementia and myoclonus is 15.2 NEW-VARIANT CREUTZFELDT–JAKOB

not specific for Creutzfeldt–Jakob disease, and other possi- DISEASE
bilities must be considered, including Hashimoto’s
encephalopathy, AIDS dementia, Whipple’s disease, suba- New-variant Creutzfeldt–Jakob disease is a very rare infec-
cute sclerosing panencephalitis, and two other prion dis- tious prion disease acquired by eating meat derived from
eases, namely new-variant Creutzfeldt–Jakob disease and cows that had bovine spongiform encephalopathy, or ‘mad
fatal familial insomnia. New-variant Creutzfeldt–Jakob dis- cow disease’. Although most cases have occurred in the
ease is only rarely associated with periodic complexes on the UK, at least one has been reported in the United States
EEG (Binelli et al. 2006), and also displays a distinctive ‘pul- (Belay et al. 2005).
vinar’ sign on MRI, with increased signal intensity seen in
the pulvinar of the thalamus. Fatal familial insomnia is
marked, as the name dramatically suggests, by severe insom- Clinical features
nia (which is only rarely prominent in Creutzfeldt–Jakob
disease [Landolt et al. 2006; Taratuto et al. 2002]) and lacks The incubation period between the ingestion of contami-
periodic complexes. Other disorders may also enter the dif- nated meat and the development of the disease is probably
ferential, such as diffuse Lewy body disease or Alzheimer’s less than 20 years. The onset of the disease is subacute, and
disease, but these rarely show the rapid progression charac- although most patients have been in their late 20s, the
teristic of Creutzfeldt–Jakob disease. range of age of onset is wide, from early adolescence to the
Periodic spike-and-slow-wave complexes, although eighth decade.
highly suggestive of Creutzfeldt–Jakob disease, may also, as Most patients present with behavioral changes such as
noted in Section 1.2, be seen in other disorders, including depression or, less commonly, personality change, with-
not only post-anoxic encephalopathy and subacute scle- drawal, agitation, insomnia, apathy, emotional lability, or
rosing panencephalitis but also herpes simplex viral psychosis, which in turn may comprise visual and auditory
encephalitis. hallucinations and Schneiderian first-rank symptoms
The presence of 14-3-3 protein reflects acute damage, (Will et al. 2000; Zeidler 1997a,b); the remainder present
and it may be seen not only in Creutzfeldt–Jakob disease but with ataxia, dysesthesiae or memory loss, or a combination
also in new-variant Creutzfeldt–Jakob disease; it is rarely of these and behavioral changes. With progression a
seen in fatal familial insomnia, Hashimoto’s encephalopa- dementia eventually appears that is often accompanied by
thy, limbic encephalitis, viral encephalitis, acute stroke (as myoclonus (Allroggen et al. 2000; Collinge and Rossor
may occur in the course of a multi-infarct dementia), and 1996; Will et al. 1996; Zeidler et al. 1997a).
multiple sclerosis (Hsich et al. 1996; Lemstra et al. 2000; FLAIR MR scanning displays a distinctive ‘pulvinar’ sign
Martinez et al. 2001; Saiz et al. 1999; Sanchez-Juan et al. in approximately three-quarters of all patients, character-
2006; Van Everbroeck et al. 2005). ized by increased signal intensity in the pulvinar of the thal-
amus (Zeidler et al. 2000). In addition to this pulvinar sign,
increased signal intensity may also occur in the basal ganglia
Treatment and the cerebral and cerebellar cortices (Collie et al. 2003).
The EEG may demonstrate generalized slowing (Zeidler
The general treatment of dementia is discussed in Section et al. 1997a). With rare exceptions (Binelli et al. 2006),
5.1. To date, the only medication shown to have any spe- periodic spike-and-slow-wave complexes are absent (Zeidler
cific usefulness in a double-blind study is flupirtine, which et al. 1997a).
may slow the progression of the disease (Otto et al. 2004); The CSF is acellular with a normal total protein; the
quinacrine is not useful (Haik et al. 2004). Early uncon- 14-3-3 protein is found in about 50 percent of cases (Green
trolled reports suggested a usefulness for amanatadine et al. 2001; Sanchez-Juan et al. 2006; Will et al. 2000).
(Braham 1971; Sanders 1979; Sanders and Dunn 1973; Tonsilar biopsy appears to be both sensitive and specific
Terzano et al. 1983), but these have not been validated. In (Hill et al. 1999).
familial cases, genetic counselling should be offered.
The question inevitably arises as to what sorts of precau- Course
tions should be in place to guard against transmission of the
disease. Although isolation does not appear to be necessary, The disease is relentlessly progressive, with most patients
routine universal precautions are appropriate. It is critical to dying within a little over a year, with a range of 18 months
avoid contamination via CSF, blood, or biopsy specimens, to 3 years (Will et al. 2000).
and it must be borne in mind that routine sterilization pro-
cedures, including autoclaving and alcohol immersion, are
not effective. In cases of accidental contact, consideration Etiology
may be given to washing with a 1:10 solution of 5 percent
common hypochlorite bleach, which is effective. Pins used As noted earlier, new-variant Creutzfeldt–Jakob disease
for sensory testing in any patient should never be used twice. occurs secondary to eating beef from cows that had bovine
p 15.qxd 3/10/08 9:51 AM Page 528
528 Prion diseases
spongiform encephalopathy (Bruce et al. 1997); in turn, The EEG may show generalized slowing but there are no
cows contract the disease by eating meal made from the periodic complexes; the CSF is normal and the 14-3-3 pro-
offal of sheep that had a transmissible spongiform tein is absent.
encephalopathy known as scrapie. Host factors appear to
play a role in susceptibility among humans in that, with
rare exceptions (Ironside et al. 2006), all patients have been Course
homozygous for methionine at codon 129 of PRNP, the
gene for normal prion proteins found on chromosome 20 For a prion disease the course is relatively slow, with death,
(Collinge et al. 1996; Will et al. 2000). on average, after 5–6 years.
Within the thalamus, basal ganglia, and also the cere-
bral and cerebellar cortices there are widespread prion Etiology
plaques surrounded by spongiform change (Will et al.
1996). In this disease prions are not restricted to the brain Gerstmann–Sträussler–Scheinker disease may occur sec-
but are also found in tonsils, lymph nodes, and the spleen ondary to any one of several mutations in the PRNP gene.
(Hill et al. 1999). It also appears that prions are present in Mutations have been noted at codons 102 (Arata et al.
the blood, and, alarmingly, there have been cases of new- 2006; Brown et al. 1991; Goldhammer et al. 1993; Hsiao
variant Creutzfeldt–Jakob disease occurring secondary to et al. 1989; Kretzchmar et al. 1992; Young et al. 1995), 105
blood transfusion (Wroe et al. 2006). (Kitamoto et al. 1993; Yamada et al. 1993), 117 (Hsiao et al.
1991b; Nochlin et al. 1989), 198 (Farlow et al. 1989; Ghetti
et al. 1989), and 217 (Hsiao et al. 1992).
Differential diagnosis Pathologically, regardless of which mutation is at fault,
all cases of Gerstmann–Sträussler–Scheinker disease share
The differential diagnosis is as described for Creutzfeldt– a common feature, namely the presence of multicentric
Jakob disease in Section 15.1. As noted here, the pulvinar sign amyloid plaques that stain positively for prion proteins
is quite important, but it must be borne in mind that it is not (Kitamoto et al. 1986; Roberts et al. 1986). In some cases,
specific for new-variant Creutzfeldt–Jakob disease and has unicentric spiky plaques, similar to those seen in kuru, may
been reported in cases of limbic encephalitis (Mihara et al. also occur, and in others neurofibrillary tangles may be
2005) and, albeit rarely, in sporadic Creutzfeldt–Jakob dis- seen. Spongiform change is either minimal or absent.
ease (Petzold et al. 2004). Although the distribution of these microscopic changes
varies, the cerebellar cortex, basal ganglia, and cerebral
cortex are generally involved.
Treatment
There is no specific treatment for this disease; general Differential diagnosis
treatment recommendations are as discussed for
Creutzfeldt–Jakob disease in Section 15.1. Strenuous efforts The differential diagnosis of dementia occurring in the
are in place to prevent bovine spongiform encephalopathy; context of ataxia is discussed in Section 5.1.
however, given the difficulty in monitoring the food chain,
continual vigilance is necessary.
Treatment
There is no specific treatment; genetic counselling should
15.3 GERSTMANN–STRÄUSSLER– be offered, and the general treatment of dementia is dis-
SCHEINKER DISEASE cussed in Section 5.1.
Gerstmann–Sträussler–Scheinker disease is a very rare,
autosomal dominantly inherited prion disease character- 15.4 FATAL FAMILIAL INSOMNIA
ized classically by ataxia and, eventually, dementia.
Fatal familial insomnia is a rare prion disease, character-
ized, as the name suggests, by severe insomnia, which is
Clinical features typically accompanied by a dementia and prominent auto-
nomic disturbances.
The onset is subacute or gradual, and usually in the sixth
decade, with a wide range from the third to the eighth
decades. Classically (Barbanti et al. 1996; Farlow et al. Clinical features
1989), patients present with a progressive ataxia with the
eventual development of a dementia; in some cases Onset is typically subacute or gradual and occurs in middle
parkinsonism or long-tract signs may also occur. years, with a wide range from late adolescence to the seventh
p 15.qxd 3/10/08 9:51 AM Page 529
15.5 Kuru 529
decade. In general (Almer et al. 1999; Gallassi et al. 1996; the autonomic disturbances are absent and one also sees a
Manetto et al. 1992; Medori et al. 1992a,b; Nagayama et al. depressed mood.
1996; Reder et al. 1995; Silburn et al. 1996; Tabernero et al.
2000), patients develop intractable insomnia, followed in
many cases by ‘oneiroid’ states in which they appear con- Treatment
fused, experience visual hallucinations, and behave as if
they were acting out dreams; in one case (Almer et al. 1999) There is no known specific treatment; general measures
‘the patient performed movements of sawing with a virtual may be undertaken, as described for Creutzfeldt–Jakob
saw and stopped bewildered when told there was no saw’. disease in Section 15.1, and sequential trials of various hyp-
Rarely, the presentation may be with a psychosis coupled notics should be attempted.
with insomnia (Dimitri et al. 2006). Paroxysms of auto-
nomic disturbance often occur, with hyperhidrosis, tachy-
cardia, hypertension, and irregular respiration. Over time
dementia appears, accompanied, variously, by ataxia, 15.5 KURU
myoclonus, and spasticity. Importantly, although insom-
nia is the initial hallmark of this disease, in some cases it Kuru is a unique human prion disease, spread by cannibal-
may appear late in the course and, rarely, it may be absent ism and present only in the Fore people of New Guinea
(Zerr et al. 1998b). (Gajdusek 1977). With the elimination of cannibalism in
The EEG shows slowing but there are no periodic com- the 1950s new infections stopped, but, given the long incu-
plexes. The CSF is generally normal although in a small bation period, the disease itself is still present.
minority the 14-3-3 protein may be found (Sanchez-Juan
et al. 2006).
Clinical features
Course After a long incubation period, spanning from 4 to 50 years

or more (Collinge et al. 2006), patients gradually develop
The disease is relentlessly progressive, with the develop- ataxia and tremor, followed, in a minority, by dementia.
ment of stupor and coma; on average, death occurs after
12–18 months.
Course
Etiology The disease is slowly progressive.
Pathologically (Almer et al. 1999; Lugaresi et al. 1986;

Manetto et al. 1992), there is extensive neuronal loss and
Etiology
astrocytosis in the anterior and mediodorsal nuclei of the
thalamus and in the inferior olives; in some cases, mild cell
The disease was spread by ritual cannibalism, which
loss and spongiform change may also be seen in the cere-
included ingestion of brain. Pathologically (Gajdusek and
bral and cerebellar cortices and in the dorsal raphe and
Zigas 1959; Kakulas et al. 1967) there is atrophy of the cere-
superior central nuclei (Almer et al. 1999).
bellar vermis and flocculonodular lobe, and microscopically
Most cases of fatal familial insomnia occur on an auto-
there is widespread spongiform change, neuronal loss, and
somal dominant basis, with mutations found at codon 178
astrocytosis, together with ‘kuru plaques’. These are distin-
of the PRNP gene (Medori et al. 1992a,b). Interestingly,
guished from the amyloid plaques found in Alzheimer’s dis-
this mutation causes fatal familial insomnia only if there is
ease, for example, by the presence of ‘spikes’ that radiate out
a methionine polymorphism at codon 129 of the same
around the circumference of the plaque.
allele; if the polymorphism at codon 129 is valine, then one
sees familial Creutzfeldt–Jakob disease rather than fatal
familial insomnia (Goldfarb et al. 1992). It also appears
that the same clinical and neuropathologic picture may Differential diagnosis
occur on a sporadic basis (Parchi et al. 1999b).
The diagnosis is only relevant in those Fore tribespeople
who engaged in cannibalism.
The diagnosis is typically suspected in cases marked by Treatment

intractable insomnia. Severe depression in the elderly may
be marked by dementia and by insomnia, but in such cases There is no known treatment.
p 15.qxd 3/10/08 9:51 AM Page 530
530 Prion diseases
REFERENCES Chou SM, Payne WN, Gibbs CG et al. Transmission and scanning
electron microscopy of spongiform change in
Allroggen H, Dennis G, Abbott RJ et al. New-variant Creutzfeldt–Jakob disease. Brain 1980; 103:885–904.
Creutzfeldt–Jakob disease: three case reports from Cochius JI, Hyman N, Esiri MM. Creutzfeldt–Jakob disease in a
Leicestershire. J Neurol Neurosurg Psychiatry 2000; 68:375–8. recipient of human pituitary-derived gonadotrophin: a second
Almer G, Hainfellner JA, Brucke T et al. Fatal familial insomnia: a case. J Neurol Neurosurg Psychiatry 1992; 55:1094–5.
new Austrian family. Brain 1999; 122:5–16. Collie DA, Summers DM, Sellar RJ et al. Diagnosing variant
Antoine JC, Michel D, Bertholon P et al. Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease with the pulvinar sign: MR imaging
after extracranial dura mater embolization for a findings in 86 neuropathologically confirmed cases. AJNR
nasopharyngeal angiofibroma. Neurology 1997; 48:1451–3. 2003; 24:1560–9.
Arata H, Takashima H, Hirano R et al. Early clinical signs and Collinge J, Rossor M. A new-variant of prion disease. Lancet 1996;
imaging findings in Gerstmann–Straussler–Scheinker 347:916–17.
syndrome (Pro102Leu). Neurology 2006; 66:1672–8. Collinge J, Sidle KCL, Meads J et al. Molecular analysis of prion
Barbanti P, Fabbrini G, Salvatore M et al. Polymorphism at codon strain variation and the aetiology of ‘new-variant’ CJD. Nature
129 or codon 219 of PRNP and clinical heterogeneity in a 1996; 383:685–90.
previously unreported family with Gerstmann– Collinge J, Whitfield J, McIntosh E et al. Kuru in the 21st
Straussler–Scheinker disease (Prp–P102L mutation). Neurology century – an acquired human prion disease with very long
1996; 47:734–41. incubation periods. Lancet 2006; 367:2068–74.
Beck E, Danile PM, Davey AJ et al. The pathogenesis of Collins SJ, Sanchez-Juan P, Masters CL et al. Determinants of
transmissible spongiform encephalopathy – an ultrastructural diagnostic investigation sensitivities across the clinical
study. Brain 1982; 105:755–86. spectrum of sporadic Creutzfeldt–Jakob disease. Brain 2006;
Belay ED, Sejvar JJ, Shieh WJ et al. Variant Creutzfeldt–Jakob 129:2278–87.
disease death, United States. Emerg Infect Dis 2005; Cooper SA, Murray KL, Will RG et al. Sporadic Creutzfeldt–Jakob
11:1351–4. disease with cerebellar ataxia at onset in the UK. J Neurol
Bernouilli C, Siegfried J, Baumgartner G et al. Danger of Neurosurg Psychiatry 2006; 77:1273–5.
accidental person to person transmission of Creutzfeldt–Jakob Dervaux A, Laine H, Czermak M et al. Creutzfeldt–Jakob disease
disease by surgery. Lancet 1977; 1:478–9. presenting as psychosis. Am J Psychiatry 2004; 161:1307–8.
Billette de Villemeur T, Beuavais P, Gourmelon M et al. Dimitri D, Jehel L, Durr A et al. Fatal familial insomnia presenting
Creutzfeldt–Jakob disease in children treated with growth as psychosis in an 18-year-old man. Neurology 2006;
hormone. Lancet 1991; 337:864–5. 67:363–4.
Billette de Villemeur T, Beslys J-P, Pradel A et al. Creutzfeldt–Jakob Duffy P, Wolf J, Collins G et al. Possible person to person
disease from contaminated growth hormone extracts in transmission of Creutzfeldt–Jakob disease. N Engl J Med 1974;
France. Neurology 1996; 47:690–5. 290:692–3.
Binelli S, Agazzi P, Giaccone G et al. Periodic Farlow MR, Yee RD, Dlouhy SR et al. Gerstmann–
electroencephalogram complexes in a patient with variant Straussler–Scheinker disease. I. Extending the clinical
Creutzfeldt–Jakob disease. Ann Neurol 2006; 59:423–7. spectrum. Neurology 1989; 39:1446–52.
Braham J. Jakob–Creutzfeldt disease: treatment by amantadine. Favereaux A, Quadrio I, Vital C et al. Pathologic prion protein
BMJ 1971; 4:212–13. spreading in the peripheral nervous system of a patient with
Brown P, Cathala F, Castaigne P et al. Creutzfeldt–Jakob sporadic Creutzfeldt–Jakob disease. Arch Neurol 2004;
disease: clinical analysis of a consecutive series of 230 61:747–50.
neuropathologically verified cases. Ann Neurol 1986; Gajdusek DC. Unconventional viruses and the origin and
20:597–602. disappearance of Kuru. Science 1977; 197:943–60.
Brown P, Goldfarb LG, Brown WT et al. Clinical and molecular Gajdusek DC, Zigas V. Clinical, pathological and epidemiological
genetic study of a large German kindred with study of the central nervous system among natives of the
Gerstmann–Straussler–Scheinker syndrome. Neurology 1991; eastern highlands of New Guinea. Am J Med 1959; 26:442–69.
41:375–9. Gallassi R, Morreale A, Montagna P et al. Fatal familial insomnia:
Brown P, Gibbs CJ, Rodgers-Johnson P et al. Human spongiform behavioral and cognitive features. Neurology 1996; 46:935–9.
encephalopathy: the National Institutes of Health series of Galvez S, Masters C, Gajdusek C. Descriptive epidemiology of
300 cases of experimentally transmitted disease. Ann Neurol Creutzfeldt–Jakob disease in Chile. Arch Neurol 1980;
1994; 35:513–29. 37:11–14.
Brown P, Preece M, Brandel JP et al. Iatrogenic Creutzfeldt-Jacob Geschwind MD, Martindale J, Miller D et al. Challenging clinical
disease at the millennium. Neurology 2000; 55:1075–81. utility of the 14-3-3 protein for the diagnosis of sporadic
Bruce ME, Will RG, Ironside JW et al. Transmissions to mice Creutzfeldt–Jakob disease. Arch Neurol 2003; 60:813–16.
indicate that ‘new variant’ CJD is caused by the BSE agent. Ghetti B, Tagliavini F, Masters CL et al. Gerstmann–
Nature 1997; 389:498–501. Straussler–Scheinker disease. II. Neurofibrillary tangles and
Burger LJ, Rowan J, Goldensohn E. Creutzfeldt-Jacob disease. Arch plaques with PrP-amyloid coexist in an affected family.
p 15.qxd 3/10/08 9:51 AM Page 531
References 531
Gibbs CJ, Asher DM, Kobrine A et al. Transmission of Ironside JW, Bishop MT, Connolly K et al. Variant
Creutzfeldt–Jakob disease to a chimpanzee by electrodes Creutzfeldt–Jakob disease: prion protein genotype analysis of
contaminated during neurosurgery. J Neurol Neurosurg positive appendix tissue samples from a retrospective
Psychiatry 1994; 57:757–8. prevalence study. BMJ 2006; 332:1186–8.
Glatzel M, Abela E, Maissen M et al. Extraneural pathologic prion Kakulas BA, Lecours AR, Gajdusek DC. Further observations on the
protein in sporadic Creutzfeldt–Jakob disease. N Engl J Med pathology of Kuru (a study of two cerebra in serial section).
2003; 349:1812–20. J Neuropathol Exp Neurol 1967; 26:85–97.
Glatzel M, Stoeck K, Seeger H et al. Human prion disease. Kitamoto T, Tateishi J, Tashima I et al. Amyloid plaques in
Molecular and clinical aspects. Arch Neurol 2005; 62:545–52. Creutzfeldt–Jakob disease stain with prion protein antibodies.
Goldfarb LG, Mitrova E, Brown P et al. Mutation in codon Ann Neurol 1986; 20:204–8.
200 of scrapie amyloid protein gene in two clusters of Kitamoto T, Amano N, Terao Y et al. A new inherited prion disease
Creutzfeldt–Jakob disease in Slovakia. Lancet 1990; (PrP-P105L mutation) showing spastic paraparesis. Ann Neurol
336:514–15. 1993; 34:808–13.
Goldfarb LG, Petersen RB, Tabaton M et al. Fatal familial insomnia Kretzchmar HA, Kufer P, Reithmuller G et al. Prion protein mutation
and familial Creutzfeldt–Jakob disease: disease phenotype at codon 102 in an Italian family with Gerstmann–Straussler–
determined by a DNA polymorphism. Science 1992; Scheinker syndrome. Neurology 1992; 42:809–10.
258:806–8. Ladogana A, Puopolo D, Poleggi A et al. High incidence of genetic
Goldhammer Y, Gabison R, Meiner Z et al. An Israeli family with human transmissible spongiform encephalopathies in Italy.
Gerstmann–Straussler–Scheinker disease manifesting the Neurology 2005; 64:1592–7.
codon 102 mutation in the prion protein gene. Neurology Landolt H-P, Gratzel M, Blatter T et al. Sleep-wake disturbances in
1993; 43:2718–19. sporadic Creutzfeldt–Jakob disease. Neurology 2006;
Green AJE, Thompson EJ, Stewart GE et al. Use of 14-3-3 protein 66:1418–24.
and other brain-specific proteins in CSF in the diagnosis of Lemstra AW, van Meegen MT, Vreyling JP et al. 14-3-3 testing in
variant Creutzfeldt–Jakob disease. J Neurol Neurosurg diagnosing Creutzfeldt–Jakob disease. A prospective study in
Psychiatry 2001; 70:744–8. 112 patients. Neurology 2000; 55:514–16.
Haik S, Brandel JP, Salomon D et al. Compassionate use of Lendvai I, Saravay SM, Steinberg MD. Creutzfeldt–Jakob disease
quinacrine in Creutzfeldt–Jakob disease fails to show presenting as secondary mania. Psychosomatics 1999;
significant effects. Neurology 2004; 63:2413–15. 40:524–5.
Hannah EL, Belay ED, Gambetti P et al. Creutzfeldt–Jakob disease Levy SR, Chiappa KH, Burke CJ et al. Early evolution and incidence
after receipt of a previously unimplicated brand of dura mater of electroencephalographic abnormalities in Cretuzfeldt–Jakob
graft. Neurology 2001; 56:1080–3. disease. J Clin Neurophysiol 1986; 3:1–21.
Healy D, Evans J. Creutzfeldt–Jakob disease after pituitary Lugaresi E, Medori R, Montagna P et al. Fatal familial insomnia
gonadotrophins. BMJ 1993; 307:517–18. and dysautonomia with selective degeneration of thalamic
Heath CA, Barver RA, Esmonde TFG et al. Dura mater associated nuclei. N Engl J Med 1986; 315:997–1003.
Cretuzfeldt–Jakob disease: experience from surveillance in the MacGowan DJL, Delanty N, Petito F et al. Isolated myoclonic alien
UK. J Neurol Neurourg Psychiatry 2006; 77:880–1. hand as the sole presentation of pathologically established
Heckmann JG, Lang CJG, Petruch F et al. Transmission of Creutzfeldt–Jakob disease: a report of two patients. J Neurol
Creutzfeldt–Jakob disease via a corneal transplant. J Neurol Neurosurg Psychiatry 1997; 63:404–7.
Neurosurg Psychiatry 1997; 63:388–90. Mandell AM, Alexander MP, Carpenter S. Creutzfeldt–Jakob disease
Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant presenting as isolated aphasia. Neurology 1989; 39:55–8.
Creutzfeldt–Jakob disease and other human prion diseases Manetto V, Medori R, Cortelli P et al. Fatal familial insomnia:
with tonsil biopsy specimens. Lancet 1999; 353:183–9. clinical and pathological study of five new cases. Neurology
Hsiao K, Doh-ura K, Kitamoto T et al. A prion protein amino acid 1992; 42:312–19.
substitution in ataxic Gerstmann–Straussler–Scheinker Martinez-Yelamos A, Saiz A, Sanchez-Valle R et al. 14-3-3
syndrome. Ann Neurol 1989; 26:137. protein in the CSF as prognostic marker in early multiple
Hsiao K, Meiner Z, Kahana E et al. Mutation of the prion protein sclerosis. Neurology 2001; 57:722–4.
gene in Libyan Jews with Creutzfeldt–Jakob disease. N Engl J Masters CL, Richardson EP. Subacute spongiform encephalopathy
Med 1991a; 324:1091–7. (Creutzfeldt–Jakob disease) – the nature and progression of
Hsiao K, Cass C, Schellenberg GD et al. A prion protein variant in a spongiform change. Brain 1978; 101:333–44.
family with the telencephalic form of Gerstmann–Straussler– May WW. Creutzfeldt–Jakob disease. Acta Neurol Scand 1986;
Scheinker syndrome. Neurology 1991b; 41:681–4. 44:1–32.
Hsiao K, Dlouhy S, Farlow MR et al. Mutant prion proteins in Medori R, Tritschler HJ, LeBlanc A et al. Fatal familial insomnia
Gerstmann–Straussler–Scheinker disease with neurofibrillary with a mutation at codon 178 of the prion protein gene.
tangles. Nat Genet 1992; 1:68–71. N Engl J Med 1992a; 326:444–9.
Hsich G, Kenney K, Gibbs CJ et al. The 14-3-3 brain protein in Medori R, Montagna P, Tritschler HJ et al. Fatal familial insomnia:
cerebrospinal fluid as a marker for transmissible spongiform a second kindred with mutation of prion protein gene at
encephalopathies. N Engl J Med 1996; 335:924–30. codon 178. Neurology 1992b; 42:669–70.
p 15.qxd 3/10/08 9:51 AM Page 532
532 Prion diseases
Mihara M, Sgase S, Konaka K et al. The ‘pulvinar sign’ in a case of Shiga Y, Miyazawa K, Sato S et al. Diffusion-weighted MRI
paraneoplastic limbic encephalitis associated with non- abnormalities as an early diagnostic marker for
Hodgkin’s lymphoma. J Neurol Neurosurg Psychiatry 2005; Creutzfeldt–Jakob disease. Neurology 2004; 63:443–9.
76:882–4. Silburn P, Cervenakova L, Varghese P et al. Fatal familial insomnia:
Miyashita K, Inuzuka T, Kondo H et al. Creutzfeldt–Jakob disease a seventh family. Neurology 1996; 47:1326–8.
in a patient with a cadaveric dural graft. Neurology 1991; Steinhoff BJ, Zerr I, Glatting M et al. Diagnostic value of periodic
41:940–1. complexes in Creutzfeldt–Jakob disease. Ann Neurol 2004;
Nagayama M, Shinohara Y, Furukawa H et al. Fatal familial 56:702–8.
insomnia with a mutation at codon 178 of the prion Tabaton M, Monaco S, Cordone MP et al. Prion deposition in
protein gene: first report from Japan. Neurology 1996; olfactory biopsy of sporadic Creutzfeldt–Jakob disease. Ann
47:1313–16. Neurol 2004; 55:294–6.
Nochlin D, Sumi SM, Bird TD et al. Familial dementia with PrP- Tabernero C, Polo JM, Sevillano MD et al. Fatal familial insomnia:
positive amyloid plaques: a variant of the Gerstmann– clinical, neuropathological, and genetic description of a
Straussler syndrome. Neurology 1989; 39:910–18. Spanish family. J Neurol Neurosurg Psychiatry 2000; 68:774–7.
Otto M, Cepek L, Ratzka R et al. Efficacy of flupirtine on cognitive Taratuto AL, Piccardo P, Reich EG et al. Insomnia associated with
function in patients with CJD: A double blind study. Neurology thalamic involvement in E220K Creutzfeldt–Jakob disease.
2004; 62:714–18. Neurology 2002; 58:362–7.
Owen F, Poulter M, Lofthouse R et al. Insertion in prion protein Terzano MG, Montanari E, Calzetti S et al. The effect of
gene in familial Creutzfeldt–Jakob disease. Lancet 1989; amantadine on arousal and EEG patterns in Creutzfeldt–Jakob
1:51–2. disease. Arch Neurol 1983; 40:555–9.
Pan K-M, Baldwin M, Nguyen J et al. Conversion of alpha-helices Tschampa H, Kallenberg K, Urbach H et al. MRI in the diagnosis of
into beta-sheets features in the formation of the scrapie prion sporadic Creutzfeldt–Jakob disease: a study on inter-observer
proteins. Proc Natl Acad Sci USA 1993; 90:962–6. agreement. Brain 2005; 128:2026–33.
Parchi P, Gise A, Capelleri S et al. Classification of sporadic Van Everbroeck BRJ, Boons J, Cras P. 14-3-3 gamma-isoform
Creutzfeldt–Jakob disease based on molecular and phenotypic detection distinguishes sporadic Creutzfeldt–Jakob disease from
analysis of 300 subjects. Ann Neurol 1999a; 46:224–33. other dementias. J Neurol Neurosurg Psychiatry 2005; 76:100–2.
Parchi P, Capellari S, Chin S et al. A subtype of sporadic prion Wieser HG, Schwarz U, Blatter T et al. Serial EEG findings in
disease mimicking fatal familial insomnia. Neurology 1999b; sporadic and iatrogenic Creutzfeldt–Jakob disease. Clin
52:1757–63. Neurophysiol 2004; 115:2467–78.
Petzold GC, Westner I, Bohner G et al. False-positive pulvinar sign Will RG, Mathews WB. A retrospective study of Creutzfeldt–Jakob
on MRI in sporadic Creutzfeldt–Jakob disease. Neurology disease in England and Wales 1970–1979 I. Clinical features.
2004; 62:1235–6. J Neurol Neurosurg Psychiatry 1984; 47:134–40.
Pocchiara M, Pupolo M, Croes EA et al. Predictors of survival in Will RG, Ironside JW, Zeidler M et al. A new-variant of
sporadic Creutzfeldt-Jakob disease and other transmissible Creutzfeldt–Jakob disease in the UK. Lancet 1996; 347:921–5.
spongiform encephalopathies. Brain 2004; 127:2348–59. Will RG, Zeidler M, Stewart GE et al. Diagnosis of new variant
Reder AT, Mednick AS, Brown P et al. Clinical and genetic studies Creutzfeldt–Jakob disease. Ann Neurol 2000; 47:575–82.
of fatal familial insomnia. Neurology 1995; 45:1068–75. Wroe SJ, Pal S, Siddique D et al. Clinical presentation and pre-
Roberts GW, Lofthouse R, Brown R et al. Prion-protein mortem diagnosis of variant Creutzfeldt–Jakob disease
immunoreactivity in human transmissible dementias. N Engl J associated with blood transfusion; a case report. Lancet 2006;
Med 1986; 315:1231–3. 368:2061–7.
Roos R, Cajdusek DC, Gibbs CJ. The clinical characteristics of Yamada M, Itoh Y, Fujigasaki H et al. A missense mutation at
transmissible Creutzfeldt–Jakob disease. Brain 1973; codon 105 with codon 129 polymorphism of the prion protein
96:1–20. gene in a new-variant of Gerstmann–Straussler–Scheinker
Rosenmann H, Meiner Z, Kahana E et al. Detection of 14-3-3 disease. Neurology 1993; 43:2723–4.
protein in the CSF of genetic Creutzfeldt–Jakob disease. Young K, Jones CK, Piccardo P et al. Gerstmann–
Neurology 1997; 49:593–5. Straussler–Scheinker disease with mutation at codon 102 and
Saiz A, Graus F, Dalmau J et al. Detection of 14-3-3 brain protein methionine at codon 129 of PRNP in previously unreported
in the cerebrospinal fluid of patients with paraneoplastic patients. Neurology 1995; 45:1127–34.
neurological disorders. Ann Neurol 1999; 46:774–7. Zanusso G, Ferrari S, Cardone F et al. Detection of pathologic
Sanchez-Juan P, Green A, Ladogana A et al. CSF tests in the prion protein in the olfactory epithelium in sporadic
differential diagnosis of Cretuzfeldt–Jakob disease. Neurology Creutzfeldt-Jacob disease N Engl J Med 2003; 348:711–19.
2006; 67:637–43. Zeidler M, Stewart GE, Barraclough CR et al. New-variant
Sanders WL. Creutzfeldt–Jakob disease treated with amantadine. Creutzfeldt–Jakob disease: neurological features and
J Neurol Neurosurg Psychiatry 1979; 42:960–1. diagnostic tests. Lancet 1997a; 350:903–7.
Sanders WL, Dunn TL. Creutzfeldt–Jakob disease treated with Zeidler M, Johnstone EC, Bamber RWK et al. New-variant
amantadine. J Neurol Neurosurg Psychiatry 1973; Creutzfeldt–Jakob disease: psychiatric features. Lancet 1997b;
36:581–4. 350:908–10.
p 15.qxd 3/10/08 9:51 AM Page 533
References 533
Zeidler M, Sellar RJ, Collie DA. The pulvinar sign on magnetic Zerr I, Bodemer M, Gefeller O et al. Detection of 14-3-3 protein in
resonance imaging in variant Creutzfeldt–Jakob disease. the cerebrospinal fluid supports the diagnosis of
Lancet 2000; 355:1412–18. Creutzfeldt–Jakob disease. Neurology 1998a; 43:32–40.
Zeng S, Kim CH, Rahman H. Psychotic symptoms presented in Zerr I, Giese A, Windl O et al. Phenotypic variability in fatal
familial Creutzfeldt–Jakob disease, subtype E220K. J Clin familial insomnia (D178N-129M) genotype. Neurology 1998b;
Psychiatry 2001; 62:734–5. 51:1398–405.
p 16.qxd 3/10/08 9:52 AM Page 534
16
Endocrinologic disorders
16.1 Cushing’s syndrome 534 16.4 Hypothyroidism 539

16.2 Adrenocortical insufficiency 536 References 541
16.1 CUSHING’S SYNDROME The neuropsychiatric features of Cushing’s syndrome

include depression, mania or hypomania, anxiety, psychosis,
Cushing’s syndrome typically manifests with various dementia, or delirium. Depression is the most prominent
neuropsychiatric features (e.g., depression), classically in a neuropsychiatric feature of Cushing’s syndrome (Spillane
patient with a ‘Cushingoid’ habitus consisting of ‘moon’ 1951); it has been noted in between one-half (Haskett 1985;
facies, truncal obesity, and violaceous abdominal striae Jeffcoate et al. 1979; Kelly 1996) and three-quarters (Cohen
(Orth 1995). This syndrome occurs secondary to the 1980; Starkman et al. 1981) of patients with Cushing’s syn-
effects of sustained hypercortisolemia, which in turn may drome and indeed may be the presenting feature (Kelly
be due to either administration of exogenous steroids (e.g., 1996). Anxiety commonly accompanies the depression
prednisone) or endogenous overproduction of steroids. creating the picture of an ‘agitated depression’. The depres-
Normally, cortisol levels are maintained within normal sion at times may be severe, with psychotic features (Cohen
limits by the hypothalamic–pituitary–adrenal axis. The 1980), which may be either mood-congruent (Anderson
hypothalamus secretes corticotrophin-releasing hormone and McHugh 1971; Maclay and Stokes 1939) or mood-
(CRH), which in turn stimulates the pituitary to produce incongruent (Trethowan and Cobb 1952), with Schneiderian
adrenocorticotrophic hormone (ACTH); ACTH then first-rank symptoms of thought broadcasting and thought
stimulates the adrenal cortex to produce cortisol, which in insertion. Both suicide attempts and completed suicides
turn exerts a negative feedback effect on the hypothalamus may occur (Jeffcoate et al. 1979).
and pituitary. A sustained, excessive production of endoge- Mania is less common than depression in Cushing’s syn-
nous cortisol by the adrenal gland may result from the drome of endogenous origin (Haskett 1985; Jeffcoate et al.
following causes: an enhanced release of CRH from the 1979; Kelly 1996), but the converse holds true in exogenous
hypothalamus or from CRH-secreting ectopic tumors; an cases, in which mania is common (Wolkowitz et al. 1990).
ACTH-secreting pituitary adenoma; ectopic ACTH pro- Anxiety of pathologic degree has been noted in about
duction (e.g., by an oat cell carcinoma of the lung); and, one-tenth of patients (Kelly 1996), but is most often seen
finally, adrenal tumors. in the context of depression.
The term ‘Cushing’s syndrome’ refers to cases of sympto- Psychosis, although rare, can occur secondary to
matic hypercortisolemia of any cause; the term ‘Cushing’s Cushing’s syndrome. One patient presented with delusions
disease’, however, is restricted to cases caused by pituitary of persecution, auditory and visual hallucinations, and
adenomas. bizarre behavior, all of which cleared with adrenalectomy
(Hickman et al. 1961); another experienced agitation, audi-
tory hallucinations, and religious and grandiose delusions,
Clinical features which again cleared with adrenalectomy (Hertz et al. 1955).
Delirium may occur (Kawashima et al. 2004) but is rare,
The mode of onset of Cushing’s syndrome is dependent on being noted in only about 1 percent of cases (Kelly 1996).
the underlying cause. Cases due to exogenous steroid use Dementia is likewise rare and is often characterized by
are of the most rapid onset, and may appear within days. prominent memory loss (Varney et al. 1984).
Cushing’s disease secondary to a pituitary adenoma may These neuropsychiatric features classically occur in the
present very gradually, over years, and cases of Cushing’s setting of a Cushingoid habitus, with, as noted earlier,
syndrome secondary to ectopic ACTH production may ‘moon’ facies, truncal obesity, and violaceous abdominal
present over months. striae. Other features include acne, hirsutism, proximal
p 16.qxd 3/10/08 9:52 AM Page 535
16.1 Cushing’s syndrome 535
myopathy, easy bruisability, hypertension, diabetes melli- ectopic tumor, this ‘gradient’ between superior petrosal or
tus, amenorrhea, and, rarely, pseudotumor cerebri. All of internal jugular blood and systemic venous blood will not
these features, however, take time to develop and thus may be present. Sampling the superior petrosal sinus is difficult
not be present in cases of Cushing’s syndrome secondary to and not without risk, but is more sensitive than sampling the
exogenous steroid use, which, as noted earlier, may develop internal jugular vein; hence, one should begin with sam-
over days. Furthermore, in cases of Cushing’s syndrome pling the internal jugular vein, reserving petrosal sampling
secondary to ectopic ACTH secretion by an oat cell carci- for cases in which this is negative (Doppman et al. 1998).
noma, one may see emaciation rather than obesity. In cases in which a pituitary tumor is suspected, high-
When Cushing’s syndrome occurs secondary to exoge- resolution magnetic resonance imaging (MRI) with gadolin-
nous steroid administration the diagnosis is fairly obvious, ium enhancement is in order, and, if positive, may obviate
as symptoms appear within days of using high dosage the need for superior petrosal or internal jugular sampling.
steroids, for example ⭓60 mg/day of prednisone. However, Unfortunately, however, most ACTH-secreting pituitary
when endogenous steroid overproduction is suspected, tumors are microadenomas and about 50 percent will escape
laboratory testing is essential to confirm the diagnosis. detection by MRI (Kaskarelis et al. 2006).
Confirmation of suspected endogenous hypercortisolemia
is sought via a 24-hour urine test for free cortisol. Serum
cortisol levels show pulsatile fluctuations during the day, Course
and hence should not be relied on. If the 24-hour urine free
cortisol level is normal, the diagnosis is effectively ruled out. The course is determined by the underlying cause. Once
In cases in which the 24-hour urinary free cortisol level is cortisol levels are returned to normal, either by stopping
elevated, further testing is required to determine the cause. exogenous steroids or by virtue of treatment of endogenous
The first step is to obtain an ACTH level. In hypercorti- causes, neuropsychiatric features gradually resolve; although
solemia secondary to an adrenal tumor, the ACTH is low, such resolution may occur within weeks to days in cases
whereas in all other cases it is elevated. If the ACTH is ele- secondary to relatively short-term treatment with high-dose
vated, the next step is to determine whether the ACTH is exogenous steroids, months may be required in endoge-
derived from an ectopic source, for example lung carcinoma, nous cases (Kelly et al. 1983).
or from a pituitary tumor, and this is accomplished with the
‘high dose’ dexamethasone suppression test (Tyrell et al.
1986). In this test, patients are given 2 mg of dexamethasone Etiology
orally every 6 hours over 2 days, and during the second day
a 24-hour urine sample is collected for measurement of free The mechanism by which hypercortisolemia causes the
cortisol. In cases of ectopic ACTH production, the tumor neuropsychiatric features noted above is not known.
secreting the ACTH is not sensitive to the feedback of dexa- As noted earlier, there are various causes for endoge-
methasone and hence continues to secrete ACTH, result- nous hypercortisolemia, including adrenal tumors, ectopic
ing in an increased free cortisol level in the 24-hour urine ACTH-secreting tumors, and pituitary tumors (Erem et al.
sample: in such cases one speaks of ‘non-suppression’ of 2003). Adrenal tumors, which may be either adenomas or
cortisol by dexamethasone. By contrast, pituitary adeno- carcinomas, account for about 15 percent of cases. Ectopic
mas do remain sensitive to dexamethasone and in these ACTH-secreting tumors likewise account for about 15 per-
cases ACTH output falls with a resulting fall in the 24-hour cent of cases; although small-cell lung cancer is the most
urine free cortisol level: in such cases one speaks of ‘sup- common of these, other tumors may also be at fault,
pression’ of cortisol by dexamethasone. An alternative, or including cancer of the thymus, pancreas, or thyroid, and
supplementary, test is the CRH stimulation test. Here, one pheochromocytoma. Pituitary adenomas are by far the
gives 1 μg/kg of ovine CRH intravenously and determines most common cause of endogenous hypercortisolemia,
both ACTH and cortisol levels 15 minutes before the infu- accounting for about 70 percent of all cases. There are also
sion and 15, 30, 60, 90, and 120 minutes afterward. Ectopic very rare reports of CRH-secreting tumors, which may be
ACTH-secreting tumors are not sensitive to CRH, and cor- located in either the hypothalamus or ectopically, as for
tisol and ACTH levels do not rise significantly. Pituitary example in thyroid cancer.
adenomas, however, are sensitive, and in such cases cortisol
and ACTH levels do rise.
In some cases the dexamethasone test may be equivocal, Differential diagnosis
and differentiating between an ectopic ACTH-secreting
tumor and a pituitary tumor may depend on sampling The appearance of neuropsychiatric symptomatology in a
venous blood flow from the pituitary. As might be expected, patient receiving relatively high doses of exogenous corti-
in cases of pituitary tumors, the ACTH level in venous blood costeroids immediately implicates the drug. Diagnostic
from either the superior petrosal sinus or the internal jugu- uncertainty may arise, however, in cases in which the con-
lar vein will be higher than that in venous blood drawn at dition that prompted the treatment with corticosteroids
phlebotomy; conversely, when the source of ACTH is an may itself affect the central nervous system, as is the case
p 16.qxd 3/10/08 9:52 AM Page 536
536 Endocrinologic disorders
with multiple sclerosis or systemic lupus erythematosus. Clinical features

In such cases, a careful history, with due attention to the
existence of neuropsychiatric symptoms before steroid treat- Acute adrenocortical insufficiency presents with nausea,
ment, may resolve the issue. In other cases it may be neces- vomiting, and abdominal pain, with a rapidly falling blood
sary to change the corticosteroid dose significantly: if the pressure, postural dizziness, and eventually hypovolemic
dose is increased and symptoms worsen (or, conversely, if shock: delirium develops, followed by stupor and coma.
the dose is decreased and symptoms lessen), the steroid is Chronic adrenocortical insufficiency presents gradually
implicated. with fatigue, listlessness, poor concentration, anorexia,
As noted earlier, mood disturbances are the most nausea, diarrhea or constipation, and abdominal pain.
common neuropsychiatric feature, and the diagnosis of Depression may occur (Engel and Margolin 1941; Varadaraj
Cushing’s syndrome may be missed in depressed or manic and Cooper 1986) and, rarely, there may be delirium
patients unless one keeps in mind the typical Cushingoid (Engel and Margolin 1941; Fang and Jaspan 1989) or
habitus. psychosis (Anglin et al. 2006; Cleghorn 1951; McFarland
1963). Blood pressure is low and postural dizziness is com-
mon. In primary cases, with a lack of cortisol feedback on
Treatment the pituitary, excessive stimulation of melanocytes by
ACTH may lead to hyperpigmentation, especially promi-
In exogenous cases, the dose of the steroid should, if possi- nent in sun-exposed areas and on the buccal and gingival
ble, be reduced. In endogenous cases, the tumor should be mucosa. Chronic adrenocortical insufficiency may also be
resected if possible. In cases of pituitary tumors, the complicated by an acute episode, for example as may occur
transphenoidal approach is utilized; however, if this is not when chronic patients are subjected to a significant physi-
possible, radiation treatment may be considered. When the ologic stress such as surgery.
tumor cannot be treated, one may consider adrenalectomy Laboratory testing begins with a serum cortisol level,
or, alternatively, a ‘chemical’ adrenalectomy may be which is reduced. An ACTH level is also obtained: in pri-
performed by administering daily doses of drugs such as mary cases ACTH levels are increased because of a lack of
ketoconazole or metyrapone, which inhibit enzymes feedback inhibition on the pituitary, whereas in secondary
responsible for steroidogenesis in the adrenal glands. After cases the ACTH level is low. In cases in which ACTH levels
adrenalectomy, whether surgical or ‘chemical’, daily main- are equivocal, further testing may be conducted with cosyn-
tenance doses of steroids will be required. Furthermore, tropin, a synthetic ACTH analogue, to determine whether
one must be alert to the development of Nelson’s syndrome, such cases are primary or secondary. Cosyntropin is given
in which ACTH tumors of the pituitary may develop with intravenously in a dose of 0.25 mg, and cortisol levels are
the appearance of hyperpigmentation in cases in which obtained 15 minute pre-injection and 30 and 60 minutes
inhibitory feedback is lacking. post-injection. In primary cases there is little or no rise
Symptomatic treatment of neuropsychiatric features in ACTH, whereas in secondary cases, presuming that the
may be required in cases in which etiologic treatment is adrenal glands have not atrophied due to chronic non-
unsuccessful or not possible or, in cases when it is, when stimulation, there should be a robust rise in ACTH.
symptoms are severe and resolution is slow. Depression Further laboratory abnormalities may be seen in primary
may be treated with antidepressants, mania with mood cases in which destruction of the adrenal glands causes
stabilizers, and psychosis with antipsychotics, as discussed decreased mineralocorticoid levels, with resulting hypona-
in Sections 6.1, 6.3, and 7.1 respectively. tremia and hyperkalemia.
16.2 ADRENOCORTICAL INSUFFICIENCY Course

Adrenocortical insufficiency may be primary, due to actual Acute adrenocortical insufficiency is a life-threatening
destruction of the adrenal gland, or secondary, due to emergency. The course of chronic adrenocortical insuffi-
pituitary failure or to abrupt discontinuation of long-term ciency is determined by the underlying cause: in the case
treatment with corticosteroids. Adrenocortical insuffi- of primary chronic adrenocortical insufficiency due to
ciency, whether primary or secondary, may be further autoimmune destruction of the adrenals, there is a gradual
subdivided into acute and chronic forms. progression of symptoms, with death occurring in perhaps
Before proceeding, a word is in order regarding the term 2 years.
‘Addison’s disease’. Some authors use this term to refer to
all cases of adrenocortical insufficiency, regardless of cause,
whereas others restrict it to primary cases, specifically Etiology
those due to autoimmune destruction of the adrenal gland.
Given this unfortunate definitional ambiguity, the term is Primary adrenocortical insufficiency is most commonly
not used further in this text. due to autoimmune destruction of the adrenal glands.
p 16.qxd 3/10/08 9:52 AM Page 537
In this disorder, other endocrine glands may also be 16.3 HYPERTHYROIDISM

targeted by the autoimmune process, and patients may
develop Hashimoto’s thyroiditis (with either hyper- Sustained elevation of thyroxine (T4) typically causes a
thyroidism or hypothyroidism), pernicious anemia with syndrome characterized by anxiety and autonomic hyper-
vitamin B12 deficiency, hypoparathyroidism with hypocal- activity; most cases are due to Graves’ disease or toxic
cemia, or diabetes mellitus. Other causes of primary multinodular goiter. Although in routine clinical work
adrenocortical insufficiency include adrenoleukodystro- most clinicians refer to all of these cases as ‘hyperthyroidism’,
phy, tuberculosis, cytomegalovirus infection (as may occur this practice, technically, is not correct. Strictly speaking,
in AIDS), sarcoidosis, amyloidosis, metastatic disease, and hyperthyroidism refers to conditions in which the thyroid
hemorrhagic infarction (as may occur during septicemia gland is producing excess amounts of thyroid hormone,
or with overvigorous anticoagulation). With the excep- and the term ‘thyrotoxicosis’ refers to the clinical syndrome
tion of hemorrhagic infarction, all of these forms of itself. Although this may seem to be splitting hairs, it does
primary adrenocortical insufficiency cause a chronic call attention to the fact that, although most cases are due
presentation. to diseases that cause excess thyroid hormone production,
Secondary adrenocortical insufficiency, as noted earlier, for example Graves’ disease, there are diseases, such as
most commonly occurs secondary to abrupt discontinua- Hashimoto’s thyroiditis, in which the elevated serum T4
tion of long-term treatment with corticosteroids. Any patient concentrations occur not because of increased production
taking supraphysiologic doses of a corticosteroid (e.g., of hormone but rather because of a ‘leakage’ of hormone
10 mg or more daily of prednisone) for more than 1 month from the inflamed gland. Clinicians’ habits, however, are
will have some suppression of ACTH output from the hard to break, and in this text the term ‘hyperthyroidism’ is
pituitary coupled with some atrophy of the adrenal cortex. used to refer to the syndrome.
Other causes of secondary adrenocortical insufficiency
include infarction, and tumors or granulomas of either the
pituitary or, rarely, the hypothalamus. These secondary Clinical features
cases may present either acutely (as for example with abrupt
discontinuation of steroid treatment) or chronically (as The age of onset varies according to the underlying etiology:
may be seen with slowly growing pituitary tumors). Graves’ disease typically appears in the twenties or thirties
and toxic multinodular goiter generally has an onset in old
age. Although in most cases symptoms appear gradually,
over weeks or months, subacute onsets may be seen, espe-
Differential diagnosis cially in relation to various physiologic stressors.
The discussion of clinical features will begin with a
Delirium occurring in acute adrenocortical insufficiency is
description of the typical picture of hyperthyroidism,
suggested by concurrent nausea, vomiting, and postural
followed by a discussion of an important variant known
dizziness. In cases occurring in the course of sepsis, the
as apathetic hyperthyroidism. Subsequently, neuropsychi-
delirium may be erroneously attributed to the systemic
atric features seen only in a minority of cases of hyper-
effects of the infection.
thyroidism are discussed, including depression, mania,
Depression, delirium, or psychosis occurring during
psychosis, dementia, and delirium. Finally, ‘thyroid storm’
chronic adrenocortical insufficiency are each suggested by
is considered.
the overall fatigue and listlessness of the patient and by the
Typically, patients are apprehensive and anxious and,
associated gastrointestinal symptomatology and postural
although fatigued and tired, they often experience restless-
dizziness.
ness and an inability to sit still. Anxiety often stands out
(Greer et al. 1973; MacCrimmon et al. 1979) and in some
cases may represent the presenting complaint (Dietch 1981).
Treatment Patients typically complain of diaphoresis, heat intolerance,
and an increased frequency of bowel movements, and,
Chronic adrenocortical insufficiency is generally treated despite an often increased appetite with increased caloric
with hydrocortisone in a dose of 20–30 mg/day, with two- intake, there may be substantial weight loss. On examina-
thirds of the dose given in the morning and one-third in tion, one finds tachycardia, widened palpebral fissures and
the afternoon, with dose increases during periods of phys- proptosis, a fine postural tremor, and generalized hyper-
iologic stress. In primary cases this should be supple- reflexia; there may also be a proximal myopathy. Women
mented with fludrocortisone in a dose of 0.05–0.1 mg/day. may complain of menstrual irregularity and men may expe-
Acute adrenocortical insufficiency often requires treat- rience erectile dysfunction. Rarely, there may be chorea
ment in an intensive care unit; normal saline with 5 per- (Fidler et al. 1971; Fishbeck and Layzer 1979; Van Uitert
cent glucose is given, along with a bolus of 100 mg of and Russakoff 1979), grand mal seizures (Jabbari and
hydrocortisone intravenously, followed by repeat doses of Huott 1980), or a motor peripheral neuropathy (Pandit
10 mg hourly. et al. 1998).
p 16.qxd 3/10/08 9:52 AM Page 538
Apathetic hyperthyroidism (Brenner 1978; Lahey 1931; Course

Thomas et al. 1970) represents a peculiar variant of hyper-
thyroidism that is generally only seen in the elderly and The course is dictated by the underlying cause. Thryoid
which is characterized by apathy and, in some, lethargy. storm, regardless of the underlying cause, may pursue a
Remarkably, of the ‘autonomic’ signs and symptoms seen fulminant course, with death in hours or days.
in typical cases, only tachycardia is common in this apa-
thetic variant: diaphoresis, tremor, and hyper-reflexia are
generally absent. Many patients will also develop atrial Etiology
fibrillation and congestive failure.
Of the neuropsychiatric features seen in hyperthyroidism, The vast majority of cases are due to Graves’ disease. Other
depression is the most common and is seen in a substantial causes include toxic multinodular goiter, toxic solitary
minority of patients (Kathol and Delahunt 1986; Trzepacz adenoma, and the thyroiditides, including lymphocytic
et al. 1988), especially in those with apathetic hyper- thyroiditis, subacute (De Quervain’s) thyroiditis, and
thyroidism (Thomas et al. 1970), in whom the only clue to Hashimoto’s thyroiditis. The thyroiditides are character-
the correct diagnosis, as just noted, may be tachycardia or ized by a ‘leakage’ of T4 from the inflamed thyroid and,
congestive heart failure (Arnold et al. 1974; Brenner 1978). typically, cause a hyperthyroidism that is time limited and
Depression in hyperthyroidism may be accompanied by that may, depending on the amount of inflammatory dam-
mood-congruent delusions (Taylor 1975) or considerable age and scarring, be followed by hypothyroidism. Rare
agitation (Van Uitert and Russakoff 1979). causes include hypothalamic tumors, pituitary adenomas
Mania is less common than depression in hyperthy- (Carlson et al. 1983; Wynne et al. 1992), inherited pituitary
roidism (Trzepacz et al. 1988), and in some cases may be of resistance to T4, production of ectopic TSH by various
the ‘mixed’ variety (Ingham and Nielsen 1931). tumors (hydatidiform mole, choriocarcinoma of the uterus,
Psychosis, although only rarely due to hyperthyroidism, and choriocarcinoma of the testis), and production of T4
may occur (Lazarus and Jaffe 1986; Steinberg 1994): one by various tumors (struma ovarii or metastatic follicular
patient developed a delusion of jealousy and, convinced carcinoma of the thyroid). Finally, hyperthyroidism may
that his wife was having an affair, had her followed; when occur as a side-effect of amiodarone, and may also be
his hyperthyroidism was treated, his psychosis resolved intentional, as in ‘thyrotoxicosis factitia’.
(Hodgson et al. 1992).
Dementia may occur in typical hyperthyroidism (Bulens
1981; Fukui et al. 2001) but is rare; by contrast, a signifi- Differential diagnosis
cant minority of patients with the apathetic variant will
develop cognitive deficits that may be severe enough to As noted earlier, anxiety is a prominent feature of hyper-
constitute a dementia (Martin and Deam 1996). Delirium thyroidism and, of the various other causes of persistent
may also occur, but appears to be very rare. anxiety discussed in Section 6.5, the one that often comes to
Thyroid storm is a dreaded complication of hyper- mind is generalized anxiety disorder. One clue to the dif-
thyroidism and typically appears in a patient with ferential here may be found on shaking the patient’s hand:
untreated hyperthyroidism who is subjected to some signif- in both hyperthyroidism and generalized anxiety disorder
icant physiologic stress, such as surgery or an infection. In the hand is moist with sweat, but in hyperthyroidism the
this setting there is a rapid escalation of all of the typical skin is warm whereas in generalized anxiety disorder it is
signs and symptoms followed by hyperthermia, delirium, cool, yielding a ‘cold and clammy’ impression.
stupor, and coma. In some cases seizures may occur and, The differential diagnosis for depression is discussed in
rarely, thyroid storm has presented with a psychosis Section 6.1. One feature of depression secondary to hyper-
(Bursten 1961; Greer and Parsons 1968). Thyroid storm thyroidism that sets it apart from depression due to other
may also occur in the setting of apathetic hyperthyroidism, causes is the presence of weight loss in the face of increased
and in such cases may present with coma in the absence of eating; by contrast, weight loss occurring in depression due
any autonomic features (Ghobrial and Ruby 2002). to other causes is generally associated with anorexia.
In almost all cases of hyperthyroidism the free T4 level Mania, psychosis, dementia, or delirium occurring second-
will be elevated and the thyroid-stimulating hormone (TSH) ary to hyperthyroidism, as discussed in Sections 6.3, 7.1,
level will be reduced. Exceptions occur in cases of ‘T3 5.1, and 5.3, respectively, is suggested by concurrent prop-
(triiodothyronine) thyrotoxicosis’, in which the free T4 tosis and autonomic signs, such as tremor and tachycardia.
level is normal; in cases in which the clinical suspicion of
hyperthyroidism is high and the free T4 is normal, the free
T3 level should be determined. Other exceptions include Treatment
the very rare cases of a hypothalamic tumor secreting
thyrotropin-releasing hormone (TRH) or a pituitary If necessary, autonomic features may be controlled with
adenoma secreting TSH: in both of these cases both the propranolol, in doses of 20–40 mg orally every 4–6 hours.
free T4 and the TSH levels are elevated. In cases characterized by increased production of T4, as
p 16.qxd 3/10/08 9:52 AM Page 539
16.4 Hypothyroidism 539
occurs in Graves’ disease, toxic multinodular goitre, and Typically, patients develop psychomotor retardation,
solitary adenomas, anti-thyroid drugs such as propylth- with slowed speech and movements; in some cases lethargy
iouracil or methimazole are generally indicated; in some and somnolence may occur. When asked a question, up to
cases radioactive iodine treatment or surgery may also be a minute may pass before the patient responds, and the
required. Once T4 levels are normalized, most of the symp- response itself, when it does come, is slow. Simple activities,
toms of hyperthyroidism gradually resolve. Symptomatic such as unfastening a button, may likewise take an inordi-
treatment of depression and other neuropsychiatric features nate amount of time to complete. Patients may appear
may or may not be required pending this resolution; if so, apathetic and lacking in initiative, and often there may be
this may be accomplished as discussed in the respective difficulty with concentration and a certain ‘fogginess’ of
sections. thought and memory (Nickel and Frame 1958). The over-
Thyroid storm constitutes a medical emergency and all appearance of hypothyroid patients is often distinctive:
requires treatment in an intensive care unit. In addition to skin becomes thickened, puffy, and even boggy, and this
propranolol and anti-thyroid drugs, sodium or potassium is particularly obvious on the face, in the supraclavicular
iodide, hydrocortisone, and cooling blankets are often fossae, and on the dorsal surfaces of the hands and feet.
required. The hair becomes thin and brittle and there may be consid-
erable hair loss; interestingly there may also be a loss of hair
on the lateral thirds of the eyebrows. Other symptoms
16.4 HYPOTHYROIDISM include a voice change towards hoarseness, cold intoler-
ance, constipation, weight gain, decreased libido, erectile
Hypothyroidism is the clinical syndrome that occurs dysfunction, and menorrhagia. Vibratory sense may be lost
secondary to a persistently low level of circulating thyrox- and the deep tendon reflexes are often reduced; the ankle
ine, or T4. A synonym for this is myxedema, a name that calls jerk is often ‘hung up’, with a delayed relaxation phase.
attention to the mucinous edema that gives rise to the Cranial nerves may be involved, with partial deafness and,
typical facial appearance seen in hypothyroidism, described rarely, a peripheral facial palsy; cerebellar ataxia (‘myxedema
below. Hypothyroidism is a common condition, found in a staggers’) (Jellinek and Kelly 1960) occurs in up to 20
little under 1 percent of the general population; it is 10–20 percent of cases. Very rarely, seizures may occur (Bryce
times more common in females than males. and Poyner 1992). Myxedematous infiltration may cause a
Thyroxine levels are maintained within normal limits carpal or tarsal tunnel syndrome; macroglossia may also
by virtue of the hypothalamic–pituitary–thyroid axis. The occur and, if severe, may be followed by obstructive sleep
hypothalamus produces TRH, which in turn stimulates the apnea. Bradycardia and hypotension are common, and
anterior pituitary to produce TSH; TSH then stimulates there may be a degree of hypothermia; pericardial and pleu-
the thyroid gland to produce T4, which in turn exerts a ral effusions may also occur. In a small minority of cases, a
negative feedback effect on both the pituitary and the hypo- syndrome of inappropriate antidiuretic hormone (ADH)
thalamus. The various causes of hypothyroidism may be secretion may occur, with hyponatremia.
grouped according to which element of the hypothalamic– In severe cases of hypothyroidism a condition known as
pituitary–thyroid axis is affected. Tertiary hypothyroidism ‘myxedema coma’ may develop. Typically this occurs in
occurs as a result of hypothalamic disease (e.g., tumors) patients with long-standing hypothyroidism who are sub-
and is characterized by a low TSH and a low T4. Secondary jected to a physiologic stress, such as surgery or a signifi-
hypothyroidism occurs with pituitary disease (e.g., tumors
cant infection, or who are given phenothiazines (Mitchell
or infarction) and likewise displays both a low TSH and
et al. 1959) or any medications with prominent sedative
low T4. Primary hypothyroidism, which is by far the most
effects. Stupor or coma develops, accompanied by hypother-
common type, occurs with disease of the thyroid itself mia (which may be severe), significant bradycardia, respi-
(e.g., Hashimoto’s thyroiditis or post-thyroidectomy) and, ratory depression, and, in a significant minority, grand mal
here, the TSH is elevated whereas the T4 is low. seizures.
Of the neuropsychiatric features seen in hypothyroidism,
Clinical features depression is most common; this may be severe and may be
accompanied by hallucinations and delusions (Whybrow
The age of onset of hypothyroidism is determined by the et al. 1969).
underlying cause. Cases occurring secondary to Hashimoto’s Psychosis occurring secondary to hypothyroidism has
thyroiditis typically appear in the late thirties or early traditionally been referred to as ‘myxedema madness’ (Asher
forties, and cases occurring after thyroidectomy may first 1949) and is often characterized by delusions of persecution
appear within weeks post-operatively. The onset and and reference, as well as auditory hallucinations (Crowley
evolution of symptoms is typically gradual. 1940; de Fine Olivarius and Roder 1970; Karnosh and Stout
The clinical picture includes not only typical features, 1935; Logothetis 1963; Reed and Bland 1977). One case of
such as psychomotor retardation, but also, in a significant myxedema madness (Ziegler 1930) deserves to be quoted
minority, neuropsychiatric features including depression, at length, as it illustrates the sometimes exquisite nature of
psychosis, and dementia. the dependence of the psychosis on the level of circulating
p 16.qxd 3/10/08 9:52 AM Page 540
thyroid hormone. The patient had undergone radiation two reasons. First, such findings may indicate that the patient
treatment for hyperthyroidism 3 years earlier and had sub- is in the very early stages of what will become clinically evi-
sequently done well with an appropriate dosage of supple- dent hypothyroidism and, given this, close monitoring is
mental thyroid hormone. At the age of 48 years, however, required. Second, such subclinically reduced free T4 levels,
she became non-compliant and soon thereafter: although not causing symptoms per se, will nevertheless
blunt the response to antidepressants or mood-stabilizing
she began to feel that her husband was paying agents in patients with major depression or bipolar disorder.
attention to another woman and that he was trying
to do away with her by means of gas or the electric
chair. During a game at a party in her own home Course
during the holidays in 1928, she refused to sit in a
chair designated for her, thinking it might be a plot to The course of hypothyroidism is determined by the under-
kill her. She also felt that her husband was trying to lying cause.
poison her and refused to take desiccated thyroid
gland at home on account of such a belief. On several Etiology
occasions subsequently, when desiccated thyroid was
administered in sufficient quantity, at the repeated As noted earlier, the various causes of hypothyroidism are
and urgent request of her physician, the delusions divided into primary, secondary, and tertiary types.
entirely disappeared and she felt so much better that Primary hypothyroidism is by far the most common type,
she concluded that it was foolish to be taking accounting for over 90 percent of cases. The most common
medicine and discontinued taking it. On such cause of primary hypothyroidism is Hashimoto’s thyroiditis,
occasions, the psychosis would slowly return in the indicated by the presence of anti-thyroid antibodies: anti-
same form as before. thyroid peroxidase antibody (also known as anti-microsomal
antibody) is most common, but anti-thyroglobulin anti-
Dementia (Akelaitis 1936; de Fine Olivarius and Roder bodies may also be present. Other causes include thyroidec-
1970; Uyematsu 1920) may present with failing memory, tomy, radioactive iodine treatment, neck irradiation, iodine
followed by deficits in calculation and orientation; in some deficiency, and various medications, including amiodarone,
cases, the dementia may be accompanied by delusions of rifampin (Takasu et al. 2005), ethionamide (McDonnell et al.
persecution and auditory hallucinations. 2005), and, most especially, lithium (Lindstedt et al. 1977),
The electroencephalogram (EEG) typically shows in which case the occurrence of hypothyroidism is most
generalized slowing. likely in patients who have anti-thyroid antibodies (Calabrese
Thyroxine levels are available as both ‘total’ T4, includ- et al. 1985).
ing both bound and free fractions, and ‘free’ T4, and in all Secondary hypothyroidism may occur with tumors or
instances a free T4 level should be obtained. This free T4, as infarction of the pituitary.
noted earlier, is reduced in all cases. The TSH level, how- Tertiary hypothyroidism may occur with tumors or
ever, may be elevated or decreased, depending on the cause infarction of the hypothalamus; other causes include
of the hypothyroidism. In primary hypothyroidism, the granulomatous disease and carbamazepine.
TSH is increased; in both secondary and tertiary cases,
however, it is reduced. Distinguishing secondary from ter-
tiary cases generally requires a TRH stimulation test. In this Differential diagnosis
test, TRH is given intravenously and TSH levels are deter-
mined just before and 20 minutes after the infusion. In cases The differential diagnoses of the syndromes of depression,
of secondary hypothyroidism, given a lack of pituitary cells psychosis, and dementia are discussed in Sections 6.1, 7.1
capable of producing TSH, the response to exogenous and 5.1 respectively. In all these cases, the chief clues to the
TRH is blunted. By contrast, in tertiary hypothyroidism, diagnosis are the typical symptoms seen in hypothyroidism,
in which a chronic lack of endogenous TRH allows for an especially the psychomotor retardation, lethargy, and the
up-regulation of TRH receptors on pituitary cells, there is distinctive ‘myxedematous’ appearance.
an enhanced response of TSH to TRH. In cases of primary hypothyroidism secondary to
Before leaving this section some words are in order Hashimoto’s thyroiditis, it must be kept in mind that the
regarding the condition known as ‘subclinical’ primary underlying autoimmune process may cause additional
hypothyroidism. Here, although the free T4 level is within disorders including primary adrenocortical insufficiency and
normal limits, the TSH level is mildly elevated. Such a com- pernicious anemia with vitamin B12 deficiency. Given that
bination of laboratory values indicates that, although the free both of these disorders may cause psychosis, and that B12
T4 may be within broadly defined limits of normal, it is nev- deficiency, in addition, may cause depression and demen-
ertheless below the individual patient’s ‘normal’ as indicated tia, it is appropriate in all cases of Hashimoto’s thyroiditis
by the rise in TSH. Although patients may not have symp- to check cortisol and B12 levels. Checking the cortisol level
toms directly related to these findings, they are significant for is also important because the treatment of hypothyroidism
p 16.qxd 3/10/08 9:52 AM Page 541
References 541
with T4 in a patient with adrenocortical insufficiency may Anglin RE, Rosebush PI, Mazurek MF. The neuropsychiatric profile
precipitate a life-threatening Addisonian crisis. of Addison’s disease: revisiting a forgotten phenomenon.
Cases of secondary or tertiary hypothyroidism may also J Neuropsychiatry Clin Neurosci 2006; 18:450–9.
be associated with other endocrinopathies, such as hyper- Arafah BM. Increased need for thyroxine in women with
prolactinemia or secondary adrenocortical insufficiency. hypothyroidism during estrogen therapy. N Engl J Med 2001;
Finally, one must clearly distinguish between Hashimoto’s 344:1743–9.
thyroiditis and Hashimoto’s encephalopathy. Both of these Arnold BM, Casal G, Higgins HP. Apathetic thyrotoxicosis. Can
disorders are associated with anti-thyroid antibodies. In Med Assoc J 1974; 111:957–8.
Hashimoto’s thyroiditis, however, the thyroid alone is Asher R. Myxoedematous madness. BMJ 1949; 2:555–62.
targeted, whereas in Hashimoto’s encephalopathy, as dis- Brenner I. Apathetic hyperthyroidism. J Clin Psychiatry 1978;
cussed in Section 17.9, the thyroid is usually spared and the 39:479–80.
autoimmune onslaught is directed against the cerebrum. Bryce GM, Poyner F. Myxoedema presenting with seizures.
Postgrad Med J 1992; 68:35–6.
Bulens C. Neurologic complications of hyperthyroidism: remission
Treatment of spastic paralysis, dementia, and optic neuropathy. Arch
Neurol 1981; 38:669–70.
Treatment with once-daily T4 is generally curative. In cases
Bunevicius R, Kazanavicius G, Zalinkevicius R et al. Effects of
of hypothyroidism of relatively recent onset in young
thyroxine as compared with thyroxine plus triiodothyronine in
patients who are otherwise healthy and lack heart disease,
patients with hypothyroidism. N Engl J Med 1999; 340:424–9.
one may begin with 50–75 μg daily, increasing in 25–50 μg
Bursten B. Psychosis associated with thyrotoxicosis. Arch Gen
increments every 2 or 3 weeks. In cases of long-standing
Psychiatry 1961; 4:267–73.
hypothyroidism, however, or in elderly patients or those in
Calabrese JR, Gulledge AD, Hahn K et al. Autoimmune thyroiditis
poor health or with significant heart disease, the starting
in manic-depressive patients treated with lithium. Am J
dose should be lower, in the range of 12.5–25 μg, and the
Psychiatry 1985; 142:1318–21.
increases should be in increments of 12.5–25 μg every 4–6
Carlson HE, Linfoot JA, Burnstein GD et al. Hyperthyroidism and
weeks. Serial T4 determinations are made, and the dose
acromegaly due to a TSH- and GH-secreting tumor: lack of
should be increased until the free T4 is within the normal
hormonal response to bromocriptine. Am J Med 1983;
range. In cases of primary hypothyroidism, TSH levels
74:915–23.
should also be obtained, with the goal of bringing TSH
Cleghorn RA. Adrenal cortical insufficiency: psychological and
down to within normal limits; in this regard it must be kept
neurological observations. Can Med Assoc J 1951; 65:449–54.
in mind that the TSH level falls very slowly and that 4–8
Cohen SI. Cushing’s syndrome: a psychiatric study of 29 patients.
weeks may be required at any given dose of T4 for the TSH
Br J Psychiatry 1980; 136:120–4.
level to plateau out. For most adult females, anywhere Crowley RM. Psychoses with myxedema. Am J Psychiatry 1940;
from 75 to 100 μg of T4 is generally an adequate mainte- 96:1105–16.
nance dose; in males the range is from 100 to 150 μg. In the
Dietch JT. Diagnosis of organic anxiety disorders. Psychosomatics
elderly, however, the maintenance dose is generally 75 μg
1981; 22:661–9.
or less. In females given conjugated estrogens an increase
Doppman JL, Oldfield EH, Nieman LK. Bilateral sampling of the
in thyroid-binding globulins may decrease the free T4,
internal jugular vein to distinguish between mechanisms of
necessitating a dose increase (Arafah 2001). adrenocorticotropic hormone-dependent Cushing syndrome.
It has been suggested that a combination of T4 and Ann Intern Med 1998; 128:33–6.
T3 produced better symptomatic relief than T4 alone Engel GL, Margolin SG. Neuropsychiatric disturbances in Addison’s
(Bunevicius et al. 1999); however, subsequent work has disease and the role of impaired carbohydrate metabolism in
failed to confirm this (Gorzinsky-Glasberg et al. 2006). the production of abnormal cerebral function. Arch Neurol
Myxedema coma constitutes a medical emergency and Psychiatry 1941; 45:881–4.
patients should be admitted to an intensive care unit. Treat- Erem C, Algun E, Osbey N et al. Clinical laboratory findings and
ment involves giving intravenous T4 in a dose of 300 μg, results of therapy in 55 patients with Cushing’s syndrome.
followed by daily intravenous doses of 50–100 μg. Intra-
J Endocrinol Invest 2003; 26:65–72.
venous hydrocortisone is also given, along with vigorous
Fang VBS, Jaspan JB. Delirium and neuromuscular symptoms in
supportive care.
an elderly man with isolated corticotroph deficiency syndrome
completely reversed with glucocorticoid replacement. J Clin
REFERENCES Endocrinol Metab 1989; 69:1073–7.
Fidler SM, O’Rourke RA, Buschbaum HW. Choreoathetosis as a
Akelaitis AJE. Psychiatric aspects of myxedema. J Nerv Ment Dis manifestation of thyrotoxicosis. Neurology 1971; 21:55–7.
1936; 83:22–36. de Fine Olivarius B, Roder E. Reversible psychosis and dementia in
Anderson AE, McHugh PR. Oat cell carcinoma with myxedema. Acta Psychiatr Scand 1970; 46:1–13.
hypercortisolemia presenting to a psychiatric hospital as a Fishbeck KH, Layzer RB. Paroxysmal choreoathetosis associated
suicide attempt. J Nerv Ment Dis 1971; 152:427–31. with thyrotoxicosis. Ann Neurol 1979; 6:453–4.
p 16.qxd 3/10/08 9:52 AM Page 542
Fukui T, Hasegawa Y, Takenaka H. Hyperthyroid dementia: Lindstedt G, Nilsson L, Walinder J et al. On the prevalence,
clinicoradiological findings and response to treatment. diagnosis and management of lithium-induced hypothyroidism
J Neurol Sci 2001; 184:81–8. in psychiatric patients. Br J Psychiatry 1977; 130:452–8.
Ghobrial MW, Ruby EB. Coma and thyroid storm in apathetic Logothetis J. Psychotic behavior as the initial indicator of adult
thyrotoxicosis. South Med J 2002; 95:552–4. myxedema. J Nerv Ment Dis 1963; 136:561–8.
Greer S, Parsons V. Schizophrenia-like psychosis in thyroid crisis. MacCrimmon DJ, Wallace JE, Goldberg WM et al. Emotional
Br J Psychiatry 1968; 114:1357–62. disturbances and cognitive deficits in hyperthyroidism.
Greer S, Ramsay I, Bagley C. Neurotoxic and thyrotoxic anxiety: Psychosom Med 1979; 41:331–40.
clinical, psychological and physiological measurements. Maclay WS, Stokes AB. Mental disorder in Cushing’s syndrome.
Br J Psychiatry 1973; 122:549–54. J Neurol Neurosurg Psychiatry 1939; 1:110–18.
Gorzinsky-Glasberg S, Fraser A, Nahsoni E et al. Thyroxine- Martin FI, Deam DR. Hyperthyroidism in elderly hospitalized
triiodothyronine combination therapy versus thyroxine patients. Clinical features and treatment outcomes. Med
monotherapy for clinical hypothyroidism: meta-analysis of J Aust 1996; 164:200–3.
randomized controlled trials. J Clin Endocrinol Metab 2006; McDonnell ME, Braverman JE, Bernardo J. Hypothyroidism due
91:2592–9. to ethionamide. N Engl J Med 2005; 352:2757–9.
Haskett RF. Diagnostic categorization of psychiatric disturbance McFarland HR. Addison’s disease and related psychoses. Compr
in Cushing’s syndrome. Am J Psychiatry 1985; 142:911–16. Psychiatry 1963; 4:90–5.
Hertz PE, Nadas E, Wojtkowiki H. Case report: Cushing’s Mitchell JRA, Surridge DHC, Willison RG. Hypothermia after
syndrome and its management. Am J Psychiatry 1955; chlorpromazine in myxoedematous psychosis. BMJ 1959;
112:144–5. 2:932–3.
Hickman JW, Atkinson RP, Flint LD et al. Transient schizophrenic Nickel SN, Frame B. Neurologic manifestations of myxedema.
reaction as a major symptom of Cushing’s syndrome. N Engl J Neurology 1958; 8:511–17.
Med 1961; 264:797–800. Orth DN. Cushing’s syndrome. N Engl J Med 1995; 332:791–803.
Hodgson RE, Murray D, Woods MR. Othello’s syndrome and Pandit L, Shankar SK, Gayathri N et al. Acute thyrotoxic
hyperthyroidism. J Nerv Ment Dis 1992; 180:663–4. neuropathy – Basedow’s paraplegia revisited. J Neurol Sci
Ingham SD, Nielsen JM. Thyroid psychosis: difficulties in 1998; 155:211–4.
diagnosis. J Nerv Ment Dis 1931; 74:271–7. Reed K, Bland RC. Masked ‘myxedema madness’. Acta Psychiatr
Jabbari B, Huott AD. Seizures in thyrotoxicosis. Epilepsia 1980; Scand 1977; 56:421–6.
21:91–6. Spillane JD. Nervous and mental disorders in Cushing’s syndrome.
Jeffcoate WJ, Silverstone JT, Edwards CRW et al. Psychiatric Brain 1951; 74:72–94.
manifestations of Cushing’s syndrome: response to lowering of Starkman MN, Schteingart DE, Schork MA. Depressed mood and
plasma cortisol. Q J Med 1979; 191:465–72. other psychiatric manifestations of Cushing’s syndrome:
Jellinek EH, Kelly RE. Cerebellar syndrome in myxoedema. Lancet relationship to hormone levels. Psychosom Med 1981;
1960; 2:225–7. 43:3–18.
Karnosh LJ, Stout RE. Psychoses of myxedema. Am J Psychiatry Steinberg PI. A case of paranoid disorder associated with
1935; 91:1263–74. hyperthyroidism. Can J Psychiatry 1994; 39:153–6.
Kaskarelis IS, Tsatalou EG, Benakis SV et al. Bilateral inferior Takasu N, Takara M, Komiya I. Rifampin-induced hypothyroidism
petrosal sinuses sampling in the routine investigation of in patients with Hashimoto’s thyroiditis. N Engl J Med 2005;
Cushing’s syndrome: a comparison with MRI. AJR 2006; 352:518–19.
187:562–70. Taylor JW. Depression in thyrotoxicosis. Am J Psychiatry 1975;
Kathol RG, Delahunt JW. The relationship of anxiety and 132:552–3.
depression to symptoms of hyperthyroidism using operational Thomas FB, Mazzaferri EL, Skillman TG. Apathetic thyrotoxicosis:
criteria. Gen Hosp Psychiatry 1986; 8:23–8. a distinctive clinical and laboratory entity. Ann Intern Med
Kawashima T, Oda M, Kund T et al. Metyrapone for delirium due 1970; 72:679–85.
to Cushing’s syndrome induced by occult ectopic Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing’s
adrenocorticotropic hormone secretion. J Clin Psychiatry 2004; syndrome. Arch Neurol Psychiatry 1952; 67:283–309.
65:1019–20. Trzepacz P, McCue M, Klein I et al. A psychiatric and
Kelly WF. Psychiatric aspects of Cushing’s syndrome. Q J Med neuropsychological study of patients with untreated Graves’
1996; 89:543–51. disease. Gen Hosp Psychiatry 1988; 10:49–55.
Kelly WF, Checkley SA, Bender DA et al. Cushing’s syndrome and Tyrell JB, Findling JW, Aron EDC et al. An overnight high-dose
depression – a prospective study of 26 patients. Br J Psychiatry dexamethazone suppression test for rapid differential
1983; 142:16–19. diagnosis of Cushing’s syndrome. Ann Intern Med 1986;
Lahey FH. Non-activated (apathetic) type of hyperthyroidism. 104:180–6.
N Engl J Med 1931; 204:747–8. Uyematsu S. A case of myxedematous psychosis. Arch Neurol
Lazarus A, Jaffe R. Resolution of thyroid-induced Psychiatry 1920; 3:252–76.
schizophreniform disorder following subtotal thyroidectomy: Van Uitert RL, Russakoff LM. Hyperthyroid chorea mimicking
case report. Gen Hosp Psychiatry 1986; 8:29–31. psychiatric disease. Am J Psychiatry 1979; 136:1208–10.
p 16.qxd 3/10/08 9:52 AM Page 543
References 543
Varadaraj R, Cooper AJ. Addison’s disease presenting with Wolkowitz OM, Rubinow D, Doran AR et al. Prednisone effects on
psychiatric features. Am J Psychiatry 1986; 143:553–4. neurochemistry and behavior. Arch Gen Psychiatry 1990;
Varney NR, Alexander B, MacIndoe JH. Reversible steroid 47:963–8.
dementia in patients without steroid psychosis. Am J Wynne AG, Gharib H, Scheithauer BW et al. Hyperthyroidism due
Psychiatry 1984; 141:369–72. to inappropriate secretion of thyrotropin in 10 patients. Am J
Whybrow PC, Prange AJ, Treadway CR. Mental changes affecting Med 1992; 92:15–24.
thyroid gland dysfunction: a reappraisal using objective Ziegler LH. Psychosis associated with myxedema. 1930; 11:20–7.
psychological measurement. Arch Gen Psychiatry 1969;
20:48–63.
p 17.qxd 3/10/08 9:52 AM Page 544
17
Immune-related disorders
17.1 Multiple sclerosis 544 17.7 Limbic encephalitis 553

17.2 Systemic lupus erythematosus 548 17.8 Sarcoidosis 555
17.3 Sjögren’s syndrome 551 17.9 Hashimoto’s encephalopathy 556
17.4 Sneddon’s syndrome 552 17.10 Sydenham’s chorea 558
17.5 Primary anti-phospholipid syndrome 552 17.11 Chorea gravidarum 560
17.6 Susac’s syndrome 553 References 561
17.1 MULTIPLE SCLEROSIS secondary to a transverse myelitis, in which case one speaks
of Devic’s disease or neuromyelitis optica. Cerebellar and
Multiple sclerosis (MS) is characterized pathologically by brainstem involvement is also common and may produce
the more or less sequential occurrence of lesions known as ataxia, intention tremor, dysarthria or scanning speech, nys-
plaques in various parts of the white matter of the central tagmus, diplopia, and vertigo. Internuclear ophthalmoplegia
nervous system, and clinically by the appearance of signs may also occur, and this should be carefully sought for as it is
and symptoms appropriate to the location of the plaques. of great diagnostic significance: although internuclear
This is a fairly common disorder, occurring in about 0.1 ophthalmoplegia may occur with other mesencephalic
percent of the general population, and is roughly two to lesions, such as tumors, infarctions or Wernicke’s
three times more common in females than males. encephalopathy, these are all quite rare in young adults and,
hence, this finding in a young person is almost specific for
MS (Keane 2005). Bladder dysfunction is quite common
Clinical features with various symptoms including urgency and frequency,
incontinence or urinary retention. Bowel dysfunction is also
Although the range of age of onset is wide, from childhood common and most frequently presents with constipation.
to the seventh decade, the vast majority of patients first fall Sexual dysfunction is very common, with decreased libido,
ill in their twenties or thirties. As discussed further below erectile dysfunction or decreased vaginal lubrication.
(see Course, below), in most cases, at least initially, MS pur- Uncommon symptoms and signs include aphasia (Achiron
sues an episodic course, and the episodes typically have a et al. 1992; Devere et al. 2000; Lacour et al. 2004; Olmos-Lau
subacute onset, over days or a week or so. Exceptions to this et al. 1977) and seizures, which may be either partial or grand
rule, however, do occur, with some onsets spanning less mal in type (Nicoletti et al. 2003), and various paroxysmal
than a day and others being quite leisurely, occurring over phenomena, such as hemifacial spasm, Lhermitte’s sign,
weeks or months. The duration of individual episodes varies trigeminal neuralgia, and lancinating pains in the extremi-
widely, from weeks to months, after which there is a gradual ties. Fatigue may also occur in MS and may be quite severe.
defervescence of symptomatology of variable degree. The Dementia of variable severity, ranging from mild,
severity of symptoms varies widely, and in some cases may almost subclinical impairment to debilitating, is eventually
be so mild that patients fail to recognize them as such. seen in the majority of patients (Franklin et al. 1989;
The most common symptoms are motor or sensory in Surridge 1969). In rare cases, dementia may constitute the
type. Spastic weakness may occur in one limb, or there may sole, or predominant, presenting feature of MS (Bergin
be a hemiparesis or paraparesis. Sensory symptoms, similar 1957; Hotopf et al. 1994; Koenig 1968; Young et al. 1976).
in distribution, may include numbness and tingling, and, in In one case, for example, the only symptom in addition to
a minority, dysesthesiae or actual pain. Visual symptomatol- the dementia was optic neuritis (Jennekens-Schinkel and
ogy is also common and may include optic neuritis with Sanders 1986), and in two others it was unsteady gait
unilateral blurring of vision or blindness; not uncommonly (Mendez and Frey 1992). In one very rare case a gradually
one may see the combination of optic neuritis and paraplegia progressive dementia constituted the only clinical evidence
p 17.qxd 3/10/08 9:52 AM Page 545
of MS (Fontaine et al. 1994). Although the correlation of

dementia and plaque location and number has not been
definitively worked out, it appears that cognitive deficits
correlate both with the total burden of plaques within the
cerebral white matter (Comi et al. 1999; Franklin et al.
1988; Ron et al. 1991) and with atrophy of the corpus cal-
losum (Huber et al. 1987), which in turn may merely
reflect overall disease activity in the hemispheric white
matter (Barnard and Triggs 1974).
Depression is eventually seen in perhaps one-quarter of
patients (Surridge 1969). Depression may occur on a reac-
tive basis in any debilitating disease, and MS is no excep-
tion. Certain facts, however, suggest strongly that
depression in MS may also be a direct result of plaque for- Figure 17.1 In the T2-weighted magnetic resonance imaging
mation. Patients with MS are more likely to experience scan on the left, there are multiple areas of increased signal
depression than are normal control subjects (Fassbender intensity corresponding to both chronic and active plaques; in the
et al. 1998) or those with comparably disabling neurologic T1-weighted scan with gadolinium enhancement on the right,
diseases that generally spare the cerebrum, such as amyo- however, only the active lesions enhance. (Reproduced from
trophic lateral sclerosis (Schiffer and Babigian 1984; Graham and Lantos 1996.)
Whitlock and Siskind 1980). Furthermore, in contrast to
what one might expect if the depression were reactive, withdrawal, ‘mystic’ visual hallucinations, and various delu-
there is little or no correlation between the occurrence of sions (Fontaine et al. 1994).
depression and the extent of the patient’s disability (Moller Magnetic resonance (MR) scanning has assumed a domi-
et al. 1994), and, regardless of the degree of overall disabil- nant role in the evaluation of patients with suspected MS.
ity, patients are more likely to experience depression when Almost all plaques demonstrate increased signal intensity on
the plaques are in the cerebrum than when they are in the T2-weighted or fluid-attenuated inversion recovery (FLAIR)
cerebellum or spinal cord (Rabins et al. 1986; Schiffer et al. imaging, and active plaques show enhancement with gadolin-
1983). Furthermore, a correlation has been noted between ium, as demonstrated in Figure 17.1. In some cases, as noted
depression and the presence of plaques in the inferior left below (see Etiology), severe plaques may undergo cystic
frontal white matter (Feinstein et al. 2004), the left arcuate change, and on T1-weighted imaging such plaques will
fasciculus (Pujol et al. 1997), and the white matter of the appear as ‘black holes’ with greatly reduced signal intensity.
right temporal lobe (Berg et al. 2000). Plaques are typically found in the centrum semiovale and in a
Euphoria may also occur in MS, and this is typically of periventricular distribution, where they tend to favor the
the ‘bland’ or non-infectious type; it has been noted in any- occipital horns.
where from one-quarter (Surridge 1969) to the vast major- The cerebrospinal fluid (CSF) is abnormal in almost all
ity of patients (Cottrell and Wilson 1926), and is correlated cases. A mild lymphocytic pleocytosis, in the range of 6–30
with cerebral rather than spinal plaque formation (Rabins cells/mm3, is seen in about one-third of cases, and the total
et al. 1986). The contrast between this euphoria and the protein is mildly elevated (rarely over 100 mg/dL) in about
patient’s actual condition can be quite dramatic: one of one-half of cases. The IgG index is elevated in over two-thirds
S.A.K. Wilson’s (1955) patients, ‘bedridden and unable to of cases, and oligoclonal bands are present in over 90 percent.
stand, remarked, “you will not believe me when I say I feel The myelin basic protein is elevated in over three-quarters of
thundering well.” ’ This bland euphoria is typically not cases. Of note, the 14-3-3 protein may be found in a little
accompanied by hyperactivity or pressure of speech and is over one-tenth of all cases (Martinez-Yelamos et al. 2001).
often seen in concert with some degree of intellectual Evoked potentials, including somatosensory, brain-
impairment (Surridge 1969). Although they are unusual, stem, and visual-evoked potentials, were once widely used
definite manic episodes may also occur in addition to this to demonstrate lesions within the respective white matter
bland euphoria (Joffe et al. 1987; Schiffer et al. 1986); pathways; however, with the advent of MR scanning, these
indeed, out of all of the reasons for admission to psychiatric are generally no longer required.
hospital for patients with MS, mania is the most common
(Pine et al. 1995).
Emotional incontinence, with uncontrollable laughter Course
or crying in the absence of a corresponding affect, is seen in
about one-tenth of patients (Feinstein et al. 1997; Surridge As noted earlier, most cases of MS are characterized by
1969), generally only in far-advanced cases. episodes of illness, and this course is referred to as relapsing
Psychosis may rarely dominate the clinical picture and remitting. The interval between episodes is extremely
(Mathews 1979; Parker 1956), and in one very rare case variable, ranging from months to two decades. Subsequent
MS presented with a psychosis characterized by social episodes may consist of exacerbations of symptoms seen in
p 17.qxd 3/10/08 9:52 AM Page 546
546 Immune-related disorders
previous episodes, or completely new symptoms, depending active plaque resolves into a chronic plaque, which is com-
on whether old plaques become reactivated or new plaques posed of a relatively well-circumscribed area of demyelin-
form. With the resolution of any episode, remission of symp- ization and gliosis, with, in severe cases, a degree of
toms is rarely complete and most patients are left with resid- cavitation. The size of plaques varies widely, from as little as
uals; over time and with recurrent episodes, this burden of a few millimeters up to several centimeters in diameter. As
residual symptoms gradually increases. Predicting the overall noted earlier, most plaques are found in the centrum semio-
pattern in patients with a relapsing and remitting course is vale and in a periventricular location (Brownell and Hughes
very difficult, and in some cases, even after long observation, 1962); plaques, of course, are also found in the cerebellar
it may still not be possible to make accurate predictions. white matter, the brainstem, and the cord. Although the vast
In addition to this relapsing and remitting pattern, the majority of plaques are found in the white matter, small gray
overall course of MS may also be characterized by a chronic matter plaques are seen at times.
progression of symptoms, and this ‘progressive’ course may Although the cause of MS remains unknown, several
be further subdivided into a ‘secondary’ or ‘primary’ type. lines of evidence suggest that it represents an autoimmune
A secondary progressive course emerges within the context disorder in genetically susceptible individuals triggered by
of an initially relapsing and remitting course, and this pat- a relatively common childhood viral infection.
tern eventually appears in the majority of relapsing and The incidence of MS rises from that seen in the general
remitting cases. A primary progressive course, that is an ill- population to that seen in first-degree relatives and finally
ness characterized by relentless and uninterrupted progres- to monozygotic twins. As noted earlier, the incidence of
sion from the start, is much less common, being seen in MS in the general population is about 0.1 percent; this rises
perhaps one-tenth of all cases. to about 2–4 percent in first-degree relatives up to 25–40
As noted earlier, the severity of symptoms seen in MS percent in monozygotic twins (Ebers et al. 1986; Mumford
varies quite widely and, in some cases, active plaques, which et al. 1994). Although this could conceivably be explained
can be seen on MRI, may escape clinical detection on the basis of a shared environment, adoption studies
(Thompson et al. 1992; Willoughby et al. 1989). With the support a genetic cause (Ebers et al. 1995). Furthermore,
routine use of MRI, more and more cases of ‘benign MS’ there is significant linkage between MS and certain human
are being discovered. On the other hand, some patients may leukocyte antigen (HLA) haplotypes.
experience devastatingly severe episodes. Such cases of MS The evidence for an infectious agent acting on this
are often referred to as ‘Marburg’ variants and are charac- fertile genetic background rests on several facts. First,
terized by large and multiple plaques, and severe symp- although found at all latitudes, MS is more common in
tomatology, with, in some cases, death in a matter of weeks temperate zones. Furthermore, if individuals remain in a
or months. high-risk temperate zone past the age of 15 years and then
Although pregnancy itself does not seem to predispose migrate to a tropical area, they ‘carry’ their increased risk
to new episodes, the first 3 months post-partum do seem with them (Dean 1967), indicating that the increased risk
to be associated with an increased risk. relates to some environmental exposure that is more com-
Symptoms of MS may undergo transient exacerbation mon in temperate zones. Second, although not without
with stress, infection, or temperature elevation, as may controversy, it appears that there have been ‘epidemics’ of
occur with a hot bath, fever, or exercise. These exacerba- MS in the Faroe Islands and in Iceland, and that these epi-
tions do not reflect inflammatory plaque activity but rather demics may have been related to the presence of British
impaired conduction through partially damaged axons, troops stationed there during World War II. Although the
and thus they should not be interpreted as relapses. nature of the presumed infection is not clear, certain evi-
Interestingly, in the past this kind of transient exacerbation dence points toward such common viral infections as
was used as a diagnostic test for MS: in such a ‘hot bath’ mononucleosis (DeLorenze et al. 2006). It must be clearly
test, the patient was immersed in hot water and observed noted, however, that the deleterious effect of any such
for the emergence of signs or symptoms. infection is not direct: there is no evidence for an actual
viral infection in MS plaques. Rather, it is suspected that
a childhood infection sensitizes the immune system in
Etiology genetically susceptible individuals and that some event in
adult life, perhaps a reactivation of a latent viral infection,
As indicated earlier, the pathologic hallmark of MS is the triggers off an immune response that incorrectly targets
plaque. Classically, active plaques consist of an area of oligodendrocytes and myelin.
perivenular mononuclear inflammation with loss of oligo-
dendrocytes and demyelinization, with relative axonal spar-
ing (Greenfield and King 1936). Recently, however, it has Differential diagnosis
become apparent that this classic view may not apply in all
cases, and that in a minority the active plaque may be char- In large part, the differential diagnosis of MS depends on
acterized by apoptosis of oligodendrocytes with relatively lit- where in the course of the disease the patient happens to
tle inflammation (Barnett and Prineas 2004). In time, the be. In cases in which the patient is encountered during the
p 17.qxd 3/10/08 9:52 AM Page 547
first episode of illness, the prime consideration is given to 3–7 days, followed by prednisone in a dose of approxi-
acute disseminated encephalomyelitis (ADEM). As discussed mately 1 mg/kg/day for 4 days, with this dose gradually
in Section 14.11, ADEM is a monophasic illness and the tapered over the following 2–3 weeks, with due consider-
first step is to determine, by MR scanning, whether or not ation being given to the clinical response. Mania may com-
there are white matter lesions consistent with old plaques plicate such a course of prednisone, and this may require
that may have been asymptomatic. If these are found, then treatment with antipsychotics or a mood stabilizer such as
the diagnosis of ADEM is effectively ruled out. In cases in lithium or valproate, as discussed in Section 6.3. In cases
which they are absent, the acute findings on MRI may be in which patients have received prior courses of steroids
helpful. In ADEM one typically finds multiple, large white that were complicated by mania, it may be appropriate to
matter lesions and, although such a picture may be seen in consider prophylactic treatment with one of these mood
some cases of MS, it is far more common to find a few rel- stabilizers.
atively small lesions. If the differential still remains in doubt,
then one may have to settle for long-term clinical observa- PREVENTIVE TREATMENTS
tion. If there are no further episodes, then ADEM remains
high on the differential; by contrast, the appearance of a Preventive treatments may be considered in patients with a
new episode argues strongly for a diagnosis of MS. relapsing and remitting course and also in those whose
In cases characterized by progressive white matter dis- course is marked by secondary progression.
ease from the onset, MS of the primary progressive type In relapsing and remitting MS, preventive treatment
must be distinguished from vitamin B12 deficiency and may be accomplished with several agents, including inter-
adrenoleukodystrophy, a differential readily accomplished ferons, glatiramer, and natalizumab.
by testing for vitamin B12 and plasma long-chain fatty acid Interferons are immunomodulatory agents, and three
levels. are effective: interferon beta-1b (Betaseron, given subcuta-
In cases in which there is an established pattern of neously every other day) (European Study Group 1998) and
relapses and remissions, consideration may be given to two preparations of interferon beta-1a (Rebif, given subcu-
Behçet’s syndrome, systemic lupus erythematosus, and taneously three times weekly [PRISMS Study Group 1998],
polyarteritis nodosa. In each of these three disorders, how- and Avonex, given intramuscularly once weekly [Rudick
ever, one also finds systemic signs that are lacking in MS: in et al. 1997]). Each of these three interferons reduces relapse
Behçet’s disease there are oral and genital ulcers; and in rates by about one-third. Choosing among them is not
lupus and polyarteritis nodosa, in addition to constitu- straightforward. All three may induce the formation of
tional signs one finds evidence of other organ involvement, neutralizing antibodies after anywhere from 6 to18 months,
such as the joints, kidneys, or gastrointestinal tract. In older which may blunt their response; this occurs in about one-
patients consideration may also be given to lacunar infarc- third of patients on Betaseron, one-fifth of patients on Rebif,
tions; however, here the clinical episodes are generally of and less than one-tenth of patients on Avonex. On this
acute onset, over perhaps minutes or hours at the most, count, Avonex appears attractive; however, recent work has
and the lesions are typically found in the internal capsule demonstrated that both Betaseron (Durelli et al. 2002) and
and basal ganglia; this is in contrast to MS in which the Rebif (Panitch et al. 2002) are more effective than Avonex.
episodes are of more gradual onset and the lesions are Glatiramer (Copaxone, given subcutaneously daily)
more commonly found higher up in the white matter, (Comi et al. 2001; Johnson et al. 1998) is a mixture of
surrounding the lateral ventricles and extending into the polypeptides that mimics myelin basic protein, thereby
centrum semiovale. presumably blunting the autoimmune assault on myelin.
Like the interferons, it reduces relapse rates by about one-
third and may also induce neutralizing antibodies.
Treatment Natalizumab (Tysabri, given intravenously once
monthly) is a humanized monoclonal antibody directed at
Treatment of MS may be divided into that directed at the human alpha-4 integrin. This molecule exists on the sur-
acute episode, preventive treatments designed to forestall face of lymphocytes and serves to bind them to vascular
future episodes or to limit secondary progression, and cell adhesion molecules (VCAM) on vascular endothelial
symptomatic treatments. Each of these aspects of treatment cells, thus allowing their transport across the vessel wall.
is now considered in turn, followed by some summary rec- When integrin is blocked, this ‘trafficking’ into the inter-
ommendations. stitial fluid is inhibited and the inflammatory response is
blunted. Natalizumab appears to reduce relapse rates by
ACUTE EPISODES roughly two-thirds (Miller et al. 2003); neutralizing anti-
bodies occur in about one-tenth of cases. Enthusiasm for
Acute episodes may be treated with intravenous methyl- natalizumab has been tempered, however, by the appear-
prednisolone, followed by oral prednisone. Although there ance of progressive multifocal leukoencephalopathy in
is no unanimity regarding dosage, a reasonable regimen treated patients; although this is a very rare complication,
consists of 250 mg of methylprednisolone every 6 hours for it is potentially fatal.
p 17.qxd 3/10/08 9:52 AM Page 548
Overall, in choosing a preventive treatment for relapsing dextromethorphan and quinidine. Whether it would
and remitting MS it is probably reasonable to begin with an respond to some of the other agents used in emotional
interferon, such as Betaseron. Should this offer little benefit, incontinence resulting from other disorders (e.g., cital-
consideration may be given to glatiramer. In clearly treat- opram in vascular cases) is not clear.
ment-resistant cases, natalizumab is a reasonable option. Psychosis is treated as outlined in Section 7.1.
Other, less well-established options for treatment-resistant
cases include intravenous immunoglobulins or immuno- SUMMARY
suppressants such as azathioprine.
In secondary progressive MS one may use an interferon, The overall treatment of patients with MS is difficult and at
either interferon beta-1b (Betaseron) (European Study times quite complex, and it is often best carried out by a spe-
Group 1998) or intramuscular interferon beta-1a (Avonex) cialized team. Except in cases of very benign MS, most
(Cohen et al. 2002). If the patient is already on one of these patients will receive preventive treatment; whenever an
agents while the course undergoes transformation from episode does occur, consideration should be given to
relapsing and remitting to secondary progression, then con- prompt acute treatment with steroids to lessen the chance of
sideration may be given to an immunosuppressant, such as any permanent damage and residual symptoms. Given the
mitoxantrone (Hartung et al. 2002) or low-dose methotrex- number of medications involved for symptomatic treat-
ate (Goodkin et al. 1995). ment, the potential for drug–drug interactions and cumula-
tive side-effects is large, and constant vigilance is required.
SYMPTOMATIC TREATMENT
Spasticity has traditionally been treated with baclofen, 17.2 SYSTEMIC LUPUS ERYTHEMATOSUS
diazepam, or tizanidine; gabapentin represents a recent addi-
tion to this armamentarium (Cutter et al. 2000). Painful Systemic lupus erythematosus (SLE or, colloquially, lupus)
dysesthesiae, trigeminal neuralgia, or lancinating pains may is a systemic autoimmune disease that involves multiple
respond to either carbamazepine or gabapentin. Intention organs, including the brain. Cerebral lupus (or as it is also
tremor may be reduced by either clonazepam or, in some referred to, neuropsychiatric systemic lupus erythemato-
cases, propranolol. Bladder dysfunction is often a focus of sus) occurs in the vast majority of cases, and may occur
treatment: urinary retention may respond to bethanechol, secondary to either a direct autoimmune assault on neu-
and spastic bladder with urinary urgency and frequency may rons (in which case one may speak of ‘lupus cerebritis’) or
be relieved by oxybutynin or tolterodine; in some cases a multiple infarctions, which may be either cardioembolic or
Foley catheter or more invasive measures may be required. secondary to a vasculopathy.
Bowel dysfunction usually consists of constipation, which SLE occurs in 0.015–0.05 percent of the general popula-
may be managed with a bowel program. Erectile dysfunction. It is far more common among females than males,
tion may be managed with a phosphodiesterase inhibitor, and among black populations than white populations, and
such as sildenafil, and decreased vaginal lubrication may in black females the prevalence rises to 0.4 percent.
be helped by lubricating agents. Seizures may be managed
with standard anti-epileptic drugs. Fatigue may respond
to amantadine in a dose of 100 mg b.i.d. (Krupp et al. 1995; Clinical features
Rosenberg and Appenzeller 1988); recent enthusiasm for
modafinil should be tempered by a negative double-blind Although lupus may appear at almost any age, including in
study (Stankoff et al. 2005). the elderly, the majority of patients fall ill between puberty
Dementia is treated as discussed in Section 5.1. Recent and 40 years of age.
work suggests that donepezil may improve cognitive func- As noted, lupus is a systemic disease and in most cases
tioning in MS (Krupp et al. 2004). cerebral lupus occurs in the setting of other symptoms,
Depression should be treated with an antidepressant. including constitutional symptoms (fatigue, fever, weight
Remarkably, there has been only one double-blind study loss) and those referable to other organ systems, such as
in this regard, which found desipramine to be superior to the musculoskeletal system, skin, heart, lungs, or kidneys
placebo (Schiffer and Wineman 1990); unfortunately, as (Johnson and Richardson 1968). Musculoskeletal symp-
might have been predicted, this was poorly tolerated. In prac- tomatology is very common and includes myalgia, arthralgia,
tice, most patients are given a selective serotonin reuptake and a non-deforming polyarthritis. Cutaneous manifesta-
inhibitor (SSRI) such as escitalopram but, if this is not effec- tions include photosensitivity, rashes (especially a malar
tive, other agents such as duloxetine might be considered. rash), and alopecia. Cardiac symptomatology incorporates
Euphoria of the ‘bland’ type rarely requires any treat- pericarditis and Libman–Sacks endocarditis. Pulmonary
ment. Should mania occur, however, treatment is con- involvement may manifest with pleurisy, which may or
ducted as described in Section 6.3. may not be accompanied by pleural effusion. Renal
As discussed in Section 4.7, emotional incontinence involvement may manifest initially with proteinuria and
may respond to amitriptyline or to a combination of cellular casts; over time renal failure may occur. Various
p 17.qxd 3/10/08 9:52 AM Page 549
17.2 Systemic lupus erythematosus 549
cytopenias, including anemia, leukopenia, or thrombocy- Magnetic resonance scanning may be normal or may
topenia, may also occur. show evidence of infarction. When infarctions are present,
Cerebral lupus (Brey et al. 2002; Feinglass et al. 1976; they tend to occur in one of two patterns. Either there are
Johnson and Richardson 1968) may manifest with depres- multiple small infarcts in either the cerebral cortex or the
sion, mania, psychosis, delirium or dementia, seizures, subcortical white matter, or one may find relatively large
chorea, or focal signs, such as hemiparesis. Although these territorial infarctions in the areas of distribution of large
findings may occur independently, patients often have a pial vessels.
mixture (Devinsky et al. 1988). The electroencephalogram (EEG) may be normal or show
Depression, in some cases accompanied by hallucina- slowing, which may be generalized or focal (Sibley et al.
tions or delusions, has been found commonly by some 1992). In patients with seizures, interictal epileptiform dis-
(Ganz et al. 1972; Miguel et al. 1994), but not all (Guze charges may or may not be present.
1967; Hugo et al. 1996), authors. Mania, although reported The CSF (Johnson and Richardson 1968; McLean et al.
(Johnson and Richardson 1968), appears rare. Psychosis is 1995; West et al. 1995) may be normal or there may be a
relatively uncommon (Guze 1967; Lim et al. 1988; Miguel mild lymphocytic pleocytosis or a mildly elevated total
et al. 1994) and, although typically characterized by delusions protein. Other abnormalities, primarily in patients with
and hallucinations, may rarely present with stuporous cata- lupus cerebritis (West et al. 1995), include an elevated IgG
tonia (Lanham et al. 1985; Mac and Pardo 1983). Rarely, index, oligoclonal bands, and the presence of anti-neu-
psychosis may constitute the presenting feature of lupus ronal antibodies.
(Agius et al. 1997). In cases in which infarction is suspected, a work-up, as
Delirium may occur (Devinsky et al. 1988; Hugo et al. described in Section 7.4, is required: appropriate tests may
1996; Miguel et al. 1994) and is often accompanied by hallu- include an echocardiogram, computed tomographic angiog-
cinations, either visual or auditory (Lief and Silverman 1960; raphy, or magnetic resonance angiography, and, as noted
O’Connor and Musher 1966). Dementia may also be seen earlier, testing for anti-phospholipid antibodies.
(Kirk et al. 1991; Johnson and Richardson 1968; MacNeil
et al. 1976; Robin et al. 1995) but is relatively uncommon
(Devinsky et al. 1988). Course
Seizures are relatively common (Devinsky et al. 1988)
and may be partial (complex partial or simple partial) or Overall, the course is characterized by a gradual waxing
grand mal in type (Mikdashi et al. 2005). Chorea may and waning of symptoms; full remissions are unusual and
occur and indeed may constitute the presentation of SLE generally not permanent. Although SLE is in general com-
(Donaldson and Espiner 1971; Fermaglich et al. 1973). patible with long-term survival, the appearance of cerebral
Focal deficits (Devinsky et al. 1988) are common and may (Rubin et al. 1985) or renal disease is an ominous sign.
include hemiparesis, aphasia, or hemianopia. Thrombotic
thrombocytopenic purpura has been noted but this is usu-
ally a terminal event (Devinsky et al. 1988). Etiology
In addition to cerebral involvement, the peripheral nerv-
ous system may also be involved, with either a peripheral Lupus is characterized by the presence of a large number of
polyneuropathy (McCombe et al. 1987) or a mononeuritis autoantibodies directed at various tissues in multiple organ
multiplex (Hughes et al. 1982). systems. Although the cause is not known, it is strongly
The anti-nuclear antibody (ANA) test is positive in suspected that the autoimmune response occurs secondary
approximately 95 percent of cases (Venables 1993), and the to some environmental trigger in genetically susceptible
serum Venereal Disease Research Laboratories (VDRL) individuals.
test may be falsely positive. As the ANA lacks specificity, It must be stated at the outset that the mechanism or
however, a positive result here must be followed up by a mechanisms underlying many of the syndromes seen in
more specific test, such as anti-native DNA (also known as cerebral lupus are not clearly understood. With this caveat
anti-double stranded DNA) or anti-Sm. During active disin mind, however, it appears that two global mechanisms
ease, the erythrocyte sedimentation rate (ESR) is often ele- may be operative (West et al. 1995): a direct autoimmune
vated and one or more complement levels (C3, C4, CH50) attack on neurons, and multiple infarctions, occurring on
are generally decreased. Consideration may also be given a variety of different bases.
to testing for the presence of serum anti-ribosomal P anti- It is clear from autopsy studies that in some cases of
bodies and for the anti-phospholipid syndrome, including cerebral lupus there is no evidence of infarction
lupus anticoagulant and anti-cardiolipin antibodies of (O’Connor and Musher 1966; Tsokos et al. 1986) and, in
both the IgG and IgM types. Anti-ribosomal P antibodies such cases, it is suspected that a cerebritis occurs secondary
may be associated with the occurrence of psychosis (Agius to anti-neuronal antibodies (Bluestein et al. 1981; Isshi and
et al. 1997; Bonfa et al. 1987; Isshi and Hirohata 1998; Hirohata 1998; Kelly and Denburg 1987); the finding of
Nojima et al. 1992; Schneebaum et al. 1991), and anti- immune complexes in the choroid plexus (Atkins et al.
phospholipid antibodies may be associated with infarction. 1972) lends support to this idea.
p 17.qxd 3/10/08 9:52 AM Page 550
Infarctions appear commonly in lupus and may occur of a depression with hallucinations and delusions, even in
on any one of several bases. Cardioembolic emboli may patients with severe extracerebral lupus, would never repre-
arise from Libman–Sacks endocarditis, valvulitis, or mural sent a normal reaction. Although important in the case of
thrombi (Devinsky et al. 1988; Mitsias and Levine 1994; depression, this concern with teasing out ‘normal’ reactions
Tsokos et al. 1986). If these emboli are large, then large to stressful events does not apply to patients with mania,
vessels, such as the middle cerebral or anterior cerebral artery, psychosis, or delirium, as none of these syndromes ever
may be occluded, with resulting large territorial infarctions; occurs as a ‘normal’ reaction.
if small there may be widespread microinfarctions through- Patients with lupus may develop renal failure with ure-
out the cortex and subcortical white matter. Thrombotic mia, which may be accompanied by hypertension, and ure-
infarctions of large- or medium-sized vessels may also mic encephalopathy or hypertensive encephalopathy may
occur, on the basis of either a fibrinoid vasculopathy (Ellis occur (Wong et al. 1991). Uremia may cause mania, delir-
and Verity 1979; Hanley et al. 1992; Johnson and ium or seizures, and hypertensive encephalopathy is char-
Richardson 1968; Malamud and Saver 1954) or the anti- acterized by delirium and seizures. Steroid treatment may
phospholipid syndrome. True vasculitis may occur (Weiner also cause neuropsychiatric side-effects, including depres-
and Allen 1991) but this appears to be rare (Devinsky et al. sion, mania, and psychosis. Finally, treatment with either
1988). Cerebral venous thrombosis may also occur but this steroids or immunosuppressants opens the way to oppor-
too seems rare. tunistic central nervous system infections (Futrell et al.
It appears that most cases of depression, mania, psy- 1992; Wong et al. 1991), which may also be associated with
chosis, and delirium occur on the basis of cerebritis; how- delirium, seizures, or focal signs.
ever, these syndromes may also occur with appropriately On a final differential diagnostic note, care must be taken
placed infarctions (e.g., depression with frontal lobe; mania to distinguish naturally occurring lupus from drug-induced
with frontal or temporal lobe, thalamus or caudate; psy- lupus. This syndrome is most commonly seen secondary to
chosis with temporal lobe or thalamus; and delirium with use of procainamide, hydralazine, or, less frequently, alpha-
temporal lobe or thalamus). Dementia may occur on the methyl dopa; it has also been rarely noted secondary to use
basis of cerebritis but appears more commonly due to mul- of other medications, including chlorpromazine, carba-
tiple infarctions. Seizures may likewise occur with cerebritis mazepine, phenytoin, and primidone. Importantly, unlike
or with infarction. Chorea may occur with cerebritis or naturally occurring lupus, drug-induced lupus rarely causes
infarction (e.g., of the basal ganglia or thalamus) and is also cerebral symptoms. When there is doubt as to whether any
associated with the presence of anti-phospholipid anti- given case of lupus is drug-induced or not, antibody levels
bodies. Focal signs generally occur on the basis of appropri- may be helpful. Although all patients with drug-induced
ately placed infarctions. lupus have a positive ANA, very few will have the more spe-
cific antibodies to native DNA or Sm. Obtaining an anti-
histone antibody level may also be helpful: whereas patients
Differential diagnosis with drug-induced lupus typically have this, it is unusual in
patients with naturally occurring lupus.
Polyarteritis nodosa, sarcoidosis, and, in older patients,
cranial arteritis may all mimic lupus to a certain degree,
and it is good practice to check for ANA in any case in Treatment
which the neuropsychiatric symptoms described above
occur in the setting of constitutional symptoms or multi- Treatment of the various features of cerebral lupus is dic-
organ disease. tated by the presumed underlying etiology, as discussed
In evaluating neuropsychiatric syndromes in patients above. In this regard, a reasonable strategy is to obtain
with established lupus, care must be taken to be sure that an MR scan to determine whether or not infarction has
the syndrome is, in fact, due to lupus rather than some occurred, and, if so, to then decide whether the identified
other cause. In this regard, special care must be taken in infarction or infarctions could reasonably be expected to
the evaluation of patients with depression. As discussed explain the patient’s symptomatology. If this is the case,
in Section 6.1, although it is normal for patients to be treatment is directed at the cause of the underlying infarc-
depressed in the face of adverse events, such as the occur- tion, as discussed in Section 7.4. In cases of infarction occur-
rence of lupus, the severity of such ‘normal’ depressions is ring in the context of the anti-phospholipid syndrome,
proportionate to the severity of the adverse event; further- preventive treatment with warfarin is probably in order.
more, such ‘normal’ depressions are typically not accompa- In the remaining cases, which are presumably due to a
nied by hallucinations or delusions. Consequently, the cerebritis, consideration may be given to treatment with
appearance of a non-psychotic depression in the context, steroids or cyclophosphamide, either individually or in
say, of imminent renal failure might be considered normal. combination. Initial treatment with steroids generally
On the other hand, the occurrence of a severe depression in involves a 3- to 7-day course of methylprednisolone, 250 mg
a patient whose lupus manifested only with a rash probably intravenously four times daily, followed by prednisone in a
does not represent a normal depression, and the occurrence dose of 1 mg/kg/day, with the dose of prednisone gradually
p 17.qxd 3/10/08 9:52 AM Page 551
17.3 Sjögren’s syndrome 551
tapered over a few weeks depending on the clinical response. T2-weighted or FLAIR MR scanning often reveals multi-
With regard to cyclophosphamide, some clinicians will uti- ple small areas of increased signal intensity in the white mat-
lize this as single-agent therapy from the start, whereas ter (Coates et al. 1999) and, in cases of dementia, increased
others will add it to the course of steroids, generally several signal intensity in the white matter may be confluent and
days into treatment with methylprednisolone. Repeat courses widespread. In patients with meningitis, contrast enhance-
of steroids or monthly infusions of cyclophosphamide are ment is seen in the meninges, as expected.
generally required to maintain remission. Remarkably, at the The CSF may be normal or may display oligoclonal
time of this writing there has been only one double-blind bands or an increased IgG index (Vrethem et al. 1990).
study comparing steroids alone with the combination of Serologic abnormalities are found in almost all patients.
steroids and cyclophosphamide (Barile-Fabris et al. 2005). Over 90 percent will have a positive ANA and some 75 per-
This study found that the addition of cyclophosphamide to cent will have a positive rheumatoid factor. Anti-SS-A
an initial course of steroids, followed by monthly cyclophos- (formerly known as anti-Ro) is found in 60–75 percent,
phamide, was greatly superior to initial treatment with and anti-SS-B (formerly known as anti-La) in about 40
steroids alone, followed by repeat courses of methylpred- percent. In doubtful cases, a lip biopsy will reveal lympho-
nisolone. However, this study primarily included patients cytic infiltrates.
with seizures and excluded patients with depression, mania,
psychosis, delirium, or dementia, and hence it is not clear
whether the results would apply to these syndromes. Course
Symptomatic treatment of depression, mania, psy-
chosis, delirium, dementia, and seizures may or may not be Overall, the course is characterized by gradual progression.
required, and is discussed in Sections 6.1, 6.3, 7.1, 5.3, 5.1,
and 7.3 respectively.
Etiology
17.3 SJÖGREN’S SYNDROME Although autoimmune factors are clearly at play in

Sjögren’s syndrome, the precise nature of the responsible
Sjögren’s syndrome is an autoimmune disease character- antibodies, and their genesis, is not known. Lymphocytic
ized by keratoconjunctivitis sicca and xerostomia (dry eyes infiltration is seen in exocrine glands and, in those with
and dry mouth: the ‘sicca syndrome’), and, in a small central nervous system disease, similar infiltrates may be
minority, by disease of the nervous system. Once thought found in a perivascular location, both in the parenchyma
to be rare, it is now known to occur in up to 2 percent of and the meninges (Caselli et al. 1991, 1993; de la Monte
those over 60 years. It is far more common in woman than et al. 1983).
men, by a ratio of 9:1.
Clinical features
The sicca syndrome may be seen in other connective tissue
The onset is very gradual and typically occurs in middle or diseases, such as systemic lupus erythematosus, systemic
later adult years. Although the sicca syndrome is present in sclerosis, rheumatoid arthritis, and polymyositis. In
all cases it may be relatively mild, and direct questioning is patients with involvement of the nervous system the most
often required to elicit these symptoms. Extraglandular important consideration is lupus, and here the differential
involvement occurs in about one-third of patients, a poly- rests on testing for anti-native DNA, which is present in
arthralgia or polyarthritis is seen in about two-thirds, and lupus but absent in Sjögren’s syndrome.
Raynaud’s phenomenon is seen in about one-third. Multiple sclerosis enters into the differential, especially
The proportion of patients who develop central nervous in patients with optic neuritis and/or myelopathy. Here the
system involvement is not known with certainty, but it differential rests on finding the typical serologic abnormal-
probably represents a very small minority (Anaya et al. ities mentioned above; in doubtful cases, a lip biopsy may
2002). Multiple areas of the nervous system may be involved be required.
(Delalande et al. 2004) and there may be stroke (Bragoni The sicca syndrome, of course, may also be caused by
et al. 1994), a gradually progressive dementia (Caselli multiple different medications.
et al. 1991, 1993; Kawashima et al. 1993), subacute aseptic
meningitis, seizures, optic neuritis, myelopathy, and, in a
very small minority, parkinsonism (Walker et al. 1999). Treatment
Peripheral nervous system involvement may also occur and
is far more common than central nervous system involve- Central nervous system involvement generally requires
ment (Goransson et al. 2006); a cranial neuropathy may also treatment with steroids or immunosuppressants, such as
occur, affecting the V, VII or VIII cranial nerves. cyclophosphamide.
p 17.qxd 3/10/08 9:52 AM Page 552
17.4 SNEDDON’S SYNDROME most cases are sporadic, familial cases have been noted
(Pettee et al. 1994).
First described by Sneddon in 1965 (Sneddon 1965), this
syndrome is characterized by livedo reticularis and cere-
brovascular disease. This is a rare disorder, more common Differential diagnosis
in woman than men, with an onset in early to middle adult
years. The diagnosis should always be suspected in any adult with
livedo reticularis and cerebrovascular disease. The primary
anti-phospholipid syndrome is distinguished by the con-
Clinical features stant presence of anti-phospholipid antibodies and by the
absence of white matter changes. Systemic lupus erythe-
Livedo reticularis is generally present for years before other matosus is suggested by finding anti-native DNA or ENA
symptoms appear. Typically, it is seen not only on the lower antibodies. Binswanger’s disease is distinguished by the later
extremities but also the trunk. age of onset and the absence of livedo reticularis. It must also
Transient ischemic attack (TIA) and stroke are com- be borne in mind that livedo reticularis may occur as a side-
mon, and, with multiple strokes, a typical multi-infarct effect to certain drugs, most notably amantadine.
dementia may occur. Patients may also present with a
gradually progressive cognitive decline and in these cases
one typically finds significant white matter disease (Adair Treatment
et al. 2001; Boesch et al. 2003; Stockhammer et al. 1993;
Tourbah et al. 1997). Long-term anticoagulation may be considered.
Magnetic resonance scanning will reveal both areas of
infarction and white matter disease. Echocardiography may
reveal valvular disease. Anti-phospholipid antibodies, either 17.5 PRIMARY ANTI-PHOSPHOLIPID
lupus anticoagulant or anti-cardiolipin antibodies, are pres- SYNDROME
ent in a minority of cases and are often transient. The ANA
may be positive; however, anti-native DNA and extractable This is a rare syndrome, found much more commonly in
nuclear antigen (ENA) antibodies are absent (Kalashnikova women than men, which has an onset in early or middle
et al. 1990). Skin biopsy generally reveals typical vascular adult years. It is characterized by recurrent arterial or venous
lesions (Stockhammer et al. 1993). thromboses, and constitutes an important cause of stroke in
younger adults (Asherson et al. 1989; Levine et al. 1990).

The course may be marked by recurrent stroke or, in Stroke, secondary to either ischemic infarction or, much less
cases with leukoencephalopathy, by a gradually progressive commonly, venous infarction, is common (Chancellor et al.
decline. 1991), and with a multiplicity of these a multi-infarct demen-
tia may occur (Coull et al. 1987; Kurita et al. 1994). Transient
ischemic attacks may also occur, and amaurosis fugax is often
Etiology seen. With occlusion of the retinal artery, blindness may
occur. Chorea has also been noted (Cervera et al. 1997).
Within the central nervous system there is a widespread, Deep venous thromboses are common, and pulmonary
non-inflammatory vasculopathy affecting primarily small- to embolism may occur. Another characteristic feature is
medium-sized arteries, with subendothelial proliferation and recurrent miscarriage.
eventual fibrosis (Geschwind et al. 1995; Hilton and Footitt Anti-phospholipid antibodies, either the lupus anticoag-
2003; Rebollo et al. 1983). Although territorial infarctions ulant or anti-cardiolipin antibodies, or both, are present in
may occur, smaller subcortical infarctions are far more com- every case. Anti-cardiolipin antibodies include IgG, IgM,
mon; furthermore, in many cases there is also widespread and IgA, and the IgG antibody is most strongly associated
white matter disease involving the periventricular area and with thrombosis. Other abnormalities include a prolonged
the centrum semiovale. Although most of these lesions prob- activated partial thromboplastin time, thrombocytopenia,
ably reflect in situ thrombosis and occlusion of involved ves- and a false-positive VDRL. The ANA may be positive, but
sels, valvular disease has also been noted and embolization anti-native DNA and anti-Sm antibodies are absent.
may play a role in some cases (Sitzer et al. 1995). A similar
vasculopathy underlies the livedo reticularis.
The mechanism underlying the vasculopathy is not Course
clear. As noted above, anti-phospholipid antibodies may
be present but their pathogenic role is uncertain. Although Recurrent thrombotic events are the rule.
p 17.qxd 3/10/08 9:52 AM Page 553
17.7 Limbic encephalitis 553
Etiology Course
In this syndrome, circulating anti-phospholipid antibodies In the natural course of events there is a more or less com-
attach to vessel walls, either arterial or venous, and induce plete remission of symptoms after 2–4 years; recurrences,
thrombus formation and fibrosis (Hughson et al. 1993). although not common, may occur.
With arteries, the cerebral vasculature is preferentially
attacked, resulting in ischemic infarction. Veins subject to
attack include not only the cerebral veins but also Etiology
peripheral veins, resulting in deep venous thromboses. In
about one-third of patients, Libman–Sacks endocarditis In the setting of a widespread cerebral microangiopathy
may occur, affecting the mitral and aortic valves, with subse- there are multiple microinfarcts affecting the white matter
quent embolization. (especially the corpus callosum) and the gray matter
(Heiskala et al. 1988; Monteiro et al. 1985). Retinal and
cochlear infarctions also occur.
Although the etiology of the angiopathy is not known,
Differential diagnosis an autoimmune mechanism is suspected.
The diagnosis should always be suspected in any young per-
son with stroke (Brey et al. 1990), especially in those with a Differential diagnosis
history of deep venous thrombosis or recurrent miscar-
riage. Anti-phospholipid antibodies may also be seen in sys- Both multiple sclerosis and systemic lupus erythematosus
temic lupus erythematosus, Sjögren’s syndrome, Sneddon’s may be considered; however, the hearing loss and visual
syndrome, and various malignancies, and with treatment disturbances suggest the correct diagnosis.
with certain drugs, including procainamide, quinidine,
hydralazine, phenytoin, valproic acid, and phenothiazines.
Of these causes of the ‘secondary’ anti-phospholipid anti- Treatment
body syndrome, lupus is the most important, and the dif-
ferential here is made by finding either anti-native DNA or Steroids or immunosuppressants, such as cyclophos-
anti-Sm antibodies. phamide, are beneficial.
Treatment 17.7 LIMBIC ENCEPHALITIS
Limbic encephalitis, first described in 1960 (Brierly et al.

Long-term anticoagulation is required.
1960), is an autoimmune disorder, characterized patholog-
ically by the presence of anti-neuronal antibodies and
inflammatory changes in the medial aspects of the tempo-
17.6 SUSAC’S SYNDROME ral lobes, and clinically, in most but not all cases, by delir-
ium and seizures. In the vast majority of cases, limbic
Susac’s syndrome, first described by Susac in 1979 encephalitis occurs on a paraneoplastic basis, most often in
(Susac et al. 1979), is a rare disorder, typically seen in young patients with small-cell lung cancer, and serum samples
adult females. The syndrome is also referred to as retino- will be positive for typical anti-neuronal antibodies, such
cochleocerebral vasculopathy, a term that, although cumber- as anti-Hu. Recent work has demonstrated, however, that
some, nicely summarizes the structures involved. in a very small minority, limbic encephalitis exists as a
non-paraneoplastic disorder associated with the presence
of anti-voltage-gated potassium channel antibodies.
Clinical features Limbic encephalitis is a rare disorder, occurring in less
than 0.1 percent of all patients with cancer.
Classically one sees the subacute onset of a delirium, often
accompanied by headache, in the setting of sensorineuronal
hearing loss and visual disturbances (Aubart-Cohen et al. Clinical features
2007; Papo et al. 1998, Petty et al. 1998).
Magnetic resonance scanning (Susac et al. 2003) typi- The onset of symptoms is typically subacute, spanning
cally reveals multiple areas of increased signal intensity on days or weeks (Alamowitch et al. 1997). Importantly, lim-
FLAIR and T2-weighted images, scattered throughout the bic encephalitis is often the presenting symptom of cancer
white and gray matter with a predilection for the corpus (Alamowitch et al. 1997; Dalmau et al. 1992), and in some
callosum. In some cases these lesions may demonstrate cases the tumor itself may remain undetected for years
contrast enhancement. after the onset of the encephalitis (Ahern et al. 1994).
p 17.qxd 3/10/08 9:52 AM Page 554
The most common presentation is with delirium marked small-cell type) (Alamowitch et al. 1997), breast, testicle
by prominent anterograde and retrograde amnesia, often (Ahern et al. 1994; Burton et al. 1988; Voltz et al. 1999),
accompanied by seizures and personality change or halluci- colon (Tsukamoto et al. 1993), pancreas, ovary (Nokura
nations (Alamowitch et al. 1997; Antoine et al. 1995; Bakheit et al. 1997), thymus (Antoine et al. 1995; Ingenito et al. 1990),
et al. 1990; Gultekin et al. 2000; Lawn et al. 2003). Other, less prostate, and bladder; cases have also been associated with
common presentations include depression (Brierly et al. lymphoma. Although there is an association between certain
1960; Corsellis et al. 1968; Glaser and Pincus 1969), isolated anti-neuronal antibodies and certain types of cancer (e.g.,
amnesia (Bak et al. 2001; Nokura et al. 1997; Sutton et al. anti-Hu with lung cancer [Anderson et al. 1988; Alamowitch
2000), seizures (Corsellis et al. 1968), somnolence (Byrne et al. 1997]; anti-Ma2 with testicular cancer [Gultekin et al.
et al. 1997), and catatonia (with ‘confusion, stereotypy, 2000; Pruss et al. 2007; Voltz et al. 1999]) there is a wide
echolalia, stiffness, verbigeration, formal thought disorder, overlap (Pittock et al. 2004, 2005); for example, anti-Hu, in
and negativism’ [Tandon et al. 1988]). Rare symptoms addition to being found in association with lung cancer, may
include abnormal movements, such as chorea (Croteau et al. also be found with cancer of the breast, prostate, colon, and
2001; Vernino et al. 2002), narcoleptic attacks with cataplexy ovary (Graus et al. 2001). Given this overlap, it is appropri-
(Rosenfeld et al. 2001), rapid eye movement (REM) sleep ate to test for the entire range of known anti-neuronal anti-
behavior disorder (Iranzo et al. 2006), and, especially in bodies. It must also be kept in mind that new anti-neuronal
association with ovarian cancer, hypoventilation with respi- antibodies are routinely discovered and, consequently, neg-
ratory failure (Dalmau et al. 2007; Vitaliani et al. 2005). ative tests for known anti-neuronal antibodies do not rule
In cases that occur on a paraneoplastic basis, one may out the diagnosis (Ances et al. 2005).
also see other paraneoplastic syndromes (Alamowitch et al. Once the diagnosis of limbic encephalitis has been
1997), including the following: cerebellar degeneration made, it is essential to find the tumor. In this regard, if rou-
with ataxia; brainstem encephalitis with nystagmus, ataxia, tine investigations are unrevealing, many clinicians will
oculomotor palsies, and vertigo; opsoclonus–myoclonus; undertake computed tomography (CT) scans of the chest,
sensory neuropathy; Lambert–Eaton myasthenic syn- abdomen, and pelvis, and, in young males, ultrasound of
drome; and the stiff-person syndrome. the testes. If the tumor escapes detection by these methods,
Early in the course, MR scanning is often normal; over consideration may be given to whole-body PET scanning.
time, however, most cases will have increased signal inten-
sity in the medial aspects of the temporal lobes on T2- Course
weighted or FLAIR imaging; these abnormalities, although
initially unilateral, typically become bilateral (Alamowitch Although the overall course is one of progression, there
et al. 1997; Bakheit et al. 1990; Gultekin et al. 2000; Lawn may at times be ‘plateaus’; however, these almost always
et al. 2003; Tsukamoto et al. 1993). give way to further decline (Alamowitch et al. 1997). True
The EEG is abnormal in almost all cases and typically spontaneous remissions, although reported (Byrne et al.
shows temporal slowing, which, similarly to the MRI find- 1997), are rare, and most patients die within months to a
ings, may initially be unilateral, only to later become bilat- year or more, either of complications of the limbic
eral. Interictal epileptiform discharges may or may not be encephalitis or from the underlying cancer.
present.
The CSF may be normal or may display any one of a
number of findings, including a mild lymphocytic pleo- Etiology
cytosis, a mildly elevated total protein, or oligoclonal
bands (Alamowitch et al. 1997; Gultekin et al. 2000). Pathologically (Henson et al. 1965) there is a lymphocytic
Although in the vast majority of cases of limbic perivascular inflammation, with neuronal loss and gliosis
encephalitis abnormalities will be found on MRI, EEG, or within the limbic system, primarily involving medial tem-
CSF assay, exceptions do occur, especially early on, and in poral structures, such as the hippocampus and the amyg-
cases in which the clinical findings are strongly suggestive of dala. As noted earlier, in the vast majority of cases this
the diagnosis but these tests are negative, positron emission inflammation occurs on a paraneoplastic basis, with anti-
tomography (PET) scanning should be considered; even in bodies raised against the cancer cross-reacting with normal
cases in which all other tests are negative, PET may reveal neuronal tissue. However, there are cases of limbic
focal hypermetabolism in one or both temporal lobes. encephalitis occurring in the context of anti-VGKC anti-
A wide variety of anti-neuronal antibodies have been bodies in which no cancer is found, and the mechanism
identified (Bataller et al. 2007; Pittock et al. 2005), including underlying the genesis of this autoimmune response
anti-Hu (also known as ANNA-1), anti-Ri (also known as remains unknown (Vincent et al. 2004).
ANNA-2), ANNA-3, anti-Ma1, anti-Ma2 (also known as
anti-Ta), anti-amphiphysin, anti-CRMP-5, and anti-voltage- Differential diagnosis
gated potassium channel (also known as anti-VGKC). In
paraneoplastic cases, various tumors have been found, Although limbic encephalitis immediately comes to mind
including cancer of the lung (most commonly of the in patients with known cancer who develop delirium with
p 17.qxd 3/10/08 9:52 AM Page 555
17.8 Sarcoidosis 555
seizures, other disorders that are not uncommon in cancer bilateral hilar lymphadenopathy or a diffuse reticulo-
must also be considered, including metastatic disease, nodular appearance. Other symptoms include erythema
Cushing’s syndrome, and opportunistic infections, such as nodosum, lupus pernio, lymphadenopathy, arthropathy,
cytomegaloviral encephalitis or progressive multifocal and parotid gland enlargement. Hepatic involvement
leukoencephalopathy. occurs in almost three-quarters of patients although hepatic
As noted earlier, in most cases limbic encephalitis failure is rare. Hypercalcemia occurs in a majority of cases,
precedes other evidence of cancer and hence in most cases and some patients may develop nephrocalcinosis and
the differential is wider, as discussed in Section 5.1. Special eventual renal failure.
consideration may be given to herpes simplex viral Involvement of the nervous system occurs in anywhere
encephalitis, hypertensive encephalopathy, the posterior from 5 to 25 percent of patients, and in a very small minor-
reversible leukoencephalopathy syndrome, Hashimoto’s ity of cases it may represent the only manifestation of sar-
encephalopathy, and Creutzfeldt–Jakob disease. coidosis. The overall symptomatology of neurosarcoidosis
has been described in a number of reports (Chapelon et al.
1990; Delaney 1977; Manz 1983; Oksanen 1986; Sharma
Treatment and Sharma 1991; Stern et al. 1985). With a basilar menin-
gitis, cranial neuropathies may occur, and with obstruction
Although treatment of the underlying cancer in paraneopla- of the outflow foramina of the fourth ventricle, hydro-
stic cases should be undertaken, it appears that, even with suc- cephalus may occur; involvement of arteries may be fol-
cessful treatment, limbic encephalitis undergoes remission in lowed by stroke. Cerebral involvement may be characterized
only a minority of cases (Burton et al. 1988). Consequently, by multiple granulomas or by relatively few large lesions,
other modalities must be considered; although there are no or even by a solitary lesion; in these cases there may be
controlled studies, various treatments, alone or in combina- dementia, delirium, seizures, or focal signs. Hypothalamic
tion, are utilized, including steroids, immunosuppressants or pituitary granulomas may present with endocrinologic
(e.g., cyclophosphamide), intravenous immunoglobulins, syndromes. The cord may also be compressed and the
and plasmapheresis (Bataller et al. 2007). The symptomatic peripheral nervous system is often involved.
treatment of delirium is discussed in Section 5.3, and of Cranial neuropathies occur in approximately one-half
seizures in Section 7.3. of all cases and, although various of the cranial nerves may
be involved (Symonds 1958), one most commonly sees a
peripheral facial palsy, which may be unilateral or bilateral
17.8 SARCOIDOSIS (Scott 1993; Sharma and Sharma 1991). The eighth cranial
nerve may also be involved with deafness, as may the optic
Sarcoidosis is an uncommon disease characterized patho- nerve or chiasm with blindness or hemianopia.
logically by the presence of sarcoid granulomas in multiple Hydrocephalus occurs in about 5 percent of cases and
organ systems, including, in a minority, the nervous system, may present with dementia and a gait disturbance.
in which case one may speak of neurosarcoidosis. In addi- Stroke is rare in sarcoidosis and appears to generally pres-
tion to a granulomatous basilar meningitis, granulomas ent with a lacunar syndrome (Brown et al. 1989; Michotte
may also be found scattered throughout the cerebrum, with et al. 1991), reflecting granulomatous involvement of the
a special predilection for the hypothalamus and pituitary. penetrating arteries.
Sarcoidosis is somewhat more common in females than Dementia does occur in sarcoidosis (Camp and Frierson
males; in the United States it is far more common in black 1962; Cordingly et al. 1981; Miller et al. 1988; Sanson et al.
people than white people, and in Europe those from north- 1996) and may be accompanied by a frontal lobe syndrome
ern countries are more commonly affected. (Hook 1954) or by delusions and hallucinations (Thompson
and Checkley 1981). Although the prevalence of this syn-
drome is uncertain, one study found cognitive deficits of
Clinical features variable degree in close to 50 percent of all patients with
neurosarcoidosis (Scott et al. 2007). Delirium has also been
Although onset in adolescence or the middle or later years noted (Douglas and Maloney 1973; Silverstein and Siltzbach
may occur, most patients fall ill in their twenties or thirties. 1965; Wiederholt and Siekers 1965) but appears to be rare.
The onset itself is often gradual, and many cases are discov- Seizures occur in about 15 percent of cases and may be
ered serendipitously when a chest radiograph reveals pul- grand mal or partial in type (Krumholz et al. 1991). Focal
monary findings characteristic of the disease. signs may occur, and reflect the location of any cerebral
Although sarcoidosis may be protean in its manifes- granulomas.
tations, certain presentations deserve note. Perhaps 90 Endocrinologic changes have been noted in up to one-
percent of patients will have pulmonary involvement, third of patients, and may consist of diabetes insipidus,
which may manifest clinically with symptoms such as hyperprolactinemia, hypothyroidism, hypogonadism, and
cough or dyspnea, or may be asymptomatic and discovered adrenocortical insufficiency (Scott et al. 1987). Hypothala-
only incidentally by chest radiograph, which may reveal mic involvement may also manifest with disturbances of
p 17.qxd 3/10/08 9:52 AM Page 556
appetite or with somnolence; rarely symptomatic nar- widely in size and number, from miliary lesions to large
colepsy may occur (Rubinstein et al. 1988). masses mimicking gliomas (Powers and Miller 1981).
Spinal cord compression by granulomas may lead to Although the mechanism underlying the appearance of
various symptomatologies, including paraplegia. these granulomas is not known, it is strongly suspected
The peripheral nervous system is involved in up to 50 that sarcoidosis represents an autoimmune disorder that is
percent of patients, and may manifest with a monon- triggered in genetically susceptible individuals by an exoge-
europathy, a mononeuritis multiplex, or a primarily sen- nous, inhaled substance.
sory polyneuropathy.
Magnetic resonance scanning with T2-weighted or
FLAIR imaging typically reveals any basilar meningitis or Differential diagnosis
macroscopic parenchymal granulomas; with gadolinium,
enhancement is seen in most of these. Neurosyphilis, tuberculosis, and fungal infections may all
The CSF is abnormal in only about 50 percent of cases. closely mimic sarcoidosis. Multiple sclerosis is often men-
Various abnormalities may occur (Kinnman and Link tioned on the differential; however, this possibility would
1984; McLean et al. 1995), including a mild lymphocytic only arise in cases of neurosarcoidosis in which lesions
pleocytosis, a mildly elevated total protein, and, in a were essentially restricted to the cerebral white matter.
minority, oligoclonal bands or an elevated IgG index; in a
very small minority the glucose level is mildly reduced. The
level of CSF angiotensin-converting enzyme is elevated in a Treatment
little over 50 percent of cases (Oksanen 1986). The serum
angiotensin-converting enzyme level is likewise elevated in Active neurosarcoidosis may be treated with prednisone in
over 50 percent of cases. a dose of approximately 1 mg/kg/day for 4–6 weeks, after
Definitive diagnosis requires biopsy evidence of typical which the dose may be gradually tapered over the following
sarcoid granulomas, and in most cases lung biopsy is months, depending on the clinical evolution. Importantly,
performed. steroids, although often effective, do not alter the natural
course of the disease, and repeat courses may be required.
In treatment-resistant cases, some clinicians will give a
Course course of intravenous methylprednisolone, whereas others
will turn to hydroxycholoquine (Sharma 1998) or to an
The course is variable. Spontaneous remission of neuro- immunosuppressant, such as cyclophosphamide, azathio-
sarcoidosis occurs after many months in about one-half of prine or methotrexate (Scott et al. 2007). Unfortunately,
cases, although relapses may occur; in the remaining cases there are no blind studies of the treatment of neuro-
the disease pursues a chronic, often fluctuating course sarcoidosis to guide these choices. Hydrocephalus may
(Pentland et al. 1985). require shunting.
Etiology 17.9 HASHIMOTO’S ENCEPHALOPATHY
The cardinal lesion in sarcoidosis is a non-caseating granu- Hashimoto’s encephalopathy, first described by Lord Brain
loma, and the pathology of neurosarcoidosis has been in 1966 (Brain et al. 1966), is an uncommon cause of delir-
described in a number of studies (Delaney 1977; Herring ium which occurs secondary to an autoimmune process
and Urich 1969; Jefferson 1957). As noted above, one typi- that targets the brain.
cally sees a granulomatous basilar meningitis, with entrap- Before proceeding further some words are in order
ment and inflammation of cranial nerves, penetrating regarding the confusion that may exist between Hashimoto’s
arteries, and, in a small minority, obstruction of the out- encephalopathy and Hashimoto’s thyroiditis, which are
flow foramina of the fourth ventricle. Granulomatous two very different diseases. The name ‘Hashimoto’ is gen-
infiltration of the hypothalamus is very common, and fur- erally associated not with an encephalopathy but with thy-
ther infiltration down the pituitary stalk may lead to gran- roiditis. Hashimoto’s thyroiditis, first described by Hakaru
uloma formation in the posterior or anterior lobe of the Hashimoto in 1912 (Hashimoto 1912), is the most com-
pituitary gland. Of note, it appears that most of the mon cause of thyroiditis and is characterized by the pres-
endocrinologic disturbances seen in neurosarcoidosis ence of anti-thyroid antibodies and by a lymphocytic
result primarily from hypothalamic disease, with pituitary infiltration of the thyroid gland; affected patients may be
function being secondarily disturbed by the lack of releas- euthyroid, transiently hyperthyroid, or, more commonly,
ing or inhibiting factors normally secreted by the hypothal- hypothyroid. Dr. Hashimoto did not note delirium in any
amus (Winnacker et al. 1968). Parenchymal granulomas of these patients with thyroiditis. In 1966, however, Lord
may be found not only in the white matter of the cerebrum Brain described a patient with thyroiditis and anti-thyroid
but also in the cortex and, as noted earlier, they may range antibodies who also had delirium and stroke-like episodes,
p 17.qxd 3/10/08 9:52 AM Page 557
17.9 Hashimoto’s encephalopathy 557
and it was this association of Hashimoto’s thyroiditis one typically sees only a mildly reduced thyroxine (T4) and
with delirium that prompted the new term, ‘Hashimoto’s a mildly elevated thyroid-stimulating hormone (TSH)
encephalopathy’. Importantly, however, as noted below, (Henchey et al. 1995; Shaw et al. 1991).
although anti-thyroid antibodies are present in all cases Elevations of anti-thyroid antibodies, either anti-thyroid
of Hashimoto’s encephalopathy, there is no association peroxidase or anti-thyroglobulin, are present in all cases.
between the encephalopathy and thyroid disease, and it Although in the vast majority of cases both of these are ele-
appears that the anti-thyroid antibodies are merely ‘inno- vated, exceptions do occur and patients may have elevation
cent bystanders’ that serve as markers of a more wide- of only one; consequently, both should be routinely tested
spread autoimmune disorder; in addition to autoantibodies for. Typically the levels of these antibodies are elevated ten-
directed at the thryoid, other autoantibodies directed at the fold or greater; importantly, however, there is no correla-
brain are also present. tion between the degree of elevation and the severity of the
A recently coined synonym for Hashimoto’s encephalopa- clinical syndrome
thy is ‘steroid-responsive encephalopathy associated with
autoimmune thyroiditis’ or ‘SREAT’. Whether this new
terminology is helpful or will gain currency remains to Course
be seen.
Although the course of Hashimoto’s encephalopathy has
not been clearly delineated, it appears to be an episodic dis-
Clinical features ease. The episodes themselves tend to persist for anywhere
from weeks up to 6 months, after which there is generally a
The clinical features have been most clearly described in remission. Repeat episodes can occur; however, it is not
two case series from the Mayo Clinic (Castillo et al. 2006; clear whether this is the case for all, or even most, patients,
Sawka et al. 2002). Although most patients are in their for- nor is it clear how long the intervals are between episodes.
ties, the age of onset varies widely, from childhood to the
eighth decade; the onset itself is typically subacute, over
days or perhaps weeks. Etiology
The overwhelming majority of patients have a delirium,
which in most cases is accompanied by any or all of tremor, Neuropathologically there is widespread perivascular lym-
myoclonus, ataxia, or seizures; seizures may be grand mal, phocytic inflammation, microglial activation, and gliosis
complex partial or, rarely, simple partial, and grand mal (Castillo et al. 2006; Chong et al. 2003; Doherty et al. 2002;
status epilepticus may occur in a small minority. Stroke- Duffey et al. 2003; Nolte et al. 2000).
like episodes are common and are typically characterized Although the mechanism underlying this inflammatory
by aphasia (Bohnen et al. 1997; Ghika-Schmid et al. 1996; change has not been positively identified, an autoimmune
Henchey et al. 1995; Shaw et al. 1991; Thrush and Boddie process is strongly suggested both by the association with
1974); hemiplegia or hemisensory loss may also occur. anti-thyroid antibodies and by the good response to
These stroke-like episodes are of brief duration, lasting in steroids. In all likelihood, however, the anti-thyroid anti-
the order of hours or a day or more, and typically undergo bodies are not pathogenic but merely represent part of a
a full remission. Very rarely Hashimoto’s encephalopathy wider autoimmune response, with other antibodies directed
may present with a psychosis (Bostantjopoulou et al. 1996) at the brain; in this regard serum anti-neuronal antibodies
or with a dementia (Galluzzi et al. 2002). have been demonstrated (Oide et al. 2004) and one study
Magnetic resonance scanning is normal in the majority of identified a particular autoantibody directed at alpha-enolase
cases; in the remainder, T2-weighted or FLAIR imaging may (Ochi et al. 2002).
disclose diffusely increased signal intensity in the cerebral
white matter (Bohnen et al. 1997) and, in a small minority,
subcortical infarctions may be noted. (Henchey et al. 1995). Differential diagnosis
Computed tomography scanning is almost always normal.
The EEG shows generalized slowing in the vast majority Various other causes of delirium, as discussed in Section
of cases, and this may be accompanied by other changes in 5.3, must be considered, including toxic deliria (serotonin
a small minority, including triphasic waves and interictal syndrome, neuroleptic malignant syndrome, delirium
epileptiform discharges (Schauble et al. 2003). tremens), metabolic deliria (Wernicke’s encephalopathy,
The CSF typically, but not always, displays various uremic encephalopathy, hepatic encephalopathy), other
abnormalities. An elevated total protein is most common; autoimmune disorders (systemic lupus erythematosus,
in a small minority there may be a mild lymphocytic pleo- limbic encephalitis), intracranial disorders (hypertensive
cytosis. Rarely, there may be oligoclonal bands or the 14-3-3 encephalopathy, posterior reversible leukoencephalopathy
protein (Hernandez Echebarria et al. 2000). syndrome), viral encephalitis, complex partial status epilep-
A small minority may have a mildly elevated ANA or ticus, and Creutzfeldt–Jakob disease (which may closely
ESR. Thyroid indices are generally normal; if abnormal mimic Hashimoto’s encephalopathy [Doherty et al. 2002]).
p 17.qxd 3/10/08 9:52 AM Page 558
In cases in which there is an associated Hashimoto’s polyarthritis, Sydenham’s chorea, subcutaneous nodules,
thyroiditis, consideration may be given to delirium sec- and erythema marginatum. Minor criteria include fever,
ondary to either hyperthyroidism or hypothyroidism, but arthralgia, a prolonged PR interval on electrocardiography,
these are very rare; Hashimoto’s thyroiditis may also be and either an elevated ESR or an elevated C-reactive protein
associated with adrenocortical insufficiency, which, again level. Acceptable laboratory evidence of recent pharyngeal
very rarely, may cause delirium. infection includes a positive throat culture or an elevated
In pursuing this differential, it must also be kept in mind anti-DNAase B, anti-streptolysin O, or anti-hyaluronidase
that anti-thyroid antibodies may be found in about 3 percent titer; of these three titers, anti-DNAase B tends to remain
of children and adolescents (Kabelitz et al. 2003) and elevated for the longest period of time, in some cases up to
8 percent of those over 60 years (Roti et al. 1992); conse- 6 months after the pharyngitis.
quently the entire clinical picture must be taken into account. Although most of the clinical manifestations of rheu-
matic fever appear about 10 days after the pharyngitis
(Taranta 1959), Sydenham’s chorea is an exception in that
Treatment the latency between the pharyngitis and the onset of the
chorea is, on average, in the order of 2 or 3 months (Taranta
Although there are no blind treatment studies, most patients 1959; Taranta and Stollerman 1956). Consequently, it is not
are given 1000 mg/day of intravenous methylprednisolone unusual to see a case of ‘pure’ chorea (Feinstein and
for 5–7 days, followed by 60–100 mg/day of oral prednisone Spagnuola 1962; Taranta and Stollerman 1956) in which
in a tapering dose over the following weeks (Castillo et al. the other manifestations of rheumatic fever have already
2006). In most cases the response is prompt, within days, undergone a full remission, leaving the chorea as the sole
and most patients do well with tapering. In some cases, how- manifestation of the disease.
ever, prolonged treatment with steroids is required, and it Sydenham’s chorea generally presents subacutely, over
appears also that some patients are resistant to steroids and several weeks (McCullogh 1938; Nausieda et al. 1980), in
require treatment with immunosuppressants (azathioprine, children aged from 8 to 15 years (Cardoso et al. 1997; Kilic
methotrexate, or cyclophosphamide), plasma exchange, or et al. 2007; Thayer 1906); later onsets, however, are certainly
intravenous immunoglobulins. Although intuitively it possible, as late, indeed, as the ninth decade (Goyal and
makes sense to monitor levels of anti-thyroid antibodies to Williams 1967). The onset itself is typically characterized by
gauge treatment response, in practice this is not useful, as in symptoms reminiscent of attention deficit/hyperactivity dis-
some cases levels may actually rise despite a good clinical order, such as restlessness, fidgetiness, irritability, and emo-
response. tional lability; choreiform movements, if present, are mild
The general treatment of delirium is discussed in Section and evanescent (Diefendorf 1912; Gerstley et al. 1935).
5.3; seizures may be treated as described in Section 7.3. When the chorea does settle in, it is usually generalized but
most prominent in the limbs and face; alternatively, one
may occasionally see hemichorea (Abt and Levinson 1916;
17.10 SYDENHAM’S CHOREA Nausieda et al. 1980); rarely, rather than chorea there may be
a profound weakness, known as ‘chorea mollis’.
Sydenham’s chorea, also known as Saint Vitus’ dance, rheu- Neuropsychiatric features are very common during
matic chorea, or chorea minor, is one of the major manifes- Sydenham’s chorea and include obsessions and compul-
tations of rheumatic fever (Anonymous 1992; Bland and sions, tics, delirium, mania or, less commonly, depression
Jones 1951, 1952), occurring in about one-quarter of all and psychosis. In addition to these features, seizures
cases (Cardoso et al. 1997). In addition to chorea, these (Ch’ien et al. 1978; Nausieda et al. 1980), either complex
patients also display other neuropsychiatric features, most partial or grand mal, may be seen in a small minority,
notably obsessions and compulsions. along with various signs, such as a positive Babinski reflex
Because of the widespread treatment of streptococcal (Ganji et al. 1988).
pharyngitis with penicillin, Sydenham’s chorea is currently Obsessions and compulsions occur most notably in
uncommon; it occurs more frequently in females than Sydenham’s chorea (Swedo et al. 1989): one prospective
males with a ratio of approximately 7:3. study reported them in 70 percent of patients (Asbahr et al.
1998), another in 82 percent (Swedo et al. 1993). The
course of these obsessions and compulsions is of interest.
Clinical features Although they tend to peak in severity along with the wors-
ening of the chorea and to remit before the chorea does, in
The diagnosis of rheumatic fever is made according to the fact they generally make their appearance before the chorea
‘Jones criteria’ (Anonymous 1992), which demand the sets in (Swedo et al. 1993); importantly, it appears that in
presence of: (i) laboratory evidence of recent pharyngeal cases of rheumatic fever it is only those patients who
infection with group A beta-hemolytic streptococci; and (ii) develop Sydenham’s chorea who develop obsessions and
either two ‘major’ criteria or one ‘major’ criterion plus two compulsions; those without chorea remain free of them
‘minor’ criteria. Major criteria include carditis, migratory (Asbahr et al. 1998).
p 17.qxd 3/10/08 9:52 AM Page 559
17.10 Sydenham’s chorea 559
Tics, similar to those seen in Tourette’s syndrome, may that other factors may be involved in recurrences or that the
also occur during Sydenham’s chorea (Creak and Guttmann preceding infection was of such low intensity as to leave no
1935). laboratory trace is not clear.
Delirium is seen in fewer than 10 percent of patients In addition to relapses of chorea consequent upon recur-
(Nausieda et al. 1980) but may be profound (Diefendorf rent group A beta-hemolytic pharyngitis, patients who have
1912). recovered from Sydenham’s chorea are also at risk for other
Mania is a rare manifestation of Sydenham’s chorea sequelae. Females with a history of Sydenham’s chorea may
(Abt and Levinson 1916; MacKenzie 1887) and may pres- develop chorea gravidarum during pregnancy (Beresford
ent as either pure mania or mixed mania (Bradley 1904; and Graham 1950; Wilson and Preece 1932a) and are also at
Ebaugh 1926; Gay 1889; Lewis and Minski 1935; Powell increased risk for developing chorea during treatment with
1889; Reaser 1940; Shaskan 1938) or, rarely, be coupled oral contraceptives (Nausieda et al. 1983). There is also sug-
with a depression (Abt and Levinson 1916; Haskell 1914). gestive evidence that some cases of obsessive–compulsive
Depression is even rarer than mania in Sydenham’s chorea disorder (Swedo 1994; Swedo et al. 1994), Tourette’s syn-
(Abt and Levinson 1916). drome (Kerbeshian et al. 1990; Swedo et al. 1994), and even
Psychosis, with hallucinations and delusions, may occur schizophrenia (Casanova et al. 1995; Wilcox and Nasrallah
in a small minority (Hammes 1922) and may symptomati- 1986, 1988) occur as sequelae.
cally resemble the psychosis seen in schizophrenia (Leys
1946; Putzel 1879).
Etiology
On average, an episode of Sydenham’s chorea gradually
remits after 5–9 months, the range being a week up to 2
Autopsy studies of patients dying during acute Sydenham’s
years or more (Aron et al. 1965; Kilic et al. 2007; Lessof
chorea have revealed two kinds of damage: vasculitic
1958; Swedo et al. 1993); very rarely Sydenhams’ chorea
and encephalitic. Vasculitic changes affecting small vessels
may be chronic, even lifelong (Gibb et al. 1985). Although
(Buchanen 1941; Buchanen et al. 1942; Poynton and Holmes
there may be some very mild residual chorea, especially evi-
1906; Van Bogaert and Bertrand 1932; Winkelman and
dent when the patient is under stress (Lessof 1958; Swedo
Eckel 1932) have been noted in the cerebral cortex and basal
et al. 1993), in most cases recovery is essentially complete.
ganglia; encephalitic changes (Bradley 1904; Buchanen et al.
The mortality rate is less than 1 percent (Abt and Levinson
1942; Colony and Malamud 1956; Coombs 1912; Gordon
1916; Bussiere and Rhea 1926; Lessof and Bywaters 1956).
and Norman 1934; Greenfield and Wolfsohn 1922; Ziegler
T2-weighted or FLAIR MR scanning may show
1927), with inflammation and neuronal loss, have been
increased signal intensity in the caudate and in the cerebral
found throughout the cerebral cortex and the basal ganglia,
white matter (Castillo et al. 1999; Emery and Vieco 1997;
without any corresponding vasculitis. Autopsies of patients
Moreau et al. 2005; Robertson and Smith 2002).
who died from unrelated causes long after recovering
The EEG is abnormal in the majority of cases, demon-
from the chorea have revealed evidence of old endarteritis
strating either posterior slowing or, in a minority, sharp
(Benda 1949) and patchy gliosis and neuronal loss (Lange
waves or interictal epileptiform discharges (Ch’ien et al.
et al. 1976).
1978).
It appears that these vasculitic and encephalitic changes
occur secondary to an autoimmune assault on the central
nervous system, which is triggered by the preceding group
Course A beta-hemolytic streptococcal pharyngitis. Serum anti-
neuronal antibodies have been detected (Kiessling et al.
The overall course of Sydenham’s chorea parallels that of
1993; Swedo et al. 1991), specifically targeting the follow-
the underlying rheumatic fever, and if there are recur-
ing structures: pial arteries and parenchymal capillaries
rences of rheumatic fever the patient is at risk for another
(Kingston and Glynn 1971); white matter astrocytes
episode of Sydenham’s chorea. Indeed, it appears that with
(Kingston and Glynn 1976); neurons, in particular those of
repeated bouts of rheumatic fever the likelihood that
the basal ganglia (Church et al. 2002; Husby et al. 1976)
future episodes of rheumatic fever will be characterized by
and certain brainstem nuclei (Husby et al. 1976); and the
Sydenham’s chorea increases (Aron et al. 1965; Bland and
ependyma (Kingston and Glynn 1976).
Jones 1951; Jones and Bland 1935). Although most recur-
rences of Sydenham’s chorea occur after about 2 years
(Nausieda et al. 1980; Schwartzman et al. 1948), in some Differential diagnosis
cases a very long interval may separate individual episodes,
in one case up to 52 years (Gibb and Lees 1989). As discussed in Section 3.4, there are few other disorders
Although most cases of recurrent episodes of Sydenham’s capable of causing self-limited episodes of chorea in child-
chorea are associated with laboratory evidence of a recent hood or adolescence. Consideration should be given
streptococcal pharyngitis, there are exceptions and some to toxicity of various medications, such as phenytoin, and
cases may appear in the absence of such indicators (Berrios to Wilson’s disease, systemic lupus erythematosus, and
et al. 1985; Korn-Lubetzki et al. 2004); whether this implies hyperthyroidism.
p 17.qxd 3/10/08 9:52 AM Page 560
Treatment chorea. Chorea gravidarum is a rare disorder, occurring in

anywhere from 0.001 percent (Wilson and Preece 1932a)
Patients should be given penicillin VK in a dose of 500 mg to 0.003 percent (Beresford and Graham 1950) of pregnan-
twice daily for 10 days, regardless of whether there is any cies. In the past, the most common of the pre-existing dis-
clinical evidence of an active pharyngitis, as it is critical to orders was Sydenham’s chorea; with the greatly decreased
eradicate all of the offending streptococci. Erythromycin incidence of this disorder, however, other conditions, such
may be substituted in patients allergic to penicillin. as the anti-phospholipid syndrome and systemic lupus
Various treatments have been proposed, including steroids erythematosus, have become more important.
(e.g., prednisone), valproic acid, carbamazepine, haloperi-
dol, and plasma exchange or intravenous immunoglobu-
lins. Of these, only prednisone has been subjected to a Clinical features
double-blind trial.
Treatment with steroids makes sense in that it targets The onset of the chorea is usually during the first half of
the underlying mechanism of the disease and could con- pregnancy, and symptoms resolve either toward the end of
ceivably, if effective, prevent the occurrence of some of the the third trimester or during the puerperium. In cases
sequelae noted above, such as obsessive–compulsive disor- occurring in women with a history of Sydenham’s chorea,
der. In the double-blind study that demonstrated the effec- anywhere from 7 percent (Wilson and Preece 1932b) to 26
tiveness of prednisone, patients were given 2 mg/kg/day for percent (Thiele 1935) may also experience hallucinations
4 weeks, after which the dose was gradually tapered (Paz or delusions; furthermore, mania or delirium may also
et al. 2006). occur (Wilson and Preece 1932b).
In contrast to steroids, valproic acid, carbamazepine,
and haloperidol all represent purely symptomatic treat-
Course
ments. One open study found valproic acid to be superior
to carbamazepine, which in turn was superior to haloperi-
With subsequent pregnancies, recurrences may occur, and
dol (Pena et al. 2002); another open study, however, found
this appears to be common in those with a history of
valproic acid and carbamazepine to be equally effective
Sydenham’s chorea (Wilson and Preece 1932a).
(Genel et al. 2002). Valproic acid and carbamazepine
are given in customary doses; haloperidol has been given
in doses ranging from 1 to 4 mg/day (Axley 1981; Shenker Etiology
et al. 1973).
A reasonable strategy would be to initiate treatment with Sydenham’s chorea greatly increases the chances of chorea
prednisone and observe the patient. In cases in which there gravidarum, which may occur in anywhere from 4 percent
is a response but it is slow and the chorea is of such severity (Beresford and Graham 1950) to an astounding 26 percent
as to threaten the patient, consideration may then be given (Wilson and Preece 1932a) of patients with a history of this
to adding a symptomatic treatment, beginning with val- condition. Chorea gravidarum has also been noted in asso-
proic acid. In cases in which there is no response to pred- ciation with the anti-phospholipid syndrome (Cervera
nisone, symptomatic treatment may also, of course, be et al. 1997; Omdal and Roalso 1992) and systemic lupus
considered, but some authors would recommend further erythematosus (Wolf and McBeath 1985). There has been
etiologic treatment, with consideration given to a course of one autopsy case, which revealed neuronal loss and gliosis
intravenous methylprednisolone (Cardoso et al. 2003) or to within the caudate nucleus (Ichikawa et al. 1980).
treatment with plasmapheresis or intravenous immuno-
globulins (Garvey et al. 2005).
Patients should also be treated with injections of peni- Differential diagnosis
cillin G benzathine, using a dose of 1.2 million units every
3–4 weeks, to prevent recurrences of streptococcal pharyn- Of the multiple causes of chorea discussed in Section 3.4,
gitis. For children or adolescents, such treatment should several may occur coincidentally with pregnancy. For exam-
probably continue for 5 years or until the age of 21 years, ple, women with schizophrenia being treated with antipsy-
whichever comes later. For adults, the decision must be chotics may stop taking the antipsychotics upon learning of
individualized, with special attention given to those at risk a pregnancy, only to then go on to develop tardive dyskine-
of contracting further streptococcal pharyngitides, such as sia; another example might be the coincidental onset of a
teachers or pediatricians. neurodegenerative disease, such as Huntington’s disease.
17.11 CHOREA GRAVIDARUM Treatment

As a result of the endocrinologic changes occurring during Although termination of pregnancy is followed by a reso-
pregnancy, women with certain disorders may develop lution of the symptoms, chorea gravidarum, given its
p 17.qxd 3/10/08 9:52 AM Page 561
References 561
essentially benign nature, is generally not considered an Bak TH, Antoun N, Balan KK et al. Memory lost, memory regained:
indication for abortion. If symptomatic treatment is neuropsychological findings and neuroimaging in two cases
required, consideration may be given to an antipsychotic, of paraneoplastic limbic encephalitis with radically
such as haloperidol (Patterson 1979) or risperidone; how- different outcomes. J Neurol Neurosurg Psychiatry 2001;
ever, in most cases it is prudent to simply let the disease run 71:40–7.
its course. Bakheit AMO, Kennedy PGE, Behan PO. Paraneoplastic limbic
encephalitis: clinico-pathological correlation. J Neurol
Neurosurg Psychiatry 1990; 53:1084–8.
REFERENCES Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L et al. Controlled
clinical trial of cyclophosphamide versus IV
Abt IA, Levinson A. A study of two-hundred twenty-six cases of methylprednisolone in severe neurological manifestations in
chorea. JAMA 1916; 67:1342–7. systemic lupus erythematosus. Ann Rheum Dis 2005;
Achiron A, Ziv I, Djaldetti R et al. Aphasia in multiple sclerosis: 64:620–5.
clinical and radiologic correlation. Neurology 1992; Barnard RO, Triggs M. Corpus callosum in multiple sclerosis. J
42:2195–7. Neurol Neurosurg Psychiatry 1974; 37:1259–64.
Adair JC, Digre KB, Swanda RM et al. Sneddon’s syndrome: a Barnett MH, Prineas JW. Relapsing and remitting multiple
cause of cognitive decline in young adults. Neuropsychiatry sclerosis: pathology of the newly forming lesions. Ann Neurol
Neuropsychol Behav Neurol 2001; 14:197–204. 2004; 55:458–60.
Agius MA, Chan JW, Chung S et al. Role of antiribosomal P Bataller L, Kleopa KA, Wu GF et al. Autonomic limbic encephalitis
protein antibodies in the diagnosis of lupus isolated to the in 39 patients: immunophenotypes and outcomes. J Neurol
central nervous system. Arch Neurol 1997; 54:862–4. Neurosurg Psychiatry 2007; 78:381–5.
Ahern GL, O’Connor M, Dalmau J et al. Paraneoplastic temporal Benda CA. Chronic rheumatic encephalitis, torsion dystonia, and
lobe epilepsy with testicular neoplasm and atypical amnesia. Hallervorden–Spatz disease. Arch Neurol Psychiatry 1949;
Neurology 1994; 44:1270–4. 61:137–63.
Alamowitch S, Graus F, Uchuya M et al. Limbic encephalitis and Beresford OD, Graham AM. Chorea gravidarum. J Obs Gynaecol Br
small cell lung cancer: clinical and immunological features. Emp 1950; 57:616–25.
Brain 1997; 120:923–8. Berg D, Supprian T, Thomas J et al. Lesion patterns with multiple
Anaya JM, Villa LA, Restrepo L et al. Central nervous system sclerosis and depression. Mult Scler 2000; 6:156–62.
compromise in primary Sjögren’s syndrome. J Clin Rheumatol Bergin JD. Rapidly progressive dementia in disseminated sclerosis.
Ances BM, Vitaliani R, Taylor RA et al. Treatment-responsive Berrios X, Quesney F, Morales A et al. Are all recurrences of ‘pure’
limbic encephalitis identified by neuronal antibodies: MRI and Sydenham chorea true recurrence of acute rheumatic fever?
PET correlates. Brain 2005; 128:1764–77. J Pediatr 1985; 107:867–72.
Anderson NE, Rosenblum MK, Graus F et al. Autoantibodies in Bland EF, Jones TD. Rheumatic fever and rheumatic heart disease:
paraneoplastic syndromes associated with small-cell lung a twenty-year report on 1000 patients followed since
cancer. Neurology 1988; 38:1391–8. childhood. Circulation 1951; 4:836–43.
Anonymous. Guidelines for the diagnosis of rheumatic fever: Bland EF, Jones TD. The natural history of rheumatic fever: a 20
Jones criteria, 1992 update. JAMA 1992; 268:2069–73. year perspective. Ann Intern Med 1952; 37:1006–26.
Antoine JC, Honnorat J, Anterion CT et al. Limbic encephalitis and Bluestein HG, Williams GW, Stebeg AD. Cerebrospinal fluid
immunological perturbations in two patients with thymoma. J antibodies to neuronal cells: association with neuropsychiatric
Neurol Neurosurg Psychiatry 1995; 58:706–10. manifestations of systemic lupus erythematosus. Am J Med
Aron AM, Freeman JM, Carter S. The natural history of 1981; 70:240–6.
Sydenham’s chorea. Am J Med 1965; 38:83–95. Boesch SM, Plorer AL, Auer AJ et al. The natural course of
Asbahr FR, Negrao AB, Gentil V et al. Obsessive-compulsive and Sneddon’s syndrome: clinical and magnetic resonance imaging
related symptoms in children and adolescents with and findings in a prospective six year observation study. J Neurol
without chorea: a prospective 6-month study. Am J Psychiatry Neurosurg Psychiatry 2003; 74:542–4.
1998; 155:1122–4. Bohnen NILJ, Parnell KJ, Harper CM. Reversible MRI findings in a
Asherson RA, Khamashta MA, Ordis-Ros J et al. The ‘primary’ patient with Hashimoto’s encephalopathy. Neurology 1997;
antiphospholipid syndrome: major clinical and serological 49:246–7.
features. Medicine 1989; 68:366–74. Bonfa E, Golembek SJ, Kaufman LD et al. Association between
Atkins CJ, Kondon JJ, Quismorio FP et al. The choroid plexus in lupus psychosis and anti-ribosomal P antibodies. N Engl J Med
systemic lupus erythematosus. Ann Intern Med 1972; 1987; 317:265–71.
76:65–72. Bostantjopoulou S, Zafiriou D, Katsarou Z et al. Hashimoto’s
Aubart-Cohen F, Klein I, Alexandra JF et al. Long-term outcome in encephalopathy: clinical and laboratory findings. Funct Neurol
Susac syndrome. Medicine 2007; 96:93–102. 1996; 11:247–51.
Axley J. Rheumatic chorea controlled with haloperidol. J Pediatr Bradley IA. A case of chorea insaniens with autopsy. Am J Insanity
1981; 72:1216–17. 1904; 60:777–85.
p 17.qxd 3/10/08 9:52 AM Page 562
Bragoni M, Di Piero V, Priori R et al. Sjögren’s syndrome Chapelon C, Ziza JM, Piette JC et al. Neurosarcoidosis: signs,
presenting as ischemic stroke. Stroke 1994; 25:2276–9. course and treatment in 36 confirmed cases. Medicine 1990;
Brain L, Jellinek EH, Ball K. Hashimoto’s disease and 69:261–76.
encephalopathy. Lancet 1966; 2:512–14. Ch’ien LT, Economides AH, Lemmi H. Sydenham’s chorea and
Brey RL, Hart RG, Sherman DG et al. Antiphospholipid antibodies seizures: clinical and electroencephalographic studies. Arch
and cerebral ischemia in young people. Neurology 1990; Neurol 1978; 35:382–5.
40:190–6. Chong JY, Rowland LP, Utiger RD. Hashimotos’s encephalopathy:
Brey RL, Holliday SL, Saklad AR et al. Neuropsychiatric syndromes syndrome or myth? Arch Neurol 2003; 60:164–71.
in lupus. Prevalence using standardized definitions. Neurology Church AJ, Cardoso F, Dale RC et al. Anti-basal ganglia antibodies
2002; 58:1214–20. in acute and persistent Sydenham’s chorea. Neurology 2002;
Brierly JB, Corsellis JAN, Hierons R et al. Subacute encephalitis of 59:227–31.
later adult life. Brain 1960; 83:357–68. Coates T, Slavotinek JP, Rischmueller M et al. Cerebral white
Brown MM, Thompson AJ, Wedzicha JA et al. Sarcoidosis matter lesions in primary Sjögren’s syndrome: a controlled
presenting with stroke. Stroke 1989; 20:400–5. study. J Rheumatol 1999; 26:1301–5.
Brownell B, Hughes JT. The distribution of plaques in the Cohen JA, Cutter GR, Fischer JS et al. Benefit of interferon beta-
cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 1a on MSFC progression in secondary progressive MS.
1962; 25:315–20. Neurology 2002; 59:679–87.
Buchanen DN. Pathologic change in chorea. Am J Dis Child 1941; Colony HS, Malamud N. Sydenham’s chorea: a clinicopathologic
62:443–4. study. Neurology 1956; 6:672–6.
Buchanen DN, Walker AK, Case TJ. The pathogenesis of chorea. J Comi G, Rovaris M, Falautano M et al. A multiparametric study of
Pediatr 1942; 20:555–75. frontal lobe dementia in multiple sclerosis. J Neurol Sci 1999;
Burton GE, Bullard DE, Walther PJ et al. Paraneoplastic limbic 171:135–44.
encephalopathy with testicular carcinoma. A reversible Comi G, Filippi M, Wolinsky JS et al. European/Canadian
neurologic syndrome. Cancer 1988; 62:2248–51. multicenter, double-blind, randomized, placebo-controlled
Bussiere HC, Rhea LJ. Acute rheumatic fever and chorea in study of the effects of glatiramer acetate on magnetic
children. Can Med Assoc J 1926; 16:35–40. resonance imaging-measured disease activity and burden in
Byrne T, Mason WP, Posner JB et al. Spontaneous neurologic patients with relapsing multiple sclerosis. Ann Neurol 2001;
improvement in anti-Hu associated encephalomyelitis. J 49:290–7.
Neurol Neurosurg Psychiatry 1997; 62:276–8. Coombs C. Cerebral rheumatism. Practitioner 1912; 88:99–106.
Camp WA, Frierson JG. Sarcoidosis of the central nervous system. Cordingly G, Navarro C, Brust JCM et al. Sarcoidosis presenting as
Arch Neurol 1962; 7:432–41. senile dementia. Neurology 1981; 31:1148–51.
Cardoso F, Eduardo C, Silva AP et al. Chorea in 50 consecutive Corsellis JAN, Goldberg GJ, Norton AR. ‘Limbic encephalitis’ and
patients with rheumatic fever. Mov Disord 1997; 12:701–3. its association with carcinoma. Brain 1968; 91:481–96.
Cardoso F, Maia D, Cunningham MC et al. Treatment of Sydenham Cottrell SS, Wilson SAK. The affective symptomatology of
chorea with corticosteroids. Mov Disord 2003; 18:1374–7. disseminated sclerosis: a study of 100 cases. J Neurol
Casanova MF, Crapanzano KA, Mannheim G et al. Sydenham’s Psychopathology 1926; 7:1–30.
chorea and schizophrenia: a case report. Schizophr Res 1995; Coull BM, Bourdette DM, Goodnight SH et al. Multiple cerebral
16:73–6. infarctions and dementia associated with anticardiolipin
Caselli RJ, Scheithauer BW, Bowles CA et al. The treatable antibodies. Stroke 1987; 18:1107–12.
dementia of Sjögren’s syndrome. Ann Neurol 1991; Creak M, Guttmann E. Chorea, tics, compulsive utterances. J Ment
30:98–101. Sci 1935; 81:834–9.
Caselli RJ, Scheithauer BW, O’Duffy JD et al. Chronic Croteau d, Owainati A, Dalmau J et al. Response to cancer therapy
inflammatory meningoencephalitis should not be mistaken for in a patient with paraneoplastic choreiform disorder.
Alzheimer’s disease. Mayo Clin Proc 1993; 68:846–53. Neurology 2001; 57:719–22.
Castillo M, Kwock L, Arbelaez A. Sydenham’s chorea: MRI and Cutter NC, Scott DD, Johnson JC et al. Gabapentin effect on
proton spectroscopy. Neuroradiology 1999; 41:943–5. spasticity in multiple sclerosis: a placebo-controlled,
Castillo P, Woodruff B, Caselli R et al. Steroid-responsive randomized trial. Arch Phys Med Rehabil 2000; 81:
encephalopathy associated with autoimmune thyroiditis. Arch 164–9.
Neurol 2006; 63:197–202. Dalmau J, Graus F, Rosenblum MK et al. Anti-Hu-associated
Cervera R, Asherson RA, Font J et al. Chorea in the paraneoplastic encephalomyelitis/sensory neuropathy. A
antiphospholipid syndrome. Clinical, radiologic, and clinical study of 71 patients. Medicine 1992; 71:59–72.
immunologic characteristics of 50 patients from our clinics Dalmau J, Tuzun E, Wu H-Y et al. Paraneoplastic anti-N-methyl-
and the recent literature. Medicine 1997; 76:203–12. D-aspartate receptor encephalitis associated with ovarian
Chancellor AM, Cull RE, Kilpatrick DC et al. Neurological disease teratoma. Ann Neurol 2007; 61:25–36.
associated with anticardiolipin antibodies in patients without Dean G. Annual incidence, prevalence and mortality in white
systemic lupus erythematosus: clinical and immunological South African-born and in white immigrants to South Africa.
features. J Neurol 1991; 238:401–7. BMJ 1967; 2:724–30.
p 17.qxd 3/10/08 9:52 AM Page 563
References 563
Delalande S, de Seze J, Fauchais AL et al. Neurologic clinical spectrum, and relationship to other features of the
manifestations in primary Sjögren syndrome: a study of 82 disease. Medicine 1976; 55:323–39.
patients. Medicine 2004; 83:280–91. Feinstein AR, Spagnuola M. The clinical pattern of acute
Delaney P. Neurologic manifestations in sarcoidosis. Ann Intern rheumatic fever. Medicine 1962; 41:279–305.
Med 1977; 87:336–45. Feinstein A, Feinstein K, Gray T et al. Prevalence and
DeLorenze GN, Munger KL, Lennette ET et al. Epstein-Barr virus neurobehavioral correlates of pathological laughing and crying
and multiple sclerosis. Evidence of association from a in multiple sclerosis. Arch Neurol 1997; 54:1116–21.
prospective study with long-term follow-up. Arch Neurol Feinstein A, Roy P, Lobaugh N et al. Structural brain abnormalities
2006; 63:839–44. in multiple sclerosis patients with major depression. Neurology
Devere TD, Trotter JL, Cross AH. Acute aphasia in multiple 2004; 62:586–90.
sclerosis. Arch Neurol 2000; 57:1207–9. Fermaglich J, Streib E, Auth T. Chorea associated with systemic
Devinsky O, Petito CK, Alonso DR. Clinical and neuropathological lupus erythematosus. Arch Neurol 1973; 28:276–7.
findings in systemic lupus erythematosus: the role of Fontaine B, Seilhean D, Tourbah A et al. Dementia in two
vasculitis, heart emboli, and thrombotic thrombocytopenic histologically confirmed cases of multiple sclerosis: one case
purpura. Ann Neurol 1988; 23:380–4. with isolated dementia and one case associated with
Diefendorf AR. Mental symptoms of acute chorea. J Nerv Ment Dis psychiatric symptoms. J Neurol Neurosurg Psychiatry 1994;
1912; 39:161–72. 57:353–9.
Doherty CP, Schlossmacher M, Torres N et al. Hashimoto’s Franklin GM, Heaton RK, Nelson LM et al. Correlations of
encephalopathy mimicking Creutzfeldt–Jakob disease: brain neuropsychological and MRI findings in chronic-progressive
biopsy findings. J Neurol Neurosurg Psychiatry 2002; multiple sclerosis. Neurology 1988; 38:1826–9.
73:601–2. Franklin GM, Nelson LM, Filley CM et al. Cognitive loss in multiple
Donaldson IM, Espiner EA. Disseminated lupus erythematosus sclerosis: case reports and review of the literature. Arch Neurol
presenting as chorea gravidarum. Arch Neurol 1971; 1989; 46:162–7.
25:240–4. Futrell N, Schultz LR, Millikan C. Central nervous system disease
Douglas AC, Maloney AFJ. Sarcoidosis of the central nervous in patients with systemic lupus erythematosus. Neurology
system. J Neurol Neurosurg Psychiatry 1973; 36:1024–33. 1992; 42:1649–57.
Duffey P, Yee S, Rein IN et al. Hashimoto’s encephalopathy: Galluzzi S, Geroldi C, Zanetti O et al. Hashimoto’s encephalopathy
postmortem findings after fatal status epilepticus. Neurology in the elderly: relationship to cognitive impairment. J Geriatr
2003; 61:1124–6. Psychiatry Neurol 2002; 15:175–9.
Durelli L, Verdun E, Barbero P et al. Every-other-day interferon Ganji S, Duncan MC, Frazier E. Sydenham’s chorea: clinical, CT
beta-1b versus once-weekly interferon beta-1a for multiple scan, and evoked potential studies. Clin Electroencephalogr
sclerosis: results of a 2-year prospective randomized 1988; 19:114–22.
multicentre study (INCOMIN). Lancet 2002; 359:1453–60. Ganz VH, Gurland BJ, Deming WE et al. The study of the
Ebaugh FG. Neuropsychiatric aspects of chorea in children. JAMA psychiatric symptoms of systemic lupus erythematosus: a
1926; 87:1083–8. biometric study. Psychosom Med 1972; 34:207–20.
Ebers GC, Bulman DE, Sodovnik AD et al. Population-based studies Garvey MA, Snider LA, Leitman SF et al. Treatment of Sydenham’s
of multiple sclerosis in twins. N Engl J Med 1986; chorea with intravenous immunoglobulin, plasma exchange or
315:1638–42. prednisone. J Child Neurol 2005; 20:424–9.
Ebers GC, Sadovnik AD, Risch NJ. A genetic basis for familial Gay W. Chorea insaniens. Brain 1889; 12:150–6.
aggregation in multiple sclerosis. Canadian Collaborative Genel F, Arslanoglu S, Uran N et al. Sydenham’s chorea:
Study Group. Nature 1995; 377:150–1. clinical findings and comparison of the efficacies of sodium
Ellis SG, Verity MA. Central nervous system involvement in valproate and carbamazepine regimens. Brain Dev 2002;
systemic lupus erythematosus: a review of neuropathologic 24:73–6.
findings in 57 cases. Semin Arthritis Rheum 1979; Gerstley JR, Wile SA, Falstein E et al. Chorea: is it a manifestation
8:212–21. of rheumatic fever? J Pediatr 1935; 6:42–50.
Emery ES, Vieco PT. Sydenham chorea: magnetic resonance Geschwind DH, FitzPatrick M, Mischel PS et al. Sneddon’s
imaging reveals permanent basal ganglia injury. Neurology syndrome is a thrombotic vasculopathy: neuropathologic and
1997; 48:531–3. neuroradiologic evidence. Neurology 1995; 43:557–60.
European Study Group on Interferon Beta-1b in Secondary Ghika-Schmid F, Ghika J, Regli F et al. Hashimoto’s myoclonic
Progressive MS. Placebo-controlled multicentre randomized encephalopathy: an underdiagnosed treatable condition? Mov
trial of interferon beta-1b in treatment of secondary Disord 1996; 11:555–62.
progressive multiple sclerosis. Lancet 1998; 352:1491–7. Gibb WRG, Lees AJ. Tendency to late recurrence following
Fassbender K, Schmidt R, Mofsner R et al. Mood disorders and rheumatic chorea. Neurology 1989; 39:999.
dysfunction of the hypothalamic-pituitary-adrenal axis in Gibb WR, Lees AJ, Scadding JW. Persistent rheumatic chorea.
multiple sclerosis. Arch Neurol 1998; 55:66–72. Neurology 1985; 35:101–2.
Feinglass EJ, Arnett FC, Dorsch CA. Neuropsychiatric Glaser G, Pincus JH. Limbic encephalitis. J Nerv Ment Dis 1969;
manifestations of systemic lupus erythematosus: diagnosis, 149:59–67.
p 17.qxd 3/10/08 9:52 AM Page 564
Goodkin DE, Rudick RA, VanderBrug Medendorp S et al. Low-dose Hotopf MH, Pollock S, Lishman WA. An unusual presentation of
(7.5 mg) oral methotrexate reduces the rate of progression in multiple sclerosis. Psychol Med 1994; 24:525–8.
chronic progressive multiple sclerosis. Ann Neurol 1995; Huber SJ, Paulson GW, Shuttleworth EC et al. Magnetic resonance
37:30–40. imaging correlates of dementia in multiple sclerosis. Arch
Goransson LG, Herigstad A, Tjensvoll AB et al. Peripheral Neurol 1987; 44:732–6.
neuropathy in primary Sjögren syndrome: a population-based Hughes RAC, Cameron JS, Hall SM et al. Multiple
study. Arch Neurol 2006; 63:1612–15. mononeuropathy as the initial presentation of SLE. J Neurol
Gordon RG, Norman RM. A case of acute toxic chorea. J Neurol 1982; 228:239–47.
Psychopathology 1934; 15:313–19. Hughson MD, McCarty GA, Sholer CM et al. Thrombotic cerebral
Goyal BK, Williams BJ. Sydenham’s chorea in an octogenarian. angiopathy in patients with the antiphospholipid syndrome.
Gerontologica Clinica 1967; 9:176–81. Mod Pathol 1993; 6:644–53.
Graham DI, Lantos PL. Greenfield’s neuropathology, 6th edn. Hugo FJ, Halland AM, Spangenberg JJ et al. DSM-III-R
London: Arnold, 1996. classification of psychiatric symptoms in systemic lupus
Graus F, Keime-Guibert F, Rene R et al. Anti-Hu-associated erythematosus. Psychosomatics 1996; 37:262–9.
paraneoplastic encephalomyelitis: analysis of 200 patients. Husby G, van de Rijn I, Zabriskie JB et al. Antibodies reacting with
Brain 2001; 124:1138–48. cytoplasm of subthalamic and caudate neurons in chorea and
Greenfield JG, King LS. Observations on the histopathology of the acute rheumatic fever. J Exp Med 1976; 144:1094–110.
cerebral lesions in disseminated sclerosis. Brain 1936; Ichikawa K, Kim RC, Givelbar H et al. Chorea gravidarum. Report
59:445–58. of a fatal case with neuropathological observations. Arch
Greenfield JG, Wolfsohn JM. The pathology of Sydenham’s chorea. Neurol 1980; 37:429–32.
Lancet 1922; 2:603–6. Ingenito GG, Berger JR, David NJ et al. Limbic encephalitis
Gultekin SH, Rosenfeld MR, Voltz R et al. Paraneoplastic limbic associated with benign thymoma. Neurology 1990;
encephalitis: neurological symptoms, immunological findings 40:382.
and tumour association in 50 patients. Brain 2000; Iranzo A, Graus F, Clover L et al. Rapid eye movement sleep
123:1481–94. disorder and potassium channel antibody-associated limbic
Guze SB. The occurrence of psychiatric illness in systemic lupus encephalitis. Ann Neurol 2006; 59:178–82.
erythematosus. Am J Psychiatry 1967; 123:1562–70. Isshi K, Hirohata S. Differential roles of the anti-ribosomal P
Hammes EM. Psychoses associated with Sydenham’s chorea. antibody and antineuronal antibody in the pathogenesis of
JAMA 1922; 79:804–7. central nervous system involvement in systemic lupus
Hanley JG, Walsh NMG, Sangalang V. Brain pathology in systemic erythematosus. Arthritis Rheum 1998; 41:1819–27.
lupus erythematosus. J Rheumatol 1992; 19:732–41. Jefferson M. Sarcoidosis of the central nervous system. Brain
Hartung HP, Gonsetta R, Konig N et al. Mitoxantrone in 1957; 80:540–56.
progressive multiple sclerosis: a placebo-controlled, double- Jennekens-Schinkel A, Sanders EACM. Decline of cognition in
blind, randomised, multicentre trial. Lancet 2002; multiple sclerosis: dissociable artifacts. J Neurol Neurosurg
360:2018–25. Psychiatry 1986; 49:1354–60.
Hashimoto H. Zur kenntnis der lymphomatosan veranderung der Joffe RT, Lippert GP, Gray TA et al. Mood disorder and multiple
schilddruse (struma ymphomatosa). Arch Klin Chir 1912; sclerosis. Arch Neurol 1987; 44:376–8.
97:219–48. Johnson KP, Brooks BR, Cohen JA et al. Extended use of glatiramer
Haskell RH. Mental disturbance associated with acute articular acetate (Copaxone) is well tolerated and maintains its clinical
rheumatism. Am J Insanity 1914; 71:361–81. effect on multiple sclerosis relapse and degree of disability.
Heiskala H, Somer H, Kovanen J et al. Microangiopathy with Neurology 1998; 50:701–8.
encephalopathy, hearing loss and arteriolar occlusions: two Johnson RT, Richardson EP. The neurological manifestations of
new cases. J Neurol Sci 1988; 8:239–50. systemic lupus erythematosus: a clinical–pathological study of
Henchey R, Cibula J, Helveston W et al. Electroencephalographic 24 cases and review of the literature. Medicine 1968;
findings in Hashimoto’s encephalopathy. Neurology 1995; 47:337–69.
45:977–81. Jones TD, Bland EF. Clinical significance of chorea as a
Henson RA, Hofman HL, Ulrich H. Encephalomyelitis with manifestation of rheumatic fever: a study in prognosis. JAMA
carcinoma. Brain 1965; 88:449–64. 1935; 105:571–7.
Hernandez Echebarria LE, Saiz A, Graus F et al. Detection of 14-3- Kabelitz M, Liesenkotter KP, Stach B et al. The prevalence of anti-
3 protein in the CSF of a patient with Hashimoto’s thyroid antibodies and autoimmune thyroiditis in children and
encephalopathy. Neurology 2000; 54:1539–40. adolescents in an iodine replete area. Eur J Endocrinol 2003;
Herring AB, Urich H. Sarcoidosis of the central nervous system. 148:301–7.
J Neurol Sci 1969; 9:405–22. Kalashnikova LA, Noasonov EL, Kushekbaeva AE et al.
Hilton DA, Footitt D. Neuropathological findings in Sneddon’s Anticardiolipin antibodies in Sneddon’s syndrome. Neurology
syndrome. Neurology 2003; 60:1181–2. 1990; 40:464–7.
Hook O. Sarcoidosis with involvement of the nervous system. Arch Kawashima N, Shindo R, Kohno M. Primary Sjögren’s syndrome
Neurol Psychiatry 1954; 71:554–75. with subcortical dementia. Intern Med 1993; 32:561–4.
p 17.qxd 3/10/08 9:52 AM Page 565
References 565
Keane JR. Internuclear ophthalmoplegia. Unusual causes in 114 of Lessoff MH, Bywaters EGL. The duration of chorea. BMJ 1956;
410 patients. Arch Neurol 2005; 62:714–17. 1:1520–3.
Kelly MC, Denburg JA. Cerebrospinal fluid immunoglobulins and Levine SR, Deegan MJ, Futrell N et al. Cerebrovascular and
neuronal antibodies in neuropsychiatric systemic lupus neurologic disease associated with antiphospholipid
erythematosus and related conditions. J Rheumatol 1987; antibodies: 48 cases. Neurology 1990; 40:1181–9.
14:740–4. Lewis A, Minski L. Chorea and psychosis. Lancet 1935; 1:536–8.
Kerbeshian J, Burd L, Pettit R. A possible post-streptococcal Leys D. Rheumatic encephalopathy. Edinburgh Med J 1946;
movement disorder with chorea and tics. Dev Med Child 53:444–9.
Neurol 1990; 32:642–4. Lief VF, Silverman T. Psychosis associated with lupus
Kiessling LS, Marotte AC, Culpepper L. Antineuronal antibodies in erythematosus disseminatus. Arch Gen Psychiatry 1960;
movement disorders. Pediatrics 1993; 92:39–43. 3:608–11.
Kilic A, Unuvar E, Tatli B et al. Neurologic and cardiac findings in Lim L, Ron MA, Ormerod IEC et al. Psychiatric and neurological
children with Sydenham chorea. Pediatr Neurol 2007; manifestations in systemic lupus erythematosus. Q J Med
36:159–64. 1988; 66:27–38.
Kingston G, Glynn LE. A cross-reaction between Str. pyogenes and Mac DS, Pardo MP. Systemic lupus erythematosus and catatonia:
human fibroblasts, endothelial cells and astrocytes. a case report. J Clin Psychiatry 1983; 44:155–6.
Immunology 1971; 21:1003–16. MacKenzie S. Report on inquiry: II. Chorea. BMJ 1887; 1:425–36.
Kingston G, Glynn LE. Anti-streptococcal antibodies reacting with MacNeil A, Grennan DM, Ward D et al. Psychiatric problems in
brain tissue I. Immunofluorescent studies. Br J Exp Pathology systemic lupus erythematosus. Br J Psychiatry 1976;
1976; 57:114–28. 128:442–5.
Kinnman J, Link H. Intrathecal production of oligoclonal IgM Malamud N, Saver G. Neuropathologic findings in disseminated
and IgG in CNS sarcoidosis. Acta Neurol Scand 1984; lupus erythematosus. Arch Neurol Psychiatry 1954;
69:97–106. 71:723–31.
Kirk A, Kertesz A, Polk MJ. Dementia with leukoencephalopathy in Manz HJ. Pathobiology of neurosarcoidosis and clinicopathologic
systemic lupus erythematosus. Can J Neurol Sci 1991; correlation. Can J Neurol Sci 1983; 10:50–5.
18:344–8. Martinez-Yelamos A, Saiz A, Sanchez-Valle R et al. 14-3-3
Koenig H. Dementia associated with the benign form of multiple protein in the CSF as prognostic marker in early multiple
sclerosis. Trans Am Neurol Assoc 1968; 93:227–31. sclerosis. Neurology 2001; 57:722–4.
Korn-Lubetzki I, Brand A, Steiner I. Recurrence of Sydenham Mathews WB. Multiple sclerosis presenting with acute remitting
chorea: implications for pathogenesis. Arch Neurol 2004; psychiatric symptoms. J Neurol Neurosurg Psychiatry 1979;
61:1261–4. 42:859–63.
Krumholz A, Stern BJ, Stern EG. Clinical implications of seizures in McCombe PA, McLeod JG, Pollard JG et al. Peripheral
neurosarcoidosis. Arch Neurol 1991; 48:842–4. sensorimotor and autonomic neuropathy associated with
Krupp LB, Coyle PK, Doescher C et al. Fatigue therapy in multiple systemic lupus erythematosus. Brain 1987; 110:533–50.
sclerosis: results of a double-blind, randomized, parallel trial McCullogh H. Encephalitis rheumatica: chorea minor of
of amantadine, pemoline, and placebo. Neurology 1995; Sydenham. J Pediatr 1938; 13:741–7.
45:1956–61. McLean BN, Miller D, Thompson D. Oligoclonal banding of IgG in
Krupp LB, Christodoulou C, Melville P et al. Donepezil improved CSF; blood–brain barrier function, and MRI findings in
memory in multiple sclerosis in a randomized clinical trial. patients with sarcoidosis, systemic lupus erythematosus, and
Neurology 2004; 63:1579–85. Behçet’s disease involving the nervous system. J Neurol
Kurita A, Hasunuma T, Mochio S et al. A young case with multi- Neurosurg Psychiatry 1995; 58:548–54.
infarct dementia associated with lupus anticoagulant. Intern Mendez MF, Frey WH. Multiple sclerosis dementia. Neurology
Med 1994; 33:373–5. 1992; 42:696.
Lacour A, de Seze J, Revenco E et al. Acute aphasia in multiple Michotte A, Dequenne P, Jacobovitz D et al. Focal neurological
sclerosis. Neurology 2004; 62:974–7. deficit with sudden onset as the first manifestation of
Lange H, Thorner G, Hopf A et al. Morphometric studies of the sarcoidosis: a case report with MRI follow-up. Eur Neurol
neuropathological changes in choreatic disease. J Neurol Sci 1991; 31:376–9.
1976; 28:401–25. Miguel EC, Rodriguez Pereira RM, de Braganca Pereira CA et al.
Lanham JG, Brown MM, Hughes GRV. Cerebral systemic lupus Psychiatric manifestations of systemic lupus erythematosus:
erythematosus presenting with catatonia. Postgrad Med J clinical features, symptoms, and signs of central nervous
1985; 61:329–30. system activity in 43 patients. Medicine 1994; 73:224–32.
Lawn ND, Westmoreland BF, Kiely MJ et al. Clinical, magnetic Mikdashi J, Krumholz A, Handwerger B. Factors at diagnosis
resonance imaging, and electroencephalographic findings in predict subsequent occurrence of seizures in systemic lupus
paraneoplastic limbic encephalitis. Mayo Clinic Proc 2003; 78; erythematosus. Neurology 2005; 64:2102–7.
1363–8. Miller DH, Kendall BE, Barter S et al. Magnetic resonance imaging
Lessof MH. Sydenham’s chorea. Guys Hospital Reports 1958; in central nervous system sarcoidosis. Neurology 1988;
107:185–206. 38:378–83.
p 17.qxd 3/10/08 9:52 AM Page 566
Miller DH, Khan OA, Sheremata WA et al. A controlled trial of Papo T, Biousse V, Lehoang P et al. Susac syndrome. Medicine
natalizumab for relapsing multiple sclerosis. N Engl J Med 1998; 77:3–11.
2003; 348:15–23. Parker N. Disseminated sclerosis presenting as schizophrenia. Med
Mitsias P, Levine SR. Large cerebral vessel occlusive disease in J Aust 1956; 1:405–7.
systemic lupus erythematosus. Neurology 1994; 44:385–93. Patterson JF. Treatment of chorea gravidarum with haloperidol.
Moller A, Wiedemann G, Rohde U et al. Correlates of cognitive South Med J 1979; 72:1220–1.
impairment and depressive mood disorder in multiple sclerosis. Paz JA, Silva CA, marques-Dias MJ. Randomized double-blind
Acta Psychiatr Scand 1994; 89:117–21. study with prednisone in Sydenham’s chorea. Pediatr Neurol
de la Monte SM, Hutchins GM, Gupta PK. Polymorphous 2006; 34:264–9.
meningitis with atypical mononuclear cells in Sjögren’s Pena J, Mora E, Cardozo J et al. Comparison of the efficacy of
syndrome. Ann Neurol 1983; 14:455–61. carbamazepine haloperidol and valproic acid in the treatment
Monteiro ML, Swanson RA, Coppeto JR et al. A microangiopathic of children with Sydenham’s chorea: clinical follow-up of 18
syndrome of encephalopathy, hearing loss, and retinal patients. Arq Neuropsiquitr 2002; 60:374–7.
arteriolar occlusions. Neurology 1985; 35:1113–21. Pentland B, Mitchell JD, Cull RE et al. Central nervous system
Moreau C, Devos D, Delmaire C et al. Progressive MRI sarcoidosis. Q J Med 1985; 56:457–65.
abnormalities in late recurrence of Sydenhams chorea. J Pettee AD, Wasserman BA, Adams NL et al. Familial Sneddon’s
Neurol 2005; 252:1341–4. syndrome: clinical, hematologic, and radiographic findings in
Mumford CJ, Wood NW, Kellar-Wood HF et al. The British Isles two brothers. Neurology 1994; 44:399–405.
Survey of multiple sclerosis in twins. Neurology 1994; Petty GW, Engel AG, Younge BR et al. Retinocochleocerebral
44:11–15. vasculopathy. Medicine 1998; 77:12–40.
Nausieda PA, Grossman BJ, Koller WC et al. Sydenham chorea: an Pine DS, Douglas CJ, Charles E et al. Patients with multiple
update. Neurology 1980; 30:331–4. sclerosis presenting to psychiatric hospitals. J Clin Psychiatry
Nausieda PA, Bielauskas LA, Bacon LD et al. Chronic dopaminergic 1995; 56:297–306.
sensitivity after Sydenham’s chorea. Neurology 1983; Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist
33:750–4. and predict cancer, not neurological syndrome. Ann Neurol
Nicoletti A, Sofia V, Biondi R et al. Epilepsy and multiple sclerosis 2004; 56:715–19.
in Sicily: a population-based study. Epilepsia 2003; Pittock SJ, Lucchinetti CF, Parisi JE et al. Amphiphysin
44:1445–8. autoimmunity: paraneoplastic accompaniments. Ann Neurol
Nojima Y, Sinota S, Yamada A et al. Correlation of antibodies to 2005; 58:96–107.
ribosomal P protein with psychosis in patients with systemic Powell E. Two fatal cases of acute chorea with insanity. Brain
lupus erythematosus. Ann Rheum Dis 1992; 51:1053–5. 1889; 12:157–60.
Nokura K, Yamamoto H, Okawara Y et al. Reversible limbic Powers WJ, Miller EM. Sarcoidosis mimicking glioma: case report
encephalitis caused by ovarian teratoma. Acta Neurol Scand and review of intracranial sarcoid mass lesions. Neurology
1997; 95:367–73. 1981; 31:907–10.
Nolte KW, Undehaun A, Sieker H et al. Hashimoto’s Poynton FJ, Holmes GM. A contribution to the study of chorea.
encephalopathy: a brainstem vasculitis? Neurology 2000; Lancet 1906; 2:982.
54:769–70. PRISMS (Prevention of Relapses and Disability by Interferon Beta-
O’Connor JF, Musher DM. Central nervous system involvement 1a Subcutaneously in Multiple Sclerosis) Study Group.
in systemic lupus erythematosus. Arch Neurol 1966; Randomized, double-blind, placebo-controlled study of
14:157–64. interferon beta-1a in relapsing/remitting multiple sclerosis.
Ochi H, Horiuchi I, Araki N et al. Proteonomic analysis of human Lancet 1998; 352:1498–504.
brain identifies alpha-enolase as a novel autoantigen in Pruss H, Voltz R, Flath B et al. Anti-ta-associated paraneopastic
Hashimoto’s encephalopathy. FEBS Lett 2002; 528:197–202. encephalitis with occult testicular intratrabecular germ
Oide T, Tokuda T, Yazaki M et al. Anti-neuronal antibody in cell neoplasia. J Neurol Neurosurg Psychiatry 2007; 78:
Hashimoto’s encephalopathy: neuropathological, 651–2.
immunochemical, and biochemical analysis of two patients. Pujol J, Bello J, Deus J et al. Lesions in the left arcuate fasciculus
J Neurol Sci 2004; 217:7–12. region and depressive symptomatology in multiple sclerosis.
Oksanen V. Neurosarcoidosis: clinical presentations and course in Neurology 1997; 49:1105–10.
50 patients. Acta Neurol Scand 1986; 73:283–90. Putzel L. Cerebral complications of chorea. Medical Record 1879;
Olmos-Lau N, Ginsberg MD, Geller JB. Aphasia in multiple 220–2.
sclerosis. Neurology 1977; 27:623–6. Rabins PV, Brooks BR, O’Donnell P et al. Structural brain
Omdal R, Roalso S. Chorea gravidarum and chorea associated correlates of emotional disorder in multiple sclerosis. Brain
with oral contraceptives – diseases due to antiphospholipid 1986; 109:585–97.
antibodies? Acta Neurol Scand 1992; 86:219–20. Reaser EF. Chorea of infectious origin. South Med J 1940;
Panitch H, Goodin DS, Francis G et al. Randomized, comparative 33:1324–8.
study of interferon beta-1a treatment regimens in MS: the Rebollo M, Val JF, Garijo F et al. Livedo reticularis and
EVIDENCE trial. Neurology 2002; 59:1496–506. cerebrovascular lesions (Sneddon’s syndrome). Clinical,
p 17.qxd 3/10/08 9:52 AM Page 567
References 567
radiological and pathological features in eight cases. Brain Scott TF. Neurosarcoidosis: progress and clinical aspects.
1983; 106:965–79. Neurology 1993; 43:8–12.
Robertson WC, Smith CD. Sydenham’s chorea in the age of MRI: a Scott TF, Yandora K, Valeri A et al. Aggressive therapy for
case report and review. Pediatr Neurol 2002; 27:6–7. neurosarcoidosis. Arch Neurol 2007; 64:691–6.
Robin C, Gonnaud P-M, Durieu I et al. Demence lupique Sharma OP. Effectiveness of chloroquine and hydroxychloroquine
progressive: deux cas avec anticorps antiphospholipides ou in treated selected patients with sarcoidosis with neurological
non. Rev Neurol 1995; 151:699–707. involvement. Arch Neurol 1998; 55:1248–54.
Ron MA, Callanan MM, Warrington EK. Cognitive abnormalities in Sharma OP, Sharma AM. Sarcoidosis of the nervous system: a
multiple sclerosis: a psychometric and MRI study. Psychol Med clinical approach. Arch Int Med 1991; 151:1317–21.
1991; 21:59–68. Shaskan D. Mental changes in chorea minor. Am J Psychiatry
Rosenberg GA, Appenzeller O. Amantadine, fatigue and multiple 1938; 95:193–202.
sclerosis. Arch Neurol 1988; 45:1104–6. Shaw PJ, Walls TJ, Newman PK et al. Hashimoto’s
Rosenfeld MR, Eichen JG, Wade DF et al. Molecular and clinical encephalopathy: a steroid-responsive disorder associated with
diversity in paraneoplastic immunity to Ma proteins. Ann high anti-thyroid antibody titers – report of 5 cases.
Roti E, Gardini F, Minelli R et al. Prevalence of anti-thyroid Shenker DM, Grossman HJ, Klawans HL. Treatment of Sydenham’s
peroxidase antibodies in serum in the elderly: comparison with chorea with haloperidol. Dev Med Child Neurol 1973;
other tests for anti-thyroid antibodies. Clin Chem 1992; 15:19–24.
38:88–92. Sibley JT, Olszynski WP, DeCoteau WE et al. The incidence and
Rubin LA, Urowitz MB, Gladman DD. Mortality in systemic lupus prognosis of central nervous system disease in systemic lupus
erythematosus: the bimodal pattern revisited. Q J Med 1985; erythematosus. J Rheumatol 1992; 19:47–52.
55:87–98. Silverstein A, Siltzbach LE. Neurologic sarcoidosis: a study of 18
Rubinstein I, Gray TA, Moldofsky H et al. Neurosarcoidosis cases. Arch Neurol 1965; 12:1–11.
associated with hypersomnolence treated with corticosteroids Sitzer M, Sohngen D, Siebler M et al. Cerebral microembolism in
and brain irradiation. Chest 1988; 94:205–6. patients with Sneddon’s syndrome. Arch Neurol 1995;
Rudick RA, Goodkin DE, Jacobs LD et al. Impact of interferon 52:271–5.
beta-1a on neurologic disability in relapsing multiple sclerosis. Sneddon JB. Cerebrovascular lesions and livedo reticularis. Br J
Neurology 1997; 49:358–63. Dermatol 1965; 77:180–5.
Sanson M, Duyckaerts C, Thibault J-L et al. Sarcoidosis presenting Stankoff B, Waubant E, Confarveux C et al. Modafinil for fatigue
as late-onset dementia. J Neurol 1996; 243:484–7. in MS. A randomized placebo-controlled double-blind study.
Sawka AM, Fatourechi V, Boeve BF et al. Rarity of encephalopathy Neurology 2005; 64:1139–43.
associated with autoimmune thyroiditis: a case series from Stern BJ, Krumholz A, Johns C et al. Sarcoidosis and its
Mayo Clinic from 1950 to 1996. Thyroid 2002; 12:227–8. neurological manifestations. Arch Neurol 1985; 42:909–17.
Schauble B, Castillo PR, Boeve BF et al. EEG findings in steroid- Stockhammer G, Felber SR, Zelger B et al. Sneddon’s syndrome:
responsive encephalopathy associated with autoimmune diagnosis by skin biopsy and MRI in 17 patients. Stroke 1993;
thyroiditis. Clin Neurophysiol 2003; 114:32–7. 24:685–90.
Schiffer RB, Babigian H. Behavioral disorders in multiple sclerosis, Surridge D. An investigation into some psychiatric aspects of
temporal lobe epilepsy and amyotrophic lateral sclerosis. An multiple sclerosis. Br J Psychiatry 1969; 115:749–64.
epidemiologic study. Arch Neurol 1984; 41:1067–9. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain
Schiffer RB, Wineman NM. Antidepressant pharmacotherapy of and retina. Neurology 1979; 29:313–16.
depression associated with multiple sclerosis. Am J Psychiatry Susac JO, Murtagh FR, Egan RA et al. MRI findings in Susac’s
1990; 147:1493–7. syndrome. Neurology 2003; 61:1783–7.
Schiffer RB, Caine ED, Bamford KA et al. Depressive episodes in Sutton I, Winer J, Rowlands D et al. Limbic encephalitis and
patients with multiple sclerosis. Am J Psychiatry 1983; antibodies to Ma2: a paraneoplastic presentation of breast
140:1498–500. cancer. J Neurol Neurosurg Psychiatry 2000; 69:266–8.
Schiffer RB, Wineman M, Weitkamp LR. Association between Swedo SE. Sydenham’s chorea: a model for childhood
bipolar affective disorder and multiple sclerosis. Am J autoimmune neuropsychiatric disorders. JAMA 1994;
Psychiatry 1986; 143:94–5. 272:1788–91.
Schneebaum AB, Singleton JD, West SG et al. Association of Swedo SE, Rapoport JL, Cheslow DL et al. High prevalence of
psychiatric manifestations with antibodies to ribosomal P obsessive–compulsive symptoms in patients with Sydenham’s
proteins in systemic lupus erythematosus. Am J Med 1991; chorea. Am J Psychiatry 1989; 146:246–9.
90:54–62. Swedo SE, Kilpatrick K, Schapiro M et al. Antineuronal antibodies
Schwartzman J, McDonald DH, Derillo L. Sydenham’s chorea: (AnA) in Sydenham’s chorea (SC) and obsessive-compulsive
report of 140 cases and review of the recent literature. Arch disorder (OCD). Pediatr Res 1991; 29:364A
Pediatr 1948; 65:6–24. Swedo SE, Leonard HL, Schapiro MB et al. Sydenham’s chorea:
Scott IA, Stocks AE, Saines N. Hypothalamic/pituitary sarcoidosis. physical and psychological symptoms of St Vitus dance.
Aust NZ J Med 1987; 17:243–5. Pediatrics 1993; 91:706–13.
p 17.qxd 3/10/08 9:52 AM Page 568
Swedo SE, Leonard HL, Kiessling LS. Speculations on antineuronal Vitaliani R, Mason W, Ances B et al. Paraneoplastic encephalitis,
antibody-mediated neuropsychiatric disorders of childhood. psychiatric symptoms, and hypoventilation in ovarian
Pediatrics 1994; 93:323–6. teratoma. Ann Neurol 2005; 58:594–604.
Symonds C. Recurrent multiple cranial nerve palsies. J Neurol Voltz R, Gultekin H, Rosenfeld MR et al. A serologic marker of
Neurosurg Psychiatry 1958; 21:95–100. paraneoplastic limbic and brain-stem encephalitis in patients
Tandon R, Walden M, Falcon S. Catatonia as a manifestation of with testicular cancer. N Engl J Med 1999; 340:1788–95.
paraneoplastic encephalopathy. J Clin Psychiatry 1988; Vrethem E, Ernerudh J, Lindstrom F et al. Immunoglobulins within
49:121–2. the central nervous system in primary Sjögren’s syndrome. J
Taranta A. Relation of isolated recurrences of Sydenham’s chorea Neurol Sci 1990; 100:186–92.
to preceding streptococcal infection. N Engl J Med 1959; Walker RH, Spiera H, Brin MF et al. Parkinsonism associated with
260:1204–10. Sjögren’s syndrome: three cases with a review of the
Taranta A, Stollerman GH. Relationship of Sydenham’s chorea to literature. Mov Disord 1999; 14:262–8.
infection with Group A streptococcus. Am J Med 1956; Weiner DK, Allen NB. Large vessel vasculitis of the central nervous
20:170–5. system in systemic lupus erythematosus: report and review of
Thayer WS. An analysis of 808 cases of chorea with special the literature. J Rheumatol 1991; 18:748–51.
reference to cardiovascular manifestations. J Am Med Assoc West SG, Emlen W, Wener MH et al. Neuropsychiatric lupus
1906; 47:1352–4. erythematosus: a 10-year prospective study on the value of
Thiele R. Clinical observations on chorea of pregnancy. Arch diagnostic tests. Am J Med 1995; 99:153–63.
Neurol Psychiatry 1935; 39:1077. Whitlock FA, Siskind MM. Depression as a major symptom of
Thompson AJ, Miller D, Youl B et al. Serial gadolinium-enhanced multiple sclerosis. J Neurol Neurosurg Psychiatry 1980;
MRI in relapsing/remitting multiple sclerosis of varying disease 43:861–5.
duration. Neurology 1992; 42:60–3. Wiederholt WC, Siekert RG. Neurological manifestations of
Thompson C, Checkley S. Short term memory deficit in a patient sarcoidosis. Neurology 1965; 15:1147–54.
with cerebral sarcoidosis. Br J Psychiatry 1981; 139:160–1. Wilcox JA, Nasrallah HA. Sydenham’s chorea and psychosis.
Thrush DC, Boddie HG. Episodic encephalopathy associated with Neuropsychobiology 1986; 15:13–14.
thyroid disorders. J Neurol Neurosurg Psychiatry 1974; Wilcox JA, Nasrallah HA. Sydenham’s chorea and
37:697–700. psychopathology. Neuropsychobiology 1988; 19:6–8.
Tourbah A, Piette JC, Iba-Zizen MT et al. The natural course of Willoughby EW, Growchowski E, Li DKB et al. Serial magnetic
cerebral lesions in Sneddon syndrome. Arch Neurol 1997; resonance scanning in multiple sclerosis. A second
54:53–60. retrospective study in relapsing patients. Ann Neurol 1989;
Tsokos GC, Tsokos M, LeRiche NGH et al. A clinical and 25:43–9.
pathological study of cerebrovascular disease in patients with Wilson P, Preece M. Chorea gravidarum. Arch Intern Med 1932a;
systemic lupus erythematosus. Semin Arthritis Rheum 1986; 49:471–533.
16:70–8. Wilson P, Preece M. Chorea gravidarum. Arch Intern Med 1932b;
Tsukamoto T, Mochizuki R, Mochizuki H et al. Paraneoplastic 49:671–97.
cerebellar degeneration and limbic encephalitis in a patient Wilson SAK. Neurology, 2nd edn. London: Butterworth & Co,
with adenocarcinoma of the colon. J Neurol Neurosurg 1954.
Psychiatry 1993; 56:713–16. Winnacker JL, Becker KL, Katz S. Endocrine aspects of sarcoidosis.
Van Bogaert L, Bertrand I. Hemorrhagic affection of cortico- N Engl J Med 1968; 278:483–92.
neostriatal site revealed clinically by acute and fatal chorea. J Winkelman NW, Eckel JL. The brain in acute rheumatic fever. Arch
Neurol Psychopathology 1932; 13:1–13. Neurol Psychiatry 1932; 28:844–70.
Venables PJW. Diagnosis and treatment of systemic lupus Wolf RE, McBeath JG. Chorea gravidarum in systemic lupus
erythematosus. BMJ 1993; 307:663–6. erythematosus. J Rheumatol 1985; 12:992–3.
Vernino S, Tuite P, Adler CH et al. Paraneoplastic chorea Wong KL, Woo EKW, Yu YL et al. Neurologic manifestations of
associated with CRMP-5 neuronal antibody and lung systemic lupus erythematosus. Q J Med 1991; 81:857–70.
carcinoma. Ann Neurol 2002; 51:625–30. Young AC, Saunders J, Ponsford JR. Mental change as an early
Vincent A, Buckley C, Schott JM et al. Potassium channel feature of multiple sclerosis. J Neurol Neurosurg Psychiatry
antibody-associated encephalopathy: a potentially 1976; 39:1008–13.
immunotherapy-responsive form of limbic encephalitis. Brain Ziegler LH. The neuropathological findings in a case of acute
2004; 127:701–12. Sydenham’s chorea. J Nerv Ment Dis 1927; 65:273–81.
p 18.qxd 3/10/08 9:52 AM Page 569
18
SLEEP DISORDERS
18.1 Somnambulism 569 18.10 Kleine–levin syndrome 579

18.2 REM sleep behavior disorder 570 18.11 Restless legs syndrome 581
18.3 Nightmare disorder 572 18.12 Periodic limb movements in sleep 582
18.4 Night terrors 572 18.13 Painful legs and moving toes 583
18.5 Nocturnal head banging 573 18.14 Circadian rhythm sleep disorder 584
18.6 Enuresis 574 18.15 Primary insomnia 585
18.7 Narcolepsy 575 18.16 Primary hypersomnia 587
18.8 Sleep apnea 577 References 587
18.9 Pickwickian syndrome (obesity–hypoventilation
syndrome) 579
18.1 SOMNAMBULISM Attempts to redirect patients or lead them back to bed

may or may not be met with success; some patients actively
Isolated episodes of sleepwalking are common in children, resist any attempts to interfere with them. If a patient is
occurring in about 15 percent (Kales et al. 1987). Recurrent, awakened, there is no dream recall. Most episodes end
frequent episodes, however, are not normal, and in these spontaneously within 15–30 minutes; some patients may
instances one speaks of somnambulism or, as it is also make it back to bed, whereas others will lie down on a
called, ‘sleepwalking disorder’. Somnambulism is not com- couch, or even the floor, and resume sleep. Upon awaken-
mon, being found in 2–3 percent of children and far fewer ing the next day, patients are either amnestic for the
adolescents or adults. episode or, at most, have only a patchy recall of the events
that transpired.
Childhood-onset cases are generally not associated with
Clinical features other neuropsychiatric disturbances; by contrast, some
(Kales et al. 1980a; Sours et al. 1963), but not all (Parkes
Somnambulism generally has an onset in children, some- 1986), authors have found an association between adult-
time between the ages of 3 and 6 years; onsets in adoles- onset cases and various forms of abnormal personality trait.
cence are uncommon, and in adult years are rare. Polysomnography reveals the onset of sleepwalking in
Sleepwalking arises from non-rapid eye movement stage IV or, at times, stage III sleep. If polysomnography is
(NREM) sleep, generally in the first third of the night (Kales required, it is useful to precede it with 38 hours of sleep
and Kales 1974; Kavey et al. 1990). Typically (Kales et al. deprivation, which greatly increases the chances of catching
1966), the patient sits up in bed; the eyes may be closed or an episode (Joncas et al. 2002). Importantly, there are no
open and, if open, the patient may look about the room with ictal discharges and no interictal epileptiform discharges.
a blank stare. Some patients merely engage in simple, stereo-
typed behavior, such as fumbling with pyjamas or sheets, but
most will get out of bed and begin to walk. Although some Course
patients may bump into furniture or walls, many are able to
navigate in such a way as to avoid obstacles. Some patients If the onset is in early childhood, a remission is likely by
may simply wander, whereas others may attempt to climb early adolescence (Kales et al. 1980a); later-onset cases,
out of windows or go down stairs. Rarely, patients may however, may persist into adult years. After a remission
engage in complex activities such as eating, writing, or even there may rarely be a recurrence of sleepwalking.
driving a car. Patients may be mute or mumble incoherently; Overall, the frequency of sleepwalking in somnambulism
some may respond to requests with a few simple words. is increased during febrile illnesses, with sleep disruption
p 18.qxd 3/10/08 9:52 AM Page 570
570 Sleep disorders
(as may be seen with shift work [Driver and Shapiro a dose of 10 mg nightly, to be effective in adults (Reid et al.
1993]), and, as noted above, with sleep deprivation. 1984). Anecdotally, clonazepam (Kavey et al. 1990) and
imipramine (Cooper 1987) were also effective.
Etiology
18.2 REM SLEEP BEHAVIOR DISORDER
Somnambulism probably occurs on a hereditary basis; it is
clearly familial (Kales et al. 1980b) and the concordance REM sleep behavior disorder is a remarkable condition in
rate is higher for monozygotic than for dizygotic twins which patients, while asleep and dreaming, literally ‘act out’
(Bakwin 1970; Hublin et al. 1997). their role in the dream, with the bedroom serving as the
‘stage’. Although in the general population this is a rare dis-
order, it is found in a significant minority of patients with
Differential diagnosis parkinsonian conditions and in these cases it is often the
presenting feature of the disease, preceding the parkinson-
At first glance, rapid eye movement (REM) sleep behavior ism by years. It is far more common in males than females.
disorder may appear quite similar to somnambulism; how-
ever, the differential is easily made by awakening the
patient and asking if he or she were dreaming during the Clinical features
episode. In REM sleep behavior disorder there is always a
dream present and the patient’s behavior during the episode The onset is generally in middle or later years, and episodes
is ‘explained’ by the dream content; by contrast, in som- occur with variable frequency, from multiple episodes
nambulism there is no associated dreaming. nightly to isolated episodes occurring every few months
Night terrors are distinguished from sleepwalking both (Olson et al. 2000).
by the extreme terror evident in the sleeping patient and by Schenck and colleagues have comprehensively described
the lack of any actual walking about. this condition (Schenck and Mahowald 1990; Schenck et al.
Sleep drunkenness may resemble sleepwalking; how- 1986, 1987, 1989). Episodes typically arise out of REM sleep,
ever, the episodes of sleep drunkenness are seen in the in the middle or last third of the night. Violent or poten-
morning as the patient struggles to awaken, in contrast to tially dangerous behavior is not at all uncommon, and
sleepwalking in which episodes occur in the early part of patients may suffer bruises, lacerations, or even fractures;
the night and are not associated with awakening. in one case (Dyken et al. 1995) a subdural hematoma was
Nocturnal complex seizures may be difficult to distin- sustained. Patients are generally difficult to awaken and, if
guish from episodes of sleepwalking (Pedley and they do come to full consciousness, they may relate a vivid
Guilleminault 1977). A history of complex partial or other dream that, in retrospect, clearly provides the context for
types of seizures during waking hours is helpful, but in lim- their behavior.
iting cases polysomnography may be required. Some examples will help to convey a sense of the
Various medications may cause sleepwalking, including remarkable phenomenology of this disorder. In one case
paroxetine (Kawashima and Yamada 2003), bupropion (Schenck et al. 1986) a 67-year-old man described his
(Khazaal et al. 2003), olanzapine (Kolivakis et al. 2001), dream and what he found when he woke up:
zolpidem (Harazin and Berigan 1999), and the combinations
of antipsychotics with lithium (Charney et al. 1979) and I was a halfback playing football, and after the
zolpidem with valproic acid (Sattar et al. 2003). Sleepwalking quarterback received the ball from the center he
may also occur during hyperthyroidism (Ajlouni et al. 2005). lateraled it sideways to me and I’m supposed to go
around end and cut back over tackle and – this is very
vivid – as I cut back over tackle there is this big 280-
Treatment pound tackle waiting, so I, according to football rules,
was to give him my shoulder and bounce him out of the
Patients and parents should be reassured regarding the essen- way, supposedly, and when I came to I was standing in
tially benign nature of somnambulism, and common sense front of our dresser and I had knocked lamps, mirrors,
precautions, such as locking windows or doors and removing and everything off the dresser, hit my head against the
potentially dangerous objects, should be taken to reduce the wall and my knee against the dresser.
risk of any injury. Should these measures fail, consideration
may be given to ‘anticipatory awakenings’ (Tobin 1993). Damage to property is not the only danger here: during
Here, one monitors the patient to determine when episodes one incident (Schenck et al. 1989), the patient ‘was awak-
are most likely to occur and then awakens the patient just ened one night by his wife’s yelling as he was choking her.
beforehand; in many cases this may provide lasting relief He was dreaming of breaking the neck of a deer he had just
after only a few nights. In limiting cases, medications may be knocked down’; during another (Culebras and Moore
utilized. The only blind study carried out found diazepam, in 1989), a 70-year-old man ‘dreamed that an alligator was
p 18.qxd 3/10/08 9:52 AM Page 571
18.2 REM sleep behavior disorder 571
trying to get into his car, and in order to prevent it, he held locus ceruleus and the substantia nigra (Turner et al.
the animal’s snout with great force . . .’ After finally being 2000). This, of course, is not unexpected; however, in cases
awakened by his wife calling him, he found himself ‘strongly in which REM sleep behavior disorder was the only mani-
grabbing her arm’. festation of Lewy body disease, this too was where the
Importantly, although the dream content, and resulting pathology was found (Uchiyama et al. 1995). Other inves-
behavior, are often aggressive, the waking behavior of these tigators, however, have cast doubt on this localization,
patients is not characterized by any increased aggressive- finding only minimal changes in these nuclei in a patient
ness (Fantini et al. 2005). with diffuse Lewy body disease who also had REM sleep
There may be an association between REM sleep behav- behavior disorder (Boeve et al. 2007).
ior disorder and other sleep disorders, including nar-
colepsy (Schenck and Mahowald 1992) and periodic leg
movements (Fantini et al. 2002). Differential diagnosis
Polysomnography is diagnostic and reveals REM sleep
during the episode, without, obviously, the expected atonia. Somnambulism is readily differentiated from REM sleep
behavior disorder by simply waking the patient during the
episode and asking about dreaming: somnambulists will
Course have no recall of any dreaming, whereas those with REM
sleep behavior disorder will recall the dream vividly. If
In the natural course of events, REM sleep behavior disor- there is any doubt, polysomnography will reveal episodes
der appears to be chronic. arising from NREM sleep in somnambulism and from
REM sleep in REM sleep behavior disorder.
Complex partial seizures arising from sleep may likewise
Etiology be distinguished from REM sleep behavior disorder by ask-
ing about dreaming, which is absent in the patient having a
REM sleep behavior disorder most commonly occurs either seizure. Furthermore, one typically also finds a history of
on an idiopathic basis or secondary to certain parkinsonian other types of seizures, such as grand mal seizures, or of
conditions; other rare causes are noted below. seizures during the day. In doubtful cases, polysomnography
Idiopathic REM sleep behavior is diagnosed when the may reveal ictal activity during the episode. Importantly,
disorder occurs in an isolated fashion. This diagnosis, how- not too much weight should be placed on finding interictal
ever, must be tentative, given that a large percentage of epileptiform discharges, as these are not uncommon inci-
these patients will eventually develop a parkinsonian con- dental findings in elderly patients with REM sleep behavior
dition. For example, diffuse Lewy body disease may follow disorder (Manni et al. 2006).
6–8 years later, and Parkinson’s disease some 3–5 years Obstructive sleep apnea may at times enter into the dif-
later (Schenck et al. 1996a; Tan et al. 1996). Indeed, in one ferential. In some cases of obstructive sleep apnea, patients,
autopsied case, REM sleep behavior disorder was the only during arousals from an apneic episode, may appear con-
manifestation of diffuse Lewy body disease (Uchiyama et al. fused and engage in complex activity (Iranzo and
1995). Santamaria 2005). Polysomnography may be required here
Parkinsonian conditions capable of causing REM sleep and reveals that these episodes do not arise from REM sleep.
behavior disorder include diffuse Lewy body disease
(Boeve et al. 2003a), Parkinson’s disease (Olson et al.
2000), and the striatonigral variant of multiple system Treatment
atrophy (Boeve et al. 2003a; Plazzi et al. 1997).
Rare causes of REM sleep behavior disorder include Although there are no blind studies of the treatment of
Alzheimer’s disease (Schenck et al. 1996b), spinocerebellar REM sleep behavior disorder, clonazepam (Schenck and
ataxia type 3 (Iranzo et al. 2003), limbic encephalitis with Mahowald 1990), in doses ranging from 0.5 to 2 mg
anti-voltage-gated potassium channel antibodies (Iranzo nightly, has become the accepted first-line treatment.
et al. 2006), and certain focal lesions. Focal lesions capable Melatonin, in doses ranging from 3 to 12 mg, constitutes
of causing REM sleep behavior disorder have all been an acceptable alternative (Boeve et al. 2003b), and in my
found in the pontine tegmentum, and include paramedian opinion should in fact be tried first as it does not carry with
infarction (Kimura et al. 2000), plaques of multiple sclero- it any risk of falls. In cases in which both of these agents are
sis (Plazzi and Montagna 2002; Tippmann-Peikert et al. either ineffective or not well tolerated, consideration may
2006), and peritumoral edema (Zambelis et al. 2002). be given to pramipexole (found to be effective in one
Although the precise structures involved in the genesis report [Schmidt et al. 2006] but only minimally so in
of REM sleep behavior disorder are not known, attention another [Fantini et al. 2003]) or donepezil (Ringman and
has been focused on certain brainstem nuclei. In cases Simmons 2000). Certain medications should probably be
occurring secondary to diffuse Lewy body disease, neu- avoided as they may aggravate the condition, including
ronal loss and Lewy bodies have been noted in both the selegiline (Louden et al. 1995) and mirtazapine (Onofrj et al.
p 18.qxd 3/10/08 9:52 AM Page 572
572 Sleep disorders
2003). Pending effective treatment, the bedroom should be are not associated with any movement, arise from REM
made as safe as possible. sleep in the last two-thirds of the night, and are clearly and
readily recalled.
Nocturnal panic attacks are easily distinguished from
18.3 NIGHTMARE DISORDER nightmares in that the panic attacks are not associated with
frightening dreams; although patients with nocturnal
Occasional nightmares, occurring at a frequency of no panic attacks awaken into panic, they do not awaken out of
more than once every few weeks, are not abnormal. When a frightening dream.
nightmares occur frequently, however, on at least a weekly Nightmares are very common in post-traumatic stress
basis, one may speak of ‘nightmare disorder’. disorder and may also be seen during a depressive episode
of a major depressive disorder or bipolar disorder, in the
course of schizophrenia, or during delirium of any cause.
Clinical features Various medications may cause nightmares, including tri-
cyclic antidepressants, selective serotonin reuptake inhibitors
The nightmares of nightmare disorder typically first appear (SSRIs), antipsychotics, levodopa, and beta-blockers.
in childhood or adolescence, often after an emotionally Nightmares may also occur during the ‘REM rebound’ seen
troubling event. during withdrawal from sedative–hypnotics or alcohol.
During a nightmare (Kales et al. 1980c), patients typically Very rarely, nightmares may constitute the only symp-
lie quite still; rarely is there much movement at all, and one tomatology of a seizure (Boller et al. 1975). Clues to this
never sees any thrashing about or complex behavior. During would be a history of other seizure types and a lack of any
the nightmare, patients may be chased, attacked, tortured, other reasonable explanation. Polysomnography may not
or preyed upon by any number of unspeakable apparitions. be helpful here, as ictal electroencephalograms (EEGs)
Typically, as the fear crescendos, patients awaken with a cry during simple partial seizures are typically normal. In
of fright and are shaky, mildly diaphoretic, and tachycardic. doubtful cases one may consider attempting a ‘diagnosis
Within moments, full alertness and orientation are by treatment response’ to an anti-epileptic drug.
achieved, and patients are then able to provide a vivid and
emotional recount of the frightening dream. Although some
are able to go directly back to sleep, most, fearful of another Treatment
nightmare, have some difficulty in this regard and may lie
awake for a half-hour or more. Avoidance of fatigue, frightening stories or shows, and,
Nightmares arise from REM sleep, typically in the mid- whenever possible, emotional stress, along with prompt
dle and last thirds of the night. treatment of any febrile illness, are all in order.
Behavioral treatments, such as densensitization or
dream rehearsal, appear to be effective (Kellner et al. 1992;
Course Neidhardt et al. 1992). When such treatment is not feasible
or is ineffective, one may consider suppressing REM sleep
As noted above, the nightmares in nightmare disorder
with a benzodiazepine, such as diazepam, or using cypro-
occur at least on a weekly basis and in some cases may
heptadine in a dose of 16–24 mg h.s. (Harsch 1986). Con-
occur multiple times a night. Fever, fatigue, emotional
sideration may also be given to prazosin, which is effective
stress, and watching frightening shows before bed may all
in the treatment of nightmares seen in post-traumatic
aggravate this condition. Although in most cases the disor-
stress disorder.
der eventually remits, in a minority it may be lifelong.
Etiology 18.4 NIGHT TERRORS
Apart from a suggestion that frequent nightmares may be Night terrors, also known as sleep terrors, sleep terror dis-
inherited (Hublin et al. 1999), little is known about the eti- order, or pavor nocturnus, occurs in 1–4 percent of chil-
ology of nightmare disorder. dren and is somewhat more common in boys than girls.
Night terrors may be distinguished from nightmares in The onset is generally in childhood, between the ages of
that night terrors are associated with overt signs of fright 4 and 12 years; rarely the onset may be delayed until early
while the patient is asleep (e.g., crying out), arise from adult years.
NREM sleep in the first third of the night, and are not asso- Attacks (Fisher et al. 1973a; Kales and Kales 1974) arise
ciated with any clear dream recall; by contrast, nightmares from stage III or IV NREM sleep in the first third of the
p 18.qxd 3/10/08 9:52 AM Page 573
18.5 Nocturnal head banging 573
night, typically before the first episode of REM sleep. may have only nocturnal attacks (Mellman and Uhde
Patients typically scream or cry out in terror, sit bolt 1990). Polysomnography is not very helpful in this differ-
upright, and appear dazed; the heart rate is increased, ential, given that nocturnal panic attacks arise from NREM
sometimes greatly so, and respiration is rapid and panting. sleep (Mellman and Uhde 1989b), just as night terrors do.
The sheets may be grasped and patients may cry out for Nocturnal complex partial seizures may closely resemble
help. Attempts to awaken the child are generally unsuc- night terrors. In one case (Tinuper et al. 1990), a teenager
cessful, and the episode generally runs its course in a mat- had nocturnal seizures characterized by ‘episodes of sudden
ter of minutes. Afterwards, patients may simply fall back arousal, screaming, grimacing, and violent, repetitive
into sleep or they may awaken; those who do awaken, movements of the trunk and all four limbs’ lasting for 5–10
although recalling the sense of terror, find either no mem- minutes. The occurrence of seizures during waking hours,
ory of a dream or merely fragments of one. Remarkably, in or a family history of epilepsy, is an important clue. In
contrast to their parents, who are generally quite shaken at doubtful cases, polysomnography will be required.
witnessing the episode, the children themselves are gener- Finally, there is a case report of adult-onset night terrors
ally able to fall back to sleep without any difficulty. occurring secondary to a thalamic tumor (Di Gennaro et al.
Otherwise typical attacks may rarely occur during day- 2004).
time naps, thus constituting a ‘pavor diurnus’.
Treatment
Course
Parents should be reassured regarding the benign nature of
The frequency of attacks varies widely, from daily or weekly night terrors, and, in most cases, as the episodes do not
attacks to widely-spaced attacks occurring at monthly or appear to bother patients much, this is all that is required.
longer intervals; in most cases attacks eventually cease, gen- Should suppression of the episodes be necessary, open
erally after about 4 years or so; uncommonly they may per- studies and case reports suggest effectiveness for diazepam
sist into adolescence or even adult years (DiMario and (2.5–106 mg) (Fisher et al. 1973b), imipramine (25–506 mg)
Emery 1987). Anxiety, stress, fatigue, and irregular sleep (Burstein et al. 1983; Cooper 1987), paroxetine (Wilson
habits may all increase the frequency of attacks. et al. 1997), and trazodone (Balon 1994).
Etiology 18.5 NOCTURNAL HEAD BANGING
Apart from the fact that sleep terrors are familial (Kales et al. Nocturnal head banging, also known as jactatio nocturna
1980b), little is known of their etiology. capitis, is characterized by repetitive head banging or
bumping during the transition into sleep. This is a com-
mon disorder in infants, seen in about 15 percent.
Clinical features
Nightmares are quite different from night terrors. Nightmare
sufferers typically have a vivid recall of the nightmare and
Head banging usually begins around the age of 9 months
are reluctant to go back to sleep for fear of having another
and typically occurs during stage I or II of sleep; the head
one; in contrast, patients with night terrors have little or no
movements are rhythmic, occurring several times a minute,
recall of any dream and, if awakened, can fall back asleep
with the head repeatedly making contact with the bed,
with little anxiety. Furthermore, nightmares arise from
bedrails, or headboard (Kravitz et al. 1960). The contact
REM sleep in the middle or last third of the night, whereas
itself is generally not very forceful, and injuries are rare.
night terrors arise from NREM sleep in the first third of the
night.
Nocturnal panic attacks are often included on the dif- Course
ferential, but these are also quite different from night ter-
rors. In nocturnal panic attacks, patients awaken from The vast majority of cases resolve by the age of 4 years; per-
sleep into the panic attack and are awake and alert during sistence into adolescence (Hashizume et al. 2002) or adult
the attack, with a full recall of it afterward. By contrast, years (Chisolm and Morehouse 1996; Whyte et al. 1991) is
patients with night terrors stay asleep during the attack and very rare.
have little, if any, recall of it if they can be awakened. Most
patients with nocturnal panic attacks will also have typical
attacks during waking hours (Mellman and Uhde 1989a), Etiology
and this history, of course, is very helpful; exceptions do
occur, however, and some patients with panic disorder The etiology is not known.
p 18.qxd 3/10/08 9:52 AM Page 574
574 Sleep disorders
Differential diagnosis years the figure drops to 1 percent (Forsythe and Redmond
1974; Forsythe and Butler 1989). The course of secondary
Nocturnal head banging must be distinguished from head enuresis is determined by the underlying cause.
banging seen during wakefulness, as may occur in mental
retardation, autism, and schizophrenia. There is also a case
report of acquired nocturnal head banging occurring after
Etiology
traumatic brain injury (Drake 1986).
In about two-thirds of cases primary enuresis is inherited
on an autosomal dominant basis (von Gontard et al. 2001).
Treatment Although it is not exactly clear what is inherited, several
mechanisms have been proposed, including delays in the
In most cases treatment is not required. Anecdotally, normal neuromuscular maturation that allows for conti-
behavior therapy and nightly clonazepam (0.5–26 mg) or nence, a smaller than normal bladder capacity, or either a
imipramine (10–25 mg) are effective. reduced secretion of vasopressin or a decreased sensitivity
of renal tubule cells to vasopressin. There is no evidence for
any association with personality variables or particular
methods of toilet training.
18.6 ENURESIS
Secondary enuresis may be seen in diabetes mellitus,
diabetes insipidus, urinary tract infections, cystic
In the normal course of events, 90 percent or more of chil-
medullary disease, sickle cell disease, bladder or urethral
dren become dry during the night by the age of 5 or 6 years.
obstructions, spastic bladder (as in cerebral palsy), com-
Persistent, recurring bedwetting past this age is considered
pression of the bladder by pelvic masses or impacted stool,
abnormal and is termed enuresis (Forsythe and Redmond
treatment with sedating drugs, clozapine or SSRIs,
1974) or, more precisely, nocturnal enuresis. Enuresis is
obstructive sleep apnea, and nocturnal seizures.
nearly twice as common in males as females.
The vast majority of cases of enuresis occur on an idio-
pathic or primary basis; secondary causes of enuresis, such Differential diagnosis
as diabetes mellitus, are relatively uncommon.
In mental retardation of moderate or greater degree, a
developmental age of 4 or more years may simply never be
Clinical features attained and, hence, in the normal course of events noctur-
nal continence does not occur.
The achievement of nocturnal continence of urine is a nor- Some authors include awake wetting in children over
mal developmental event, and, in most cases of primary the age of 5 or 6 years under the rubric of enuresis; how-
enuresis, this developmental milestone is simply never ever, this may not be appropriate as in these cases the wet-
attained at the expected age. In a minority of cases of pri- ting is usually intentional or secondary to a resistance on
mary enuresis, however, continence is attained and main- the child’s part to make the trip to the bathroom, as may be
tained, sometimes for long periods up to a year, after which seen in young children who are reluctant to leave their
it is lost. Secondary enuresis may have an onset at any time, friends in the playground and simply cannot ‘hold it’.
from middle childhood to adult years, depending on the
underlying cause.
In primary enuresis bedwetting typically occurs in the Treatment
first half of the night. Children may or may not awaken
during the bedwetting; if they do, it is always after urina- Primary enuresis may respond to a number of different
tion has begun. Although wetting tends to be more com- treatments. Behavioral treatments should probably be
mon in NREM sleep and is generally not associated with tried first. Caffeinated beverages are eliminated and, except
dreaming, (Pierce et al. 1961), it may occur during REM for ice chips for thirst or small sips of water for toothbrush-
sleep (Mikkelsen et al. 1980; Neveus et al. 1999). ing, fluids are withheld for the 3 hours leading up to bed-
In primary enuresis there are no associated symptoms. time, and the bladder is emptied just before going to bed. If
In secondary enuresis, however, one may find polyuria, the child remains dry through the night, a reward, perhaps
dribbling, or dysuria, depending on the underlying cause. a ‘gold star’ or a small present, is given the next morning. If
bedwetting does occur the child should strip the bed but
parents should take care of cleaning the sheets and bed and
Course there should be no punishment. Many children respond
favorably to this program in about a month. If it is unsuc-
In the natural course of events, primary enuresis typically cessful, it should be supplemented with an ‘enuresis alarm’
undergoes a spontaneous remission: by the age of 12 years, (Forsythe and Butler 1989). Use of these alarms, which are
only 3 percent of children are still bedwetting, and by adult inexpensive devices triggered by minute amounts of urine,
p 18.qxd 3/10/08 9:52 AM Page 575
18.7 Narcolepsy 575
is generally followed by gradual improvement over weeks otherwise lively and engaging conversations at the dinner
or months. Once dryness has been maintained for a month, table. Undisturbed, patients may sleep for minutes or even
the program and, if utilized, the alarm, may be discontin- up to half an hour, after which they awaken, feeling more
ued; should a relapse occur, a repeat course may be given. or less refreshed. Importantly, waking patients from a nar-
If behavioral measures fail, medications may be consid- coleptic attack is not at all difficult and may be accom-
ered; of the various medications shown to be effective in plished by a light touch or simply by calling the patient’s
double-blind trials, imipramine and desmopressin are name. Distinctively, the narcoleptic attack itself consists of
both considered first-line treatments. Overall, imipramine REM sleep (Dement et al. 1964, 1966; Hishikawa and
takes longer to work and tends to cause more side-effects; Kaneko 1965; Hishikawa et al. 1968), and most patients
desmopressin, although easier to use, is not without liabil- will be able to recall dreams upon awakening. Narcoleptic
ities, however, in that it carries a small risk of hypo- attacks are most frequent in the afternoon or evening and
natremia, with delirium or seizures (Dehoorne et al. 2006; may recur anywhere from once to dozens of times per day.
Odeh and Oliven 2001). Imipramine may be started at a Nocturnal sleep is often broken and some patients may
dose of approximately 1 mg/kg and increased in 0.5 mg/kg complain of insomnia; indeed, for most patients, the total
increments every 2 weeks until control is established, lim- 24-hour sleep time is actually not increased.
iting side-effects occur, or a maximum dose of about Cataplectic attacks tend to begin several years after the
2.5 mg/kg is reached (Fritz et al. 1994). Desmopressin is narcoleptic attacks make their appearance and may be
given orally at bedtime in a dose of 0.2–0.6 mg (Schulman either generalized or focal. Typically, the cataplectic attack
et al. 2001). Once continence has been achieved with either is precipitated by some strong emotion, such as laughter,
imipramine or desmopressin, treatment should be contin- fear, anger, or a sudden surprise. In the generalized form,
ued until continence has been maintained for anywhere all voluntary muscle power, except for that of the
from 1 to 3 months, after which the medication may be diaphragm and, at times, the extraocular muscles, is
tapered over the following 3 months; relapses may be treated diminished or lost, and the head droops forward, the jaw
with reinstitution of the previously effective regimen. sags, the knees buckle, and patients may sink and collapse
Treatment of secondary enuresis is directed at the to the floor. In the focal type, the sudden muscle weakness
underlying cause. is confined to one part, for example the neck musculature,
with consequent head droop, the forearm and hand mus-
culature, with items being dropped, or the extraocular
18.7 NARCOLEPSY muscles, with diplopia. Most attacks last for about a
minute. During the attack, patients, even if fully paralyzed,
Narcolepsy is characterized by narcoleptic attacks and, in remain conscious and alert, and are able, upon recovery, to
most case, cataplexy; sleep paralysis and either hypnagogic give a full description of the event. In some cases, cata-
or hypnopompic hallucinations may also occur in a minor- plectic attacks may be prolonged, lasting 5 minutes or more,
ity. In addition to this classic tetrad, a minority of patients and during such lengthy attacks, patients may experience
will also experience episodes of ‘automatic behavior’. vivid visual hallucinations. Very prolonged attacks, lasting
Narcolepsy occurs in 0.025–0.05 percent of the general 20 minutes or more, are referred to as ‘status cataplecticus’,
population and is equally common in males and females. and these may be precipitated by the sudden discontinua-
tion of certain medications, such as fluoxetine (Poryazova
et al. 2005). The frequency with which cataplexy occurs
Clinical features varies widely, from a mere handful of attacks through the
patient’s lifetime to multiple attacks daily.
The basic clinical features of narcolepsy have been Sleep paralysis may occur upon either falling asleep or
described in a number of reports (Adie 1926; Kales et al. awakening. Although fully conscious, patients find them-
1982; Parkes et al. 1975; Wilson 1928). Of the classic tetrad selves unable to move. Most attacks last only a minute or so,
of symptoms, narcoleptic attacks occur in all patients, cat- and some may be accompanied by visual hallucinations.
aplexy in about three-quarters, sleep paralysis in one-third, Importantly, although patients appear to the observer to be
and hypnagogic or hypnopompic hallucinations in about sound asleep, they may nevertheless be easily awakened by
one-third; only about 1 in 10 patients experience the full simply calling their names or lightly touching them.
tetrad. In over 90 percent of cases, the first manifestation of Hypnagogic hallucinations appear upon falling asleep,
the illness is a narcoleptic attack and, although this may being generally visual and quite vivid and complex, as if the
appear anywhere from childhood to the middle years, most patient were dreaming while still awake. Hypnopompic hal-
patients fall ill in their late teens or early adult years. lucinations are quite similar and appear upon awakening.
Narcoleptic attacks are ushered in by an overwhelming In addition to the classic tetrad just described, perhaps
and irresistible desire to sleep; although such attacks are one-third or so of patients will also experience episodes of
most likely to occur in situations conducive to drowsiness, ‘automatic behavior’. During these episodes, patients
such as long-distance driving or sitting through a boring appear to be half-asleep and, although they may continue
lecture or meeting, they can occur at any time, even during to engage in complex behavior, such as driving a car, there
p 18.qxd 3/10/08 9:52 AM Page 576
576 Sleep disorders
is generally a decrement in the quality of behavior: if writ- Mendelian inheritance in the remaining vast majority of
ing, patients may write a gibberish scrawl, and, if speaking, cases. Recent work has focused on the possibility that these
they may engage in incoherent muttering. Importantly, hypocretin-containing neurons may be lost on an autoim-
upon coming to full alertness, these patients generally have mune basis, and it is felt that such an autoimmune attack
no recall of what they did during the event; thus, a patient may be triggered by some, as yet unknown, environmental
who drove automatically may, upon ‘coming to’, have no trigger in genetically susceptible patients; to date, however,
idea of how many exits were passed. autoantibodies have not been detected. With this theory in
Furthermore, a small minority of patients with nar- mind, some patients have been openly treated with intra-
colepsy will also have other sleep disorders, including perivenous immunoglobulins, and in such cases a reduction in
odic limb movements of sleep, sleep apnea, and REM sleep the frequency of cataplexy was reported (Dauvilliers 2006).
behavior disorder.
The clinical diagnosis of narcolepsy may be confirmed
with the multiple sleep latency test (MSLT). In narcolepsy, Differential diagnosis
REM sleep occurs soon after sleep onset (Rechtschaffen
et al. 1963), and the MSLT is designed to capture this. The The combination of narcolepsy and cataplexy is virtually
results, however, must be interpreted in light of the overall pathognomonic for narcolepsy. As noted earlier, however,
clinical picture, as false negatives may occur. False positives in most patients the illness begins with narcolepsy alone
may also be found in various conditions, including psy- and, consequently, early in the course of the disease, when
chomotorically retarded, hypersomnic depressions, sleep only narcoleptic attacks are present, other causes of ‘exces-
apnea, and alcohol or sedative/hypnotic withdrawal. sive daytime sleepiness’ must be considered, including,
Some clinicians will also test patients to see if they are especially, sleep apnea, the Pickwickian syndrome, peri-
positive for the HLA-DQB1*0602 haplotype. This haplo- odic leg movements of sleep, restless legs syndrome, the
type is found in about 20 percent of the general population Kleine–Levin syndrome, psychomotorically retarded
but in almost all patients with narcolepsy; consequently, depressions, and alcohol or sedative–hypnotic withdrawal.
whereas a negative test for this haplotype argues against the All of these other disorders have distinctive features, as
diagnosis, a positive test is of little diagnostic value. described in the respective sections, and the sleepiness seen
in them rarely occurs as discrete attacks.
True sleep attacks may be seen as a side-effect of direct
Course dopamine agonists, such as bromocriptine, pergolide,
pramipexole, and ropinirole (Ferreira et al. 2000; Frucht et al.
Although in a small minority there may be temporary 1999; Hauser et al. 2000), and secondary to various hypo-
remissions and, rarely, permanent remissions, for the vast thalamic lesions, including tumors (Aldrich and Naylor
majority of patients narcolepsy is a chronic, lifelong disease. 1989), sarcoid granulomas (Aldrich and Naylor 1989), and
infarction (Scammell et al. 2001). The combination of
sleep attacks and cataplexy has been reported secondary to
Etiology hypothalamic irradiation (Dempsey et al. 2003), lesions in
the upper brainstem or floor of the third ventricle (Clavelou
The various clinical features of narcolepsy each seem to et al. 1995), and brainstem gliomas (Stahl et al. 1980), as a
represent an ‘intrusion’ of REM sleep into waking life. The symptom of limbic encephalitis (Rosenfeld et al. 2001), and
narcoleptic attack itself appears to be nothing but an as a sequela to traumatic brain injury (Lankford et al. 1994)
episode of REM sleep, and the other features appear to rep- and encephalitis lethargica (Adie 1926; Fournier and
resent a fragment of REM sleep, namely atonia, with or Helguera 1934).
without associated dream imagery. Consequently, research
has focused on those structures involved in sleep, namely
the hypothalamus and various brainstem nuclei. Treatment
Neuropathologic studies have demonstrated a loss of
hyocretin-containing neurons in the lateral hypothalamus Activities such as driving or operating hazardous machin-
(Blouin et al. 2005; Crocker et al. 2005), and cerebrospinal ery should be prohibited until narcoleptic and cataplectic
fluid (CSF) studies have shown low hypocretin levels in attacks have been brought under control.
almost all patients (Ebrahim et al. 2003; Mignot et al. Narcoleptic attacks may be partially eliminated by brief
2002). The mechanism underlying these changes, however, scheduled naps (Roehrs et al. 1986; Rogers et al. 2001),
is not clear. Although the prevalence of narcolepsy is judiciously spread out during the day. In most cases, how-
increased among family members of patients with nar- ever, pharmacologic treatment is required, and this gener-
colepsy, it still remains low, at approximately 5 percent ally involves the use of modafinil or methylphenidate.
(Guilleminault et al. 1989), and although there has been Modafinil is currently preferred and may be started at a
one atypical case associated with a mutation in the gene for dose of 200 mg once daily in the morning; in some cases, a
hypocretin (Peyron et al. 2000), there is no evidence for total of 400 mg may be required (Broughton et al. 1997; US
p 18.qxd 3/10/08 9:52 AM Page 577
18.8 Sleep apnea 577
Modafinil in Narcolepsy Multicenter Study Group 1998, of the preceding two types: initially one sees a lack of inspi-
2000), generally divided into a morning and early afternoon ratory effort, as in the central type; this is soon followed by
dose (Schwartz et al. 2005a). Methylphenidate (Mitler et al. inspiratory effort of the diaphragmatic and intercostal
1986a) may be used as a second-line agent and is given in a musculature, which, due to oropharyngeal obstruction, is
total daily dose of 20–60 mg, equally divided into a morning not followed by inspiration.
and early afternoon schedule. Tolerance to methylphenidate Of these three types, obstructive sleep apnea is the most
may occur, and in these cases the drug should be gradually common, followed by the mixed type; pure central types
tapered over a few days followed by a ‘drug holiday’ for are relatively rare.
another day or two, after which it may be gradually Sleep apnea is a common disorder, found in anywhere
restarted, with a resumption of effect. Importantly, neither from 2 to 4 percent of the adult population over 40 years; it
modafinil nor methylphenidate are effective against cata- is at least twice as common in males as in females.
plexy. Alternatives to modafinil or methylphenidate include
selegiline (in a dose of 20–40 mg) (Hublin et al. 1994; Mayer
et al. 1995) and sodium oxybate (Black and Houghton Clinical features
2006).
Cataplectic attacks may be prevented by selegiline Although sleep apnea can occur at any age, it generally
(Hublin et al. 1994) and by sodium oxybate (Black and appears in middle years.
Houghton 2006). Open studies or case reports also suggest Apneic episodes last anywhere from 10 seconds up to 2
usefulness for clomipramine (Schacter and Parkes 1980), minutes, and may occur anywhere from 30 to several hun-
fluvoxamine (Schacter and Parkes 1980), fluoxetine (Frey dred times a night. In addition to episodes of complete
and Darbonne 1994), citalopram (Thirumalai and Shubin apnea, patients will often also have hypopneic episodes, in
2000), escitalopram (Sonka et al. 2006), and venlafaxine which, although some inspiration occurs, it is at least 50
(Guilleminault et al. 2000). percent less than that seen with a normal breath. The sever-
Overall, the vast majority of patients are treated with ity of sleep apnea is often quantified by the ‘apnea index’ or
either modafinil or methylphenidate. When cataplexy the ‘apnea–hypopnea index’, which is equal to either the
requires treatment it would appear logical to add either total number of apneic episodes per night or the total
selegiline or sodium oxybate, given that they have ‘double- number of apneic plus hypopneic episodes per night
blind support’; however, in practice, these are not often divided by the number of hours spent in sleep. At a mini-
used. Selegiline, in the doses required, is no longer a selec- mum, one wishes to see an apnea index of greater than 5 or
tive monoamine oxidase B (MAO-B) inhibitor, and hence an apnea–hypopnea index greater than 10.
the low tyramine diet is required, making this problematic. In obstructive sleep apnea episodes (Strollo and Rogers
Sodium oxybate has high abuse potential and must be 1996; Whyte et al. 1989), the patient, often an obese, mid-
taken in the middle of the night, and is rarely used. In prac- dle-aged man, presents with a chief complaint of daytime
tice, when cataplexy does require treatment, most patients sleepiness, which may or may not be accompanied by com-
seem to do quite well on one of the antidepressants, such as plaints of broken sleep. Almost universal is a history of fre-
escitalopram or venlafaxine. quent loud snoring, which may have prompted equally
loud complaints from the patient’s bed partner. Upon
observing these patients while they sleep, for example
18.8 SLEEP APNEA while making rounds early in the morning, one may see a
characteristic episode: oral and nasal airflow ceases despite
Sleep apnea, sometimes also referred to as ‘breathing- increasingly vigorous diaphragmatic and intercostal mus-
related sleep disorder’, may manifest in one of three differ- cular activity, until finally the obstruction resolves with a
ent types, namely obstructive, central, and mixed. The loud, gasping snort, at which point the patient may or may
common denominator in all of these types is the appear- not awaken; should awakening occur it lasts only seconds,
ance of frequent apneic episodes during sleep, and com- after which sleep once again occurs.
plaints of either daytime sleepiness or, less commonly, In central sleep apnea, patients tend to complain of
insomnia. Cognitive deficits (including delirium and insomnia and restless sleep, and there may or may not be any
dementia) and depression are also common. daytime drowsiness. As snoring is typically absent, there may
During episodes of obstructive sleep apnea the oropha- be no complaints from the patient’s bed partner, who may be
ryngeal airway closes and, despite ongoing vigorous inspi- unaware of the problem. The typical episode of central sleep
ratory efforts of the diaphragmatic and intercostal apnea is far less dramatic than an obstructive one, as patients
musculature, air flow at the mouth and nares ceases. By con- with central sleep apnea simply stop breathing: the chest and
trast, in central sleep apnea, cessation of air flow occurs not diaphragm are relaxed and there is no airflow. Eventually,
because of any obstruction but because of a lack of inspira- inspiratory effort occurs with easy inspiration, and, at this
tory effort due to inappropriate relaxation of the diaphrag- point, the patient often has a transient awakening.
matic and intercostal musculature. In the mixed type of Mixed apneic episodes pursue a biphasic course. After
sleep apnea, there is, as the name suggests, a combination an initial period of central apnea an inspiratory effort
p 18.qxd 3/10/08 9:52 AM Page 578
578 Sleep disorders
begins but is met by oropharyngeal obstruction, causing a (in which the tongue falls back to occlude the airway); lin-
period of obstructive apnea. Clinically, these patients resem- gual hypertrophy (as may be seen in hypothyroidism,
ble more the obstructive than the central type, and one often acromegaly, or Down’s syndrome); and, most commonly,
hears complaints of snoring and daytime sleepiness. obesity. Occasionally, no obvious cause is found for the
In addition to complaints of daytime sleepiness or obstruction, and in such cases it is suspected that there is a
insomnia, patients with sleep apnea typically also experience failure of the brainstem mechanisms responsible for main-
a dry mouth and a dull headache in the morning. There may taining the patency of the airway during sleep.
also be sleep drunkenness, in which patients experience a Central episodes are seen in association with obesity
brief period of confusion as they struggle to awaken in the and congestive heart failure and may also occur in multiple
morning. Enuresis may occur (Kramer et al. 1998) and erec- system atrophy and with medullary lesions, for example
tile dysfunction is common (Goncalves et al. 2005). infarctions, tumors, multiple sclerosis, or syringobulbia.
Cognitive deficits are common. There may be difficulty
with concentration and patients may complain of feeling
‘fuzzy’ or ‘wooden-headed’ during the day; there may also Differential diagnosis
be minor deficits in short-term memory and difficulty in
making decisions. Mechanical ability is impaired, and traf- The Pickwickian syndrome may resemble obstructive sleep
fic accidents are more frequent in patients with obstructive apnea in that most Pickwickian patients are middle-aged
sleep apnea than in the general public (George et al. 1987). or older obese men with a history of excessive daytime
In an uncertain percentage of patients, delirium may occur sleepiness. Waking blood gases, however, tell the tale, as
(Dyken et al. 2004; Lee 1998; Munoz et al. 1998; Sandberg they reveal hypercarbia in the Pickwickian syndrome but
et al. 2001; Whitney and Gannon 1996); in my experience are normal in patients with obstructive sleep apnea while
this has not been at all uncommon. Rarely, rather than they are awake. It must be borne in mind, however, that
delirium there may be a dementia (Scheltens et al. 1991; these two syndromes often co-exist.
Steiner et al. 1999). Narcolepsy is distinguished by the fact that in this con-
Depressive symptoms are also common (Millman et al. dition daytime sleepiness comes in discrete attacks, in
1989; Schwartz et al. 2005b), with indecisiveness, low self- contrast to the chronic, waxing and waning sleepiness seen
esteem, helplessness, tearfulness, and, in some cases, suici- in obstructive sleep apnea.
dal ideation.
During episodes of sleep apnea, hypercapnia and
hypoxia occur, and cyanosis may be seen. With frequent Treatment
episodes of hypercapnia, pulmonary hypertension may
occur, leading to cor pulmonale. Systemic hypertension is In obstructive sleep apnea, correction of the underlying
common. Arrhythmias may occur during episodes, includ- cause, such as obesity (Smith et al. 1985), may be followed
ing sinus bradycardia, sinus tachycardia, sinus arrest, atrial by significant relief. In very mild cases, some relief may also
flutter, premature ventricular contractions, and ventricu- be gained by having patients sleep on their sides, a position
lar tachycardia. that favors airway patency (Cartwright et al. 1985, 1991).
Sleep apnea may also aggravate epilepsy (Malow et al. Mild cases may also be treated with either protriptyline,
2000) and increase the risk of stroke and death (Yaggi et al. 10–20 mg at bedtime (Brownell et al. 1982), or paroxetine,
2005). 20 mg at bedtime (Kraiczi et al. 1999). In most cases, how-
Polysomnography should be considered in all cases of ever, a continuous positive airway pressure (CPAP) or
suspected sleep apnea, not only to document its presence bi-level positive airway pressure (BIPAP) device is required,
and the type of sleep apneic episodes but also to determine and the relief gained with these devices may be pronounced:
the presence of arrhythmias. Often, overnight oximetry is not only daytime sleepiness but also cognitive difficulties
performed as a screening test; however, this does not (including delirium or dementia), depression, erectile dys-
appear to be as sensitive as polysomnography. function, and enuresis are all improved or cleared. In those
who cannot tolerate one of these devices, or in those in
whom they are ineffective, the use of orthodontic devices or
Course surgery may be contemplated. Orthodontic devices serve to
keep the jaw advanced, thus preventing the tongue from
Sleep apnea is chronic. occluding the airway. Surgical options include uvulo-
palatopharyngoplasty or uvuloplasty, and, in severe and
limiting cases, tracheostomy. Another option in cases in
Etiology which the devices are not tolerated or not fully effective is
modafinil, which, in doses of 200–400 mg daily, may par-
Obstructive episodes may occur secondary to various con- tially relieve daytime sleepiness (Kingshott et al. 2001).
ditions, either singly or in combination, including the fol- In central sleep apnea, acetazolamide, in a dose of 250 mg
lowing: hypertrophy of the adenoids or tonsils; micrognathia four times daily, may provide some relief (White et al. 1982);
p 18.qxd 3/10/08 9:52 AM Page 579
18.10 Kleine-Levin syndrome 579
however, its effectiveness often wanes. In severe cases, below leads to chronic alveolar hypoventilation. The result-
diaphragmatic pacing may be required. ing hypercapnia causes the somnolence.
The treatment of mixed episodes is similar to that of the
obstructive type.
Regardless of the type of sleep apnea present, care must Differential diagnosis
be taken to avoid alcohol (Scrima et al. 1982) or any med-
ication that might depress respiratory drive, including As noted, most patients with the Pickwickian syndrome
sedative–hypnotics (Mendelson et al. 1981), anxiolytics, also have obstructive sleep apnea, and the somnolence that
sedating antidepressants, opioids, etc. Of note, sildenafil, they experience is often attributed entirely to the sleep
which may be prescribed for the erectile dysfunction seen apnea. The differential between the combination of the
in obstructive sleep apnea, may also worsen the apnea Pickwickian syndrome plus sleep apnea and sleep apnea
(Roizenblatt et al. 2006) and consequently care must be alone rests on measurement of daytime arterial blood
taken in its use. gases: in the combination, one finds waking hypercapnia
and hypoxemia, whereas in sleep apnea alone, waking
blood gases are normal.
18.9 PICKWICKIAN SYNDROME
(OBESITY–HYPOVENTILATION SYNDROME)
Treatment
The constellation of extreme obesity, a ruddy complexion,
and somnolence has long been recognized and was exem- Weight loss is critical and effective (Chiang et al. 1980).
plified by the fat boy in Charles Dickens’s The Pickwick Alcohol, sedative–hypnotics, and any other medications
Papers. Following the lead given by Dickens, Burwell et al. that may reduce respiratory drive, such as antihistamines
(1956) coined the term ‘Pickwickian syndrome’; a more or opioids, should be avoided. Concurrent obstructive
recent name is ‘obesity–hypoventilation syndrome’ and, sleep apnea is treated as described in the preceding section.
although this is gaining currency, it lacks the color and flair Supplemental oxygen is sometimes recommended but this
of the eponym. As noted below, the extreme obesity in this must be administered with caution as it may precipitate
syndrome leads to waking hypoventilation. respiratory failure. In some cases oral medroxyproges-
terone may improve daytime ventilatory status (Sutton
Clinical features et al. 1975). The usefulness, if any, of modafinil or stimu-
lants such as methylphenidate is unclear.
Patients are extremely obese and often have a ruddy com-
plexion; they are typically somnolent and lethargic and
have difficulty paying attention or concentrating on things 18.10 KLEINE–LEVIN SYNDROME
(Burwell et al. 1956; Drachman and Gumnit 1962; Nowbar
et al. 2004; Sieker et al. 1955; Ward and Kelsey 1962). The Kleine–Levin syndrome, first described by Kleine
Arterial blood gases drawn while patients are awake reveal (1925) and Levin (1936), is a rare disorder characterized by
significant hypercapnia and hypoxemia; erythrocytosis episodes of hypersomnolence and associated symptoms
may occur as may pulmonary hypertension and cor pul- (most notably hyperphagia), which occurs primarily in
monale. Although, as might be expected, most patients adolescence and most commonly in males.
also have obstructive sleep apnea, this is not inevitable, and
some patients with the Pickwickian syndrome may have
normal sleep (Kessler et al. 2001). Clinical features
Course The clinical features of the Kleine–Levin syndrome have

been described in a number of case series (Critchley 1962;
In general, this parallels the course of the underlying obe- Critchley and Hoffman 1942; Dauvilliers et al. 2002;
sity. These extremely obese patients are prone to venous Gadoth et al. 2001) and a recent comprehensive review
stasis and deep venous thrombosis, and any acute worsen- (Arnulf et al. 2005). As noted, this is an episodic disorder,
ing of their clinical status should always prompt a search and the first episode, although able to occur at almost any
for pulmonary emboli. age, from early childhood to the ninth decade, appears in
late adolescence in the vast majority. Although in the
majority of cases the first episode is preceded by an infec-
Etiology tion, often viral, subsequent episodes generally occur with-
out any precipitating factors. The episodes themselves
The burden of excess adipose tissue encircling the chest and generally last in the order of two weeks; however, the range
also pushing up the diaphragm from the obese abdomen is wide, from days up to 3 months.
p 18.qxd 3/10/08 9:52 AM Page 580
580 Sleep disorders
Episodes may be ushered in by a brief prodrome, lasting Magnetic resonance scanning is normal, as is assay of
perhaps days, of malaise, headache, and lethargy. During the CSF. In the majority of cases the EEG displays diffuse
the episode proper, all patients experience hypersomnia, slowing during an episode, with at times an accentuation
often sleeping 18 or more hours per day. During waking of this in the temporal or frontotemporal areas. There are
hours, about three-quarters of patients will also experience no ictal or interictal epileptiform discharges, and in
hyperphagia. Mood changes are seen in over half of all between episodes the EEG normalizes. Polysomnography
patients and typically consist of depression. Cognitive may reveal reduced REM latency, frequent awakenings,
changes, such as confusion, are also seen in the majority. and decreased delta sleep (Pike and Stores 1994; Reynolds
Hypersexuality occurs in a little less than half of patients et al. 1980), and the MSLT may reveal sleep-onset REM
and may manifest with exhibitionism, unwelcome sexual (Reynolds et al. 1984).
advances, and frequent, and at times public, masturbation.
Delusions and hallucinations may appear in a small minor-
ity, as may unusual behaviors such as persistent humming Course
and singing.
As noted, hypersomnia and hyperphagia constitute the Although the long-term course has not been clearly delin-
primary symptomatology seen during an episode. Levin eated, it appears that in about two-thirds of patients there
(1936) noted that ‘the patient sleeps excessively day and are recurrent episodes, with the intervals between episodes
night, in extreme instances waking only to eat and go to the ranging from weeks to years but averaging about 6 months;
toilet. He can always be roused. When roused he is usually in many of the cases in which there are recurrences, the
irritable and wants to be left alone so that he can go back to subsequent episodes become less severe and more widely
sleep. He is abnormally hungry and eats excessively’. The spaced out and, after perhaps 4 or more years, episodes
hyperphagia seen during the episode is often indiscriminate, finally cease to occur.
and patients may eat whatever is at hand (Critchley 1962), In the intervals between episodes, although it appears
beg for food from other patients (Garland et al. 1965), or that the vast majority of patients return to normal, there is
indulge in unusual food preferences (Will et al. 1988). some suggestive evidence that there may be some residual
Mood changes tend toward depression, often tinged with quarrelsomeness and slightly reduced academic ability
irritability. Critchley (1962) noted that ‘in the majority . . . (Sagar et al. 1990).
the patient when awake is intensely irritable and resentful
. . . a few patients are actually hostile in their behavior . . .
in his attitude toward others he may be uninhibited, inso- Etiology
lent, and quarrelsome’.
Cognitive changes most frequently manifest with con- I could find three autopsy reports: one (Carpenter et al.
fusion; however, there may also be short-term memory 1982) noted widespread microgliosis in the thalamus, with
loss and incoherence. little neuronal loss; another (Fenzi et al. 1993) found
Hypersexuality may be very problematic: one patient microgliosis not only in the thalamus but also in the mid-
masturbated in public (Fernandez et al. 1990) and another brain; and the third (Koerber et al. 1984) reported only
continued his ‘vigorous attempts at masturbation’ during mild depigmentation of the substantia nigra and locus
the interview, refusing laboratory testing unless ‘the house ceruleus, without evidence of Lewy bodies. The role of the
physician was prepared to “come into bed and give me a thalamus in this disorder is further highlighted by a single
feel over” ’(Garland et al. 1965). photon emission computed tomography (SPECT) study
Delusions, which are typically of persecution, and hal- (Huang et al. 2005) that found hypoperfusion of the thal-
lucinations, which may be either auditory or visual, are ami in seven out of seven patients tested, with resolution of
seen in a small minority and tend to be fragmentary. this abnormality upon recovery.
Unusual behaviors may also be seen. Some authors have Although the mechanism underlying these changes is
commented that patients would ‘sing inappropriately’ not clear, the frequency with which the first episode fol-
(Chiles and Wilkus 1976); in one case the patient ‘fre- lows an infectious illness has suggested an autoimmune
quently burst into song’ but sang the same song over and basis (Dauvilliers et al. 2002), with the infection triggering
over again (Garland et al. 1965). In other cases patients an immune attack on diencephalic or mesencephalic
may pace, wring their hands, tear out their hair, or engage structures.
in body rocking.
As noted earlier, most episodes last in the order of 2
weeks. Upon recovery, most patients are more or less Differential diagnosis
amnestic for the events that occurred during the episode
(Critchley 1962; Levin 1936), and some may experience a The overall clinical picture of one or more episodes of
residual mood disturbance (Critchley 1962), tending hypersomnolence and hyperphagia is fairly distinctive.
towards either depression (Gallinek 1954) or elation Consideration might be given to a diagnosis of depression
(Gilbert 1964), which passes within a week or so. as depressive episodes in major depressive disorder or,
p 18.qxd 3/10/08 9:52 AM Page 581
18.11 Restless legs syndrome 581
especially, bipolar disorder may be characterized by The majority of patients will also experience periodic
depressed mood, increased need for sleep, and increased movements of sleep (Montplaisir et al. 1997; Ondo and
appetite, thus mimicking the episodes seen in the Jankovic 1996), described in Section 18.12.
Kleine–Levin syndrome. Certain features of the Kleine–Levin
syndrome, however, remain distinctive, including the
Course
indiscriminate nature of the hyperphagia and, especially,
the hypersexuality.
Primary restless legs syndrome is generally chronic, and
symptoms may either wax and wane in intensity over time
or progressively worsen. The course of the secondary form
Treatment is determined by the underlying cause. Certain medica-
tions, such as the SSRIs paroxetine (Sanz-Fuentenebro et al.
There are no controlled treatment studies. Anecdotally,
1996) and citalopram (Perroud et al. 2007), may exacerbate
lithium may reduce the severity or frequency of episodes
symptoms.
(Dauvilliers et al. 2002; Goldberg 1983; Muratori et al.
2002; Ogura et al. 1976; Poppe et al. 2003), and success has
also been reported with carbamazepine (Dauvilliers et al. Etiology
2002). Modafinil (Dauvilliers et al. 2002) and amphet-
amines (Gallinek 1962) have also been used to reduce the The primary, or idiopathic, form of restless legs syndrome is
somnolence seen during an episode. familial and displays genetic heterogeneity, with both auto-
somal dominant and recessive patterns being recognized
(Levchenko et al. 2006; Trenkwalder et al. 1996;
18.11 RESTLESS LEGS SYNDROME Winkelmann et al. 2000, 2002). Although the underlying
mechanism has not been clearly delineated, it appears that
The restless legs syndrome, also known as Ekbom’s syn- this primary form occurs secondary to a disturbance in iron
drome, is a common disorder, with a lifetime prevalence of transport in the substantia nigra. Both magnetic resonance
about 5 percent. As the name implies it is characterized by imaging (MRI) (Allen et al. 2001) and transcranial sono-
the experience of restlessness in the legs, an experience so graphic (Schmidauer et al. 2005) studies have demonstrated
disagreeable and uncomfortable that it keeps patients from a lack of iron in the substantia nigra, and CSF studies have
falling asleep. This disorder occurs in two forms: a primary disclosed decreased ferritin and increased transferrin levels
form, which in all likelihood is inherited, and a secondary (Earley et al. 2000). Although neuropathologic studies have
form, which occurs on the basis of numerous other disor- not demonstrated any cell loss or gliosis in the substantia
ders such as iron deficiency anemia or various sensory nigra, or any tau or synuclein pathology in neuromelanin
polyneuropathies. cells (Pittock et al. 2004), there does appear to be a deficiency
of transferrin receptors on these cells (Connor et al. 2003,
2004), which is consistent with a functional derangement of
Clinical features iron transport into them. Importantly, this putative distur-
bance in iron transport in the central nervous system is not
In both primary and secondary forms the onset is generally mirrored by any systemic disturbances in iron transport or
gradual. Primary forms typically first appear in early adult metabolism, and there is no association between the primary
years, whereas the age of onset of secondary forms is deter- form of restless legs syndrome and iron deficiency anemia.
mined by the underlying condition; for the most part, Secondary restless legs syndrome, by contrast, is associ-
however, the onset of the secondary form tends to be in ated with iron deficiency anemia (Rangarajan and D’Souza
middle or later years. 2007). Other causes include sensory polyneuropathies
Clinically (Ekbom 1960; Montplaisir et al. 1997; Ondo (Gemignani et al. 2006; Polydefkis et al. 2000), uremia
and Jankovic 1996), patients report that when they lie (Winkelmann et al. 1996, 2000), chronic hemodialysis
down, or even merely sit down, they feel a restlessness deep (Kawauchi et al. 2006), Parkinson’s disease (Krishnan et al.
within the legs, especially in the calves; some may also 2003), multiple sclerosis (Manconi et al. 2007), spinal cord
experience formication, with a sense of crawling under the lesions (Hartmann et al. 1999), spinal anesthesia with either
skin, or an aching discomfort. Often the experience is so bupivacaine or mepivacaine (Hogl et al. 2002), mirtazapine
uncomfortable that patients feel impelled to get up and (Agargun et al. 2002), and pregnancy (Manconi et al. 2004).
walk about, which brings some relief. Over time, the rest- Most of these causes are either obvious or readily deter-
lessness may begin to involve the upper extremities. mined, with the exception of sensory polyneuropathy. In
At night, falling asleep may be almost impossible, and some cases secondary to polyneuropathy, the restless legs
patients may either try and lay still and bear the discomfort syndrome may be the only clinical evidence, and hence it is
or spend hours out of bed, pacing about. Typically, symp- appropriate to consider nerve conduction velocity studies in
toms lessen by early morning hours and patients may then doubtful cases (Ondo and Jankovic 1996). In the case of
be able to get some sleep. pregnancy, symptoms typically resolve shortly after delivery.
p 18.qxd 3/10/08 9:52 AM Page 582
582 Sleep disorders
Differential diagnosis Oxycodone (Walters et al. 1993) is effective in a dose of

about 15 mg at bedtime, and clonidine in a dose of
The chief differential possibility is akathisia. In akathisia, as 0.025–0.05 mg (Wagner et al. 1996).
described in Section 3.10, patients experience a restlessness Although most texts recommend trying a dopaminergic
when seated or lying down and may feel impelled to get up; agent first, the possibility of ‘augmentation’, which is
hence, they present a picture similar to that of the restless unique to this group, may give one pause. In my experi-
legs syndrome. Two features, however, enable a differenti- ence gabapentin has proved quite satisfactory as a first-line
ation to be made (Walters et al. 1991). First, when patients agent. If a dopaminergic agent is used, either pramipexole
with the restless legs syndrome get up they tend to pace or ropinirole should be used first, as they are probably
about, whereas those with akathisia often ‘march in place’. more effective than levodopa and are less likely to cause
Second, patients with the restless legs syndrome often get augmentation. Clonazepam is another reasonable choice.
some relief by massaging their calves, a manuever that is Enthusiasm for oxycodone is tempered by its abuse poten-
useless in akathisia. tial, and clonidine carries a significant side-effect burden.
Treatment 18.12 PERIODIC LIMB MOVEMENTS IN SLEEP

In secondary cases the underlying cause should, if possible, Periodic limb movements in sleep is characterized by mul-
be treated, as this may bring relief. In secondary cases in tiple jerkings of one or both legs during sleep. This disorder
which treatment of the underlying cause is either not pos- has traditionally been referred to as nocturnal myoclonus;
sible or ineffective, and in primary cases, various medica- however, this is a misnomer because, as pointed out below,
tions may be considered, including the following: the abnormal movements seen in this disorder are not
levodopa, direct-acting dopaminergic agents, gabapentin, truly myoclonic in character but, when fully developed,
clonazepam, oxycodone, and clonidine. Each is discussed resemble more a ‘triple flexion’ response.
in turn, followed by some overall recommendations. Patients may or may not be awakened by the abnormal
Levodopa, in combination with carbidopa (Benes et al. movements; if they are awakened and also complain of
1999; Brodeur et al. 1988), may be started at a dose of either insomnia or daytime sleepiness, then it is customary
100 mg levodopa and 25 mg carbidopa, which may be dou- to speak not of ‘periodic limb movements in sleep’ but
bled if needed after 3–7 days. Of the direct-acting dopami- rather ‘periodic limb movement disorder’; this in turn may
nergic agents that are effective in the restless legs syndrome, occur on either an idiopathic basis or secondary to various
pramipexole (Montplaisir et al. 1999; Winkelmann et al. other disorders. Periodic limb movement disorder is com-
2006) and ropinirole (Trenkwalder et al. 2004) are currently mon, seen in at least 4 percent of the general population.
used. Starting doses are 0.125 mg of pramipexole or 0.5 mg
of ropinirole, and the dose may be increased in similar incre-
ments every 3–7 days up to a maximum of 0.75 mg of Clinical features
pramipexole or 4 mg of ropinirole. All of these dopaminer-
gic agents may be either given as a single dose 1–3 hours The onset of the disorder may occur at any time from early
before bedtime or divided into two doses, given in the early adult years to old age.
evening and then at bedtime. Importantly, treatment with The jerking movement itself may occur in one or both of
all of these dopaminergic agents may be associated with the the lower extremities. Upon observation, one sees dorsi-
phenomenon of ‘augmentation’, in which, over long periods flexion at the ankle accompanied in most cases by dorsiflex-
of time, the symptoms of restless legs syndrome worsen. ion of the great toe; in many cases these movements are
Although this is most commonly seen as a side-effect of levo- accompanied by flexion at the knee and hip, thus mimicking
dopa (Allen and Earley 1996), it may also occur with a classic triple flexion response (Coleman et al. 1980; Smith
direct-acting agents (Ondo et al. 2004). Another drawback 1985; de Weerd et al. 2004). The jerkings evolve over any-
associated with direct-acting agents is the possible emer- where from 0.5 to 4 seconds, and repeat every 20–120 sec-
gence of pathological gambling, as has been noted with onds during episodes that last from minutes to hours.
pramipexole (Tippmann-Peikert et al. 2007). Episodes occur during NREM sleep and may recur through-
Gabapentin (Garcia-Borreguero et al. 2002) may be out the night. The jerkings may or may not be accompanied
started at a low dose of 300–400 mg and increased every few by an awakening and, if they are, patients may complain of
days in similar increments up to a maximum of 3600 mg; either insomnia or daytime sleepiness. Despite these com-
the dose should be divided into an early evening dose, equal plaints, patients themselves may be unaware of the jerkings,
to one-third of the total, and a bedtime dose of the remain- and an accurate history of these nocturnal events may
der; most patients respond to a total daily dose of 1800 mg. depend on their description by a bed partner, who may
Clonazepam (Saletu et al. 2001) may be started at a dose complain of being repeatedly ‘kicked’ during the night.
of 0.5 mg per hour before bedtime, with similar increments A minority of patients will also have the restless legs
every 3–7 days up to a maximum of 2 mg. syndrome.
p 18.qxd 3/10/08 9:52 AM Page 583
18.13 Painful legs and moving toes 583
Course study bupropion was also effective (Nofzinger et al. 2000),

as was selegiline (Grewal et al. 2002).
Idiopathic periodic limb movement disorder appears to be
chronic; the course of the secondary form is determined by
the underlying cause. Tricyclic antidepressants may exac- 18.13 PAINFUL LEGS AND MOVING TOES
erbate this disorder (Ware et al. 1984).
As the name implies, this syndrome is characterized by
pain in the legs (which may be quite severe) and involun-
Etiology tary movements of the toes, all resulting in insomnia. This
is a rare but potentially devastating condition.
The idiopathic form appears to be inherited and, as indi-
cated by single photon emission computed tomography
(SPECT) studies, is associated with a deficiency of post- Clinical features
synaptic dopamine receptors in the striatum (Staedt et al.
1995). Although the mechanism underlying the abnormal The syndrome (Dressler et al. 1994; Spillane et al. 1971)
movements is not known, their strong resemblance to a generally has an onset in the sixth or seventh decades. In
Babinski response suggests that they result from a lack of most cases pain appears first and, although symptoms may
normal supraspinal inhibition (Smith 1985). begin unilaterally, bilateral involvement eventually ensues.
Secondary forms have been associated with congestive As noted by Spillane et al. (1971), the pain varies ‘in inten-
heart failure (Hanley and Zuberi-Khokhar 1996), chronic sity from discomfort to a pain of great severity . . . an ache,
hemodialysis (Rijsman et al. 2004), alcohol withdrawal an intense pressure, a tightness, a feeling that the toes were
(Gann et al. 2002), and spinal cord lesions (Lee et al. 1996). pulling or being pulled, a throbbing, bursting, crushing . . .
Rare cases have also been reported secondary to lacunar [or] a deep burning’ and the movements consist of a ‘sinu-
infarctions in the corona radiata (Kang et al. 2004) and in ous clawing and re-straightening, fanning and circular
the pons (Kim et al. 2003). movements of the toes’. The effect of the toe movements
can be remarkable: one of Spillane et al.’s patients ‘was sur-
prised to see that the toes were actually moving “as though
Differential diagnosis they were playing a piano on their own” ’. The symptoms
are not relieved by walking about and insomnia can be
Isolated jerkings, occurring at a frequency of up to five per severe (Montagna et al. 1983). When sleep does come, the
hour, may be an incidental finding on polysomnography abnormal movements cease.
(Mendelson 1996) and are not associated with any
symptoms.
Hypnic jerks (Oswald 1959), also known as ‘sleep starts’,
are a normal accompaniment of the transition into sleep.
Course
They differ from the jerkings seen in periodic limb move-
In most case this syndrome appears to be chronic.
ments in that they are very brief, typically involve all four
extremities, and occur only as the individual is falling asleep.
Myoclonus, discussed in Section 3.2, is distinguished
from the jerkings of periodic limb movements by its Etiology
‘shock-like’ rapid onset, in contrast to the relatively
leisurely evolution of the jerking movement. The syndrome has been noted secondary to lesions of the
cord, posterior lumbar roots, and peripheral nerves, and
with trauma to the back or feet (Dressler et al. 1994; Ikeda
Treatment et al. 2004; Montagna et al. 1983; Nathan 1978; Pla et al.
1996; Schott 1981). Interestingly, lesions or trauma need
Various medications are effective, including levodopa/car- not be bilateral; unilateral lesions may be followed initially
bidopa (Becker et al. 1993; Brodeur et al. 1988; Kaplan et al. by an ipsilateral onset, but eventually the contralateral
1993), pramipexole (Montplaisir et al. 1999), gabapentin extremity becomes involved.
(Garcia-Borreguero et al. 2002), clonazepam (Mitler et al.
1986b; Ohanna et al. 1985; Peled and Lavie 1987; Saletu
et al. 2001), and oxycodone (Walters et al. 1993). The choice Differential diagnosis
among these and their method of use are similar to that
noted for restless legs syndrome in Section 18.11; of note, The restless legs syndrome is distinguished by an absence of
‘augmentation’, as may be seen with dopaminergic agents pain and abnormal movements, and by the characteristic
in the restless legs syndrome, has not been reported in peri- relief obtained by walking about. Reflex sympathetic dystro-
odic limb movement disorder. Interestingly, in an open phy is distinguished by the lack of abnormal movements.
p 18.qxd 3/10/08 9:52 AM Page 584
584 Sleep disorders
Treatment asleep at socially approved times. Patients often stay awake

until the early morning hours and are then unable to awaken
There are no controlled treatment studies. Case reports early enough in the morning to get to school or work on
indicate relief with gabapentin and clonazepam, and with time. Importantly, if such ‘night owls’ are allowed to ‘sleep
epidural block, lumbar sympathectomy, and utilization of in’ they get a normal amount of sleep and awaken refreshed.
transcutaneous electrical nerve stimulation (TENS). In most cases, this syndrome has an onset in adolescence.
The advanced sleep phase syndrome, which is generally
restricted to the elderly, is characterized by an urge to go to
18.14 CIRCADIAN RHYTHM SLEEP DISORDER sleep very early in the evening. Such individuals then
awaken some 7 or so hours later, in the very early morning.
The onset and duration of sleep, as is the case with most bio- These ‘morning larks’ awaken refreshed and get a start on
logical rhythms, is under the control of the suprachiasmatic the day long before their companions.
nucleus of the hypothalamus, which functions as the body’s In the non-24-hour sleep syndrome there is a failure of
‘internal clock’. Under its influence, most people begin to feel entrainment of the internal clock to the normally occur-
sleepy in the evening, go to sleep between the hours of 2000 ring 24-hour schedule. Given that the internal clock, when
and 2400, sleep for 7 or 8 hours, and then awaken, generally allowed to ‘run free’, has a cycle length some 15–30 min-
feeling refreshed. Social demands for work and other func- utes longer than 24 hours, such patients experience pro-
tions are built around this biologically determined schedule. gressively worsening insomnia, followed by hypersomnia,
Whenever there is a mismatch between social demands until their free-running internal clock finally completes
for sleep and wakefulness and this biologically determined enough cycles to bring it into alignment with the normal
rhythm, one speaks of a circadian rhythm sleep disorder. environmental 24-hour cycle.
Such mismatches may occur in one of two ways: either the In the irregular sleep–wake syndrome the urge to sleep
timing of social demands changes or the internal ‘clock’ seems to come at random, with no clear-cut relationship to
changes. Examples of the first type of change include the any cycle, whether environmental or internal.
sleep disturbance that comes with transmeridian jet travel
(‘jet lag’) or with shift work. Examples of the second type of
change include the delayed sleep phase syndrome, the Etiology
advanced sleep phase syndrome, the non-24-hour sleep
syndrome, and the irregular sleep–wake syndrome. Jet lag and the shift work type of sleep disorder occur sec-
As a whole, circadian rhythm sleep disorders are very ondary to the environmental changes, which create a mis-
common. ‘Jet lag’ occurs routinely in air travelers and match between the newly enforced sleep–wake schedule
some seven million Americans are exposed to the deleteri- and the ongoing workings of the internal clock.
ous effects of shift work. The delayed sleep phase syndrome The delayed sleep phase syndrome may have a genetic
occurs in roughly 7 percent of adolescents; the non-24-hour basis. Associations have been found with polymorphisms of
sleep syndrome and the irregular sleep–wake syndrome, by the ‘circadian clock gene’ hPER3 (Pereira et al. 2005), poly-
contrast, are uncommon. morphisms of the gene encoding an enzyme that is responsi-
ble for phosphorylation of clock proteins (Takano et al.
2004), and polymorphisms of the gene coding for the rate-
Clinical features limiting enzyme responsible for melatonin synthesis (Hohjoh
et al. 2003). Uncommonly, this syndrome may occur after
Jet lag occurs with air travel that crosses five or more closed head injury (Ayalon et al. 2007; Quinto et al. 2000).
meridians. With eastward flight, the traveler’s internal The advanced sleep phase syndrome occurs most com-
clock is phase-delayed relative to the local schedule, and monly on a sporadic basis in the elderly, and, in these cases,
travelers tend to feel awake long past the local ‘bedtime’, is presumed to be secondary to age-related changes in the
with resulting insomnia. With westward travel, which is suprachiasmatic nucleus or related structures. Rarely, the
generally better tolerated, the traveler’s internal clock is syndrome may occur on a familial basis, with autosomal
phase-advanced relative to the local time, and travelers dominant inheritance (Reid et al. 2001); in some such cases,
find themselves sleepy quite early in the evening. mutations have been found in hPER2 (Xu et al. 2005).
Shift work sleep disorder occurs when individuals, nor- The non-24-hour sleep syndrome generally occurs in
mally accustomed to working during the day and sleeping patients who are blind secondary to lesions affecting the
at night, are shifted to night-time work. Although a minor- optic chiasm, optic nerves, or eyes. Anatomically, entrain-
ity of individuals adjust to this change fairly rapidly, most ment of the suprachiasmatic nucleus to the environmental
do not, and, under the influence of their internal clock, light–dark schedule is dependent on fibers of the retino-
they feel sleepy during the night while at work and have hypothalamic tract, which arise in the retina and then tra-
trouble sleeping during their daytime off-hours. verse the optic nerves to the optic chiasm from where they
The delayed sleep phase syndrome (Weitzman et al. ascend into the hypothalamus. With bilateral lesions of
1981, Wyatt 2004) is characterized by an inability to fall these tracts, the internal clock ‘runs free’. Less commonly,
p 18.qxd 3/10/08 9:52 AM Page 585
18.15 Primary insomnia 585
this syndrome may occur in sighted patients, and such light for 2 or 3 hours after arising (Watanabe et al. 1999).
cases have been noted after head trauma (Boivin et al. Another method of resetting the internal clock involves what
2003) and in otherwise normal individuals with disorders is known as ‘chronotherapy’ (Czeisler et al. 1981). Here,
of melatonin metabolism (McArthur et al. 1996, Nakamura patients advance their sleep time progressively by 3 hours
et al. 1997). every day until, after 5 or 6 days (depending on when their
The irregular sleep–wake syndrome is generally seen only original sleep time was), their new sleep time coincides with
in patients with diffuse brain disease, whether congenital or environmental demands, which are then rigidly adhered to.
acquired (e.g., after traumatic brain injury [Ayalon et al. Although effective, this procedure is difficult to implement.
2007]), and in such cases it is presumed that the suprachias- Advanced sleep phase syndrome rarely requires treat-
matic nucleus has been damaged or destroyed. ment, as it rarely causes significant problems. Evening
bright light treatment may be considered, but there are no
controlled studies regarding such use.
Differential diagnosis In case reports, the non-24-hour sleep syndrome has
been successfully treated with melatonin (Hayakawa et al.
The diagnosis of the jet lag and shift work types of sleep 1998, Palm et al. 1991). In sighted patients, and in those
disorder is usually self-evident. In the other types, routine whose blindness is due to retrochiasmal lesions, morning
history taking alone generally suffices; however, in some bright-light treatment may be considered.
cases it may be necessary to have the patient or a caretaker Anecdotally, the irregular sleep–wake syndrome has
keep a ‘sleep log’ for a couple of weeks; polysomnography been improved with melatonin (Pillar et al. 1998).
is rarely required.
In evaluating patients with suspected delayed sleep
phase syndrome, non-24 hour sleep syndrome or irregular 18.15 PRIMARY INSOMNIA
sleep–wake syndrome, consideration should be given to
the effects of alcohol or stimulants, and to the presence of Primary insomnia remains a diagnosis of exclusion and
various psychiatric disorders that can disturb sleep, espe- should be withheld until other causes of insomnia, discussed
cially depression, anxiety, mania, and schizophrenia. below, are ruled out. Primary insomnia occurs in one of two
forms. The most common form, psychophysiologic insom-
nia, occurs in anywhere from 1 to 10 percent of the general
Treatment population and in up to 25 percent of the elderly. The other
form, referred to as idiopathic insomnia, is quite rare.
Both bedtime melatonin and appropriately timed expo-
sure to bright light are useful in most of these disorders. If
Clinical features
melatonin is used, the immediate-release type should be
prescribed, in doses ranging from 3 to 6 mg.
Psychophysiologic insomnia (Hauri and Fisher 1986) typi-
Jet lag is approached by rigidly adhering to the local bed-
cally has an onset in middle or later years, and, generally,
time; an additional strategy is to adjust one’s internal clock
but not always, follows upon some stressful life event.
before departure by adhering progressively closer, over 2 or
Idiopathic insomnia, by contrast, appears much earlier,
3 days, to the anticipated bedtime at one’s destination. Upon
either in childhood or infancy.
arrival, melatonin use for 5 days may also help. Zolpidem, in
Patients typically have trouble falling asleep, experience
a dose of 5–10 mg, also appears to be effective; however,
multiple awakenings, and have an overall reduced total
melatonin and zolpidem should not be used in combination
sleep time. Most patients are fretful about their insomnia
as this may result in confusion (Suhner et al. 2001).
and, while lying in bed, may find themselves worrying con-
Shift work sleep disorder is treated by use of bright light
stantly over their inability to achieve sleep.
during night-time work (5000 Lux or more) and use of sun-
glasses or goggles during daytime hours (Crowley et al. 2003;
Czeisler et al. 1990). Melatonin does not appear to be Course
robustly effective (Cavallo et al. 2005), however, it is worth
a try. Many individuals also utilize hypnotics, such as Psychophysiologic insomnia remits in about 50 percent of
zolpidem; although there are no data to support this use, it patients within a year; in the remainder it tends to persist,
is probably preferable to drinking oneself to sleep. Use of with its severity waxing and waning over time.
modafinil during the day is marginally helpful (Czeisler Idiopathic insomnia tends to be chronic.
et al. 2005).
Delayed sleep phase syndrome may be treated with a
combination of modalities including administration of mela- Pathology and etiology
tonin sometime between the hours of 1900 and 2100
(Kayumov et al. 2001), dim lights in the evening, rigid Psychophysiologic insomnia, as noted earlier, generally
adherence to a normal wake-up time, and exposure to bright occurs after some stressful life event. When stressed, most
p 18.qxd 3/10/08 9:52 AM Page 586
586 Sleep disorders
individuals will experience some insomnia, but, in the use only. Evenings should be reserved for relaxing
overwhelming majority, this is transient. In those destined activities, the bedroom should be darkened and quiet, and
to develop psychophysiologic insomnia, however, a certain the bed should be reserved for sleep or sexual activity. If
anxiety appears over whether or not sleep will come. This sleep does not come, patients should do something else,
anxiety then makes sleep less likely to occur and a vicious perhaps reading, until drowsiness occurs. Whether insom-
cycle may be established in which a failure to sleep engen- nia occurs or not, the wake-up time should be strictly
ders more anticipatory anxiety, which in turn makes the adhered to.
insomnia worse. Once this pattern is firmly established, the Should insomnia persist despite good sleep hygiene,
bed, rather than being seen as a place for relaxation and consideration may be given to cognitive behavioral
restoration, becomes an anxiety-provoking stimulus in therapy, which is not only effective acutely (Edinger et al.
itself. Interestingly, in such cases patients may sleep better 2001) but also confers enduring benefits (Backhaus
on the couch or in a hotel. Whether or not other etiologic et al. 2001). Should cognitive behavioral therapy be inef-
factors exist in psychophysiologic insomnia is not clear; a fective or impractical, pharmacologic treatment may be
recent report, however, did note reduced nocturnal mela- considered.
tonin levels in patients compared with control subjects Zolpidem, 10 mg h.s., is effective (Perlis et al. 2004) and
(Riemann et al. 2002a). is perhaps the most widely prescribed hypnotic for primary
Idiopathic insomnia is presumed to be secondary to dys- insomnia; it generally has no residual effects the next day
function of hypothalamic or brainstem structures involved (Staner et al. 2005) or any rebound insomnia upon discon-
in sleep. tinuation after chronic use; there have, however, been rare
reports of somnambulism with zolpidem (Morgenthaler
and Silber 2002, Yang et al. 2005). Eszopiclone is an alter-
native choice (Zammit et al. 2004).
Differential diagnosis Melatonin was effective in one double-blind study
(Zhdanova et al. 2001) but not another (Almeida Montes
Other sleep disorders, discussed in other sections in this
et al. 2003), in doses ranging from 0.1 to 6 mg given in the
chapter, must be considered, including sleep apnea, rest-
evening. Ramelteon, a selective melatonin receptor ago-
less legs syndrome, periodic leg movements of sleep, and
nist, also appears to be effective (Erman et al. 2006).
the syndrome of painful legs and moving toes.
Doxepin, in doses of 25 to 50 mg h.s., is effective, but in
Depression is perhaps one of the most common causes
a small minority may be followed by severe rebound
of insomnia, and one should always inquire about the pres-
insomnia upon discontinuation after chronic use (Hajak
ence of other vegetative symptoms. Generalized anxiety
et al. 2001). Trimipramine, another tricyclic antidepressant,
disorder, post-traumatic stress disorder, and schizophre-
is also effective in doses of 100–200 mg h.s. (Hohagen et al.
nia must also be considered.
1994, Riemann et al. 2002b), and does not appear to sup-
Caffeine and other stimulants taken too late in the day
press REM sleep or cause rebound insomnia. Trazodone is
cause insomnia, and insomnia is universal and often very
very widely used in doses ranging from 25–100 mg h.s.;
severe and long-lasting in alcohol withdrawal.
however, there is little evidence for its effectiveness
Painful conditions, such as heartburn or arthritis, rou-
(Mendelson 2005).
tinely disturb sleep.
Benzodiazepines (e.g., lorazepam, diazepam) and anti-
Finally, one must consider whether the patient suffers
histamines (e.g., hydroxyzine, diphenhydramine) are often
from ‘sleep state misperception’ or is merely an otherwise
prescribed, but there are no double-blind studies support-
normal ‘short sleeper’. Sleep state misperception is said to
ing their use in primary insomnia.
exist in cases in which, despite often bitter complaints of
Choosing among these various agents requires consid-
insomnia, polysomnography reveals normal sleep. Before
erable clinical judgment. Given the excellent tolerability of
making this diagnosis, however, it must be borne in mind
melatonin, starting with this agent, using a dose of 3–6 mg
that some patients with psychophysiologic insomnia sleep
in the evening, is a reasonable choice. At present, there are
better when they are away from home. When this is sus-
no comparative studies of melatonin and ramelteon; the
pected, it may be appropriate to perform polysomno-
latter agent, however, represents another reasonable first
graphy at the patient’s home before making the diagnosis.
choice. Should melatoninergic agents fail, consideration
‘Short sleepers’ are individuals who, despite getting little
may be given to zolpidem or eszopiclone; doxepin and
sleep, awake refreshed and have no complaints.
trimipramine, although effective, tend to cause consider-
able side-effects. Trazodone should also be considered if
melatoninergic agents fail.
Treatment The foregoing discussion of pharmacologic treatment
concerns the psychophysiologic form of primary insom-
Good sleep hygiene is essential. Naps should not be taken, nia; in cases of idiopathic insomnia in children, melatonin,
and patients should get some exercise every day. Caffeine 5 mg in the evening, appears to be effective (Smits et al.
and other stimulants should be reserved for morning 2001).
p 18.qxd 3/10/08 9:52 AM Page 587
References 587
18.16 PRIMARY HYPERSOMNIA legs and moving toes, and the advanced sleep phase type of
circadian rhythm sleep disorder. Narcolepsy is also often
Primary or essential hypersomnia is a rare disorder charac- considered; however, the naps seen in narcolepsy, unlike
terized by chronic persistent hypersomnolence (Bassetti those of primary hypersomnia, come in irresistible attacks
and Aldrich 1997, Billiard et al. 1998). and, when they are over, leave the patient feeling refreshed;
furthermore, the MSLT in narcolepsy typically demon-
strates sleep-onset REM.
Clinical features Excessive daytime sleepiness may also be seen in
myotonic muscular dystrophy, hypothyroidism, as a sequela
The onset is gradual, typically occurring in late adoles- to infectious mononucleosis, and with lesions of the hypo-
cence. Nocturnal sleep is prolonged to anywhere from 8 to thalamus (Eisensehr et al. 2003), thalamus (Bassetti
14 hours, and, upon awakening in the morning, patients et al. 1996), or pons (Ganji et al. 1996). Chronic use of sedat-
are typically groggy and have trouble ‘getting going’; a ing medications, such as benzodiazepines, tricyclic anti-
minority may also experience sleep drunkenness. Patients depressants, certain anti-epileptic drugs, antihistamines,
report persistent drowsiness during the day and often take and opioids must also be considered on the differential.
long naps, which, as with their nocturnal sleep, leave them Finally, there are individuals known as ‘long sleepers’
unrefreshed. Importantly, these naps do not occur as irre- who require more than 8 hours of sleep a night. In contrast
sistible attacks but rather are preceded by a gradually to patients with primary hypersomnia, however, these
increasing drowsiness, which can often be resisted. individuals awaken refreshed and are not subject to unre-
The MSLT, although characterized by a reduced sleep freshing naps during the day.
latency, does not reveal sleep-onset REM.
Treatment
Course
There are no controlled studies; case series (Bassetti and
For most, primary hypersomnia is a chronic condition; Aldrich 1997) suggest that some patients improve with
spontaneous improvement is seen in only about 10 percent. stimulants, and consideration may be given to either
methylphenidate or modafinil.
Etiology
Primary hypersomnia may occur sporadically or on a REFERENCES
familial basis. Recent work has demonstrated reduced lev-
els of hypocretin in the CSF (Ebrahim et al. 2003), suggest- Adie WJ. Idiopathic narcolepsy: a disease sui generis; with
ing hypothalamic dysfunction. remarks on the mechanism of sleep. Brain 1926; 49:257–306.
Agargun MY, Kara H, Ozbek H et al. Restless legs syndrome
induced by mirtazapine. J Clin Psychiatry 2002; 63:1179.
Differential diagnosis Ajlouni KM, Ahmad AT, El-Zaheri MM et al. Sleepwalking
associated with hyperthyroidism. Endocr Pract 2005; 11:5–10.
Although some authorities subsume not only chronic but Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the
also intermittent forms of hypersomnia under the rubric of diencephalon. Neurology 1989; 39:1505–8.
‘primary hypersomnia’, in this text the diagnosis of pri- Allen RP, Earley CJ. Augmentation of the restless legs syndrome
mary hypersomnia is reserved for chronic cases only. with carbidopa/levodopa. Sleep 1996; 19:205–13.
Consequently, the first task in differential diagnosis is to Allen R, Barker PB, Wehrl F et al. MRI measurements of brain iron
determine whether the hypersomnolence is chronic or in patients with restless legs syndrome. Neurology 2001;
occurs in episodes. Episodic hypersomnolence may occur 56:263–5.
in the Kleine–Levin syndrome, in association with men- Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J et al.
struation (Sachs et al. 1982), with intermittent use of sedat- Treatment of primary insomnia with melatonin: a double-
ing medications, and, most importantly, in certain blind, placebo-controlled, crossover study. J Psychiatry
depressive illnesses. Depressive episodes of bipolar disor- Neurosci 2003; 28:191–6.
der are often characterized by severe hypersomnia, and in Arnulf I, Zeitzer JM, File J et al. Kleine–Levin syndrome: a
taking the history one must be alert to other vegetative systematic review of 186 cases in the literature. Brain 2005;
symptoms and to any history of mania. 128:2763–76.
Once it is established that the patient indeed has chronic Ayalon L, Borodkin K, Dishon L et al. Circadian rhythm sleep
hypersomnia, other disorders must be distinguished. Sleep disorders following mild traumatic brain injury. Neurology
disorders characterized by excessive daytime sleepiness 2007; 68:1136–40.
include sleep apnea, the Pickwickian syndrome, restless Backhaus J, Hohagen F, Voderholzer U et al. Long-term
legs syndrome, periodic limb movement disorder, painful effectiveness of a short-term cognitive-behavioral group
p 18.qxd 3/10/08 9:52 AM Page 588
588 Sleep disorders
treatment for primary insomnia. Eur Arch Psychiatry Clin Cartwright RD, Lloyd S, Lilie J et al. Sleep position training as
Neurosci 2001; 251:35–41. treatment for sleep apnea syndrome: a preliminary study.
Bakwin HI. Sleepwalking in twins. Lancet 1970; 2:446–7. Sleep 1985; 8:87–94.
Balon R. Sleep terror disorder and insomnia treated with Cartwright RD, Ristanovic R, Diaz F et al. A comparative study of
trazodone: a case report. Ann Clin Psychiatry 1994; 6:161–3. treatments for positional sleep apnea. Sleep 1991; 14:546–52.
Bassetti C, Aldrich MS. Idiopathic hypersomnia. A series of 42 Cavallo A, Ris MD, Succop P et al. Melatonin treatment of
patients. Brain 1997; 120:1423–35. pediatric residents for adaptation to night shift work. Ambul
Bassetti C, Mathis J, Gugger M et al. Hypersomnia following Pediatr 2005; 5:172–7.
paramedian thalamic stroke: a report of 12 patients. Ann Charney DS, Kales A, Soldatos CR et al. Somnambulistic-like
Neurol 1996; 39:471–80. episodes secondary to combined lithium-neuroleptic
Becker PM, Jamieson AO, Brown WD. Dopaminergic agents in treatment. Br J Psychiatry 1979; 135:418–24.
restless legs syndrome and periodic limb movements of sleep: Chiang ST, Lee PY, Liu SY. Pulmonary function in a typical case of
response and complications of extended treatment in 49 Pickwickian syndrome. Respiration 1980; 39:105–13.
cases. Sleep 1993; 16:713–16. Chiles JA, Wilkus RJ. Behavioral manifestations of the
Benes H, Kurella B, Kummer J et al. Rapid onset of action of Kleine–Levin syndrome. Dis Nerv Syst 1976; 37:646–8.
levodopa in restless legs syndrome: a double-blind, randomized, Chisolm T, Morehouse RL. Adult headbanging: sleep studies and
multicenter, crossover trial. Sleep 1999; 22:1073–81. treatment. Sleep 1996; 19:343–6.
Billiard M, Merle C, Carlander B et al. Idiopathic hypersomnia. Clavelou P, Tournilhac M, Vidal C et al. Narcolepsy associated
Psychiatry Clin Neurosci 1998; 52:125–9. with arteriovenous malformation of the diencephalon. Sleep
Black J, Houghton WC. Sodium oxybate improves excessive 1995; 18:202–5.
daytime sleepiness in narcolepsy. Sleep 2006; 29:939–46. Coleman RM, Pollack CP, Weitzman ED. Periodic movements in
Blouin AM, Thannickal TC, Worley PF et al. NARP immunostaining sleep (nocturnal myoclonus): relationship to sleep disorders.
of human hypocretin (orexin) neurons. Loss in narcolepsy. Ann Neurol 1980; 8:416–21.
Neurology 2005; 65:1189–92. Connor JR, Boyer PJ, Menzies SL et al. Neuropathological
Boeve BF, Silber MH, Parisi JE et al. Synucleinopathy pathology examination suggests impaired brain iron acquisition in
and REM sleep behavior disorder plus dementia or restless legs syndrome. Neurology 2003; 61:304–9.
parkinsonism. Neurology 2003a; 61:40–5. Connor JR, Wang XS, Patton SM et al. Decreased transferrin
Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM receptor expression by neuromelanin cells in restless legs
sleep behavior disorder in neurologic disorders: results in 14 syndrome. Neurology 2004; 62:1563–7.
patients. Sleep Med 2003b; 4:281–4. Cooper AJ. Treatment of co-existent night-terrors and
Boeve BF, Dickson DW, Olson EJ et al. Insights into REM sleep somnambulism in adults with imipramine and diazepam. J Clin
behavior disorder pathophysiology in brainstem-predominant Psychiatry 1987; 48:209–10.
Lewy body disease. Sleep Med 2007; 8:60–4. Critchley M. Periodic hypersomnia and megaphagia in adolescent
Boivin DB, James FO, Santo JB et al. Non-24-hour sleep-wake males. Brain 1962; 85:627–56.
syndrome following a car accident. Neurology 2003; Critchley M, Hoffman HL. The syndrome of periodic somnolence
60:1841–3. and morbid hunger (Kleine–Levin syndrome). BMJ 1942;
Boller F, Wright DG, Cavalieri R et al. Paroxysmal ‘nightmares’. 1:137–9.
Sequel of a stroke responsive to diphenylhydantoin. Neurology Crocker A, Espana RA, Papadopoulou M et al. Concomitant loss of
1975; 25:1026–8. dynorphin NARP and orexin in narcolepsy. Neurology 2005;
Brodeur C, Monplaisir J, Godbout R et al. Treatment of restless 65:1184–8.
legs syndrome and periodic movements during sleep with Crowley SJ, Lee C, Tseng CY et al. Combinations of bright light,
I-dopa: a double-blind, controlled study. Neurology 1988; scheduled dark, sunglasses, and melatonin to facilitate
38:1845–8. circadian entrainment to night shift work. J Biol Rhythms
Broughton RJ, Fleming JAE, George CFP et al. Randomized, 2003; 18:513–23.
double-blind, placebo-controlled crossover trial of modafinil in Culebras A, Moore JT. Magnetic resonance findings in REM sleep
the treatment of excessive daytime sleepiness in narcolepsy. behavior disorder. Neurology 1989; 39:1519–23.
Neurology 1997; 49:444–51. Czeisler CA, Richardson GS, Coleman RM et al. Chronotherapy:
Brownell LG, West P, Sweatman P et al. Protriptyline in resetting the circadian clocks of patients with delayed sleep
obstructive sleep apnea: a double-blind trial. N Engl J Med phase insomnia. Sleep 1981; 4:1–21.
1982; 307:1037–42. Czeisler CA, Johnson MP, Duffy JF et al. Exposure to bright light
Burstein A, Burstein A, Freehold NJ. Treatment of night terrors and darkness to treat physiologic maladaptation to night
with imipramine. J Clin Psychiatry 1983; 44:82. work. N Engl J Med 1990; 322:1253–9.
Burwell CS, Robin ED, Whaley RD et al. Extreme obesity Czeisler CA, Walsh JK, Roth T et al. Modafinil for excessive
associated with alveolar hypoventilation: a Pickwickian daytime sleepiness associated with shift-work sleep disorder.
syndrome. Am J Med 1956; 21:811–18. N Engl J Med 2005; 353:476–86.
Carpenter S, Yassa R, Ochs R. A pathologic basis for Kleine–Levin Dauvilliers Y. Follow-up of four narcolepsy patients treated with
syndrome. Arch Neurol 1982; 39:25–8. intravenous immunoglobulins. Ann Neurol 2006; 60:153.
p 18.qxd 3/10/08 9:52 AM Page 589
References 589
Dauvilliers Y, Mayer G, Lecendreux M et al. Kleine–Levin Fenzi F, Simonati A, Crosato F et al. Clinical features of
syndrome. An autoimmune hypothesis based on clinical and Kleine–Levin syndrome with localized encephalitis.
genetic analyses. Neurology 2002; 59:1739–45. Neuropediatrics 1993; 24:292–5.
Dehoorne JL, Raes AM, van Laecke E et al. Desmopressin toxicity Fernandez J-M, Lara I, Gila L et al. Disturbed hypothalamic-
due to prolonged half-life in 18 patients with nocturnal pituitary axis in idiopathic recurring hypersomnia syndrome.
enuresis. J Urol 2006; 176:754–7. Acta Neurol Scand 1990; 82:361–3.
Dement WC, Rechtschaffen AR, Gulevich GD. A polygraphic study Ferreira JJ, Galitzky M, Montrastruc JL et al. Sleep attacks and
of the narcoleptic sleep attacks. Electroencephalogr Clin Parkinson’s disease treatment. Lancet 2000; 355:1333–4.
Neurophysiol 1964; 17:608–9. Fisher C, Kahn E, Edwards A et al. A psychophysiological study of
Dement WC, Rechtschaffen AR, Gulevick GD. The nature of the nightmares and night terrors. I. Physiological aspects of the
narcoleptic sleep attack. Neurology 1966; 16:18–33. stage 4 night terror. J Nerv Ment Dis 1973a; 157:75–98.
Dempsey OJ, McGeoch P, de Silva RN et al. Acquired narcolepsy in Fisher C, Kahn E, Edwards A et al. A psychophysiological study of
an acromegalic patient who underwent pituitary irradiation. nightmares and night terrors: the suppression of stage
Neurology 2003; 61:537–40. 4 night terrors with diazepam. Arch Gen Psychiatry 1973b;
Di Gennaro G, Autret A, Mascia A et al. Night terrors 28:252–9.
associated with thalamic lesion. Clin Neurophysiol 2004; Forsythe WI, Butler RJ. Fifty years of enuretic alarms. Arch Dis
115:2489–92. Child 1989; 64:879–85.
DiMario FJ, Emery ES. The natural history of night terrors. Clin Forsythe WI, Redmond A. Enuresis and spontaneous cure rate of
Pediatr 1987; 26:505–11. 1129 enuretics. Arch Dis Child 1974; 49:259–63.
Drachman DB, Gumnit R. Periodic alteration of consciousness in Fournier JCM, Helguera RAL. Postencephalitic narcolepsy and
the ‘Pickwickian syndrome’. Arch Neurol 1962; 6:471–7. cataplexy: muscle and motor nerves electrical inexcitability
Drake ME. Jactatio nocturna after head injury. Neurology 1986; during the attack of cataplexy. J Nerv Ment Dis 1934;
36:867–8. 80:159–62.
Dressler D, Thompson PD, Marsden CD. The syndrome of painful Frey J, Darbonne C. Fluoxetine suppresses human cataplexy: a
legs and moving toes. Mov Disord 1994; 9:13–21. pilot study. Neurology 1994; 44:707–9.
Driver HS, Shapiro CM. Parasomnias. BMJ 1993; 306:921–4. Fritz GK, Rockney RM, Yeung AS. Plasma levels and efficacy of
Dyken ME, Lin-Dyken DC, Seaba P et al. Violent sleep-related imipramine treatment for enuresis. J Am Acad Child Adolesc
behavior leading to subdural hematoma. Arch Neurol 1995; Psychiatry 1994; 33:60–4.
52:318–21. Frucht S, Rogers JD, Greene PE et al. Falling asleep at the wheel:
Dyken ME, Yamada T, Glenn CL et al. Obstructive sleep apnea motor vehicle mishaps in persons taking pramipexole and
associated with cerebral hypoxemia and death. Neurology ropinirole. Neurology 1999; 52:1908–10.
2004; 62:491–3. Gadoth N, Kesler A, Vainstein G et al. Clinical and
Earley CJ, Connor JR, Beard JL et al. Abnormalities in CSF polysomnographic characteristics of 34 patients with
concentrations of ferritin and transferrin in restless legs Kleine–Levin syndrome. J Sleep Res 2001; 10:337–41.
syndrome. Neurology 2000; 54:1698–700. Gallinek A. Syndrome of episodes of hypersomnia, bulimia and
Ebrahim IO, Sharieff MK, de Laly S et al. Hypocretin (orexin) abnormal mental states. JAMA 1954; 154:1081–3.
deficiency in narcolepsy and primary hypersomnia. J Neurol Gallinek A. The Kleine–Levin syndrome: hypersomnia, bulimia, and
Neurosurg Psychiatry 2003; 74:127–30. abnormal mental states. World Neurology 1962; 3:235–43.
Edinger JD, Wohlgemuth WK, Radtke RA et al. Cognitive Ganji SS, Ferriss GS, Rao J et al. Hypersomnia associated
behavioral therapy for treatment of chronic primary insomnia: with a focal pontine lesion. Clin Electroencephalogr 1996;
a randomized controlled trial. JAMA 2001; 285:1856–64. 27:52–6.
Eisensehr I, Noachter S, von Schlippenbach C et al. Hypersomnia Gann H, Feige B, Fesihi S et al. Periodic limb movements during
associated with bilateral posterior hypothalamic lesions. A sleep in alcohol dependent patients. Eur Arch Psychiatry Clin
polysomniographic case study. Eur Neurol 2003; 49:169–72. Neurosci 2002; 252:124–9.
Ekbom KA. Restless legs syndrome. Neurology 1960; 10:868–73. Garcia-Borreguero D, Larrosa O, de la Llave Y et al. Treatment of
Erman M, Seiden D, Zammit G et al. An efficacy, safety, and dose- restless legs syndrome with gabapentin. A double-blind cross-
response study of ramelteon in patients with chronic primary over study. Neurology 2002; 59:1573–9.
insomnia. Sleep Med 2006; 7:17–24. Garland H, Sumner D, Fourman P. The Kleine–Levin syndrome:
Fantini ML, Michaud M, Gosselin N et al. Periodic leg movements some further observations. Neurology 1965; 15:1161–7.
in REM sleep behavior disorder and related autonomic and Gemignani F, Brindani F, Negrotti A et al. Restless legs syndrome
EEG activation. Neurology 2002; 59:1889–94. and polyneuropathy. Mov Disord 2006; 21:1254–7.
Fantini ML, Gagnon J-F, Filipini D et al. The effects of George CF, Nickerson PW, Janley PJ et al. Sleep apnoea patients
pramipexole in REM sleep behavior disorder. Neurology 2003; have more automobile accidents. Lancet 1987; 2:447.
61:1418–20. Gilbert GJ. Periodic hypersomnia and bulimia: the Kleine–Levin
Fantini ML, Cona A, Clerici S et al. Aggressive dream content syndrome. Neurology 1964; 14:844–50.
without daytime aggressiveness in REM sleep behavior Goldberg MA. The treatment of Kleine–Levin syndrome with
disorder. Neurology 2005; 65:1010–15. lithium. Can J Psychiatry 1983; 28:491–3.
p 18.qxd 3/10/08 9:52 AM Page 590
590 Sleep disorders
Goncalves MA, Guilleminault C, Ramos E et al. Erectile Hublin C, Kaprio J, Partinen M et al. Prevalence and genetics of
dysfunction, obstructive sleep apnea syndrome and nasal CPAP sleepwalking: a population-based twin study. Neurology 1997;
treatment. Sleep Med 2005; 6:333–9. 48:177–81.
von Gontard A, Scaumberg H, Hollmann E et al. The genetics of Hublin C, Kaprio J, Partinen M et al. Nightmares: familial
enuresis: a review. J Urol 2001; 166:2438–43. aggregation and association with psychiatric disorders in a
Grewal M, Hawa R, Shapiro C. Treatment of periodic limb nationwide twin cohort. Am J Med Genet 1999; 88:329–36.
movements in sleep with selegiline HCl. Mov Disord 2002; Ikeda K, Deguchi K, Touge T et al. Painful legs and moving toes
17:398–401. syndrome associated with herpes zoster myelitis. J Neurol Sci
Guilleminault C, Mignot E, Grumet FC. Familial patterns of 2004; 219:147–50.
narcolepsy. Lancet 1989; 2:1376–9. Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea
Guilleminault C, Aftab FA, Daradeniz D et al. problems associated mimicking REM sleep behavior disorder. Sleep 2005; 28:203–6.
with switch to modafinil – a novel alerting agent in Iranzo A, Munoz E, Santamaria J et al. REM sleep behavior
narcolepsy. Eur J Neurol 2000; 7:381–4. disorder and vocal cord paralysis in Machado-Joseph disease.
Hajak G, Rodenbeck A, Voderholzer U et al. Doxepin in the treatment Mov Disord 2003; 18:1179–83.
of primary insomnia: a placebo-controlled, double-blind, Iranz A, Graus F, Clover L et al. Rapid eye movement sleep
polysomnographic study. J Clin Psychiatry 2001; 62:453–63. behavior disorder and potassium channel antibody-associated
Hanley PJ, Zuberi-Khokhar N. Periodic limb movements during limbic encephalitis. Ann Neurol 2006; 59:178–82.
sleep in patients with congestive heart failure. Chest 1996; Joncas S, Zadra A, Paquet J et al. The value of sleep deprivation as
109:1497–502. a diagnostic tool in adult sleepwalkers. Neurology 2002;
Harazin J, Berigan TR. Zolpidem tartrate and somnambulism. Mil 58:936–40.
Med 1999; 164:669–70. Kales A, Kales JD. Sleep disorders: recent findings in the diagnosis
Harsch HH. Cyproheptadine for recurrent nightmares. Am J and treatment of disturbed sleep. N Engl J Med 1974;
Psychiatry 1986; 143:1491–2. 290:487–99.
Hartmann M, Pfister R, Pfadenhauer K. Restless legs syndrome Kales A, Jacobson A, Paulson MJ et al. Somnambulism:
associated with spinal cord lesions. J Neurol Neurosurg psychophysiological correlates. Arch Gen Psychiatry 1966;
Psychiatry 1999; 66:688–9. 14:586–94.
Hashizume V, Yoshijima H, Uchimura N et al. Case of head Kales A, Soldatos CR, Caldwell AB et al. Somnambulism: clinical
banging continuing into adolescence. Psychiatry Clin Neurosci characteristics and personality patterns. Arch Gen Psychiatry
2002; 56:255–6. 1980a; 37:1406–10.
Hauri P, Fisher J. Persistent psychophysiologic (learned) insomnia. Kales A, Soldatos CR, Bixler EO et al. Hereditary factors in
Sleep 1986; 9:38–53. sleepwalking and nightmares. Br J Psychiatry 1980b;
Hauser RA, Gauger L, McDowell Anderson W et al. Pramipexole- 137:111–18.
induced somnolence and episodes of daytime sleep. Mov Kales A, Soldatos CR, Caldwell AB et al. Nightmares: clinical
Disord 2000; 15:658–63. characteristics and personality patterns. Am J Psychiatry
Hayakawa T, Kamei Y, Urata J et al. Trials of bright light exposure 1980c; 137:1197–201.
and melatonin administration in a patient with non-24 hour Kales A, Cadieux RJ, Soldatos CR et al. Narcolepsy–cataplexy.
sleep-wake syndrome. Psychiatry Clin Neurosci 1998; 52:261–2. I. Clinical and electroencephalographic characteristics. Arch
Hishikawa Y, Kaneko Z. Electroencephalographic study on Neurol 1982; 39:164–8.
narcolepsy. Electroencephalogr Clin Neurophysiol 1965; Kales A, Soldatos CR, Kales JD. Sleep disorders: insomnia,
18:249–59. sleepwalking, night terrors, nightmares and enuresis. Ann Int
Hishikawa Y, Nanno H, Tachibana M et al. The nature of sleep Med 1987; 106:582–92.
attack and other symptoms of narcolepsy. Electroencephalogr Kang SY, Sohn YH, Lee IK et al. Unilateral periodic limb
Clin Neurophysiol 1968; 24:1–10. movements in sleep after supratentorial cerebral infarction.
Hogl B, Frauscher B, Seppi K et al. Transient restless legs Parkinsonism Relat Disord 2004; 10:429–31.
syndrome after spinal anesthesia. A prospective study. Kaplan PW, Allen RP, Buchholz DW et al. A double-blind, placebo-
Neurology 2002; 59:1705–7. controlled study of the treatment of periodic limb movements
Hohagen R, Monteero RF, Weiss E et al. Treatment of primary in sleep using carbidopa/levodopa and propoxyphene. Sleep
insomnia with trimipramine: an alternative to benzodiazepine 1993; 16:7171–23.
hypnotics? Eur Arch Psychiatry Clin Neurosci 1994; Kavey NB, Whyte J, Resor SR et al. Somnambulism in adults.
244:65–72. Neurology 1990; 40:749–52.
Hohjoh H, Takasu M, Shishikura K et al. Significant association of Kawashima T, Yamada S. Paroxetine-induced somnambulism.
the arylalkylamine N-acetyltransferase (AA-NAT) gene with J Clin Psychiatry 2003; 64:483.
delayed sleep phase syndrome. Neurogenetics 2003; 4:151–3. Kawauchi A, Inoue Y, Hashimotot T et al. Restless legs syndrome
Huang YS, Guilleminault C, Kao PF et al. SPECT findings in the in hemodialysis patients: health-related quality of life and
Kleine–Levin syndrome. Sleep 2005; 28:955–60. laboratory data analysis. Clin Nephrol 2006; 66:440–6.
Hublin C, Partinen M, Heinonen EH et al. Selegiline in the Kayumov L, Brown G, Jindal R et al. A randomized, double-blind,
treatment of narcolepsy. Neurology 1994; 44:2095–101. placebo-controlled crossover study of the effect of exogenous
p 18.qxd 3/10/08 9:52 AM Page 591
References 591
melatonin on delayed sleep phase syndrome. Psychosom Med Malow BA, Levy K, Maturen K et al. Obstructive sleep apnea is
2001; 63:40–8. common in medically refractory epilepsy patients. Neurology
Kellner R, Neidhardt J, Krakow B et al. Changes in chronic 2000; 55:1002–7.
nightmares after one session of desensitization or rehearsal Manconi M, Govoni V, De Vito A et al. Restless legs syndrome and
instructions. Am J Psychiatry 1992; 149:659–63. pregnancy. Neurology 2004; 63:1065–9.
Kessler R, Chaouat A, Shinkewitch P et al. The obesity- Manconi M, Fabbrini M, Bonanni E et al. High prevalence of
hypoventilation syndrome revisited: a prospective study of 34 restless legs syndrome in multiple sclerosis. Eur J Neurol 2007;
consecutive cases. Chest 2001; 120:369–76. 14:534–9.
Khazaal Y, Krenz S, Zullino DF. Bupropion-induced somnambulism. Manni R, Terzaghi M, Zambrelli E et al. Interictal, potentially
Addict Biol 2003; 8:359–62. misleading, epileptiform EEG abnormalities in REM sleep
Kim JS, Lee SB, Park SK et al. Periodic limb movement during behavior disorder. Sleep 2006; 29:934–7.
sleep developed after pontine lesion. Mov Disord 2003; Mayer G, Ewert Meier K, Hephata K. Selegiline hydrochloride
18:1403–5. treatment in narcolepsy: a double-blind, placebo-controlled
Kimura K, Tachbana N, Kohyama J et al. A discrete pontine study. Clin Neuropharmacol 1995; 18:306–19.
ischemic lesion could cause REM sleep behavior disorder. Mellman TA, Uhde TW. Sleep panic attacks: new clinical findings and
Neurology 2000; 55:894–5. theoretical implications. Am J Psychiatry 1989a; 146:1204–7.
Kingshott RN, Vennelle M, Coleman EL et al. Randomized, double- Mellman TA, Uhde TW. Electroencephalographic sleep in panic
blind, placebo-controlled crossover trial of modafinil in the disorder: a focus on sleep-related panic attacks. Arch Gen
treatment of residual excessive daytime sleepiness in the sleep Psychiatry 1989b; 46:178–89.
apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001; Mellman TA, Uhde TW. Patients with frequent sleep panic: clinical
163:918–23. findings and response to medication treatment. J Clin
Kleine W. Periodische schlafsucht. Monatsschriff fur Psychiatrie Psychiatry 1990; 51:513–16.
und Neurologie 1925; 57:285–320. Mendelson WB. Are periodic leg movements associated with
Koerber RK, Torkelson R, Haven G et al. Increased cerebrospinal clinical sleep disturbance? Sleep 1996; 19:219–23.
fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in Mendelson WB. A review of the evidence for the efficacy and
Kleine–Levin syndrome. Neurology 1984; 34:1597–600. safety of trazodone in insomnia. J Clin Psychiatry 2005;
Kolivakis TT, Margolese HC, Beauclair L et al. Olanzapine-induced 66:469–76.
somnambulism. Am J Psychiatry 2001; 158:1158. Mendelson WB, Garnett D, Gillin JC. Single case study:
Kraiczi H, Hedner J, Dahlof et al. Effect of serotonin reuptake flurazepam-induced sleep apnea syndrome in a patient with
inhibition on breathing during sleep and daytime symptoms in insomnia and mild sleep-related respiratory changes. J Nerv
obstructive sleep apnea. Sleep 1999; 22:61–7. Ment Dis 1981; 169:261–4.
Kramer NR, Bonitati AE, Millman RP. Enuresis and obstructive Mignot E, Lammers GJ, Ripley B et al. The role of cerebrospinal
sleep apnea. Chest 1998; 114:634–7. fluid hypocretin measurement in the diagnosis of narcolepsy
Kravitz H, Rosenthall V, Teplitz Z et al. A study of head-banging in and other hypersomnias. Arch Neurol 2002; 59; 1553–62.
infants and children. Dis Nerv Syst 1960; 21:203–8. Mikkelsen EJ, Rapoport JL, Nee L et al. Childhood enuresis. I. Sleep
Krishnan PR, Bhatia M, Behari M. Restless legs syndrome in patterns and psychopathology. Arch Gen Psychiatry 1980;
Parkinson’s disease: a case-controlled study. Mov Disord 2003; 37:1139–44.
18:181–5. Millman RP, Fogel BS, McNamara ME et al. Depression as a
Lankford DA, Wellman J, O’Hara C. Posttraumatic narcolepsy in manifestation of obstructive sleep apnea: reversal with nasal
mild to moderate closed head injury. Sleep 1994; 17(suppl. continuous positive airway pressure. J Clin Psychiatry 1989;
8):S25–8. 50:348–51.
Lee JW. Recurrent delirium associated with obstructive sleep Mitler MM, Shafor R, Hajdukovich R et al. Treatment of
apnea. Gen Hosp Psychiatry 1998; 20:120–2. narcolepsy: objective studies on methylphenidate, pemoline,
Lee MS, Choi YC, Lee SH et al. Sleep-related periodic leg and protriptyline. Sleep 1986a; 9:260–4.
movements associated with spinal cord lesions. Mov Disord Mitler MM, Browman CP, Menn SJ et al. Nocturnal myoclonus:
1996; 11:719–22. treatment efficacy of clonazepam and temazepam. Sleep
Levchenko A, Provost S, Montplaisir J-Y et al. A novel autosomal 1986b; 9:385–92.
dominant restless legs syndrome locus maps to chromosome Montagna P, Cirignotta F, Sacquegna T et al. ‘Painful legs and
20p13. Neurology 2006; 67:900–1. moving toes’ associated with polyneuropathy. J Neurol
Levin M. Periodic somnolence and morbid hunger: a new Neurosurg Psychiatry 1983; 46:399–403.
syndrome. Brain 1936; 59:494–504. Montplaisir J, Boucher S, Poirier G et al. Clinical,
Louden MB, Morehead MA, Schmidt HS. Activation by selegiline polysomnographic and genetic characteristics of restless legs
(Eldepryl) of REM sleep behavior disorder in parkinsonism. syndrome: a study of 133 patients diagnosed with new
W V Med J 1995; 91:101. standard criteria. Mov Disord 1997; 12:61–5.
McArthur AJ, Levy AJ, Sack RL. Non-24 hour sleep-wake Montplaisir J, Nicolas A, Denesle R et al. Restless legs syndrome
syndrome in a sighted man: circadian rhythm studies and improved by pramipexole: a double-blind randomized trial.
efficacy of melatonin treatment. Sleep 1996; 19:544–53. Neurology 1999; 52:938–43.
p 18.qxd 3/10/08 9:52 AM Page 592
592 Sleep disorders
Morgenthaler TI, Silber MH. Amnestic sleep-related eating Pedley TA, Guilleminault C. Episodic nocturnal wanderings
disorder associated with zolpidem. Sleep Med 2002; responsive to anticonvulsant drug therapy. Ann Neurol 1977;
3:323–7. 2:30–5.
Munoz X, Marti S, Sumalla J et al. Acute delirium as a Peled R, Lavie P. Double-blind evaluation of clonazepam on
manifestation of obstructive sleep apnea syndrome. Am J periodic leg movements in sleep. J Neurol Neurosurg
Respir Crit Care Med 1998; 158:1306–7. Psychiatry 1987; 50:1679–81.
Muratori R, Bertini N, Masi G. Efficacy of lithium treatment in Pereira DS, Tufik S, Louzada FM et al. Association of the length
Kleine–Levin syndrome. Eur Psychiatry 2002; 17; 232–3. polymorphism in the human Per3 gene with the delayed sleep
Nakamura K, Hashimoto S, Honma S et al. Daily melatonin intake phase syndrome: does latitude have an influence upon it?
resets circadian rhythms of a sighted man with non-24 hour Sleep 2005; 28:29–32.
sleep-wake syndrome who lacks the nocturnal melatonin rise. Perlis ML, McCall WV, Krystal AD et al. Long-term, non-nightly
Psychiatry Clin Neurosci 1997; 51:121–7. administration of zolpidem in the treatment of patients with
Nathan PW. Painful legs and moving toes: evidence on the site of primary insomnia. J Clin Psychiatry 2004; 65:1128–37.
the lesion. J Neurol Neurosurg Psychiatry 1978; 41:934–9. Perroud N, Lazignac C, Baleydier B et al. Restless legs syndrome
Neveus T, Stenberg A, Lackgren G et al. Sleep of children with induced by citalopram: a psychiatric emergency? Gen Hosp
enuresis: a polysomnographic study. Pediatrics 1999; Psychiatry 2007; 29:72–4.
103:1193–7. Peyron C, Faraco J, Rogers W et al. A mutation in a case of early
Neidhardt EJ, Krakow B, Kellner R. The beneficial effects of one onset narcolepsy and a generalized absence of hypocretin
treatment session and recording of nightmares on chronic peptides in human narcoleptic brains. Nat Med 2000;
nightmare sufferers. Sleep 1992; 15:470–3. 6:991–7.
Nofzinger EA, Fasiczka A, Berman S et al. Buropion SR reduces Pierce CM, Whitman RM, Gay ML. Enuresis and dreaming:
periodic limb movements associated with arousals from sleep experimental studies. Arch Gen Psychiatry 1961; 4:166–70.
in depressed patients with periodic limb movement disorder. J Pike M, Stores G. Kleine–Levin syndrome: a cause of diagnostic
Clin Psychiatry 2000; 61:858–62. confusion. Arch Dis Child 1994; 71:355–7.
Nowbar S, Burkart KM, Gonzales R et al. Obesity-associated Pillar G, Etzioni A, Shahar E et al. Melatonin treatment in an
hypoventilation in hospitalized patients: prevalence, effects, institutionalized child with psychomotor retardation and an
and outcome. Am J Med 2004; 116:58–9. irregular sleep-wake pattern. Arch Dis Child 1998; 79:63–4.
Odeh M, Oliven A. Coma and seizures due to severe hyponatremia Pittock SJ, Parrett T, Adler CH et al. Neuropathology of primary
and water intoxication in an adult with intranasal restless legs syndrome: absence of specific tau- and alpha-
desmopressin therapy for nocturnal enuresis. J Clin Pharmacol synucelin pathology. Mov Disord 2004; 19:695–9.
2001; 41:582–4. Pla MER, Dillingham TR, Spellman LT et al. Painful legs and
Ogura C, Okuma T, Nakazawa A. Treatment of periodic moving toes associated with tarsal tunnel syndrome and
somnolence with lithium carbonate. Arch Neurol 1976; accessory soleus muscle. Mov Disord 1996; 11:82–6.
33:143. Plazzi G, Montagna P. Remitting REM sleep behavior disorder
Ohanna N, Peled R, Rubin AH et al. Periodic leg movements in as the initial sign of multiple sclerosis. Sleep Med 2002;
sleep: effect of clonazepam treatment. Neurology 1985; 3:437–9.
35:408–11. Plazzi G, Corsini R, Provini F et al. REM sleep behavior disorders in
Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep multiple system atrophy. Neurology 1997; 48:1094–7.
behavior disorder: demographic, clinical and laboratory Polydefkis M, Allen RP, Hauer P et al. Subclinical sensory
findings in 93 cases. Brain 2000; 123:331–9. neuropathy in late-onset restless legs syndrome. Neurology
Ondo W, Jankovic J. Restless legs syndrome: clinicopathologic 2000; 55:1115–21.
correlates. Neurology 1996; 47:1435–41. Poppe M, Freibel D, Reuner U et al. The Kleine–Levin syndrome –
Ondo W, Romanyshyn J, Vuong KD et al. Long-term treatment of effects of treatment with lithium. Neuropediatrics 2003;
restless legs syndrome with dopamine agonists. Arch Neurol 34:113–19.
2004; 61:1393–7. Poryazova R, Siccoli M, Werth E et al. Unusually prolonged
Onofrj M, Luciano AL, Thomas A et al. Mirtazapine induces REM rebound cataplexy after withdrawal of fluoxetine. Neurology
sleep behavior disorder (RBD) in parkinsonism. Neurology 2005; 65:967–8.
2003; 60:113–15. Quinto C, Gellido C, Chokroverty S et al. Posttraumatic delayed
Oswald I. Sudden bodily jerks on falling asleep. Brain 1959; sleep phase syndrome. Neurology 2000; 54:250–2.
82:92–103. Rangarajan S, D’Souza GA. Restless legs syndrome in Indian
Palm L, Blennow G, Wetterberg L. Correction of non-24 hour patients having iron deficiency anemia in a tertiary care
sleep/wake cycle by melatonin in a blind retarded boy. Ann hospital. Sleep Med 2007; 8:247–51.
Neurol 1991; 29:336–9. Rechtschaffen A, Wolpert EA, Dement WC et al. Nocturnal sleep
Parkes JD. The parasomnias. Lancet 1986; 2:1021–5. of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;
Parkes JD, Baraitser M, Marsden CD et al. Natural history of 15:599–609.
symptoms and treatment of the narcoleptic syndrome. Acta Reid KJ, Chang AM, Dubocovich ML et al. Familial advanced sleep
Neurol Scand 1975; 52:337–53. phase syndrome. Arch Neurol 2001; 58:1089–94.
p 18.qxd 3/10/08 9:52 AM Page 593
References 593
Reid WH, Haffke EA, Chu CC. Diazepam in intractable Scheltens P, Visscher F, Van Keimpema ARJ et al. Sleep apnea
sleepwalking: a pilot study. Hillside J Clin Psychiatry 1984; syndrome presenting with cognitive impairment. Neurology
6:49–55. 1991; 41:155.
Reynolds CF, Black RS, Coble P et al. Similarities in EEG sleep Schenck CH, Mahowald MW. Polysomnographic, neurologic,
findings for Kleine–Levin syndrome and unipolar depression. psychiatric, and clinical outcome report on 70 consecutive
Am J Psychiatry 1980; 137:116–18. cases with REM sleep behavior disorder (RBD): sustained
Reynolds CF, Kupfer DJ, Christiansen CL et al. Multiple sleep clonazepam efficacy in 89.5 percent of 57 treated patients.
latency test findings in Kleine–Levin syndrome. J Nerv Ment Cleve Clin J Med 1990; 57(suppl.):S9–23.
Dis 1984; 172:41–4. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy:
Riemann D, Klein T, Todenbeck A et al. Nocturnal cortisol and rapid-eye-movement (REM) sleep without atonia and REM
melatonin secretion in primary insomnia. Psychiatry Res sleep behavior disorder. Ann Neurol 1992; 32:3–10.
2002a; 113:17–27. Schenck CH, Bundlie SR, Ettinger MG et al. Chronic behavioral
Riemann D, Voderholzer U, Cohrs S et al. Trimipramine in primary disorders of human REM sleep: a new category of parasomnia.
insomnia: results of a polysomnographic double-blind study. Sleep 1986; 9:293–308.
Pharmacopsychiatry 2002b; 35:165–74. Schenck CH, Bundlie SR, Patterson AL et al. Rapid eye movement
Rijsman RM, de Weerd AW, Stam CJ et al. Periodic limb sleep behavior disorder. A treatable parasomnia affecting older
movement disorder and restless legs syndrome in dialysis adults. JAMA 1987; 257:1786–9.
patients. Nephrology 2004; 9:353–61. Schenck CH, Milner DM, Hurwitz TD et al. A polysomnographic
Ringman JM, Simmons JH. Treatment of REM sleep behavior and clinical report on sleep-related injury in 100 adult
disorder with donepezil; a report of three cases. Neurology patients. Am J Psychiatry 1989; 146:1166–73.
2000; 55:870–1. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a
Roehrs TA, Zorick FJ, Wittig RM et al. Alerting effects of naps in parkinsonian disorder in 38% of 29 older men initially
patients with narcolepsy. Sleep 1986; 9:194–9. diagnosed with idiopathic rapid eye movement sleep behavior
Rogers AE, Aldrich MS, Liu X. A comparison of three different disorder. Neurology 1996a; 46:388–93.
sleep schedules for reducing daytime sleepiness in narcolepsy. Schenck CH, Garcia-Rill E, Skinner RD et al. A case of REM sleep
Sleep 2001; 24:385–91. behavior disorder with autopsy-confirmed Alzheimer’s disease:
Roizenblatt S, Guilleminault C, Poyares D et al. A double-blind, postmortem brain stem histochemical analyses. Biol Psychiatry
placebo-controlled, crossover study of sildenafil in obstructive 1996b; 40:422–5.
sleep apnea. Arch Int Med 2006; 166:1763–7. Schmidauer C, Sojer M, Seppi K et al. Transcranial ultrasound
Rosenfeld MR, Eichen JG, Wade DF et al. Molecular and clinical shows migral hypoechogenicity in restless legs syndrome. Ann
diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2005; 58:630–4.
Neurol 2001; 50:339–48. Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM
Sachs S, Persson HE, Hagenfeldt K. Menstruation-related periodic sleep behavior disorder: results from a case series. Sleep Med
hypersomnia: a case study with successful treatment. 2006; 7:418–23.
Neurology 1982; 32:1376–9. Schott GD. ‘Painful legs and moving toes’: the role of trauma.
Sagar RS, Khandelwal SK, Gupta S. Interepisodic morbidity in J Neurol Neurosurg Psychiatry 1981; 44:344–6.
Kleine–Levin syndrome. Br J Psychiatry 1990; 157:139–41. Schulman SI, Stokes A, Salzman PM. The efficacy and safety of
Saletu M, Anderer P, Saletu-Zyhlarz G et al. Restless legs oral desmopressin in children with primary nocturnal enuresis.
syndrome (RLS) and periodic limb movement disorder (PLMD): J Urol 2001; 166:2427–31.
acute placebo-controlled sleep laboratory studies with Schwartz JRL, Feldman NT, Bogan RK. Dose effects of modafinil in
clonazepam. Eur Neuropsychopharmacol 2001; sustaining wakefulness in narcolepsy patients with residual
11:153–61. evening sleepiness. J Neuropsychiatry Clin Neurosci 2005a;
Sandberg O, Franklin KA, Bucht G et al. Sleep apnea, delirium, 17:405–12.
depressed mood, cognition and ADL ability after stroke. J Am Schwartz DJ, Kohler WC, Katarinos G. Symptoms of depression in
Geriatr Soc 2001; 49:391–7. individuals with obstructive sleep apnea may be amenable to
Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A et al. Restless treatment with continuous positive airway pressure. Chest
legs syndrome and paroxetine. Acta Psychiatr Scand 1996; 2005b; 128:1304–9.
94:482–4. Scrima L, Broudy M, Nay KN et al. Increased severity of obstructive
Sattar SP, Ramaswamy S, Bhatia SC, Petty F. Somnambulism due sleep apnea after bedtime alcohol ingestion: diagnostic potential
to a probable interaction of valproic acid and zolpidem. Ann and proposed mechanism of action. Sleep 1982; 5:318–28.
Pharmacother 2003; 37:1429–33. Sieker HO, Estes EH, Kelser GA et al. Cardiopulmonary syndrome
Scammell TE, Nishino S, Mignot E et al. Narcolepsy and low CSF with extreme obesity. J Clin Invest 1955; 34:916.
orexin (hypocretin) concentration after a diencephalic stroke. Smith PL, Gold AR, Meyers DA et al. Weight loss in mildly to
Neurology 2001; 56:1751–3. moderately obese patients with obstructive sleep apnea. Ann
Schacter M, Parkes JD. Fluvoxamine and clomipramine in the Intern Med 1985; 103:850–5.
treatment of cataplexy. J Neurol Neurosurg Psychiatry 1980; Smith RC. Relationship of periodic movements in sleep (nocturnal
43:171–4. myoclonus) and the Babinski sign. Sleep 1985; 8:239–43.
p 18.qxd 3/10/08 9:52 AM Page 594
594 Sleep disorders
Smits MG, Nagtegaal EE, van der Heijden J et al. Melatonin for TREAT RLS 1 study, a 12 week, randomized, placebo controlled
chronic sleep onset insomnia in children: a randomized study in 10 European countries. J Neurol Neurosurg Psychiatry
placebo-controlled trial. J Child Neurol 2001; 16:86–92. 2004; 75:92–7.
Sonka K, Kemlink D, Pretl M. Cataplexy treated with escitalopram Turner RS, D’Amato CJ, Chervin RD et al. The pathology of REM
– clinical experience. Neurol Endocrinol Lett 2006; 27:174–6. sleep behavior disorder with comorbid Lewy body dementia.
Sours JA, Frumkin P, Indermill RR. Somnambulism: its clinical Neurology 2000; 55:1730–2.
significance and dynamic meaning in late adolescence and Uchiyama M, Isse K, Tanaka K et al. Incidental Lewy body disease
adulthood. Arch Gen Psychiatry 1963; 9:400–13. in a patient with REM sleep behavior disorder. Neurology
Spillane JD, Nathan PW, Kelly RE et al. Painful legs and moving 1995; 45:709–12.
toes. Brain 1971; 94:541–56. US Modafinil in Narcolepsy Multicenter Study Group. Randomized
Staedt J, Stoppe G, Kogler A et al. Nocturnal myoclonus syndrome trial of modafinil for the treatment of pathological
(periodic movements in sleep) related to central dopamine D2- somnolence in narcolepsy. Ann Neurol 1998; 43:88–97.
receptor alteration Eur Arch Psychiatry Clin Neurosci 1995; US Modafinil in Narcolepsy Multicenter Study Group. Randomized
245:8–10. trial of modafinil as a treatment for the excessive daytime
Stahl SM, Layzer RB, Aminoff MJ et al. Continuous cataplexy in a sleepiness of narcolepsy. Neurology 2000; 54:1166–75.
patient with a midbrain tumor: the limp man syndrome. Wagner ML, Walters AS, Coleman RG et al. Randomized, double-
Neurology 1980; 30:1115–18. blind, placebo-controlled study of clonidine in restless legs
Staner L, Ertle S, Boeijinga P et al. Next-day residual effects of syndrome. Sleep 1996; 19:52–8.
hypnotics in DSM-IV primary insomnia: a driving simulator Walters AS, Hening W, Rubinstein M et al. A clinical and
study with simultaneous electroencephalographic monitoring. polysomnographic comparison of neuroleptic-induced
Psychopharmacology 2005; 181:790–8. akathisia and the idiopathic restless legs syndrome. Sleep
Steiner MC, Ward MJ, Ali NJ. Dementia and snoring. Lancet 1999; 1991; 14:339–45.
353:204. Walters AS, Wagner ML, Hening WA et al. Successful treatment of
Strollo PJ, Rogers RM. Obstructive sleep apnea. N Engl J Med idiopathic restless legs syndrome in a randomized double-
1996; 334:99–104. blind trial of oxycodone versus placebo. Sleep 1993;
Suhner A, Schlagenhauf P, Hofer I et al. Effectiveness and 16:327–32.
tolerability of melatonin and zolpidem for the alleviation of jet Ward WA, Kelsey WM. The Pickwickian syndrome: a review of the
lag. Aviat Space Environ Med 2001; 72:638–46. literature and report of a case. J Pediatr 1962; 61:745–50.
Sutton FD, Zwillich CW, Creagh CE et al. Progesterone for Ware JC, Brown FU, Moorad PJ et al. Nocturnal myoclonus and
outpatient treatment of Pickwickian syndrome. Ann Intern tricyclic antidepressants. Sleep Res 1984; 13:72.
Med 1975; 83:476–9. Watanabe T, Kajimura N, Kato M et al. Effects of phototherapy in
Takano A, Uchiyama M, Kajimura N et al. A missense variation in patients with delayed sleep phase syndrome. Psychiatry Clin
human casein kinase I epsilon gene that induces functional Neurosci 1999; 53:231–3.
alteration and shows an inverse association with circadian de Weerd AW, Rijsman RM, Brinkley A. Activity patterns of leg
rhythm sleep disorders. Neuropsychopharmacology 2004; muscles in periodic limb movement disorder. J Neurol
Tan A, Selgado M, Fahn S. Rapid eye movement sleep behavior Weitzman ED, Cseisler CA, Coleman RM et al. Delayed sleep phase
disorder preceding Parkinson’s disease with therapeutic syndrome. A chronobiological disorder with sleep-onset
response to levodopa. Mov Disord 1996; 11:214–16. insomnia. Arch Gen Psychiatry 1981; 38:737–46.
Thirumalai SS, Shubin RA. The use of citalopram in resistant White DP, Zwillich CW, Pickett CK et al. Central sleep apnea.
cataplexy. Sleep Med 2000; 1:313–16. Improvement with acetazolamide therapy. Arch Int Med 1982;
Tinuper P, Cerullo A, Cirignotta F et al. Nocturnal paroxysmal 142:1816–19.
dystonia: three cases with evidence for an epileptic frontal Whitney JF, Gannon DE. Obstructive sleep apnea presenting as
lobe origin of seizures. Epilepsia 1990; 31:549–56. acute delirium. Am J Emerg Med 1996; 14:270–1.
Tippmann-Peikert M, Boeve BF, Keegam BM. REM sleep behavior Whyte KF, Allen MB, Jeffrey AA et al. Clinical features of the sleep
disorder initiated by acute brainstem multiple sclerosis. apnoea/hypopnoea syndrome. Q J Med 1989; 72:659–66.
Neurology 2006; 66:1277–9. Whyte J, Kavey NB, Gidro-Frank S. A self-destructive variant of
Tippmann-Peikert M, Park G, Boeve BF et al. Pathologic gambling jactatio capitis nocturna. J Nerv Ment Dis 1991; 179:49–50.
in patients with restless legs syndrome treated with Will RG, Young JPR, Thomas DJ. Kleine-Levin syndrome: report of
dopaminergic agonists. Neurology 2007; 68:301–3. two cases with onset of symptoms precipitated by head
Tobin JD. Treatment of somnambulism with anticipatory trauma. Br J Psychiatry 1988; 152:410–12.
awakening. J Pediatr 1993; 122:426–7. Wilson SAK. The narcolepsies. Brain 1928; 51:63–109.
Trenkwalder C, Seidel VC, Gasser T et al. Clinical symptoms and Wilson SJ, Lillywhite AR, Potokar JP et al. Adult night terrors and
possible anticipation in a large kindred of familial restless legs paroxetine. Lancet 1997; 350:185.
syndrome. Mov Disord 1996; 11:389–94. Winkelmann JW, Chertow GM, Lazarus JM. Restless legs
Trenkwalder C, Garcia-Borreguero D, Montagna P et al. Ropinirole syndrome in end-stage renal disease. Am J Kidney Dis 1996;
in the treatment of restless legs syndrome: results from the 28:372–8.
p 18.qxd 3/10/08 9:52 AM Page 595
References 595
Winkelmann J, Wetter TC, Collado-Seidel V et al. Clinical Yaggi HK, Concato J, Kernan WM et al. Obstructive sleep apnea as
characteristics of the hereditary restless legs syndrome in a a risk factor for stroke and death. N Engl J Med 2005;
population of 300 patients. Sleep 2000; 23:597–602. 353:2034–45.
Winkelmann J, Muller-Myhsok B, Wittchen H-U et al. Complex Yang W, Dollear M, Muthukrishnan SR. One rare side effect of
segregation analysis of restless legs syndrome provides zolpidem – sleepwalking: a case report. Arch Phys Med Rehabil
evidence of an autosomal dominant mode of inheritance in 2005; 86:1265–6.
early age at onset families. Ann Neurol 2002; 52:297–302. Zambelis T, Paparrigopoulos T, Soldatos CR. REM sleep behavior
Winkelmann JW, Sethi KD, Kushida CA et al. Efficacy and safety of disorder associated with a neurinoma of the left pontocerebellar
pramipexole in restless legs syndrome. Neurology 2006; angle. J Neurol Neurosurg Psychiatry 2002; 72:821–2.
67:1034–9. Zammit GK, McNabb LJ, Caron J et al. Efficacy and safety of
Wyatt JK. Delayed sleep phase syndrome: pathophysiology and eszopiclone across 6 weeks of treatment for primary insomnia.
treatment options. Sleep 2004; 27:1195–203. Curr Med Res Opin 2004; 20:1979–91.
Xu Y, Padiath QS, Shapiro RE et al. Functional consequences of a Zhdanova IV, Wurtman RJ, Regan MM et al. Melatonin treatment
CKIdelta mutation causing familial advanced sleep phase for age-related insomnia. J Clin Endocrincol Metabol 2001;
syndrome. Nature 2005; 434:640–4. 86:4727–30.
p 19.qxd 3/10/08 9:53 AM Page 596
19
Brain tumors and hydrocephalus
19.1 Brain tumors 596 19.3 Normal pressure hydrocephalus 602

19.2 Hydrocephalus 600 References 604
19.1 BRAIN TUMORS In most cases the headache reflects stretching of pain-
sensitive structures; should increased intracranial pressure
Neoplastic brain tumors may be broadly divided into two occur, the headache may worsen and be joined, classically,
types, namely those neoplasms that are primary to the by projectile vomiting.
brain, such as gliomas or meningiomas, and those that rep- Non-focal symptoms often reflect increased intracranial
resent metastases from systemic cancers, such as lung or pressure and may include dizziness, ‘fuzziness’ of thought,
breast cancer. and somnolence (Davison and Demuth 1945, 1946;
McKendree and Feinier 1927).
Focal signs and specific syndromes typically reflect com-
Clinical features pression of brain tissue by the tumor mass or peri-tumoral
edema. Traditional focal signs, such as hemiplegia, aphasia,
Although brain tumors may occur at any age, most patients apraxia, and hemianopia, may occur and may serve to both
are middle-aged or older. The onset itself ranges from acute lateralize and localize the tumor; compression or stretch-
to insidious, depending in large part on the aggressiveness ing of cranial nerves may result in appropriate cranial nerve
of the tumor involved. Certain gliomas, such as glioblas- palsies. Specific syndromes seen with tumors include, most
toma multiforme, may evolve rapidly over several weeks or commonly, dementia and personality change; other spe-
months, whereas some meningiomas may attain a large size cific syndromes, seen in a small minority, include delirium,
without ever causing symptoms (Olivero et al. 1995) and amnesia, mania, depression, and psychosis.
may indeed be found incidentally on imaging for other Dementia is classically seen with tumors of the frontal
reasons or at autopsy. lobe (Sachs 1950) or corpus callosum (Alpers and Grant
The symptomatology of brain tumors varies according 1931; Moersch 1925), and in such cases it is often accom-
to their location, size, the extent of peri-tumoral vasogenic panied by apathy, dullness, and somnolence (Williamson
edema, and the appearance of increased intracranial pres- 1896) or by a frontal lobe syndrome (Frazier 1936). Tumors
sure; there is generally little room for expansion within the of the thalamus and hypothalamus (Alpers 1937; Liss 1958;
intracranial vault and, with growth of a tumor and, espe- Strauss and Globus 1931) may also cause dementia, and
cially, expansion of vasogenic edema, there is an inevitable with hypothalamic tumors one often sees additional symp-
rise in overall intracranial pressure, which may eventually toms (Beal et al. 1981), such as hypersomnolence, weight
produce symptoms in its own right. gain or diabetes insipidus.
The overall symptomatology seen with brain tumors Personality change may be seen with tumors of the frontal
may be divided into the following domains: headache; non- lobe (Direkze et al. 1971; Strauss and Keschner 1935) or
focal symptoms; focal signs and specific syndromes, such as temporal lobe and, rarely, with tumors of the thalamus or
dementia or personality change; and seizures. Each of these hypothalamus. Although this personality change may be
is considered in turn below. non-specific, in cases of frontal lobe tumors one classically
Headache (Forsyth and Posner 1993) may be general- sees an accompanying frontal lobe syndrome (Avery 1971).
ized or have a unilateral predominance, in which case it Delirium may occur with tumors of the temporal lobe
may have some lateralizing value. The headache itself tends (Keschner et al. 1936) or the hypothalamus (Alpers 1940).
to be dull and may be severe. Classically, it is worst in the Amnesia, with isolated short-term memory loss, may be
morning upon awakening and is worsened by recumbancy. seen with tumors that impinge on any part of the circuit of
p 19.qxd 3/10/08 9:53 AM Page 597
Papez, for example the fornix (e.g., by a subsplenial tumor), search must be made for a primary tumor and this may
the mamillary bodies (e.g., by a craniopharyngioma), and include CT of the chest, abdomen, and pelvis, and, in lim-
the thalamus. iting cases, total body positron emission tomography (PET)
Mania may uncommonly occur with tumors of the scanning.
mesencephalon, hypothalamus, thalamus, cingulate gyrus,
or frontal lobe.
Depression may rarely constitute the presentation of a Course
tumor, as has been noted with a tumor of the anterior por-
tion of the corpus callosum (Ironside and Guttmacher 1929). The natural course varies widely, depending on the malig-
Psychosis may occur with tumors, most commonly of the nancy of the tumor itself, ranging from as little as months
temporal lobe (Gal 1958; Keschner et al. 1936; Malamud in the case of glioblastoma multiforme up to a decade or
1967; Strobos 1953; Tucker et al. 1986); other locations more with low-grade gliomas.
include the frontal lobe (Strauss and Keschner 1935) and
the corpus callosum (Murthy et al. 1997).
Finally, a few words are in order regarding tumors located Etiology
in the hypothalamus. As noted earlier, these may present
with dementia, personality change, delirium, amnesia, or As noted earlier, brain tumors may be either primary to the
mania. Other symptoms may also be seen, including dia- central nervous system or metastatic; of these two broad
betes insipidus, anorexia with profound weight loss (Heron types, metastatic tumors are more common.
and Johnston 1976; White et al. 1977), and hyperphagia with
extreme weight gain (Fulton and Bailey 1929; Liss 1958), PRIMARY TUMORS
which may, in rare instances, be accompanied by episodic
rage (Haugh and Markesbery 1983; Reeves and Plum 1969). Of the primary brain tumors, gliomas and meningiomas
Seizures are eventually seen in approximately one-third constitute the vast majority of cases. Primary central nerv-
of all brain tumor cases, and may be simple partial, com- ous system lymphoma, once rare, has become increasingly
plex partial, or grand mal in type. In some cases of small, common, both in immunocompromised and immuno-
slowly growing tumors, such as oligodendrogliomas or competent patients. Other primary brain tumors, seen in a
low-grade astrocytomas, seizures may constitute the sole small minority, include neuromas, medulloblastoma,
symptomatology of the underlying tumor for long periods gangliocytoma, pituitary adenoma, craniopharyngioma,
of time. pineal tumors, hemangioblastoma, and colloid cyst of the
With growth of the tumor and enlargement of the area third ventricle. Each of these is considered further below.
of peri-tumoral edema, the clinical picture evolves, with Gliomas include astrocytomas, oligodendrogliomas,
worsening of initial symptoms and addition of new ones. and ependymomas. Astrocytomas are by far the most com-
In some cases, hydrocephalus may occur, with symptoms as mon type and may be divided into four grades according to
discussed in Section 19.2. In other cases, there may be acute their malignancy, namely grades I, II, III, and IV. Grades
clinical exacerbations due to either intratumoral hemor- I and II astrocytoma, or ‘low-grade’ astrocytomas, are slow
rhage or infarction secondary to arterial compression. growing, whereas grades III and IV, or ‘malignant’ or ‘high-
Magnetic resonance (MR) scanning should, if possible, grade’ astrocytomas, tend to be rather aggressive. Grade IV
be obtained in all cases, and this should generally be with astrocytoma is also known as glioblastoma multiforme;
gadolinium enhancement. Computed tomography (CT) this is the most common of the gliomas and is extremely
scanning, again with enhancement, is an alternative, but far aggressive. Astrocytomas tend to occur in the white matter
less sensitive technique. of the frontal, temporal, or parietal lobes, but may also be
Lumbar puncture, although not routine, may be appro- found in the cerebellum or brainstem. On MR scanning,
priate when certain tumors are suspected, such as primary low-grade astrocytomas have decreased signal intensity on
central nervous system lymphoma or leptomeningeal T1-weighted imaging and display homogenous increased
carcinomatosis. signal intensity on T2-weighted imaging; there may or may
Although in most cases of metastatic disease the sys- not be enhancement. High-grade astrocytomas may appear
temic cancer is already known, in a minority of cases, per- heterogenous on T1- and T2-weighted imaging, and typi-
haps up to one-quarter, the metastasis represents the cally undergo enhancement, which, especially in the case of
presentation of the systemic cancer, and, consequently, in glioblastoma multiforme, may be ring-shaped. Over long
evaluating patients with a brain tumor who do not appar- periods of time, low-grade astrocytomas may undergo malig-
ently have systemic cancer, this possibility must always be nant transformation. A variant form of glioma is known as
kept in mind. One clue to the metastatic nature of the dis- gliomatosis cerebri. This is a very aggressive growth char-
ease is the number of tumors: whereas primary tumors, acterized not by a discrete mass but by a widespread infiltra-
with the exception of primary central nervous system lym- tion of one or both hemispheres of the cerebrum, primarily
phoma, are generally singular, metastatic disease generally of the white matter; patients typically present with delir-
manifests with two or more lesions. In such cases, a diligent ium, headache, and seizures, and MR scanning may reveal
p 19.qxd 3/10/08 9:53 AM Page 598
598 Brain tumors and hydrocephalus
a Foster Kennedy syndrome may occur, with ipsilateral

anosmia, ipsilateral optic atrophy, and contralateral
papilledema. Suprasellar meningiomas may cause a bitem-
poral hemianopia and pituitary failure, and meningiomas
of the sphenoid ridge may present with extraocular nerve
palsies and proptosis. All meningiomas may also be associ-
ated with seizures. Rarely, rather than presenting as a cir-
cumscribed mass, meningiomas may present ‘en plaque’ as
a sheath-like structure.
Primary central nervous system lymphoma, once rare, has
recently shown an increasing incidence, and this appears to
be the case not only in immunocompromised patients, such
as transplant patients (Schneck and Penn 1970) and those
with AIDS (Feiden et al. 1993; Lang et al. 1989), but also in
immunocompetent elderly patients. These tumors may be
single or multiple and typically show bright, homogenous
enhancement (Lai et al. 2002). Although most are found in
the cerebrum, often in a periventricular location, they may
also occur in the cerebellum or brainstem. They often seed
Figure 19.1 A sagittal T1-weighted magnetic resonance scan into the cerebrospinal fluid (CSF), and a suspicion of
demonstrates the clear demarcation between a meningioma and primary central nervous system lymphoma is one situation
the surrounding tissue. (Reproduced from Gillespie and Jackson where a lumbar puncture should be seriously considered.
2000.) Neuromas, although capable of arising from cranial nerves
V, VII, IX, or X, are by far most commonly associated with
cranial nerve VIII, in which case they are referred to as
diffusely increased signal intensity in the white matter, acoustic neuromas. These acoustic neuromas constitute
which may undergo enhancement. the most common cause of a cerebellopontine angle tumor
Oligodendrogliomas arise from oligodendrocytes and and typically present with hearing loss, accompanied in
are indolent growths (Wilkinson et al. 1987) found typi- most cases by dysequilibrium and tinnitus; with growth of
cally in the white matter of the frontal or temporal lobes, the tumor and compression of cranial nerves V and VII,
which often present with seizures; on MR scanning they there may be facial numbness and a peripheral facial palsy;
present as non-enhancing masses with increased signal rarely, a trigeminal neuralgia may occur (Harner and Laws
intensity on T2-weighted images, and on CT scans one may 1983). In cases in which the cerebellum is compressed,
appreciate calcification. there may be nystagmus and ataxia.
Ependymomas, although most commonly seen in chil- Medulloblastomas, although generally seen only in chil-
dren, may present in early adult years. These tumors arise dren, may occasionally occur in adults. These are typically
from ependymal cells of the fourth, third, or lateral ventri- found in the midline cerebellum and often protrude into
cles, and may cause symptoms either by causing obstruc- the fourth ventricle, causing hydrocephalus.
tive hydrocephalus or by extending into the adjacent brain Gangliocytomas (Kernohan et al. 1932) are composed of
parenchyma; they may undergo calcification and may neural elements, and gangliogliomas (Morris et al. 1993) of
show enhancement. both neural and glial elements. These are rare, indolent
Meningiomas are very slow growing tumors that arise tumors, generally found in the temporal, frontal, or parietal
from arachnoidal cells and which have an attachment to cortices, which typically present with seizures.
the dura. These are well-demarcated, extra-axial tumors Pituitary adenomas may be subclassified according to
that produce symptoms by compression of the subjacent either their size or their endocrinologic status. Macroade-
brain parenchyma, from which they are clearly separated, nomas are larger than 1 cm, whereas microadenomas,
as illustrated in Figure 19.1. Although they may or may not which are more common, are smaller. Endocrinologically,
be readily discernible on T2-weighted scans, they do more than 80 percent of adenomas are secretory, with the
undergo homogenous enhancement. There are several remainder being non-productive. Pituitary adenomas may
favored locations. Meningiomas of the falx cerebri, by cause symptoms by either compression of adjacent tissue
compression of the medial aspects of the frontal or parietal or secondary to the secretion of various hormones. With
cortices, may cause dementia or paraparesis. Lateral con- compression of adjacent pituitary tissue there may be
vexity meningiomas may cause various focal signs, such as pituitary failure, with, for example, hypothyroidism or
hemiplegia or aphasia. Olfactory groove meningiomas may adrenocortical insufficiency. Lateral extension of a
cause anosmia, blindness, and, by upward extension macroadenoma into the adjacent cavernous sinus may
against the frontal lobe, dementia; should they attain a size cause an oculomotor palsy or facial numbness in the areas
capable of causing increased intracranial pressure, of the first or second divisions of the trigeminal nerve.
p 19.qxd 3/10/08 9:53 AM Page 599
In turn, upward extension of a macroadenoma may impinge

on the optic chiasm, with a bitemporal hemianopia; on the
hypothalamus, with diabetes insipidus; or, in extreme cases,
on the frontal lobe, with cognitive changes and seizures.
Endocrinologic changes seen with secretory tumors most
commonly involve hyperprolactinemia, with amenorrhea in
females and gynecomastia and erectile dysfunction in males.
Excess growth hormone and adrenocorticotropic hormone
(ACTH) secretion are the next most common changes and
may cause acromegaly or Cushing’s disease respectively.
Gonadotropin and thyroid-stimulating hormone (TSH)
excess are rare. Importantly, in about 10 percent of secreting
adenomas, two or more hormones may be excessively pro-
duced. In addition, in some cases of macroadenomas there
may be ‘kinking’ of the pituitary stalk, and in such cases
dopamine delivery to the posterior pituitary may be
impaired with a resultant secondary hyperprolactinemia.
Magnetic resonance scanning is typically positive with
macroadenomas; however, microadenomas of less than
3 mm in diameter may escape detection. In rare instances,
Figure 19.2 This unenhanced computed tomography scan
pituitary adenomas may undergo hemorrhage or infarction,
demonstrates a colloid cyst, which, by obstructing the foramen of
producing the syndrome of ‘pituitary apoplexy’ with severe
Monro, has caused obstructive hydrocephalus with dilation of the
headache, diplopia, blindness, and, critically, an acute case of
lateral ventricles. (Reproduced from Gillespie and Jackson 2000.)
adrenocortical insufficiency, which may be fatal.
Craniopharyngiomas are lobulated, calcified tumors
that, although most commonly occurring in children, may METASTATIC TUMORS
occur in patients of any age. They typically arise from the
junction of the infundibulum and pituitary gland, and may Metastases may arise from various different primary
produce a variety of symptoms, depending on which direc- tumors and almost always reach the brain via hematoge-
tion they grow in. With upward extension and impinge- nous spread. By far the most common source is lung can-
ment of the hypothalamus, there may be diabetes insipidus cer, primarily the non-small-cell type, followed by breast
and obesity, and with compression of the third ventricle, cancer and melanoma and then by various other tumors,
hydrocephalus may occur. Compression of the optic chiasm including those of the colon and rectum, kidney, gallblad-
may cause a bitemporal hemianopia, and with downward der, liver, thyroid, testicle, prostate, uterus or ovary, and
extension various forms of pituitary failure may appear. pancreas; both systemic lymphoma (primarily of the non-
Pineal tumors include not only pinealomas but also Hodgkin’s type) and leukemia may also metastasize to the
germ cell tumors, gliomas, and teratomas. These tumors brain. Of all these primaries, melanoma and testicular can-
cause symptoms primarily by compression of the adjacent cer, although not common, exhibit the greatest propensity
quadrigeminal plate and the underlying aqueduct of Sylvius, for metastasis to the brain.
with a Parinaud syndrome (limitation of upgaze and an Two-thirds of metastases eventually settle in the brain
Argyll Robertson pupil) and obstructive hydrocephalus parenchyma, whereas the remainder lodge either in the
respectively. leptomeninges (where they create a condition known as
Hemangioblastomas (Boughey et al. 1990) are cystic leptomeningeal carcinomatosis) or in the dura. Parenchymal
masses found in the cerebellum, which typically contain an metastases may be found throughout the cerebrum (Delattre
enhancing nodule on MR scanning. They are found in chil- et al. 1988a); they are found in the hemispheres in about
dren or young adults, usually present with cerebellar symp- three-quarters of cases, in the cerebellum in about one-
toms, and may occur as part of von Hippel–Lindau disease. eighth, and in the brainstem or thalamus in the remainder;
Colloid cysts of the third ventricle are rare cystic masses that of those lodging in the hemispheres, all lobes may be
may cause dementia (Kelly 1951), either by compression of involved, including, in descending order, the frontal, pari-
the surrounding thalamus (Faris and Terrence 1989; Lobosky etal, occipital, and temporal lobes.
et al. 1984) or as a result of obstructive hydrocephalus, as illus- Metastases to the parenchyma generally appear as
trated in Figure 19.2. Interestingly, by virtue of a ‘ball-valve’ homogenously enhancing masses, often with considerable
effect, in which the foramen of Monro is intermittently peri-tumoral edema; in high-grade malignancies, however,
occluded, these tumors may also cause intermittent elevations central necrosis may lead to a ring-enhancing pattern.
of intraventricular pressure. Thus, patients may experience Although solitary lesions may occur, multiple tumors, as
intermittent headache, unsteadiness, and confusion, and noted earlier, are more common, and indeed at autopsy
report that these symptoms are posture-dependent. one may find widespread, microscopic foci.
p 19.qxd 3/10/08 9:53 AM Page 600
Leptomeningeal carcinomatosis occurs when tumor cells when there are multiple lesions, and may also be used pre-
that are widely distributed throughout the subarachnoid ventively, for example in metastatic disease in which there
space spread into subjacent tissue, leading to delirium and is a strong presumption that miliary metastases have
cranial nerve palsies; obstruction of CSF outflow may also already occurred.
lead to hydrocephalus. Magnetic resonance scanning typi- With few exceptions, chemotherapy has traditionally
cally reveals meningeal enhancement, and tumor cells may played only a limited role; recent advances, however, may
be found with lumbar puncture; this may have to be repeated be changing this picture.
multiple times, however, to avoid a false negative result. Dexamethasone is indicated in cases characterized by
Although spread to the leptomeninges may occur with considerable peri-tumoral edema, and is generally given in
almost every type of primary tumor, it is, as noted earlier, a a dose of 4 mg q.i.d.; the results are often prompt, within a
relatively uncommon occurrence. The exception occurs with day, and are at times dramatic.
systemic lymphoma or leukemia, which, unique among the Anti-epileptic drugs should generally be held in reserve
primaries, tend to preferentially seed into the leptomeninges. until patients have seizures, as there is little evidence for a
Dural metastases may occur via direct spread to the dura prophylactic effect. Enzyme-inducing drugs, such as pheny-
or by virtue of an inward extension of a calvarial metastasis. toin, carbamazepine, and phenobarbital, should be avoided
Symptoms are produced by virtue of compression of subja- if chemotherapy is utilized or contemplated, as they may
cent tissues and may include focal signs and seizures. reduce levels of chemotherapeutic agents; furthermore, the
use of phenytoin in patients undergoing radiation treat-
ment has been associated with a high incidence of severe
Differential diagnosis rash (Delattre et al. 1988b). In general, other agents, such as
levetiracetam, gabapentin, or divalproex, should be consid-
In evaluating a mass lesion, consideration must be given
ered first.
not only to primary or metastatic neoplasms but also to
In cases characterized by pituitary involvement, hor-
sarcoid granulomas, syphilitic gummas, tuberculomas,
mone replacement therapy is often required after surgery
and bacterial abscesses. Furthermore, in patients immuno-
or radiotherapy. Prolactinomas, unique among the
compromised by acquired immune deficiency syndrome
pituitary adenomas, may be treated medically, with
(AIDS) or chemotherapy, opportunistic infections enter
bromocriptine.
the differential, including toxoplasmosis and fungal infec-
The general treatment of dementia, personality change,
tions. Patients who have undergone focal radiation treat-
delirium, amnesia, mania, depression, and psychosis is dis-
ment may subsequently develop a new mass lesion as part
cussed in the respective sections.
of a late-delayed radiation encephalopathy, and the dis-
It must be borne in mind that not all tumors require
tinction between this and tumor recurrence is discussed in
treatment. Indolent, asymptomatic tumors, such as small
Section 11.5.
meningiomas or low-grade gliomas, may merely be moni-
In evaluating patients with metastatic lesions who
tored clinically and with serial MRI scans.
develop delirium, care must be taken not to immediately
attribute this to the tumor, because in most cases such a
change occurs on a metabolic basis (Clouston et al. 1992).
19.2 HYDROCEPHALUS
Another consideration here is the development of a para-
neoplastic limbic encephalitis.
The overall volume of CSF is about 140 mL: about 20 mL is
contained within the lateral ventricles, 5 mL within the
Treatment third and fourth ventricles, with the remainder found in
the subarachnoid space surrounding the brain and cord.
Treatment may involve any one or a combination of Cerebrospinal fluid is produced at a rate of about
surgery, radiation treatment, chemotherapy, and use of 20 mL/hour, and about three-quarters of the total CSF pro-
dexamethasone and anti-epileptic drugs; neurosurgical and duction occurs in the choroid plexus, with the rest origi-
neuro-oncologic consultation is appropriate in all cases. nating via transependymal flow. Cerebrospinal fluid
Surgery may be curative in cases of single, well- produced within the lateral ventricles normally flows
demarcated, accessible lesions, such as meningiomas or through the foramina of Monro into the third ventricle
low-grade gliomas. With large, highly infiltrative tumors, and then via the aqueduct of Sylvius into the fourth ventri-
such as glioblastoma multiforme, cure is not expected, but cle, from where it exits via the foramina of Magendie and
debulking of the tumor may improve the patient’s overall Luschka into the subarachnoid space surrounding the
functioning. In other cases, surgery may be required to brainstem. From here, the CSF circulates around the cord
obtain tissue for diagnostic purposes. and brain, and finally arrives at the cerebral convexity,
Radiation treatment may be focal or whole brain. Focal where it exits the subarachnoid space via the villi of the
irradiation may be considered in patients who are not good arachnoid granulations into the dural sinuses.
surgical candidates or in whom the tumor mass or masses Hydrocephalus is characterized by an enlargement of
are inaccessible. Whole-brain radiation may be considered one or more of the ventricles as a result of an increase in
p 19.qxd 3/10/08 9:53 AM Page 601
19.2 Hydrocephalus 601
CSF pressure. It may be usefully divided into two types: or urinary incontinence may also occur. On examination
non-communicating and communicating. In non- there may be generalized hyper-reflexia and bilaterally
communicating hydrocephalus, the overall ‘communica- positive Babinski signs.
tion’ between the ventricular system and the brainstem Although ventriculomegaly is evident on both CT and
subarachnoid space is partially or totally blocked at some MR scanning (as illustrated in Figure 19.3), MR scanning is
point, thus hindering or totally preventing the egress of preferred as it is more likely to reveal the underlying cause
CSF from the ventricles into the subarachnoid space. By of any obstructive hydrocephalus. In addition, on T2-
contrast, in communicating hydrocephalus, this ‘commu- weighted or fluid-attenuated inversion recovery (FLAIR)
nication’ is unimpeded and CSF flows freely from the ven- images one typically sees evidence of transependymal flow
tricular system into the brainstem subarachnoid space. of CSF from the ventricles into the immediately subjacent
Non-communicating hydrocephalus may occur with white matter, producing a hazy rim of increased signal
obstruction of CSF flow at various locations. With obstruc- intensity in a periventricular distribution.
tion of one of the foramen of Monro, only one of the lateral Lumbar puncture may or may not be necessary; in cases
ventricles enlarges, whereas with obstruction of both fora- of non-communicating hydrocephalus, the opening pres-
men, both lateral ventricles become enlarged. Obstruction sure is normal; in cases of communicating hydrocephalus
at the aqueduct of Sylvius is followed by enlargement of the it is generally increased, except in the condition known as
third and both lateral ventricles, and obstruction at the exit normal pressure hydrocephalus (see Section 19.3).
foramina of Magendie and Luschka entails expansion of all
four ventricles.
Communicating hydrocephalus typically occurs as a Course
result of an obstruction at the level of the arachnoid villi, and
is associated with enlargement of all of the ventricles. Rarely, Acute hydrocephalus is a catastrophic event, with a rapid
communicating hydrocephalus may occur not because of an evolution of symptoms. Chronic hydrocephalus, by con-
obstruction at any point but rather because of a grossly trast, is marked by a very slow progression of symptoms as
excessive production of CSF, which overwhelms the the pressure of the CSF very slowly increases. In most cases,
drainage system. however, a new ‘equilibrium’ is eventually reached between
Although hydrocephalus may occur at any age, from CSF production and outflow, and in this situation,
infancy to senescence, in this text only adult or later-onset although the ventricles remain under increased pressure,
cases are considered. they do not undergo any further expansion. When this
development occurs, the previously ‘active’ hydrocephalus
Clinical features
From a clinical point of view it is very useful to divide
hydrocephalus into two forms, namely acute and chronic,
depending on their mode of onset.
Acute hydrocephalus is a form of non-communicating
hydrocephalus in which there is a complete, or near-
complete, obstruction of CSF flow. This form of hydro-
cephalus is characterized clinically by a rapid onset of
symptoms, over days, hours, or even quicker. Patients pres-
ent with headache, stupor, and vomiting, and, without
treatment, coma and death may rapidly ensue.
Chronic hydrocephalus may represent either a commu-
nicating or a non-communicating condition; when it
occurs as a result of non-communicating hydrocephalus,
one finds only a partial obstruction. Clinically (Gustafson
and Hagberg 1978; Harrison et al. 1974), chronic hydro-
cephalus typically presents gradually, or even insidiously,
and is characterized by a dementia marked by forgetful-
ness, apathy, and a generalized slowing of thought and
behavior; rarely, akinetic mutism may occur (Messert et al.
1966). A gait disturbance also occurs, and this may either
precede or follow the onset of the dementia. The gait may Figure 19.3 Massive enlargement of the lateral ventricles in
be shuffling, apraxic, or ‘magnetic’ in type; in this last type a case of communicating hydrocephalus, as demonstrated on a
of gait, it appears as if the patient’s feet are ‘stuck’ to the floor, T2-weighted magnetic resonance scan. (Reproduced from Gillespie
as if held there by magnets. Urinary urgency or frequency and Jackson 2000.)
p 19.qxd 3/10/08 9:53 AM Page 602
is said to have undergone ‘arrest’, and such ‘arrested’ cases at the size of the cortical sulci and determine whether or
of hydrocephalus clinically manifest a plateau of symptoms, not these are enlarged. In true hydrocephalus, although
with a subsequently stable clinical course. there may be some enlargement of the sulci, the ventricular
enlargement is proportionately much greater, often
markedly so. By contrast, in hydrocephalus ex vacuo, there
Etiology is always sulcal enlargement, and the degree of sulcal
enlargement is proportionate to the degree of ventricular
In non-communicating hydrocephalus the obstruction enlargement. A second clue is the presence or absence of
may occur at various sites and may be caused by various evidence of transependymal flow on MR scanning: this is
different lesions. Thus, the foramen of Monro may be present in true hydrocephalus but not in hydrocephalus ex
obstructed by a tumor, such as an astrocytoma, or by a vacuo, given that the ventricular contents are not under
colloid cyst of the third ventricle, and the third ventricle any increased pressure.
may be occluded by a tumor (Riddoch 1936). The aqueduct From a clinical point of view, the dementia seen in
of Sylvius may be stenotic (Nag and Falconer 1966; hydrocephalus may mimic that caused by Alzheimer’s
Wilkinson et al. 1966) or may suffer post-infectious scar- disease or Binswanger’s disease; however, imaging will
ring; it may also be compressed by adjacent tumors, such as immediately indicate the correct diagnosis.
pineal tumors. The fourth ventricle may be compressed by
cerebellar lesions, such as tumors, hemorrhages, or infarc-
tions. The exit foramina of Magendie and Luschka may be Treatment
occluded by scarring, as may occur after an episode of viral
or bacterial meningitis, or in the course of an indolent basi- Neurosurgical consultation should be considered in all
lar meningitis, as may be seen in meningovascular syphilis, cases as patients may be candidates for either ventricu-
tuberculosis, or fungal infections; scarring and obstruction loperitoneal shunting or, in cases of non-communicating
may also occur after a subarachnoid hemorrhage, either hydrocephalus in which the obstruction is distal to the
spontaneous or as may be seen with traumatic brain injury. third ventricle, endoscopic third ventriculostomy (Farin
Communicating hydrocephalus is most commonly seen et al. 2006). Importantly, shunting may be effective even in
with obstruction of outflow at the arachnoid granulations. cases of arrested hydrocephalus (Larsson et al. 1999). The
Although such obstruction most commonly occurs after general treatment of dementia is discussed in Section 5.1.
subarachnoid hemorrhage (Ellington and Margolis 1969;
Theander and Granholm 1967), it may also occur in a con-
dition known as leptomeningeal carcinomatosis, discussed 19.3 NORMAL PRESSURE HYDROCEPHALUS
in Section 19.1; rarely, egress of CSF through the arachnoid
villi may be slowed in cases of extremely elevated total pro- As described in the preceding section, hydrocephalus may
tein values, as may be seen in some cases of spinal tumor or be subdivided into communicating or non-communicating
polyneuritis. As noted earlier, another rare mechanism and chronic or acute types. Normal pressure hydrocephalus is
underlying communicating hydrocephalus is actual over- a form of chronic communicating hydrocephalus that
production of CSF, as has been seen with papilloma of the occurs on an idiopathic basis. Classically, it presents with
choroid plexus (Eisenberg et al. 1974). Finally, the condi- the triad of gait disturbance, dementia, and urinary incon-
tion known as normal pressure hydrocephalus is a very tinence or urgency (Adams et al. 1965; Gallassi et al. 1991;
important cause of communicating hydrocephalus; this is Hill et al. 1967).
discussed in detail in Section 19.3.
Clinical features
The onset of symptoms is typically gradual and generally
The first task in making the differential diagnosis is to dis- occurs in late middle age or later.
tinguish ‘true’ hydrocephalus from a condition known as Of the classic triad of symptoms, the gait disturbance
‘hydrocephalus ex vacuo’. In true hydrocephalus, ventricu- typically constitutes the first evidence of this disorder.
lar enlargement occurs as the result of an increase in pres- Patients may walk with short steps on a somewhat widened
sure within the ventricles. By contrast, in hydrocephalus ex base, and sometimes there is a degree of shuffling, but the
vacuo, ventricular enlargement occurs not because of any distinctive feature is what is often referred to as a ‘mag-
pressure increase but merely secondary to shrinkage of the netic’ gait. Here, patients have difficulty initiating steps, as
surrounding brain parenchyma, as may be seen in normal if their feet are held in place on the floor by a large magnet;
ageing or in various neurodegenerative conditions such as some may complain that it feels as if their feet are ‘glued to
Alzheimer’s disease. There are two imaging clues that allow the floor’.
one to differentiate between these two forms of ventricular The dementia of normal pressure hydrocephalus is
enlargement. First, and most importantly, one should look characterized by forgetfulness, slowness of thought and
p 19.qxd 3/10/08 9:53 AM Page 603
19.3 Normal pressure hydrocephalus 603
action, apathy, and indifference. Rarely the clinical picture that normal pressure hydrocephalus may co-exist with any
may be dominated by a personality change (Rice and of these other disorders, thus producing a mixed diagnos-
Gendelman 1973) or depression (Pujol et al. 1989), and tic picture.
even more rarely by aggressiveness (Crowell et al. 1973; Normal pressure hydrocephalus must also be distin-
Sandyk 1984) or mania (Kwentus and Hart 1987). guished from other causes of chronic communicating hydro-
Urinary incontinence is considered the third symptom cephalus, such as subarachnoid hemorrhage, as described
of the triad; however, this may be only intermittent and in the preceding section.
patients may not complain of it. At times, rather than
incontinence there may only be urinary urgency.
On examination there may be generalized hyper- Treatment
reflexia and the Babinski sign may be positive bilaterally;
snout and grasp reflexes may also be present. Ventriculoperitoneal shunting should be considered in all
Computed tomography or MR scanning reveals cases. Among patients who do respond, the gait distur-
enlargement of the lateral ventricles out of proportion to bance generally improves first, followed by the dementia
any sulcal enlargement that may be present. If lumbar and urinary symptoms; at times the overall response
puncture is performed, the opening pressure is typically may be dramatic (Graff-Radford et al. 1989; Raftapoulos
normal. et al. 1994).
Selecting patients for shunting is at times difficult.
Certainly, in cases in which the classic triad is definitely
present and imaging reveals unequivocal hydrocephalus,
Course
one should strongly consider surgery. However, these
features may not all be present and in such cases one may
In most cases there is a gradual progression of symptoms
consider a number of ancillary tests, including the ‘tap test’,
and some patients may eventually develop akinetic mutism
prolonged external lumbar drainage, and the ‘infusion’ test
and an inability to stand. Often, however, the hydro-
(Kathlon et al. 2002; Sand et al. 1994; Walchenbach et al.
cephalus may become arrested, and symptoms may
2002).
‘plateau out’.
In both the tap test and external lumbar drainage the
patient’s gait is videotaped on at least two occasions and a
detailed mental status examination performed. In the tap
Etiology test, 30–45 mL of fluid are withdrawn within 2 hours of the
test and the patient’s gait re-videotaped along with a repeat
Although, as just noted, the opening pressure on lumbar performance of the mental status examination. In the
puncture is generally normal, it appears that in these external lumbar drainage procedure, an external lumbar
patients there are indeed elevations in CSF pressure but catheter is placed and about 50 mL of fluid is withdrawn
that these elevations occur only intermittently, typically at daily for 3–5 days, with repeated videotaping of gait and
night (Packard 1982). In this condition the hydrocephalus mental status examinations. In both of these tests one
is of the communicating type and it appears that the looks for an improvement in gait or cognition as evidence
intermittently increased pressure occurs secondary to an that chronic drainage via a ventriculoperitoneal shunt will
impaired outflow of CSF through the arachnoid villi confer long-term benefit.
(Borgesen and Gjerris 1987). The mechanism underlying In the infusion test normal saline is infused into the
this impaired outflow, however, is not known. Given this lumbar cistern and outflow resistance measured: increased
uncertainty as to the underlying cause, some authors prefer resistance indicates the presence of impaired egress of CSF
to refer to this condition not as ‘normal pressure hydro- through the arachnoid villi and thus confirms the diagnos-
cephalus’ but rather as ‘idiopathic chronic communicating tic suspicion of normal pressure hydrocephalus.
hydrocephalus’. The decision as to which of these three ancillary tests to
The mechanism whereby symptoms appear probably use is not straightforward and practices differ in this
relates to stretching of the long periventricular axonal fibers. regard. The tap test is simplest to perform but may have
false negatives; external lumbar drainage and the infusion
test are more difficult to perform but are more sensitive.
Differential diagnosis Overall, it may be appropriate to do a tap test first and, if
this is negative, proceed to either external lumbar drainage
From a clinical point of view, consideration must be given or an infusion test. It must be borne in mind, however, that
to other disorders such as Alzheimer’s disease and none of these tests is completely accurate in predicting the
Binswanger’s disease, and certain parkinsonian disorders response to shunting, and they may yield false negatives in
(e.g., diffuse Lewy body disease), and the diagnosis of nor- this regard. Consequently, even when these tests are all
mal pressure hydrocephalus may only become apparent negative, one may still consider shunting in clinically
after neuroimaging. It must be borne in mind, of course, appropriate cases.
p 19.qxd 3/10/08 9:53 AM Page 604
REFERENCES Forsyth PA, Posner JB. Headaches in patients with brain tumors: a
study of 111 patients. Neurology 1993; 43:1678–83.
Adams RD, Fisher CM, Hakim S et al. Symptomatic occult Frazier CH. Tumor involving the frontal lobe alone: a symptomatic
hydrocephalus with ‘normal’ cerebrospinal fluid pressure. survey of one hundred and five verified cases. Arch Neurol
N Engl J Med 1965; 273:117–26. Psychiatry 1936; 35:525–71.
Alpers BJ. Relation of the hypothalamus to disorders of Fulton JF, Bailey P. Tumors in the region of the third ventricle:
personality: report of a case. Arch Neurol Psychiatry 1937; their diagnosis and relation to pathological sleep. J Nerv Ment
38:291–303. Dis 1929; 69:1–25.
Alpers BJ. Personality and emotional disorders associated with Gal P. Mental symptoms in cases of tumor of the temporal lobe.
hypothalamic lesions. In: Fulton JF, Ranson SW, Frantz AM Am J Psychiatry 1958; 115:157–60.
eds. Research publications. Association for Research in Nervous Gallassi R, Morreale A, Montagna P et al. Binswanger’s disease
and Mental Disease. Vol. XX. The hypothalamus and central and normal-pressure hydrocephalus: clinical and neuro-
levels of autonomic function. Baltimore: William & Wilkins, radiological comparison. Arch Neurol 1991; 48:1156–9.
1940. Gillespie J, Jackson A. MRI and CT of the brain. London: Arnold, 2000.
Alpers BJ, Grant FC. The clinical syndrome of the corpus callosum. Graff-Radford NR, Godersky JC, Jones MP. Variable predicting
Arch Neurol Psychiatry 1931; 25:67–86. surgical outcome in symptomatic hydrocephalus in the elderly.
Avery TL. Seven cases of frontal tumor with psychiatric Neurology 1989; 39:1601–4.
presentation. Br J Psychiatry 1971; 119:19–23. Gustafson L, Hagberg B. Recovery in hydrocephalic dementia after
Beal MF, Kleinman GM, Ojemann RG et al. Gangliocytoma of third shunt operation. J Neurol Neurosurg Psychiatry 1978; 41:940–7.
ventricle: hyperphagia, somnolence, and dementia. Neurology Harner SG, Laws ER. Clinical findings in patients with acoustic
1981; 31:1224–8. neurinoma. Mayo Clin Proc 1983; 58:721–8.
Borgesen SE, Gjerris F. Relationships between intracranial Harrison MJG, Robert CM, Uttley D. Benign aqueductal stenosis in
pressure, ventricular size, and resistance to CSF outflow. adults. J Neurol Neurosurg Psychiatry 1974; 37:1322–8.
J Neurosurg 1987; 67:535–9. Haugh RM, Markesbery WR. Hypothalamic astrocytoma:
Boughey AM, Fletcher NA, Harding AE. Central nervous system syndrome of hyperphagia, obesity and disturbances of
haemangioblastoma: a clinical and genetic study of 52 cases. behavior and endocrine and autonomic function. Arch Neurol
J Neurol Neurosurg Psychiatry 1990; 53:644–8. 1983; 40:560–3.
Clouston PD, DeAngelis LM, Posner JB. The spectrum of Heron GB, Johnston DA. Hypothalamic tumor presenting as
neurological disease in patients with systemic cancer. Ann anorexia nervosa. Am J Psychiatry 1976; 133:580–2.
Neurol 1992; 31:268–73. Hill ME, Lougheed WM, Barnett HJM. A treatable form of
Crowell RM, Tew JM, Mark VH. Aggressive dementia associated with dementia due to normal-pressure, communicating
normal pressure hydrocephalus. Neurology 1973; 23:461–4. hydrocephalus. Can Med Assoc J 1967; 97:1309–11.
Davison C, Demuth EL. Disturbances in sleep mechanism: a Ironside R, Guttmacher M. The corpus callosum and its tumors.
clinicopathologic study. I. Lesions at the cortical level. Arch Brain 1929; 52:442–83.
Neurol Psychiatry 1945; 53:399–406. Kathlon B, Sundbarg G, Rehncrona S. Comparison between the
Davison C, Demuth EL. Disturbances in sleep mechanism: a lumbar infusion and CSF tap tests to predict outcome after
clinicopathologic study. III. Lesions at the diencephalic level shunt surgery in suspected normal pressure hydrocephalus.
(hypothalamus). Arch Neurol Psychiatry1946; 55:111–25. J Neurol Neurosurg Psychiatry 2002; 73:721–6.
Delattre JY, Krol G, Thaler HT et al. Distribution of brain Kelly R. Colloid cysts of the third ventricle: analysis of twenty-
metastases. Arch Neurol 1988a; 45:741–4. nine cases. Brain 1951; 74:23–65.
Delattre JY, Safai B, Posner JB. Erythema multiforme and Kernohan JW, Learmonth JR, Doyle JB. Neuroblastomas and
Stevens–Johnson syndrome in patients receiving cranial gangliocytoma of the central nervous system. Brain 1932;
irradiation and phenytoin. Neurology 1988b; 38:194–8. 55:287–310.
Direkze M, Bayliss SG, Cutting JC. Primary tumors of the frontal Keschner M, Bender MB, Strauss I. Mental symptoms in cases of
lobe. Br J Clin Pract 1971; 25:207–13. tumor of the temporal lobe. Arch Neurol Psychiatry 1936;
Eisenberg HM, McComb JG, Lorenzo AV. Cerebrospinal fluid 35:572–96.
overproduction and hydrocephalus associated with choroid Kwentus JA, Hart RP, Normal pressure hydrocephalus presenting
plexus papilloma. J Neurosurg 1974; 40:381–5. as mania. J Nerv Ment Dis 1987; 175:500–2.
Ellington E, Margolis G. Block of arachnoid villus by subarachnoid Lai R, Rosenblum MK, DeAngelis LM. Primary CNS lymphoma:
hemorrhage. J Neurosurg 1969; 30:651–7. a whole-brain disease? Neurology 2002; 59:1557–62.
Farin A, Aryan HE, Ozgur BM et al. Endoscopic third Lang W, Miklossy J, Deruaz JP et al. Neuropathology of the
ventriculostomy. J Clin Neurosci 2006; 13:663–70. acquired immune deficiency syndrome (AIDS): a report of 135
Faris AA, Terrence CF. Limbic system symptomatology associated consecutive autopsy cases from Switzerland. Acta Neuropathol
with colloid cyst of the third ventricle. J Neurol 1989; 236:60–1. 1989; 77:379–90.
Feiden W, Bise K, Steude U et al. The stereotactic biopsy diagnosis Larsson A, Stephenson H, Wikkelso C. Adult patients with
of focal intracerebral lesions in AIDS patients. Acta Neurol ‘asymptomatic’ and ‘compensated’ hydrocephalus benefit from
Scand 1993; 87:228–33. surgery. Acta Neurol Scand 1999; 99:81–90.
p 19.qxd 3/10/08 9:53 AM Page 605
References 605
Liss L. Pituicytoma, a tumor of the hypothalamus. Arch Neurol Sachs E. Meningiomas with dementia as the first and presenting
Psychiatry 1958; 80:567–76. feature. J Ment Sci 1950; 96:998–1007.
Lobosky JM, Vangilder JC, Damasio AR. Behavioral manifestations Sand T, Bovin G, Grimse R et al. Idiopathic normal pressure
of third ventricular colloid cysts. J Neurol Neurosurg Psychiatry hydrocephalus: the CSF tap-test may predict the clinical
1984; 47:1075–80. response to shunting. Acta Neurol Scand 1994; 89:311–16.
Malamud N. Psychiatric disorder with intracranial tumors of Sandyk R. Aggressive dementia in normal-pressure hydrocephalus.
limbic system. Arch Neurol 1967; 17:113–23. S Afr Med J 1984; 65:114.
McKendree CA, Feinier L. Somnolence: its occurrence and Schneck SA, Penn I. Cerebral neoplasms associated with renal
significance in cerebral neoplasms. Arch Neurol Psychiatry transplantation. Arch Neurol 1970; 22:226–33.
1927; 17:44–56. Strauss I, Globus JH. Tumor of the brain with disturbance in
Messert B, Henke TK, Langheim W. Syndrome of akinetic mutism temperature regulation. Arch Neurol Psychiatry 1931;
associated with obstructive hydrocephalus. Neurology 1966; 25:506–22.
16:635–49. Strauss I, Keschner M. Mental symptoms in cases of tumor of the
Moersch FP. Psychic manifestations in cases of brain tumors. frontal lobe. Arch Neurol Psychiatry 1935; 33:986–1007.
Am J Psychiatry 1925; 81:707–24. Strobos RRJ. Tumors of the temporal lobe. Neurology 1953;
Morris HH, Estes ML, Gilmore R et al. Chronic intractable epilepsy 3:752–60.
as the only symptom of primary brain tumor. Epilepsia 1993; Theander S, Granholm L. Sequelae after spontaneous subarachnoid
34:1038–43. hemorrhage, with special reference to hydrocephalus and
Murthy P, Jayakumar PN, Sampat S. Of insects and eggs: a case Korsakoff’s syndrome. Acta Neurol Scand 1967; 43:479–88.
report. J Neurol Neurosurg Psychiatry 1997; 63:522–3. Tucker GJ, Price TRP, Johnson VB et al. Phenomenology of
Nag TK, Falconer MA. Non-tumoral stenosis of the aqueduct in temporal lobe dysfunction: a link to atypical psychosis: a
adults. BMJ 1966; 2:1168–70. series of cases. J Nerv Ment Dis 1986; 174:348–56.
Olivero WC, Lister JR, Elwood PW. The natural history and growth Walchenbach R, Geiger E, Thomeer RTWM et al. The value of
rate of asymptomatic meningiomas. J Neurosurg 1995; temporary external lumbar CSF drainage in predicting the
83:222–4. outcome of shunting on normal pressure hydrocephalus.
Packard JD. Adult communicating hydrocephalus. Br J Hosp Med J Neurol Neurosurg Psychiatry 2002; 72:503–6.
1982; 27:35–44. White JH, Kelly P, Dorman K. Clinical picture of atypical anorexia
Pujol J, Leal S, Fluvia X et al. Psychiatric aspects of normal nervosa associated with a hypothalamic tumor. Am J
pressure hydrocephalus. Br J Psychiatry 1989; 154(suppl. Psychiatry 1977; 134:323–5.
4):77–80. Wilkinson HA, Lemay M, Drew JH. Adult aqueductal stenosis.
Raftapoulos C, Deleval J, Chaskis C et al. Cognitive recovery in Arch Neurol 1966; 15:643–8.
idiopathic normal pressure hydrocephalus: a prospective study. Wilkinson IM, Anderson JR, Holmes AE. Oligodendroglioma: an
Neurosurgery 1994; 35:397–405. analysis of 42 cases. J Neurol Neurosurg Psychiatry 1987;
Reeves AG, Plum F. Hyperphagia, rage and dementia 50:304–12.
accompanying a ventromedial hypothalamic neoplasm. Arch Williamson RT. On the symptomatology of gross lesions (tumors
Neurol 1969; 20:616–24. and abscesses) involving the pre-frontal regions of the brain.
Rice E, Gendelman S. Psychiatric aspects of normal pressure Brain 1896; 19:346–65.
hydrocephalus. JAMA 1973; 223:409–12.
Riddoch G. Progressive dementia, without headache or changes in
the optic discs, due to tumors of the third ventricle. Brain
1936; 59:225–33.
20
Idiopathic psychotic, mood, and anxiety disorders
20.1 Schizophrenia 606 20.10 Panic disorder 631

20.2 Schizoaffective disorder 614 20.11 Agoraphobia 634
20.3 Delusional disorder 615 20.12 Specific (simple) phobia 635
20.4 Post-partum psychosis 617 20.13 Social phobia 636
20.5 Bipolar disorder 618 20.14 Obsessive–compulsive disorder 638
20.6 Major depressive disorder 624 20.15 Post-traumatic stress disorder 639
20.7 Premenstrual dysphoric disorder 629 20.16 Generalized anxiety disorder 641
20.8 Post-partum depression 630 References 643
20.9 Post-partum blues 631
20.1 SCHIZOPHRENIA members may recall a stretch of time when the patient
‘changed’ and was no longer ‘himself’; prior interests and
Schizophrenia is a chronic, more or less debilitating psy- hobbies may have been abandoned and replaced by a cer-
chosis that occurs in about 1 percent of the general popula- tain irritable seclusiveness or perhaps suspiciousness.
tion and which is equally common in males and females. The mode of onset ranges from acute to gradual. Acute
This illness was first noted by Morel in 1860 (Anonymous onsets occur over weeks or months and may be initially
1954), who referred to it as démence précoce. A full descrip- marked by perplexity or depressive symptoms; patients
tion of the disease, however, had to await the efforts of Emil may recognize that something is going wrong, and some
Kraepelin. Kraepelin, who latinized the name to dementia may make desperate attempts to bring order and structure
praecox, was a German psychiatrist of the late nineteenth into a life that is rapidly fragmenting. By contrast, gradual
and early twentieth centuries, whose work remains a guid- onsets, which may span months or a year or more, may not
ing force for modern psychiatry. The current name for the be particularly disturbing to the patient; there may be fleet-
disease, schizophrenia, was coined by Eugen Bleuler, a ing, whispering auditory hallucinations, vague intima-
Swiss psychiatrist who amplified Kraepelin’s original tions, or strange occurrences.
descriptions. Another guiding light in the elucidation of the Although the symptomatology of schizophrenia may be
disease was the German psychiatrist Kurt Schneider, who quite varied, in most cases one sees hallucinations, delusions,
isolated certain symptoms, now known as Schneiderian disorganized speech, and catatonic or bizarre behavior.
first rank symptoms, which, although not pathognomonic Negative symptoms (e.g., flattening of affect) are also often
of the disease, are very, very suggestive. seen and, as with all typologies, there is also a category of mis-
cellaneous symptoms, the most important of which is tran-
sient disturbances of mood. Generally, based on the overall
Clinical features constellation of symptoms, one may classify any given case of
schizophrenia into one of several subtypes, namely paranoid,
The age of onset of schizophrenia, although generally
catatonic, disorganized (also known as hebephrenic), or sim-
falling in the late teens or early twenties, may range from
ple schizophrenia; in a large minority, however, there
late childhood to the seventh decade (Brodaty et al. 1999;
appears to be a mixture of these subtypes, and in such cases
Grahame 1984). A prodrome may or may not be present; in
one speaks of ‘undifferentiated’ schizophrenia. Each of these
some cases the premorbid personality may have been com-
symptoms and subtypes is now considered in some detail.
pletely normal, whereas in others, peculiarities may have
been present for years or even decades (Walker and Lewine
1990). In cases in which the prodrome begins in childhood, HALLUCINATIONS
history may reveal introversion and peculiar interests. In
cases in which the prodrome appears in teenage years or Hallucinations may occur in the auditory, visual, gusta-
later, well after the patient’s personality has formed, family tory, olfactory, and tactile realms (Mueser et al. 1990).
p 20.qxd 3/10/08 9:58 AM Page 607
Auditory hallucinations are most common in schizo- even be contradictory. An exception to this rule is seen in the
phrenia and, as noted by Kraepelin (1919), it is ‘the hearing paranoid subtype of schizophrenia, in which one may find a
of voices’ (italics in original) that is by far most ‘peculiarly certain degree of systematization of the patients delusions
characteristic’ of schizophrenia. Voices may come from into a more or less coherent corpus of beliefs.
inside the body or perhaps the air; sometimes they are Delusions of persecution are particularly common.
sent by electronic devices or emerge from the walls or fur- Patients may believe that there is a conspiracy against them,
niture. They often speak in short phrases and may at times for example that the police have coordinated their efforts
manifest as commands, which patients may or may not be with co-workers or neighbors or that perhaps the mafia is
able to resist. Certain auditory hallucinations, included involved or certain underground organizations. Patients
among the Schneiderian first rank symptoms although not may believe that they are being followed, that their tele-
specific for schizophrenia, are highly suggestive: these phone conversations are being listened to, and that their
include voices that repeat the patient’s thoughts, voices mail is being cleverly opened. Some patients may endure
that comment on what the patient is doing, and voices that these persecutions stoically, whereas others may engage in
argue with each other. For most patients the voices sound what to them appears to be a justifiable self-defense and
as real as the voice of another person, and they may talk fight back. Some may flee the area, seeking safety in another
back to them or argue with them. At times when the voices town or state. In some cases, if the delusion of persecution
are loud or unpleasant, patients may try and drown them is a bizarre one, the response may be proportionately
out by listening to music or watching television. In addi- bizarre: one patient, believing that ‘rays’ were being sent
tion to voices, patients may also hear sounds, such as the through the ceiling to kill him, proceeded to cover the ceil-
ringing of bells, footsteps, or tapping on the walls or ing in aluminum foil in order to protect himself.
windows. Delusions of grandeur are also common and may coex-
Visual hallucinations, although common, play a much ist with delusions of persecution. Patients may believe that
less prominent role in the overall symptomatology than they have developed great inventions and that others per-
auditory hallucinations. Often they are poorly formed and secute them out of envy. Some believe that they have been
indistinct and perhaps seen only fleetingly, ‘out of the corner elected by God, that millions of dollars are held privately
of the eye’. In some cases, however, they may be detailed, for them, that heads of state secretly await their advice on
vivid, and compelling: strange people walk the halls; the foreign affairs. Although some patients may harbour these
devil appears in violent red straight ahead; heads may float beliefs quietly, others may feel compelled to make an
through the air; and reptilian creatures may crawl the floors. announcement. One patient took out a full-page advertise-
Gustatory and olfactory hallucinations are uncommon ment in the newspaper in which he described his plans for
but may at times be quite compelling. Patients may smell ‘world peace’ through alliances with ‘extraterrestrial
poison gas and inspect the air ducts to find the source. beings’ that had chosen him as their emissary.
Tastes, often foul and bitter, may appear on the tongue, Delusions of reference are intimately related to delu-
and patients may become convinced that their drinks have sions of persecution and to delusions of reference, and
been fouled by poisons. serve, as it were, to reinforce them. Here, patients believe
Tactile hallucinations may also occur and may be quite that chance events, rather than being innocuous and
varied. Patients may feel electric currents course over their unrelated to them, in fact bear special meaning and
bodies; they may complain that fluids are poured on them pertain specifically to them. Newspaper headlines seem to
at night or that they are pricked by needles from behind; in be a kind of code, which only the patient can decipher,
some cases they may experience movements deep inside, informing him or her that the time is near; street lights
such as crampings and twistings. which blink on are a sign to those pursuing the patient
that the time has come to ‘move in’. The patient with
DELUSIONS grandiose delusions may hear church bells on Sunday
morning and know that they serve as an announcement of
Delusions are almost universal in schizophrenia and, his or her glory. For patients with delusions of reference,
although their content is extremely varied, certain themes at times all things seem pregnant with meaning: there
stand out, including delusions of persecution, delusions of are no more chance occurrences, no accidents, and no
grandeur, delusions of reference, and a number of coincidences.
Schneiderian first rank symptoms. These false beliefs may Schneiderian first rank symptoms may comprise delu-
either grow slowly in the patient or occur suddenly, as if in an sions, including thought broadcasting, thought withdrawal,
enlightenment. Although some patients may entertain some thought insertion, and delusions of influence, control, or
lingering doubts as to the veracity of these beliefs, for most passivity. In thought broadcasting, patients believe that
they are as self-evidently true as any other belief. Occasionally thoughts can leave the head without being spoken or writ-
patients may argue with others about these beliefs, and even ten, and that others may ‘pick up’ these thoughts directly;
attempt to convince others of their truth, but more often they some patients say that it works ‘like a radio’ and they may
do not press their case on the unbeliever. Most patients hold feel no need to speak their thoughts as they assume that
multiple delusions; these are often not well elaborated and others, perhaps including the doctors, have already picked
are often poorly coordinated with each other, and they may up the ‘broadcast’. Thought withdrawal is characterized by
p 20.qxd 3/10/08 9:58 AM Page 608
608 Idiopathic psychotic, mood, and anxiety disorders
the experience of having one’s thoughts directly withdrawn In some cases, rather than loosening of associations one
from the mind. In such cases, patients suddenly become may see mere tangentiality or circumstantiality. In tangen-
bereft of thoughts and are left with blank minds; some may tiality, in response to a question, thoughts proceed off on a
elaborate on the experience and speak of electrical or mag- tangent and patients never get around to giving an answer;
netic devices that remove the thoughts. Patients who expe- in circumstantiality, the responses are circuitous and
rience thought withdrawal while speaking may exhibit the patients take a long ‘round about’ path before they finally
sign known as ‘thought blocking’. Here, in the middle of ‘get to the point’.
speaking, patients abruptly cease talking and become silent; Neologisms may also occur, in which, in the course of
this happens because they just as abruptly find themselves speaking, the patient may use a word that seems to have no
with no thoughts to speak. Thought insertion represents meaning. For example, one patient, when asked if he wanted
the converse of thought withdrawal, and in this experience anything, replied, ‘Yes, please, some bufkuf.’ When asked
patients believe that thoughts that are not their own have the meaning of ‘bufkuf’, the patient responded, ‘Oh, you
been ‘inserted’ directly into their minds; these ‘alien’ know,’ and made no further attempt to define or explain it.
thoughts exist as a kind of cognitive ‘foreign body’, and
patients may elaborate on the experience and believe that CATATONIC OR BIZARRE BEHAVIOR
strange devices, perhaps using magnets, are responsible for
their appearance. Delusions of influence, control or passiv- Catatonia may occur in one of two forms, namely stuporous
ity are characterized by the belief on the patient’s part that catatonia and excited catatonia. Both forms may be seen in
their thoughts, feelings, or actions are somehow directly schizophrenia and, indeed, it is not uncommon to see indi-
influenced or controlled by some outside force or agency, vidual patients with the catatonic subtype of schizophrenia
and that they have somehow become like robots or passive exhibit both forms at different times (Morrison 1973). In stu-
automatons, without any independence of will. Some again porous catatonia one sees immobility, catalepsy, and mutism,
may elaborate on these beliefs and speak of being under the which may be joined by posturing, echolalia or echopraxia,
influence of a spell or perhaps of an electrical or magnetic negativism, or automatic obedience, whereas in excited cata-
machine, or perhaps a distant computer. tonia one sees bizarre, frenzied, purposeless behavior. All of
Other delusions may also occur. Indeed, any imaginable these symptoms are discussed in detail in Section 3.11.
belief may be held, no matter how fantastic: angels live in In addition to catatonic symptoms there may be other
the patient’s nose; a small person is seated at a chair in the bizarre aspects to schizophrenia, including mannerisms,
external auditory canal and whispers to the patient; parents bizarre affect, and an overall disorganization and disinte-
have risen from the grave, etc. gration of behavior.
Mannerisms, as discussed in Section 4.27, represent
DISORGANIZED SPEECH bizarre or odd caricatures of gestures, speech, or behavior.
In a manneristic gesture, the patient may offer a hand to
In considering the sign of disorganized speech we are con- shake with the fingers splayed out, or the fingers may inter-
cerned not with the content of speech, which may be com- mittently writhe in a peculiar, contorted way. In manneris-
posed of delusions, but rather with the form of speech. tic speech, cadence, modulation or volume may be erratic
This ‘formal thought disorder’ is most often referred to as and dysmodulated. One patient spoke in a ‘sing-song’
‘loosening of associations’, but may sometimes be termed voice and, in another, random syllables were accented in a
‘derailment’. Thought and speech become illogical and pompous way. Overall behavior may undergo manneristic
incoherent; thoughts are juxtaposed that have no conceiv- transformation; one patient walked in a stiff-legged fash-
able connection and family members may complain that ion, rigidly swinging only one arm with each step.
the patient ‘doesn’t make sense’; there is a lack of ‘goal- Bizarre affect may manifest in a variety of ways. In some
directedness’, and thoughts, lacking such an organizing cases facial expression appears theatrical, wooden, or
goal, become disparate and unconnected. At its most under a peculiar constraint, for example patients may
extreme, loosening of associations produces a ‘word salad’ report feeling joy but the rapturous facial expression may
in which successive spoken words have no more inherent appear brittle, tenuous, and disconnected. In other cases
connection with each other than do the tossed leaves of a there may be inappropriate affect. Here, as described in
salad. In one case, a patient, after being asked about the Section 4.26, one finds a disconnection between what the
previous day’s activities, replied, ‘The sun bestrides the patient feels and what ‘shows’ on his face, as, for example,
mouse doctor. In the morning, if you wish. Twenty-five in the case of a patient who, although feeling sadness at the
dollars is a lot of money! Large faces and eyes. Terrible death of a parent, was seen to involuntarily snicker.
smells. Rats in the socket. Can there be darkness? Oh, if you There may also be a bizarre disintegration of the patient’s
only knew!’ Here, any inner connection between the vari- overall behavior and demeanor, and it is this sign that often
ous ideas and concepts is lost; it is as if they come at ran- makes these patients ‘stand out’ in public. Patients become
dom. Typically, patients are unconcerned with their untidy and may neglect to clean their clothes or to bathe.
incoherence; if asked to explain what they mean, they make Dress and grooming may become bizarre: several layers of
little, if any, effort at clarification. clothing may be worn, even when it is hot outside, and bits
p 20.qxd 3/10/08 9:58 AM Page 609
of string or cloth may festoon jackets or shirts. Patients may prognoses, as noted further below, but also because knowl-
cut off their eyebrows or make deep gashes in their arms or edge of a patient’s subtype diagnosis may allow the clinician
legs. Some seem almost analgesic: one patient bit out part of to predict how the patient will act in any given situation.
his biceps muscle; another eviscerated himself, ‘just to see’ After discussing the paranoid, catatonic, disorganized,
what was inside. In some cases the bizarre behavior may be simple, and undifferentiated subtypes of schizophrenia,
in response to delusions, as, for example, when a patient some comments will also be offered on an alternative
wrapped his legs in aluminum foil to ‘keep the bugs off’. mode of subdividing schizophrenia, namely into ‘reactive’
and ‘process’ types.
NEGATIVE SYMPTOMS Paranoid schizophrenia tends to have a somewhat later
onset, sometimes as late as in middle years, and is character-
‘Negative’, or ‘defect’, symptoms (Andreasen 1982;
ized primarily by hallucinations and delusions; dis-
Andreasen and Olson 1982; Andreasen et al. 1990a)
organized speech, catatonic or bizarre behavior, and
include flattening of affect, poverty of thought or speech,
negative symptoms are either absent or relatively minor.
and avolition.
Hallucinations are generally auditory and delusions are
Flattening of affect, also known as mere ‘blunting’ of
generally of persecution and reference. In paranoid schizo-
affect when less severe, is, as discussed further in Section
phrenia, more so than in any other subtype, the delusions
4.25, characterized by a lifeless and wooden facial expres-
tend to be systematized and, on first glance, even plausible.
sion accompanied by a corresponding dearth or diminu-
Voices may warn patients that their supervisors are plotting
tion of all feelings.
against them. Patients may begin to suspect that people are
Poverty of speech and poverty of thought are often
talking about them, perhaps laughing at them behind their
referred to collectively as ‘alogia’. Poverty of speech is said
backs. Newspaper headlines pertain to them; the CIA may
to be present when patients, although speaking a normal
be involved or perhaps the FBI. At times patients may
amount, seem to ‘say’ very little; there is a dearth of mean-
appeal to the authorities for help, but often they suffer their
ingful content and speech is often composed of stock
persecutions in rigid silence; occasionally they may try to
phrases. In poverty of thought, by contrast, patients speak
escape, perhaps by moving to another area, or they may
little, essentially because there is a wide-ranging and far-
turn on their supposed attackers, sometimes violently.
reaching impoverishment of their entire thinking; patients
Often, allied with delusions of persecution, there may also
may complain that their heads are ‘empty’ and that, sim-
be delusions of grandeur. Patients believe that they are
ply, nothing comes to mind; there are no stirrings.
being persecuted not for some trivial reason; they suspect
Avolition, referred to by Kraepelin as ‘annihilation of
that others know that they have developed great inventions.
the will’, is allied to poverty of thought in that avolitional
Rarely, grandiose delusions may be more prominent than
patients simply do not experience any impulses, desires,
persecutory ones, and they may even dominate the clinical
stirrings or inclinations; if left undisturbed they may spend
picture. One patient believed himself to be the anointed of
hours or days in quietude, doing nothing.
God; he heard trumpets proclaiming his advent and was
MISCELLANEOUS SYMPTOMS prepared to announce himself to the world.
Catatonic schizophrenia, as the name obviously indi-
Of the miscellaneous symptoms seen in schizophrenia, per- cates, is dominated by catatonic symptoms. As described in
haps the most important are transient disturbances of Section 3.11, catatonia occurs in both stuporous and
mood, which may tend toward depression, mania, or anxi- excited forms and, although some patients with catatonic
ety. Patients may complain of depressive symptoms, such as schizophrenia may demonstrate only one form throughout
feeling depressed, being tired or having trouble sleeping; the course of the illness, in most cases, as noted earlier,
some may demonstrate some euphoria and increased energy these two forms are seen to alternate in the same patient.
and talkativeness, whereas others may complain of feeling The duration of these forms is quite variable, ranging from
anxious and tremulous. Indeed, at first glance these symp- hours on one extreme to months or years on the other. The
toms may seem to dominate the clinical picture; however, transition from one form to another may be quite unpre-
on a closer and wider look one finds that they are transient, dictable and, at times, quite sudden; in one case a chroni-
lasting only hours or days, are mild overall, and, relative to cally stuporous patient, without any warning, suddenly
other symptoms, such as hallucinations and delusions, play jumped from his bed, screamed incoherently, and paced
only a very minor role in the overall clinical picture. agitatedly from one wall to another, only to lapse into
Agitation may also be seen, and this may occur either as a immobility and muteness an hour later.
non-specific part of an exacerbation of the disease or as a Disorganized schizophrenia, also known classically as
reaction to delusions of persecution or threatening voices. hebephrenic schizophrenia, tends to have an earlier onset
than the other subtypes and to develop very slowly.
SUBTYPES Although hallucinations and delusions are present, they
generally play a minor role and the clinical picture is domi-
Classifying patients as to subtype is useful not only because nated by disorganized speech and bizarre behavior. Overall,
the various subtypes pursue different courses with different the behavior of these patients seems at times to represent a
p 20.qxd 3/10/08 9:58 AM Page 610
caricature of childish silliness. Senselessly, they may busy Course

themselves, first with this and then with that, generally to
no purpose and often with silly, shallow giggling. At times Schizophrenia is a chronic, lifelong disease and most
they may be withdrawn and inaccessible. When delusions patients suffer considerable disability throughout their
are at all prominent, they tend to be hypochondriacal in lives (McGlashan 1984; Tsuang et al. 1979). In most cases,
nature and very unsystematized. In some cases there may the disease exhibits one of two courses: an overall waxing
also be disorganized speech, with marked loosening of asso- and waning course or a chronic, slow progression.
ciations to the point of a fatuous, drivelling incoherence. The waxing and waning course is characterized by exac-
Simple schizophrenia (Black and Boffeli 1989; Kendler erbations and partial remissions. The pattern of these
et al. 1994a), also known as ‘simple deteriorative disorder’, changes is often quite irregular, as are the durations of the
has the earliest age of onset, often appearing in childhood, exacerbations and partial remissions, which may range
with a very slow and insidious onset, stretching over years. from weeks to months or even years. In some cases, after a
Hallucinations, delusions, and disorganized speech are partial remission patients may develop a depressive
sparse, and indeed are for the most part absent, and the episode, commonly referred to as ‘post-psychotic depres-
clinical picture is dominated by negative symptoms. Over sion’ (Mandel et al. 1982); this is an important develop-
the years, these patients fall away from any acquaintances ment as the risk of suicide is higher during this time.
that they may have had and often become distant and emo- Importantly, this sustained depressive episode must not be
tionally dead. They may appear shiftless and some may confused with the frequently observed, transient, minor
accuse them of being ‘lazy’. Few thoughts, desires or incli- depressive symptoms that may occasionally accompany an
nations disturb them and they may appear quite content to exacerbation of psychotic symptoms. Overall, this waxing
lie in bed or sit in a darkened room all day. For the most and waning course may persist throughout the life of the
part they do little to attract the attention of others and may patient or, in many cases, it may give way, after anywhere
pass their lives in homeless shelters. from 5 to 20 years, to a stable chronicity.
Undifferentiated schizophrenia is said to be present The chronic progressive course may be evident from the
when the clinical picture of any given case does not fit well onset of the disease, as for example in the simple subtype,
into any one of the foregoing subtypes. This is not uncom- or may become evident only after the initial onslaught has
monly the case, and it also appears that, over long periods of settled some. Over long periods of time, there is a very
time, the clinical picture, which initially did fit a particular gradual progression, after which many patients eventually
subtype, may gradually change and become less distinctive. ‘burn out’ with no further changes.
This transition from a recognized specific subtype to an As noted earlier, the subtype diagnosis may enable
undifferentiated presentation appears to be most common some predictions to be made as to course (Fenton and
with the catatonic and disorganized subtypes; by contrast, McGlashan 1991; Kendler et al. 1994b). Thus, the paranoid
the paranoid and simple subtypes tend to ‘run true’. and catatonic subtypes tend to pursue a waxing and wan-
As noted earlier, in addition to these classic subtypes there ing course and, of these two, the overall prognosis appears
is an alternative proposal for classifying schizophrenia, which to be better for the paranoid subtype. The disorganized
divides the illness into two types: ‘reactive’ schizophrenia, and simple subtypes, by contrast, tend to demonstrate a
also known as ‘good prognosis’ or ‘type I’ schizophrenia, and slowly progressive course.
‘process’ schizophrenia, also known as ‘poor prognosis’ or Schizophrenia may have a fatal outcome. Patients with
‘type II’ schizophrenia. In reactive schizophrenia, the pre- catatonic schizophrenia of the stuporous type may die of
morbid personality tends to be normal and the onset, which aspiration pneumonia or extensive decubiti. Suicide occurs
is marked by depression and perplexity, is acute and occurs in about 10 percent of patients (Tsuang 1978); overall, about
generally in adult years, often following some obvious social one-third will make a suicide attempt (Allebeck et al. 1987).
or personal stress; hallucinations and delusions, with some Before leaving this discussion of the course of schizo-
speech disorganization, dominate the clinical picture. In phrenia it is appropriate to consider whether or not, in the
process schizophrenia, by contrast, the premorbid personal- natural course of events and in the absence of treatment,
ity is often abnormal and the onset is insidious, often in schizophrenia ever undergoes a full, complete, and sponta-
childhood or adolescence, and without any recognizable pre- neous remission. Certainly, in cases that exhibit a waxing and
cipitants; negative symptoms tend to dominate the clinical waning course, the partial remissions may be far-reaching
picture. As might be expected, the overall prognosis is favor- and, to casual inspection, it may appear that the patient has
able for ‘reactive’ cases and quite poor for ‘process’ ones. recovered. Closer inspection, however, almost always reveals
Although this reactive–process dichotomy is useful, many lingering residual symptoms in these ‘recovered’ patients,
patients do not fit neatly into one type or the other but rather such as fleeting hallucinations, odd beliefs, mannerisms, or a
demonstrate a mix of features. Furthermore, it is not clear certain poverty of thought. Consequently, in perusing the lit-
whether this scheme represents an advance over the classic erature on the course of schizophrenia, one must pay careful
subtyping; indeed, one might say that the ‘reactive’ types rep- attention to the definition used by the authors for ‘recovery’
resent paranoid schizophrenia whereas the ‘process’ types or ‘remission’, for often it is a broad one that looks more to
include disorganized and simple schizophrenia. social functioning than to a true absence of all symptoms.
p 20.qxd 3/10/08 9:58 AM Page 611
In this regard one may recall Bleuler’s opinion (Bleuler 1950) rises to about 50 percent. Furthermore, adoption studies
that a full cure, a restitutio ad integrum, never occurs; have made clear that the increased prevalence in first-
although he saw ‘far reaching improvements’ to the point of degree relatives reflects genetic and not environmental fac-
‘social restitution’, he was always able, upon careful examina- tors (Kendler and Gruenberg 1984; Kety 1987; Tienari et al.
tion, to ‘see distinct signs of the disease’. 2003). Of course, genetics cannot explain the entire picture
or one would expect a much higher concordance rate in
monozygotic twins, and consequently one must look to
Etiology environmental factors. Several have been proposed,
including obstetrical complications (Kendell et al. 1996),
Both computed tomographic (CT) and magnetic reso- maternal malnutrition (Susser and Lin 1992), and in utero
nance imaging (MRI) studies have amply demonstrated exposure to certain viral illnesses (Murray 1994), for exam-
the presence of ventricular dilation and cortical atrophy, ple influenza and rubella (Brown et al. 2001). All of these
most prominently in the temporal cortex (Andreasen et al. factors can cause disorders of neuronal migration, and it
1990b; Chua and McKenna 1995; Jaskiw et al. 1994; may be that what is inherited in schizophrenia is not the
Nopoulos et al. 1995; Suddah et al. 1989; Turner et al. disease per se but rather a defect that renders the fetal brain
1986). Furthermore, several studies have also demon- particularly vulnerable to certain of these factors.
strated a correlation between the degree of atrophy seen in If indeed the neuropathology of schizophrenia repre-
the left temporal cortex and the severity of such psychotic sents a non-progressive disorder of neuronal migration,
symptoms as loosening of associations and auditory hallu- one must also explain why the onset of the disease is
cinations (Barta et al. 1990; Hirayasu et al. 2000; Menon delayed until the late teenage or early adult years. One
et al. 1995; Shenton et al. 1992). Autopsy studies support hypothesis is that the phenotypic expression of the disease
the results of neuroimaging, demonstrating a reduced vol- is dependent upon an interaction between the fixed neu-
ume in the medial temporal lobe structures (Bogerts et al. ronal migration defect and the normally evolving neu-
1985, 1990) and a prominence of ventricular enlargement roanatomic changes seen during adolescence. During
in the temporal horn (Crow et al. 1989). normal childhood and adolescence there is a progressive
Microscopic studies have demonstrated the presence of and selective ‘pruning’ of dendrites, and, according to this
an excessive number of interstitial neurons within the hypothesis, the ability of the fixed neuronal migration
white matter (Akbarian et al. 1993a,b, 1996; Rioux et al. defect to express itself clinically may have to wait until a
2003) and neuronal disarray within the temporal lobe, specific degree and type of ‘pruning’ has ‘cleared the way’.
specifically the hippocampus (Conrad et al. 1991). Although this neurodevelopmental theory of the etiology
Furthermore, although not without controversy, some of schizophrenia has much to recommend it, the case is not
subcortical structures may suffer neuronal loss (Byne et al. proven and readers are encouraged to watch the literature.
2002; Kreczmanski et al. 2007). Strikingly, and impor-
tantly, gliosis is absent (Bogerts et al. 1985; Bruton et al.
1990; Roberts et al. 1987). Differential diagnosis
Although the mechanism underlying these anatomic
changes is not known with certainty, it is strongly sus- Although a host of disorders enters the differential diagno-
pected that they represent a disorder of neuronal migra- sis, only certain of them play a large part, thus making the
tion. In the normal course of development, neurons differential task a little less daunting. These include mood
migrate along radial glial fibers from the ventricular area disorders (i.e., bipolar disorder and major depressive dis-
through the embryonic white matter to the overlying corti- order), schizoaffective disorder, delusional disorder, alco-
cal subplate, where they come to rest in an orderly fashion holic psychoses, several personality disorders, and two
to create the laminated cortex. Furthermore, and again putative disorders known as schizophreniform disorder
normally, a small number of these neurons fail to migrate and brief psychotic disorder.
through the white matter and remain there as interstitial Bipolar disorder, discussed in Section 20.5, is character-
neurons. The findings noted above of an increased number ized by episodes of mania and depression, whereas major
of interstitial neurons and neuronal disarray in the cortex depressive disorder, as noted in Section 20.6, is marked by
are consistent with the hypothesis of a failure of normal depressive episodes alone. Both manic episodes, as seen in
migration in schizophrenia. bipolar disorder, and depressive episodes, as seen in either
The mechanism underlying such a failure of normal bipolar disorder or major depressive disorder, may be
migration, although not clear, may involve one or more characterized by psychotic symptoms.
environmental insults acting on a genetically determined Manic episodes, discussed in Section 6.3, often show a
vulnerability. As noted earlier, schizophrenia occurs in progression in which typical manic symptoms are joined by
about 1 percent of the general population; however, hallucinations and delusions and, in some, disorganized
among first-degree relatives the prevalence rises to about 5 speech, and if one sees the patient at this stage of mania and
percent, whereas among dizygotic twins it is about 20 per- if there is no history, consideration might be given to a diag-
cent and among monozygtic twins the concordance rate nosis of hebephrenic, catatonic or paranoid schizophrenia.
p 20.qxd 3/10/08 9:58 AM Page 612
If, however, one has a reliable history, the differential diag- catatonic stupor, either into relatively normal mobility or
nosis is fairly straightforward. In mania, mood symptoms, into a brief period of excitation; such a lysis, occurring over
namely heightened mood, increased energy, and decreased seconds or minutes, simply is not seen in depression.
need for sleep, occur first and are present in a sustained and Schizoaffective disorder, as described further in Section
prominent fashion before the onset of hallucinations, delu- 20.2, is an illness characterized by the chronic presence of
sions, or disorganized speech. By contrast, in schizophrenia psychotic symptoms, such as hallucinations, delusions, or
one finds that the course is marked by the presence of hallu- disorganized speech, and by intermittent episodes of either
cinations before the onset of any mood symptoms; further- mania or depression, during which the pre-existing psy-
more, as noted earlier, any manic symptoms seen in chotic symptoms undergo an exacerbation. The differential
schizophrenia are transient and relatively mild. Certain point that allows a distinction from schizophrenia is that
other features may also help in the differential diagnosis the mood disturbances, whether manic or depressed, are
between mania and schizophrenia. In mania, euphoria is full, severe, and sustained, generally lasting at least weeks, in
typically ‘infectious’ and deeply felt, and this contrasts with marked contrast to the mood changes that may be seen in
the euphoria seen, for example, in hebephrenic schizophre- schizophrenia, which are fragmentary, mild, and transient.
nia, which is shallow and silly and which, rather than being Delusional disorder, as noted in Section 20.3, is charac-
infectious, typically leaves the interviewer unmoved. terized by delusions and thus may be confused with para-
Furthermore, the hyperactivity of mania is typically outgo- noid schizophrenia. The differential here rests on the
ing and extroverted, and this is in marked contrast to the degree of plausibility and systematization of the delusions
behavior of the excited catatonic patient, who typically and on the absence of other symptoms. Delusional disor-
avoids contact. Finally, in cases in which the heightened der is marked by delusions that are often quite plausible
mood is one of irritability rather than euphoria, the manic and typically very well systematized, and by the absence of
patient is typically ‘on the attack’, which contrasts with the other symptoms, in particular hallucinations, disorganized
irritable paranoid schizophrenic, who is more ‘on guard’; speech, and bizarre behavior. By contrast, although there
although both irritable manics and irritable paranoid schiz- may be some plausibility and systematization to the delu-
ophrenics are dangerous, the manic patient is recklessly so, sions seen in paranoid schizophrenia, close inspection typ-
in contrast to the paranoid schizophrenic, who may become ically reveals some fragmentation and inconsistencies and
violent only if approached in what appears, to the patient at almost always at least some hints of auditory hallucina-
least, to be a potentially hostile manner. tions, speech disorganization, and bizarreness.
Depression, as discussed in Section 6.1, may likewise, at Alcoholic psychoses, namely alcoholic hallucinosis and
its depth, be characterized by hallucinations and delusions, alcoholic paranoia, discussed in Sections 22.9 and 22.10,
and this may be seen in depressive episodes of either bipo- respectively, may be characterized by delusions and hallu-
lar disorder or major depressive disorder. As with manic cinations, and thus mimic paranoid schizophrenia. The
symptoms, however, the differential is fairly straightfor- differential here rests on the history: if the psychosis in
ward providing that one has a reliable history: in depression question occurred only after many years of alcoholism
characterized by hallucinations and delusions, these symp- with repeated episodes of delirium tremens, then a case
toms only occur well after the typical depressive symptoms may be made for an alcoholic psychosis; in cases, however,
have become well-established and severe; by contrast, in in which delusions or hallucinations occurred early on,
schizophrenia, delusions and hallucinations precede the perhaps in adolescence or early adult years, and only after
advent of depressive symptoms. Furthermore, the depres- a relatively brief drinking career, then one would be hard
sive symptoms seen in schizophrenia are generally transient pressed to explain them on the basis of alcoholism.
and are typically not severe. The nature of the delusions Several personality disorders, namely those of the para-
seen in depression may also be helpful. In depression, the noid, borderline, and schizotypal types, may occasionally
delusions are ‘mood-congruent’ in that they ‘make sense’ in offer some diagnostic difficulties. Patients with paranoid per-
light of the prevailing mood. Thus, patients with depression sonality disorder are chronically distrustful and on guard,
may come to believe that they have committed unpardon- quick to take offense and to read malevolence into what oth-
able sins or that their insides are drying up and dying, as is ers do, and prone to harbor deep, long-standing resentments;
only fitting for such miserable sinners. By contrast, in under great stress they may develop delusions of persecution
schizophrenic patients who experience some depressive and thus may resemble patients with paranoid schizophre-
symptoms, the delusions are often ‘mood-incongruent’ and nia. In patients with paranoid schizophrenia, however, close
indeed often bear no conceivable relationship to depres- inspection will reveal other symptoms, such as delusions of
sion, as, for example, in the case of a schizophrenic who other types (e.g., delusions of grander) or hallucinations,
complained of feeling depressed and then went on to talk which are not seen in the personality disorder; furthermore,
about the ‘telepathy’ that made his toe tingle. Finally, con- in paranoid schizophrenia one often also sees some lack of
sideration may be given to differentiating a severe depres- full systematization of the delusions, in contrast to the per-
sive episode from a catatonic stupor. In both conditions sonality disorder in which logic is preserved. Borderline per-
one may see immobility and mutism; however, with pro- sonality disorder is characterized by a chronic instability in all
longed observation one may chance to see a sudden ‘lysis’ of aspects of the patient’s life, accompanied by intense loneliness
p 20.qxd 3/10/08 9:58 AM Page 613
and dramatic and stormy emotions; when under great stress, dosage and side-effects. Of these first-generation agents,
these patients may at times also develop delusions, either of both haloperidol and fluphenazine are available in intra-
persecution or reference, and may also experience auditory muscular ‘depot’ formulations, which are given, on aver-
hallucinations. The distinction from schizophrenia rests on age, once every 4 or 2 weeks respectively. All other things
the stormy instability that characterizes these patients’ lives being equal, of the first-generation agents, haloperidol is
and on the fact that the psychotic symptoms appear only at probably a reasonable first choice.
times of great stress; this is in contrast to schizophrenia, in Second-generation agents include clozapine, olanzapine,
which they are present throughout the course, even during risperidone, quetiapine, aripiprazole, and ziprasidone.
stress-free periods. Schizotypal personality disorder is char- Choosing among these agents is not straightforward. With
acterized by chronic aloofness and by peculiar thoughts and regard to effectiveness, clozapine is clearly superior; however,
behavior, and thus may mimic simple schizophrenia. The its side-effect profile, especially the risk of agranulocytosis,
differential here rests on the overall course: in the personality limits its use to treatment-resistant cases. Of the other
disorder there is no deterioration, whereas in simple schizo- agents, although there is controversy here, it appears that
phrenia one sees a very slow progression. olanzapine may have an edge in terms of overall effectiveness
Schizophreniform disorder and brief psychotic disorder (Lieberman et al. 2005). This advantage, however, is severely
(also known as brief reactive psychosis) are both character- tempered by the tendency of olanzapine to cause metabolic
ized by symptoms that are similar to those seen in schizo- derangements, including weight gain, hyperlipidemia, and
phrenia; however, where they differ is in their supposed diabetes. Both risperidone and quetiapine may also cause
course. Patients who experience a full, complete, and spon- these metabolic derangements, but are much less likely to do
taneous remission within 1 month are said to have brief so; risperidone, alone among the second-generation agents,
psychotic disorder, whereas those whose illness lasts longer is available in a long-acting intramuscular ‘depot’ formula-
than 1 month but less than 6 months are said to have tion, providing benefit for 2 weeks. Aripiprazole and zipras-
schizophreniform disorder. However, there is a debate as idone stand out in that they are not associated with metabolic
to whether such disorders actually exist. Certainly, there changes. Overall, and all other things being equal, if a second-
are patients with schizophrenia who are treated with generation agent is used, it may be reasonable to start with
antipsychotics early in the course of the illness and who risperidone; however, again, it must be acknowledged that
experience a complete, antipsychotic-induced remission of this is an area of great controversy.
symptoms; however, in these cases, if treatment is discon- In deciding which antipsychotic, whether first or second
tinued, symptoms gradually recur. What is at issue here is generation, to prescribe, the first step is to obtain an accurate
whether there are, in fact, cases in which symptoms spon- treatment history, and this may require not only questioning
taneously and completely undergo a lasting remission the patient but also reviewing records and interviewing fam-
without treatment. I have never seen such a case, nor am I ily members. If there is a history of a good response com-
aware of any such well-documented cases in the literature. bined with good tolerability, then it makes sense to use the
Other causes of psychosis are discussed in Section 7.1 same drug again. In treatment-naive patients, or in cases in
and, although most of these are rare, the reader is encour- which prior treatments were unsatisfactory, other consider-
aged to gain familiarity with them. ations come into play. Although not without controversy, it
appears that, overall, second-generation agents are more
effective and better tolerated than first-generation ones, and,
Treatment consequently, it may be reasonable to select a second-gener-
ation agent. Of the second-generation agents, risperidone, as
In almost all cases, treatment involves the use of an noted above, is a reasonable choice, both regarding efficacy
antipsychotic drug. These agents may be broadly divided and side-effects, and this also allows one to move to intra-
into two different categories, namely first-generation and muscular ‘depot’ treatments in cases of non-compliance. It
second-generation or, as they are often also termed, typical must be emphasized, however, that the choice of an agent is
and atypical agents. not simple or straightforward, and often multiple trials of
First-generation agents are further subdivided into different agents must be performed before a regimen is
‘high-potency’ (haloperidol, fluphenazine, perphenazine, found that is reasonably effective and well-tolerated.
trifluoperazine, and thiothixene), ‘low-potency’ (chlor- Regardless of which agent is chosen, it is important that
promazine and thioridazine), and ‘medium-potency’ one gives it an ‘adequate’ trial before moving on to another,
(loxapine and molindone) drugs. High-potency drugs not only in terms of dose but also duration. In general,
require lower milligram doses and are more likely to cause assuming an adequate dose is used, one should observe the
extrapyramidal side-effects (e.g., parkinsonism, dystonia, patient for at least 2 weeks to get a reasonable idea as to
akathisia, akinesia). Low-potency drugs require higher response. In cases characterized by significant agitation, one
doses and are less likely to cause extrapyramidal side- may, as described in Section 6.4, consider adding adjunctive
effects, but are prone to cause sedation, hypotension, and lorazepam to either risperidone or haloperidol, and contin-
anticholinergic effects. Medium-potency drugs, as might uing this until the agitation has passed, after which the
be expected, fall in-between regarding both milligram patient may be continued on the antipsychotic alone. If the
p 20.qxd 3/10/08 9:58 AM Page 614
overall initial response is only partial, but otherwise prom- but at times may manifest only with an exacerbation of psy-
ising, one may elect to observe the patient for another 4 chotic symptoms (Van Putten 1975; Van Putten et al. 1974);
weeks and, if the response is good, then move to mainte- unless this is properly diagnosed, a ‘vicious cycle’ may occur,
nance treatment, as described below. If the response to the in which the exacerbation is mistakenly attributed to the
first agent is poor, or the side-effects are unacceptable, then underlying schizophrenia, prompting an increased dose of
a trial with a different agent should be considered. Should the antipsychotic with a consequent worsening of the psy-
patients fail to get a good response to adequate trials of two chosis. Although these side-effects are classically seen with
agents, one may be dealing with a treatment-resistant case. first-generation agents, they may also, albeit rarely, occur
In such cases several options are available, including a trial with second-generation ones.
of clozapine, trials of other agents, or simply ‘living with’ a Post-psychotic depression may occur after psychotic
less than optimal treatment regimen. As regards effective- symptoms have partially remitted, either spontaneously or
ness, clozapine is clearly head and shoulders above all other by virtue of antipsychotic treatment. These sustained
antipsychotics in treatment-resistant cases, and indeed may depressions must be treated as they carry a significant risk
yield some of the most gratifying treatment responses in all of suicide. Treatment may be accomplished with an anti-
of medical practice; however, its side-effect profile gives depressant (Siris et al. 1987), such as a selective serotonin
pause to many patients and physicians. If clozapine is not reuptake inhibitor (SSRI), or, in severe cases, with electro-
an option, some clinicians will try trial after trial of different convulsive therapy (ECT). Of interest, ECT may also be
agents, hoping to find one that ‘works’; provided that effective in the acute treatment of catatonic schizophrenia.
patients have the fortitude, this is not an unreasonable In addition to treatment with antipsychotics and rou-
strategy, as in some cases patients will simply have idiosyn- tine supportive care, many patients will also require exten-
cratic and unpredictable ‘good’ responses to one agent but sive assistance in gaining housing and sheltered employment;
not others. In some cases, however, patients will opt to stay social skills training and cognitive–behavioral treatment
with a regimen that, although perhaps providing less relief may also be beneficial. Insight-oriented or psychodynami-
than is hoped for, is at least tolerable. cally oriented psychotherapy is generally contraindicated,
Maintenance treatment is appropriate in almost all as it may make patients worse.
cases. Initially, patients should be maintained on a dose that Hospitalization is required for most patients at some
is similar to, if not identical to, that utilized during initial point in their illness and, in many cases, repeated admis-
treatment. Once patients are stable, cautious dose adjust- sions occur. In some cases involuntary hospitalization is
ments may be considered every 3–4 months. As noted ear- required and may be life-saving. Partial hospitalization or
lier, in many cases the course of schizophrenia is ‘day hospitals’ may enable some severely ill patients to be
characterized by gradually occurring exacerbations and maintained in the community.
partial remissions, and in such cases it is appropriate to try
to ‘titrate’ the dose to the underlying severity of the disease,
always seeking the lowest possible dose consistent with 20.2 SCHIZOAFFECTIVE DISORDER
acceptable symptomatic control. This serves not only to
reduce cost and side-effect burden but also reduces the risk The term ‘schizoaffective’ has had many definitions since it
of tardive dyskinesia (this dreaded complication of long- was first coined by Kasanin in 1933. As conceived of here,
term treatment with antipsychotics, primarily first-genera- schizoaffective disorder is characterized by chronic,
tion agents, is discussed further in Section 22.2). In a unremitting psychotic symptoms, similar to those seen in
minority of cases, the underlying course is so favorable, and schizophrenia, upon which are superimposed full episodes
the partial spontaneous remissions so profound, that it may of either depression or mania, during which the pre-existing
be possible to taper the dose to almost nothing, at which psychotic symptoms undergo an exacerbation. Although the
point some patients and physicians may consider stopping prevalence of schizoaffective disorder is not known with cer-
treatment. This is a difficult decision. Schizophrenia is a tainty, it is probably far less common than schizophrenia.
chronic disease and, although far-reaching spontaneous
partial remissions do occur, exacerbations may be expected
at some point in the future. Consequently, it is necessary to Clinical features
continue seeing patients in regular follow-up visits and to
discuss with them, and with family, the importance of call- The onset is typically in the late teens or early twenties, and,
ing immediately should symptoms recur. viewed over time, this disorder, as suggested above, appears
In both initial and maintenance treatment phases there to represent a superimposition of a mood disorder, such as
are two side-effects that must always be kept in mind, major depressive disorder or bipolar disorder, upon schizo-
namely akinesia and akathisia. Akinesia, as noted in Section phrenia. Thus, these patients typically present with a psy-
3.9, may leave patients psychomotorically retarded and, in chosis similar to that described in the preceding section for
the unwary clinician, may prompt a misdiagnosis of depres- schizophrenia, and the symptoms (e.g., hallucinations, delu-
sion (King et al. 1995; Van Putten and May 1978). Akathisia, sions, disorganized speech, etc.) persist in a chronic, gener-
described in Section 3.10, classically renders patients restless ally lifelong fashion. Periodically, however, these chronic
p 20.qxd 3/10/08 9:58 AM Page 615
20.3 Delusional disorder 615
symptoms are joined by either a depressive episode or a disorder, psychotic symptoms are always present: they are
manic episode (with symptoms as described in Sections 6.1 present during the mood episodes and also in the intervals
and 6.3 respectively). Characteristically, whenever a depres- between these episodes.
sive or manic episode does occur, the chronically persistent
psychotic symptoms become more severe, only to eventually
return to their previous level of severity once the mood Treatment
episode has run its course.
As might be expected, the treatment of schizoaffective disor-
der borrows heavily from the treatments for schizophrenia
Course and for either major depressive disorder or bipolar disorder.
In general, most patients are treated with an antipsychotic,
Although it is clear that the psychotic symptoms remain following the scheme described for schizophrenia in the pre-
chronic, the frequency with which episodes of depression or ceding section. This will generally control psychotic symp-
mania occur has not been well studied. In some cases it toms and may also decrease the severity of mood symptoms
appears that only depressive episodes occur, and here one in some cases. In cases in which either depressive or manic
speaks of schizoaffective disorder, depressed type; in others episodes continue to occur to a problematic degree of sever-
one sees both depressive and manic episodes or manic ity despite antipsychotic treatment, one may consider use of
episodes alone, and in these cases one speaks of schizoaffec- an antidepressant or a mood stabilizer (e.g., lithium, carba-
tive disorder, bipolar type. The overall outcome of this disor- mazepine, or divalproex). In patients with schizoaffective
der, although not as favorable as that of the mood disorders, disorder, depressed type, an antidepressant alone may be
is better than that seen in schizophrenia (Jager et al. 2004). adequate to bring the depressive episode under control, and
once this has been accomplished one may consider using an
antidepressant on a preventive basis. In patients with
Etiology schizoaffective disorder, bipolar type, a mood stabilizer may
be used. This may not only control depressive or manic
Family studies suggest that schizoaffective disorder may
episodes but may also prevent their occurrence. In cases in
either ‘run true’ or result from a ‘double loading’ of genetic
which depressive symptoms seen in the bipolar type are not
susceptibilities for both schizophrenia and either major
controlled by a mood stabilizer alone, one may add an anti-
depressive disorder or bipolar disorder (Angst et al. 1979;
depressant, but it is critical to make sure that the patient is
Cohen et al. 1972; Kendler et al. 1995; Lauren et al. 2005;
‘covered’ with a mood stabilizer first to guard against the
Pope et al. 1980).
emergence of an antidepressant-induced manic episode.
Other modalities of treatment are as discussed in the sec-
tions on schizophrenia (Section 20.1), major depressive dis-
Differential diagnosis order (Section 20.6), and bipolar disorder (Section 20.5).
Schizoaffective disorder must be distinguished both from
schizophrenia and from mood disorders.
In schizophrenia, as noted in the preceding section, one 20.3 DELUSIONAL DISORDER
may see mood disturbances, but these differ fundamentally
from the episodes of depression or mania seen in schizo- Delusional disorder is a chronic disorder characterized by
affective disorder. The mood changes seen in schizophre- the gradual appearance of one or more delusions that
nia are transient, fragmentary, and generally mild, whereas eventually elaborate into a coherent system (Kendler 1980,
those seen in a depressive or manic episode are sustained, 1988; Kraepelin 1921). In contrast to the delusions seen in
pervasive and severe, typically enduring at least for weeks. schizophrenia, the delusions of delusional disorder have a
Post-psychotic depression (McGlashan and Carpenter certain plausibility, and the eventual delusional system is
1976), as seen in some cases of schizophrenia, is distin- within itself quite logical.
guished by the fact that there is no exacerbation of psy- The traditional name for this disorder, as originally
chotic symptoms during the depression. bestowed by Kraepelin, was paranoia, and although this
In major depressive disorder or bipolar disorder, term is still seen in the literature, delusional disorder is
episodes of mood disturbance may, when severe, be accom- probably a better name, for two reasons. First, it empha-
panied by delusions and hallucinations; however, the differ- sizes the cardinal aspect of this disorder, namely the pres-
ential may be easily made if one simply attends to the overall ence and prominence of delusions. Second, it avoids the
course of the illness. In mood episodes of major depressive unfortunate association of paranoia with persecution, and
disorder or bipolar disorder, psychotic symptoms occur reminds us that delusions of persecution are but one of
only within the context of the mood episode, generally at many types of delusions seen in this disorder.
their height, and are not present in the intervals between This is an uncommon disorder, with a lifetime preva-
mood episodes. By singular contrast, in schizoaffective lence falling between 0.01 and 0.05 percent.
p 20.qxd 3/10/08 9:58 AM Page 616
Clinical features the disparity between the magnitude of the patients’ sense
of being unjustly harmed and the trivial, insignificant
The onset is generally in early adult years, although some nature of the original inciting insult to their sense of justice
may not fall ill until the age of 50 years (Winokur 1977). brings to light the pathologic nature of their behavior.
Generally, these patients experience a lengthy prodrome, In the grandiose subtype, the dominant theme of
with evanescent delusions or perhaps intimations that grandiosity may come to light in a variety of ways. Patients
things are not ‘right’. Eventually, persistent and clear-cut may believe themselves to be secret ‘captains of industry’
delusions occur, and the illness begins to assume its defin- whose advice is sought by leaders in the financial commu-
itive form. This transition to active illness may at times be nity. Others may entertain delusions of high descent. One
sudden, and patients may experience a sort of ‘epiphany’ in man believed that his mother was an heiress who, out of
which lurking suspicions and concerns suddenly crystallize shame for her out-of-wedlock pregnancy, gave him up for
into beliefs; often, however, the transition from prodrome adoption to a poor family; the patient, believing that an
to active illness is gradual, almost furtive. inheritance would soon be his, quit his job as he felt no
Although the most common type of delusion seen in need for his income anymore. Others may believe them-
delusional disorder is that of persecution, other themes may selves to be great, although unrecognized, inventors, and
be prominent: jealousy, grandiosity, erotic longing, liti- toil on in their homes, littering their walls with fantastic
giousness, and bodily concerns may all occur. Regardless of diagrams and sketches of their magnificent creations.
which delusion is most prominent, however, one typically In the erotomanic subtype (also known as de
also sees delusions of reference. Furthermore, as noted ear- Clerambault’s syndrome), patients come to believe that they
lier, the delusions experienced by these patients often fit are loved by someone else, generally someone of much
together quite logically, and the entire corpus of beliefs is higher social station. The clinical picture is dominated by the
well systematized. Often, one finds that all of the delusions patient’s belief that the imagined lover, for some reason or
appear to stem from one delusional ‘premise’ and that this other, cannot openly express the love. For example, one
premise often has a certain plausibility to it. woman believed that the mayor was in love with her and was
Traditionally, delusional disorder has been divided into unable to tell her this openly as he was married. She saw him
several subtypes, depending on the type of delusion pres- at a political rally and he turned his gaze from her, a move she
ent (Winokur 1977); thus, there are persecutory, interpreted as evidence that he could not bear the unrequited
grandiose, erotomanic, jealous, and somatic subtypes, and longing he surely must have felt had he looked at her. The
these are described further below. However, this division is newspaper hinted at a strain in his marriage, and the patient
somewhat artificial given that, although one type of delu- believed that, had it not been for the mayor’s high moral
sion will dominate the picture, two or more may be pres- character, he would immediately have divorced his wife. This
ent, thus creating a ‘mixed’ picture. attitude of hopeful expectation lasted for years, throughout
In the persecutory subtype the dominant delusion is which the patient occasionally sent ‘secret’ letters to the
one of being persecuted or conspired against. Patients feel mayor at this office. Eventually, unable to wait longer she
singled out; they are watched and followed. Delusions of began stalking the mayor’s wife, and called him to say that
reference typically appear, and patients may believe that she would soon ‘dispose’ of his wife, thus freeing him.
people on the street talk about them. Patients may move to In the jealous subtype, the patient becomes convinced
another city to avoid their persecutors, and may feel safe that his or her spouse or lover is being unfaithful. The
for a while, but eventually their persecutors catch up with patient not only ‘sees’ evidence for the infidelity but may
them. These patients may at times be dangerous and may seek it out. The spouse is a few minutes late getting home
attack others in what, to them, appears to be justified self- from work and the patient believes that only passionate
defense (Kennedy et al. 1992). lovemaking could have caused the delay. Sheets and under-
The litigious subtype may be the most difficult to diag- clothing are inspected for telltale stains; telephone conversa-
nose as the initial delusion may appear very plausible and tions are listened in on; a private detective may be hired. The
the ensuing delusions may have an almost unassailable logic patient may insist that the spouse stay at home, and at times
to them. During the onset of the illness, patients are typi- spouses may become virtual prisoners in their own homes.
cally involved in legal proceedings that go badly for them. A In the somatic subtype patients believe, despite reassur-
suit may be lost or, if won, the award may appear to the ances to the contrary from their physicians, that they have a
patient to be too low. Patients become convinced that serious disease. Although the ‘symptoms’ may be mild, per-
someone is at fault: their attornies are incompetent; the haps a minor headache, patients are convinced that the
judges were biased; the juries were prejudiced. Patients may underlying disease is severe, perhaps a brain tumor. Two
pore over trial manuscripts until, finally, some irregularity, atypical variations on this subtype deserve mention, namely
no matter how minor, is found. New attornies are then the olfactory reference syndrome (Videbech 1966) and par-
hired and appeals are filed, and a series of legal proceedings asittosis (Andrews et al. 1986; Mitchell 1989). In the olfac-
is embarked upon. With each failed legal manuever, tory reference syndrome patients are convinced that they
patients may become more convinced that the legal system are emanating a foul odor from the mouth or some other
as a whole is conspiring in the denial of justice. Eventually, orifice, and may anxiously ask others if they smell it also.
p 20.qxd 3/10/08 9:58 AM Page 617
20.4 Post-Partum psychosis 617
In parasitosis patients believe that the skin is infested: they hears voices telling him that a ‘super computer’ is monitor-
may complain that they feel bugs crawling and may dig ing his thoughts. However, this very refusal to confide in
under the skin to find them. the physician is a valuable clue. In paranoid schizophrenia,
In addition to delusions, some patients with delusional suspicions are mercurial and focus on others in seconds;
disorder may also have hallucinations, but these generally thus the physician may be suspected moments after the
play only a minor role in the clinical picture and are consis- interview begins. In delusional disorder, by contrast,
tent with the delusions. For example, a persecuted patient patients take time to size others up, and indeed are often
may hear a voice warning him that his life is in danger or an quite willing to confide in the physician.
erotomanic patient may hear voices whispering caressing Of the multiple other causes of psychosis considered in
words. Mood and affect may be unremarkable or may show Section 7.1, special consideration should be given to alco-
changes, again consistent with the delusions: the persecuted holic paranoia. This is one of the alcoholic psychoses and,
patient may become quite irritable and the grandiose as noted in Section 22.10, is characterized by delusions of
patient may experience a shallow, contented euphoria. persecution or jealousy; however, in this condition one
Overall, regardless of subtype, the behavior of these always finds a history of chronic alcoholism that precedes
patients may be quite normal in areas of their lives that are the onset of the delusions by years or decades.
not touched by their delusions. For example, a patient with Hypochondriasis may enter the differential for the somatic
the persecutory subtype who believed that co-workers at subtype of delusional disorder. As noted in Section 7.7, how-
the factory were conspiring against him, but who was free ever, in hypochondriasis the patient’s concerns about having
of delusional concerns regarding all others, led an unre- a serious illness do not amount to delusions; patients with
markable life at home and sang in the choir at church, took hypochondriasis do respond, albeit perhaps only temporarily,
his children to baseball games, and was considered a ‘good to reassurance from the physician, whereas patients with the
neighbor’. somatic subtype of delusional disorder do not.
Course Treatment
Although partial remissions may occur, for the most part Treatment generally involves the use of an antipsychotic;
delusional disorder appears to pursue a chronic waxing however, in most cases, gaining the patient’s agreement to
and waning course (Opjordsmoen and Rettersol 1991). take medication may be quite difficult. These patients see
nothing wrong with themselves or their beliefs, and if told
they have ‘delusions’ may be quite offended. Consequently,
Etiology great tact and diplomacy are required, and the subject of
medication may often have to be approached obliquely;
Although the etiology is not known, delusional disorder
whereas the persecuted patient might never accept a pre-
appears to be familial; importantly, there is no evidence of
scription for ‘psychosis’, he might well agree to ‘try’ a med-
any genetic relationship with schizophrenia (Kendler et al.
icine to help him maintain his composure in the face of all
1982, 1985; Watt 1985; Winokur 1985).
the tribulations he is facing. An antipsychotic may be cho-
sen using the scheme discussed in the section on schizo-
Differential diagnosis phrenia; importantly, one should choose a medication with
a low propensity for side-effects and start at a low dose, as
Schizophrenia is distinguished on two counts, namely the patients with delusional disorder are typically prone to seize
lack of systematization and the presence of other symp- on the occurrence of a side-effect, no matter how trivial, as
toms. As noted, in delusional disorder the various delusions a reason to never take medication of any sort again. The
are logically connected into a well-systematized corpus of somatic subtype may constitute an exception to the forego-
beliefs. By contrast, in schizophrenia there is always some ing as there are case reports of this subtype responding to
lack of connectedness among the various delusions, which antidepressants such as clomipramine (Wada et al. 1999) or
at times may be flatly contradictory. Furthermore, in paroxetine (Hayashi et al. 2004).
schizophrenia one sees other symptoms, such as bizarre Occasionally, hospitalization may be required to pro-
delusions, prominent hallucinations, speech disorganiza- tect others, for example in the persecutory or erotomanic
tion, etc. In some cases, however, it may be difficult to dif- subtypes.
ferentiate paranoid schizophrenia from the persecutory
subtype of delusional disorder. In paranoid schizophrenia,
the patient’s guardedness and suspiciousness may be such 20.4 POST-PARTUM PSYCHOSIS
that only the fact of the ‘conspiracy’ is leaked to the physi-
cian, with all else held in secret. Thus the patient may not Post-partum psychosis, also known as puerperal psychosis, is
reveal certain bizarre beliefs, for example that a listening a rare disorder, occurring in less than 2 per 1000 deliveries; it
device has been placed in his abdomen or that he constantly is more common in primaparous than multiparous women.
p 20.qxd 3/10/08 9:58 AM Page 618
Clinical features be used as described in Section 20.5. In other cases one may
use an antipsychotic, and the choice among these may be
Symptoms generally have an abrupt onset, anywhere from made utilizing the guidelines offered in Section 20.1.
days to a few weeks after delivery (Brockington et al. 1981; Consideration may also be given to sublingual estradiol: in
Munoz 1985). Clinically (Bagedahl-Strindlund 1986; one non-blind study, 1 mg four to five times daily yielded
Brockington et al. 1981; Hadley 1941; Kumar et al. 1983; impressive results (Ahokas et al. 2000b). Regardless of
Munoz 1985), mood changes are prominent and, although which pharmacologic strategy is employed, it should
depressive features may occur, manic symptoms are much always be possible, given the natural course of this disor-
more common. Delusions may appear and often center on der, to eventually taper and discontinue treatment.
the baby, who may variously be considered evil or the As patients begin to improve, attempts should be made
Messiah; auditory hallucinations may also occur and may to gradually guide them into appropriate interactions with
be command in type, instructing the patient to do things to their babies; however, these visits should always be closely
the baby. Confusion and variable disorientation may also monitored until patients have recovered.
be seen. Infanticide may occur in up to 4 percent of cases, Subsequent to recovery, patients should be counselled
and suicide may also occur. regarding the risk of recurrence after future pregnancies. If
patients do become pregnant again, close monitoring is
Course required post-partum, and a case may also be made for
prophylactic use of lithium (Austin 1992; Stewart 1988) or
In the natural course of events, symptoms undergo a grad- whichever other agent was effective during the earlier
ual, spontaneous, and full remission after a matter of weeks episode, with treatment beginning either immediately
or months. Close to one-third of patients will have another post-delivery or, in some highly selected cases, shortly
episode should they have another child (Davidson and before anticipated delivery.
Robertson 1985; Kendell et al. 1987).
20.5 BIPOLAR DISORDER
Etiology
Bipolar disorder is characterized by the occurrence of at
Although the etiology is not known, it is strongly suspected least one manic or mixed-manic episode during the
that the psychosis occurs secondary to the effects of pro- patient’s lifetime; most patients will also have one or more
foundly changing hormonal levels on the central nervous depressive episodes at other times. In the intervals between
system (Ahokas et al. 2000a,b). these episodes, most patients return to their normal state of
well-being. Thus, bipolar disorder is properly considered an
Differential diagnosis ‘episodic’, ‘periodic’, or ‘cyclic’ illness, with patients ‘cycling’
up into a manic or mixed-manic episode, then returning to
Both schizophrenia and schizoaffective disorder may normal and cycling ‘down’ into a depressive episode, from
undergo symptomatic exacerbation in the post-partum which they likewise eventually more or less fully recover.
period; however, here, given that these are chronic ill- Bipolar disorder has a lifetime prevalence of roughly 1.5
nesses, one also sees symptoms before delivery, indeed typ- percent and is equally common in males and females.
ically long before the patient became pregnant. A synonym for bipolar disorder is ‘manic-depressive ill-
In bipolar disorder there is an increased risk of mania in ness, circular type’; however, this terminology is gradually
the post-partum period (Bratfos and Haug 1966), thus fading from use. In the past it was believed that patients
presenting a picture similar to that of post-partum psy- with what is now termed bipolar disorder and patients
chosis. In most cases, however, one will find a history of with major depressive disorder actually suffered from the
prior episodes of mania (or depression) occurring outside same illness, namely manic-depressive illness, which
the post-partum time span. merely manifested in different forms. Those who had both
Eclampsia may present with delirium immediately manic episodes and depressive episodes during their life-
post-partum; however, here one finds associated symp- times were considered to have the ‘circular’ form, whereas
toms, such as hypertension and proteinuria. There are also those who had only depressive episodes during their life-
rare case reports of psychosis occurring secondary to treat- times were considered to have the ‘depressive’ form. Given
ment with bromocriptine (Canterbury et al. 1987), which that it is now clear that bipolar disorder and major depres-
may be used to suppress lactation. sive disorder are different diseases, it may be appropriate to
leave the term ‘manic-depressive illness’ to history.
Treatment
Clinical features
Hospitalization is generally indicated. When manic symp-
toms are prominent, case reports suggest the usefulness of The onset of bipolar disorder is heralded by the appearance
lithium, and divalproex may also be considered; they may of a first episode of illness, which may be manic, depressive,
p 20.qxd 3/10/08 9:58 AM Page 619
or mixed-manic. In general, most patients have their first resist at least inwardly smiling when in the presence of a
episode in their late teens or early twenties, and by the age euphoric manic. Irritable manics, by contrast, are irascible,
of 50 years, over 90 percent of patients will have had their first fault-finding, and accusatory, and when their intemperate
episode. The range of age of onset is, however, wide, from as demands are not immediately met, they may erupt into a
young as 11 years (McHarg 1954) up to the eighth decade tirade of curses and threats, and indeed may become vio-
(Charron et al. 1991), even as late as the age of 79 years lently assaultive. Increased energy leaves these patients
(Summers 1983). Each type of episode is described in turn. strangers to fatigue and in little need of sleep. Pressured
speech is rapid and voluble. Patients have much to say, their
MANIC EPISODE thoughts come rapidly and race pell-mell, and in extreme
cases they cannot speak fast enough to express them.
Manic episodes are often preceded by a prodrome, lasting Although patients may, with great urging, be able momen-
from a few days to a few months, of mild and often indis- tarily to dam up their words, such respites, when an inter-
tinct manic symptoms. At times, however, there may be lit- viewer may be able to get a few words in, are but transient
tle or no prodrome and the episode may appear quite events before the dam bursts and the interviewer is again
abruptly; when this occurs, patients often unaccountably inundated with a torrent of words. Such pressured speech is
wake up in the middle of the night full of energy and vigor, also typically characterized by flight of ideas, in which
thus manifesting the so-called ‘manic alert’. patients’ interests change abruptly from one subject to
The overall symptomatology of mania has been well another, successive subjects having little in common with
described (Abrams and Taylor 1981; Black and Nasrallah each other. Pressure of activity impels patients to be ever on
1989; Bowman and Raymond 1931; Brockington et al. the go and perpetually involved in schemes, plans, projects,
1980; Carlson and Goodwin 1973; Kraepelin 1921; Lipkin and activities, activities in which they also often seek to
et al. 1970; Rosenthal et al. 1979, 1980; Stevens 1904; Winokur involve others. Patients may also demonstrate distractibility,
1984). As discussed in Section 6.3, mania may be divided in which their attention changes mercurially from one sub-
into three stages: hypomania or stage I mania; acute mania ject to another. As might be expected, hypomanic patients
or stage II mania; and delirious mania or stage III mania. All often become involved in impetuous and ill-considered ven-
patients who enter a manic episode experience hypomania tures: there may be spending sprees, intense, injudicious,
and most progress to acute mania; however, only a minor- and often sexual, relationships, and ruinous business ven-
ity eventually reach delirious mania. By convention, tures. Attempts to reason with such patients, and to bring
patients whose manic episodes never pass beyond hypoma- them back to some good judgment, are typically in vain.
nia are said to have ‘bipolar II disorder’, whereas those who, Hypomanic patients rarely see anything wrong with them-
during at least one episode of mania, pass beyond hypoma- selves; indeed, they often opine that if only others saw as they
nia are said to have ‘bipolar I disorder’. did, and partook of their confidence, all would be well.
The rapidity with which patients pass from hypomania Acute, or stage II, mania is characterized by an intensifi-
through acute mania and on to delirious mania varies from cation of all of the symptoms seen in hypomania and by the
a week to a few days to, rarely, hours; indeed, in hyperacute appearance of delusions. The mood becomes extraordinar-
onsets, patients may already have passed through hypoma- ily heightened and labile, and irritability may be quite pro-
nia before being brought to medical attention. The duration nounced, with unpredictable assaults and tirades. Energy
of an entire manic episode varies from the extremes of only seems boundless, and the pressure of activity and speech
a few days up to many years, or even a decade (Wertham may begin to fragment the overall behavior; patients may
1929). On average, however, most first episodes of mania shout, then cry, hop on the floor or race to the nurses’ sta-
last from several weeks to several months. In general, once tion, making one demand, then an opposite one, and be
the peak of the episode is reached, symptoms gradually sub- completely incapable of channelling themselves towards
side and, after remission finally occurs, many patients, look- any one overall purpose. Delusions are typically either of
ing back over what they did, often feel guilt and remorse. grandeur or of persecution, according to the mood of the
Hypomania, or stage I mania, is characterized by the car- patient. Euphoric patients may announce their divinity or
dinal manic symptoms of heightened mood, increased lavish listeners with promises to share their great wealth;
energy and decreased need for sleep, pressure of speech and irritable patients may accuse others of irrationally thwart-
flight of ideas, and pressure of activity (Abrams and Taylor ing and persecuting them. Patients may also hear voices.
1976a; Beigel and Murphy 1971a; Clayton et al. 1965; Delirious, or stage III, mania represents the height of
Loudon et al. 1977; Taylor and Abrams 1973; Winokur and mania and is characterized by a sometimes startling meta-
Tsuang 1975; Winokur et al. 1969). The heightened mood morphosis. The cardinal symptoms of mania may fade,
may be one of either euphoria or irritability, or a mixture of and speech and behavior may become profoundly frag-
the two, and is often quite labile. Euphoric patients are in mented (Bond 1980). Loosening of associations may
great good cheer and wish to share their immense enjoy- occur, and patients are often confused; some may become
ment with others; they are often full of jokes, puns, and wise- mute. Hallucinations and delusions abound and, in addi-
cracks, and their humor is often irresistibly infectious to tion to delusions of grandeur or persecution, one may also
those around them. Indeed, it is the rare physician who can see bizarre delusions, including Schneiderian first rank
p 20.qxd 3/10/08 9:58 AM Page 620
symptoms (Jampala et al. 1989). Catatonic stupor may The duration of the euthymic interval varies from as lit-
appear, with immobility, waxy flexibility, and bizarre postur- tle as a few hours or days (Bunney et al. 1972; Sitaram et al.
ing (Abrams and Taylor 1976b; Taylor and Abrams 1977). 1978) up to years, or even decades. In contrast to this inter-
patient variability, however, one may often find a remark-
DEPRESSIVE EPISODE able intrapatient regularity, and indeed in some patients the
euthymic intervals are so regular that it is possible to pre-
As discussed in Section 6.1, depression manifests with dict, even to the month, when the next episode will occur.
depressed or irritable mood, low self-esteem or guilt, pes- Occasionally, one may also see a seasonal pattern, with
simism, difficulty with concentration and forgetfulness, manic episodes more likely in the spring or early summer,
anhedonia, anergia, sleep and appetite disturbances, and and depressive ones in the fall or winter. Manic episodes in
psychomotor change. In depression seen in bipolar disor- patients with bipolar disorder may also become ‘entrained’
der there tends to be an increased need for sleep and to certain biologic events, such as the puerperium (Bratfos
increased appetite and psychomotor retardation, which and Haug 1966; Viguera et al. 2000) or the premenstruum
may be profound (Beigel and Murphy 1971b; Hartmann (D’Mello et al. 1993).
1968; Johnson 1984; Mitchell et al. 2001). Delusions and The total number of episodes experienced by a patient
hallucinations may occur (Guze et al. 1975) and are ‘mood- depends, of course, not only on the duration of the euthymic
congruent’, in that they seem fitting when viewed in the interval but also on the duration of the episodes themselves.
context of the patient’s overall mood. Patients may believe On one extreme, the euthymic interval may be so long that
themselves to be the worst of sinners and that they are to be patients have only a couple of episodes in their lifetimes;
taken into imprisonment or to execution. Voices may indeed, in the natural course of events, some patients may
accuse and condemn them, urging them on to suicide. die before they were ‘scheduled’ for another episode, and
Depressive episodes of bipolar disorder tend to come on thus they end up having only one episode in their entire life.
subacutely, over several weeks (Casper et al. 1985; Winokur On the other extreme, patients with very brief episodes and
et al. 1993), and last 6 months or so; the range here, how- brief intervals may have literally hundreds of episodes per
ever, is wide, from as little as weeks up to years. year (Bunney and Hartmann 1965; Jenner et al. 1967); such
an extremely high frequency of episodes, however, is very
MIXED MANIC EPISODE
rare. Patients with more than four episodes per year are
termed ‘rapid cyclers’ (Bauer et al. 1994; Dunner et al. 1977).
Mixed mania (Himmelhoch et al. 1976; Kotin and Interestingly, it appears that, in some instances, rapid
Goodwin 1972; McElroy et al. 1992) is a variant of mania cycling is associated with subclinical hypothyroidism (Bauer
in which there is a strong admixture of depressive symp- et al. 1990; Cowdry et al. 1983) (as may be induced by treat-
toms. In some cases, manic and depressive symptoms may ment with lithium [Terao 1993]).
rapidly alternate, and in others they may exist simultane- The sequence of episodes is also quite variable. It is rare
ously. Euphoric patients, singing and proclaiming their to find patients whose courses are characterized by regularly
glory and beneficence, may suddenly be thrust into the alternating manic and depressive episodes. Most patients
profoundest of despair, weeping, bereft of all hope and experience either a preponderance of manic or a preponder-
energy, and intensely suicidal. Mixtures of manic and ance of depressive episodes throughout their lives. Thus, to
depressive symptoms may present a startling clinical pic- look at two extremes, whereas one patient may have six
ture: one patient strode through the ward, shouting episodes of depression and only one of mania throughout
unstoppably that he was the greatest of sinners and would his life, another might have a dozen episodes of mania but
die of unspeakable tortures; another, weeping uncontrol- only one of depression. Indeed, albeit very rarely, one may
lably with a look of utter despair, proclaimed to feel won- encounter ‘unipolar’ manic patients who have only manic
derful, at peace and transcendently happy. episodes throughout their lives, never experiencing a
Mixed manic episodes are relatively uncommon and depressive one (Pfohl et al. 1982; Shulman and Tohen 1994).
tend to last longer than straight manic ones. Bipolar disorder may present with either a depressive
episode or a manic one. Importantly, in cases in which the
first episode is depressive, it appears that, in over 90 percent
Course of cases, a manic episode will ensue within either 10 years or
a total of five episodes of depression, whichever comes first
As noted earlier, bipolar disorder is an episodic disorder (Dunner et al. 1976).
and its course is characterized in most patients by the As noted earlier, during the intervals between episodes,
intermittent appearance, over the lifespan, of episodes of most patients are euthymic and free of mood symptoms. In
illness, in-between which most patients experience about one-quarter of cases, however, the intervals may be
‘euthymic’ intervals during which they more or less return ‘colored’ by very mild mood symptoms, and the ‘direction’
to their normal state of health. Both the duration of the or ‘polarity’ of this coloring correlates with the preponder-
euthymic intervals and the sequencing of episodes varies ance of episodes. Thus, a patient who tends to have very mild,
widely among patients. ‘sub-hypomanic’ symptoms during the interval is more likely
p 20.qxd 3/10/08 9:58 AM Page 621
to have manic than depressive episodes, whereas a patient patients who are currently manic (Janowsky et al. 1973), and
whose intervals are clouded by minor depressive symptoms the latency to rapid eye movement (REM) sleep upon infu-
is more likely to have depressive than manic episodes. sion of arecoline is shortened in bipolar patients compared
Occasionally, one may find cases in which certain events, with control subjects.
pharmacologic or otherwise, may more or less reliably pre- Although speculative, taken together these findings are
cipitate a manic episode. These include serotoninergic consistent with the notion that bipolar disorder represents
agents, such as tryptophan or 5-hydroxytryptophan; an inherited disturbance of the structure or function of
noradrenergic or dopaminergic agents, such as cocaine, hypothalamic and brainstem nuclei.
amphetamine, methylphenidate, various sympathomimet-
ics, levodopa, or direct-acting dopaminergics such as
bromocriptine; alcohol or sedative–hypnotic withdrawal, or Differential diagnosis
sudden discontinuation of clonidine; and treatment with
steroids, such as prednisone. Most notably, antidepressants In considering a diagnosis of bipolar disorder, the first step
may also precipitate mania; although this is more likely with is to ensure that the patient either has had a manic episode
tricyclic antidepressants, it has also been noted with newer or is in the midst of one. As noted in Section 6.3, hypoma-
antidepressants such as SSRIs, venlafaxine, and bupropion. nia is a distinctive syndrome and is difficult to confuse with
Other agents capable of inducing mania include herbal anything else. Difficulties arise, however, when one either
preparations, such as St. John’s wort (Moses and Mallinger lacks this history or happens to see the patient when the
2000), and phototherapy. stage of hypomania has already been passed and the patient
Suicide occurs in 10–20 percent of patients with bipolar is now in acute mania or delirious mania. Acute mania may
disorder, and although most suicides tend to occur during be confused with the syndrome of psychosis, given the pres-
a depressive episode, patients in the uncommon mix- ence of delusions and hallucinations; however, in acute
edmanic episodes are actually at highest risk. mania the cardinal manic symptoms (e.g., heightened
mood, increased energy, etc.) are still prominent and offer a
clue. In delirious mania, however, these cardinal symp-
Etiology toms, as noted above, may fade from the picture and, at this
point, in addition to a syndromal diagnosis of psychosis,
Bipolar disorder has a definite genetic component. The inci- one may also entertain syndromal diagnoses of catatonia or
dence of bipolar disorder is higher among the first-degree delirium. It must be emphasized that the easiest and best
relatives of probands than among the general population way to make a correct syndromal diagnosis of mania is to
(Gershon et al. 1982; Tsuang et al. 1985), and the monozy- obtain an accurate history. This may be laborious at times
gotic concordance rate is higher than the dizygotic one as patients in acute mania or delirious mania are generally
(Bertelsen et al. 1977; Kieseppa et al. 2004). Furthermore, unable to provide a reliable history, and consequently one
adoption studies have demonstrated that the prevalence of may have to contact friends, family members, or co-workers;
bipolar disorder is several-fold higher among the biologic the best diagnostic strategy is to establish a typical clinical
parents of patients with bipolar disorder than among their evolution of symptoms, from normalcy to hypomania and
adoptive parents (Mendlewicz and Rainer 1977). Although then on to acute and perhaps delirious mania.
genetic studies have offered tantalizing clues, replication of Once the syndromal diagnosis of mania is established,
positive findings has been difficult. In all likelihood, multi- the next step is to determine the cause of the mania.
ple genes on multiple different chromosomes are involved, Although bipolar disorder is by far the most common cause
each conferring a susceptibility to the disease. of mania, multiple other etiologies, as discussed in Section
Neuropathologic findings are sparse but suggest hypo- 6.3, are possible. Of the disorders discussed there, the idio-
thalamic and brainstem involvement. Within the hypothal- pathic ones, namely cyclothymia, schizoaffective disorder,
amus, overall neuronal loss has been noted in the and post-partum psychosis, figure most prominently on the
paraventricular nucleus (Manaye et al. 2005), with, however, differential. Cyclothymia is in all likelihood merely a forme
an increased number of corticotrophin-releasing hormone fruste of bipolar disorder (Akiskal et al. 1977), and patients
(CRH)-containing cells (Bao et al. 2005); within the brain- experience recurrent episodes of very mild hypomania and
stem, disturbances have been noted in the locus ceruleus correspondingly very mild depression. Schizoaffective dis-
and the dorsal raphe nucleus (Baumann and Bogerts 2001). order is immediately distinguished by the course. In
Endocrinologic changes strongly suggest hypothalamic schizoaffective disorder the intervals between episodes of
disturbances: the dexamethasone suppression test (DST) is mania or depression are marked by psychotic symptoms,
generally positive (Rush et al. 1997; Watson et al. 2004), and such as delusions, hallucinations, and loosening of associa-
the thyroid-stimulating hormone (TSH) response to thy- tions, and this is in stark contrast to the intervals of bipolar
rotropin-releasing hormone (TRH) stimulation is blunted disorder, in which such psychotic symptoms are never seen.
(Extein et al. 1980). It also appears that there may be a dis- Post-partum psychosis is characterized by a psychosis, often
turbance of cholinergic transmission in bipolar disorder: the with prominent manic symptoms, occurring in the post-
infusion of physostigmine reliably precipitates depression in partum period, and is distinguished from bipolar disorder
p 20.qxd 3/10/08 9:58 AM Page 622
by its course. In post-partum psychosis, symptoms occur Most manic patients require admission to a locked unit.
only in the post-partum period, whereas in bipolar disor- Stimulation, including visitors, phone calls, and mail,
der, although episodes of mania may occur post-partum, should be kept to an absolute minimum, as they routinely
they are also seen at other times in the patient’s life. Other exacerbate symptoms. In some cases seclusion is required,
disorders noted in Section 6.3, although less common, must and certain patients, still possessed of some insight, may
also be considered, and the reader is encouraged to review demand seclusion as they know that the reduced stimula-
that section. tion of the seclusion room will allow for some reduction in
their symptoms.
Continuation treatment is designed to prevent the
Treatment recurrence of symptoms once they have been brought
under control during the acute phase of treatment.
The treatment of bipolar disorder involves acute, continua- Generally, this is accomplished by continuing the regimen
tion, and preventive treatments for manic and mixed-manic that was effective during the acute phase, and doing so for
episodes and for depressive episodes. This almost always the anticipated duration of the manic episode. In many
involves the use of one of the mood-stabilizer agents, includ- cases, if a combination of a mood stabilizer plus an
ing lithium, carbamazepine, divalproex, and lamotrigine. antipsychotic were required, it may be possible to discon-
tinue the antipsychotic and maintain the patient on the
MANIC AND MIXED-MANIC EPISODES mood stabilizer alone; should symptoms recur, the
antipsychotic may be restarted. As noted earlier, most
Acute treatment of a manic or mixed-manic episode almost manic episodes last on average from weeks to months;
always involves the administration of one of the mood sta- however, given the wide variability here, the best guide is
bilizers (lithium, divalproex, or carbamazepine; lamotrig- the individual patient’s past history.
ine has not been shown to be effective in the acute If a decision is made not to enter into a preventive phase
treatment of mania) or an antipsychotic (either a second- of treatment, then continuation treatment may be discon-
generation agent [olanzapine, risperidone, quetiapine, arip- tinued after the current episode has gone into a spontaneous
iprazole, or ziprasidone] or a first-generation agent [e.g., remission. This is sometimes difficult, especially if one does
chlorpromazine or haloperidol]) or, most commonly, a not have a reliable history regarding the length of earlier
combination of a mood stabilizer plus one of the antipsy- episodes. Certainly, if the patient is having any manic symp-
chotics. Although there are no hard and fast guidelines for toms, no matter how mild, treatment should be continued,
choosing which agent or agents to use, some general guide- and in general it is best to hold off on discontinuing treat-
lines may be offered. Certainly, if the patient has a history of ment until the patient’s personal life is fairly stable.
an excellent response to a particular agent or combination Before moving on to a consideration of the preventive
of agents, then this should be seriously considered. Lacking phase of treatment, some further words are in order
such a history, and assuming that there are no significant regarding lithium. If lithium was used during the acute
contraindications, then one should consider either lithium phase it may be necessary to reduce the dose once symp-
or divalproex; although lithium has by far the longest track toms have been brought under control; in many patients,
record, divalproex is extraordinarily easy to use and may even though the dose of lithium is held constant, the blood
have an edge over lithium in mixed episodes. Another defi- level will rise as symptoms come under control, and
nite advantage of divalproex is the rapidity of response patients may develop significant, and unexpected, side-
when a ‘loading’ strategy is used, with patients often show- effects. Furthermore, if lithium was used during continua-
ing a response within a matter of days, in contrast to the tion treatment and the decision is to forego preventive
week or two ‘lag period’ seen with lithium. Carbamazepine treatment, then the dose of lithium should be tapered
is not as well tolerated as either divalproex or lithium, and gradually over a few weeks, as it appears that abrupt dis-
may be a little less effective than lithium. Among the continuation of lithium may predispose to a recurrence of
antipsychotics, the first choice is probably olanzapine, as it mania (Baldessarini et al. 1996, 1997). Although this effect
has the longest track record in this regard. However, if for has not been demonstrated for divalproex or carba-
some reason chronic treatment with an antipsychotic is mazepine, prudence dictates following a similar strategy.
anticipated, concerns about the metabolic effects of olanza- Preventive treatment should be seriously considered in
pine might prompt one to consider a different antipsy- all cases, and the decision as to whether or not to embark
chotic, such as quetiapine or risperidone. on preventive treatment should be made with reference to
When symptoms are relatively mild, as may be seen in several factors, including the frequency of episodes, the
hypomania, utilization of a mood stabilizer alone may be rapidity with which they develop, and the anticipated side-
sufficient. However, when acute or delirious mania has effect burden. Frequent episodes, perhaps occurring more
occurred, one typically has to use a combination of a mood than once every 2 years, usually constitute an indication for
stabilizer plus an antipsychotic. In very severe cases that preventive treatment; a frequency of once every 5 years or
fail to respond to combination treatment, one may also more, however, may be such that the risk of another
consider ECT. episode is outweighed by the need to take the medicine
p 20.qxd 3/10/08 9:58 AM Page 623
chronically and having to suffer any attendant side-effects. mood stabilizer. In this regard, given the relative ineffective-
Severe episodes, however, even if infrequent, may warrant ness of lamotrigine as an anti-manic agent, if one is adding an
prevention. In cases in which episodes develop very slowly, antidepressant it is prudent to have one of the other mood
patients may be able to ‘catch’ themselves in time, and stabilizers (i.e., lithium, divalproex, or carbamazepine) in
treatment may be instituted on an outpatient basis; in cases place. The choice of an antidepressant is discussed in Section
in which episodes come on acutely, however, patients may 20.6. If possible, some clinicians prefer avoiding the use of
be defenseless and thus in need of preventive treatment. antidepressants, not only because they may precipitate manic
If preventive treatment is elected, the patient may be episodes but also because there is some evidence that they
maintained on the agent or combination of agents that may alter the course of the illness, making future episodes of
proved effective during continuation treatment. Of the mania more likely (Altschuler et al. 1995).
mood stabilizers, lithium has the longest track record and, Recently demonstrated additional options for the acute
all other things being equal, is the treatment of first choice; treatment of depression include the combination of
however, carbamazepine and divalproex also constitute rea- olanzapine plus fluoxetine and, interestingly, monother-
sonable alternatives. If lithium is utilized, the blood level apy with quetiapine.
should be kept between 0.6 and 1 mEq/L. The optimum pre- Once depressive symptoms have been relieved, treat-
ventive doses for divalproex and carbamazepine have not ment should be continued to prevent a reappearance of
been determined; prudence suggests continuing the same symptoms. If the depression has responded to a mood sta-
dose as was effective in the continuation phase of treatment. bilizer alone, one may then simply continue this. If, how-
Should ‘breakthrough’ symptoms of mania occur it is criti- ever, in addition to a mood stabilizer an antidepressant has
cal to determine thyroid status, as even ‘chemical’ hypothy- been required, the ongoing risk of an antidepressant-
roidism, with a normal free thyroxine (T4) but an elevated precipitated mania will dictate an attempt at some point to
TSH, may blunt the effectiveness of a mood stabilizer. discontinue the antidepressant and see if the patient can be
Should breakthrough mania occur despite normal thyroid maintained on the mood stabilizer alone. Deciding when to
status and good compliance, consideration may be given to discontinue an antidepressant is not straightforward.
switching to monotherapy with another mood stabilizer or Certainly, if a reliable history indicates that the patient’s
to using a combination of mood stabilizers (e.g., lithium depressive episodes routinely last for a more or less definite
plus divalproex or lithium plus carbamazepine). and predictable length of time, one could discontinue the
Some clinicians may opt for using an antipsychotic such antidepressant if that time has elapsed. Lacking this guid-
as olanzapine for preventive treatment; however, although ance, however, one may wish to wait until the patient has
this is becoming increasingly popular, caution may be nec- been euthymic for a significant period of time, at least
essary for two reasons. First, although olanzapine has been weeks, before attempting a discontinuation; should symp-
shown to be effective in this regard, its track record is not toms recur, then one may simply restart the antidepressant.
as long as that of lithium, for example. Second, this may be Once the current depressive episode has run its course,
a problematic option if the potential long-term side-effects patients may be considered for preventive treatment with a
of olanzapine occur, such as weight gain, diabetes, and mood stabilizer: carbamazepine, lithium, or lamotrigine
hyperlipidemia. are effective, with lamotrigine being more effective than
lithium in the prevention of depressive episodes.
DEPRESSIVE EPISODES
SUMMARY
Treatment of a depressive episode of bipolar disorder may
involve the use of a mood stabilizer alone; traditionally, if this In planning the treatment of a chronic disorder such as
is ineffective an antidepressant is added. If patients are not bipolar disorder, the most important decision to make is
already taking a mood stabilizer, one should be started; in which drug to use over the long haul. Although not with-
this regard, although lamotrigine has not been shown to be out controversy, it is probably appropriate to consider one
effective in the acute treatment of mania, it is effective in the of the mood stabilizers for long-term treatment. Among
acute treatment of depression. If the patient is taking lithium the mood stabilizers, lithium remains the ‘one to beat’ as it
or divalproex and a depression occurs, it may be appropriate is effective in all phases of treatment; carbamazepine is also
to switch to either carbamazepine or lamotrigine, as these effective in all phases but its side-effect burden is typically
may be more effective against depression. In evaluating the significantly greater. Divalproex is a reasonable choice for
effectiveness of this strategy, one must keep in mind that two mania-predominant cases of bipolar disorder; however,
or more weeks may be required before depression lifts. the lack of demonstrated effectiveness in the acute or pre-
In cases in which depression persists, or is so severe that ventive treatment of depression may give the clinician
one does not wish to risk a failure of a mood stabilizer, it pause in recommending this agent. Lamotrigine, until it is
is appropriate to consider adding an antidepressant. shown to be effective for mania, should probably be
Importantly, however, given that all antidepressants may reserved for cases that are heavily depression predominant.
precipitate a manic episode, antidepressants should not be These summary recommendations, however, must
used alone but must always be used in combination with a be taken as only the broadest possible of guidelines, and
p 20.qxd 3/10/08 9:58 AM Page 624
treatment must be individualized, with due regard to the and some patients may describe a rapid fall from emotional
peculiarities of each case. well-being into a full depressive episode in as little as a week
or two. Such acute onsets, however, are the exception rather
than the rule. In about 50 percent of cases the duration of a
20.6 MAJOR DEPRESSIVE DISORDER depressive episode of major depressive disorder ranges from
6 to 12 months; longer durations, up to 2 years, may be seen
Major depressive disorder, often referred to simply as major in about 10 percent of cases. Eventually, symptoms gradu-
depression, is characterized by the occurrence of one or ally undergo a more or less full remission.
more depressive episodes during the patient’s lifetime. At times depressive episodes may appear to be precipi-
Synonyms for this disorder include unipolar affective disor- tated by a stressful life event, typically a serious loss, such as
der, melancholia, and manic-depressive illness, depressed the death of a loved one, divorce, or the loss of a job. At
type. ‘Unipolar’ highlights the critical difference between times, however, close enquiry will reveal that the stressful
major depressive disorder and bipolar disorder, namely the life event, rather than actually precipitating the depressive
fact that the patient with major depressive disorder has episode, was itself caused by the depressive episode. For
episodes that go only toward one ‘pole’, namely the depres- example, a married person, in the midst of a long pro-
sive one, whereas the patient with bipolar disorder, in addi- drome, may be sufficiently irritable to cause the spouse to
tion to depressive episodes, will also have episodes that go leave. In such cases, although the patient may blame the
to the other, or manic, pole. Melancholia is the most depression on the separation, in fact it was the depressive
ancient term for this disorder; it comes from the Greek prodrome that caused the separation. This is not to say, of
word meaning ‘black bile’, reflecting the Greek’s humoral course, that independent precipitating events do not at
theory of this disorder. Manic-depressive illness, depressed times trigger depressive episodes, for they do. However, it
type, the final synonym for this disorder, is problematic for appears that in this group of patients with precipitated
two reasons. First, as originally conceived by Kraepelin, depressive episodes, subsequent episodes tend to become
manic-depressive illness was a disorder that subsumed what independent and to occur autonomously without any pre-
today are recognized as two disorders, namely major cipitating events (Brown et al. 1994; Frank et al. 1994).
depressive disorder and bipolar disorder. Kraepelin felt that As discussed in Section 6.1, depressive episodes are char-
these two disorders were merely variants or subtypes of one acterized by a number of symptoms, including depressed or
overarching disorder, but recognizing the clinical differ- irritable mood; low self-esteem, guilt or pessimism; suicidal
ences of these variants he spoke of a ‘depressive’ type and a ideation; difficulty with concentration or forgetfulness;
‘circular’ type. Given the separateness of major depressive anhedonia; anergia; sleep disturbance; appetite distur-
disorder and bipolar disorder, however, it may no longer be bance; and psychomotor change. Patients may also describe
appropriate to use the overarching term. The second reason an overall diurnal variation in the severity of their depres-
has to do with common usage. In the United States, when sion, with symptoms being more intense in the morning.
clinicians use the term ‘manic-depressive illness’, most are Delusions and hallucinations may also occur, as may cer-
referring to bipolar disorder, and hence to use it to refer to tain other symptoms, such as anxiety attacks.
major depressive disorder may lead to confusion. Mood is typically depressed but may be primarily irrita-
Major depressive disorder is a common disorder, ble; some patients may also complain of anxiety. In some
occurring in at least 5 percent of the general population; cases, however, although possessed of a depressed affect,
amongst adults it is twice as common in women as in men. patients may deny feeling depressed but may rather speak
of a sense of discouragement, lassitude, or a feeling of
being weighed down. Occasionally one may see patients
Clinical features who ‘put on’ a ‘happy face’, and feign a normal affect
despite experiencing a depressed mood. Such a ‘smiling
Major depression is characterized by the occurrence of depression’ may mislead the diagnostician who fails to
episodes of depression, in between which patients return to specifically enquire after the patient’s mood.
more or less normal functioning. Although the first episode Self-esteem typically sinks and the workings of con-
of depression generally appears in the mid-twenties, the range science become prominent. Patients may consider them-
in age of onset is wide, from childhood to the ninth decade. selves worthless and as having never done anything of value;
Depressive episodes tend to appear gradually, even insid- in looking over their past, they see their sins multiplied.
iously. Typically, there is a long prodrome, often lasting Indeed, in reviewing the past, patients seem ‘blind’ to any
months, characterized by fleeting and often indefinite symp- accomplishments and fix only on their misdeeds and short-
toms such as moodiness, anxiety or fatigue. Furthermore, comings, which, as they recall them, may become magnified
when the depressive episode finally does settle in, the various to heinous proportions. Some patients may give way to
symptoms often appear haltingly and with differing severi- rumination, in which their failings and defects repeat them-
ties, and it is consequently rare that a patient can date the selves again and again in a litany of hopelessness. Pessimism
onset with any sort of precision. This is not to say, however, is common and patients see no hope for the future; to them
that acute and obvious onsets are not seen. They do occur, there are no prospects and all appears bleak.
p 20.qxd 3/10/08 9:58 AM Page 625
Suicidal ideation is almost always present. At times this patient cannot fall back to sleep at all. As they lie awake,
may be merely passive and patients may wish aloud that they many patients experience ruminations or restless, unpro-
might die of some disease or accident. Conversely, it may be ductive thoughts. When the morning finally does come,
active, and patients may consider hanging or shooting them- patients find themselves unrefreshed and exhausted, as if
selves, jumping from bridges, or overdosing on their medica- they had not slept at all. Rarely, rather than experiencing
tions. Often, and seemingly paradoxically, the risk of suicide insomnia, patients with major depressive disorder may
is greatest as patients begin to recover. Still seeing themselves complain of hypersomnia, wherein they sleep excessively,
as worthless and hopeless sinners, these patients, now with sometimes for up to 18 hours.
some relief from fatigue, may find themselves with enough Appetite is routinely lost and many patients lose weight,
energy to carry out their suicidal plans. The overall suicide sometimes in substantial amounts (Stunkard et al. 1990).
rate in major depressive disorder is about 4 percent; among Food may lose its taste or become unpalatable, and some
those with depressive episodes severe enough to prompt hos- patients may complain that food tastes like cardboard or
pitalization, however, the rate rises to about 9 percent. leaves them nauseated. Uncommonly, patients may expe-
Difficulty with concentration (Roy-Byrne et al. 1986) may rience an increased appetite and may gain weight.
be particularly troubling. Patients may complain of a dull Psychomotor change tends toward agitation. When
heavy-headedness, as if they are ‘in a fog’; attempts to read slight, this agitation may be experienced as a mere inner
may be especially painful as patients read and re-read the restlessness. When more severe, however, there may be
same paragraph but never find themselves understanding hand-wringing and incessant pacing: patients may com-
what they read. Short-term memory may become difficult, plain that they cannot keep still; they may lament their fate
and patients may be unable to recall where they put their keys out loud and give way to wailing and repetitive pleas for
or what was said just minutes before. Making decisions, even help. The tension of these patients may be extreme, almost
simple ones, may become an almost insuperable task; every- palpable, and yet, despite their piteous pleas for help, they
thing appears too complicated, with too many possibilities cannot be comforted, no matter what is done for them.
and choices. In some cases of severe depression in the elderly, Psychomotor retardation, although uncommon, may also
cognitive decrements may be severe enough to constitute a occur. In this, thoughts come slowly and sluggishly, if at all,
dementia (Rabins et al. 1984), which may be particularly and speech, when it occurs, is slow and halting. Some
severe. One 76-year-old became disoriented to time, was patients may sit immobile for hours, and if asked to do
unable to recall any items after 3 minutes, and presented something may complain that they can’t, that it is too diffi-
cachectic and curled up in a fetal position (McAllister and cult. In severe cases patients may not move for any reason;
Price 1982); a 66-year-old was disoriented to time and place, they may go without bathing or changing their clothes, and
confused, and incontinent (Kramer 1982); both recovered some may defecate or urinate in the chair or on the bed.
with adequate antidepressant treatment. Delusions and hallucinations may occur in about 15 per-
Anhedonia manifests with a lack of interest in formerly cent of the depressive episodes of major depressive disorder,
pleasurable activities; sports and hobbies, etc. no longer most commonly in cases in which the depressive symptoms
arouse patients and, if they force themselves to partake, are quite severe (Lykouras et al. 1986; Maj et al. 1990).
they take no pleasure in such activities and merely go Delusions are mood-congruent in that, in some extreme,
through the motions. Libido is routinely lost and there is fantastic way, they are appropriate to the patients’ moods
no pleasure in sexual activity. and views of themselves. Guilt may be extreme and patients
Anergia manifests with a dearth of energy, and patients may confess to unspeakable sins: they have poisoned their
may complain of feeling tired, fatigued, lifeless, or drained. children; family or friends are imprisoned for crimes that
Occasionally, patients may complain of having too much they, the patients, have committed. They may believe that
energy; however, on closer questioning one finds rather they are condemned to Hell, that they have only hours to
that patients have a ‘nervous energy’, more akin to agita- live. Delusions of persecution are common and have a pecu-
tion; such ‘increased energy’ is useless to the patient and is liar twist to them. In contrast to patients with schizophrenia,
always overshadowed by a sense of imminent and impend- who have delusions of persecution and protest that they are
ing exhaustion. innocent victims, depressive patients with delusions of per-
Sleep disturbance tends toward insomnia, which may secution typically feel that they deserve their persecutions
be a torment to the patient. Although many complain of for their miserable sins and shortcomings. Delusions of
what is technically known as ‘initial’ insomnia, or trouble poverty and nihilistic delusions may also occur and are
falling asleep, the most characteristic kind of insomnia in entirely consistent with these patients’ views of themselves as
depression comes later in the night as either ‘middle’ or worthless and hopeless. They may believe that they are with-
‘terminal’ insomnia. In middle insomnia the patient awak- out any funds and are completely bankrupt and unable to
ens in the middle of the night for no particular reason and pay any bills, and that their families will go destitute. Those
then has great difficulty falling back to sleep, often lying with nihilistic delusions may believe that they are near death:
awake for an hour or more before sleep finally comes. their insides have turned to dust or concrete; their brains
Terminal insomnia, also known as ‘early morning awaken- have shrivelled up; the heart has dried up for lack of blood.
ing’, comes later in the night, and, here, once awake, the In extreme cases patients may believe that they are dead, and
p 20.qxd 3/10/08 9:58 AM Page 626
some may believe that all are dead, that death has finally environmental events proposed, it appears that early child-
achieved complete dominion over the world. Auditory hal- hood loss may be the most important. Events may also
lucinations may also occur and generally reflect the patients’ serve as precipitants for episodes in adult life; however, as
delusions. Voices may accuse them of crimes or sins, or noted earlier, the importance of precipitants fades with
announce that their well-deserved punishment is at hand. successive episodes to the point where, over long periods of
Visual hallucinations occasionally occur, and patients may time, episodes become, as it were, autonomous.
see corpses or accusatory spirits. In some cases patients may There is abundant evidence for endocrinologic distur-
develop stuporous catatonia (Starkstein et al. 1996). bances in depression, all of which point to disturbances in
Other symptoms seen during a minority of depressive the hypothalamus. Within the hypothalamus, for example,
episodes include anxiety attacks (Van Valkenburg et al. the level of messenger RNA for CRH in the paraventricular
1984) and what have been called ‘anger attacks’, in which nucleus is elevated (Raadsheer et al. 1995), as is the cere-
generally hostile and irritable patients occasionally experi- brospinal fluid (CSF) level of CRH (Nemeroff et al. 1984);
ence episodes of violence and autonomic arousal (Fava et al. consistent with this, the low-dose DST test is generally pos-
1993). Obsessions and compulsions may also appear: a par- itive (Carroll et al. 1968, 1976). The thyroid axis also shows
ticularly common obsession is the ‘horrific temptation’ to disturbances: the CSF level of TRH is elevated (Banki et al.
use a knife or gun to kill a loved one, and a consequent over- 1988), and, consistent with this, the response of TSH to
whelming necessity to rid the house of all potential weapons exogenous TRH is blunted (Prange et al. 1972).
and to avoid any contact with them outside the house. Abnormalities in brainstem structures responsible for
REM sleep are suggested by the fact that REM sleep latency
is reduced in depression (Hauri et al. 1974; Rush et al.
Course 1986), and by the response to cholinergic agents.
Normally, REM sleep may be induced by cholinergic stim-
Major depressive disorder is a relapsing and remitting ill- ulation; however, in patients with major depressive disor-
ness (Thase 1990), characterized in most patients by the der the latency to REM sleep with such cholinergic agents
recurrence of depressive episodes throughout their lives, in as arecoline (Gillin et al. 1991) and donepezil (Perlis et al.
between which they return to a more or less normal mood. 2002) is shorter than in control subjects.
As noted earlier, in about 50 percent of cases, depressive The undoubted success of antidepressant medications has
episodes will undergo a spontaneous remission within focused attention on biogenic amines. Given that all antide-
6–12 months. The duration of the interval between succes- pressants have effects on either noradrenergic or serotonin-
sive episodes ranges widely, from as little as 1 year up to ergic functioning, it appears reasonable to assume that there
decades, with an overall average of about 5 years. In genis a complementary disturbance in these amines in patients
eral, however, with repeated episodes the interval between with major depressive disorder. Despite enormous research
episodes tends to shorten, and the episodes themselves efforts, however, it has been difficult to isolate definite abnor-
tend to lengthen, such that, over a very long period of time, malities here. One notable exception involves the effects of
successive episodes may eventually ‘merge’ to create a tryptophan depletion. Tryptophan is the dietary precursor of
chronic, non-remitting condition. serotonin and, in patients with an antidepressant-induced
Recently, much attention has been focused on patients remission of depression, tryptophan depletion is promptly
whose depressive episodes seem entrained to the changing followed by a relapse of depressive symptoms (Aberg-Wistedt
seasons. In patients with this seasonal pattern of illness, et al. 1998; Delgado et al. 1990; Smith et al. 1997).
depressive episodes appear to occur far more commonly in Relatively speaking, neuropathologic studies are in their
the fall or winter than in the spring or summer. infancy in this disorder. Some studies have suggested
changes in the dorsolateral prefrontal cortex; however, in
my opinion the endocrinologic and sleep abnormalities
Etiology point rather to the diencephalon or brainstem as the most
likely sites for any changes. In this regard, several, albeit
Hereditary factors appear to play a role: the prevalence of preliminary, findings have been reported, including the
major depression is higher in the relatives of patients than following; an increased number of neurons in the
of control subjects, and the monozygotic concordance rate mediodorsal nucleus of the thalamus (Young et al. 2004);
is significantly higher than the dizygotic one (McGuffin an overall decreased number of neurons in the para-
et al. 1996). To date, however, genetic studies have not ventricular nucleus of the hypothalamus (Manaye et al.
identified genes or loci that may be confidently associated 2005) with a relative increase in the number of CRH-con-
with this illness, indicating in all likelihood that, from a taining neurons in the same nucleus (Bao et al. 2005).
genetic point of view, this is a complex disorder, involving Integrating all of the foregoing findings into a coherent
multiple genes and multiple modes of inheritance. theory is problematic and involves some speculation. With
Hereditary factors, although clearly important, do this caveat in mind, however, it may be reasonable to propose
not appear to provide a complete account, and environ- that major depressive disorder represents an interaction
mental factors also seem to play a role. Among the various between certain environmental events and an inherited
p 20.qxd 3/10/08 9:58 AM Page 627
abnormality of noradrenergic, serotoninergic or cholinergic Overall, although the various antidepressants are of
functioning, of variable degree, associated with subtle neu- approximately equal effectiveness, there is some evidence
roanatomic changes in the thalamus, hypothalamus or mes- that tricyclics and venlafaxine may have an edge over the
encephalon. others, and that trazodone may be somewhat less effective.
These differences, however, are modest at best.
A personal history of a good response to a particular
Differential diagnosis agent is a good predictor of future response, and a family
history of a good response may also predict a good response,
The first step in differential diagnosis is to ensure that the but this relationship may not be as robust.
patient either has, or has had, a depressive episode, for with- Side-effects sometimes loom large in the patient’s over-
out this, of course, a diagnosis of major depressive disorder all reaction to an antidepressant. Where weight gain is a
cannot be made. As discussed in Section 6.1, not all patients concern, SSRIs, duloxetine, and bupropion are good
who complain of depression or who appear depressed have choices, and certainly preferable, in this regard, to tricyclics
a true depressive episode; almost all persons, at some point and mirtazapine. Sexual side-effects (e.g., erectile dysfunc-
in their lives, will have some depressive symptoms as a nor- tion, decreased vaginal lubrication, decreased libido) are
mal reaction to adverse life circumstances, and these must common with most antidepressants, with the notable
be distinguished, using the guidelines outlined in that sec- exceptions of mirtazapine and bupropion. Orthostatic
tion, from a depressive episode. hypotension, of particular concern in the elderly, is unlikely
Once it has been determined that a true depressive with SSRIs, venlafaxine, mirtazapine, and bupropion, but
episode has occurred, the next step is to determine whether common with tricyclics and trazodone. Cardiac arrhyth-
this has been caused by a major depressive disorder or one mias may be induced by tricyclics, but SSRIs are particularly
of the many other causes of depression discussed in Section benign in this regard. The seizure threshold may be reduced
6.1, a section that the reader is strongly advised to review. by tricyclics, venlafaxine, and bupropion; in this regard,
particular attention must be given to any history of bulimia
nervosa, as such patients appear to be particularly at risk for
Treatment seizures if treated with bupropion. Sedation may be prob-
lematic with tricyclics (with the exception of nortriptyline,
The overall pharmacologic treatment of major depressive desipramine, and protriptyline), mirtazapine, and trazodone,
disorder is conveniently divided into three phases: acute but is generally negligible with the other agents.
treatment designed to initially relieve symptoms during a Drug–drug interactions are a constant concern, and in
depressive episode; continuation treatment to prevent the this regard the SSRIs (especially citalopram and escitalo-
re-emergence of symptoms; and maintenance or prophy- pram) are the ‘cleanest’ of agents. Conversely, there are so
lactic treatment aimed at preventing the occurrence of many drug–drug interactions with MAOIs that these
subsequent episodes. Although this text focuses on phar- agents generally constitute a last choice.
macologic treatment, consideration may also be given, in Lethality in overdose is always a concern in prescribing
mild to moderate cases, to psychotherapy (e.g., cognitive– for depressed patients, and in this regard the SSRIs are by
behavioral therapy). far the safest agents, followed by duloxetine, venlafaxine,
mirtazapine, and bupropion; the tricyclics and MAOIs are
ACUTE TREATMENT by far the most dangerous of the antidepressants.
All other things being equal, and lacking clear guidance
Before beginning treatment a decision must be made as to from a personal or strong family history, a first choice may
whether or not to admit the patient. Indications for hospi- reasonably be made from the following: an SSRI, dul-
talization include the following: significant suicide risk; oxetine, venlafaxine, mirtazapine, or bupropion. Regardless
depressive symptoms of such severity as to preclude inde- of which agent is chosen it must be given an ‘adequate’ trial,
pendent functioning at home and work; significant con- which involves not only an ‘adequate’ dose but also an ‘ade-
current illness that requires inpatient monitoring; and a quate’ duration. Even with an average or above-average
need for acute treatment with ECT. dose, one should not expect to see any improvement for the
Acute treatment generally begins with the selection of an first week or two; by the fourth week, however, if there has
antidepressant medication from one of the following groups: been no improvement at all it is unlikely that the patient
tricyclics (e.g., nortriptyline), SSRIs (e.g., escitalopram), will get a response, at least at the dose used (Quitkin et al.
monoamine oxidase inhibitors (MAOIs; e.g., selegiline), and 1996). If there is improvement by the fourth week, then the
a large miscellaneous group (including duloxetine, venlafax- patient should be advised that it may take up to 3 months to
ine, mirtazapine, bupropion, and trazodone). Several con- see a full response.
siderations come into play when making this selection, In cases in which there has been little or no response by 4
including overall effectiveness, a personal or family history of weeks, one should, if not already done, check the free T4 and
response to a particular agent, anticipated side-effects, poten- TSH levels. Hypothyroidism, even if only ‘chemical’ (with a
tial drug–drug interactions, and, finally, lethality in overdose. normal free T4 but an elevated TSH), blunts the response to
p 20.qxd 3/10/08 9:58 AM Page 628
antidepressants and must be corrected. If the patient is Before leaving this discussion of the acute treatment of
euthyroid, and the side-effect burden is readily tolerable, depression, some words are in order regarding certain
one may at this point consider simply increasing the dose; other treatments, including herbal remedies (i.e., St. John’s
with the sole exception of nortriptyline (which has a true wort), omega-3 fatty acids, phototherapy, alprazolam,
‘therapeutic window’) it appears that for most other anti- buspirone, vagal nerve stimulation, and transcranial mag-
depressants the dose–response curve is linear, and thus it is a netic stimulation. St. Johns wort and omega-3 fatty acids
reasonable strategy to gradually push the dose to the maxi- may be beneficial in mild depressions, but cannot be
mum recommended, waiting weeks each time to see if there counted on in anything more severe. Phototherapy is
is an initial response. generally reserved for mild depressions occurring in
If the patient does not respond to an increased dose, or if patients whose illnesses demonstrate a seasonal pattern, as
side-effects preclude this approach, then one may consider described earlier. Alprazolam may be effective in mild to
either switching to a different antidepressant or trying a moderate depressions, but the 3–6 mg dose required car-
combination of agents. Switching antidepressants is a viable ries such a significant risk of neuroadaptation that most
option but in doing so one should probably switch to an clinicians shy away from using it. Buspirone, in doses of
antidepressant of a different pharmacologic class; changing 60 mg or more daily, may be effective in mild to moderate
from one SSRI to another, or from one tricyclic to another, depression, but is not commonly employed. Vagal nerve
makes little sense. In making a switch one must be wary of stimulation has not been shown to be effective in double-
drug–drug interactions. For example, given the long half-life blind studies and cannot be recommended. Although the
of some SSRIs and their ability to inhibit the metabolism of place of transcranial magnetic stimulation is still not clear,
tricyclics, in switching from an SSRI to a tricyclic one must it is my belief that this will emerge as a viable option.
either allow time for the SSRI to wash out or alternatively
start with a low dose of the tricyclic. Combination treatment CONTINUATION TREATMENT
is also viable but only a few combinations have been found
to be effective, including lithium plus a tricyclic or an SSRI; Once acute treatment has effected a remission of depressive
triiodothyronine (50 μg) plus a tricyclic or an SSRI; olanzap- symptoms, continuation treatment is required. It must be
ine plus fluoxetine; aripiprazole plus an SSRI or venlafaxine; kept in mind that antidepressants, rather than ‘curing’
and, finally, an MAOI plus a tricyclic. This last option is depression, merely suppress symptoms, and consequently if
potentially dangerous and should probably only be under- treatment is discontinued before the depressive episode has
taken by a specialist. Regardless of whether one switches or run its course, symptoms will gradually recur. In general,
uses a combination strategy, one must again allow for an continuation treatment involves a continuation of the regi-
‘adequate trial’, ensuring that doses are adequate and that at men that was effective for acute treatment. In a minority of
least 4 weeks are allowed to assess the response. cases it may be possible to scale back treatment without any
Should depression prove resistant to a switch or to a loss of effectiveness (e.g., in monotherapy cases, allowing a
combination, one might consider different single agents or dose reduction, or in combination therapy, discontinuing
different combinations. How far one goes with this one of the agents); however, this must be carried out care-
approach depends largely on the severity of the depression. fully given the risk of relapse. If ECT was required, one
If the symptoms are tolerable and the risk of suicide is low, should consider either ‘continuation ECT’ or antidepressant
then further trials may be reasonable; if however, symp- treatment, for example either with an SSRI (e.g., paroxetine)
toms are severe or there is a significant risk of death, one or with a combination of nortriptyline and lithium.
should strongly consider ECT. Continuation treatment should persist for the duration
Although the foregoing schema for the acute treatment of of the depressive episode. In cases in which the patient has a
depression is in general applicable to most cases, exceptions history of depressive episodes of fairly uniform and discrete
do occur. First, in severe cases requiring hospitalization, duration, this may be used as a guide for determining the
many physicians will routinely check thyroid status and begin length of continuation treatment. In most cases, however,
either with high-dose monotherapy or with a combination. such guidance is not available, either because the current
Second, for the highly suicidal patient, or in other life-threat- episode is the first or because prior episodes were of such
ening cases (e.g., in severely debilitated elderly patients), mov- indistinct onset and offset that a reliable estimation of their
ing immediately to ECT may be appropriate, as ECT is clearly duration is not possible. In these cases, continuation treat-
not only the most effective treatment for depression but also, ment should probably be performed until the patient has
with proper technique, remains quite safe. Third, there is been symptom free for 6 consecutive months (Altamura
some controversy regarding the treatment of ‘psychotic and Percudani 1993; Kupfer et al. 1992; Prien and Kupfer
depression’, that is depression that is accompanied by delu- 1986; Reimherr et al. 1998). This guideline is based on the
sions or hallucinations. Traditionally, patients with psychotic assumption that no treatment is perfect and that, given the
depression have been treated with the combination of an waxing and waning nature of symptoms, one will find that,
antipsychotic plus an antidepressant, or with ECT. However, when symptoms rise to a ‘peak’, they ‘break through’ the
it appears that in many of these cases, prolonged treatment antidepressant ‘barrier’ to the point where they cause dis-
with high-dosage monotherapy may be just as effective. tress. Furthermore, the longer a patient goes without such a
p 20.qxd 3/10/08 9:58 AM Page 629
20.7 Premenstrual dysphoric disorder 629
breakthrough, the more likely it becomes that the underly- headache, mastalgia, bloating (particularly with swelling of
ing episode has finally gone into a spontaneous remission, the hands and feet), clumsiness, nausea, and constipation.
and it appears that 6 months represents a reasonable dura- Some patients, concerned over their irritability, may
tion for this to occur. When the time does come to consider voluntarily isolate themselves, and family members may
discontinuation of treatment, given that a small risk of soon learn to ‘leave well enough alone’ during this part of
relapse still exists, one may wish to schedule the discontin- the menstrual cycle.
uation for a time in the patient’s life when a relapse would
not have disastrous consequences.
Course
MAINTENANCE TREATMENT Over long periods of time the depressive episodes may
Given that the majority of patients will eventually have become more severe and may appear progressively earlier
another episode, it is reasonable to discuss maintenance or in the menstrual cycle, to the point where, in some cases,
preventive treatment. Prevention should be strongly con- the episode may begin 3 weeks before menstrual flow.
sidered in cases in which past history suggests that, in the Eventually, with menopause, the episodes cease to occur.
natural course of events, the euthymic interval between
episodes is less than 2 years, or in cases in which, regardless Etiology
of the frequency of episodes, the episodes themselves have
been so severe that one would not wish to risk a relapse, no Premenstrual dysphoric disorder is familial and may bear a
matter how far in the future that might occur. If patients relationship to major depressive disorder, given that the
do elect for maintenance therapy one may simply continue prevalence of major depressive disorder is higher in the rel-
the antidepressant regimen used in continuation therapy. atives of probands than in the general population.
In cases in which ECT was required for continuation ther- There is ample evidence for a disturbance in serotonin-
apy it is not clear whether ongoing ECT is required, and ergic functioning in patients with premenstrual dysphoric
one may opt for an antidepressant regimen. disorder. Fenfluramine, a serotoninergic agent, normally
stimulates prolactin secretion, and the prolactin response
to this agent in premenstrual dysphoric disorder is blunted
20.7 PREMENSTRUAL DYSPHORIC DISORDER (Fitzgerald et al. 1997). Furthermore, symptoms may be
exacerbated either by administration of a serotonin-
Premenstrual dysphoric disorder, also known as the pre- blocking agent (Roca et al. 2002) or by tryptophan deple-
menstrual syndrome or late luteal phase dysphoric disor- tion (Menkes et al. 1994). Finally, whereas serotoninergic
der, is characterized by recurrent, relatively brief, agents (e.g., SSRIs) are effective in this disorder, non-
depressive episodes that are tightly entrained to the events serotoninergic antidepressants (e.g., desipramine [Freeman
of the menstrual cycle. This is a common disorder, occur- et al. 1999] and bupropion [Pearlstein et al. 1997]) are not.
ring in about 5 percent of all menstruating females. Overall, although speculative, it may be reasonable to
hypothesize that in premenstrual dysphoric disorder there
is an inherited disturbance of serotoninergic functioning,
Clinical features probably in mesencephalic or hypothalamic structures,
that is episodically triggered by the dramatic hormonal
The onset of this disorder is generally between menarche changes seen during the transition from the follicular to
and the late twenties, and its most remarkable aspect is the the luteal phase of the normal menstrual cycle.
timing of the depressive episodes, which have a fairly
abrupt onset, anywhere from 3 to 10 days before menstru-
ation begins, and then just as rapidly remit, 2–3 days after Differential diagnosis
menstrual flow commences.
During the depressive episode, the mood (Bloch et al. The key to making this diagnosis is to monitor the patient
1997) is variously depressed, sad, anxious, or, classically, over at least several menstrual cycles to establish the classic
irritable; often there is considerable lability with inexplica- onset and duration of the episodes and, very importantly,
ble crying spells or unwonted anger, and many patients to demonstrate that during the follicular phase patients are
complain of feeling ‘out of control’. Patients may have dif- symptom free. Essentially, there is no other disorder that
ficulty with concentration or paying attention to things, mimics this remarkable pattern.
and may lose interest in work, hobbies, or sexual activity. Of the multiple other causes of depression discussed in
There may be prominent fatigue, and some may become Section 6.1, major depressive disorder, bipolar disorder,
lethargic. Sleep disturbance is common and may be toward and post-partum depression may also be kept in mind. In
either insomnia or hypersomnia. Appetite may also change these disorders, depressive episodes may be quite pro-
and is often increased with associated cravings for sweets longed and may undergo an exacerbation during the luteal
or chocolates. Other symptoms may also occur, including phase. If this exacerbation is sufficiently severe, patients
p 20.qxd 3/10/08 9:58 AM Page 630
may mistakenly report that they feel ‘better’ during the fol- involve ‘horrific temptations’ to do harm to the baby
licular phase, thus lulling the diagnostician into a mistaken (Wisner et al. 1999). Rarely, infanticide may occur, and, as
conclusion. Close examination in these cases, however, with any depression, suicide remains a risk.
reveals that, although patients do indeed feel better during
the follicular phase, this is only relatively so, and in fact the
depressive symptoms are present throughout all phases of Course
the menstrual cycle, in stark contrast to the pattern seen in
premenstrual dysphoric disorder. Although most patients experience a spontaneous remis-
Dysmenorrhea, characterized by cramps, headaches, sion within months or years, the depression may be chronic
and bloating, is easily distinguished by its course, beginning in a minority. Those who do recover are at increased risk for
not before but after the commencement of menstrual flow. another episode after a subsequent pregnancy.
Treatment Etiology
SSRIs, including fluoxetine (20 mg) (Cohen et al. 2002; Post-partum depression may occur secondary to an
Pearlstein and Stone 1994; Pearlstein et al. 1997; Steiner unusual sensitivity of mood-regulating central nervous
et al. 1995), paroxetine (20 mg) (Landen et al. 2007), and ser- system structures to the profound endocrinologic changes
traline (50–150 mg) (Freeman et al. 1999, 2004; Yonkers et that occur post-partum. One particularly interesting study
al. 1997; Young et al. 1998), constitute the mainstay of (Bloch et al. 2000) looked at two groups of women: both
treatment, and these may be taken either chronically on a groups had a history of depressive episodes, but in one they
daily basis or on a timed basis relative to the timing of the were confined to the post-partum period, whereas in the
episode itself, such that they are started just before the other, depressive episodes occurred at times outside this
anticipated onset of symptoms and then stopped several period. All patients were euthymic at the time of the study,
days into menstrual flow. Venlafaxine (50–200 mg) and all were given supraphysiologic doses of estradiol and
(Freeman et al. 2001), taken chronically, is another option, progesterone for 8 weeks, after which these hormones were
as is alprazolam (1–4 mg) (Freeman et al. 1995), taken dur- abruptly discontinued. In the group of women with a his-
ing the luteal phase. Recently, effectiveness has also been tory of post-partum depression, the hormone withdrawal
demonstrated for an herbal preparation, Vitex agnus-castus was followed by a depressive episode in the majority,
(Atmaca et al. 2003; Schellenberg 2001). In my opinion, whereas in the group with a history of depression outside
treatment should begin with one of the SSRIs; venlafaxine the post-partum period, there were no depressions.
may also be considered, but alprazolam, given the risks of
neuroadaptation, should probably be held in reserve. The
place of Vitex agnus-castus is not as yet clear. Differential diagnosis
Of the many causes of depression discussed in Section 6.1,

20.8 POST-PARTUM DEPRESSION several figure prominently in the differential diagnosis of
post-partum depression, including major depressive disor-
In the strict sense used here, post-partum depression is der, bipolar disorder, post-partum blues, and hypothy-
characterized by the occurrence of depressive episodes roidism. Patients with major depressive disorder or bipolar
only in the post-partum period (Cooper and Murray disorder may have depressive episodes in the post-partum
1995); as such it must be distinguished from cases of major period; however, as stressed earlier, these patients also have
depressive disorder, for example, in which depressive episodes at other times. In cases in which a depressive episode
episodes, although at times occurring in the post-partum occurring in the post-partum period represents the first ever
period, also occur at other times in the patient’s life. This is episode in the patient’s life, long-term follow-up will be
probably a common disorder. required to determine whether any future episodes occur and,
if so, whether they are unrelated to pregnancy or are confined
to the post-partum period. The post-partum blues are distin-
Clinical features guished by their early onset, within days, and rapid resolution,
within 2 weeks; there are also symptomatic differences here,
The onset of the depressive episode is anywhere from several with the post-partum blues being marked by prominent labil-
weeks to several months post-partum. Mood is depressed ity. Hypothyroidism, especially that due to Hashimoto’s thy-
and often accompanied by a considerable amount of anxiety roiditis, is not uncommon post-partum, and determining a
(Hendrick et al. 2000). Self-esteem falls, particularly in free T4 level and a TSH level should be part of the work-up.
regard to the patient’s estimate of her abilities as a mother. Sheehan’s syndrome is suggested by a failure of lactation,
There may be poor concentration, anhedonia, fatigue, initial persistent amenorrhea, and, often, by loss of pubic and
insomnia, and anorexia. Obsessions may occur and typically axillary hair.
p 20.qxd 3/10/08 9:58 AM Page 631
Treatment levels (Harris et al. 1994), whereas another did not (Kuevi
et al. 1983); one study noted a relationship with lower allo-
Various treatment modalities are available. Double-blind pregnanolone levels (Nappi et al. 2001). Disturbances in
studies support the effectiveness of antidepressants, such as tryptophan metabolism have also been suggested: one study
fluoxetine (Appleby et al. 1997), sertraline, and nortripty- found lower levels in relation to post-partum blues (Kohl
line (Wisner et al. 2006). One double-blind study also et al. 2005), whereas another, although finding normal levels,
found transdermal estrogen to be effective (Gregoire et al. demonstrated a reduced ratio of tryptophan to other large
1996), and an open study suggested effectiveness for sublin- neutral amino acids (Bailara et al. 2006); notably, however,
gual estradiol (Ahokas et al. 2001). Both cognitive–behavioral treatment with tryptophan is not effective (Harris 1980).
and interpersonal therapy also appear to be effective. Finally, two studies have noted an association between an
Given the risk of recurrence with subsequent pregnan- increased number of platelet alpha-2 autoreceptors and the
cies, attempts have been made to develop preventive treat- occurrence of the blues (Best et al. 1988; Metz et al. 1983).
ments. In this regard, one double-blind study found that
sertraline was effective (Wisner et al. 2004), whereas
another surprisingly found no preventive effect with nor- Differential diagnosis
triptyline (Wisner et al. 2001).
Post-partum depression is distinguished by its later onset
(usually at least several weeks post-partum), longer dura-
20.9 POST-PARTUM BLUES tion (at least months), and by the absence of lability. It
must be borne in mind, however, that, like any other post-
The post-partum blues, also known as maternity blues or partum women, patients with the post-partum blues may
baby blues, is a common disturbance, seen in about half of go on to develop a post-partum depression and hence any
all women. Although such a high incidence may suggest that persistence of symptoms beyond a couple of weeks should
this is a ‘normal’ phenomenon, the fact that the symptoma- prompt a diagnostic re-evaluation.
tology is often strikingly out of character for the patient
argues rather that the ‘blues’ represent a specific disorder. Treatment
Given the brevity of the syndrome, treatment with anti-

Clinical features depressants is not indicated, as a spontaneous remission
may be anticipated before an antidepressant could be
Clinically (Pitt 1973; Rohde et al. 1997; Yalom et al. 1968), expected to take effect. Support, reassurance, and assis-
the onset is acute, usually within the first few days post- tance are generally sufficient; in some cases a brief course
partum. Mood may be depressed, irritable or fearfully anx- of treatment with a benzodiazepine, such as lorazepam,
ious. Crying spells are frequent, and there may be a striking may be considered, but it must be kept in mind that these
lability of affect; crying spells may come and go with drugs do appear in the breast milk.
remarkable rapidity, and at times the patient may actually
be laughing and claim to feel happy with her delivery, yet be
absolutely unable to stop the tears cascading down past her 20.10 PANIC DISORDER
smile. There may also be minor degrees of difficulty with
concentration, fatigue, and insomnia. Symptoms tend to Panic disorder is characterized by the repeated occurrence
peak within a couple of days and then gradually undergo a of discrete anxiety attacks, which, in the context of this dis-
full remission by the end of the second post-partum week. order, are referred to as ‘panic attacks’. This is a common
disorder, with a lifetime prevalence of 1–2 percent, and is
several times more common in females than males.
Course
Although the post-partum blues may recur after subse- Clinical features
quent pregnancies, they tend to be less severe.
The first panic attack generally occurs in late adolescence
or early adult years; later onsets, in the fourth decade, are
Etiology not uncommon and, albeit rarely, onsets have been noted
in childhood or the fifth decade.
Although the post-partum blues is almost certainly related The panic attack itself usually comes on acutely, often
to the profound hormonal and neurophysiologic changes within a minute, and symptoms crescendo rapidly. Anxiety is
present in the immediate post-partum period, as yet it has typically severe, and patients may report the classic ‘sense of
not been possible to develop a unified theory. One study impending doom’, as if some catastrophic event were loom-
found a relationship with lower post-partum progesterone ing; some fear that they are having a heart attack, others that
p 20.qxd 3/10/08 9:58 AM Page 632
they are about to ‘go crazy’. Uncommonly, however, one these agents will result in pharmacologic blood levels before
may see attacks in which the feeling of anxiety is mild relative the attack runs its course. In cases in which chronic use of
to other symptoms, and rarely patients may deny any signif- these agents leads to neuroadaptation, any attempt to stop
icant anxiety at all; although the existence of these ‘panic them may lead to a withdrawal state that, in turn, may pre-
attacks without panic’ was initially controversial, there is no cipitate further attacks, thus setting up a vicious cycle.
doubt that they do in fact occur (Russell et al. 1991). Other
symptoms include tremor, tachycardia, palpitations, chest
pain, dyspnea, dizziness, nausea, diaphoresis, and acral Etiology
parasthesiae; rarely, one may see hemianesthesia, macropsia,
or microspia (Coyle and Sterman 1986). Chest pain may be Panic disorder is probably hereditary: as the degree of con-
most alarming to patients, and, as this pain may at times sanguinity rises from unrelated persons to first-degree rel-
radiate to the left shoulder or left side of the neck, it may like- atives, then to dizygotic and finally monozygotic twins, so
wise cause some alarm in emergency room physicians. The too does the risk of having panic disorder (Crowe et al.
attack itself generally lasts about 5–15 minutes, but may per- 1983; Noyes et al. 1986; Torgerson 1990). Genetic studies,
sist for up to an hour; symptoms then remit over a few min- however, have not as yet yielded robust findings, and nei-
utes, after which patients may feel ‘shaken’, drained, and ther the mode of inheritance nor candidate loci have been
apprehensive for up to a few hours. Although most attacks clearly demonstrated.
occur during waking hours, some patients may have noctur- The discovery of ‘panicogens’ has been one of the major
nal attacks (Mellman and Uhde 1989a), and, in a small fruits of the research efforts into panic disorder. Panicogens
minority, attacks may only occur nocturnally (Mellman and are substances that, although innocuous in normal control
Uhde 1990). Nocturnal attacks arise from non-rapid eye subjects, reliably produce panic attacks in patients with
movement (NREM) sleep (Mellman and Uhde 1989b) and panic disorder. Importantly, these panicogen-induced
often awaken the patient, who typically has trouble falling attacks are identical to spontaneously occurring attacks
back asleep and is able to recall the panic the next morning and, furthermore, may be prevented by the same medicines
(Hauri et al. 1989). that are effective in the treatment of panic disorder.
In most cases, panic attacks occur spontaneously, with- Panicogens include inhalation of 5 percent or 35 percent
out any precipitating factors; patients may complain that carbon dioxide (Gorman et al. 1988), intravenous sodium
they ‘come out of the blue’ and strike without warning. lactate (Cowley and Arana 1990; Liebowitz et al. 1984), caf-
feine (Charney et al. 1985), yohimbine (Charney et al.
1992), isoproterenol (Pohl et al. 1988), intravenous meta-
Course chlorophenylpiperazine (Kahn and Wetzler 1991),
flumazenil (Nutt et al. 1990) (although not all studies con-
The frequency with which panic attacks occur varies widely cur with this [Strohle et al. 1998]), and cholecystokinin
among patients, from the extremes of multiple attacks tetrapeptide (Bradwejn et al. 1991).
daily to only one attack every few months. The overall Various neurotransmitters have also been implicated,
course of the disorder appears to follow one of two pat- including norepinephrine, serotonin, and GABA.
terns. In one, the frequency of attacks may vary over years Norepinephrine is implicated by the panicogenic effects of
or decades, with the patient never experiencing any pro- caffeine, yohimbine, and isoproterenol, and also by studies
longed attack-free interval. In the other, one does see pro- reporting a blunted response of growth hormone to cloni-
longed attack-free intervals, and in patients with this dine administration. Serotonin involvement is suggested
pattern one may speak of panic disorder with an episodic by the response to the panicogen meta-chlorophenylpiper-
course; the ‘episodes’, characterized by recurrent attacks, azine and by studies involving manipulation of serotonin
are separated from each other by prolonged intervals in levels. For example, depletion of the serotonin precursor
which no spontaneous attacks occur. tryptophan increases the effectiveness of panicogens such
Over time, and with repeated attacks, most patients begin as flumazenil (Bell et al. 2002), whereas the administration
to develop a chronic, anxious apprehension that another of L-5-hydroxytrptophan, a serotonin precursor, will blunt
attack may be just around the corner. This ‘anticipatory anx- the panicogenic effect of carbon dioxide inhalation
iety’ may induce patients to avoid situations in which, should (Schruers et al. 2002). GABAergic involvement is suggested
they have an attack, they might not be able to find immediate by the panicogenic effect of flumazenil and also by studies
help; thus patients may avoid travelling by plane or boat, or that have demonstrated reduced levels of GABA within the
even on limited access highways. Should this anticipatory occipital cortex (Goddard et al. 2001).
anxiety become very severe, patients may develop the syn- Although there are no neuropathologic findings, imag-
drome of agoraphobia, described in the next section. ing studies have yielded interesting results. Gray matter
Abuse of alcohol or benzodiazepines is a serious risk. density appears lower in the left parahippocampal gyrus
Some patients may use these to quell their anticipatory anx- (Massana et al. 2003a), and positron emission tomography
iety, whereas others will consume them during the attack (PET) studies have revealed altered metabolism in the left
itself, in the mistaken belief that oral administration of parahippocampal gyrus (Bisaga et al. 1998; Nordahl et al.
p 20.qxd 3/10/08 9:58 AM Page 633
1990); furthermore, a recent study demonstrated atrophy disorder; if their occurrence is confined solely within the
of both amygdalae (Massana et al. 2003b). Finally, a single limits of the depressive episode, an additional diagnosis of
photon emission computed tomography (SPECT) study panic disorder is not warranted. However, if one can
revealed a decrease in presynaptic serotonin reuptake demonstrate that the anxiety attacks preceded the onset of
transporters within the midbrain, thalamus, and temporal the depressive episode, or persisted beyond the resolution
lobes (Maron et al. 2004). of the episode, then the additional diagnosis is appropriate.
Integrating all of these findings into a coherent theory Of the other causes of anxiety attacks noted in Section
regarding the pathophysiology of panic disorder is prob- 6.5, some of the most common are simple phobia, social
lematic and does require some speculation. With this caveat phobia, post-traumatic stress disorder, and obsessive–
in mind it appears plausible to say that panic disorder compulsive disorder. In all of these disorders, however, the
results from an inherited disturbance in the metabolism of anxiety attacks are precipitated. For example, if the simple
norepinephrine, serotonin, and/or GABA in one or more of phobic has to approach a snake, the social phobic public
the central nervous system structures that subserve the speaking, the post-traumatic patient a situation reminis-
experience of anxiety. Candidate structures include the cent of the original trauma, or the obsessive–compulsive a
locus ceruleus, the dorsal raphe nucleus, the para- contaminated object, a severe anxiety attack may indeed
hippocampal gyrus, hippocampus, and amygdala. The locus occur. If however, these precipitating situations may be
ceruleus is noradrenergic and the dorsal raphe nucleus is avoided, these patients remain free of attacks.
serotoninergic, and both send fibres to a large number of Of the less common causes of anxiety attacks noted in
structures, including the parahippocampus, hippocampus, Section 6.5, special consideration should be given to myocar-
and amygdala, structures that are rich in GABA receptors. dial infarction or angina, paroxysmal atrial tachycardia,
Stimulation of the parahippocampus, hippocampus, and, hypoglycemia, hyperventilation, and simple partial seizures.
especially, the amygdala is well-known to produce anxiety. As noted earlier, panic attacks may be accompanied by chest
If one considers the amygdala as being the ‘final common pain, which may radiate to the neck or shoulder, hence sug-
pathway’ in the development of anxiety, then dysfunction gesting a diagnosis of cardiac disease, and in these cases the
of any one of these upstream structures, or of the amygdala general medical setting is very helpful. Clearly, if the patient
itself, could produce an attack. It has been proposed that is elderly and has known risk factors and no history of panic
one possible ‘trigger’ for the activation of this circuitry is an attacks, then one would lean toward a diagnosis of coronary
abnormal sensitivity of brainstem structures to distur- artery disease; by contrast, if the patient is young and lacks
bances in the acid–base balance (Klein 1993). Such a sensi- risk factors, one might be inclined to lean toward a diagnosis
tivity, in turn, could explain the panicogenic effects of of panic disorder. An episode of paroxysmal atrial tachycar-
lactate infusion and carbon dioxide inhalation. dia may occasionally prompt considerable anxiety in the suf-
Before leaving this section on etiology, some words are ferer. However, here one finds a hyperacute onset of the
in order regarding mitral valve prolapse. Although there is tachycardia, over a second or so, in contrast to the build-up
a clear association between this disorder and panic disor- of a panic attack, which occurs over a minute or so; further-
der (Katerndahl 1993), it is probably not etiologic in a more, in paroxysmal atrial tachycardia a valsalva manuever
direct sense. In all likelihood the association is probably may terminate the attack, whereas such a manuever has no
secondary to some, as yet unidentified, common factor effect on a panic attack. Hypoglycemia should be suspected
that underlies both disorders. in the case of a diabetic who has missed a meal, and in whom
the attack is associated with hunger; prompt relief with glu-
cose confirms the suspicion. Hyperventilation is suggested by
Differential diagnosis the prominent dyspnea and by relief with re-breathing
through a paper bag. Simple partial seizures are suggested by
As noted earlier, the term ‘panic attack’ refers to an anxiety an exquisitely paroxysmal onset, over seconds, and by a his-
attack that happens to occur secondary to panic disorder, tory in most cases of other, more obvious seizure types, such
and, consequently, in pursuing the differential diagnosis of as complex partial seizures or grand mal seizures.
panic disorder one must consider the various other causes
of anxiety attacks, as discussed in Section 6.5.
Occasionally, an otherwise normal individual will have Treatment
an anxiety attack, and, after thorough investigation, no
clear cause may be found. In such cases one is tempted to Pharmacologic treatment of panic disorder has as its goal
make a diagnosis of panic disorder; however, by conven- the prevention of future panic attacks, and the first step
tion, this diagnosis should probably be withheld until sub- is to choose one of the various medications that are effective
sequent attacks have occurred and one is able to in this regard, including antidepressants (SSRIs, tricyclics,
demonstrate that, at least at some point in the course, a fre- or MAOIs), benzodiazepines, and inositol. Cognitive–
quency of once monthly or more has been observed. behavioral therapy (Beck et al. 1992) also appears to be
Anxiety attacks may also be seen as part of the depres- effective; if this is tried first and is less than fully effective,
sive episodes of either major depressive disorder or bipolar then one may simply proceed to pharmacologic treatment.
p 20.qxd 3/10/08 9:58 AM Page 634
Among the antidepressants, the following SSRIs, with et al. 1993a), lean toward trying an antidepressant first.
their average effective doses, may be used: fluoxetine However, in some cases, especially those characterized by
(20 mg) (Michelson et al. 2001), paroxetine (40 mg) very frequent attacks and considerable anticipatory anxiety,
(Ballenger et al. 1998; Oehrberg et al. 1995), sertraline some clinicians will ‘split the difference’ and start the patient
(50–150 mg) (Dohl et al. 1998; Londborg et al. 1998), on a combination of a benzodiazepine and an antidepre-
citalopram (20 mg) (Wade et al. 1997), escitalopram ssant (e.g., clonazepam and an SSRI), with plans to gradually
(10 mg) (Stahl et al. 2003), and fluvoxamine (150 mg) taper the benzodiazepine once enough time has passed for
(Hoehn-Saric et al. 1993). Of the tricyclics, one may use the antidepressant to take effect.
imipramine (150–200 mg) (Mavissakalian and Perel 1989) Inositol is a naturally occurring isomer of glucose that is
or clomipramine (50–150 mg) (Modigh et al. 1992). Of the normally converted to inositol 1,4,5-triphosphate, which
MAOIs, one may use phenelzine (30–90 mg). As all of these in turn functions as an intracellular second messenger, and
are of approximately equal effectiveness, the choice among doses of 6000–9000 mg b.i.d. have been found to be supe-
them is generally based on side-effect profile and ease of rior to placebo and comparable to fluvoxamine in prevent-
use, and with these criteria as guides, an SSRI is probably ing panic attacks (Palatnik et al. 2001). Although
the first choice (with the exception of fluvoxamine, whose experience with inositol is relatively limited, it would cer-
side-effects and many problematic drug–drug interactions tainly be a reasonable option in cases of intolerance to
make this a second choice). A tricyclic, such as imipramine, other agents or for patients who prefer ‘natural’ remedies.
constitutes a reasonable alternative; however, the MAOI
phenelzine, given the difficulty with its use, should be held
in distant reserve. Regardless of which antidepressant is 20.11 AGORAPHOBIA
chosen, it is important to start with a low dose, as initiation
of treatment at a full dose may cause a ‘flurry’ of panic Agoraphobia is derived from the Greek meaning literally a
attacks. Thus, one should start with anywhere from one- fear of the marketplace or, more generally, a fear of open
tenth to one-third of the full dose (breaking up tablets, if spaces. However, on close questioning, what becomes
need be), followed by upward titration in similar incre- apparent is that patients suffering from agoraphobia do
ments every week or so. Importantly, however, although not in fact fear a particular place or situation, but rather the
most patients require, and eventually tolerate, a full dose, possibility of becoming ill or incapacitated in some fashion
there is a small minority of patients who do not tolerate or other and either not being able to escape or not being
anything more than a minimal dose, which they do benefit able to get immediate help.
from; consequently, if patients do not tolerate a dose escala- As discussed further below, there are probably two
tion, one option is to continue with a low dose and see if kinds of agoraphobia (Horwarth et al. 1993; Lelliott et al.
they respond. Once an optimum dose has been reached, it 1989). In one type, seen in the vast majority of cases, ago-
may take up to 3 months to see a good prophylactic effect. raphobia represents a complication of panic disorder, and
Among the benzodiazepines, choices include clonazepam what patients fear is being incapacitated by a panic attack
(Rosenbaum et al. 1997; Tesar et al. 1991), alprazolam while away from home and safety; in the other type, there
(Ballenger et al. 1988), lorazepam (Schweizer et al. 1990), and is no history of panic disorder, and patients seem unable to
diazepam (Noyes et al. 1996). Each should be started at a low clearly delineate what they fear might happen.
dose, with the understanding that dose increases may be The lifetime prevalence of agoraphobia ranges from 1 to
required to prevent attacks. Total daily starting doses and 5 percent; it is probably two to four times more common
potential final doses are as follows: clonazepam, starting in females than males.
at 0.5–1.5 mg, increasing to 1–4 mg; aprazolam, starting at
0.75–1.5 mg, increasing to 1.5–6 mg; lorazepam, starting
at 1–2 mg, increasing to 2–6 mg; and diazepam, starting at Clinical features
4–10 mg and increasing to 10–60 mg. In general, the total
daily dose should be divided into a twice- or thrice-daily The onset is generally in the twenties or thirties; in those
schedule. Clearly, given the wide ranges of starting and cases in which agoraphobia represents a complication of
potential final doses here, considerable clinical judgment is panic disorder, anywhere from as little as a few days to up
required. Importantly, however, and unlike the antidepres- to a year or more may elapse between the occurrence of the
sants, these benzodiazepines are immediately effective once first panic attack and the onset of the agoraphobia.
the ‘right’ dose has been reached; consequently, if patients A large number of places and situations may be feared and
continue to have attacks, this is an indication that their cur- avoided (Page 1994), including travelling on airplanes or
rent dose will not be effective and that the dose should trains, travelling across bridges or through tunnels, and, in
promptly be increased. extreme cases, simply waiting in long lines, and the prospect
Many clinicians, concerned about the possibility of neu- of being caught in such a situation may fill patients with a
roadaptation with benzodiazepines, and the risk of precipi- catastrophic, yet difficult to describe, sense of dread (Goisman
tating a flurry of attacks if the patient runs out of medication et al. 1995). Some patients become completely housebound
or tapers the dose too rapidly (Pecknold et al. 1988; Rickels and literally may never set foot outside the house for years.
p 20.qxd 3/10/08 9:58 AM Page 635
20.12 Specific (simple) phobia 635
Interestingly, in many cases patients are able to temporarily apprehension. Although adult patients acknowledge the
overcome their agoraphobia if they take their ‘safety’ with irrationality of their fear, they go out of their way to avoid
them by travelling with a good and trusted friend. the feared object. First described by Hippocrates, this con-
dition is quite common, occurring in at least 10 percent of
the general population; it is about twice as frequent in
Course females as in males.
In the past it was fashionable to subdivide specific pho-
Agoraphobia is a chronic disorder and tends to gradually bia according to the feared object or situation, and thus
worsen over long periods of time. one reads of arachnophobia, acrophobia, claustrophobia,
etc. For the most part, however, this subdividing added lit-
tle to our understanding of the disorder, with one probable
Etiology exception, namely blood-injury phobia, which, as noted
below, may be a unique specific phobia.
In cases occurring secondary to panic disorder, the normal
anticipatory anxiety about having another panic attack
becomes so severe and pervasive that patients cannot bear Clinical features
venturing into ‘unsafe’ situations. In those cases that occur
in the absence of panic disorder, patients, although The age of onset of specific phobia ranges from childhood
describing well the dread they feel over being in agorapho- to early adult years: animal phobias and blood-injury pho-
bic situations, cannot clearly explain, either to themselves bia tend to first appear in childhood, whereas the other
or others, what it is they fear might happen, and the etiol- phobias may first appear at any point from childhood to
ogy in these cases is simply not known. adult years (Marks and Gelder 1966).
A wide range of objects or situations may come to be
feared, including snakes, spiders, heights, being in closed
Differential diagnosis spaces, darkness, storms, and the sight of blood. Although
most patients with specific phobia have only one phobia, in
In social phobia of the generalized subtype (also known as a minority two or more may be present.
social anxiety disorder), patients may fear and avoid many On approaching the feared object or situation, or even
different situations. The difference here is that social pho- upon simply imagining doing so, patients experience the
bics fear that they will do something that embarrasses or acute onset of an anxiety attack, characterized by anxiety,
humiliates them, whereas agoraphobics fear that some- tremor, tachycardia, diaphoresis, and piloerection; in some
thing will happen to them, such as a panic attack. cases, these symptoms may be accompanied by deperson-
In illnesses characterized by delusions of persecution, alization. Some patients may be able to steel themselves
patients may avoid going out for fear that people will talk and stay nearby, but for the most part the fear and anxiety
about them, spy on them, assault them, etc. This may be is so great that they must escape, no matter how humiliat-
seen in schizophrenia, schizoaffective disorder, the persecu- ing or embarrassing such behavior might be for them.
tory subtype of delusional disorder, and depressive episodes Importantly, as soon as patients can get away, the anxiety
of either major depressive disorder or bipolar disorder. ceases and patients, although perhaps a little ‘shaken’ by
the experience, promptly return to normal.
Blood-injury phobia, as indicated earlier, may be unique.
Treatment A common example is found in patients who are phobic
about having a venipuncture (Chapman et al. 1993). If these
Agoraphobia may be treated either with cognitive–behav- patients can force themselves to hold still for the phle-
ioral therapy or a behavioral program of graded exposure, botomist, they typically experience a biphasic symptomatol-
in which the patient gradually and sequentially takes pro- ogy. Initially, there is anxiety and tachycardia, similar to that
gressively greater ‘steps’ toward and into the feared situa- seen in the anxiety attack just described; soon after, however,
tion. Critically, however, in those cases occurring secondary these sympathetic symptoms give way to a parasympathetic
to panic disorder, one must first treat the panic disorder response, with hypotension and either pre-syncope or actual
and render the patient free of panic attacks. The occurrence fainting (Curtis and Thyer 1983). It is this second phase that
of even one panic attack can, and often does, destroy any gives blood-injury phobia its unique status.
gains made by cognitive–behavioral or exposure therapy.
Course
20.12 SPECIFIC (SIMPLE) PHOBIA
Phobias with an onset in childhood tend to remit within
The patient with a specific phobia, or, as it was formerly months or a year or so. In cases of childhood-onset phobias
known, a simple phobia, experiences extreme anxiety upon that persist, and in cases characterized by later onsets in ado-
approaching something that for others arouses little or no lescence or early adult years, the course tends to be chronic.
p 20.qxd 3/10/08 9:58 AM Page 636
Etiology Treatment
Specific phobias run in families (Fyer et al. 1990), although Both desensitization and cognitive–behavioral therapy are
it is not clear whether this reflects environmental or genetic effective. The place of pharmacologic therapy of specific
factors, or both. Some authors believe that children phobias is not entirely clear. Many patients are prescribed
become phobic by virtue of modeling their parents’ benzodiazepines on a chronic basis; however, there is no
behavior; however, this theory begs the question as to the research support for this and it runs the risk of neuro-
source of the parents’ phobias. Other authors suggest that adaptation. Brief, ‘one time’ use of benzodiazepines may,
phobias represent a vestigial remnant from our ancient however, have a place, as for example in the pre-treatment
evolutionary history, when an instinctual avoidance of cer- of a claustrophobic patient before an MRI study in a
tain objects, such as snakes, could have conferred consider- ‘closed’ system. There is also one study that found paroxe-
able survival value. In support of this evolutionary view is tine to be superior to placebo (Benjamin et al. 2000).
the fact that certain monkeys who have never had any con-
tact with a snake nevertheless react with extreme fear upon
seeing one. 20.13 SOCIAL PHOBIA
In the case of blood-injury phobia, it appears that there
is an underlying chronic dysfunction of the autonomic In social phobia, patients fear that if they attempt to do cer-
nervous system, which predisposes these patients to the tain things in public they will appear inept, foolish, or
development of vaso-vagal syncope (Accurso et al. 2001; inadequate, and thus suffer shame, humiliation, or embar-
Donadio et al. 2007). rassment. Feeling this way, patients, although admitting
that their fears are perhaps groundless, nevertheless
become intensely anxious on approaching these situations
Differential diagnosis and may go to great lengths to avoid them.
Importantly, there are two subtypes of social phobia,
Specific phobia must be distinguished from social phobia namely the generalized type (also known as social anxiety
of the circumscribed type, certain cases of obsessive– disorder) and the circumscribed type (Heimberg et al.
compulsive disorder, and post-traumatic stress disorder. 1990; Mannuzza et al. 1995). The generalized subtype is
Social phobia of the circumscribed type may be distin- characterized by fears that span multiple situations,
guished from specific phobia by the fact that, in social phobia, whereas in the circumscribed subtype only one or two spe-
what is feared is humiliation or embarrassment in certain cific situations are feared.
situations, rather than the situation per se. For example, the This is a common disorder, occurring in anywhere from
patient with a circumscribed social phobia of public speak- 3 to 13 percent of the adult population; it is more frequent
ing, although terrified at the prospect of speaking when in females than males.
others are present, may, when rehearsing the speech in pri-
vate, have little or no anxiety: here, it is the apprehension
of embarrassing oneself when speaking, rather than speak- Clinical features
ing itself, which the patient fears. This is in contrast to the
patient with a specific phobia, for example of snakes, who The onset of social phobia ranges from late childhood to
reacts with anxiety upon seeing the snake regardless of the early adult years, with most patients falling ill in their
whether this occurs in public or in private. Certain cases of mid-teens (Marks and Gelder 1966). Pre-morbidly, in
obsessive–compulsive disorder may also cause diagnostic some cases there is a history of shyness and easy blushing.
concern, for example when patients have a fear of contam- The actual onset itself is heralded by the first wave of irra-
ination and avoid various objects or situations, such as tional anxiety over doing something in public.
shaking hands or using a public restroom. In these cases, In the generalized subtype, patients fear multiple situa-
however, the reaction to the feared object or situation per- tions, including, for example, answering questions in class,
sists long after contact ceases, for example when the patient asking others out for dates, or attending meetings; in some
with obsessive–compulsive disorder washes his or her cases patients may have a global fear of interacting socially
hands repeatedly; this is in contrast to specific phobia, in in any situation.
which patients return to normal promptly upon dis- In the circumscribed subtype there may be a fear of pub-
engaging from the phobic object or situation. Post-traumatic lic speaking, or fears that one will tremble when writing in
stress disorder may be confused with specific phobia when public, misplay notes when giving a musical performance,
post-traumatic patients report avoiding certain situations. choke when eating in public, or, in males, be unable to uri-
Here, however, one finds that the avoided situations have a nate in a public restroom. Regardless of the specific circum-
specific meaning for patients in that they are reminiscent scribed fear involved, it is important to note that it is not the
of an earlier traumatic event; this is in contrast to social activity itself that is feared but rather the performance
phobia, in which patients admit that the fear is ‘irrational’ of that activity in public. Thus, the patient with a fear of
and not based on any earlier event. public speaking who is paralyzed into muteness upon
p 20.qxd 3/10/08 9:58 AM Page 637
20.13 Social phobia 637
approaching the podium with an audience present may Specific phobia may be readily distinguished from
nevertheless be able to make the speech flawlessly on social phobia of the circumscribed type by asking patients
rehearsal in an empty hall. whether they can engage in the fearful behavior when in
If patients do approach the phobic situation (or at private; the patient with a specific phobia, for example of
times, merely imagine doing so), they experience an anxi- snakes, is no more able to approach the snake in private
ety attack of variable severity, with anxiety, tremor, tachy- than in public, whereas the patient with a circumscribed
cardia, diaphoresis, and dyspnea. In some cases patients social phobia, for example of speaking in public, may, as
may be able to endure the anxiety and proceed with the noted earlier, go through a rehearsal of the speech without
performance; however, in many cases the anxiety is simply anxiety, provided that there is no audience.
‘too much’ and patients may refuse to go on. One variation Similarly to the generalized type of social phobia, body
on this reaction is known as erythrophobia. Here, what dysmorphic disorder is characterized by a fear of humilia-
patients are concerned about is excessive blushing in pub- tion or embarrassment in public; however, in body dys-
lic. In some cases there may actually be an obvious, scarlet morphic disorder the fear arises from the patients’ beliefs
blush; however, in others the blush is actually not noted by that they are in some way misshapen or deformed, rather
others but is simply experienced by the patient as a sense of than from a concern that they might suffer embarrassment
flushing or uncomfortable warmth. because of something they do.
Certain conditions, by their very symptoms, may occa-
sion some embarrassment, and in such cases a separate
Course diagnosis of social phobia is not made. Examples include
the tremor of essential tremor or Parkinson’s disease, and
Social phobia appears to be a chronic disorder. developmental stuttering.
One must also distinguish between normal fears and
Etiology social phobia. Most individuals experience some appre-
hension or ‘stage fright’ when first approaching certain sit-
The etiology of the two types of social phobia may not be uations; however, in contrast to social phobia, the fear is
the same, and hence they are considered separately. not overwhelming and, importantly, diminishes after a few
Generalized social phobia, which has been subjected to ‘dress rehearsals’.
the most study, appears to be familial (Fyer et al. 1993) and
to be associated with disturbances in various neurotrans-
mitter systems, including serotonin, endogenous benzodi- Treatment
azepines, and dopamine. With regard to serotonin, several
abnormalities have been noted, including an aggravation A large number of medications are effective in the general-
of symptoms with depletion of the serotonin precursor ized type of social phobia, including various antidepressants,
tryptophan (Argyropoulos et al. 2004), a decrease in the clonazepam, and two anti-epileptic drugs, gabapentin and
serotonin-1A binding potential both on platelets and neu- pregabalin. Effective antidepressants include sertraline
rons in the amygdala and cingulate cortex (Lanzenberger 50–200 mg/day (Katzelnick et al. 1995), paroxetine
et al. 2007), and an augmented cortisol response to the 20–40 mg/day (Allgulander 1999; Baldwin et al. 1999; Stein
serotoninergic agent fenfluramine (Tancer et al. 1994). In et al. 1998), escitalopram 10–20 mg/day (Kasper et al. 2005),
looking at endogenous benzodiazepine function, there fluvoxamine 150 mg/day (Stein et al. 1999; van Vliet et al.
appears to be a reduced number of platelet benzodiazepine 1994), venlafaxine 75–225 mg/day (Liebowitz et al. 2005),
receptors (Johnson et al. 1998). Finally, both a reduced and phenelzine 60–90 mg/day (Heimberg et al. 1998;
density of dopamine receptors in the striatum (Schneier Liebowitz et al. 1992; Versiani et al. 1992). The benzodi-
et al. 2000) and a decrease in striatal dopamine reuptake azepine clonazepam 0.5–3.0 mg/day (Davidson et al. 1993) is
sites (Tiihonen et al. 1997a) have also been noted. also effective, as are the anti-epileptics gabapentin
Regarding the circumscribed type of social phobia, little 900–3600 mg/day (Pande et al. 1999) and pregabalin
can be said except that it is suspected to reflect a distur- 600 mg/day (Pande et al. 2004). All other things being equal,
bance in noradrenergic functioning. one of the antidepressants (with the exception of phenelzine,
which, given the difficulty in its use, should be held in
reserve) is a reasonable first choice. Although experience
Differential diagnosis with gabapentin and pregabalin is limited in social phobia,
they might be a reasonable second choice; of the two,
Agoraphobia may be distinguished from the generalized gabapentin is probably preferable. Although clonazepam is
type of social phobia by the source of the patients’ fear often used, the potential for neuroadaptation may give one
about going out in public. In the agoraphobic, what is pause. Cognitive–behavioral therapy may be considered but
feared is having a panic attack, whether anyone is around appears to be slightly less effective than medication.
or not; this is in contrast to social phobics who fear that Circumscribed social phobia, especially fears of speaking,
they will do something humiliating or embarrassing. writing, or giving a musical performance, may be treated
p 20.qxd 3/10/08 9:58 AM Page 638
with a beta-blocker such as propranolol, given on an ‘as much time arranging and then rearranging things on the
needed’ (p.r.n.) basis in anticipation of the public perform- desk or in the closet, always finding afterwards on inspection,
ance (Brantigan et al. 1982; Hartley et al. 1983; James et al. however, that some critical point of symmetry has been
1977; Liden and Gottfries 1974). The dose of propranolol missed. These counters and arrangers are sometimes at a loss
ranges from 20 to 60 mg, and the drug appears to work not to explain what they fear might happen should they fail to
so much by reducing anxiety per se as by reducing auto- act; it is as if a there is a nameless dread motivating them.
nomic symptoms, such that patients no longer ‘shake like a Although most compulsive behaviors are visible and evident
leaf’. Behavioral desensitization may also be helpful. to others, some patients may at times engage in ‘silent’ or pri-
vate compulsions, for example repeating the Lord’s Prayer to
themselves a certain number of times. Almost all patients, at
20.14 OBSESSIVE–COMPULSIVE DISORDER least initially, recognize the ‘senselessness’ or irrationality of
their compulsions and will attempt to resist them (Stern and
Obsessive–compulsive disorder is characterized by obses- Cobb 1978); over the years, however, many will give in, car-
sions and compulsions (Rasmussen and Tsuang 1986). It is a rying out the compulsions without even a token show of
common disorder, with a lifetime prevalence of 2–5 percent. resistance. In a small minority of cases, patients may lose
insight into the irrationality of their compulsive behavior and
Clinical features become convinced, to a delusional degree, that their behavior
is in fact reasonable and appropriate (Eisen and Rasmussen
Most patients fall ill in adolescence or early adult years; 1993; Insel and Akiskal 1986). Such patients with psychotic
although onset in childhood is not rare, onset past the age obsessive–compulsive disorder, now finding their compul-
of 40 years is quite rare. sions reasonable, pursue them with purpose rather than
The majority of patients experience both obsessions and resisting them. One patient (Gordon 1950), after 25 years of
compulsions (Foa et al. 1995). Somewhat less than 25 per- resisting the urge to repeat his prayers for fear that he had left
cent will have only obsessions and about 5 percent will a word out, eventually came to believe that he was in fact a
have only compulsions; very rarely one finds patients with sinner and that God had given him the compulsion to specif-
a subtype known as primary obsessive slowness. ically ensure that he said the prayers with the perfection that
Obsessions are unwanted, intrusive, and troubling ideas, salvation and eternal life demanded; subsequently, he freely
impulses or images, often related to sexual or violent gave himself to the repeating of his prayers whenever he had
themes. A minister recurrently found himself thinking of the slightest doubt that he had left anything out.
bestiality; a neurologist found himself repeatedly experienc- Primary obsessive slowness is characterized by the trans-
ing an urge to question his patients about their bowel move- formation of routine daily activities into lengthy, meticu-
ments; and a young mother, to her distress, continually had lous rituals. Dressing or preparing a meal may take literally
thoughts of her toddler being run over by a truck. Most hours; the sequence and form of each step in the process is
patients are, at the very least, distressed by these obsessions, carefully and scrupulously observed, and any deviation
and many are horrified. All, at least initially, will try their leads to an accretion of severe anxiety. Only when com-
best to somehow stop the obsessions from occurring. pletely satisfied that the job has been perfectly done can the
Compulsions arise in response to irrational fears or con- patient move on to the next task of the day. Patients with
cerns, and in some way or other they serve to allay these fears. primary obsessive slowness typically have had, or continue
These strong urges give patients no peace, typically waxing to have, other compulsions, such as checking or washing.
ever stronger as patients try to resist carrying them out.
Compulsions are often categorized according to what
Course
patients feel compelled to do: thus, for example, there are
checkers, washers, touchers, counters, and arrangers. A
Although obsessive–compulsive disorder generally pursues a
‘checker’, after going upstairs to bed, had doubts that he had
chronic course, exceptions do occur: in a small minority, per-
turned off the electric light downstairs and felt compelled to
haps 5 percent, symptoms undergo a complete, or near-
go back downstairs to check on it; despite finding the light
complete, spontaneous remission; in such cases, however,
off, however, the fear again arose once he had returned
relapses generally occur in the following years. Although in
upstairs, forcing him to go back once again, the process being
most chronic cases symptoms tend to wax and wane in sever-
repeated many times before the patient could finally get to
ity and frequency over long periods of time, in 10–15 percent
bed (Tuke 1894). ‘Washers’ are convinced that they have
the course is progressively downhill until patients’ lives are
been contaminated in some way, perhaps by dirt, ‘germs’, or
literally consumed by their obsessions and compulsions.
fecal material, and feel compelled to wash their hands, no
matter how clean they may be or how many times they have
already been washed; some may wash to the point of rawness, Etiology
yet still feel unclean. ‘Counters’ feel compelled to count to a
certain number and do it repeatedly, whereas ‘arrangers’, Obsessive–compulsive disorder is familial (Grabe et al. 2006;
under the compulsion to arrange things ‘just so’, may spend Pauls et al. 1995), and genetic research, although inconclusive,
p 20.qxd 3/10/08 9:58 AM Page 639
20.15 Post-Traumatic stress disorder 639
is promising (Shugart et al. 2006); in some cases it appears cognitive–behavioral therapy; most patients do best with a
that obsessive–compulsive disorder may represent a pheno- combination of medication and one of these two tech-
typic variant of the same genes responsible for Tourette’s niques (Foa et al. 2005).
syndrome (Apter et al. 1993; Frankel et al. 1986). Although Serotoninergic drugs effective in obsessive–compulsive
neuropathologic studies are lacking, PET studies (Baxter disorder include clomipramine, venlafaxine, and the SSRIs.
et al. 1987, 1992; Benkelfat et al. 1990; Perani et al. 1995; Clomipramine is effective in the dose range 200–250 mg/day
Saxena et al. 2002) have demonstrated increased metabolic (Clomipramine Collaborative Study Group 1991), ven-
activity in the orbitofrontal cortex, caudate, and thalamus. lafaxine in a dose of 300 mg (Denys et al. 2003), fluoxetine
Furthermore, several lines of evidence suggest a disturbance (Bergeron et al. 2002; Pigott et al. 1990) in doses of
in serotoninergic functioning: all of the medicines effective in 20–60 mg/day (Tollefson et al. 1994), fluvoxamine
this disorder are serotoninergic; meta-chlorophenylpiper- (Freeman et al. 1994; Hollander et al. 2003a; Koran et al.
azine, a mixed agonist/antagonist at post-synaptic serotonin 1996) in doses of 100–300 mg/day, sertraline in doses of
receptors, generally increases the severity of symptoms 50–200 mg/day (Bergeron et al. 2002; Greist et al. 1995;
(Broocks et al. 1998; Hollander et al. 1992); and SPECT stud- Krong et al. 1999), paroxetine (Hollander et al. 2003b; Zohar
ies suggest disturbances in serotonin binding within the mid- and Judge 1996) in doses of 40–60 mg/day, and escitalopram
brain (Hasselbach et al. 2007) and caudate (Adams et al. in a dose of 20 mg/day (Stein et al. 2007). Most clinicians will
2005), and serotonin reuptake mechanisms within the thala- start with an SSRI, given their favorable side-effect profile
mus and brainstem (Hesse et al. 2005). relative to clomipramine (Zohar and Judge 1996); venlafax-
In a minority of childhood-onset cases it appears that ine represents a new addition to this armamentarium, and
obsessive–compulsive disorder occurs on an autoimmune its place is not as yet clear. Importantly, regardless of which
basis, via a mechanism similar to that seen in Sydenham’s medication is used, 6 weeks must be allowed to see an initial
chorea, and such patients are said to have one of the ‘PAN- response, and a full response may not be seen for 3 months.
DAS’ or ‘pediatric autoimmune neuropsychiatric disorders When an initial trial of medication fails, several strategies
associated with streptococcal infections’ (Swedo et al. 1998). are available. First, one may consider an increased dose, for
In these cases, as in Sydenham’s chorea, a preceding beta- example increasing the dose of sertraline up to 400 mg
hemolytic streptococcal pharyngitis initiates an autoimmune (Ninan et al. 2006). If dosage increase is either not tolerated
attack on the basal ganglia, resulting in obsessions and com- or ineffective, then one may consider switching from one
pulsions. Whether this group of patients should be consid- agent to another, for example from an SSRI to clomipramine
ered to have obsessive–compulsive disorder or a phenotype is or venlafaxine. Another option is to add an antipsychotic,
a nosologic question that has not as yet been answered. In such as risperidone (1–3 mg) (Li et al. 2005; McDougle et al.
any case, PANDAS should be suspected in cases in which 2000), haloperidol (2–5 mg) (Li et al. 2005; McDougle et al.
either the onset of the disorder or exacerbations are related to 1994, 2000), quetiapine (300–400 mg) (Denys et al. 2004), or
streptococcal pharyngitides, and the work-up should pro- olanzapine (5–20 mg) (Bystritsky et al. 2004). Of these
ceed as outlined for Sydenham’s chorea in Section 17.10. antipsychotics, risperidone is probably the treatment of first
Importantly, there is no relationship between obsessive– choice, as it is better tolerated than haloperidol (Li et al.
compulsive disorder and obsessive–compulsive personality 2005); experience with quetiapine is limited; and the long-
disorder. Although in the past, the personality disorder was term metabolic effects of olanzapine give one pause.
felt to provide the ‘fertile’ soil for the development of Importantly, these antipsychotics are effective only as aug-
obsessive–compulsive disorder, there is no evidence for this, menting agents and are not useful in monotherapy. In severe
and patients with obsessive–compulsive disorder are no and treatment-resistant cases, consideration may be given to
more likely to have a pre-existing obsessive–compulsive per- cingulotomy (Baer et al. 1995; Dougherty et al. 2002; Hay
sonality disorder than any other personality disorder (Baer et al. 1993), anterior capsulotomy, or deep brain stimulation
et al. 1990; Black et al. 1993; Joffe et al. 1988). of the anterior capsules (Greenberg et al. 2006).
In acute cases of obsessive–compulsive disorder occur-
ring as part of PANDAS, it is tempting to consider utilizing
Differential diagnosis the same sort of acute treatment as is recommended for
Sydenham’s chorea; although prednisone has not been
The differential diagnosis of obsessions and compulsions is studied in this regard, one study did report benefit from
discussed in detail in Section 4.17, and the reader is plasma exchange (Perlmutter et al. 1999). In chronic
encouraged to review that section. cases one might also consider preventive treatment with
benzathine penicillin.
Treatment
20.15 POST-TRAUMATIC STRESS DISORDER
Effective therapy involves the use of a serotoninergic med-
ication or either the behavioral techniques of exposure and Post-traumatic stress disorder (PTSD) may occur in prac-
response prevention (Foa et al. 1984; Steketee et al. 1982) or tically anyone who has been exposed to an overwhelmingly
p 20.qxd 3/10/08 9:58 AM Page 640
traumatic event, for example combat (Lee et al. 1995), tor- Patients tend to be anxious, tense, and easily startled.
ture (Basoglu et al. 1994; Ramsey et al. 1993), concentra- Although often fatigued, they try to remain alert, as if on
tion camps (Kinzie et al. 1984), mass shootings (North guard against some fresh onslaught. There may be diffi-
et al. 1994), earthquakes (Goenjian et al. 1994), or fire, as culty with concentration, insomnia, and lability of mood;
in the famous Coconut Grove disaster in Boston in 1943 irritability is common, and patients may become enraged
(Adler 1943). Subsequent to the trauma, patients, in vari- with little or no provocation.
ous fashions, re-experience the event over and over again; Over time, a full depressive episode may occur, and alco-
there is also a general withdrawal from present life, and hol abuse or alcoholism may also occur, in which case one
patients tend to be anxious and easily startled. This is prob- typically sees a florid exacerbation of the symptoms of PTSD.
ably a common disorder, occurring in anywhere from 1 to
9 percent of the general population; it is probably more
frequent in females than males. Course
Clinical features In about 50 percent of cases, symptoms undergo a gradual

and spontaneous remission within months of the onset,
As trauma may occur at any age, so too may PTSD; however, and this appears to be more common in cases with an acute
given that the most common precipitants for PTSD, such as onset shortly after the original trauma. A chronic course
combat, occur in early adult years, most cases have an onset may also occur, and this appears likely when either symp-
in the twenties. Symptoms may appear either acutely, within toms have persisted beyond 6 months or the onset was
days or weeks after the trauma, or in a delayed fashion, after delayed. When the course is chronic, symptoms tend to
a latency of months to many years (Watson et al. 1988); wax and wane over years or decades.
indeed, in one case of PTSD secondary to combat in World
War II, the syndrome was delayed for three decades (Van
Dyke et al. 1985). In cases of delayed onset, the latency Etiology
period is generally, but not always, marked by dysphoria and
a tendency to avoid situations reminiscent of the original By far the best predictor of PTSD is the type and severity of
trauma. Although delayed onsets typically occur subacutely, the trauma itself. Products of human cruelty, such as tor-
occasionally the latent interval will end abruptly if the ture or incarceration in a concentration camp, commonly
patient experiences a new trauma similar to the original one. produce this disorder. Furthermore, events that catch per-
Although it is not possible to predict with any degree of cer- sons by surprise and then leave them without social sup-
tainty who, after a trauma, will go on to develop PTSD, it port afterward, such as a typhoon that devastates a
appears that a history of dissociation during the trauma por- community, likewise provide fertile ground for the devel-
tends a greater risk (Birmes et al. 2003; Koopman et al. 1994; opment of this disorder. Conversely, certain traumatic
Shalev et al. 1996). events, such as mild motor vehicle accidents, are less likely
Clinically (Gersons and Carlier 1992), in one fashion or to precipitate PTSD.
another, patients become numb to the world around them. However, the fact that not all persons exposed to severe
Events that used to arouse interest now leave them unaf- trauma develop the disorder, coupled with the finding that
fected and unmoved; they may complain of feeling ‘dead some individuals may develop PTSD after relatively mild
inside’ or of having no feelings at all, and some may appear trauma (Feinstein and Dolan 1991; McFarlane 1989), indi-
listless and detached. cates that other factors are involved. Twin studies have
The experience of the trauma lives on in these patients, suggested a genetic susceptibility; however, it is not clear
and they typically have intense, intrusive, and vivid memo- whether the inherited factor is a susceptibility to the devel-
ries of it. Nightmares are common and, unlike most night- opment of PTSD per se or rather a tendency to become
mares, these have little of the fantastic in them; rather they involved in high-risk activities.
tend to stick to the persistently disturbing facts. At times Endocrinologic and biochemical studies have yielded
the waking recollections of the trauma may be more com- interesting results. The autonomic symptomatology seen in
pelling and vivid than the patients’ actual surroundings, this disorder, such as a heightened startle response (Butler
and they may experience ‘flashbacks’ in which they act as if et al. 1990; Shalev et al. 1992) and sensitivity to stimuli rem-
the original trauma were actually occurring; in extreme iniscent of the original trauma (Pitman et al. 1987), imme-
cases, these flashbacks may be characterized by visual and diately suggests disturbances of catecholamines, and indeed
auditory hallucinations that recreate the original trauma. both CSF (Geracioti et al. 2001) and 24-hour urine levels
Situations that remind patients of the trauma tend to be (Young and Breslau 2004) of norepinephrine are increased;
avoided. Veterans may refuse to view war movies, and furthermore, intravenous administration of yohimbine, a
World War II concentration camp survivors may avoid noradrenergic agonist, will increase the severity of symp-
anything German. If unavoidably trapped in such a situa- toms (Southwick et al. 1993). Of the endocrinologic studies
tion, patients become intensely anxious and some may carried out on PTSD, the hypothalamic–pituitary–adrenal
have an anxiety attack. axis has been most extensively studied and shows unique
p 20.qxd 3/10/08 9:58 AM Page 641
20.16 Generalized anxiety disorder 641
abnormalities. Cerebrospinal fluid levels of CRH are Malingerers and those with factitious illness, as dis-
increased (Baker et al. 1999, 2005), and this is similar to cussed in Section 7.8, may feign PTSD. In those feigning
what is seen in major depressive disorder. However, the combat-related PTSD, a review of military records may
cortisol response to dexamethasone, rather than being reveal the lie; in cases, however, in which an actual trauma
blunted as is seen in depression, is enhanced in PTSD did occur, for example a motor vehicle accident, the diag-
(Goenjian et al. 1996; Yehuda et al. 1993, 2004). nosis may have to wait upon resolution of pending litiga-
Hippocampal atrophy has been demonstrated by some tion, after which the ‘PTSD’ magically resolves.
(Bremner et al. 1995, 2003; Lindauer et al. 2006; Villarreal
et al. 2002), but not all (Bonne et al. 2001; Jatzko et al.
2006; Woodward et al. 2006), studies. The significance of Treatment
this finding is not clear. There are, at present, no prospec-
tive MRI studies of patients before and after trauma, and Cognitive–behavioral therapy appears to be effective.
hence it is not clear if hippocampal atrophy precedes the Certain antidepressants are also effective, including
trauma and perhaps represents an underlying anatomic phenelzine (Frank et al. 1988), imipramine (Davidson et al.
vulnerability, or merely represents an epiphenomenon, 1990), venlafaxine (Davidson et al. 2006), mirtazapine
perhaps related to the physiologic effects of stress. (Davidson et al. 2003), and the SSRIs fluoxetine (Connor
There is, apparently, only one neuropathologic study of et al. 1999; Martenyi et al. 2002; van der Kolk et al. 1994),
PTSD (Bracha et al. 2005). This study demonstrated a paroxetine (Marshall et al. 2001; Tucker et al. 2001), and
reduction in neuronal cell number in the locus ceruleus in sertraline (Brady et al. 2000; Davidson et al. 2001),
PTSD patients compared with control subjects. (although not all studies are in agreement regarding the
Overall, it appears reasonable to invoke a ‘stress–diathesis’ effectiveness of fluoxetine [Martenyi et al. 2007] or sertra-
model for the etiology of PTSD. However, although the line [Freidman et al. 2007]). Of the antidepressants, the
‘stress’ is clear, the nature of the diathesis is not. It may be, SSRIs have the longest track record, and one of these is gen-
however, that there are changes in certain structures that erally used first; consideration, however, may also be given
subserve emotional reactivity and remembrance, such as to mirtazapine or venlafaxine; imipramine is generally not
the locus ceruleus and the hippocampus, which may in turn as well tolerated, and phenelzine is difficult to use.
be related to disturbances in catecholamine activity and the Regardless of which antidepressant is chosen, a high dose
function of the hypothalamic–pituitary–adrenal axis. may be required, and at least 6 weeks should be allowed to
pass before assessing any effects. In cases in which the anti-
depressant is either poorly tolerated or ineffective, consid-
Differential diagnosis eration may be given to switching to a different
antidepressant or, in patients on an SSRI, to augmentation
After a significant trauma, rather than developing PTSD, with either risperidone (1–2 mg) (Bartzokis et al. 2005;
individuals may develop a major depressive disorder, and the Reich et al. 2004) or olanzapine (10 mg) (Stein et al. 2002);
resulting depressive episode may at times be difficult to dis- of these two antipsychotics, risperidone is generally better
tinguish from the symptoms seen in PTSD. Certain features, tolerated over the long haul and should probably be tried
however, may enable a differential diagnosis to be made. first. Another medication to consider is prazosin. This
Patients with depression have a depressed mood rather than a alpha-1 antagonist has been shown in double-blind work to
sense of numbness or detachment; furthermore, patients reduce the nightmares seen in PTSD (Raskind et al. 2003,
with depression may experience ruminations, which are 2007), and may be started at 1 mg in the evening, with the
heavy, leaden recollections of misfortune, thus standing in dose increased in similar increments every few days until
contrast to the starkly vivid and mercurial recollections and patients obtain relief or limiting side-effects occur; most
flashbacks seen in PTSD. As noted earlier, patients with PTSD patients respond to a dose of about 13 mg. There is also sug-
may develop a depressive episode, but in these cases one sees gestive work indicating that daytime prazosin may provide
clear-cut PTSD preceding the onset of the depression. further relief (Taylor et al. 2006). A non-blind study also
In cases in which the original trauma was a head injury, suggests that cyproheptadine, in a night-time dose of
one must distinguish the features of a traumatic brain 4–12 mg, may reduce nightmares (Gupta et al. 1998).
injury or a post-concussion syndrome from PTSD, and As noted earlier, alcohol abuse or alcoholism not uncom-
this may be difficult. Certainly, one cannot entertain the monly accompany PTSD, and when this is the case it is criti-
diagnosis of PTSD in such cases unless patients display evi- cal to treat these, either first or concomitantly with the PTSD.
dence of involuntarily re-experiencing the original event,
such as vivid memories, nightmares or flashbacks. In post-
head trauma patients who do display such symptoms, 20.16 GENERALIZED ANXIETY DISORDER
other symptoms, such as poor concentration, fatigue,
insomnia, lability, and irritability, may individually occur Generalized anxiety disorder is characterized by a persistent,
secondary to a combined effect of the traumatic brain ‘free-floating’ anxiety, which is accompanied by autonomic
injury (or post-concussion syndrome) and PTSD. symptoms such as tremor. Although the lifetime prevalence
p 20.qxd 3/10/08 9:58 AM Page 642
of this disorder has been estimated to be as high as 5 percent, In some patients, depressive episodes may be marked by
there has been some doubt expressed regarding this; as psychomotor change with agitation, and such patients may
noted below, it may be difficult to distinguish generalized experience restlessness, hand-wringing, and considerable
anxiety disorder from a chronic agitated depression, and tension, thus mimicking the picture seen in generalized
such misdiagnoses may have inflated the prevalence figures. anxiety disorder. Closer inquiry, however, will reveal addi-
tional symptoms in the depressed patient that are not seen
in generalized anxiety disorder, such as crying spells, anhe-
Clinical features donia, and anergia.
Other causes of persistent anxiety are discussed in
The onset is gradual and may occur in either teenage or Section 6.5. Of these, particular attention should be given
early adult years. to chronic use of caffeine or sympathomimetics, and to
Clinically (Anderson et al. 1984; Hoehn-Saric et al. 1989; alcohol or sedative–hypnotic withdrawal.
Marten et al. 1993; Nisita et al. 1990; Starcevic et al. 1994),
patients experience a chronic, pervasive sense of anxious
apprehension and tension. They frequently worry about the Treatment
future and are easily startled. Some complain of a sense of
shakiness, and there may be a mild degree of a fine postural Both cognitive–behavioral therapy and numerous medica-
tremor of the hands. There is occasionally tachycardia, and tions appear to be effective. Various antidepressants are
the skin is often cold and clammy. Insomnia may occur, effective, including imipramine (Hoehn-Saric et al. 1988;
and many complain of nausea and headache. Some patients Kahn et al. 1986; Rickels et al. 1993b), trazodone (Rickels
can offer no explanation for their symptoms, whereas et al. 1993b), venlafaxine (Davidson et al. 1999; Gelenberg
others will offer ‘reasons’ and blame their state on some life et al. 2000; Rickels et al. 2000), duloxetine (Endicott et al.
event or other. Observation over time, however, reveals that 2007), and the SSRIs paroxetine (Ball et al. 2005; Bielski
the anxiety is in fact autonomous and ‘free-floating’. et al. 2005; Pollack et al. 2001; Rickels et al. 2003), sertraline
(Allgulander et al. 2004; Ball et al. 2005; Brawman-Mintzer
et al. 2006; Dahl et al. 2005), and escitalopram (Bielski
Course et al. 2005). Alprazolam (Elie and Lamontagne 1984;
Enkelmann 1991; Hoehn-Saric et al. 1988), lorazepam
This appears to be a chronic disorder, with symptoms wax- (Laakmann et al. 1998), and diazepam (Elie and
ing and waning in intensity over the years or decades. In Lamontagne 1984; Rickels et al. 1993b) are likewise effec-
some cases there appear to be spontaneous remissions; tive, and consideration may also be given to hydroxyzine
however, it is not clear in what percentage of these cases (Lader and Scotto 1998; Llorca et al. 2002), buspirone
relapses eventually occur. (Enkelmann 1991; Laakmann et al. 1998; Lader and Scotto
1998; Rickels et al. 1988; Sramek et al. 1996), and pre-
Etiology gabalin (Montgomery et al. 2006; Rickels et al. 2005). The
antidepressants should be given in doses comparable to
Both family (Newman and Bland 2006; Noyes et al. 1987) those used in depression; total daily doses for the other
and twin studies (Hettema et al. 2001; Kendler et al. 1992) agents are 2–6 mg for alprazolam, 3 mg for lorazepam,
suggest a genetic role in generalized anxiety disorder, and 15–25 mg for diazepam, 50 mg for hydroxyzine, 15 mg for
although it is not entirely clear what is inherited, several buspirone, and 300–600 mg for pregabalin. Although
findings suggest abnormalities in GABAergic and nora- choosing among the various medications is not straight-
drenergic functioning. GAGAergic dysfunction is indicated forward, all other things being equal it is probably reason-
by the effectiveness of benzodiazepines in this disorder and able to start with an antidepressant: venlafaxine,
by the finding of reduced benzodiazepine receptor sites, not duloxetine, or one of the SSRIs constitute reasonable first
only on peripheral blood lymphocytes (Rocca et al. 1998) choices. Antidepressants take weeks to become effective,
but also in the left temporal pole (Tiihonen et al. 1997b). however, and many clinicians lean toward using one of the
Noradrenergic dysfunction is suggested both by the resem- benzodiazepines, given their prompt onset of effect;
blance of the symptoms seen in generalized anxiety disor- however, this advantage must be weighed against the high
der and those produced by noradrenergic agents and also probability of neuroadaptation and the rebound anxiety
by the presence of a reduced number of alpha-2 adrenergic that accompanies any missed doses or attempts at tapering.
receptors on platelets (Cameron et al. 1990). Hydroxyzine is also rapidly effective; however, although it
does not cause neuroadaptation, it does carry a consider-
able anticholinergic side-effect burden. Buspirone remains
Differential diagnosis a reasonable alternative but has never become particularly
popular. Pregabalin is the newest agent available for use
The most important disorder on the differential is a in this disorder, and its place in the armamentarium is not
chronic depressive episode of a major depressive disorder. as yet clear.
p 20.qxd 3/10/08 9:58 AM Page 643
References 643
REFERENCES methodologies, and future directions. J Clin Psychiatry 1993;

54(suppl. 8):29–37.
Aberg-Wistedt A, Hasselmark L, Stain-Malmgren R et al. Altschuler LL, Post RM, Leverich GS. Antidepressant-induced
Serotoninergic ‘vulnerability’ in affective disorder: a study of mania and cycle acceleration: a controversy revisited. Am J
the tryptophan depletion test and relationships between Psychiatry 1995; 152:1130–8.
peripheral and central serotonin indexes in citalopram Anderson JD, Noyes R, Crowe RR. A comparison of panic disorder
responders. Acta Psychiatr Scand 1998; 97:374–8. and generalized anxiety disorder. Am J Psychiatry 1984;
Abrams R, Taylor MA. Manic and schizoaffective disorder, manic 141:572–5.
type: a comparison. Am J Psychiatry 1976a; 133:1445–7. Andreasen NC. Negative symptoms in schizophrenia: definition
Abrams R, Taylor MA. Catatonia: a prospective clinical study. Arch and reliability. Arch Gen Psychiatry 1982; 39:784–8.
Gen Psychiatry 1976b; 33:579–81. Andreasen NC, Olson S. Negative versus positive schizophrenia:
Abrams R, Taylor MA. Importance of schizophrenic symptoms in definition and validation. Arch Gen Psychiatry 1982; 39:789–94.
the diagnosis of mania. Am J Psychiatry 1981; 138:658–61. Andreasen NC, Flaum M, Swayze VW et al. Positive and negative
Accurso V, Winnicki M, Shamsuzzaman AS et al. Predisposition to symptoms in schizophrenia: a critical reappraisal. Arch Gen
vasovagal syncope in subjects with blood/injury phobia. Psychiatry 1990a; 47:615–21.
Circulation 2001; 104:903–7. Andreasen NC, Swayze VW, Flaum M et al. Ventricular enlargement
Adams KH, Hansen ES, Pinborg LH et al. Patients with in schizophrenia: evaluation with computed tomographic
obsessive–compulsive disorder have increased 5-HT2A scanning. Arch Gen Psychiatry 1990b; 47:1008–15.
receptor binding in the caudate nuclei. Int J Andrews E, Ballard J, Walter-Ryan WG. Monosymptomatic
Neuropsychopharmacol 2005; 8:391–401. hypochondriacal psychosis manifesting as delusions of
Adler A. Neuropsychiatric complications in victims of Boston’s infestation: case studies of treatment with haloperidol. J Clin
Coconut Grove disaster. JAMA 1943; 123:1098–101. Psychiatry 1986; 47:188–90.
Ahokas A, Aito M, Turianinen S. Association between oestradiol Angst J, Felder W, Lohmeyer B. Schizoaffective disorders. I. Results
and puerperal psychosis. Acta Psychiatr 2000a; 101:167–9. of a genetic investigation. J Affect Disord 1979; 1:139–53.
Ahokas A, Aito M, Rimon R. Positive treatment effect of estradiol Anonymous. Historical notes: earliest use of the term dementia
in postpartum psychosis: A pilot study. J Clin Psychiatry praecox. Am J Psychiatry 1954; 111:470.
2000b; 61:166–9. Appleby L, Warner R, Whitton A et al. A controlled study of
Ahokas A, Kaukrnta J, Wahlbek K et al. Estrogen deficiency in fluoxetine and cognitive behavioral counselling in the
severe postpartum depression: successful treatment with treatment of postnatal depression. BMJ 1997; 314:932–6.
sublingual physiologic 17 beta-estradiol: a preliminary study. Apter A, Pauls DL, Bleich A et al. An epidemiologic study of Gilles
J Clin Psychiatry 2001; 62:332–6. de la Tourette’s syndrome in Israel. Arch Gen Psychiatry 1993;
Akbarian S, Bunney WE, Potkin SG et al. Altered distribution of 50:734–8.
nicotinamide-adenine dinucleotide phosphate-diaphorase Argyropoulos SV, Hood SD, Adrover M et al. Tryptophan depletion
cells in frontal lobe of schizophrenics implies disturbances reverses the therapeutic effect of selective serotonin reuptake
of cortical development. Arch Gen Psychiatry 1993a; inhibitors in social anxiety disorder. Biol Psychiatry 2004;
50:169–77. 56:503–9.
Akbarian S, Vinuela A, Kim JJ et al. Distorted distribution of Atmaca M, Kumru S, Tezcan E. Fluoxetine versus agnus castus
nicotinamide-adenine dinucleotide phosphate-diaphorase extract in the treatment of premenstrual dysphoric disorder.
neurons in temporal lobe of schizophrenics implies anomalous Hum Psychopharmacol 2003; 1:191–5.
cortical development. Arch Gen Psychiatry 1993b; 50:178–87. Austin MP. Puerperal affective psychosis: is there a case for
Akbarian S, Kim JJ, Potkin SG et al. Maldistribution of interstitial lithium prophylaxis? Br J Psychiatry 1992; 161:692–4.
neurons in prefrontal white matter of the brains of Baer L, Jenike MA, Ricciardi JN et al. Standardized assessment of
schizophrenic patients. Arch Gen Psychiatry 1996; 53:425–36. personality disorders in obsessive-compulsive disorder. Arch
Akiskal HS, Djenderedjian AM, Rosenthal RH et al. Cyclothymic Gen Psychiatry 1990; 47:826–30.
disorder: validating criteria for inclusion in the bipolar Baer L, Rauch SL, Ballantine HT et al. Cingulotomy for intractable
affective group. Am J Psychiatry 1977; 134:1227–33. obsessive-compulsive disorder: prospective long-term follow-
Allebeck P, Varla A, Kristjansson E et al. Risk factor for suicide up of 18 patients. Arch Gen Psychiatry 1995; 52:384–92.
among patients with schizophrenia. Acta Psychiatr Scand Bagedahl-Strindlund M. Postpartum mental illness: timing of illness
1987; 76:414–19. onset and its relation to symptoms and sociodemographic
Allgulander C. Paroxetine in social anxiety disorder: a randomized characteristics. Acta Psychiatr Scand 1986; 74:490–6.
placebo-controlled study. Acta Psychiatr Scand 1999; Bailara KM, Henry C, Lestage J et al. Decreased brain tryptophan
100:193–8. availability as a partial determinant of post-partum blues.
Allgulander C, Dahl AA, Austin C et al. Efficacy of sertraline in a Psychoneuroendocrinology 2006; 31:407–13.
12-week trial for generalized anxiety disorder. Am J Psychiatry Baker DG, West SA, Nicholson WE et al. Serial CSF corticotropin-
2004; 161:1642–9. releasing hormone levels and adrenocortical activity in combat
Altamura AC, Percudani M. The use of antidepressants for long- veterans with posttraumatic stress disorder. Am J Psychiatry
term treatment of recurrent depression: rationale, current 1999; 156:585–8.
p 20.qxd 3/10/08 9:58 AM Page 644
Baker DG, Ekhator NN, Kasckow JW et al. Higher levels of basal Beigel A, Murphy DL. Assessing clinical characteristics of the
serial CSF cortisol in combat veterans with posttraumatic manic state. Am J Psychiatry 1971a; 128:688–94.
stress disorder. Am J Psychiatry 2005; 162:992–4. Beigel A, Murphy DL. Unipolar and bipolar affective illness:
Baldessarini RJ, Tondo L, Faeda GL et al. Effects of the rate of differences in clinical characteristics accompanying
discontinuing lithium maintenance treatment in bipolar depression. Arch Gen Psychiatry 1971b; 24:215–20.
disorder. J Clin Psychiatry 1996; 57:441–8. Bell C, Forshall S, Andover M et al. Does 5-HT restrain panic?
Baldessarini RJ, Tondo L, Floris G et al. Reduced morbidity after A tryptophan depletion study in panic disorder patients
gradual discontinuation of lithium treatment for bipolar I and II recovered on paroxetine. Psychopharmacol 2002; 16:5–14.
disorders: a replication study. Am J Psychiatry 1997; 154:551–3. Benjamin J, BenZion IZ, Karbofsky E et al. Double-blind placebo-
Baldwin D, Bobes J, Stein DJ et al. Paroxetine in social controlled pilot study of paroxetine for specific phobia.
phobia/social anxiety disorder: randomized, double-blind, Psychopharmacology 2000; 149:194–6.
placebo-controlled study. Br J Psychiatry 1999; 175:120–6. Benkelfat C, Nordahl TE, Semple WE et al. Local cerebral glucose
Ball SG, Kuhn A, Wall D et al. Selective serotonin reuptake metabolic rates in obsessive-compulsive disorder: patients
inhibitor treatment for generalized anxiety disorder: a double- treated with clomipramine. Arch Gen Psychiatry 1990; 47:840–8.
blind, prospective comparison between paroxetine and Bergeron R, Ravindram AV, Chaput Y et al. Sertraline and
sertraline. J Clin Psychiatry 2005; 66:94–9. fluoxetine treatment of obsessive-compulsive disorder: results
Ballenger JC, Burows CD, DuPont RL et al. Alprazolam in panic of a double-blind, 6-month treatment study. J Clin
disorder and agoraphobia: results from a multicenter trial. I. Psychopharmacol 2002; 22:148–54.
Efficacy in short-term treatment. Arch Gen Psychiatry 1988; Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-
45:413–22. depressive disorders. Br J Psychiatry 1977; 130:330–51.
Ballenger JC, Wheadon DE, Steiner M et al. Double-blind, fixed- Best NR, Wiley M, Stump K et al. Binding of tritiated yohimbine to
dose, placebo-controlled study of paroxetine in the treatment platelets in women with maternity blues. Psychol Med 1988;
of panic disorder. Am J Psychiatry 1998; 155:36–42. 18:837–42.
Banki CM, Bissette G, Arato M et al. Elevation of immunoreactive CSF Bielski RJ, Bose A, Chang CC. A double-blind comparison of
TRH in depressed patients. Am J Psychiatry 1988; 145:1525–31. excitalopram and aroxetine in the long-term treatment of
Bao A-M, Hestiantoro A, Van Someren EJW et al. Colocalization of generalized anxiety disorder. Ann Clin Psychiatry 2005; 17:65–9.
corticotropin-releasing hormone and oestrogen receptor-alpha Birmes P, Brunet A, Carreras D et al. The predictive power of
in the paraventricular nucleus of the hypothalamus in mood peritraumatic dissociation and acute stress symptoms for
disorders. Brain 2005; 128:1301–13. posttraumatic stress symptoms: a three-month prospective
Barta PE, Pearlson GD, Powers RE et al. Auditory hallucinations study. Am J Psychiatry 2003; 160:1337–9.
and smaller superior temporal gyral volume in schizophrenia. Bisaga A, Katz JL, Antonini A et al. Cerebral glucose metabolism in
Am J Psychiatry 1990; 146:1457–62. women with panic disorder. Am J Psychiatry 1998; 155:1178–83.
Bartzokis G, Lu PH, Turner J et al. Adjunctive risperidone in the Black DW, Boffeli TJ. Simple schizophrenia: past, present and
treatment of chronic combat-related posttraumatic stress future. Am J Psychiatry 1989; 146:1267–73.
disorder. Biol Psychiatry 2005; 57:474–9. Black DW, Nasrallah H. Hallucinations and delusions in 1,715
Basoglu M, Paker M, Paker O et al. Psychological effects of patients with unipolar and bipolar affective disorders.
torture: a comparison of tortured with nontortured political Psychopathology 1989; 22:28–34.
activists in Turkey. Am J Psychiatry 1994; 151:76–81. Black DW, Noyes R, Pfohl B et al. Personality disorder in
Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar obsessive-compulsive volunteers, well comparison subjects,
affective disorder. I. Association with grade I hypothyroidism. and their first-degree relatives. Am J Psychiatry 1993;
Arch Gen Psychiatry 1990; 47:427–32. 150:1226–32.
Bauer MS, Calabrese J, Dunner DL et al. Multisite data reanalysis Bleuler E. Dementia praecox or the group of schizophrenias. New
of the validity of rapid cycling as a course modifier for bipolar York: International Universities Press, 1950.
disorder in DSM-IV. Am J Psychiatry 1994; 151:506–15. Bloch M, Schmidt PJ, Rubinow DR. Premenstrual syndrome:
Baumann B, Bogerts B. Neuroanatomical studies on bipolar evidence of symptom stability across cycles. Am J Psychiatry
disorder. Br J Psychiatry 2001; 41(suppl.):142–7. 1997; 154:1741–6.
Baxter LR, Phelps ME, Mazziotta JC et al. Local cerebral glucose Bloch M, Schmidt PJ, Danaceau M et al. Effects of gonadal
metabolic rates in obsessive-compulsive disorder: a steroids in women with a history of postpartum depression.
comparison with rates in unipolar depression and in normal Am J Psychiatry 2000; 157:924–30.
controls. Arch Gen Psychiatry 1987; 44:211–18. Bogerts B, Meertz E, Schonfeldt-Bausch R. Basal ganglia and
Baxter LR, Schwartz JM, Bergman KS et al. Caudate glucose limbic system pathology in schizophrenia: a morphometric
metabolic rate changes with both drug and behavior therapy study of brain volume and shrinkage. Arch Gen Psychiatry
for obsessive-compulsive disorder. Arch Gen Psychiatry 1992; 1985; 42:784–91.
49:681–9. Bogerts B, Falkai P, Haupts M et al. Post-mortem volume
Beck AT, Sokol L, Clark DA et al. A crossover study of focused measurements of limbic system and basal ganglia structures in
cognitive therapy for panic disorder. Am J Psychiatry 1992; chronic schizophrenics. Initial results from a new brain
149:778–83. collection. Schizophren Res 1990; 3:295–301.
p 20.qxd 3/10/08 9:58 AM Page 645
References 645
Bond TC. Recognition of acute delirious mania. Arch Gen Bunney WE, Hartmann EL. Study of a patient with a 48–hour
Psychiatry 1980; 37:553–4. manic-depressive cycle. Arch Gen Psychiatry 1965; 12:611–18.
Bonne O, Brandes D, Gilboa A et al. Longitudinal MRI study of Bunney WE, Murphy DL, Goodwin FK et al. The ‘switch process’ in
hippocampal volume in trauma survivors with PTSD. Am J manic-depressive illness. Arch Gen Psychiatry 1972;
Psychiatry 2001; 158:1248–51. 27:295–302.
Bowman KM, Raymond AF. A statistical study of hallucinations in Butler RW, Braff DL, Rausch J et al. Physiological evidence of
the manic-depressive psychoses. Am J Psychiatry 1931; 88: exaggerated startle response in a subgroup of Vietnam
299–309. veterans with combat-related posttraumatic stress disorder.
Bracha HS, Garcia-Rill E, Mrak RE et al. Postmortem locus Am J Psychiatry 1990; 147:1308–12.
coeruleus neuron count in three American veterans with Byne W, Buschbaum MS, Mattiace LA et al. Postmortem
probable or possible war-related PTSD. J Neuropsychiatry Clin assessment of thalamic nuclear volumes in subjects with
Neurosci 2005; 17:503–9. schizophrenia. Am J Psychiatry 2002; 159:59–65.
Bradwejn J, Koszycki D, Shriqui C. Enhanced sensitivity to Bystritsky A, Ackerman DL, Rosen RM et al. Augmentation of
cholecystokinin tetrapeptide in panic disorder. Clinical and sertraline reuptake inhibition in refractory obsessive-
behavioral findings. Arch Gen Psychiatry 1991; 48:603–10. compulsive disorder using adjunctive olanzapine: a placebo-
Brady K, Pearlstein T, Asnis GM et al. Efficacy and safety of controlled trial. J Clin Psychiatry 2004; 65:565–8.
sertraline treatment of posttraumatic stress disorder: a Cameron OG, Smith CB, Lee MA et al. Adrenergic status in anxiety
randomized controlled trial. JAMA 2000; 283:1837–44. disorders: platelet alpha-2-adrenergic receptor binding, blood
Brantigan CO, Brantigan TA, Joseph N. Effect of beta blockade and pressure, pulse and plasma catecholamines in panic and
beta stimulation on stage fright. Am J Med 1982; 72:88–94. generalized anxiety disorder patients and in normal subjects.
Bratfos O, Haug JO. Puerperal mental disorders in manic- Biol Psychiatry 1990; 28:2–20.
depressive females. Acta Psychiatr Scand 1966; 42:285–94. Canterbury RJ, Haskins B, Kahn N et al. Postpartum psychosis
Brawman-Mintzer O, Knapp RG, Rynn M et al. Sertraline induced by bromocriptine. South Med J 1987; 80:1463–4.
treatment for generalized anxiety disorder: a randomized, Carlson GA, Goodwin FK. The stages of mania: a longitudinal
double-blind, placebo-controlled study. J Clin Psychiatry 2006; analysis of the manic episode. Arch Gen Psychiatry 1973;
67:874–81. 28:221–8.
Bremner JD, Randall P, Scott TM et al. MRI-based measurement of Carroll BJ, Martin FI, Davis B. Pituitary-adrenal function in
hippocampal volume in patients with combat-related depression. Lancet 1968; 2:1373–4.
posttraumatic stress disorder. Am J Psychiatry 1995; Carroll BJ, Curtis GC, Mendels J. Neuroendocrine regulation in
152:973–81. depression. Arch Gen Psychiatry 1976; 33:1039–44.
Bremner JD, Vythilingam M, Vermetten E et al. MRI and PET study Casper RC, Redmond E, Katz MM et al. Somatic symptoms in
of deficits in hippocampal structure and function in women primary affective disorder: presence and relationship to the
with childhood sexual abuse and posttraumatic stress classification of depression. Arch Gen Psychiatry 1985;
disorder. Am J Psychiatry 2003; 160:924–32. 42:1098–104.
Brockington IF, Wainwright S, Kendell RE. Manic patients with Chapman TF, Fyer AJ, Mannuzza S et al. A comparison of treated and
schizophrenic or paranoid symptoms. Psychol Med 1980; untreated simple phobia. Am J Psychiatry 1993; 150:816–18.
10:73–83. Charney DS, Henninger GR, Jatlow PI. Increased anxiogenic
Brockington IF, Cernik KF, Schofield EM et al. Puerperal psychosis: effects of caffeine in panic disorders. Arch Gen Psychiatry
phenomena and diagnosis. Arch Gen Psychiatry 1981; 1985; 42:233–43.
38:829–33. Charney DS, Woods SW, Krystal JH et al. Noradrenergic neuronal
Brodaty H, Sachdev P, Rose N et al. Schizophrenia with onset dysregulation in panic disorder: the effects of intravenous
after age 50 years. I. Phenomenology and risk factors. Br J yohimbine and clonidine in panic disorder patients. Acta
Psychiatry 1999; 175:410–15. Psychiatr Scand 1992; 86:273–82.
Broocks A, Pigott TA, Hill JL et al. Acute intravenous Charron M, Fortin L, Paquette I. De novo mania among elderly
administration of ondansetron and m-CPP, alone and in people. Acta Psychiatr Scand 1991; 84:503–7.
combination, in patients with obsessive-compulsive disorder Chua SE, McKenna PJ. Schizophrenia – a brain disease? A critical
(OCD): behavioral and biological results. Psychiatry Res 1998; review of structural and functional cerebral abnormality in the
79:11–20. disorder. Br J Psychiatry 1995; 166:563–82.
Brown AS, Cohen P, Harkavy-Friedman J et al. Prenatal rubella, Clayton P, Pitts FN, Winokur G. Affective disorders. IV. Mania.
premorbid abnormalities, and adult schizophrenia. Biol Compr Psychiatry 1965; 3:313–22.
Psychiatry 2001; 49:473–86. Clomipramine Collaborative Study Group. Clomipramine in the
Brown GW, Harris TO, Hepworth C et al. Life events and treatment of patients with obsessive-compulsive disorder.
endogenous depression: a puzzle re-examined. Arch Gen Arch Gen Psychiatry 1991; 48:730–8.
Psychiatry 1994; 51:525–34. Cohen LS, Mier C, Brown EW et al. Premenstrual daily fluoxetine
Bruton CJ, Crow TJ, Frith CD et al. Schizophrenia and the brain: a for premenstrual dysphoric disorder: a placebo-controlled,
prospective clinico-pathological study. Psychol Med 1990; clinical trial using computerized diaries. Obstet Gynecol 2002;
20:285–304. 100:435–44.
p 20.qxd 3/10/08 9:58 AM Page 646
Cohen SM, Allen MG, Pollin W et al. Relationship of Denys D, van der Wee N, van Megen HJGM et al. A double blind
schizoaffective psychosis to manic-depressive psychosis and comparison of venlafaxine and paroxetine in obsessive-
schizophrenia: findings in 15,909 veteran pairs. Arch Gen compulsive disorder. J Clin Psychopharmacol 2003; 23:568–75.
Psychiatry 1972; 26:539–46. Denys D, de Geus F, van Megen HJGM et al. A double-blind,
Connor KM, Sutherland SM, Tupler LA et al. Fluoxetine in post- randomized, placebo-controlled trial of quetiapine addition in
traumatic stress disorder. Br J Psychiatry 1999; 175:17–22. patients with obsessive-compulsive disorder refractory to
Conrad AJ, Abebe T, Austin R et al. Hippocampal pyramidal cell serotonin reuptake inhibitors. J Clin Psychiatry 2004; 65:1040–8.
disarray in schizophrenia as a bilateral phenomenon. Arch Gen D’Mello DA, Pinheiro AL, Lalinet-Michaud M. Premenstrual mania:
Psychiatry 1991; 48:413–17. two case reports. J Nerv Ment Dis 1993; 181:330–1.
Cooper PJ, Murray L. Course and recurrence of postnatal Dohl RB, Wolkow RM, Clary CM. Sertraline in the treatment of
depression. Evidence for the specificity of the diagnostic panic disorder: a double-blind multicenter trial. Am J
concept. Br J Psychiatry 1995; 166:191–5. Psychiatry 1998; 155:1189–95.
Cowdry RW, Wehr TA, Zis AP et al. Thyroid abnormalities Donadio V, Liguori R, Elam M et al. Arousal elicits exaggerated
associated with rapid-cycling bipolar illness. Arch Gen inhibition of sympathetic nerve activity in phobic syncope
Psychiatry 1983; 40:414–20. patients. Brain 2007; 130:1653–7.
Cowley DS, Arana GW. The diagnostic utility of lactate sensitivity Dougherty DD, Baer L, Cosgrove GR et al. Prospective long-term
in panic disorder. Arch Gen Psychiatry 1990; 47:277–84. follow-up of 44 patients who received cingulotomy for
Coyle PK, Sterman AB. Focal neurologic symptoms in panic treatment-refractory obsessive-compulsive disorder. Am J
attacks. Am J Psychiatry 1986; 143:648–9. Psychiatry 2002; 159:269–75.
Crow TJ, Ball J, Bloom SR et al. Schizophrenia as an anomaly of Dunner DL, Fleiss JL, Fieve RR. The course of development of
development of cerebral asymmetry: a post-mortem study and mania in patients with recurrent depression. Am J Psychiatry
a proposal concerning the genetic basis of the disease. Arch 1976; 133:905–8.
Gen Psychiatry 1989; 46:1145–50. Dunner DL, Patrick V, Fieve RR. Rapid cycling manic depressive
Crowe RR, Noyes R, Pauls DL et al. A family study of panic patients. Compr Psychiatry 1977; 18:561–6.
disorder. Arch Gen Psychiatry 1983; 40:1065–9. Eisen JL, Rasmussen SA. Obsessive-compulsive disorder with
Curtis GC, Thyer B. Fainting on exposure to phobic stimuli. Am J psychotic features. J Clin Psychiatry 1993; 54:373–9.
Psychiatry 1983; 140:771–4. Elie R, Lamontagne Y. Alprazolam and diazepam in the treatment
Dahl AA, Ravindran A, Allgulander C et al. Sertraline in generalized of generalized anxiety. J Clin Psychopharmacol 1984; 4:125–9.
anxiety disorder: efficacy in treating the psychic and somatic Endicott J, Russell JM, Raskin J et al. Duoxetine treatment for role
anxiety factors. Act Pschiatr Scand 2005; 111:429–35. functioning in generalized anxiety disorder: three independent
Davidson J, Robertson E. A follow-up study of postpartum illness, studies. J Clin Psychiatry 2007; 68:518–24.
1946–1978. Acta Psychiatr Scand 1985; 71:451–7. Enkelmann R. Alprazolam versus buspirone in the treatment of
Davidson JRT, Kudler HS, Smith R et al. Treatment of outpatients with generalized anxiety disorder.
posttraumatic stress disorder with amitriptyline and placebo. Psychopharmacology 1991; 105:428–32.
Arch Gen Psychiatry 1990; 47:259–66. Extein I, Pottash AL, Gold MS et al. Differentiating mania from
Davidson J, Potts N, Richichi E et al. Treatment of social phobia schizophrenia by the TRH test. Am J Psychiatry 1980;
with clonazepam and placebo. J Clin Psychopharmacol 1993; 137:981–2.
13:423–8. Fava M, Rosenbaum JF, Pava JA et al. Anger attacks in unipolar
Davidson JRT, DuPont RL, Hedges D et al. Efficacy, safety, and depression. I. Clinical correlates and response to fluoxetine
tolerability of venlafaxine extended release and buspirone in treatment. Am J Psychiatry 1993; 150:1158–63.
outpatients with generalized anxiety disorder. J Clin Psychiatry Feinstein A, Dolan R. Predictors of post-traumatic stress disorder
1999; 60:528–35. following physical trauma: an examination of the stressor
Davidson JRT, Rothbaum BO, van der Kolk BA et al. Multicenter, criterion. Psychol Med 1991; 21:85–91.
double-blind comparison of sertraline and placebo in the Fenton WS, McGlashan TH. Natural history of schizophrenia
treatment of posttraumatic stress disorder. Arch Gen subtypes. I. Longitudinal study of paranoid, hebephrenic and
Psychiatry 2001; 58:485–92. undifferentiated schizophrenia. Arch Gen Psychiatry 1991;
Davidson JR, Weisler RH, Butterfield MI et al. Mirtazapine vs 48:969–77.
placebo in posttraumatic stress disorder: a pilot trial. Biol Fitzgerald M, Malone KM, Li S et al. Blunted serotonin response to
Psychiatry 2003; 53:188–91. fenfluramine challenge in premenstrual dysphoric disorder. Am
Davidson J, Baldwin D, Stein DJ et al. Treatment of posttraumatic J Psychiatry 1997; 154:556–8.
stress disorder with venlafaxine extended release: a 6-month Foa EB, Steketee G, Grayson JB et al. Deliberate exposure and
randomized controlled trial. Arch Gen Psychiatry 2006; blocking of obsessive compulsive rituals: immediate and long-
63:1158–65. term effect. Behav Ther 1984; 15:450–72.
Delgado PL, Charney DS, Price LH et al. Serotonin function and Foa EB, Kozak MJ, Goodman WK et al. DSM-IV field trial: obsessive-
the mechanism of antidepressant action: reversal of compulsive disorder. Am J Psychiatry 1995; 152:90–6.
antidepressant-induced remission by rapid depletion of plasma Foa EB, Liebowitz MR, Kozak MJ et al. Randomized, placebo-
tryptophan. Arch Gen Psychiatry 1990; 47:411–18. controlled trial of exposure and ritual prevention,
p 20.qxd 3/10/08 9:58 AM Page 647
References 647
clomipramine, and their combination in the treatment of Goenjian AK, Najarian LM, Pynoos RS et al. Posttraumatic stress
obsessive-compulsive disorder. Am J Psychiatry 2005; disorder in elderly and younger adults after the 1988
162:151–61. earthquake in Armenia. Am J Psychiatry 1994; 151:895–901.
Frank E, Anderson B, Reynolds CF et al. Life events and the Goenjian AK, Yehuda R, Pynoos RS et al. Basal cortisol
research diagnostic criteria endogenous subtype: a dexamethasone suppression of cortisol and MHPG in
confirmation of the distinction using the Bedford College adolescents after the 1988 earthquake in Armenia. Am J
methods. Arch Gen Psychiatry 1994; 51:519–24. Psychiatry 1996; 153:929–34.
Frank JB, Kosten TR, Giller EL et al. A randomized clinical trial of Goisman RM, Warshaw MG, Steketee GS et al. DSM-IV and the
phenelzine and imipramine for posttraumatic stress disorder. disappearance of agoraphobia without a history of panic
Am J Psychiatry 1988; 145:1289–91. disorder: new data on a controversial diagnosis. Am J
Frankel M, Cummings JL, Robertson MM et al. Obsessions and Psychiatry 1995; 152:1438–43.
compulsions in Gilles de la Tourette’s syndrome. Neurology Gordon A. Transition of obsessions into delusions. Am J Psychiatry
1986; 36:378–82. 1950; 107:455–8.
Freeman CP, Trimble MR, Deakin JF et al. Fluvoxamine versus Gorman JM, Fyer MR, Goetz R et al. Ventilatory physiology of
clomipramine in the treatment of obsessive-compulsive patients with panic disorder. Arch Gen Psychiatry 1988; 45:31–9.
disorder: a multi-center, randomized, double-blinded, parallel Grabe HJ, Ruhrmann S, Ettelt S et al. Familiarity of obsessive-
group comparison. J Clin Psychiatry 1994; 55:301–5. compulsive disorder in nonclinical and clinical subjects. Am J
Freeman EW, Rickels K, Sondheimer SJ et al. A double-blind trial Psychiatry 2006; 163:1986–92.
of oral progesterone, alprazolam and placebo in the treatment Grahame PS. Schizophrenia in old age (late paraphrenia). Br J
of severe premenstrual syndrome. JAMA 1995; 27:51–4. Psychiatry 1984; 145:493–5.
Freeman EW, Rickels K, Sondheimer SJ et al. Differential response Greenberg BD, Malone DA, Friehs GM et al. Three-year outcomes
to antidepressants in women with premenstrual in deep brain stimulation for highly resistant obsessive-
syndrome/premenstrual dysphoric disorder: a randomized compulsive disorder. Neuropsychopharmacology 2006;
controlled trial. Arch Gen Psychiatry 1999; 56:932–9. 31:2384–93.
Freeman EW, Rickels K, Yonkers KA et al. Venlafaxine in the Gregoire AJ, Kumar L, Everitt B et al. Transdermal oestrogen for
treatment of premenstrual dysphoric disorder. Obstet Gynecol treatment of severe postnatal depression. Lancet 1996;
2001; 98:737–44. 347:930–3.
Freeman EW, Rickels K, Sondheimer SJ et al. Continuous or Greist J, Chouinard G, DuBoff E et al. Double-blind parallel
intermittent dosing with sertraline for patients with severe comparison of three dosages of sertraline and placebo in
premenstrual syndrome or premenstrual dysphoric disorder. outpatients with obsessive-compulsive disorder. Arch Gen
Am J Psychiatry 2004; 161:343–51. Psychiatry 1995; 52:289–95.
Freidman MJ, Marmar CR, Baker DG et al. Randomized, double- Gupta S, Popli A, Bathurst E et al. Efficacy of cyproheptadine for
blind comparison of sertraline and placebo for posttraumatic nightmares associated with posttraumatic stress disorder.
stress disorder in a Department of Veterans Affairs setting. Compr Psychiatry 1998; 39:160–4.
J Clin Psychiatry 2007; 68:711–20. Guze SB, Woodruff RA, Clayton PJ. The significance of psychotic
Fyer AJ, Mannuzza S, Gallops MS et al. Familial transmission of affective disorders. Arch Gen Psychiatry 1975; 32:1147–50.
simple phobias and fears: a preliminary report. Arch Gen Hadley HG. A case of puerperal psychosis recovering from four
Psychiatry 1990; 47:252–6. attacks. J Nerv Ment Dis 1941; 94:540–1.
Fyer AJ, Mannuzza S, Chapman TF et al. A direct interview family Harris B. Prospective trial of L-tryptophan in maternity blues. Br J
study of social phobia. Arch Gen Psychiatry 1993; 50:286–93. Psychiatry 1980; 137:233–5.
Gelenberg AJ, Lydiard RB, Rudolph RL et al. Efficacy of venlafaxine Harris B, Lovett L, Newcombe RG et al. Maternity blues and major
extended-release capsules in nondepressed outpatients with endocrine changes: Cardiff puerperal mood and hormone
generalized anxiety disorder. JAMA 2000; 283:3082–8. study II. BMJ 1994; 308:949–53.
Geracioti TD, Baker DG, Ekhatur NN et al. CSF norepinephrine Hartley LR, Ungapen S, Davie I et al. The effect of beta adrenergic
concentrations in posttraumatic stress disorder. Am J blocking drugs on speakers’ performance and memory. Br J
Gershon ES, Hamovit J, Guroff JJ et al. A family study of Hartmann E. Longitudinal studies of sleep and dream patterns in
schizoaffective, bipolar I, bipolar II, unipolar and normal manic-depressive patients. Arch Gen Psychiatry 1968;
control probands. Arch Gen Psychiatry 1982; 39:1157–67. 19:312–29.
Gersons BPR, Carlier IVE. Post-traumatic stress disorder: the Hasselbach SG, Hansen ES, Jakosen TB et al. Reduced midbrain-
history of a recent concept. Br J Psychiatry 1992; 161:742–8. pons serotonin receptor binding in patients with obsessive-
Gillin JC, Sutton L, Ruiz C et al. The cholinergic rapid eye compulsive disorder. Acta Psychiatr Scand 2007;
movement induction test with arecoline in depression. Arch 115:388–94.
Gen Psychiatry 1991; 48:264–70. Hauri PJ, Chernik D, Hawkins D et al. Sleep of depressed patients
Goddard AW, Mason GF, Almai A et al. Reductions in occipital in remission. Arch Gen Psychiatry 1974; 31:386–91.
cortex GABA levels in panic disorder detected with 1h-magnetic Hauri PJ, Friedman M, Ravaruis CL. Sleep in patients with
resonance spectography. Arch Gen Psychiatry 2001; 58:556–61. spontaneous panic attacks. Sleep 1989; 12:323–37.
p 20.qxd 3/10/08 9:58 AM Page 648
Hay P, Sachdev P, Cummings S et al. Treatment of obsessive- Jager M, Bottlender R, Strauss A et al. Fifteen-year follow-up of
compulsive disorder by psychosurgery. Acta Psychiatr Scand ICD-10 schizoaffective disorders compared with schizophrenia
1993; 87:197–207. and affective disorders. Acta Psychiatr Scand 2004; 109:30–7.
Hayashi H, Oshino S, Ishikawa J et al. Paroxetine treatment of James IM, Griffith DNW, Pearson RM et al. Effect of oxyprenolol
delusional disorder, somatic subtype. Hum Psychopharmacol on stage-fright in musicians. Lancet 1977; 2:952–4.
2004; 19:351–2. Jampala VC, Taylor MA, Abrams R. The diagnostic implication of
Heimberg RG, Hope DA, Dodge CS et al. DSM-III-R subtypes of formal thought disorder in mania and schizophrenia: a
social phobia: comparison of generalized social phobics and reassessment. Am J Psychiatry 1989; 146:459–63.
public speaking phobics. J Nerv Ment Dis 1990; 178:172–9. Janowsky DS, El-Yousof MK, David JM et al. Parasympathetic
Heimberg RG, Liebowitz MR, Hope DA et al. Cognitive behavioral suppression of manic symptoms by physostigmine. Arch Gen
group therapy vs. phenelzine therapy for social phobia. Arch Psychiatry 1973; 28:542–7.
Gen Psychiatry 1998; 55:1133–41. Jaskiw GE, Juliano DM, Goldberg TE et al. Cerebral ventricular
Hendrick V, Altshuler L, Strouse T et al. Postpartum and non enlargement in schizophreniform disorder does not progress. A
postpartum depression: differences in presentation and seven year follow-up study. Schizophren Res 1994; 14:23–8.
response to pharmacologic treatment. Depress Anxiety 2000; Jatzko A, Rothenhofer S, Schmitt A et al. Hippocampal volume in
11:66–72. chronic posttraumatic stress disorder (PTSD): MRI study using
Hesse S, Muller U, Lincke T et al. Serotonin and dopamine two different evaluation methods. J Affect Disord 2006;
transporter imaging in patients with obsessive-compulsive 94:121–6.
disorder. Psychiatry Res 2005; 140:63–72. Jenner FA, Gjessing LR, Cox JR et al. A manic depressive psychotic
Hettema JM, Prescott CA, Kendler KS. A population-based twin with a persistent forty-eight hour cycle. Br J Psychiatry 1967;
study of generalized anxiety disorder in men and women. 113:895–910.
J Nerv Ment Dis 2001; 189:413–20. Joffe RT, Swinson RP, Regan JJ. Personality features of obsessive-
Himmelhoch JM, Mulla D, Neil JF et al. Incidence and significance compulsive disorder. Am J Psychiatry 1988; 145:1127–9.
of mixed affective states in a bipolar population. Arch Gen Johnson J. Stupor: review of 25 cases. Acta Psychiatr Scand 1984;
Psychiatry 1976; 33:1062–6. 70:370–7.
Hirayasu Y, McCarley RW, Salisbury DF et al. Planum temporale Johnson MR, Marazziti D, Brawman-Mintzer O et al. Abnormal
and Heschl gyrus volume reduction in schizophrenia: a peripheral benzodiazepine receptor density associated with
magnetic resonance imaging study of first-episode patients. generalized social phobia. Biol Psychiatry 1998; 43:306–9.
Arch Gen Psychiatry 2000; 57:692–9. Kahn RJ, McNair DM, Lipman RS et al. Imipramine and
Hoehn-Saric R, McLeod DR, Zimmerli WD. Differential effects of chlordiazepoxide in depressive and anxiety disorders. II. Efficacy
alprazolam and imipramine in generalized anxiety disorder: in anxious outpatients. Arch Gen Psychiatry 1986; 43:79–85.
somatic versus psychic symptoms. J Clin Psychiatry 1988; Kahn RS, Wetzler S. m-Chlorophenylpiperazine as a probe of
49:293–301. serotonin function. Biol Psychiatry 1991; 30:1139–66.
Hoehn-Saric R, McLeod DR, Zimmerli WD. Somatic manifestations Kasper S, Stein DJ, Loft H et al. Escitalopram in the treatment of
in women with generalized anxiety disorder. Arch Gen social anxiety disorder: randomized, placebo-controlled,
Psychiatry 1989; 46:1113–19. flexible-dosage study. Br J Psychiatry 2005; 186:222–6.
Hoehn-Saric R, McLeod DR, Hipsley PA. Effect of fluvoxamine on Katerndahl DA. Panic and prolapse: meta-analysis. J Nerv Ment
panic disorder. J Clin Psychopharmacol 1993; 13:321–6. Dis 1993; 181:539–44.
Hollander E, DeCaria CM, Nitescu A et al. Serotoninergic function Katzelnick DJ, Kobak KA, Greist JH et al. Sertraline for social
in obsessive-compulsive disorder: behavioral and phobia: a double-blind, placebo-controlled crossover study.
neuroendocrine responses to m-chlorophenylpiperazine and Am J Psychiatry 1995; 152:1368–71.
fenfluramine in patients and healthy volunteers. Arch Gen Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal
Psychiatry 1992; 49:21–8. psychoses. Br J Psychiatry 1987; 150:662–73.
Hollander E, Koran LM, Goodman WK et al. A double-blind, Kendell RE, Juszczak E, Cole SK. Obstetric complications and
placebo-controlled study of the efficacy and safety of schizophrenia: a case control study based on standardized
controlled-release fluvoxamine in patients with obsessive- obstetric records. Br J Psychiatry 1996; 168:556–61.
compulsive disorder. J Clin Psychiatry 2003a; 64:640–7. Kendler KS. The nosological validity of paranoia (simple delusional
Hollander E, Allen A, Steiner M et al. Acute and long-term disorder): a review. Arch Gen Psychiatry 1980; 37:699–706.
treatment and prevention of relapse of obsessive-compulsive Kendler KS. Kraepelin and the diagnostic concept of paranoia.
disorder with paroxetine. J Clin Psychiatry 2003b; Compr Psychiatry 1988; 29:4–11.
64:1113–21. Kendler KS, Gruenberg AM. An independent analysis of the Danish
Horwarth E, Lish JD, Johnson J et al. Agoraphobia without panic: Adoption Study of Schizophrenia. IV. The relationship between
clinical reappraisal of an epidemiologic finding. Am J psychiatric disorders as defined by DSM-III in the relatives and
Psychiatry 1993; 150:1496–501. adoptees. Arch Gen Psychiatry 1984; 41:555–64.
Insel TR, Akiskal HS. Obsessive-compulsive disorder with psychotic Kendler KS, Gruenberg AM, Strauss JS. An independent analysis of
features: a phenomenologic analysis. Am J Psychiatry 1986; the Copenhagen sample of the Danish Adoption Study of
143:1527–33. Schizophrenia. III. The relationship between paranoid
p 20.qxd 3/10/08 9:58 AM Page 649
References 649
psychosis (delusional disorder) and the schizophrenia spectrum Kreczmanski P, Heinsen H, Mantua V et al. Volume, neuron
disorders. Arch Gen Psychiatry 1982; 38:985–7. density and total neuron number in five subcortical regions in
Kendler KS, Masterson CC, Davis KL. Psychiatric illness in first- schizophrenia. Brain 2007; 130:678–92.
degree relatives of patients with paranoid psychosis, Krong MH, Apter J, Asnis G et al. Placebo-controlled multicenter
schizophrenia and medical illness. Br J Psychiatry 1985; study of sertraline treatment for obsessive-compulsive
147:524–31. disorder. J Clin Psychopharmacol 1999; 19:172–6.
Kendler KS, Neale MC, Kessler RC et al. Generalized anxiety Kuevi V, Causon R, Dixson AF et al. Plasma amine and hormone
disorder in women: a population-based twin study. Arch Gen changes in ‘post-partum blues’. Clin Endocrinol 1983;
Psychiatry 1992; 49:267–72. 19:39–46.
Kendler KS, McGuire M, Gruenberg AM et al. An epidemiologic, Kumar R, Issacs S, Meltzer E. Recurrent post-partum psychosis: a
clinical and family study of simple schizophrenia in County model for prospective clinical investigation. Br J Psychiatry
Roscommon, Ireland. Am J Psychiatry 1994a; 151:27–34. 1983; 142:618–20.
Kendler KS, McGuire M, Gruenberg AM et al. Outcome and family Kupfer DJ, Frank E, Perel JM et al. Five-year outcome for
study of the subtypes of schizophrenia in the West of Ireland. maintenance therapies in recurrent depression. Arch Gen
Am J Psychiatry 1994b; 151:849–56. Psychiatry 1992; 49:769–73.
Kendler KS, McGuire M, Gruenberg AM et al. Examining the Laakmann G, Schule C, Lorkowski G et al. Buspirone and
validity of DSM-III-R schizoaffective disorder and its putative lorazepam in the treatment of generalized anxiety disorder in
subtypes in the Roscommon family study. Am J Psychiatry outpatients. Psychopharmacology 1998; 136:357–66.
1995; 152:755–64. Lader M, Scotto JC. A multicentre double-blind comparison of
Kennedy HG, Kemp LI, Dyer DE. Fear and anger in delusional hydroxyzine, buspirone and placebo in patients with
(paranoid) disorder: the association with violence. Br J generalized anxiety disorder. Psychopharmacology 1998;
Psychiatry 1992; 160:488–92. 139:402–6.
Kety SS. The significance of genetic factors in the etiology of Landen M, Nissbrandt H, Allgulander C et al. Placebo-controlled
schizophrenia: results from the national study of adoptees in trial comparing intermittent and continuous paroxetine in
Denmark. J Psychiatr Res 1987; 21:423–9. premenstrual dysphoric disorder. Neuropsychopharmacology
Kieseppa T, Partonen T, Haukka J et al. High concordance of 2007; 32:153–61.
bipolar I disorder in a nationwide sample of twins. Am J Lanzenberger RR, Mitterhauser M, Spindelegger C et al. Reduced
Psychiatry 2004; 161:1814–21. serotonin-1A receptor binding in social anxiety disorder. Biol
King DJ, Burke M, Lucas RA. Antipsychotic drug-induced Psychiatry 2007; 61:1081–9.
dysphoria. Br J Psychiatry 1995; 167:480–2. Lauren TM, Labouriau R, Licht RW et al. Family history of
Kinzie JD, Fredrickson RH, Ben R et al. Posttraumatic stress psychiatric illness as a risk factor for schizoaffective disorder:
disorder among survivors of Cambodian concentration camps. A Danish register-based cohort study. Arch Gen Psychiatry
Am J Psychiatry 1984; 141:645–50. 2005; 62:841–8.
Klein DF. False suffocation alarms, spontaneous panics, and Lee KA, Vaillant GE, Torrey WC et al. A 50-year prospective study
related conditions: an integrative hypothesis. Arch Gen of the psychological sequelae of World War II combat. Am J
Kohl C, Walch T, Huber R et al. Measurement of tryptophan, Lelliott P, Marks I, McNamee G et al. Onset of panic disorder with
kynurenine and neopterin in women with and without agoraphobia. Arch Gen Psychiatry 1989; 46:1000–8.
postpartum blues. J Affect Disord 2005; 86:135–42. Li X, May RS, Tolbert LC et al. Risperidone and haloperidol
van der Kolk BA, Dreyfuss D, Michaels M et al. Fluoxetine in augmentation of serotonin reuptake inhibitors in refractory
posttraumatic stress disorder. J Clin Psychiatry 1994; obsessive-compulsive disorder: a crossover study. J Clin
55:517–22. Psychiatry 2005; 66:736–43.
Koopman C, Classen C, Spiegel D. Predictors of posttraumatic Liden S, Gottfries CG. Beta-blocking agents in the treatment of
stress symptoms among survivors of the Oakland/Berkeley, catecholamine-induced symptoms in musicians. Lancet 1974;
Calif., firestorm. Am J Psychiatry 1994; 151:888–94. 2:529.
Koran LM, McElroy SL, Davidson JR et al. Fluvoxamine versus Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of
clomipramine for obsessive-compulsive disorder: a double- antipsychotic drugs in patients with chronic schizophrenia.
blind comparison. J Clin Psychopharmacol 1996; 16:121–9. N Engl J Med 2005; 353:1209–23.
Kotin J, Goodwin FK. Depression during mania: clinical Liebowitz MR, Fyer AJ, Gorman JM et al. Lactate provocation of
observations and theoretical implications. Am J Psychiatry panic attacks. I. Clinical and behavioral findings. Arch Gen
1972; 129:679–86. Psychiatry 1984; 41:764–70.
Kraepelin E. Dementia praecox and paraphrenia, 1919. Liebowitz MR, Schneier F, Campeas R et al. Phenelzine versus
Huntington, New York: Robert E. Krieger, 1971. atenolol in social phobia: a placebo-controlled comparison.
Kraepelin E. Manic-depressive insanity and paranoia, 1921. New Arch Gen Psychiatry 1992; 39:290–300.
York: Arno Press, 1976. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended
Kramer BA. Depressive pseudodementia. Compr Psychiatry 1982; release vs placebo and paroxetine in social anxiety disorder.
p 20.qxd 3/10/08 9:58 AM Page 650
Lindauer RJ, Olff M, van Meijel EP et al. Cortisol, learning, memory Mannuzza S, Schneier FR. Chapman TF et al. Generalized social
and attention in relation to smaller hippocampal volume in phobia: reliability and validity. Arch Gen Psychiatry 1995;
police officers with posttraumatic stress disorder. Biol 52:230–7.
Psychiatry 2006; 59:171–7. Marks IM, Gelder MG. Different ages of onset in varieties of
Lipkin KM, Dyrud J, Meyer GD. The many faces of mania; phobia. Am J Psychiatry 1966; 123:218–21.
therapeutic trial of lithium carbonate. Arch Gen Psychiatry Maron E, Kuikka JT, Shlik J et al. Reduced brain serotonin
1970; 22:262–7. transporter binding in patients with panic disorder. Psychiatry
Llorca P-M, Spadone C, Sol L et al. Efficacy and safety of Res 2004; 132:173–81.
hydroxyzine in the treatment of generalized anxiety disorder: Marshall RD, Beebe KL, Oldham M et al. Efficacy and safety of
a 3-month double-blind study. J Clin Psychiatry 2002; paroxetine treatment for chronic PTSD: a fixed-dose, placebo-
63:1020–7. controlled study. Am J Psychiatry 2001; 158:1982–8.
Londborg PD, Wolkow R, Smith WT et al. Sertraline in the Marten PA, Brown TA, Barlow DH et al. Evaluation of the ratings
treatment of panic disorder. Br J Psychiatry 1998; 173:54–60. comprising the associated symptom criteria of DSM-III-R
Loudon JB, Blackburn IM, Ashworth CM. A study of the generalized anxiety disorder. J Nerv Ment Dis 1993; 181:676–82.
symptomatology and course of manic illness using a new Martenyi F, Brown EB, Zhang H et al. Fluoxetine versus placebo in
scale. Psychol Med 1977; 7:723–9. posttraumatic stress disorder. J Clin Psychiatry 2002;
Lykouras E, Malliargas D, Christdoulou GN et al. Delusional 63:199–206.
depression: phenomenology and response to treatment. Acta Martenyi F, Brown EB, Caldwell CD. Failed efficacy of fluoxetine
Psychiatr Scand 1986; 73:324–9. in the treatment of posttraumatic stress disorder: results of a
McAllister TW, Price TRP. Severe depressive pseudodementia with fixed-dose. placebo-controlled study. J Clin Psychopharmacol
and without dementia. Am J Psychiatry 1982; 139:626–9. 2007; 27:166–70.
McDougle CJ, Goodman WK, Leckman JF et al. Haloperidol Massana G, Serra-Grabulosa JM, Salgado-Pineda P et al.
addition to fluvoxamine-refractory obsessive-compulsive Parahippocampal gray matter density in panic disorder: a
disorder: a double-blind, placebo-controlled study in patients voxel-based morphometric study. Am J Psychiatry 2003a;
with and without tics. Arch Gen Psychiatry 1994; 51: 160:566–8.
302–8. Massana G, Serra-Grabulosa JM, Salgado-Pineda P et al.
McDougle CJ, Epperson CN, Pelton GH et al. A double-blind, Amygdalar atrophy in panic disorder patients detected by
placebo-controlled study of risperidone addition in serotonin volumetric magnetic resonance imaging. Neuroimage 2003b;
reuptake inhibitor-refractory obsessive-compulsive disorder. 19:80–90.
Arch Gen Psychiatry 2000; 57:794–801. Mavissakalian MR, Perel JM. Imipramine dose-response
McElroy SL, Keck PE, Pope HG et al. Clinical and research relationship in panic disorder with agoraphobia: preliminary
implications of the diagnosis of dysphoric or mixed mania. Am findings. Arch Gen Psychiatry 1989; 46:127–31.
J Psychiatry 1992; 149:1633–44. Mellman TA, Uhde TW. Sleep panic attacks: new clinical findings
McFarlane AC. The aetiology of post-traumatic morbidity: and theoretical implications. Am J Psychiatry 1989a;
predisposing, precipitating and perpetuating factors. Br J 146:1204–7.
Psychiatry 1989; 154:221–8. Mellman TA, Uhde TW. Electroencephalographic sleep in panic
McGlashan TH. The Chestnut Lodge Follow-Up Study. II. Long- disorder: focus on sleep-related panic attacks. Arch Gen
term outcome of schizophrenia and the affective disorders. Psychiatry 1989b; 46:178–89.
Arch Gen Psychiatry 1984; 41:586–601. Mellman TA, Uhde TW. Patients with frequent sleep panic: clinical
McGlashan TH, Carpenter WT. Postpsychotic depression in findings and response to medication treatment. J Clin
schizophrenia. Arch Gen Psychiatry 1976; 33:231–9. Psychiatry 1990; 51:513–16.
McGuffin P, Katz R, Watkins S et al. A hospital-based twin Mendlewicz J, Rainer JD. Adoption study supporting genetic
register of the heritability of DSM-IV unipolar depression. Arch transmission in manic-depressive illness. Nature 1977;
Gen Psychiatry 1996; 53:129–36. 268:327–9.
McHarg JF. Mania in childhood: report of a case. Arch Neurol Menkes DB, Coates DC, Fawcett JP. Acute tryptophan depletion
Psychiatry 1954; 72:531–9. aggravates premenstrual syndrome. J Affect Disord 1994;
Maj M, Pirozzi R, DiCaprio EL. Major depression with mood- 32:37–44.
congruent psychotic features: a distinct diagnostic entity or a Menon RR, Barta PE, Aylward EH et al. Posterior superior temporal
more severe subtype of depression? Acta Psychiatr Scand gyrus in schizophrenia: grey matter changes and clinical
1990; 82:439–44. correlates. Schizophren Res 1995; 16:127–35.
Manaye KF, Lei DL, Tizabi Y et al. Selective neuron loss in the Metz A, Stump K, Cowen PJ et al. Changes in platelet alpha 2-
paraventricular nucleus of hypothalamus in patients suffering autoreceptor binding post partum: possible relation to
from major depression and bipolar disorder. J Neuropathol Exp maternity blues. Lancet 1983; 1:495–8.
Neurol 2005; 64:224–9. Michelson D, Allgulander C, Dantendorfer K et al. Efficacy of usual
Mandel MR, Severe JB, Schooler NR et al. Development and antidepressant dosing regimens of fluoxetine in panic
prediction of postpsychotic depression in neuroleptic-treated disorder: randomized, placebo-controlled trial. Br J Psychiatry
schizophrenia. Arch Gen Psychiatry 1982; 39:197–203. 2001; 179:514–18.
p 20.qxd 3/10/08 9:58 AM Page 651
References 651
Mitchell C. Successful treatment of chronic delusional Oehrberg S, Christiansen PE, Behnke K et al. Paroxetine in the
parasittosis. Br J Psychiatry 1989; 155:556–7. treatment of panic disorder: a randomized, double-blind,
Mitchell PB, Wilhelm K, Parker G et al. The clinical features of placebo-controlled study. Br J Psychiatry 1995; 167:374–9.
bipolar depression: a comparison with matched major Opjordsmoen R, Rettersol N. Delusional disorder: the predictive
depressive patients. J Clin Psychiatry 2001; 62:212–16. validity of the concept. Acta Psychiatr Scand 1991; 84:250–4.
Modigh K, Westberg P, Eriksson E. Superiority of clomipramine Page AC. Distinguishing panic disorder and agoraphobia from
over imipramine in the treatment of panic disorder: a placebo- social phobia. J Nerv Ment Dis 1994; 182:611–17.
controlled trial. J Clin Psychopharmacol 1992; 12:251–61. Palatnik A, Frolov K, Fux M et al. Double-blind, controlled,
Montgomery SA, Tobias K, Zornberg GL et al. Efficacy and safety crossover trial of inositol versus fluvoxamine for the treatment
of pregabalin in the treatment of generalized anxiety disorder: of panic disorder. J Clin Psychopharmacol 2001; 21:335–9.
a 6-week multicenter, randomized, double-blind, placebo- Pande AC, Davidson JRT, Jefferson JW et al. Treatment of social
controlled comparison of pregabalin and venlafaxine. J Clin phobia with gabapentin: a placebo-controlled study. J Clin
Psychiatry 2006; 67:771–82. Psychopharmacol 1999; 19:341–8.
Morrison JR. Catatonia: retarded and excited types. Arch Gen Pande AC, Feltner DE, Jefferson JW et al. Efficacy of the novel
Psychiatry 1973; 28:39–41. anxiolytic pregabalin in social anxiety disorder: a placebo-
Moses EL, Mallinger AG. St. John’s wort: three cases of possible controlled, multicenter study. J Clin Psychopharmacol 2004;
mania induction. J Clin Psychopharmacol 2000; 20:115–17. 24:141–9.
Mueser KT, Bellack AS, Brady EU. Hallucinations in schizophrenia. Pauls DL, Alsobrook JP, Goodman W et al. A family study of
Acta Psychiatr Scand 1990; 82:26–9. obsessive-compulsive disorder. Am J Psychiatry 1995;
Munoz RA. Postpartum psychosis as a discrete entity. J Clin 152:76–84.
Psychiatry 1985; 46:182–4. Pearlstein TB, Stone AB. Long-term fluoxetine treatment of late
Murray RM. Neurodevelopmental schizophrenia: the rediscovery of luteal phase dysphoric disorder. J Clin Psychiatry 1994;
dementia praecox. Br J Psychiatry 1994; 165(suppl. 25):6–12. 55:332–5.
Nappi RE, Petraglia F, Luisi S et al. Serum allopregnanolone in Pearlstein TB, Stone AB, Lund SA et al. Comparison of fluoxetine,
women with postpartum ‘blues’. Obstet Gynecol 2001; 97:77–80. bupropion, and placebo in the treatment of premenstrual
Nemeroff CB, Widerlow E, Bissete G et al. Elevated concentrations dysphoric disorder. J Clin Psychopharmacol 1997; 17:261–6.
of CSF corticotropin-releasing factor-like immunoreactivity in Pecknold JC, Swinson RP, Krich K et al. Alprazolam in panic
depressed patients. Science 1984; 226:1342–4. disorder and agoraphobia: results from a multicenter trial. III.
Newman SC, Bland RC. A population-based family study of DSM-III Discontinuation effects. Arch Gen Psychiatry 1988; 45:429–36.
generalized anxiety disorder. Psychol Med 2006; 36:1275–81. Perani D, Colombo C, Bressi S et al. [18F]FDG PET study in
Ninan PT, Koran LM, Kiev A et al. High-dose sertraline strategy for obsessive-compulsive disorder: a clinical/metabolic correlation
nonresponders to acute treatment of obsessive-compulsive study after treatment. Br J Psychiatry 1995; 166:244–50.
disorder; a multicenter double-blind trial. J Clin Psychiatry Perlis ML, Smith MT, Orff HJ et al. The effects of orally
2006; 67:15–22. administered cholinergic agonists on REM sleep in major
Nisita C, Petracca A, Akiskal HS et al. Delimitation of generalized depression. Biol Psychiatry 2002; 51:457–62.
anxiety disorder: clinical comparisons with panic and major Perlmutter SJ, Leitman SF, Garvey MA et al. Therapeutic plasma
depressive disorder. Compr Psychiatry 1990; 31:409–15. exchange and intravenous immunoglobulin for obsessive-
Nopoulos P, Torres I, Flaun M et al. Brain morphology in first- compulsive disorder and tic disorders in childhood. Lancet
episode schizophrenia. Am J Psychiatry 1995; 152:1721–3. 1999; 354:1153–8.
Nordahl TE, Semple WE, Gross M et al. Cerebral glucose metabolic Pfohl B, Vaquez N, Nasrallah H. Unipolar vs. bipolar mania: a
differences in patients with panic disorder. review of 247 patients. Br J Psychiatry 1982; 141:453–8.
Neuropsychopharmacology 1990; 3:261–72. Pigott TA, Pato MT, Bernstein SE et al. Controlled comparisons of
North CS, Smith EM, Spitznagel EL. Posttraumatic stress disorder clomipramine and fluoxetine in the treatment of obsessive-
in survivors of a mass shooting. Am J Psychiatry 1994; compulsive disorder: behavioral and biological results. Arch
151:82–8. Gen Psychiatry 1990; 47:926–32.
Noyes R, Crowe RR, Harris EL et al. Relationship between panic Pitman RK, Orr SP, Forgue DF et al. Psychophysiologic assessment
disorder and agoraphobia. A family study. Arch Gen Psychiatry of post-traumatic stress disorder imagery in Vietnam combat
1986; 43:227–32. veterans. Arch Gen Psychiatry 1987; 44:970–5.
Noyes R, Clarkson C, Crow RR et al. A family study of generalized Pitt B. Maternity blues. Br J Psychiatry 1973; 122:431–3.
anxiety disorder. Am J Psychiatry 1987; 144:1019–24. Pohl R, Yeragani VK, Balon R et al. Isoproterenol-induced panic
Noyes R, Burows GD, Reich JH et al. Diazepam versus alprazolam attacks. Biol Psychiatry 1988; 24:891–902.
for the treatment of panic disorder. J Clin Psychiatry 1996; Pollack MH, Zaninelli R, Goddard A et al. Paroxetine in the
57:349–55. treatment of generalized anxiety disorder: results of a
Nutt DJ, Glue P, Lawson C et al. Flumazenil provocation of panic placebo-controlled, flexible-dosage trial. J Clin Psychiatry
attacks: evidence for altered benzodiazepine receptor 2001; 62:350–7.
sensitivity in panic disorder. Arch Gen Psychiatry 1990; Pope HG, Lipinski JF, Cohen BM et al. ‘Schizoaffective disorder’, an
47:917–25. invalid diagnosis? A comparison of schizoaffective disorder,
p 20.qxd 3/10/08 9:58 AM Page 652
schizophrenia and affective disorder. Am J Psychiatry 1980; double-blind, placebo-controlled trial of pregabalin and
137:921–7. alprazolam. Arch Gen Psychiatry 2005; 62:1022–33.
Prange AJ, Lara PP, Wilson IC et al. Effect of thyrotropin-releasing Rioux L, Nissanov J, Lauber K et al. Distribution of microtubule-
hormone in depression. Lancet 1972; 2:999–1002. associated protein MAP2-immunoreactive interstitial neurons
Prien RF, Kupfer DJ. Continuation drug therapy for major in the parahippocampal white matter in subjects with
depression episodes: how long should it be maintained? Am J schizophrenia. Am J Psychiatry 2003; 160:149–55.
Psychiatry 1986; 143:18–23. Roberts GW, Colter N, Lofthouse RM et al. Is there gliosis in
Quitkin FM, McGrath PJ, Stewart JW et al. Chronological schizophrenia? Investigation of the temporal lobe. Biol
milestones to guide drug change. When should clinicians Psychiatry 1987; 22:1459–68.
switch antidepressants? Arch Gen Psychiatry 1996; 53:785–92. Roca CA, Schmidt PJ, Smith MJ et al. Effects of metergoline on
Raadsheer FC, van Heerikhuize JJ, Lucassen PJ et al. symptoms in women with premenstrual dysphoric disorder.
Corticotropin-releasing hormone mRNA in the paraventricular Am J Psychiatry 2002; 159:1876–81.
nucleus of patients with Alzheimer’s disease and depression. Rocca P, Beoni AM, Eva C et al. Peripheral benzodiazepine
Am J Psychiatry 1995; 152:1372–6. receptor messenger RNA is decreased in lymphocytes of
Rabins PV, Merchant A, Nestadt G. Criteria for diagnosing generalized anxiety disorder patients. Biol Psychiatry 1998;
reversible dementia caused by depression: validation by 2-year 43:767–73.
follow-up. Br J Psychiatry 1984; 144:488–92. Rohde LA, Busnello E, Wolf A et al. Maternity blues in Brazilian
Ramsey R, Gorst-Unsworth C, Turner S. Psychiatric morbidity in women. Acta Psychiatr Scand 1997; 95:231–5.
survivors of state violence including torture. Br J Psychiatry Rosenbaum JF, Moroz G, Bowden CL et al. Clonazepam in the
1993; 162:55–9. treatment of panic disorder with or without agoraphobia: a
Raskind MA, Peskind ER, Kanter ED et al. Reduction of nightmares dose–response study of efficacy, safety and discontinuance.
and other PTSD symptoms in adult veterans by prazosin: a J Clin Psychopharmacol 1997; 17:390–6.
placebo-controlled study. Am J Psychiatry 2003; 160:371–3. Rosenthal NE, Rosenthal LN, Stallone F et al. Psychosis as a
Raskind MA, Peskind EF, Hoff DJ et al. A parallel group placebo predictor of response to lithium maintenance treatment in
controlled study of prazosin for trauma nightmares and sleep bipolar affective disorder. J Affect Disord 1979; 1:237–45.
disturbances in combat veterans with post-traumatic stress Rosenthal NE, Rosenthal LN, Stallone F et al. Toward the
disorder. Biol Psychiatry 2007; 61:928–34. validation of RDC schizoaffective disorder. Arch Gen Psychiatry
Rasmussen SA, Tsuang MT. Clinical characteristics and family 1980; 37:804–10.
history in DSM-III obsessive-compulsive disorder. Am J Roy-Byrne PR, Weingartner H, Bierer LM et al. Effortful and
Psychiatry 1986; 143:317–22. automatic cognitive processes in depression. Arch Gen
Reich DB, Winternitz S, Hennen J et al. A preliminary study of Psychiatry 1986; 43:265–7.
risperidone in the treatment of posttraumatic stress disorder Rush AJ, Erman MK, Giles DE et al. Polysomnographic findings in
related to childhood abuse in women. J Clin Psychiatry 2004; recently drug free and clinically remitted depressed patients.
Reimherr FW, Amsterdam JD, Quitkin FM et al. Optimal length of Rush AJ, Giles DE, Schlesser MA et al. Dexamethasone response,
continuation therapy in depression: a prospective assessment thyrotropin-releasing hormone stimulation, rapid eye
during long-term fluoxetine treatment. Am J Psychiatry 1998; movement latency and subtypes of depression. Biol Psychiatry
155:1247–53. 1997; 41:915–28.
Rickels K, Schweizer E, Csanalosi I et al. Long-term treatment of Russell JL, Kushner MG, Beitman BD et al. Nonfearful panic
anxiety and risk of withdrawal: prospective comparison of disorder in neurology patients validated by lactate challenge.
clorazepate and buspirone. Arch Gen Psychiatry 1988; Am J Psychiatry 1991; 148:361–4.
45:444–50. Saxena S, Brody AL, Ho ML et al. Differential cerebral metabolic
Rickels K, Schweizer E, Weiss S et al. Maintenance drug treatment changes with paroxetine treatment of obsessive-compulsive
for panic disorder. II. Short- and long-term outcome after drug disorder vs major depression. Arch Gen Psychiatry 2002;
taper. Arch Gen Psychiatry 1993a; 50:61–8. 59:250–61.
Rickels K, Downing R, Schweizer E et al. Antidepressants for the Schellenberg R. Treatment for the premenstrual syndrome with
treatment of generalized anxiety disorder: a placebo- agnus castus fruit extract: prospective, randomized, placebo
controlled comparison of imipramine, trazodone and controlled study. BMJ 2001; 322:134–7.
diazepam. Arch Gen Psychiatry 1993b; 50:884–95. Schneier FR, Liebowitz MR, Abi-Dargham A et al. Low dopamine
Rickels K, Pollack MH, Sheehan DV et al. Efficacy of extended- D(2) receptor binding potential in social phobia. Am J
release venlafaxine in nondepressed outpatients with generalized Psychiatry 2000; 157:457–9.
anxiety disorder. Am J Psychiatry 2000; 157:968–74. Schruers K, van Diest R, Overbeek T et al. Acute L-5-
Rickels K, Zaninelli R, McCafferty J et al. Paroxetine treatment of hydroxytryptophan administration inhibits carbon-dioxide-
generalized anxiety disorder: a double-blind, placebo- induced panic in panic disorder patients. Psychiatry Res 2002;
controlled study. Am J Psychiatry 2003; 160:745–56. 113:237–43.
Rickels K, Pollack MH, Feltner DE et al. Pregabalin for treatment Schweizer E, Pohl R, Balon R et al. Lorazepam vs. alprazolam in the
of generalized anxiety disorder. A 4-week, multicenter, treatment of panic disorder. Pharmacopsychiatry 1990; 23:90–3.
p 20.qxd 3/10/08 9:58 AM Page 653
References 653
Shalev AY, Orr SP, Peri T et al. Physiologic responses to loud tones Steiner M, Steinberg S, Stewart D et al. Fluoxetine in the
in Israeli patients with posttraumatic stress disorder. Arch Gen treatment of premenstrual dysphoria. N Engl J Med 1995;
Psychiatry 1992; 49:870–5. 332:1529–34.
Shalev AY, Peri T, Cangetti L et al. Predictors of PTSD in injured Steketee F, Foa EB, Grayson JB. Recent advances in the behavioral
trauma survivors: a prospective study. Am J Psychiatry 1996; treatment of obsessive-compulsives. Arch Gen Psychiatry
153:219–25. 1982; 39:1365–71.
Shenton ME, Kikinis R, Jolesz FA et al. Abnormalities of the left Stern RS, Cobb JP. Phenomenology of obsessive-compulsive
temporal lobe and thought disorder in schizophrenia: a neurosis. Br J Psychiatry 1978; 132:233–9.
quantitative magnetic resonance imaging study. N Engl J Med Stevens JW. Manic-depressive insanity, with the report of a
1992; 327:604–12. typical case. J Nerv Ment Dis 1904; 31:513–25.
Shugart YY, Samuels J, Willour VL et al. Genomewide linkage scan Stewart DE. Prophylactic lithium in postpartum affective
for obsessive-compulsive disorder: evidence for susceptibility psychosis. J Nerv Ment Dis 1988; 176:485–9.
loci on chromosomes 3q, 7p, 15q, and 6q. Mol Psychiatry Strohle A, Kellner M, Yassouridis A et al. Effect of flumazenil in
2006; 11:736–70. lactate-sensitive patients with panic disorder. Am J Psychiatry
Shulman KI, Tohen M. Unipolar mania revisited: evidence from an 1998; 155:610–12.
elderly cohort. Br J Psychiatry 1994; 164:547–9. Stunkard AJ, Fernstrom MH, Price A et al. Direction of weight gain
Siris SG, Morgan V, Fagerstrom R et al. Adjunctive imipramine in in recurrent depression: consistency across episodes. Arch Gen
the treatment of postpsychotic depression: a controlled trial. Psychiatry 1990; 47:857–60.
Arch Gen Psychiatry 1987; 44:533–9. Suddah RL, Casanova MF, Goldberg TE et al. Temporal lobe
Sitaram N, Gillen JC, Bunney WE. The switch process in manic- pathology in schizophrenia: a quantitative magnetic
depressive illness: circadian variation in time of switch and resonance imaging study. Am J Psychiatry 1989; 146:464–72.
sleep and manic ratings before and after switch. Acta Summers WK. Mania with onset in the eighth decade: two cases
Psychiatr Scand 1978; 58:267–78. and a review. J Clin Psychiatry 1983; 44:141–3.
Smith KA, Fairburn CG, Cowen PJ. Relapse of depression Susser ES, Lin SP. Schizophrenia after prenatal exposure to the
after rapid depletion of tryptophan. Lancet 1997; 349: Dutch Hunger Winter of 1944–1945. Arch Gen Psychiatry
915–19. 1992; 49:983–8.
Southwick SM, Krystal JH, Morgan CA et al. Abnormal Swedo SE, Leonard HL, Garvey M et al. Pediatric autoimmune
noradrenergic function in post-traumatic stress disorder. Arch neuropsychiatric disorders associated with streptococcal
Gen Psychiatry 1993; 50:31–7. infections: clinical description of the first 50 cases. Am J
Sramek JJ, Tansman M, Suri A et al. Efficacy of buspirone in Psychiatry 1998; 155:264–71.
generalized anxiety disorder with coexisting mild depressive Tancer ME, Mailman RB, Stein MB et al. Neuroendocrine
symptoms. J Clin Psychiatry 1996; 57:287–91. responsivity to monoaminergic system probe in generalized
Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic social phobia. Anxiety 1994; 1:216–23.
disorder; a randomized, double-blind, placebo-controlled trial. Taylor FB, Lowe K, Thompson C et al. Daytime prazosin reduces
J Clin Psychiatry 2003; 64:1322–7. psychological distress to trauma specific cues in civilian
Starcevic V, Fallon S, Uhlenhuth EH. The frequency and severity of trauma posttraumatic stress disorder. Biol Psychiatry 2006;
generalized anxiety disorder symptoms: toward a less 59:577–81.
cumbersome conceptualization. J Nerv Ment Dis 1994; Taylor MA, Abrams R. The phenomenology of mania: a new
182:80–4. look at some old patients. Arch Gen Psychiatry 1973;
Starkstein SE, Petraca G, Teson A et al. Catatonia in depression: 29:520–2.
prevalence, clinical correlates, and validation of a scale. Taylor MA, Abrams R. Catatonia: prevalence and importance in
J Neurol Neurosurg Psychiatry 1996; 60:326–32. the manic phase of manic-depressive illness. Arch Gen
Stein DJ, Anderson EW, Tonnoir B et al. Escitalopram in obsessive- Psychiatry 1977; 34:1223–5.
compulsive disorder: a randomized, placebo-controlled, Terao T. Subclinical hypothyroidism in recurrent mania. Biol
paroxetine-referenced, fixed-dose, 24-week study. Curr Med Psychiatry 1993; 38:853–4.
Res Opin 2007; 23:701–11. Tesar GE, Rosenbaum JF, Pollack MH et al. Double-blind, placebo-
Stein MB, Liebowitz MD, Lydiard RB et al. Paroxetine treatment of controlled comparison of clonazepam and alprazolam for
generalized social phobia (social anxiety disorder). JAMA panic disorder. J Clin Psychiatry 1991; 52:69–76.
1998; 280:708–13. Thase ME. Relapse and recurrence in unipolar major depression:
Stein MB, Fyer AJ, Davidson JRT et al. Fluvoxamine treatment of short-term and long-term approaches. Compr Psychiatry 1990;
social phobia (social anxiety disorder): a double-blind, 51(suppl. 26):51–7.
placebo-controlled study. Am J Psychiatry 1999; Tienari P, Wynne LC, Laksy K et al. Genetic boundaries of the
156:756–60. schizophrenic spectrum: evidence from the Finnish adoptive
Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI- family study. Am J Psychiatry 2003; 160:1587–94.
resistant combat-related PTSD: a double-blind, placebo- Tiihonen J, Kuikka J, Bergstrom K et al. Dopamine reuptake site
controlled study. Am J Psychiatry 2002; densities in patients with social phobia. Am J Psychiatry
159:1777–9. 1997a; 154:239–42.
p 20.qxd 3/10/08 9:58 AM Page 654
References 654
Tiihonen J, Kuikka J, Rasanen P et al. Cerebral benzodiazepine Wade AG, Lepola U, Koponen HJ et al. The effect of citalopram
receptor binding and distribution in generalized anxiety in panic disorders. Br J Psychiatry 1997; 170:549–53.
disorder: a fractal analysis. Mol Psychiatry 1997b; 2:463–71. Walker E, Lewine RJ. Prediction of adult-onset schizophrenia from
Tollefson GD, Rampey AH, Potvin JH et al. A multicenter childhood home movies of the patients. Am J Psychiatry 1990;
investigation of fixed-dose fluoxetine in the treatment of 147:1052–6.
obsessive-compulsive disorder. Arch Gen Psychiatry 1994; Watson CG, Kucala T, Manifold V et al. Differences between post
51:559–67. traumatic stress disorder patients with delayed and undelayed
Torgerson S. Comorbidity of major depression and anxiety onset. J Nerv Ment Dis 1988; 176:568–72.
disorders in twin pairs. Am J Psychiatry 1990; 147:1199–202. Watson S, Gallagher P, Ritchie JC et al. Hypothalamic-pituitary-
Tsuang MT. Suicide in schizophrenics, manics, depressives, and adrenal axis function in patients with bipolar disorder. Br J
surgical controls: a comparison with general population Psychiatry 2004; 184:496–502.
suicide mortality. Arch Gen Psychiatry 1978; 35:153–5. Watt JAG. The relationship of paranoid states to schizophrenia.
Tsuang MT, Woolson RF, Fleming JA. Long-term outcome of major Am J Psychiatry 1985; 142:1456–8.
psychoses. I. Schizophrenia and affective disorders compared Wertham FI. A group of benign psychoses: prolonged manic
with psychiatrically symptom-free surgical controls. Arch Gen excitements. Am J Psychiatry 1929; 86:17–78.
Psychiatry 1979; 36:1295–304. Winokur G. Delusional disorder (paranoia). Compr Psychiatry
Tsuang MT, Faraone SV, Fleming JA. Familial transmission of 1977; 18:511–21.
major affective disorders: is there evidence supporting the Winokur G. Psychosis in bipolar and unipolar affective illness with
distinction between unipolar and bipolar disorders? Br J special reference to schizo-affective disorder. Br J Psychiatry
Psychiatry 1985; 146:268–71. 1984; 145:236–42.
Tucker P, Zaninelli R, Yehuda R et al. Paroxetine in the treatment of Winokur G. Familial psychopathology in delusional disorder.
chronic posttraumatic stress disorder: results of a placebo- Compr Psychiatry 1985; 26:241–8.
controlled, flexibile dosage trial. J Clin Psychiatry 2001; 62:860–8. Winokur G, Tsuang MT. Elation versus irritability in mania. Compr
Tuke DH. Imperative ideas. Brain 1894; 17:179–97. Psychiatry 1975; 16:435–6.
Turner SW, Toone BK, Brett-Jones JR. Computerized tomographic Winokur G, Clayton PJ, Reich T. Manic depressive illness. St. Louis,
scan changes in early schizophrenia – preliminary findings. MO: Mosby, 1969.
Psychol Med 1986; 16:219–25. Winokur G, Coryell W, Endicott J et al. Further distinction
Van Dyke C, Zilberg NJ, McKinnon JA. Posttraumatic stress between manic-depressive illness (bipolar disorder) and
disorder: a thirty-year delay in a World War II veteran. Am J primary depressive disorder (unipolar depression). Am J
Van Putten T. The many faces of akathisia. Compr Psychiatry Wisner KL, Peindel KS, Gigliotti T et al. Obsessions and
1975; 16:43–7. compulsions in women with postpartum depression. J Clin
Van Putten T, May PRA. ‘Akinetic depression’ in schizophrenia. Psychiatry 1999; 60:17–80.
Arch Gen Psychiatry 1978; 35:1101–7. Wisner KL, Perel JM, Peindel KS et al. Prevention of postpartum
Van Putten T, Multalipassi LR, Malkin MD. Phenothiazine-induced depression: a randomized clinical trial. J Clin Psychiatry 2001;
decompensation. Arch Gen Psychiatry 1974; 30:102–5. 62:82–6.
Van Valkenburg C, Winokur G, Behar D et al. Depressed women Wisner KL, Perel JM, Peindel KS et al. Prevention of postpartum
with panic attacks. J Clin Psychiatry 1984; 45:367–9. depression: a pilot randomized clinical trial. Am J Psychiatry
Versiani M, Nardi AE, Mundim FD et al. Pharmacotherapy of social 2004; 161:1290–2.
phobia: a controlled study with moclobemide and phenelzine. Wisner KL, Hanusa BH, Perel JM et al. Postpartum depression: a
Br J Psychiatry 1992; 161:353–60. randomized trial of sertraline versus nortriptyline. J Clin
Videbech T. Chronic olfactory paranoid syndromes. Acta Psychiatr Psychopharmacol 2006; 26:353–60.
Scand 1966; 42:183–213. Woodward SH, Kaloupek DG, Streeter CC et al. Hippocampal
Viguera AC, Nonacs R, Cohen LS et al. Risk of recurrence of volume, PTSD, and alcoholism in combat veterans. Am J
bipolar disorder in pregnant and nonpregnant women after Psychiatry 2006; 163:674–81.
discontinuing lithium maintenance. Am J Psychiatry 2000; Yalom ID, Lunde DT, Moos RH et al. ‘Postpartum blues’ syndrome:
157:179–84. a description and related variables. Arch Gen Psychiatry 1968;
Villarreal G, Hamilton DA, Petropoulos H et al. Reduced 18:16–27.
hippocampal volume and total white matter volume in Yehuda R, Southwick SM, Krystal JH et al. Enhanced suppression
posttraumatic stress disorder. Biol Psychiatry 2002; 52:119–25. of cortisol following dexamethasone administration in
van Vliet IM, den Boer JA, Westenberg HG. posttraumatic stress disorder. Am J Psychiatry 1993;
Psychopharmacological treatment of social phobia: a double 150:83–6.
blind placebo controlled study with fluvoxamine. Yehuda R, Golier JA, Hallian SL et al. The ACTH response to
Psychopharmacology 1994; 115:128–34. dexamethasone in PTSD. Am J Psychiatry 2004;
Wada T, Kawakatsu S, Nadaoka T et al. Clomipramine treatment 161:1397–403.
of delusional disorder, somatic type. Int Clin Psychopharmacol Yonkers KA, Halbreich U, Freeman E et al. Symptomatic
1999; 14:181–3. improvement of premenstrual dysphoric disorder with
p 20.qxd 3/10/08 9:58 AM Page 655
References 655
sertraline treatment: a randomized controlled trial. JAMA Young SA, Hurt PH, Benedek DM et al. Treatment of premenstrual
1997; 278:983–8. dysphoric disorder with sertraline during the luteal phase: a
Young EA, Breslau N. Cortisol and catecholamines in randomized, double-blind, placebo-controlled crossover trial. J
posttraumatic stress disorder: an epidemiologic community Clin Psychiatry 1998; 59:76–80.
study. Arch Gen Psychiatry 2004; 61:394–401. Zohar J, Judge R. Paroxetine versus clomipramine in the
Young KA, Holcomb LA, Yazdani U et al. Elevated neuron number treatment of obsessive-compulsive disorder. Br J Psychiatry
in the limbic thalamus in major depression. Am J Psychiatry 1996; 169:468–74.
2004; 161:1270–7.
p 21.qxd 3/10/08 9:58 AM Page 656
21
Substance use disorders
21.1 Stimulants 656 21.8 Cannabis 670

21.2 Cocaine 657 21.9 Opioids 671
21.3 Hallucinogens 659 21.10 Nicotine 673
21.4 Phencyclidine and ketamine 660 21.11 Caffeine 675
21.5 Alcohol 661 21.12 Methanol 675
21.6 Sedatives, hypnotics, and anxiolytics 667 21.13 Isopropanol 676
21.7 Inhalents (solvents) 669 References 677
21.1 STIMULANTS there may be a hypertensive encephalopathy. Regardless of

the degree of intoxication, most patients recover within
Of the many stimulants that are used for intoxication, hours to a day or so.
amphetamine, dextroamphetamine, and methamphet- In some cases, delusions and hallucinations, rather than
amine are most commonly utilized; some patients may also being fleeting, may dominate the clinical picture of the
abuse methylphenidate. These drugs may be taken orally intoxication, and in some of these cases, such symptoms
or, after being crushed and dissolved, intravenously. may persist beyond the resolution of the intoxication, thus
Occasionally they may be ‘snorted’ intranasally, and puri- yielding a stimulant-induced psychosis. Although this is
fied methamphetamine (‘ice’) may also be smoked. typically seen only with intravenous stimulant use, it has
been reported after high-dosage oral use. In this psychosis
(Angrist and Gershon 1970; Bell 1973; Derlet et al. 1989;
Clinical features Ellinwood 1967; Griffith et al. 1972; Iwanami et al. 1994)
patients experience delusions of persecution and reference,
Mild intoxication (Hollister and Gillespie 1970) is charac- and, in some cases, hallucinations, which may in turn be
terized by increased energy, varying degrees of elation, either auditory or visual. In some cases there may be bizarre
increased self-confidence, and talkativeness; the pupils are delusions, including Schneiderian first rank symptoms
dilated, the blood pressure, both systolic and diastolic, is (Janowsky and Risch 1979). Rarely, patients with delusions
increased, the heart rate may be increased or reflexively of persecution have resorted to murder to ‘protect’ them-
decreased, and the deep tendon reflexes are diffusely brisk. selves (Ellinwood 1971). This amphetamine-induced psy-
With more severe intoxication there may be agitation and chosis generally clears within a matter of days or weeks, but
some bizarre behavior: often patients take a particular it may occasionally last many months. Those who resume
interest in things mechanical, and hours may be spent first daily use of stimulants may display ‘sensitization’, in which
taking apart, and then trying to put back together, various the psychosis recurs at progressively lower and lower doses.
items, such as clocks, radios, televisions, etc. Fleeting delu- With chronic use of stimulants, both tolerance and
sions of persecution and auditory hallucinations may withdrawal may occur. With the development of tolerance,
occur. In severe intoxication a delirium may ensue, with patients require ever larger doses to achieve euphoria, in
confusion, incoherence, and disorientation. Abnormal some cases up to several grams daily. A withdrawal syn-
movements, such as bruxism, chorea (Lundh and Tunving drome (Kramer et al. 1967; Watson et al. 1972) may appear
1981), and, in some cases, generalized dystonia, may occur; with abstinence after long-term use, and is characterized
intracerebral hemorrhage has also been reported by irritability, fatigue, suicidal ideation, and sleep distur-
(Harrington et al. 1983; Yen et al. 1994) and grand mal bance, either hypersomnia or less commonly insomnia.
seizures may also occur. The temperature rises, there may This ‘crash’, as the withdrawal syndrome is often referred
be extreme diaphoresis, and patients may experience nausea, to, typically undergoes considerable clearing within days or
vomiting, abdominal cramping, and diarrhea. Arrhythmias a week or more; however, mild symptomatology may
may appear, and with severe elevations of blood pressure linger for weeks or months.
p 21.qxd 3/10/08 9:58 AM Page 657
21.2 Cocaine 657
Course Withdrawal symptomatology, if severe and accomp-

anied by suicidal ideation, may require hospitalization.
Recreational use of stimulants is not uncommon, and such Pharmacologic treatment is generally not indicated.
occasional use generally causes few, if any, consequences. The overall treatment of stimulant addiction has as its
Some patients may develop an abusive pattern of use, how- goal abstinence. Hospitalization is often required to break
ever, and continue to seek intoxication despite suffering the pattern of use, and long-term involvement with groups
social or legal consequences. Addiction is said to occur when such as Cocaine Anonymous or Narcotics Anonymous
a craving develops for the stimulant, accompanied by the may be helpful.
phenomena of tolerance and withdrawal; such patients may
use stimulants on a daily basis, in relatively modest doses, or
display a ‘binge’ pattern (Kramer et al. 1967), in which they 21.2 COCAINE
use ever-escalating doses until, after a matter of days or
more, they either run out of money or become so debilitated Several different preparations of cocaine are available ille-
that they have to stop, after which they suffer through a gally. Cocaine hydrochloride is a white powder that may be
withdrawal syndrome before going on yet another binge. insufflated (‘snorted’) into the nasal passages where it is
absorbed through the nasal mucosa; it is also water soluble
and thus may be dissolved and injected intravenously.
Etiology Cocaine hydrochloride is destroyed by heat and is thus not
suitable for smoking; it may, however, be treated with
It appears that the euphoria seen with stimulants occurs sodium bicarbonate and then either extracted with ether to
secondary to dopamine release within the ventral striatum yield a ‘free base’ preparation or warmed to create a ‘rock’
(Drevets et al. 2001), whereas the autonomic symptom- of ‘crack’ cocaine. Both the free base and crack prepara-
atology is mediated by enhanced noradrenergic tone tions evaporate with heating and thus may be smoked.
(Nurnberger et al. 1984).
Clinical features
The onset of intoxication varies according to the prepara-
Intoxication with cocaine may be clinically indistinguish- tion used; after snorting, peak levels are reached within
able from stimulant intoxication, and the differential may 30–60 minutes, whereas after intravenous injection or
rest on history or drug screening. smoking, peak levels occur within seconds, creating a
Lacking a history (as is often the case, given the deceit and much more intense intoxication. During intoxication
denial seen in many cases), the elation and talkativeness of (Kleber and Gawin 1984), patients become euphoric,
the intoxication may suggest mania, and the irritability, hyperalert, talkative, and grandiose. Hyperactivity is com-
fatigue, and sleep disturbance of withdrawal may suggest mon, and with higher doses agitation may occur
depression. Drug screening is helpful here; however, obser- (Fischman et al. 1976). Some patients may experience
vation in a controlled environment will also tell the tale, as visual hallucinations, and these are typically of insects,
the symptoms resolve over the expected time period. which are often referred to as ‘cocaine bugs’; these halluci-
The stimulant-induced psychosis represents one of the nations may be accompanied by tactile hallucinations of
toxic psychoses, discussed in Section 7.1, and is suggested bugs crawling beneath the skin, and some patients may
by its emergence during an intoxication and its resolution excoriate themselves in an attempt to ‘get’ them. With mild
during enforced abstinence. intoxication libido increases, and in males there may be
delayed ejaculation; with more severe intoxication, how-
ever, there may be erectile dysfunction. In severe intoxica-
Treatment tion, especially after intravenous use or smoking, a
delirium may occur, with confusion, incoherence, lability,
Intoxication, if mild, may be managed with simple obser- and delusions and hallucinations. Other symptoms and
vation. In severe cases one may utilize an antipsychotic signs include mydriasis, hypertension, headache, nausea
such as haloperidol, in a dose of approximately 5 mg, either and vomiting, tachycardia, and arrhythmias or cardiac
as the concentrate or parenterally, with repeat doses every arrest (Hsue et al. 2007). Uncommonly, there may be
hour or so until the patient is calm, limiting side-effects occur chorea (‘crack dancing’) (Daras et al. 1994), tics (Pascual-
or a maximum dose of approximate 20 mg is reached. Leone and Dhuna 1990), myocardial infarction (Virmani
Stimulant psychosis may be treated with an antipsy- et al. 1988), rhabdomyolysis (Roth et al. 1988), stroke (due
chotic, such as haloperidol (5–10 mg) or risperidone to infarction, intracerebral hemorrhage or subarachnoid
(2–4 mg), with the understanding that the medication hemorrhage [Klonoff et al. 1989; Lichtenfeld et al. 1986;
may, given the natural course of the disorder, be eventually Nolte et al. 1996]), and, with chronic, repeated use, a cere-
discontinued. bral vasculitis (Fredericks et al. 1991; Krendel et al. 1990).
p 21.qxd 3/10/08 9:58 AM Page 658
658 Substance use disorders
Intoxication after snorting cocaine lasts from 30 to 60 min- characterized by ‘binges’, lasting anywhere from hours to a
utes, whereas after intravenous administration or smoking week, during which cocaine may be injected or smoked very
it lasts only 5–20 minutes. frequently, sometimes every 10 or 15 minutes; with such
Cocaine is rapidly metabolized by plasma and hepatic frequent use, however, the euphoria of the intoxication
esterases to such inactive metabolites as benzoylecgonine, becomes progressively briefer and the crashes progressively
and this metabolite may be found in the urine for up to a more severe, until finally either exhaustion or a lack of
week; of note, in some cases the level of this metabolite funds ends the binge. The intervals between binges vary
may fluctuate, such that a ‘negative’ urine test may occa- widely, from only a few days to up to weeks or months.
sionally be followed by a ‘positive’ one (Burke et al. 1990).
Shortly after resolution of the intoxication, most patients
will experience a ‘crash’, lasting from hours to a day, charac- Etiology
terized by fatigue, depressed mood, irritability, and anxiety.
Given that this ‘crash’ may occur with first-time use of Within the central nervous system cocaine both inhibits
cocaine as well as after widely spaced repeat intoxications, it the reuptake and facilitates the release of monoamines by
may not be appropriate to consider it a withdrawal syn- pre-synaptic neurons. Although both serotonin and nor-
drome. Clear-cut withdrawal, however, does occur with epinephrine are involved, it appears that the euphoriant
chronic use and indeed may appear after only a few days of effects of cocaine are related to the increased concentration
heavy use. The withdrawal symptoms (Weddington et al. of dopamine at the terminals of the mesolimbic and meso-
1990) include not only those seen in the ‘crash’ but also cortical dopaminergic pathways.
anhedonia, hyperphagia, insomnia, and, often, suicidal
ideation; furthermore, during withdrawal there is typically a
tense craving for more cocaine. This withdrawal reaches a
maximum of severity within a few days and then gradually A clinical differentiation of cocaine intoxication from
remits over days or weeks. Rarely, dystonia may appear dur- stimulant intoxication may not be possible, and the differ-
ing withdrawal (Choy-Kwong and Lipton 1989). ential often rests on history or a drug screen.
Tolerance may develop rapidly with repeated use; Withdrawal may suggest depression and, when the his-
indeed, with a ‘run’ of intravenous use, tolerance may tory of cocaine use is unavailable, the differential may rest
appear within a day. Unfortunately, this tolerance applies on observation in a controlled environment, which will
only to the euphoriant effects of cocaine and not to its reveal the fairly rapid resolution of symptoms.
potentially lethal cardiovascular effects. The diagnosis of a persistent cocaine psychosis is gener-
After approximately two or more years of frequent cocaine ally straightforward as it is difficult to hide the history of
use, intoxications may become characterized by delusions chronic cocaine addiction. If, however, this history is not
of persecution and of reference, and by auditory hallucina- available, then the differential for psychosis, as discussed in
tions (Brady et al. 1991; Rosse et al. 1994; Satel et al. 1991; Section 7.1, must be pursued.
Sherer et al. 1988). Although initially these symptoms tend
to resolve shortly after the intoxication resolves (Brady
et al. 1991), over time, and with repeated episodes, they Treatment
appear with lower doses and also tend to last much longer
(Bartlett et al. 1997), in some cases creating a psychosis that For most cases of intoxication and post-intoxication
may persist for weeks (Manschreck et al. 1987), despite ‘crashes’, simple observation is sufficient. Even in cases of
abstinence. severe intoxication with delirium, observation, given the
brevity of the intoxication, is again generally all that is
required; if, however, agitation is severe, one may give a
Course dose of parenteral haloperidol in a dose of 5–10 mg.
Patients with severe withdrawal and suicidal ideation may
Recreational use of cocaine, that is occasional intoxications require hospitalization to protect themselves; hospitaliza-
without consequences, is generally seen only with ‘snort- tion may also be required in cases of cocaine abuse or
ing’. Abusive use, with legal, social, and medical conse- addiction to effect a period of abstinence, during which
quences, may also occur with snorting but is more common other measures may be initiated.
when cocaine is taken intravenously or smoked. Cocaine is The overall goal of treatment of cocaine abuse or addic-
one of the most, perhaps the most, addictive substances in tion is abstinence from cocaine and other substances, such
the world, and craving may develop rapidly, leading to as alcohol, benzodiazepines, and opioids. Patients may be
chronic, frequent use and the development of tolerance and referred to organizations such as Cocaine Anonymous or
withdrawal. When addiction does set in, the pattern of Narcotics Anonymous, and some may undergo cognitive
cocaine use may be either continuous or episodic. behavioral therapy. The efficacy of pharmacologic treatment
Continuous use is characterized by daily intoxication, for cocaine addiction is uncertain. Earlier claims for the
either via snorting, injection, or smoking. Episodic use is effectiveness of dopaminergic agents, such as amantadine,
p 21.qxd 3/10/08 9:58 AM Page 659
21.3 Hallucinogens 659
levodopa or direct-acting dopaminergic agents (e.g., bromo- quite intense ‘rush’, which is then followed by a heightened
criptine) have not survived attempts at replication. More sense of empathy and connectedness with others. Second,
recent work has focused on other agents, such as modafinil it has become immensely popular, especially among young
(Dackis et al. 2005), baclofen (Shoptaw et al. 2003), disulfi- adults who may use it during all-night parties known as
ram (Carroll et al. 2004), tiagabine (Gonzalez et al. 2007), ‘raves’. Third, in addition to the possibility of a ‘bad trip’
topiramate (Kampman et al. 2004), and ondansetron (Kosten and Price 1992; Liester et al. 1992; Whitaker-
(Johnson et al. 2006), but, in my opinion, experience with Azmita and Aronson 1989; Winstock 1991), MDMA may
these more recent pharmacologic approaches is as yet too cause significant complications, including arrhythmias,
limited to warrant their widespread use. cardiac arrest, severe hyponatremia, hyperpyrexia, rhab-
domyolysis with renal failure, and hepatitis (Fahal et al.
1992; Greene et al. 2003; Hartung et al. 2002; Shearman et
al. 1992). In addition to these immediately obvious seque-
21.3 HALLUCINOGENS lae, there is also evidence that MDMA may cause long-
lasting, and perhaps permanent, short-term memory loss
The hallucinogens (also known as psychotomimetics) can
(Bolla et al. 1998; Gouzoulis-Mayfrank et al. 2000;
be roughly divided into two groups, namely the indolealky-
Zakzanis et al. 2001).
lamines and the phenylalkylamines. Of the indolealky-
Tolerance develops rapidly to the intoxicating effects of
lamines, the prototype is lysergic acid diethylamide (LSD);
all of the hallucinogens (with the sole exception of DMT),
other members include psilocybin, dimethyltryptamine
and most patients must wait a few days before they can
(DMT), and 5-methoxy-N,N-diisopropyltryptamine (‘Foxy’).
again achieve intoxication (Isbell et al. 1956). Interestingly,
Among the phenylalkylamines, mescaline is the prototype,
despite the occurrence of tolerance, withdrawal phenom-
and this is joined by numerous other compounds including
ena do not occur.
dimethoxymethylamphetamine (DOM), dimethoxyam-
A small minority of patients may develop certain seque-
phetamine (DMA), methylenedioxyamphetamine (MDA),
lae after intoxication, including flashbacks, mood changes,
3,4-methylenedioxy-N-ethylamphetamine (MDEA or
or a psychosis.
‘Eve’), and the very popular 3,4-methylenedioxymetham-
Flashbacks (Abraham 1983; Frosch et al. 1965; Horowitz
phetamine (MDMA or ‘Ecstasy’). With the exception of
1969) may occur in up to one-quarter of patients, during
DMT, which must be insufflated, smoked, or injected
which, although not intoxicated, patients re-experience one
(Strassman et al. 1994a,b), all of the hallucinogens are active
or more of the symptoms that occurred during a prior
orally and are usually taken in this fashion.
intoxication; classically, patients experience visual halluci-
nations, which may be complex or quite simple, or may
consist of ‘trailing’, a kind of palinopsia in which after-
Clinical features images follow along after patients divert their gaze away
from an object. As with the hallucinations occurring during
Intoxication begins within 20–60 minutes after oral inges- intoxication, patients retain insight and recognize the flash-
tion and is characterized by a profound, ‘cosmic’ sense, backs as unreal. Flashbacks may occur spontaneously or
without any drowsiness or sedation (Bercel et al. 1956; may be precipitated by moving into a darkened area or by
Freedman 1968; Hollister et al. 1960; Isbell et al. 1956; the use of alcohol, cannabis, or an antipsychotic drug.
Ungerleider et al. 1966). Patients may experience vivid Flashbacks may be infrequent or occur multiple times daily,
memories, and commonplace events may appear exceed- and they may remit spontaneously after a few weeks or
ingly meaningful. Visual illusions and hallucinations are months or persist indefinitely. When flashbacks occur fre-
common, and a minority may experience synesthesiae or quently, chronically, and cause distress, by convention one
simple auditory hallucinations; importantly, patients speaks of ‘hallucinogen persisting perception disorder’.
maintain insight during intoxication and recognize the Mood changes may appear shortly after intoxication
hallucinations as being unreal. Mild degrees of tachycardia, resolves, generally within a few days, and may consist of
elevated blood pressure, mydriasis, fine tremor, hyper- depression or, less commonly, mania. These mood changes
reflexia, and poor coordination may be seen, and the tem- are typically quite brief, lasting in the order of days, and only
perature may be elevated. In a minority of cases the rarely weeks, after which patients return to their baseline.
intoxication may turn into a ‘bad trip’, with the develop- Psychosis (McGuire et al. 1994) may emerge with reso-
ment of severe anxiety, which may be accompanied by lution of the intoxication; it is generally characterized by
delusions of persecution and of reference (Kuramochi and one or more of the hallucinations or delusions seen during
Takahashi 1964). Most intoxications last in the order of the intoxication, with the critical difference that insight is
6–24 hours; exceptions include psilocybin and DMT, lost and patients now experience them as real and react to
which produce shorter intoxications lasting 2–6 hours. them accordingly. Although this ‘hallucinogen-induced
Intoxication with MDMA (‘Ecstasy’) deserves special psychotic disorder’ generally remits spontaneously after a
mention for several reasons. First, unlike the other hallu- few days, in a small minority it may persist for weeks,
cinogens, intoxication is characterized by an initial, often months, or longer.
p 21.qxd 3/10/08 9:58 AM Page 660

Recreational use of hallucinogens is very common among Intoxication with phencyclidine may be roughly character-
adolescents and young adults; it is typically confined to ized as mild, moderate, or severe; ketamine is less potent
occasional use without consequences at parties or social than phencyclidine and only rarely produces the severe
gatherings. Hallucinogen abuse, that is repeated use and potentially life-threatening intoxication not uncom-
despite significant consequences, is relatively rare. Neither monly seen with phencyclidine. Both of these drugs may be
craving nor, as pointed out earlier, withdrawal occur, and ingested, ‘snorted’ intranasally, smoked, or injected.
addiction is not seen. Mild intoxication (Javitt and Zukin 1991; Luby et al.
1959; McCarron et al. 1981; Meyer et al. 1959; Pearlson
1981; Weiner et al. 2000) is characterized by euphoria and
Etiology a peculiar sense of detachment or dissociation. Patients
may feel as if they are floating, and their bodies may, to
All of the hallucinogens exhibit complex agonist and them, appear misshapened. Lability, agitation, or lethargy
antagonist effects at either pre- or post-synaptic serotonin may appear, and behavior may become bizarre and unpre-
receptors, and in the case of MDMA there may be destruc- dictable, with violence in some cases. Patients may com-
tion of serotoninergic neurons (McCann et al. 1998; plain of nausea, vomiting, or vertigo, and examination may
Ricaurte et al. 1988). disclose dysarthria, ataxia, nystagmus (which may be rota-
tory, horizontal, or vertical), myoclonus, tremor, increased
deep tendon reflexes, decreased pin-prick sensation in the
Differential diagnosis extremities, and autonomic signs, such as an elevated tem-
perature, tachycardia, an elevated respiratory rate, elevated
Mild intoxication with phencyclidine may be quite similar blood pressure, diaphoresis, and flushing; rather than
to that seen with hallucinogens, but is suggested by nystag- mydriasis, however, one typically sees miosis.
mus, dysarthria, and ataxia. Moderate intoxication is characterized by a delirium,
Hallucinogen-induced flashbacks, mood changes, and which may be accompanied by delusions and visual hallu-
psychosis are all indicated by the preceding intoxication. cinations (Allen and Young 1978). Abnormal movements
When this history is lacking, disorders noted in the differ- may appear, including facial grimacing, posturing, stereo-
ential diagnosis for hallucinations, depression, mania, and typies, dystonia, and opisthotonus; grand mal seizures may
psychosis may be considered. also occur (Alldredge et al. 1989). Agitation may be
extreme, and in some cases rhabdomyolysis occurs, with
renal failure.
Treatment Severe intoxication is characterized by stupor or coma
(McCarron et al. 1981). In stupor, patients may be quite still
‘Bad trips’ may be managed by supportive observation; in or may evidence random, purposeless movements;
some cases lorazepam may be helpful. Post-intoxication myoclonus is frequent and the deep tendon reflexes are
mood changes, if severe, may require hospitalization for sup- greatly increased. With even higher doses coma supervenes;
portive care until they run their course. Post-intoxication this is a kind of ‘coma vigil’ in which the eyes are open and
psychosis may likewise require hospitalization and, if pro- the patient appears vigilant, but shows no response to pain
longed, may be treated with an antipsychotic such as olanza- or to anything else. The temperature rises further, as does
pine. Flashbacks generally do not require treatment but, if the blood pressure, and in some cases a hypertensive
frequent and troubling, consideration may be given to the encephalopathy occurs. The electroencephalogram (EEG)
use of clonazepam in a dose of 2 mg daily (Lerner et al. 2003). in these cases shows profound generalized slowing.
The duration of intoxication with ketamine, which has
a half-life of about 3 hours, is approximately 4–6 hours.
21.4 PHENCYCLIDINE AND KETAMINE Phencyclidine intoxication is longer for two reasons. First,
the half-life of phencyclidine is longer, anywhere from 7 to
Phencyclidine and its closely related derivative ketamine are 20 hours. Second, phencyclidine is a weak base and hence
both arylcyclohexylamines that were developed as ‘dissocia- is ‘trapped’ in the stomach; phencyclidine is also lipophilic
tive’ anesthetics. The frequent occurrence of post-operative and is therefore taken up into adipocytes. Thus protected
psychosis with phencyclidine has led to its abandonment in from hepatic metabolism, phencyclidine may linger for
medical practice; however, ketamine is still used, both as an prolonged periods, and indeed may be detectable in the
anesthetic and as an analgesic. Both drugs are used as intox- blood for weeks or longer after a single dose. Overall,
icants, and the use of ketamine in this regard appears to be intoxication with phencyclidine tends to last from half a
on the rise. Phencyclidine is also known as PCP, ‘angel dust’, day up to many days and, during the overall resolution of
‘hog’, and ‘peace pill’, and ketamine may be referred to as phencyclidine intoxication, the clinical picture may fluctu-
‘K’, ‘special K’, ‘vitamin K’, ‘cat valium’, ‘kat’ or ‘kit-kat’. ate fairly widely.
p 21.qxd 3/10/08 9:58 AM Page 661
21.5 Alcohol 661
Tolerance does not appear to occur and it is unclear if a the characteristic signs seen in arylcyclohexylamine intoxi-
withdrawal syndrome exists. Some patients, shortly after cation, including dysarthria, ataxia, and nystagmus; fur-
resolution of the intoxication, may complain of a ‘letdown’ thermore, in hallucinogen intoxication one sees mydriasis
lasting a day or so, with dysphoria, irritability, and insom- rather than the miosis of arylcyclohexylamine intoxication.
nia; however, as this can occur after the first dose of either In the absence of a history of ingestion, the delirium of
drug, and does not worsen with prolonged use, it is proba- moderate intoxication and the stupor or coma of severe
bly not appropriate to consider it a withdrawal syndrome. intoxication may present a diagnostic puzzle in the emer-
A minority of patients may experience persistent seque- gency room, with the differential being pursued as out-
lae after intoxication, including mood changes, psychosis, lined in Section 5.3.
delirium, or dementia. Although these are described below The various post-intoxication sequelae are suggested by
as discrete entities, it must be borne in mind that individ- the history of intoxication; lacking this, the differential
ual patients may at times have a mixture of these sequelae. expands, as discussed in the sections on the respective syn-
Mood changes tend toward mania, and manic symp- dromes.
toms may persist for days to a week or more. Depression
may also occur but tends to be seen only in long-term,
heavy users; such depressions may be relatively long-lasting, Treatment
persisting sometimes for many weeks.
Psychosis is characterized by a persistence of the delu- Intoxicated patients should be observed in a supervised
sions and hallucinations that are seen in moderate degrees setting. Patients should be separated from unnecessary
of intoxication; although this syndrome tends to resolve stimulation, and isolation in a quiet, dimly lit, well-
spontaneously within days to a week or so, there are rare protected room with constant monitoring is often best;
reports of a chronic psychosis occurring after heavy use of unlike hallucinogen-intoxicated patients, arylcyclohexy-
phencyclidine. lamine-intoxicated patients do not respond well to verbal
Delirium, as noted earlier, may be seen during moderate support, and cannot be ‘talked down’. Restraints may be
intoxication, and this may persist beyond the resolution of required but should be used sparingly given that patients
other signs and symptoms, lasting from days up to a week. who struggle against them may undergo worse rhabdomy-
Dementia constitutes a rare sequela of prolonged and olysis (Lahmeyer and Stock 1983). Agitation, delusions,
very heavy use of phencyclidine, and this may persist for and hallucinations, if problematic, may be treated with an
months and up to a year or more, despite abstinence. antipsychotic such as haloperidol (Giannini et al. 1984).
Patients may develop decreased short-term memory, con- Dystonia, if severe, and opisthotonus may be treated with
creteness, an expressive aphasia, and a personality change intravenous lorazepam, and seizures may be treated with
with dysphoria, irritability, and impulsivity. intravenous lorazepam and, if repetitive, fosphenytoin.
Vigorous general medical care may be required for hyper-
Course thermia, hypertension, and rhabdomyolysis.
In the case of phencyclidine, which is ‘trapped’ in the
Occasional recreational use of either phencyclidine or ket- gastric fluid, consideration may be given to treatment with
amine, without consequences, is not uncommon in late activated charcoal followed by continuous nasogastric suc-
adolescence or early adult years. Prolonged and repeated tioning.
use, despite medical or social consequences, appears The treatment of the various post-intoxication sequelae
uncommon, and such abuse of these drugs tends to resolve is discussed in the respective sections on these syndromes.
while patients are still in their twenties. Craving does not Once intoxication and any post-intoxication sequelae
appear to occur and addiction is not seen. have resolved, efforts should be undertaken to ensure
abstinence, which may include involvement in Narcotics
Etiology Anonymous.
Both phencyclidine and ketamine act as non-competitive

antagonists at cation channels within the N-methyl-D- 21.5 ALCOHOL
aspartic acid (NMDA) receptor complex, and, although
numerous other receptors are also affected, it is this action This section deals with the various disorders and phenom-
at the NMDA receptor that appears to be responsible for ena associated with alcohol use, including alcohol intoxi-
the intoxicating effect of these drugs. cation, blackouts, pathological intoxication, tolerance to
alcohol, alcohol withdrawal, alcohol withdrawal seizures,
Differential diagnosis delirium tremens, and various other disorders often seen
in association with alcohol use, such as head trauma. The
Hallucinogen intoxication resembles mild intoxication full panoply of these is often seen in alcoholism, and this
with phencyclidine or ketamine, although it lacks some of disorder is also discussed.
p 21.qxd 3/10/08 9:58 AM Page 662
Clinical features the amnesia is not complete and patients can recall some of
what happened (Tamerin et al. 1971).
Alcohol intoxication of mild degree is characterized by Pathological intoxication (Perr 1986), although long
euphoria, talkativeness, and a degree of disinhibition; in written of (Banay 1944; May and Ebaugh 1953), is a con-
some patients there may be some irritability or dysphoria troversial diagnosis (Coid 1979). Putatively, patients, after
rather than euphoria. In moderate intoxication, the behav- only a small amount of alcohol, undergo a dramatic
ior becomes coarse and the thinking is slow and unclear. change, becoming uncharacteristically irritable and often
There is facial flushing, conjunctival injection, dysarthria, violent. One study was able to reproduce these symptoms
nystagmus, and ataxia. With severe intoxication there is in patients thought to have suffered pathologic intoxica-
drowsiness, stupor, and disabling ataxia; coma may ensue, tion (Maletzky 1976), whereas another was not (Bach-
with respiratory depression and death. y-Rita et al. 1971); if indeed pathologic intoxication does
The blood alcohol level (BAL) is customarily reported in exist, it is probably rare.
milligrams/deciliter or, as it is often worded, milligrams Tolerance to alcohol typically develops gradually with
percent (mg%). In an alcohol-naive subject, mild intoxica- chronic, repeated intoxications, and greater and greater
tion is seen at 100 mg%, moderate intoxication at 200 mg%, amounts must be drunk to achieve the desired intoxica-
and severe intoxication at 300 mg%; in the alcohol-naive tion. Thus, whereas in the alcohol-naive patient levels of
patient, levels of 400 mg% generally cause coma, and levels 100 mg% typically cause intoxication, those with tolerance
of approximately 500 mg%, respiratory depression. may need to reach a level of 300 mg% before they begin to
In general, in a 70-kg subject, the rapid consumption of ‘feel’ the alcohol; indeed, in some cases alcohol-tolerant
15 mL of pure, 100% ethanol will elevate the BAL by about patients may sustain levels of 500 mg% without loss of con-
15–20 mg%, and this amount of pure ethanol is generally sciousness (Adachi et al. 1991; Minion et al. 1989).
found in one mixed drink, one can of beer, or one glass of Interestingly, late in the course of alcoholism, some
wine. In those with normal hepatic function, ethanol is patients may fairly rapidly ‘lose’ their tolerance. In such
metabolized at a rate of 5–10 mL/hour. Of interest, females cases, patients who had previously been able to consume a
tend to become intoxicated with a smaller amount of liter of liquor and still be standing may now find them-
ingested alcohol than males, and this may be because of a selves hopelessly and severely intoxicated after only a few
reduction in gastric alcohol dehydrogenase activity, thus drinks.
allowing a greater percentage of the ingested alcohol to Alcohol withdrawal (Isbell et al. 1955), colloquially
escape this initial metabolic step (Frezza et al. 1990). known as the ‘shakes’, although generally seen only in alco-
After the intoxication has passed, patients may experi- holics, may be seen in anyone who engages in heavy, pro-
ence a ‘hangover’, which may last from hours up to a day. longed drinking. The symptoms appear gradually,
This is characterized by headache, malaise, dysphoria, nau- anywhere from 4 to 12 hours after the BAL has fallen below
sea, mild tremulousness, and diaphoresis. the patient’s ‘threshold’ for intoxication. Importantly, this
Blackouts may occur during moderate or severe alcohol implies that for some patients, such as alcoholics who have
intoxication and consist of transient episodes of antero- developed tolerance, withdrawal symptoms may appear
grade amnesia, lasting anywhere from minutes to days, while the patient is still drinking, provided that the alcohol
depending on how long the BAL remains high (Goodwin consumption has ‘slowed down’ sufficiently.
1971; Goodwin et al. 1969a). During a blackout, patients’ Symptoms include tremulousness, anxiety, easy starta-
behavior may, to casual inspection, not appear to be bility, poor memory and concentration, fleeting and
changed: patients may recall what they were doing at the poorly formed visual or auditory hallucinations, insomnia
start of the blackout and may also be able to keep track of (Johnson et al. 1970), elevated temperature, pulse and sys-
ongoing events sufficiently well that they are able to keep tolic blood pressure, mydriasis, generalized hyper-reflexia,
up a conversation, play cards, etc. If, however, short-term diaphoresis, nausea and vomiting, and diarrhea. The most
memory is tested during the blackout, one finds that prominent symptom of alcohol withdrawal, however, is
patients are unable to recall anything that happened much tremor, and it is from this that the syndrome derives its
more than 5 minutes earlier. Furthermore, once the black- colloquial name. The tremor is postural, rapid, and ranges
out ends, the time period covered by the blackout remains in amplitude from fine to coarse; it may be confined to the
an ‘island of amnesia’ to patients, who can recall little or outstretched hands or be more widespread, even general-
nothing of the events that transpired during the blackout. ized, involving the eyelids and tongue in severe cases.
Should blacked-out patients fall asleep during the black- Rarely one may see transient myoclonus or chorea.
out, they may, upon awakening the next day, anxiously ask Most patients recognize that a drink will ‘solve’ their
acquaintances what they did the night before. Those who problem, and many will take some ‘hair of the dog that bit
are still awake when the blackout abruptly ends may be you’. This does offer temporary relief of the shakes but of
quite startled at their situation; one patient (Goodwin et al. course threatens to set off a vicious cycle.
1969b) ‘found himself dancing with no recollection of what Alcohol withdrawal generally peaks within a couple of
he had been doing during the previous six hours’. A variant days and then gradually settles over the next 2 or 3 days.
of blackouts, known as ‘brownouts’, may occur in which Among recreational or abusive drinkers, the symptoms
p 21.qxd 3/10/08 9:58 AM Page 663
21.5 Alcohol 663
may gradually resolve fully within a week, but among alco- Other disorders often accompany alcohol intoxication,
holics, residual symptoms may persist for up to 6 months. especially in patients with alcoholism. Falls and motor
Alcohol withdrawal seizures, also known as ‘rum fits’, are vehicle accidents are common, and traumatic brain injury
a rare accompaniment of the alcohol withdrawal syn- (Section 7.5), especially with subdural hematoma (Section
drome, seen only in a few percent of alcoholics (Schuckit et 11.1), is not uncommon. Vitamin deficiencies may occur:
al. 1993); typically they occur only after many years of thiamine deficiency may cause a Wernicke’s encephalopa-
heavy drinking and repeated episodes of alcohol with- thy (Section 13.4), and the much less commonly seen
drawal. They may occur within hours to 2 days after either niacin deficiency may cause the acute, encephalopathic
a cessation of alcohol use or a substantial reduction in the form of pellagra (Section 13.3). Among alcoholics, recur-
amount consumed and typically consist of grand mal rent attacks of alcoholic hepatitis may lead to hepatic cir-
seizures, which may, in about one-quarter of cases, have rhosis and, in some, to a hepatic encephalopathy (Section
focal features. Most patients have only one seizure; occa- 13.19). Alcoholics are also prone to infection and aspira-
sionally patients may experience two or three, or even a tion pneumonia is not uncommon; bacterial meningitis
half-dozen, and very rarely status epilepticus may occur. may also occur but this is relatively rare. Hypoglycemia
Delirium tremens (Lundquist 1961; Nielsen 1965; may occur, not only due to malnourishment but also to the
Rosenbaum et al. 1941), also known as alcohol withdrawal direct inhibitory effect alcohol has on hepatic gluconeoge-
delirium or simply the ‘DTs’, is generally seen only in alco- nesis; hypomagnesemia may also be seen. Gastritis, bleed-
holics who have been drinking heavily for many years and ing esophageal varices, and pancreatitis may likewise
who have had repeated episodes of alcohol withdrawal; the occur. Chronic hyponatremia may be seen in some cases,
presence of a concurrent illness, such as pneumonia, and its overly rapid correction may cause central pontine
hepatic failure, or gastrointestinal bleeding, increases the myelinolysis (Section 13.17).
risk. Clinically, patients first develop a typical alcohol with- Patients who have survived a Wernicke’s encephalopa-
drawal syndrome, and in about 10 percent of cases there thy may be left with the chronic amnesia of Korsakoff’s
may be an alcohol withdrawal seizure. After anywhere syndrome (Section 13.4). Long-term, chronic alcoholism
from hours to a week or more, but generally within 2–3 may also be associated with the gradual development of
days, there is a dramatic exacerbation of the typical alcohol various other disorders, including alcoholic dementia
withdrawal symptoms accompanied by the appearance of (Section 22.8), alcohol hallucinosis (Section 22.9), alco-
delirium. In addition to confusion, disorientation, and holic paranoia (Section 22.10), Marchiafava–Bignami dis-
short-term memory loss, patients typically also experience ease (Section 22.11), alcoholic cerebellar degeneration, and
hallucinations and delusions. Visual hallucinations are alcoholic polyneuropathy.
most common, and they tend to be extremely vivid and
complex, typically involving animals or insects: dogs may
circle the bed; rats eat at the toes; bugs crawl on the arms Course
and face and the patient may try and swat them away.
Tactile hallucinations may accompany the visual ones, and Recreational or ‘social’ use of alcohol is almost ubiquitous in
the patient may feel animals tearing at the flesh or bugs bit- most parts of the world, but the intoxications here are gen-
ing into the skin. Auditory hallucinations may occur. erally mild and, although a significant minority of recre-
Patients may hear bells, whistles, or alarms, and at times ational drinkers may experience blackouts and some may
voices; when voices do occur they tend to be critical and suffer head trauma, the other consequences of alcohol use
persecutory. Delusions are common and tend to be perse- described above do not occur. Alcohol abuse is character-
cutory and referential. Patients may believe that staff are ized by recurrent intoxication despite significant medical,
conspiring against them to have them killed and may social, and legal consequences, and these patients, in addi-
believe that chance conversations refer especially to them. tion to episodes of intoxication of moderate or severe
Delirium tremens is fatal in 5–20 percent of cases, with degree, commonly experience blackouts and may develop a
patients succumbing to concurrent illnesses such as pneu- degree of tolerance and experience minor episodes of the
monia, hepatic failure, cardiac arrhythmias, or hypov- alcohol withdrawal syndrome; these patients, however, do
olemic shock. Those who survive generally experience a not have a craving for alcohol and, albeit with some effort,
gradual remission of symptoms within a day to 2 or 3 are able to either moderate their drinking or stop altogether.
weeks, with most recovering within several days. Alcoholism emerges from alcohol abuse and is signalled by
Rarely, one may see a variant of delirium tremens the development of craving, with an inability to ‘leave it
known as delirium tremens sine tremore (trembling delir- alone’, and by clear-cut tolerance and frequent episodes of
ium without tremor). Here, the tremor and other auto- moderate or severe alcohol withdrawal; alcoholics are also
nomic symptoms classically associated with delirium prone to alcohol withdrawal seizures, delirium tremens, and
tremens are either minimal or absent, and patients present all of the other disorders described earlier, such as head
with a ‘quiet’ delirium, seemingly undisturbed while all trauma and Wernicke’s encephalopathy.
the time experiencing confusion, hallucinations, and Alcoholism is a common disorder, seen in about 10 per-
delusions. cent of the adult population in the United States, and is
p 21.qxd 3/10/08 9:58 AM Page 664
much more frequent in males than females. In most cases of (or other sedative–hypnotics) and ethylene glycol, there is
alcoholism, excessive alcohol use begins in the late teens or no odor of alcohol on the breath, and in the case of ethyl-
early twenties, and progressively and gradually worsens ene glycol one will also see an increased anion gap. Both
until the full clinical picture is reached after a decade or so; isopropyl alcohol and methanol intoxication may be
exceptions to this pattern do occur, however, and in some accompanied by an odor of alcohol; however, in these
cases the onset may be delayed until middle years or the intoxications there is prominent nausea and vomiting and,
progression may be unusually rapid. Among alcoholics, furthermore, in methanol intoxication one finds bilateral
drinking becomes the primary need in life, and patients dimming or loss of vision. Consideration must also be
continue to drink despite disastrous consequences. Denial given to some of the other disorders that may accompany
is ubiquitous, and almost all alcoholics will strenuously intoxication, especially in cases in which intoxicated
deny that they have a problem with drinking or they will patients fail to sober up within the expected time frame,
attempt to rationalize it in one way or another. Most alco- including especially head trauma, infection, hypoglycemia,
holics, at least initially, will try at times to control their and hypomagnesemia.
drinking, perhaps after a hospital stay, incarceration for Blackouts must be distinguished from certain other
driving while intoxicated, or the angry departure of a causes of episodic anterograde amnesia, as discussed in
spouse, and some may experience some success at this, only Section 5.4. Transient global amnesia and pure epileptic
to soon find themselves again hopelessly intoxicated. The amnesia are distinguished by the absence of other signs of
overall course of alcoholism may be episodic or chronic. intoxication, such as dysarthria. Concussion may occur
The episodic course is characterized by more or less lengthy during intoxication, but the evidence of head injury is
episodes, or ‘binges’, during which there are frequent, generally obvious.
closely spaced intoxications; these binges may last anywhere Alcohol withdrawal may be clinically indistinguishable
from weeks to months, and in between them patients gen- from withdrawal from benzodiazepines or other sedative–
erally remain abstinent. The chronic course may be appar- hypnotics, and the diagnosis therefore rests on the history
ent from the onset of the alcoholism or may supervene of substance use, keeping in mind that many patients will
upon a prior episodic course; in this chronic course there also use these other agents in addition to alcohol.
are repeated, more or less closely spaced intoxications with- Hypoglycemia, not uncommonly seen in intoxicated alco-
out any intervening periods of sobriety of any significant holics, may produce a similar picture (Fredericks and
length. Regardless of whether the course is episodic or Lazor 1963; de Moura et al. 1967) and, as noted below, a
chronic, spontaneous, full remissions are rare and most blood glucose determination should be standard.
alcoholics continue to drink despite losing jobs, friends, Alcohol withdrawal seizures, in a sense, should be con-
families, and their health, and indeed they continue to do so sidered a ‘rule-out’ diagnosis, given the large number of
until they are either institutionalized or dead. other conditions that may produce grand mal seizures in
alcoholics. To begin with, patients with epilepsy of any
cause are more likely to have seizures during alcohol with-
Etiology drawal. Seizures may also occur secondary to some of the
other disorders noted above, including head trauma,
Alcohol intoxication may reflect not only increases in mem- Wernicke’s encephalopathy, hepatic encephalopathy, hypo-
brane fluidity, with consequent changes in ion channel func- glycemia, hypomagnesemia, and the rare cases of bacterial
tion, but also alcohol-mediated sensitization of gamma- meningitis or Marchiafava–Bignami disease.
aminobutyric acid (GABA) receptors and inhibition of Delirium tremens may be clinically indistinguishable
NMDA glutamate receptors. With repeated, frequent intoxi- from benzodiazepine or sedative–hypnotic withdrawal
cations, it is suspected that there is a chronic down-regulation delirium, and the differential here rests on the history of
of GABA receptors and an up-regulation of NMDA substance use. Other disorders capable of causing a ‘trem-
receptors, and that it is these changes that predispose to the bling delirium’ with marked autonomic signs include the
development of the alcohol withdrawal syndrome and delir- serotonin syndrome, the neuroleptic malignant syndrome,
ium tremens. The mechanisms underlying blackouts, patho- thyroid storm, and hypoglycemia. In some cases, alcohol
logic intoxication, and alcohol withdrawal seizures are not withdrawal may be accompanied by a delirium secondary
clear. Although the etiology of alcoholism itself is not known, to one of the other disorders seen in alcoholics, thus pro-
it is clear that hereditary factors play a major role, accounting ducing a clinical picture that may be easily passed off as
for approximately 60 percent of cases. delirium tremens rather than an etiologically multifactor-
ial delirium; consideration should therefore be given to
the presence of Wernicke’s encephalopathy, hepatic
Differential diagnosis encephalopathy, traumatic brain injury, hypomagnesemia,
encephalopathic pellagra, Marchiafava–Bignami disease,
Alcohol intoxication may be mimicked by intoxication with meningitis, pneumonia with sepsis, and, in patients who
various other substances, but certain signs allow for a dif- have undergone correction of hyponatremia, central pon-
ferential. In the case of intoxication with benzodiazepines tine myelinolysis.
p 21.qxd 3/10/08 9:58 AM Page 665
21.5 Alcohol 665
Treatment hours for breakthrough tremor, and on succeeding days

the total daily dose is increased until eventually the regular
Alcohol intoxication is generally managed by observation dose is sufficient to control tremor without the need for
and routine general medical supportive care. An estimate any further as-needed doses. At this point, as-needed doses
should be made as to the time of the last drink and a BAL are discontinued and the patient is then placed on a taper-
should be obtained, after which one may calculate the time ing dose whereby the total daily dose is decreased every
required for the alcohol to wash out. With very high blood succeeding day by an amount that is approximately equal
levels respiratory failure may occur, necessitating intuba- to 20 percent of the total required for control; in this fash-
tion, and in some cases hemodialysis may be appropriate. ion the dose may be tapered and then discontinued over
In older, debilitated, or alcoholic patients, or those who about 4 or 5 days. Other benzodiazepines may also be con-
demonstrate withdrawal or seizures, routine laboratory sidered, such as chlordiazepoxide (25–50 mg) or diazepam
tests should be obtained, including a complete blood count (5–10 mg); however, these agents have long half-lives and
(CBC), electrolytes, glucose, magnesium, ammonia, biliru- active metabolites making them more difficult to use.
bin, liver enzymes, stool for occult blood, and an electro- Regardless of which benzodiazepine is used, such a pro-
cardiogram (ECG); if there is any suspicion of pneumonia gram generally requires admission. Most outpatients are
or head trauma, a chest radiograph or computed tomogra- simply unable to discipline themselves to follow the pro-
phy (CT) scan, respectively, should also be obtained. gram and will either abort it, take enough of the benzodi-
Patients should also receive 100 mg of thiamine parenter- azepine to cause intoxication, or resume drinking.
ally, followed by 100 mg daily of parenteral or oral thi- Both carbamazepine (Malcolm et al. 1989; Seifert et al.
amine; glucose and food should, if possible, be withheld 2004; Stuppacek et al. 1992) and divalproex (Reoux et al.
until 2 hours have passed from the administration of the 2001) are generally equally as effective as a benzodiazepine
initial dose of parenteral thiamine. in suppressing the tremor and other autonomic sympto-
Blackouts are managed by simple observation until matology of alcohol withdrawal. In otherwise healthy
serial mental status examinations have demonstrated a patients with normal hepatic function, one may begin with
recovery of short-term memory function. carbamazepine in a dose of 200 mg three or four times
Pathological intoxication is likewise managed by obser- daily or with divalproex in a total daily loading dose of
vation; however, here, seclusion and, at times, restraints 20 mg/kg, divided into two or three doses; subsequent dose
may be required until the intoxication has passed. adjustments may then be made based on the clinical
Alcohol withdrawal may or may not require pharmaco- response, side-effects, and blood levels. As both of these
logic treatment. For some alcoholics and alcohol abusers, agents may take a day or two to quell the symptoms of
the ‘shakes’ may constitute a valuable lesson that strength- alcohol withdrawal, many clinicians will combine their use
ens the motivation for sobriety, and provided that their with as-needed doses of lorazepam, as described above;
general medical condition is such that the overall auto- generally, after 3 days at the most, no further lorazepam
nomic symptomatology does not constitute a risk, it may will be required, and the patient may then be continued on
be appropriate to simply let such patients ‘shake it out’. the AED alone for about a week, that is to say, long enough
However, when autonomic symptoms are intolerable, for the alcohol withdrawal to run its natural course, after
serve no instructive purpose, or pose a threat to the patient which it may be rapidly tapered and discontinued. Some
(e.g., as may occur in those with epilepsy or cardiac disease), clinicians, however, may elect to continue divalproex for a
then pharmacologic treatment is indicated. Traditionally, a matter of months. As noted earlier, among alcoholics the
benzodiazepine has been used; however, either carba- withdrawal syndrome may persist in a smoldering fashion
mazepine or dialproex constitute reasonable alternatives, for up to 6 months, and in such cases, after discharge, the
and, as discussed further below, a combination of a benzo- temptation to drink or take sedatives to quell these symp-
diazepine plus one of these anti-epilepsy drugs (AEDs) toms, particularly the insomnia, may be very strong.
may also be used. Some clinicians advocate the use of alco- Continuing divalproex has been shown to be useful in this
hol itself, generally via an intravenous drip; however, the regard, and may therefore actually increase the chances of
hepatotoxicity of alcohol may give one pause here. long-term sobriety. One of the great advantages of using an
Of the benzodiazepines, lorazepam, given its short half- AED is that it ends the struggle that may occur between the
life and lack of metabolites, is recommended. Oral admin- patient who demands ever more lorazepam and the clini-
istration is preferred; however, if this is not practicable, cian who suspects that the patient’s demands reflect not
roughly the same dose may be given parenterally. Initially the pain of withdrawal but rather a desire for intoxication.
2 mg is given (or less in the elderly or debilitated), followed There is debate as to whether a course of benzodi-
by 2 mg every 2 hours until the tremor is controlled and the azepines or a course of an AED is preferable. Given that
patient is calm. The next day the patient is placed on a reg- lorazepam, as noted below, is effective both in preventing
ular total daily dose that is roughly equivalent to the total recurrent withdrawal seizures and in treating delirium
amount that was required on the first day, with this total tremens, whereas the AEDs have not been shown to be
dose divided into three or four doses; provision is also effective in these regards, many clinicians feel safer using
made for ongoing as-needed doses of 1 or 2 mg every 2 lorazepam. Others, noting that the combination strategy
p 21.qxd 3/10/08 9:58 AM Page 666
provides coverage with lorazepam during the first few days Overall, the goal of treatment of alcoholism is absti-
of withdrawal, when the risk of seizures and delirium nence. Although attempts have been made to enable alco-
tremens is highest, and the advantage of getting away from holics to continue drinking in a ‘controlled’ fashion, these
potentially intoxicating substances as soon as possible, find are not reliable and cannot be recommended: the goal of
the combination strategy acceptable. Clinical judgment is abstinence must be stated to alcoholics clearly, starkly, and
clearly required here. Certainly, if there is a history of with- unmistakably. Whether the same applies to alcohol abusers
drawal seizures or delirium tremens, then one should is not clear; however, given the risk that alcohol abuse may
strongly consider a full course of lorazepam, or, if a combi- evolve into alcoholism or that, if it doesn’t, further drink-
nation strategy is otherwise very attractive, a longer initial ing may get out of control with disastrous consequences, it
course of lorazepam should be considered before phasing is prudent to advance the same goal to alcohol abusers.
into treatment with an AED alone. Although some alcoholics are able to stop drinking by
Alcohol withdrawal seizures generally present in the an extraordinary act of will, this is rare and the vast major-
context of an alcohol withdrawal syndrome, and it has ity will continue to drink unless they receive help. In such
been shown that after a first seizure the intravenous cases, various psychosocial methods are helpful and may
administration of 2 mg of lorazepam will reduce the risk of be offered. Pharmacologic treatment of alcoholism, utiliz-
a second seizure over the next 6 hours (D’Onofrio et al. ing acamprosate, naltrexone, topiramate, disulfiram, or
1999). It is therefore probably reasonable to treat these divalproex, although at times helpful, is adjunctive only
patients with lorazepam, as described for alcohol with- and cannot replace psychosocial treatments.
drawal, either throughout the course of the withdrawal or, Various psychotherapies, such as cognitive behavioral
if a combination strategy is used, for the first few days, after therapy, have been utilized, and in some cases are success-
which carbamazepine or divalproex may be used alone. ful. A referral to Alcoholics Anonymous (AA), however,
Should status epilepticus occur, most clinicians will give should be considered, regardless of whether patients are
fosphenytoin. referred to psychotherapy. Many patients are also hospital-
Delirium tremens represents a medical emergency. ized in residential treatment facilities, and this may be nec-
Patients should be treated with intravenous lorazepam in essary to effect a period of sobriety of sufficient length to
doses of 2 mg every 1–2 hours until they are lightly sedated, allow patients to begin to think clearly again; during such
and massive doses may be required to accomplish this. stays patients are often engaged in various psychotherapies
Once patients are comfortable and the autonomic signs are and, importantly, are often taken to AA meetings.
well controlled, the dose of lorazepam may then be gin- Alcoholics Anonymous is the oldest treatment
gerly tapered, generally in daily decrements approximately approach to alcoholism and, if participated in fully, has an
equivalent to 10 percent of the total daily dose required for excellent success rate. The key word here is ‘fully’: no treat-
initial control. In many cases, lorazepam, although capable ment works unless patients are compliant, and AA is no
of calming patients and quelling tremor and other auto- exception. Patients must be told that much will be
nomic symptoms, does not control hallucinations and expected of them but that, if they persist, they will become
delusions, and in these cases an antipsychotic should be sober. Alcoholics Anonymous meetings are available
considered, such as haloperidol or risperidone. Haloperidol around the world, and in the United States contact may be
may be given in a dose of 1–5 mg, and risperidone in doses made by simply calling directory assistance in virtually any
of 0.25–1 mg every hour, until symptoms are acceptably city. Patients should be instructed to attend meetings as
controlled, limiting side-effects occur, or a maximum dose frequently as possible, ideally attending ‘ninety meetings in
of approximately 20 mg of haloperidol or 5 mg of risperi- ninety days’, and to get an AA ‘sponsor’. Should patients
done is achieved. Once symptoms are controlled, the protest that they don’t have the time to go to a meeting
antipsychotic should be continued in approximately the every day, they may be gently, but clearly, reminded that
same total daily dose (divided into two or three doses) they have a debilitating and potentially fatal disease, and
until the symptoms have been well controlled for at least a that the time spent at meetings will pay off not only in
few consecutive days, after which the drug may generally keeping them alive but also in salvaging what is left of their
be tapered and discontinued over the following few days. careers and relationships.
Further suggestions for the overall treatment of delirium Of the medications to be considered, naltrexone, acam-
are discussed in Section 5.3. prosate, and possibly topiramate may each partially reduce
In addition to the routine laboratory tests described ear- either the urge to drink or the intoxication that occurs with
lier, a careful search should be made for other illnesses, drinking; disulfiram, by contrast, induces a toxic ‘Antabuse
such as pneumonia, pancreatitis, gastrointestinal bleeding, reaction’ if patients do drink, thus adding another motiva-
hepatic failure, etc., as one or more of these is usually pres- tion to remain sober, and divalproex, as noted earlier, may
ent. Diaphoresis, vomiting, and diarrhea may cause dehy- ease some of the lingering residual withdrawal symptoms,
dration, and massive fluid replacement may be required. especially insomnia, thus removing these as motivations to
In those rare cases of delirium tremens sine tremore, drink or use sedatives.
antipsychotics alone, coupled with other measures dis- Naltrexone, given only to patients with normal hepatic
cussed in Section 5.3, may be all that is required. function, is used orally in a dose of 50 mg daily, and
p 21.qxd 3/10/08 9:58 AM Page 667
21.6 Sedatives, hypnotics, and anxiolytics 667
acamprosate, in patients with normal renal function, is given with alcohol or other substances, such as opioids, stimu-
in a dose of 666 mg three times daily; it appears that naltrex- lants or cocaine, they may at times be used in isolation.
one is more effective than acamprosate (Morley et al. 2006), Table 21.1 lists these various agents, grouped according to
although the combination of naltrexone plus acamprosate their half-lives, as short acting (generally less than 6 hours),
appears to be more effective than naltrexone alone (Kiefer intermediate acting (6–18 hours) or long acting (generally
et al. 2003). Topiramate is used in total daily doses of approx- over 24 hours). This classification is useful as it allows one
imately 100–200 mg (Johnson et al. 2003). Each one of these to make a rough prediction as to when withdrawal, with-
three agents has been shown to reduce the number of drink- drawal seizures, or withdrawal delirium is likely to occur.
ing days in patients who do ‘slip’ and drink, although the The popularity of these various agents has changed over
overall results are modest at best. Disulfiram is begun in a time. The barbiturates, meprobamate, and chloral hydrate,
dose of 500 mg daily, with the dose reduced to 250 mg daily once commonly abused, have been supplanted by the ben-
after 1 or 2 weeks; patients should be given a graphic descrip- zodiazepines, among which alprazolam, lorazepam, and
tion of the toxic reaction that they may expect should they diazepam are most popular.
ingest even a miniscule amount of alcohol, and, given the
potential toxicity of disulfiram, treatment is generally main- Clinical features
tained for only a matter of months. Divalproex neither
reduces the urge to drink nor the intoxication that occurs As indicated, the clinical features of sedative–hypnotic use
with drinking, but may, in doses similar to those used for are similar to those of alcohol, and thus one may see seda-
alcohol withdrawal, reduce lingering withdrawal symptoma- tive–hypnotic intoxication, blackouts, tolerance, with-
tology. Choosing among these medications is not straightfor- drawal, withdrawal seizures, and withdrawal delirium.
ward. Out of naltrexone, acamprosate, and topiramate, all Each of these is discussed below in turn.
other things being equal, it is probably reasonable to begin When mild, sedative–hypnotic intoxication with barbi-
with naltrexone. Given its toxicity, disulfiram should be turates (Curran 1938, 1944; Isbell et al. 1950), meproba-
reserved for highly motivated patients. The place of dival- mate (Roache and Griffiths 1987), or benzodiazepines is
proex is not as yet clear; however, if it has been used during characterized by euphoria, a degree of affective lability, and
treatment of alcohol withdrawal, and one can predict a lin- disinhibition. With moderate intoxication, reaction time is
gering withdrawal, it is reasonable to continue it. slowed, lethargy and drowsiness appear, and patients often
Although these medications may be helpful, patients develop nystagmus, dysarthria, and ataxia; falls may occur,
must not be allowed to think that their use can substitute with possible head injury. With severe intoxication stupor
for involvement in psychosocial treatments. Many patients or coma may occur, with respiratory depression and death.
fondly hope for a ‘magic bullet’ that will resolve their alco- Sedative–hypnotic blackouts are quite similar to those
holism, and such hopes must be firmly dashed. The overall seen with alcohol; although possible with long-acting
role of the physician in the treatment of alcoholism per se is
generally limited to treatment of some of the complica-
tions of alcoholism (e.g., hepatic failure) and to treatment Table 21.1 Sedative–hypnotics grouped by duration of effect
of any concurrent disorders, such as depression, panic dis-
Short-acting (less than 6 hours) Triazolam
order, or schizophrenia. As a general rule, in prescribing
Alprazolam
medications for these or any other conditions, potentially
Zolpidem
intoxicating drugs, such as benzodiazepines or opioids,
Zaleplon
should be avoided as they may trigger off a desire to drink;
Intermediate-acting (6–18 hours) Oxazepam
exceptions to this rule are few.
Temazepam
Alcoholism is a chronic disease and hence relapses are
Lorazepam
to be expected; these occur most frequently in the first 6
Chlordiazepoxide
months of treatment. Relapses, or ‘slips’, therefore,
Meprobamate
although certainly undesirable, should not be taken as an
Chloral hydrate
indication of failure but rather as an indication for patients
Long-acting (greater than 24 hours) Quazepam
to redouble their efforts.
Prazepam
Halazepam
Flurazepam
21.6 SEDATIVES, HYPNOTICS, AND Clonazepam
ANXIOLYTICS Diazepam
Amobarbital
The sedatives, hypnotics, and anxiolytics, including the
Secobarbital
benzodiazepines and related drugs, comprise a large group
Pentobarbital
of agents, often collectively referred to as the ‘sedative–
Phenobarbital
hypnotics’, each of which has an effect similar to that of
Butalbital
alcohol. Although most commonly used in conjunction
p 21.qxd 3/10/08 9:58 AM Page 668
benzodiazepines such as diazepam (Wolkowitz et al. 1987), Sedative–hypnotic abuse is said to occur when patients
they are more common with short-acting, high-potency ben- continue to seek intoxication despite experiencing black-
zodiazepines (Scharf et al. 1987) such as triazolam (Ewing et outs and social or legal consequences, and the onset of
al. 1988; Greenblatt et al. 1991; Morris and Estes 1987). addiction is heralded by the development of craving, toler-
Tolerance may appear with long-term use and at times ance, and withdrawal phenomena, such as a withdrawal
may be quite remarkable: some patients may end up taking syndrome, seizures, or delirium. As noted earlier, concur-
hundreds of milligrams of diazepam daily, with little or no rent use of other substances, especially alcohol, is com-
evidence of sedation. mon, and ‘pure-culture’ sedative–hypnotic abuse or
Sedative–hypnotic withdrawal, as seen with benzodi- addiction is relatively rare.
azepines (Busto et al. 1986; Covi et al. 1973; Hollister et al.
1961; Juergens and Morse 1988; Murphy et al. 1984, 1989;
Rickels et al. 1990; Shader et al. 1993; Tyrer et al. 1983) and Etiology
barbiturates (Fraser et al. 1958; Isbell et al. 1950), is charac-
terized by anxiety, irritability, insomnia, tremor, tachycardia, Both the benzodiazepines and the barbiturates, by some-
diaphoresis, nausea and vomiting, and postural hypoten- what different mechanisms, enhance chloride flux via
sion. The onset of the withdrawal syndrome varies according GABA receptors upon stimulation by endogenous GABA,
to the half-life of the agent: roughly speaking, for short- and it is by virtue of this that intoxication occurs.
acting agents withdrawal starts in less than a day; for inter- Presumably, with prolonged use, down-regulation of these
mediate-acting agents, 2–3 days; and for long-acting agents, receptors occurs, with the consequent development of tol-
2–6 days. For certain very-long-acting agents, such as erance and withdrawal phenomena.
diazepam or phenobarbital, the blood level may fall so slowly
that there is, in effect, a ‘self-tapering’, with, in many cases, a Differential diagnosis
substantially less severe withdrawal syndrome. The dura-
tion of withdrawal likewise varies with the half-life of the Sedative–hypnotic intoxication is clinically indistinguish-
agent. Roughly speaking, for short- and intermediate- able from alcohol, isopropyl alcohol, and methanol intoxi-
acting agents, symptoms peak within 1–3 days and persist cation except for the fact that sedative–hypnotic-intoxicated
for 1–2 weeks, whereas for long-acting agents the peak patients do not have an odor of alcohol on their breath.
arrives in 5–7 days and the syndrome may persist for up to 2 Ethylene glycol intoxication, which also lacks an odor of
or 3 weeks. As with alcohol withdrawal, some patients may alcohol, is distinguished by an increased anion gap. In
experience lingering, low-level withdrawal symptoms for cases in which patients fail to recover from an intoxication
weeks or months after withdrawing from benzodiazepines within the expected time frame, other disorders, for exam-
(Ashton 1984; Shader et al. 1993). In addition to this typical ple traumatic brain injury, should be considered.
picture of withdrawal, a recent report described the occur- Sedative–hypnotic blackouts must be distinguished
rence of stuporous catatonia as a withdrawal phenomenon from other causes of episodic anterograde amnesia, as dis-
of benzodiazepines (Rosebush and Mazurek 1996). cussed in Section 5.4.
Sedative–hypnotic withdrawal seizures typically occur Sedative–hypnotic withdrawal is basically indistin-
within the context of withdrawal symptomatology and, guishable from alcohol withdrawal, and the diagnosis must
although these may occur with benzodiazepines (e.g., apra- rest on an accurate history of substance use, keeping in
zolam [Breier et al. 1984; Noyes et al. 1986]), they are much mind that many patients may have a ‘mixed’ picture of
more common with barbiturates, in which case there is a both sedative–hypnotic and alcohol withdrawal.
significant risk of multiple seizures and status epilepticus. Sedative–hypnotic seizures, as with alcohol-withdrawal
Sedative–hypnotic withdrawal delirium, noted with ben- seizures, constitute a ‘rule-out diagnosis’, and consideration
zodiazepines (such as alprazolam [Levy 1984; Zipursky et al. must be given to pre-existing epilepsy and head trauma.
1985] and flunitrazepam, lorazepam, and triazolam [Heritch Sedative–hypnotic withdrawal delirium may be indis-
et al. 1987; Martinez-Cano et al. 1995]) and barbiturates tinguishable from delirium tremens and the diagnosis may
(Fraser et al. 1958; Isbell et al. 1950), typically emerges out of rest on an accurate history, keeping in mind that, as for
a withdrawal syndrome and is characterized by an intensifi- withdrawal, a ‘mixed’ picture may be present. Consideration
cation of those symptoms, accompanied by confusion, dismay also be given to other causes of delirium with tremor,
orientation, agitation, hallucinations, and persecutory including the serotonin syndrome, the neuroleptic malig-
delusions. In the natural course of events, the delirium tends nant syndrome, thyroid storm, and hypoglycemia.
to clear in anywhere from days to a couple of weeks.
Treatment
Course
Sedative–hypnotic intoxication typically requires only
Recreational use of these agents, particularly the benzodi- observation and general medical support. In cases of ben-
azepines, is common among adolescents and young adults. zodiazepine intoxication in which respiratory depression
p 21.qxd 3/10/08 9:58 AM Page 669
21.7 Inhalents (solvents) 669
threatens, flumazenil may be given (Brogden and Goa contains various mixtures of aliphatic and aromatic hydro-
1991); however, caution is needed here in cases in which carbons, some of which may be halogenated; of all of these
tolerance has developed, as flumazenil may precipitate a intoxicating hydrocarbons, toluene appears to be the most
withdrawal syndrome with seizures. significant.
Sedative–hypnotic blackouts require only observation
until serial mental status examinations have revealed a
restoration of short-term memory, and the intoxication Clinical features
itself has resolved.
Sedative–hypnotic withdrawal should probably be Intoxication is obtained either by soaking a rag in the
treated with the same agent that the patient is addicted to. volatile substance and holding it to the face or by placing
This is particularly the case for barbiturate withdrawal, the substance in a plastic or paper bag and then inhaling;
which is not controlled by benzodiazepines, and alprazo- when a bag is used it may leave a telltale circular rash on the
lam withdrawal, which may not respond to other benzodi- face. The intoxication (Evans and Raistrick 1987) occurs
azepines such as diazepam (Zipursky et al. 1985). For within minutes and is characterized by a dreamy euphoria,
benzodiazepine withdrawal, a strategy similar to that drowsiness, dizziness, dysarthria, diplopia, nystagmus, and
described for the treatment of alcohol withdrawal in the ataxia. Some may also experience confusion and hallucina-
preceding section may be utilized, with equivalent doses tions, which may be either visual or, less commonly, audi-
(e.g., lorazepam 2 mg, alprazolam 1 mg, diazepam 10 mg, tory, and others may become irritable and impulsive.
chlordiazepoxide 25 mg). In the case of barbiturate with- Cardiac arrhythmias may occur and may be fatal (GS King
drawal it is traditional to utilize phenobarbital, with doses et al. 1985; Steffee et al. 1996). Convulsions, coma, and res-
of 90–120 mg every 1–2 hours until symptoms are con- piratory depression may also be seen (King et al. 1981), as
trolled, after which the dose may, as with the benzodi- may acute hepatitis and renal failure (Gupta et al. 1991;
azepines, be gradually tapered. Taverner et al. 1988). If leaded gasoline is sniffed, intoxica-
An alternative to consider in the case of benzodiazepine tion may be accompanied by chorea and myoclonus
withdrawal is carbamazepine (Schweizer et al. 1991). Once (Goldings and Stewart 1982).
symptoms have been adequately controlled with the ben- Tolerance may develop and, when this occurs, with-
zodiazepine, one may add carbamazepine in a dose of 200 mg drawal may also appear. Withdrawal (Evans and Raistrick
three or four times daily, after which the benzodiazepine 1987; Watson 1979) occurs within 1–2 days of abstinence
may be rapidly tapered over a day or two. Importantly, car- and is characterized by irritability, sweating, tremulous-
bamazepine is not effective for barbiturate withdrawal and ness, and insomnia, all of which generally remit within a
may also be ineffective in the case of alprazolam. matter of days.
Sedative–hypnotic withdrawal seizures should be With long-term use a dementia may occur (discussed in
treated by rapidly reinstituting the sedative–hypnotic in Section 22.12), as may a severe motor peripheral polyneu-
question, with the goal of completely controlling any con- ropathy (Altenkirch et al. 1977; PJ King et al. 1985).
current withdrawal symptomatology.
Sedative–hypnotic withdrawal delirium demands vig-
Course
orous treatment of the withdrawal syndrome, with the goal
of producing a light degree of sedation. Should hallucina-
Occasional, recreational use of inhalants is not uncommon
tions and delusions persist in a troubling fashion, an
among adolescents; abuse and addiction appear to be far
antipsychotic, as described in Section 5.3, may be required.
less common. In many cases other substances are also used,
Once symptoms have been brought under control, the
especially alcohol and opioids.
sedative–hypnotic may be gradually tapered in daily decre-
ments approximately equivalent to 10 percent of the total
daily dose initially required to effect control. Etiology
Overall, the goal of treatment in the case of abuse or
addiction is abstinence. Those addicted to sedative– Although the intoxicating hydrocarbons clearly have an
hypnotics alone, or to a combination of a sedative–hypnotic effect on lipid neuronal cell membranes, the precise mech-
and alcohol, may do well in AA. anism whereby intoxication occurs is not known.
21.7 INHALENTS (SOLVENTS) Differential diagnosis
The volatile ingredients of many readily available products Intoxication with alcohol or sedative–hypnotics may yield
are often inhaled for intoxication. These include airplane or a somewhat similar clinical picture. The odor of solvents
model glue, paint thinner, kerosene, gasoline, fingernail pol- on clothing or skin may be a clue, as may a rash on the face;
ish remover, the propellants in aerosol sprays and spray if toluene has been used it may be detected in the blood for
paints, and typewriter correction fluid. Each of these products days (King et al. 1981).
p 21.qxd 3/10/08 9:58 AM Page 670
Treatment safety in some other way. This ‘cannabis-induced psy-

chotic disorder’ generally outlasts the intoxication itself
Simple observation is generally sufficient. Patients who and indeed may persist for days. Before leaving this discus-
also abuse or are dependent on alcohol or opioids may be sion of psychosis, mention should also be made of the pos-
referred to Alcoholics Anonymous or Narcotics Anonymous; sible occurrence of a chronic psychosis secondary to cannabis
the optimal treatment of those who are solely involved with use. This is a controversial notion. Although there is no
inhalants is not clear. doubt that, in the midst of chronic cannabis use, some
patients will develop a psychosis with delusions of persecu-
tion and auditory hallucinations which may persist for
21.8 CANNABIS years into abstinence, what is in doubt is whether this psy-
chosis was caused by cannabis or merely represents the
The name ‘cannabis’ comes from the Greek word for hemp occurrence of paranoid schizophrenia in a patient who also
and refers specifically to the flowering tops of the hemp happens to have a history of chronic cannabis use.
plant, Cannabis sativa. In the United States, the two most Delirium (Chopra and Smith 1974; Palsson et al. 1982)
common preparations of cannabis are marijuana and may also occur during an intoxication, but generally only
hashish. Marijuana (also known as ‘grass’, ‘pot’, ‘reefer’, when very high doses have been taken. Patients become
‘weed’ or ‘Mary Jane’) is simply a dried collection of the confused, agitated, and at times incoherent; delusions and
flowers and nearby leaves and sprouts of the hemp plant hallucinations may also occur. This delirium may either clear
and, although at times ingested, it is usually rolled into a as the intoxication does, or may persist for up to a few days.
cigarette and smoked. Hashish is a more potent prepara- Tolerance to cannabis can develop and is manifest by a
tion, composed of the resin scraped from the leaves and decreased euphoric response and a diminution of the
flowers of the plant, and is usually smoked. tachycardia and elevated supine blood pressure normally
seen during intoxication.
Withdrawal (Duffy et al. 1996; Haney et al. 1999;
Clinical features Mendelson et al. 1984) may occur in tolerant patients, and
typically appears anywhere from 3 to 12 hours after the res-
Intoxication with cannabis (Allentuck and Bowman 1942; olution of intoxication. Symptoms are typically mild and
Bromberg 1934; Clark and Nakashima 1968; Clark et al. consist of anxiety, irritability, restlessness, a fine tremor,
1970; Klonoff et al. 1973; Melges 1976) is characterized by diaphoresis, and insomnia. Withdrawal symptoms reach a
a dreamy sense of well-being, an unusual heightening of peak intensity within 1–2 days and then resolve after a total
the senses, and a feeling that time is slowing down or disin- of 4–5 days.
tegrating (Melges et al. 1970). Thinking becomes slowed
and patients often develop a heightened sense of the
ridiculous, laughing and giggling at otherwise prosaic Course
things; in some cases depersonalization or derealization
may occur. Typically, intoxication is accompanied by con- Recreational use of cannabis is extremely common among
junctival injection, dry mouth, increased appetite, mild adolescents and young adults, and most of these individu-
ataxia, mild tachycardia, and a combination of increased als either stop entirely or greatly reduce their use as they
supine blood pressure and orthostatic hypotension. In begin to assume adult responsibilities. Cannabis abuse is
general, symptoms undergo substantial resolution after 3 marked by frequent intoxication despite social and legal
or 4 hours. Tetrahydrocannabinol (THC) or its metabo- consequences, and dependence is heralded by the onset of
lites, however, may be detected in the urine for 2–6 days in tolerance and withdrawal. Overall, abuse and dependence
infrequent users, and in chronic heavy users the urine may are far less common than recreational use, occurring in no
remain positive for several weeks. more than 5 percent of adolescents and young adults.
In a minority of cases of intoxication, complications
may occur, including anxiety, psychosis, and delirium.
Anxiety may occur during otherwise unremarkable Etiology
intoxications and may at times crescendo to constitute an
anxiety attack (Bromberg 1934), with tremor, tachycardia, The principal intoxicant in cannabis is the delta-9 isomer
and palpitations; typically the anxiety resolves as does the of THC (Isbell et al. 1967). Marijuana contains anywhere
intoxication. from 1 to 15 percent THC, whereas the more potent hashish
Psychosis (Kroll 1975; Mathers and Ghodse 1992; contains anywhere from 10 to 60 percent. THC is highly
Talbott and Teague 1969; Weil 1970) may also occur dur- lipid soluble and readily crosses the blood–brain barrier. Two
ing an intoxication and patients may develop delusions of endogenous cannabinoid receptors have been identified
persecution, which may be accompanied by auditory or within the central nervous system, namely CB1 and CB2;
visual hallucinations. Patients may become quite agitated CB1 receptors appear to be responsible for the euphoria
in the midst of this, and some will flee the scene or seek and are concentrated in the cerebral cortex, hippocampus,
p 21.qxd 3/10/08 9:58 AM Page 671
21.9 Opioids 671
basal ganglia, and cerebellar cortex, and recent data suggest is then injected. Most addicts progress from ‘skin pop-
that different polymorphisms in the gene for CB1 may ping’, or subcutaneous injection, to ‘mainlining’ the drug
confer different risks for the development of cannabis intravenously. Occasionally heroin may be snorted or
addiction (Hopfer et al. 2006). smoked, or, in the process known as ‘chasing the dragon’,
heated, with subsequent inhalation of the heroin vapor.
Clinical features
Uncomplicated intoxication with cannabis may be mim-
icked by intoxication with alcohol, sedative–hypnotics, Intoxication with opioids is intensely seductive. Within
inhalants, and opioids, and cannabis intoxication compli- moments of intravenous injection, the user may be
cated by psychosis or delirium may be confused with hallu- rewarded by an intense ‘rush’. The body is suffused with
cinogen or phencyclidine intoxication; furthermore, many warmth, and orgasmic sensations may be experienced. In
patients may present with a mixed intoxication, having uti- less than a minute the rush tends to pass, to be replaced by
lized both cannabis and one or more of these other sub- a drowsy, vaguely euphoric feeling that may last for hours
stances. History and urine drug screens may be required to and which is accompanied by difficulty with concentration
make the differential diagnosis. and dysarthria. The pupils are generally constricted, peri-
stalsis is slowed, and constipation ensues; urinary hesi-
tancy or retention may also occur.
Treatment Meperidine and pentazocine intoxication have distinctive
features. Meperidine is metabolized to normeperidine, and
Uncomplicated intoxication generally requires only obser- this metabolite may cause agitation, tremor, mydriasis,
vation until the intoxication has passed. Anxiety, if trou- increased deep tendon reflexes, and, occasionally, myoclonus
bling, may be relieved by diazepam, in a dose of 10 mg. or seizures (Kaiko et al. 1983). Pentazocine intoxication,
Psychosis, if problematic, may be treated with a dose of an when high doses are utilized, may be accompanied by dys-
antipsychotic, such as 5 mg of haloperidol or 1–2 mg of phoria, anxiety, hallucinations, and bizarre thoughts, along
risperidone, with repeat doses as needed. Delirious with dizziness and diaphoresis (Challoner et al. 1990).
patients should be closely monitored until the delirium has Overdoses of opioids are not uncommon. The purity of
passed, and may be treated as outlined in Section 5.3. ‘street’ heroin varies widely, and the unwary user may unin-
Cannabis withdrawal generally does not require treatment. tentionally take a lethal amount; furthermore, some addicts,
The overall goal of treatment in abusers and addicts is after a period of abstinence during which tolerance is lost,
abstinence, and various forms of psychotherapy have been may resume use with a dose that, although prior to the loss
attempted. Unfortunately, many adolescents and young of tolerance produced only intoxication, is now sufficient to
adults simply see nothing wrong with their use, and often cause overdose. Overdose itself is characterized by stupor or
drop out of treatment. coma, accompanied by hypotension and respiratory depres-
sion. Pupils are initially pinpoint; however, with the advent
of cerebral anoxia, mydriasis appears. Pulmonary edema
21.9 OPIOIDS and seizures may occur, and death is usually due to respira-
tory arrest. Those who survive may be left with an anoxic
An opiate is any intoxicant normally found in opium. The dementia or sequelae of watershed infarctions.
term ‘opioid’ is more general and refers to any substance, Tolerance may develop to almost all of the effects of
either natural or synthetic, that has effects similar to opioids (with the exception of miosis and constipation)
opium. and addicts may progressively increase their doses to
Opium is obtained from the juice of the poppy plant, and obtain intoxication, sometimes to stunning levels of a
two opiates are found within opium, namely morphine and gram or more of morphine.
codeine. Synthetic and semi-synthetic derivatives include Withdrawal is characterized initially by a sense of
heroin, oxycodone, hydromorphone, meperidine, penta- uneasiness and a craving for the drug; soon after, yawning,
zocine, methadone, and buprenorphine: these last two lacrimation, and rhinorrhea appear, accompanied in some
derivatives, although often used in the treatment of opioid cases by diaphoresis. After several hours, patients may fall
withdrawal and addiction, may also be used for intoxication into a restless sleep known as ‘yen’ sleep. Upon awakening,
(Torrens et al. 1993). Of all of the opioids, oxycodone and all of the earlier symptoms intensify and patients become
heroin are the most commonly used for intoxication. irritable, dysphoric, restless, and demanding. Patients
Although these drugs may be taken orally for intoxica- begin to experience waves of goose flesh that may be so
tion, most users prefer a parenteral route as the effect is severe that they resemble the skin of a plucked turkey, an
more immediate and intense; tablets may be crushed, disappearance that prompted the phrase ‘going cold turkey’.
solved, and filtered (often utilizing cigarette filters) to yield Intense bone and muscle pain, especially in the back, arms,
a more or less adulterated and contaminated liquid, which and legs, also occurs, and patients may engage in seemingly
p 21.qxd 3/10/08 9:58 AM Page 672
involuntary kicking movements, a phenomenon that gave environment of most patients who become addicted,
rise to another synonym for opioid withdrawal, namely whose parents are often themselves afflicted with opioid
‘kicking the habit’. Insomnia may be severe. The pupils are addiction, alcoholism, or other substance use disorders.
dilated and the temperature, pulse, and blood pressure are
all increased. Nausea, vomiting, intestinal cramping, and
diarrhea occur, and the resulting fluid loss may be so severe Differential diagnosis
that it causes circulatory collapse.
Withdrawal usually begins within the first day of absti- Opioid intoxication may be partially mimicked by intoxi-
nence, peaks in a matter of days, and then generally subsides cation with alcohol, sedative–hypnotics or inhalants; how-
over a week or so; in heavy users, however, a protracted ever, these intoxications generally lack the intense miosis
withdrawal syndrome may persist for weeks up to 6 months, characteristic of most opioid intoxications; in doubtful
and is characterized by dysphoria, irritability, anhedonia, cases drug screening will resolve the issue. It must be borne
insomnia, and drug craving (Martin and Jasinski 1969). in mind, however, that many patients will use other sub-
Other disorders may accompany opioid abuse or addic- stances in addition to opioids: cocaine may be used to
tion. Intravenous use brings the risk of bacteremia with reduce sedation, and alcohol or sedative–hypnotics may be
pulmonary abscess, endocarditis, cerebral abscess, cerebral employed to ease the pain of withdrawal.
mycotic aneurysm, meningitis, osteomyelitis, and tetanus.
Parenteral users often share needles and are thus at risk for
acquired immune deficiency syndrome (AIDS), syphilis, Treatment
and hepatitis. Furthermore, the presence of particulates in
the injected fluid (as may occur when cigarette filters are Intoxication, if mild, may require only simple observation.
used) may lead to pulmonary fibrosis, pulmonary hyper- In severe intoxication, however, consideration should be
tension, and cor pulmonale. Particulates may also collect given to treatment with naloxone; however, care must be
in regional lymph nodes causing a chronic lymphadenopa- taken to avoid ‘overshooting’ in addicts and producing a
thy with edema, especially of the hands. hyperacute withdrawal syndrome.
‘Skin popping’ may be followed by cellulitis or ulcera- Withdrawal should generally only be attempted on a
tion, and those who inject heroin intramuscularly may secure inpatient unit, and, given the intense drug craving
develop a myositis, with, in some cases, ossification. seen during withdrawal, patients should be confined to the
Patients who ‘chase the dragon’ and inhale heroin vapor ward until the withdrawal has run its course; visitation, if
may develop a leukoencephalopathy with dementia allowed at all, must be closely and continuously supervised.
accompanied by other signs such as ataxia, mutism, or Currently, there are three traditional approaches that
quadriparesis. (Kriegstein et al. 1999). remain standard for withdrawal: ‘cold turkey’, withdrawal
Illegally manufactured ‘street’ meperidine may be with opioids, or treatment with clonidine. Recent work
contaminated with a by-product, methyl-phenyl- also suggests effectiveness for buspirone.
tetrahydropyridine (MPTP), which in turn may cause a Very few patients opt to go ‘cold turkey’; however, as
chronic parkinsonian condition. withdrawal is not life threatening, this may be appropriate
for some. Prochlorperazine may be given for nausea and
vomiting, diphenoxylate for diarrhea, and amitriptyline
Course
(in a dose of approximately 50 mg at bedtime) for insom-
nia (Srisurapanont and Jarusuraisin 1998), and these may
Recreational use of opioids is uncommon and most patients
also be made available for those who undergo treatment
pass fairly rapidly to abuse and addiction. Although some
with either opioids or clonidine.
addicts, notably physicians who may have ready access to
Withdrawal utilizing an opioid may be accomplished
opioids, are able to maintain their social positions, most
with methadone, buprenorphine, or, if the patient had
addicts quickly lose whatever gainful employ they may have
been using another illicit substance (e.g., oxycodone), with
had and turn to crime to support their addiction. Those who
that agent. Treatment is generally commenced as with-
become deeply involved in the drug ‘subculture’ are liable to
drawal symptoms appear. Methadone may be started in a
have a violent death at the hands of others; suicide attempts
dose of 10–20 mg, with repeat doses every 4 hours as
are also not uncommon, and those who do survive often end
needed to suppress symptoms. Most patients are stabilized
up losing all in their pursuit of the drug.
on a dose ranging from 20 to 40 mg daily, after which the
total daily dose may be reduced in decrements of 5–10 mg
Etiology daily. Buprenorphine may be given sublingually in an ini-
tial dose of 4–6 mg, with repeat doses as needed every 2
The intoxicant effects of opioids are mediated by their hours until symptoms are suppressed, a process that gener-
binding to mu and, to a lesser extent, kappa receptors ally requires anywhere from 8 to 32 mg; once the patient is
within the central nervous system. Genetic factors appear stabilized, the dose may be gradually tapered in daily
to increase the risk of addiction, as does the childhood decrements of 2–4 mg.
p 21.qxd 3/10/08 9:58 AM Page 673
21.10 Nicotine 673
Clonidine (Charney et al. 1981; Gold et al. 1978; Jasinski psychotherapy or referred to Narcotics Anonymous; many
et al. 1985) is not nearly as effective at suppressing with- also require a lengthy inpatient stay, not only to get over
drawal symptoms as opioids. Overall, it is most effective withdrawal but also to begin their rehabilitation efforts.
against nausea and diarrhea, and insomnia may also be Consideration may also be given to treatment with 50 mg
partially relieved; however, clonidine has little effect on of naltrexone daily, which blocks opioid-induced euphoria
drug craving, restlessness, and ‘kicking’. Once withdrawal and thus effectively blocks the overwhelmingly reinforcing
begins, clonidine is given in a dose ranging from 0.1 to ‘rush’ that patients get if they ‘slip’.
0.3 mg, with repeat doses every 2–3 hours until maximum In the United States, methadone maintenance is avail-
effect is obtained. The initial total dose is then given on a able only in specially licensed facilities. In some cases
daily basis in four divided doses, with provision for further indefinite maintenance is anticipated, and such patients
as-needed doses, after which the total daily dose is titrated are generally treated with doses of 80–120 mg of
up based on how much is given in as-needed doses until no methadone daily. In other cases consideration is given to
further as-needed doses are required; most patients are sta- eventual abstinence, and here patients are initially main-
bilized by a total daily dose ranging from 0.6 to 2.4 mg. The tained on doses ranging from 20 to 60 mg; once patients
patient is then generally ‘covered’ by this final dose for have consistently tested drug free for a year or so, attempts
about a week to a week and a half, that is to say for the are then made to reduce the dose of methadone in decre-
expected duration of the withdrawal, after which the dose ments of 5–10 percent of the total daily dose every week
may be tapered over 3 or 4 days and then discontinued. until the drug can be discontinued.
Buspirone, in a remarkable double-blind study (Buydens- Buprenorphine maintenance, given the less stringent
Branchey et al. 2005), was as effective in opioid withdrawal controls imposed on its use, is becoming popular, and is
as methadone. Patients were treated with a total dose of 30 conducted by individual physicians on an outpatient basis.
or 45 mg of buspirone, and this was maintained throughout Treatment is conducted with a combination product of
a 12-day withdrawal period. sublingual buprenorphine and naloxone: naloxone itself is
Choosing among these treatment options for with- not absorbed, but its presence serves as a deterrent to any-
drawal is not straightforward, with one exception: preg- one who would consider crushing the tablet and taking it
nant females should be withdrawn with opioids as any of intravenously, as the intravenously active naloxone will
the other options risks fetal death. Presuming that the block the intoxication. Most patients are managed with
patient is not pregnant, however, any one of these options doses ranging from 16 to 32 mg three times weekly. As with
is viable. Going ‘cold turkey’, as noted, is rarely chosen by methadone, some patients are continued indefinitely on
patients given the intense suffering associated with with- the drug, whereas in other cases attempts may be made to
drawal; however, some may prefer this. In those who do eventually taper it.
want pharmacologic treatment, most prefer withdrawal Maintenance with either methadone or buprenorphine
with opioids. However, a case may be made for treatment clearly ‘works’ in that such maintained patients are less
with clonidine or, perhaps, a combination of clonidine and likely to become intoxicated with illicitly obtained opioids
buspirone; in this scenario, patients may be started on bus- or to engage in the criminal behavior that often accompa-
pirone immediately and ‘covered’ with clonidine for any nies addiction. Both methadone and buprenorphine, how-
breakthrough symptoms, with the buspirone continued ever, as noted earlier, may produce intoxication, and
for the anticipated duration of the withdrawal. supplies obtained through maintenance programs have
Before leaving this discussion of the treatment of with- been used for this purpose.
drawal, some words are in order regarding what is known
as ‘rapid’ or ‘ultra-rapid’ detoxification. Although details
differ among various programs, in most cases patients are
21.10 NICOTINE
first ‘covered’ with clonidine and an anti-emetic and then
Although nicotine is the substance in question here, this
either sedated or anesthetized. In this state they are then
section might just as well be entitled ‘tobacco’, for tobacco
given naloxone and naltrexone and a hyperacute withdrawal
is the only ‘vehicle’ by which abuse or addiction to nicotine
is produced. Consciousness is then allowed to return and
occurs. Of the various ways that tobacco is used, cigarette
patients are continued on the naltrexone and, temporarily,
smoking is by far the most clinically important; although
on the clonidine and anti-emetic. Although these pro-
both chewing tobacco and smoking cigars or pipes can cause
grams are heavily advertised, it has not been established
addiction, their numbers pale in comparison to cigarettes.
whether they increase the odds of abstinence or whether
With each cigarette smoked, anywhere from 1 to 3 mg of
any purported successes outweigh the risks of anesthesia.
nicotine is delivered (Benowitz and Henningfield 1994).
Overall, in some cases the goal is abstinence from all
opioids, whereas in others the goal is to reduce the frequency
of intoxication by providing maintenance treatment with Clinical features
either methadone or buprenorphine.
Abstinence, although very difficult to achieve, is clearly Intoxication with nicotine is mild: especially with the first
preferable, and patients desiring this option may be seen in cigarette of the day, there is a sense of satisfaction and a
p 21.qxd 3/10/08 9:58 AM Page 674
reduction in any irritability. With this intoxication there clearly understood, genetic factors appear to play a signifi-
may be a mild tachycardia, elevation of blood pressure, and cant role (Kendler et al. 2000).
an increase in peristaltic activity, and in some cases there
may be palpitations; tobacco-naive patients may also expe-
rience nausea and vomiting. Overall, appetite decreases
and frequent smokers may lose some weight.
There is generally no diagnostic difficulty; in those who
Tolerance occurs rapidly and, by the end of a day spent
deny smoking, but who appear to be doing so, one may
smoking, there is little effect from a cigarette. Such toler-
obtain a urine screen for cotinine, one of the metabolites of
ance, however, rapidly decreases, such that by the next day
nicotine, which has a half-life of about 20 hours.
intoxication may again be achieved. Despite these daily
fluctuations, however, a chronic tolerance does develop.
Whereas a tobacco-naive patient may, as noted above, Treatment
experience toxic nausea and vomiting with one cigarette,
the nicotine addict may be able to smoke dozens of ciga- Patients should choose a ‘quit date’, which ideally should
rettes a day without any immediate adverse effects. fall during a relatively stress-free time in the not-too-distant
Withdrawal symptoms (Hughes and Hatsukami 1986; future. Patients should be instructed to stop smoking on
Hughes et al. 1991a) may appear within anywhere from that day and to avoid, if possible, situations or gatherings
hours to a day of abstinence. There is a restless craving for where smoking is likely to occur. Individual or group ther-
a cigarette, and patients become tense and irritable. apy with a cognitive–behavioral approach is helpful and
Headache, difficulty concentrating, and insomnia may should be offered to patients. Various pharmacologic
occur, as may increased appetite with, in some, substantial approaches are also available, including varenicline, bupro-
weight gain. Withdrawal generally peaks within days and pion, nortriptyline, and various preparations of nicotine.
then gradually subsides over a matter of weeks; in some, Importantly, both bupropion and nortriptyline are effective
however, mild withdrawal symptoms may persist for regardless of whether patients are depressed or not.
months, and in many cases the craving for a cigarette may Varenicline is a partial agonist at alpha4beta2 nicotinic
recur intermittently for years, often at times of stress. acetylcholine receptors, and reduces both nicotine intoxi-
Other disorders may appear in association with tobacco cation and craving. Treatment is begun 1 week before the
use, and these occur not as a result of the effects of nicotine quit date with 0.5 mg/day for 3 days, then 0.5 mg twice
itself but rather of the by-products of tobacco. Smoked daily for 3 days, and finally 1 mg twice daily thereafter, with
tobacco produces over 4000 different compounds, in both treatment continued for 3–12 months.
gaseous and particulate form. Gaseous components Bupropion is started 1 week before the quit date at
include carbon monoxide and hydrogen cyanide, whereas 150 mg daily and increased 3 days later to 150 mg twice
particulates contain a substance known as ‘tar’, which for daily, and then continued for 3–12 months.
the most part contains polycyclic aromated hydrocarbons. Nortriptyline is started 1 week before the quit date at
With chronic smoking, patients are at risk for cancer of the 25 mg daily, increased to 50 mg daily after 3 days, and then
mouth, larynx, and lung, chronic obstructive pulmonary to 75 mg 3 days later, after which it is continued for 3–12
disease (COPD), coronary artery disease, cerebrovascular months. Although studies measuring blood levels have not
disease, peripheral vascular disease, Raynaud’s phenome- been performed, it would not be unreasonable to check a
non, gingivitis, gastroesophageal reflux, cancer of the blood level after a week or so of the full dose and to make
esophagus, and peptic ulcer disease. Smoking during preg- appropriate adjustments based on the results.
nancy may cause spontaneous abortion, abruptio placen- Nicotine is available in a 24-hour patch delivering vari-
tae, and low birth weight. ous strengths of nicotine (commonly 7, 14, and 21 mg) and,
for as-needed dosage, in lozenges and gum tablets (both
available in 2-mg sizes) and a nasal spray (delivering
Course 0.5 mg). If a nicotine preparation is used, it should be
started on the quit date. If the patch is used, the 21-mg size
Recreational use of nicotine is very rare; those who start
should be used for a ‘pack a day’ smoker, with lower doses
smoking usually either stop in short order or go on to fairly
used for those who smoke less; the initial strength is then
rapidly develop nicotine addiction (with craving, toler-
continued until the patient has been abstinent for at least a
ance, and withdrawal) and persistent use, despite the
couple of weeks, after which one steps down to the next
development of one or more of the other disorders associ-
lowest size, which is then continued until the patient has
ated with tobacco use.
been abstinent for at least another 2 continuous weeks,
until finally the patch is discontinued. The as-needed
Etiology preparations are utilized with the goal of gradually reducing
the number of doses until they too can be discontinued.
Although the mechanisms that determine which patients Overall, it appears that varenicline is superior to bupro-
will stop and which will go on to develop addiction are not pion (Gonzales et al. 2006), which in turn appears superior
p 21.qxd 3/10/08 9:58 AM Page 675
21.12 Methanol 675
to nortriptyline (Wagena et al. 2005). Consideration may tolerance has occurred, withdrawal symptoms (Griffiths
also be given to combination treatment with bupropion et al. 1990; Hughes et al. 1991b; Silverman et al. 1992;
plus nicotine or nortriptyline plus nicotine, and it appears Strain et al. 1994) may appear anywhere from 12 to 24
that the combination of bupropion and nicotine may be hours after the last dose, with headache, poor concentra-
modestly more effective than bupropion alone (Jorenby tion, fatigue, anxiety, and depressed mood; these with-
et al. 1999). The combination of varenicline and nicotine is drawal symptoms tend to gradually subside within days to
not recommended. Nicotine alone, although superior a week of abstinence.
to placebo, is the least effective of the pharmacologic Other disorders associated with chronic caffeine use
approaches. Overall, it appears reasonable to start with include gastroesophageal reflux disease, peptic ulcer, fibro-
varenicline; should that prove ineffective or not tolerated, cystic disease, and hypertension; caffeine may also precipi-
then consideration may be given to bupropion with tate anxiety attacks seen in panic disorder (Boulenger et al.
or without supplemental nicotine. An exception to this 1984; Charney et al. 1985).
general rule is major depressive disorder. For reasons that
are not clear, patients with major depressive disorder, even
if they are not currently in the midst of a depressive Course
episode, are at high risk for recurrence of depression in the
first few months of abstinence from nicotine (Glassman Recreational use of caffeine is extraordinarily common.
et al. 2001), and for such patients it is appropriate to con- Abusive use, that is continued use despite recurrent intox-
sider treatment with either bupropion or nortriptyline. ication or the aggravation of some of the other disorders
Although the combination of varenicline and bupropion seen in association with caffeine use, is relatively uncom-
has not been formally evaluated, it may be considered an mon. Craving for caffeine does not appear to occur.
option in some cases.
Regardless of which approach is used, during the first
year at least, relapses are the rule rather than the exception,
Etiology
and such ‘slips’ should not be seen as failures. As weight
The intoxicating effects of caffeine appear to be mediated
gain is common during the first year, patients should be
by its competitive blockade of central nervous system
warned about this and instructed to begin a program of
adenosine receptors.
diet and exercise should they start to gain weight.
21.11 CAFFEINE
There is generally little difficulty here as the history is read-
Caffeine is the most commonly used substance in the ily obtained. Occasionally, patients with chronic caffeine
Western world. A cup of coffee contains about 100 mg of intoxication may present a picture which is similar to that
caffeine, a cup of tea about 50 mg, and over-the-counter seen in generalized anxiety disorder; however, the differen-
‘stimulant’, analgesic, and ‘cold’ remedies may contain tial is straightforward provided that the patient can abstain
anywhere from 25 to 200 mg. from caffeine for a few days (Greden 1974).
Clinical features Treatment

In caffeine-naive patients, about 100 mg of caffeine pro- With the exception of severe intoxication (which may
duces an increased sense of alertness and decreased fatigue. require intensive supportive care), specific treatment is
At doses ranging from 200 to 500 mg, however, intoxica- generally not required. In those with troublesome with-
tion (Hughes et al. 1991b; Rapoport et al. 1981) occurs, drawal, patients may be gradually tapered off their regular
with apprehensiveness, restlessness, tremor, tachycardia, dose in daily decrements approximately equal to 10 per-
headache, and insomnia. With higher doses, up to cent of the initial total daily dose.
1000 mg, an anxiety attack may occur, and some patients
may become very agitated; tremor and tachycardia are pro-
nounced and there may be premature beats and muscle 21.12 METHANOL
twitches. At doses of 5 g or more, severe intoxication
occurs and there may be serious ventricular arrhythmias, Methanol, also known as methyl alcohol or ‘wood alcohol’,
grand mal seizures, respiratory depression, and death is found in ‘canned heat’ preparations such as ‘Sterno’, in
(Curatolo and Robertson 1983). Most intoxications clear certain solvents and paint thinners, and as a ‘denaturant’
within 6–12 hours. added to ethanol, which is then sold tax-free as ‘denatured
Tolerance to caffeine may appear after only a couple alcohol’ for use as a cleaner. Methanol is at times used by
of weeks’ use of 500 mg or more daily. In cases in which desperate alcoholics when no other source of intoxication
p 21.qxd 3/10/08 9:58 AM Page 676
is at hand; methanol intoxication may also occur acciden- ethylene glycol intoxication by the absence of an odor of
tally with inhalation of fumes, absorption through the skin, alcohol.
or inadvertent ingestion. A confusing diagnostic picture may emerge when both
Methanol is metabolized first via alcohol dehydroge- methanol and ethanol are consumed, as may occur when
nase to formaldehyde and then via aldehyde dehydroge- denatured alcohol is ingested. As noted earlier, ethanol
nase to formic acid, which is the ultimate cause of the inhibits the metabolism of methanol to formic acid, and
devastating sequelae of methanol intoxication; formic acid hence the evolution of the second phase of methanol intox-
is not only directly toxic to neuronal mitochondria but also ication may be delayed until the ethanol is cleared, after
produces a severe systemic acidosis. Importantly, this is the which the remaining methanol is converted to formic acid.
same metabolic pathway used by ethanol, a fact of consid-
erable importance regarding not only the evolution of
methanol intoxication but also one of the traditional treat- Treatment
ments of this intoxication.
Methanol intoxication constitutes a medical emergency. If
Clinical features patients are seen within 2 hours of ingestion, gastric lavage
may be performed. Throughout treatment one must mon-
Clinically (Bennet et al. 1953; Erlanson et al. 1965; Hovda itor pH, bicarbonate levels, the anion gap, and methanol
et al. 2005; Kaplan 1962; Paasma et al. 2007; Wood and levels: initial methanol levels above 20 mg/dL are consid-
Buller 1904) the intoxication seen with methanol evolves ered toxic, and levels above 50 mg/dL are potentially life-
in a biphasic fashion. The initial response, occurring in threatening.
response to the methanol itself, is characterized by eupho- The cornerstone of treatment rests on delaying the
ria, headache, and nausea, all accompanied by an odor of transformation of methanol to formic acid. In the past this
alcohol on the breath. Subsequently, as formic acid begins was accomplished by giving ethanol, which binds preferen-
to accumulate in the following hours, there may be delir- tially to the enzymes responsible for the metabolism of
ium, restlessness, dizziness, vomiting, and bilateral blur- methanol to formic acid, thus preventing an overly rapid
ring or dimming of vision; with more severe intoxication, accumulation of formic acid. A more recent, and far better,
seizures, respiratory depression, and coma may supervene. option involves the administration of fomepizole, a drug
Methanol levels are generally above 30 mg/dL, and a meta- that inhibits alcohol dehydrogenase (Brent et al. 2001).
bolic acidosis is present with an increased anion gap Folic acid hastens the excretion of formic acid and may be
reflecting the presence of formic acid. Untreated, methanol given in doses of 50 mg intravenously every 6 hours. In
intoxication may be fatal in up to one-third of cases; those cases in which the foregoing measures are ineffective,
who survive generally recover from the intoxication in hemodialysis may be utilized to remove formic acid.
1–3 days, but may be left with one or more sequelae, such
as visual loss (Wood and Buller 1904), parkinson-
ism (Guggenheim et al. 1971), or dementia (McLean et al. 21.13 ISOPROPANOL
1980). Magnetic resonance scanning may reveal areas of
increased signal intensity on fluid-attenuated inversion Isopropanol, also known as isopropyl alcohol, is found in
recovery (FLAIR) and diffusion-weighted images in the aftershave lotions, hand lotions, hair tonics, and in ‘rub-
putamina and subcortical white matter. bing alcohol’. Among desperate alcoholics it may be
known as ‘rubby dubby’, with reference to the source in
rubbing alcohol, or as ‘blue heaven’, the latter name
Course
derived from the blue coloring often added to rubbing
alcohol. In part, isopropyl alcohol is metabolized via alco-
Repeated ingestion of methanol is uncommon, as most
hol dehydrogenase to acetone.
alcoholics learn their lesson.

Secondary to the direct toxicity of formic acid, there are wide- Intoxication (Lacouture et al. 1983; Rich et al. 1990) is
spread petechial hemorrhages involving the cortex, putamen characterized by mild euphoria, an odor of alcohol on the
(Erlanson et al. 1965; McLean et al. 1980), retina, and optic breath, dizziness, and ataxia, and may also be accompanied
nerve (Benton and Calhoun 1953; Sharpe et al. 1982). by headache, nausea, vomiting, and, in some cases,
hematemesis. With high doses, severe intoxication may
Differential diagnosis occur, with coma and respiratory depression. Isopropanol,
as noted, is converted to acetone, leading to both acetone-
Ethanol and isopropanol intoxication are distinguished by mia and acetonuria. The intoxication generally passes
the absence of features such as visual loss and delirium, and within 12 hours.
p 21.qxd 3/10/08 9:58 AM Page 677
References 677
Tolerance may occur; whereas 250 mL may constitute a Bach-y-Rita G, Lion JR, Climent CE et al. Episodic dyscontrol: a
lethal dose in a non-tolerant patient, alcoholics may be study of 130 violent patients. Am J Psychiatry 1971;
able to consume this much with little untoward effect. 127:1473–8.
Although withdrawal probably occurs, this has not been Banay RS. Pathologic reaction to alcohol. I. Review of the literature
documented. and original case reports. Q J Stud Alcohol 1944; 4:580–605.
Bartlett E, Hallin A, Chapman B et al. Selective sensitization to
the psychosis-inducing effects of cocaine: a possible marker
Course for addiction relapse vulnerability? Neuropsychopharmacology
1997; 16:77–82.
Isopropanol is generally taken by alcoholics for want of Bell DS. The experimental reproduction of amphetamine
something better and, once alcohol is available, its use is psychosis. Arch Gen Psychiatry 1973; 29:35–40.
abandoned. Bennet IL, Cary FM, Mitchell GL et al. Acute methyl alcohol
poisoning: a review based on experience in an outbreak of 323
cases. Medicine 1953; 32:431–63.
Etiology Benowitz NL, Henningfield JE. Establishing a nicotine threshold
for addiction. The implications for tobacco regulation. N Engl J
The mechanism whereby isopropanol produces intoxica- Med 1994; 331:123–5.
tion is probably similar to that for ethanol. Benton ED, Calhoun FP. The ocular effects of methyl alcohol
poisoning. Report of a catastrophe involving 320 persons. Arch
Ophthalmol 1953; 36:1677–85.
Bercel NA, Travis LE, Olinger LB et al. Model psychoses induced by
LSD-25 in normals. I. Psychophysiological investigations, with
The prominent nausea, with, in some cases, hematemesis,
special reference to the mechanism of the paranoid reaction.
helps to distinguish isopropanol from ethanol or methanol
Arch Neurol Psychiatry 1956; 75:588–611.
intoxication; furthermore, the absence of dimming of
Bolla KI, McCann UD, Ricaurte GA. Memory impairment in
vision argues against methanol intoxication. Ethylene gly-
abstinent MDMA (‘Ecstasy’) users. Neurology 1998;
col intoxication is suggested by an absence of the odor of
51:1532–7.
alcohol on the breath.
Boulenger JP, Uhde TW, Wolff EA et al. Increased sensitivity to
caffeine in patients with panic disorder: preliminary evidence.
Treatment Arch Gen Psychiatry 1984; 41:1067–71.
Brady KT, Lydiard RB, Malcolm R et al. Cocaine-induced psychosis.
If patients are seen within 2 hours of ingestion, gastric J Clin Psychiatry 1991; 52:509–12.
lavage may be performed. Hemodialysis (Freireich et al. Breier A, Charney DS, Nelson JC. Seizures induced by abrupt
1967) should be considered in cases of severe intoxication discontinuation of alprazolam. Am J Psychiatry 1984;
or when the isopropanol level is over 400 mg/dL. 141:1606–7.
Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment
of methanol poisoning. N Engl J Med 2001; 344:424–9.
REFERENCES Brogden RN, Goa KL. Flumazenil. A reappraisal of its
pharmacological properties and therapeutic efficacy as a
Abraham HD. Visual phenomenology of the LSD flashback. Arch benzodiazepine antagonist. Drugs 1991; 42:1061–89.
Gen Psychiatry 1983; 40:884–9. Bromberg W. Marijuana intoxication. Am J Psychiatry 1934;
Adachi J, Mizoi Y, Fukunaga T et al. Degrees of alcohol 91:303–30.
intoxication in 117 hospitalized cases. J Stud Alcohol 1991; Burke WM, Ravi NV, Dhopesh V et al. Prolonged presence of
52:448–53. metabolite in urine after compulsive cocaine use. J Clin
Alldredge BK, Lowenstein DH, Simon RP. Seizures associated with Psychiatry 1990; 51:145–8.
recreational drug abuse. Neurology 1989; 39:1037–9. Busto U, Sellers EM, Naranjo CA et al. Withdrawal reactions after
Allen RM, Young SJ. Phencyclidine induced psychosis. Am J long-term therapeutic use of benzodiazepines. N Engl J Med
Psychiatry 1978; 135:1081–4. 1986; 315:854–7.
Allentuck S, Bowman SM. The psychiatric aspects of marijuana Buydens-Branchey L, Brancey M, Reel-Brander C. Efficacy of
intoxication. Am J Psychiatry 1942; 99:248–50. buspirone in the treatment of opioid withdrawal. J Clin
Altenkirch H, Mager J, Stoltenburg G et al. Toxic polyneuropathies Psychopharmacol 2005; 25:230–6.
after sniffing a glue thinner. J Neurol 1977; 214:137–52. Carroll KM, Fenton LR, Ball SA et al. Efficacy of disulfiram and
Angrist B, Gershon S. The phenomenology of experimentally cognitive behavior therapy in cocaine-dependent outpatients:
induced amphetamine psychosis. Biol Psychiatry 1970; a randomized placebo-controlled trial. Arch Gen Psychiatry
2:95–107. 2004; 61:264–72.
Ashton H. Benzodiazepine withdrawal: an unfinished story. BMJ Challoner KR, McCarron MM, Newton EJ. Pentazocine (Talwin)
1984; 288:1135–40. intoxication: report of 57 cases. J Emerg Med 1990; 8:67–74.
p 21.qxd 3/10/08 9:58 AM Page 678
Charney DS, Sternberg DE, Kleber HD et al. The clinical use of Ewing JA, Elliot WJ, Maio LD et al. You don’t have to be a
clonidine in abrupt withdrawal from methadone: effects on neuroscientist to forget everything with triazolam but it helps.
blood pressure and specific signs and symptoms. Arch Gen JAMA 1988; 259:350–2.
Psychiatry 1981; 38:1273–7. Fahal IH, Sallomi DF, Yaqoob M et al. Acute renal failure after
Charney DS, Heninger GR, Jatlow PI. Increased anxiogenic effects ecstasy. BMJ 1992; 305:29.
of caffeine in panic disorders. Arch Gen Psychiatry 1985; Fischman MW, Schuster CR, Resnekov L et al. Cardiovascular and
42:233–43. subjective effects of intravenous cocaine administration in
Chopra GS, Smith JW. Psychotic reactions following marijuana humans. Arch Gen Psychiatry 1976; 33:983–9.
use in East Indians. Arch Gen Psychiatry 1974; 30:24–7. Fraser HF, Wiler A, Essig CF et al. Degree of physical dependence
Choy-Kwong M, Lipton RB. Dystonia related to cocaine induced by secobarbital or pentobarbital. JAMA 1958;
withdrawal: a case report and pathogenic hypothesis. 166:126–9.
Neurology 1989; 39:996–7. Fredericks EJ, Lazor MZ. Recurrent hypoglycemia associated with
Clark LD, Nakashima EN. Experimental studies of marijuana. Am J acute alcoholism. Ann Int Med 1963; 59:90–4.
Psychiatry 1968; 125:379–84. Fredericks RK, Lefkowitz DS, Challa VR et al. Cerebral vasculitis
Clark LD, Hughes R, Nakashima EN. Behavioral effects of associated with cocaine abuse. Stroke 1991; 22:1437–9.
marijuana. Arch Gen Psychiatry 1970; 23:193–8. Freedman DX. On the use and abuse of LSD. Arch Gen Psychiatry
Coid J. Mania a potu: a critical review of pathological 1968; 18:330–47.
intoxication. Psychol Med 1979; 9:709–19. Freireich AW, Cinqu TJ, Xanthaky G et al. Hemodialysis for
Covi L, Lipman RS, Pattison JH et al. Length of treatment with isopropanol poisoning. N Engl J Med 1967; 277:699.
anxiolytic sedatives and response to their sudden withdrawal. Frezza M, di Padova C, Pozzato G et al. High blood alcohol levels
Acta Psychiatr Scand 1973; 49:51. in women: the role of decreased gastric alcohol
Curatolo PW, Robertson D. The health consequences of caffeine. dehydrogenase activity and first-pass metabolism. N Engl J
Ann Intern Med 1983; 98:641–53. Med 1990; 322:95–9.
Curran FJ. The symptoms and treatment of barbiturate Frosch WA, Robbins ES, Stern M. Untoward reactions to lysergic
intoxication and psychosis. Am J Psychiatry 1938; 95:73–85. acid diethylamide (LSD) resulting in hospitalization. N Engl J
Curran FJ. Current views on the neuropsychiatric effects of Med 1965; 273:1235–9.
barbiturates and bromides. J Nerv Ment Dis 1944; Giannini AJ, Eighan MS, Loiselle RH et al. Comparison of
100:142–69. haloperidol and chlorpromazine in the treatment of
Dackis CA, Kampman KM, Lynch KG et al. A double-blind, phencyclidine psychosis. J Clin Pharmacol 1984; 24:202–4.
placebo-controlled trial of modafinil for cocaine dependence. Glassman AH, Covey LS, Stetner F et al. Smoking cessation and
Neuropsychopharmacology 2005; 30:205–11. the course of major depression: a follow-up study. Lancet
Daras M, Koppel BS, Atos-Radzion E. Cocaine-induced 2001; 357:1929–32.
choreoathetoid movements (‘crack dancing’). Neurology 1994; Gold MS, Redmond DE, Kleber HD. Clonidine blocks acute opiate
44:751–2. withdrawal symptoms. Lancet 1978; 2:599.
de Moura MC, Correla JP, Madeira F. Clinical alcohol Goldings AS, Stewart RM. Organic lead encephalopathy:
hypoglycemia. Ann Int Med 1967; 66:893–905. behavioral change and movement disorder following gasoline
Derlet RW, Rice P, Horowitz BZ et al. Amphetamine toxicity: inhalation. J Clin Psychiatry 1982; 43:70–2.
experience with 127 cases. J Emerg Med 1989; 7:157–61. Gonzales D, Rennard ST, Nides M et al. Varenicline, an
D’Onofrio G, Rathlev NK, Ulrich AS et al. Lorazepam for the alpha4beta2 nicotinic acetylcholine receptor partial agonist,
prevention of recurrent seizures related to alcohol. N Engl J vs. sustained-release bupropion and placebo for smoking
Med 1999; 340:915–19. cessation: a randomized controlled trial. JAMA 2006;
Drevets WC, Gautier C, Price JC et al. Amphetamine-induced 296:47–55.
dopamine release in human ventral striatum correlates with Gonzalez D, Desai R, Sofuoglu M et al. Clinical efficacy of
euphoria. Biol Psychiatry 2001; 49:81–96. gabapentin versus tiagabine for reducing cocaine use among
Duffy A, Millin R. Case study: withdrawal syndrome in adolescent cocaine dependent methadone-treated patients. Drug Alcohol
chronic cannabis users. J Am Acad Child Adol Psychiatry 1996; Depend 2007; 87:1–9.
35:1618–21. Goodwin DW. Two species of alcoholic ‘blackout.’ Am J Psychiatry
Ellinwood EH. Amphetamine psychosis. I. Description of the 1971; 127:1665–70.
individuals and the process. J Nerv Ment Dis 1967; Goodwin DW, Crane JB, Guze SB. Alcoholic ‘blackouts’: a review
144:273–83. and clinical study of 100 alcoholics. Am J Psychiatry 1969a;
Ellinwood EH. Assault and homicide associated with 126:191–8.
amphetamine abuse. Am J Psychiatry 1971; 127:1170–5. Goodwin DW, Crane JB, Guze SB. Phenomenological aspects of
Erlanson P, Fritz H, Hagstam KE et al. Severe methanol the alcoholic ‘blackout’. Br J Psychiatry 1969b; 115:1033–8.
intoxication. Arch Med Scand 1965; 177:393–408. Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F et al.
Evans AC, Raistrick D. Phenomenology of intoxication with Impaired cognitive performance in drug free users of
toluene-based adhesives and butane gas. Br J Psychiatry 1987; recreational ecstasy (MDMA). J Neurol Neurosurg Psychiatry
150:769–73. 2000; 68:719–25.
p 21.qxd 3/10/08 9:58 AM Page 679
References 679
Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J Hughes JR, Higgins ST, Bickel WK et al. Caffeine self-
Psychiatry 1974; 131:1089–92. administration, withdrawal, and adverse effects among coffee
Greenblatt DJ, Harmatz JS, Shapiro L et al. Sensitivity to triazolam drinkers. Arch Gen Psychiatry 1991b; 48:611–17.
in the elderly. N Engl J Med 1991; 324:1691–8. Isbell H, Altschul S, Kornetsky CH et al. Chronic barbiturate
Greene SL, Dargan PI, O’Connor N et al. Multiple toxicity from intoxication. Arch Neurol Psychiatry 1950; 64:1–28.
3,4-methlenedioxymethamphetamine (‘Ecstasy’). Am J Emerg Isbell H, Fraser HF, Wickler A et al. An experimental study of
Med 2003; 21:121–4. etiology of ‘rum fits’ and delirium tremens. Q J Stud Alcohol
Griffith JD, Cavanaugh J, Held J et al. Dextroamphetamine: 1955; 16:1–33.
evaluation of psychotomimetic properties in man. Arch Gen Isbell H, Belleville RE, Fraser HF et al. Studies on lysergic acid
Psychiatry 1972; 26:97–100. diethylamide (LSD-25). I. Effects in former morphine addicts
Griffiths RR, Evans SM, Heishman SJ et al. Low-dose caffeine and development of tolerance during chronic intoxication.
physical dependence in humans. J Pharmacol Exp Ther 1990; Arch Neurol Psychiatry 1956; 76:468–78.
255:1123–32. Isbell H, Gorodetzky CW, Jasinski D et al. Effects of (–) 9-trans-
Guggenheim MA, Courch JR, Weinberg W. Motor dysfunction as a tetrahydrocannabinol in man. Psychopharmacologia 1967;
permanent complication of methanol intoxication: 11:184–8.
presentation of a case with a beneficial response to levodopa Iwanami A, Sugiyama A, Kuroki N et al. Patients with
treatment. Arch Neurol 1971; 24:550–4. methamphetamine psychosis admitted to a psychiatric
Gupta RK, van der Meulen J, Johny KV. Oliguric acute renal failure hospital in Japan. Acta Psychiatr Scand 1994; 89:428–32.
due to glue-sniffing. Case report. Scand J Urol Nephrol 1991; Janowsky DS, Risch C. Amphetamine psychosis and psychotic
25:247–50. symptoms. Psychopharmacology 1979; 65:73–7.
Haney M, Ward AS, Comer SD et al. Abstinence symptoms Jasinski DR, Johnson RE, Kocher TR. Clonidine in morphine
following oral THC administration to humans. withdrawal: differential effects on signs and symptoms. Arch
Psychopharmacology 1999; 141:385–94. Gen Psychiatry 1985; 42:1063–6.
Harrington H, Heller HA, Dawson D et al. Intracerebral Javitt DC, Zukin SR. Recent advances in the phencyclidine model
hemorrhage and oral amphetamine. Arch Neurol 1983; of schizophrenia. Am J Psychiatry 1991; 148:1301–8.
40:503–7. Johnson BA, Ait-Daoud N, Bowden CL et al. Oral topiramate for
Hartung TK, Schofield E, Short AI et al. Hyponatremic states treatment of alcohol dependence: a randomized controlled
following 3,4-methylenedioxymethamphetamine (MDMA, trial. Lancet 2003; 361:1677–85.
‘ecstasy’) ingestion. Q J Med 2002; 95:431–7. Johnson BA, Roache JD, Ait-Daoud N et al. A preliminary
Heritch AJ, Capwell R, Roy-Byrne PR. A case of psychosis and randomized double-blind, placebo-controlled study of the
delirium following withdrawal from triazolam. J Clin safety and efficacy of ondansetron in the treatment of cocaine
Psychiatry 1987; 48:168–9. dependence. Drug Alcohol Depend 2006; 84:256–63.
Hollister LE, Gillespie HK. Marijuana, ethanol, and Johnson LC, Burdick JA, Smith J. Sleep during alcohol intake and
dextroamphetamine: mood and mental function alterations. withdrawal in the chronic alcoholic. Arch Gen Psychiatry 1970;
Arch Gen Psychiatry 1970; 23:199–203. 22:406–18.
Hollister LE, Prusmack JJ, Paulsen JAS et al. Comparison of three Jorenby DE, Leischow SJ, Nides MA et al. A controlled trial of
psychotropic drugs (psilocybin, JB-329, IT-290) in volunteer sustained-release bupropion, a nicotine patch, or both for
subjects. J Nerv Ment Dis 1960; 131:428–34. smoking cessation. N Engl J Med 1999; 340:685–91.
Hollister LE, Motzenbecker FP, Degan RO. Withdrawal reactions Juergens SM, Morse RM. Alprazolam dependence in seven
from chlordiazepoxide (Librium). Psychopharmacology 1961; patients. Am J Psychiatry 1988; 145:625–7.
2:63–8. Kaiko RF, Foley KM, Grabinski PY et al. Central nervous system
Hopfer CJ, Young SE, Purcell S et al. Cannabis receptor haplotype excitatory effects of meperidine in cancer patients. Ann Neurol
associated with fewer cannabis dependence symptoms in 1983; 13:180–5.
adolescents. Am J Genet B Neuropsychiatr Genet 2006; Kampman KM, Pettinati H, Lynch KG et al. A pilot trial of
141:895–901. topiramate for the treatment of cocaine dependence. Drug
Horowitz MJ. Flashbacks: recurrent intrusive images after the use Alcohol Depend 2004; 75:233–40.
of LSD. Am J Psychiatry 1969; 126:565–9. Kaplan K. Methyl alcohol poisoning. Am J Med Sci 1962; 244:170–4.
Hovda KE, Hunderi OH, Tajjord AB et al. Methanol outbreak in Kendler KS, Thornton LM, Pedersen NL. Tobacco consumption in
Norway: epidemiology, clinical features and prognostic signs. J Swedish twins reared apart and reared together. Arch Gen
Intern Med 2005; 258:181–90. Psychiatry 2000; 57:886–92.
Hsue PY McManus D, Selby V et al. Cardiac arrest in patients who Kiefer F, Jahn H, Tarnaske T et al. Comparing and combining
smoke crack cocaine. Am J Cardiol 2007; 99:822–4. naltrexone and acamprosate in relapse prevention of
Hughes JR, Hatsukami D. Signs and symptoms of tobacco alcoholism: a double-blind, placebo-controlled study. Arch
withdrawal. Arch Gen Psychiatry 1986; 43:289–94. Gen Psychiatry 2003; 60:92–9.
Hughes JR, Gust SW, Skoog K et al. Symptoms of tobacco King GS, Smialek JE, Trouthman WG. Sudden deaths in
withdrawal: a replication and extension. Arch Gen Psychiatry adolescents resulting from inhalation of typewriter correction
1991a; 48:52–9. fluid. JAMA 1985; 253:1604–9.
p 21.qxd 3/10/08 9:58 AM Page 680
King MD, Day RE, Oliver JS et al. Solvent encephalopathy. BMJ McCarron MM, Schulze BW, Thompson GA et al. Acute
1981; 283:663–5. phencyclidine intoxication: clinical patterns, complications,
King PJ, Morris JG, Pollard JD. Glue sniffing neuropathy. Aust N Z J and treatment. Ann Emerg Med 1981; 10:290–7.
Med 1985; 15:293–9. McGuire PK, Cope H, Fahy TA. Diversity of psychopathology
Kleber HD, Gawin FH. The spectrum of cocaine abuse and its associated with use of 3–4,methylenedioxyamphetamine
treatment. J Clin Psychiatry 1984; 45(suppl. 2):18–23. (‘Ecstasy’). Br J Psychiatry 1994; 165:391–5.
Klonoff DC, Andrews BT, Obana WG. Stroke associated with McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical
cocaine use. Arch Neurol 1989; 46:989–93. and pathological study. Ann Neurol 1980; 8:161–7.
Klonoff H, Low M, Marcus A. Neuropsychological effects of Malcolm R, Ballenger JC, Sturgis ET et al. Double-blind controlled
marijuana. Can Med Assoc J 1973; 108:150–7. trial comparing carbamazepine to oxazepam treatment of
Kosten TR, Price LH. Phenomenology and sequelae of 3,4- alcohol withdrawal. Am J Psychiatry 1989; 146:617–21.
methylenedioxymethamphetamine use. J Nerv Ment Dis 1992; Maletzky BM. The diagnosis of pathological intoxication. Q J Stud
180:353–4. Alcohol 1976; 37:1215–28.
Kramer JC, Fischman VS, Littlefield DC. Amphetamine abuse Manschreck TC, Allen DF, Neville M. Freebase psychosis: cases
patterns and effects of high doses taken intravenously. JAMA from a Bahamian epidemic of cocaine abuse. Compr Psychiatry
1967; 201:305–9. 1987; 28:555–64.
Krendel DA, Ditter SM, Frankel MR. Biopsy-proven cerebral vasculitis Martin WA, Jasinski DR. Physiological parameters of morphine
associated with cocaine abuse. Neurology 1990; 40:1092–4. dependence in man – tolerance, early abstinence and
Kriegstein AR, Shungu DC, Millar WS et al. Leukoencephalopathy protracted abstinence. J Psychiatr Res 1969; 7:7–9.
and raised brain lactate from heroin vapor inhalation (‘chasing Martinez-Cano H, Vela-Bueon A, de Iceta M et al. Benzodiazepine
the dragon’). Neurology 1999; 53:1765–73. withdrawal syndrome seizures. Pharmacopsychiatry 1995;
Kroll P. Psychoses associated with marijuana abuse in Thailand. J 28:257–62.
Nerv Ment Dis 1975; 161:149–56. Mathers DC, Ghodse AH. Cannabis and psychotic illness. Br J
Kuramochi H, Takahashi R. Psychopathology of LSD intoxication: Psychiatry 1992; 161:648–53.
study of experimental psychosis induced by LSD-25: May PRA, Ebaugh FG. Pathological intoxication, alcoholic
description of LSD symptoms in normal oriental subjects. Arch hallucinosis, and other reactions to alcohol: a clinical study. Q
Gen Psychiatry 1964; 11:151–61. J Stud Alcohol 1953; 14:200–27.
Lacouture PG, Watson S, Abrams A et al. Acute isopropyl alcohol Melges FT. Tracking difficulties and paranoid ideation during
intoxication: diagnosis and management. Am J Med 1983; hashish and alcohol intoxication. Am J Psychiatry 1976;
75:680–4. 133:1024–8.
Lahmeyer HW, Stock PG. Phencyclidine intoxication, physical Melges FT, Tinklenberg JR, Hollister LE et al. Temporal
restraint and acute renal failure. J Clin Psychiatry 1983; disintegration and depersonalization during marijuana
44:184–5. intoxication. Arch Gen Psychiatry 1970; 23:204–10.
Lerner AG, Gelkopf M, Skladman I et al. Clonazepam treatment of Mendelson JH, Mello NK, Lex BW et al. Marijuana withdrawal
lysergic acid diethylamide-induced hallucinogen persisting syndrome in a woman. Am J Psychiatry 1984; 141:1289–90.
perception disorder with anxiety features. Int Clin Meyer JS, Greifenstein F, Devault M. A new drug causing
Psychopharmacol 2003; 18:101–5. symptoms of sensory deprivation. J Nerv Ment Dis 1959;
Levy AB. Delirium and seizures due to abrupt alprazolam 129:54–61.
withdrawal: case report. J Clin Psychiatry 1984; 45:38–9. Minion GE, Slovid CM, Boutiette L. Severe alcohol intoxication: a
Lichtenfeld J, Rubin DB, Feldman RS. Subarachnoid hemorrhage study of 204 consecutive patients. Clin Toxicol 1989; 27:375–84.
precipitated by cocaine snorting. Arch Neurol 1986; 41:223–4. Morley KC, Teesson M, Reid SC et al. Naltrexone versus
Liester MB, Grob CS, Bravo GL et al. Phenomenology and sequelae acamprosate in the treatment of alcohol dependence: a multi-
of 3,4-methylenedioxymethamphetamine use. J Nerv Ment Dis centre, randomized, double-blind, placebo-controlled trial.
1992; 180:345–52. Addiction 2006; 101:1451–62.
Luby ED, Cohen BD, Rosenbaum G et al. Study of a new Morris HH, Estes ML. Traveler’s amnesia: transient global amnesia
schizophrenomimetic drug – Sernyl. Arch Neurol Psychiatry due to triazolam. JAMA 1987; 258:945–6.
1959; 81:363–9. Murphy SM, Owen RT, Tyrer PJ. Withdrawal symptoms after six
Lundh H, Tunving K. An extrapyramidal choreiform syndrome weeks’ treatment with diazepam. Lancet 1984; 2:1389.
caused by amphetamine addiction. J Neurol Neurosurg Murphy SM, Owen RT, Tyrer PJ. Comparative assessment of
Psychiatry 1981; 44:728–30. efficacy and withdrawal symptoms after 6 and 12 weeks’
Lundquist G. Delirium tremens: a comparative study of treatment with diazepam or buspirone. Br J Psychiatry 1989;
pathogenesis, course and prognosis. Acta Psychiatr Neurol 154:529–34.
Scand 1961; 36:443–66. Nielsen J. Delirium tremens in Copenhagen. Acta Psychiatr Scand
McCann UD, Szabo Z, Scheffel U et al. Positron emission 1965; 41(suppl. 187):1–92.
tomographic evidence of toxic effect of MDMA (‘Ecstasy’) on Nolte KB, Brass LM, Fletterick CF. Intracranial hemorrhage
brain serotonin neurons in human beings. Lancet 1998; associated with cocaine abuse: a prospective autopsy study.
352:1433–7. Neurology 1996; 46:1291–6.
p 21.qxd 3/10/08 9:58 AM Page 681
References 681
Noyes R, Perry PJ, Crowe RR et al. Seizures following withdrawal therapy: effects on withdrawal severity and outcome. Arch
of alprazolam. J Nerv Ment Dis 1986; 174:50–2. Gen Psychiatry 1991; 48:448–52.
Nurnberger JL, Simmons-Aling S, Kessler L et al. Separate Seifert J, Peters E, Jahn K et al. Treatment of alcohol withdrawal:
mechanisms for behavioral, cardiovascular, and hormonal clomethiazole vs. carbamazepine and the effect on memory
responses to dextroamphetamine in man. performance – a pilot study. Addict Biol 2004; 9:43–51.
Psychopharmacology 1984; 84:200–4. Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety
Paasma R, Hovda KE, Tikkerberi A et al. Methanol mass poisoning disorders. N Engl J Med 1993; 328:1398–405.
in Estonia: outbreak in 154 patients. Clin Toxicol 2007; Sharpe JA, Hostovsky M, Bilbao JM et al. Methanol optic
45:152–7. neuropathy: a histopathological study. Neurology 1982;
Palsson A, Thulin SO, Tunving K. Cannabis psychosis in south 32:1093–100.
Sweden. Acta Psychiatr Scand 1982; 66:311–21. Shearman JD, Chapman RWG, Satsangi J et al. Misuse of ecstasy.
Pascual-Leone A, Dhuna A. Cocaine-associated multifocal tics. BMJ 1992; 305:309.
Neurology 1990; 40:999–1000. Sherer MA, Kumor KM, Cone EJ et al. Suspiciousness induced by
Pearlson GD. Psychiatric and medical syndromes associated with four-hour intravenous infusion of cocaine. Preliminary
phencyclidine (PCP) abuse. Johns Hopkins Med J 1981; findings. Arch Gen Psychiatry 1988; 45:673–7.
148:25–33. Shoptaw S, Yang X, Rotheram-Fuller EJ et al. Randomized
Perr IN. Pathological intoxication and alcohol idiosyncratic placebo-controlled trial of baclofen for cocaine dependence:
intoxication. I. Diagnostic and clinical aspects. J Forensic Sci preliminary effects for individuals with chronic patterns of
1986; 31:806–11. cocaine use. J Clin Psychiatry 2003; 64:1440–8.
Rapoport JL, Jensvold M, Elkins R et al. Behavioral and cognitive Silverman K, Evans SM, Strain EC et al. Withdrawal syndrome
effects of caffeine in boys and adult males. J Nerv Ment Dis after the double-blind cessation of caffeine consumption. N
1981; 169:726–32. Engl J Med 1992; 327:1109–14.
Reoux JP, Saxon AJ, Malte CA et al. Divalproex sodium in alcohol Srisurapanont M, Jarusuraisin N. Amitriptyline vs. lorazepam in
withdrawal: a randomized double-blind placebo-controlled the treatment of opiate-withdrawal insomnia: a randomized
trial. Alcohol Clin Exp Res 2001; 25:1324–9. double-blind study. Acta Psychiatr Scand 1998; 97:233–5.
Ricaurte GA, Forno LS, Wilson MA et al. (⫾ )3,4- Steffee CH, Davis GJ, Nicol KK. A whiff of death: fatal volatile
methylenedioxymethamphetamine selectively damages central solvent inhalation abuse. South Med J. 1996; 89:879–84.
serotoninergic neurons in nonhuman primates. JAMA 1988; Strain EG, Mumford GK, Silverman K et al. Caffeine dependence
260:51–5. syndrome: evidence from case histories and experimental
Rich J, Scheife RT, Katz N et al. Isopropyl alcohol intoxication. evaluations. JAMA 1994; 272:1043–8.
Arch Neurol 1990; 47:322–4. Strassman RJ, Qualls CR. Dose–response study of N,N-
Rickels K, Schweizer E, Case G et al. Long-term therapeutic use of dimethyltryptamine in humans. I. Neuroendocrine, autonomic,
benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen and cardiovascular effects. Arch Gen Psychiatry 1994a;
Psychiatry 1990; 47:899–907. 51:85–97.
Roache J, Griffiths RR. Lorazepam and meprobamate dose effects Strassman, RJ, Qualls CR, Uhlenhuth EH et al. Dose-response of
in humans: behavioral effects and abuse liability. J Pharmacol N,N-dimethyltryptamine in humans. II. Subjective effects and
Exp Ther 1987; 243:978–88. preliminary results of a new rating scale. Arch Gen Psychiatry
Rosebush PI, Mazurek MF. Catatonia after benzodiazepine 1994b; 51:98–108.
withdrawal. J Clin Psychopharmacol 1996; 16:315–19. Stuppacek CH, Pycha R, Miller C et al. Carbamazepine versus
Rosenbaum M, Lewis M, Piker P et al. Convulsive seizures in oxazepam in the treatment of alcohol withdrawal: a double-
delirium tremens. Arch Neurol Psychiatry 1941; 45:486–93. blind study. Alcohol Alcoholism 1992; 27:153–8.
Rosse RB, Collins JP, Fay-McCarthy M et al. Phenomenologic Talbott JA, Teague JW. Marijuana psychosis. JAMA 1969;
comparison of the idiopathic psychosis of schizophrenia and 210:299–302.
drug-induced cocaine and phencyclidine psychoses: a Tamerin JS, Weiner S, Poppen R et al. Alcohol and memory:
retrospective study. Clin Neuropharmacol 1994; 17:349–69. amnesia and short-term memory function during
Roth D, Alarcon FJ, Fernandez JA. Acute rhabdomyolysis associated experimentally induced intoxication. Am J Psychiatry 1971;
with cocaine intoxication. N Engl J Med 1988; 319:673–7. 128:1659–64.
Satel SL, Southwick SM, Gawin FH. Clinical features of cocaine- Taverner D, Harrison DJ, Bell GM. Acute renal failure due to
induced paranoia. Am J Psychiatry 1991; 148:495–8. interstitial nephritis induced by ‘glue sniffing’ with subsequent
Scharf MB, Saskin P, Fletcher K. Benzodiazepine-induced amnesia: recovery. Scott Med J 1988; 33:246–7.
clinical laboratory findings. J Clin Psychiatry 1987; Monograph Torrens M, San L, Cami J. Buprenorphine versus heroin
5:14–17. dependence: comparison of toxicologic and psychopathologic
Schuckit MA, Smith TL, Anthenelli R et al. Clinical course of characteristics. Am J Psychiatry 1993; 150:822–4.
alcoholism in 636 male inpatients. Am J Psychiatry 1993; Tyrer HR, Owen R, Dawling S. Gradual withdrawal of diazepam
150:786–92. after long-term therapy. Lancet 1983; 1:1402–6.
Schweizer E, Rickels KV, Case WG et al. Carbamazepine treat- Ungerleider JT, Fisher DD, Fuller M. The dangers of LSD. JAMA
ment in patients discontinuing long-term benzodiazepine 1966; 197:389–92.
p 21.qxd 3/10/08 9:58 AM Page 682
Virmani R, Robinowitz M, Smialek JE et al. Cardiovascular effects Whitaker-Azmita PM, Aronson TA. ‘Ecstasy’ (MDMA)-induced
of cocaine: an autopsy study of 40 patients. Am Heart J 1988; panic. Am J Psychiatry 1989; 146:119.
115:1068–76. Winstock AR. Chronic paranoid psychosis after misuse of MDMA.
Wagena EJ, Knipschild PG, Huibers MJ et al. Efficacy of bupropion BMJ 1991; 302:1150–1.
and nortriptyline for smoking cessation among people at risk Wolkowitz OM, Weingartner H, Thompson K et al. Diazepam-
of or with chronic obstructive pulmonary disease. Arch Int induced amnesia: a neuropharmacological model of an
Med 2005; 165:2286–92. ‘organic amnesic syndrome’. Am J Psychiatry 1987; 144:25–9.
Watson JM. Glue sniffing: two case reports. Practitioner 1979; Wood CA, Buller F. Poisoning by wood alcohol. Cases of death and
222:845–7. blindness from Columbian spirits and other methylated
Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: preparations. JAMA 1904; 43:972–7, 1058–62, 1117–23,
affective state, sleep patterns, and MHPG excretion. Am J 1213–21.
Psychiatry 1972; 129:263–9. Yen DJ, Wang SJ, Ju TH et al. Stroke associated with
Weddington WW, Brown BS, Haertzen CA et al. Changes in mood, methamphetamine inhalation. Eur Neurol 1994; 34:16–22.
craving, and sleep during short-term abstinence reported by Zakzanis KK, Young DA. Memory impairment in abstinent MDMA
male cocaine addicts. Arch Gen Psychiatry 1990; 47:861–8. (‘Ecstasy’) users: a longitudinal investigation. Neurology 2001;
Weil AJ. Adverse reactions to marijuana. N Engl J Med 1970; 56:966–9.
282:997–1000. Zipursky RB, Baker RW, Zimmer B. Alprazolam withdrawal
Weiner AL, Vieira L. McKay CA et al. Ketamine abusers presenting delirium unresponsive to diazepam: case report. J Clin
to the emergency department: a case series. J Emerg Med Psychiatry 1985; 46:344–5.
2000; 18:447–51.
p 22.qxd 3/10/08 10:01 AM Page 683
22
Medication and substance-induced disorders
22.1 Neuroleptic malignant syndrome 683 22.8 Alcoholic dementia 692

22.2 Tardive dyskinesia 685 22.9 Alcohol hallucinosis 693
22.3 Supersensitivity psychosis 688 22.10 Alcoholic paranoia 694
22.4 Rabbit syndrome 689 22.11 Marchiafava–Bignami disease 694
22.5 Serotonin syndrome 689 22.12 Inhalent–Induced dementia 695
22.6 Anticholinergic delirium 690 References 695
22.1 NEUROLEPTIC MALIGNANT SYNDROME The full syndrome, as noted, is characterized by delirium,
fever, rigidity, and autonomic instability, and, although it
The neuroleptic malignant syndrome is a rare and poten- typically presents with rigidity, any one of these elements
tially fatal disorder characterized by delirium, fever, rigid- may be the presenting feature (Addonizio et al. 1987;
ity, and autonomic instability, which occurs secondary to Caroff 1980; Kellam 1987; Pope et al. 1986; Rosebush and
an abrupt diminution of dopaminergic tone, either due to Stewart 1989; Velamoor et al. 1994). Delirium may be pro-
the use of a dopamine-blocking agent, such as an antipsy- found, and patients may also develop stuporous catatonia
chotic, or, much less commonly, to discontinuation of a (Koch et al. 2000). Fever is generally over 38.9°C (102°F)
dopaminergic agent, such as levodopa. and, although most patients have at least some tempera-
Before proceeding further, some words are in order ture elevation, there are rare reports of the syndrome
regarding the name of this syndrome. This syndrome was occurring without fever (Peiris et al. 2000). Rigidity may be
first described in association with the use of antipsychotics; of either the lead pipe or cogwheel type, is typically gener-
at the time, the original name for an antipsychotic, namely alized, and may be profound, to the point of compromis-
‘neuroleptic’, was in use, and consequently this malignant ing chest wall movement. Rigidity may be accompanied by
syndrome was referred to as the neuroleptic malignant a generalized, coarse tremor and, in some cases, dystonia
syndrome. With the discovery that a reduction in dopami- or chorea may occur. Autonomic instability manifests with
nergic tone secondary to discontinuation of a dopaminer- pallor, diaphoresis, tachycardia, and elevated blood pres-
gic agent could also cause the syndrome, it might have sure, which may be quite labile.
been appropriate to change the name, perhaps to some- Rhabdomyolysis may occur (Jones and Dawson 1989),
thing like ‘hypodopaminergic malignant syndrome’; how- with myoglobinuria and, in some cases, acute renal failure.
ever, this didn’t occur. Another name change might also The white blood cell count is typically elevated to around
have been appropriate when ‘neuroleptic’ fell out of favor 15 000 cells/mm3, and the creatine phosphokinase level is
and the term ‘antipsychotic’ gained currency, such as to likewise increased, often to around 15 000 units/L. Lactate
‘antipsychotic malignant syndrome’; however, this too dehydrogenase, serum glutamic oxaloacetic transaminase,
failed to occur. Hence we are left with ‘neuroleptic malig- and alkaline phosphatase levels are also often elevated.
nant syndrome’, a term that, apparently, is going to persist. Aspiration or pulmonary emboli may occur and, in some
cases, respiratory failure may occur secondary to extreme
rigidity of the chest wall. A minority of patients develop
disseminated intravascular coagulation.
Clinical features
The onset is usually within a day or two of the diminution Course

in dopaminergic tone; exceptionally, the syndrome may
appear within an hour or, at the other extreme, be delayed The mortality rate is between 10 and 20 percent. Those
for weeks (Keck et al. 1987). who survive generally recover without sequelae within a
p 22.qxd 3/10/08 10:01 AM Page 684
684 Medication and substance-induced disorders
week or two, although an exception to this rule occurs in Differential diagnosis

the case of the neuroleptic malignant syndrome occurring
secondary to treatment with long-acting depot prepara- Malignant hyperthermia is distinguished by its associ-
tions of the antipsychotics fluphenazine, haloperidol or ation with the use of inhalational anesthetic agents or
risperidone, in which the syndrome generally extends for a succinylcholine.
month or more. Heat stroke is suggested by the appearance of symptoms
Rarely, rigidity or catatonia may persist for months, even during a ‘heat wave’ or secondary to strenuous exercise in
in cases in which a depot antipsychotic has not been used hot weather; furthermore, in heat stroke the skin is hot and
(Caroff et al. 2000). dry and there is no rigidity, in contest to the diaphoresis
and rigidity seen in the neuroleptic malignant syndrome.
Recently, a very similar syndrome has been described
secondary to abrupt discontinuation of long-term treat-
Etiology ment with either oral (Turner and Gainsborough 2001) or
intrathecal (Coffey et al. 2002) baclofen. Whether this
As noted earlier, the syndrome occurs secondary to an represents a distinct syndrome or merely a subtype of the
abrupt diminution of dopaminergic tone, and most neuroleptic malignant syndrome is not clear; in any case,
commonly this occurs secondary to either initiation of treat- symptoms subside with reinstitution of treatment.
ment with an antipsychotic or a substantial dose increase Patients with parkinsonism, for example patients with
(Kellam 1990). Although most cases have occurred Parkinson’s disease, who become febrile, for example
secondary to treatment with first-generation agents, such secondary to an infection, may resemble patients with the
as haloperidol, the neuroleptic malignant syndrome has neuroleptic malignant syndrome. Here, however, history
also been seen with second-generation agents, such as may reveal that the doses of the patient’s dopaminergic
risperidone (Levin et al. 1996; Meterissian 1996), olanzap- agents have not been reduced; furthermore, the tremor
ine (Levenson 1999; Suh et al. 2003), quetiapine (Sing et al. seen in parkinsonism is typically pill-rolling, in contrast to
2002), aripiprazole (Brunelle et al. 2007), ziprasidone the coarse tremor of the neuroleptic malignant syndrome.
(Ozen et al. 2007), and clozapine (Anderson and Powers Moderate or severe intoxication with phencyclidine is
1991; Das Gupta and Young 1991; Miller et al. 1991; distinguished by the absence of rigidity and by the presence
Sachdev et al. 1995). Other dopamine blockers may also of nystagmus or myoclonus. Severe intoxication with stim-
cause the syndrome, such as metoclopramide (Friedman ulants or with cocaine (Daras et al. 1995) may produce
et al. 1987) and promethazine (Mendhekar and Andrade delirium with diaphoresis, elevated temperature and pulse,
2005). The syndrome has also occurred secondary to and, in some cases, rigidity; hence, whenever there is
treatment with the antidepressant amoxapine (Taylor and doubt, a drug screen should be ordered.
Schwartz 1988); however, in all likelihood the cause here is Stauder’s lethal catatonia, discussed in Section 3.11,
not amoxapine but one of its metabolites, loxapine, which may arise out of excited catatonia and is characterized by
is also a first-generation antipsychotic. There are also reports severe agitation with fever, tachycardia, and a leukocytosis;
of the syndrome occurring after an antidepressant was with progression, stupor may supervene. As almost all cases
added to a stable dose of an antipsychotic, for example with of excited catatonia occur in schizophrenia, and as most
the addition of venlafaxine to trifluoperazine (Nimmagadda patients with schizophrenia are treated with an antipsy-
et al. 2000) or paroxetine to olanzapine (Kontaxakis et al. chotic, the overall clinical picture may appear similar to the
2003). neuroleptic malignant syndrome. Helpful diagnostic points
The neuroleptic malignant syndrome has also been seen include the history of preceding excited catatonia and the
upon the cessation of treatment with not only levodopa fact that lethal catatonia first presents with an increase
(Friedman et al. 1984; Gibb and Griffith 1986; Keyser and in agitation, in contrast to the neuroleptic malignant syn-
Rodnitzky 1991; Sechi et al. 1984; Toru et al. 1981) but also drome, which typically presents with rigidity and delirium
amantadine (Cunningham et al. 1991; Harsch 1987) and a (Castillo et al. 1989).
combination of levodopa and bromocriptine (Figa-
Talamanca et al. 1985). In addition, the neuroleptic malig-
nant syndrome has been reported secondary to the use of Treatment
the dopamine-depleting drug tetrabenazine (Ossemann
et al. 1996). The neuroleptic malignant syndrome constitutes a medical
Although the mechanism by which this abrupt diminu- emergency. Intensive supportive care is required, with par-
tion of dopaminergic tone produces the syndrome is not ticular attention to fluid and electrolyte balance; adequate
known with certainty, it is suspected that there is a corre- hydration must be assured to reduce the risk of renal fail-
sponding profound disturbance of hypothalamic function- ure. Cooling blankets may be required, as may ventilatory
ing, and indeed in one autopsied case necrotic changes support. In addition to these measures it is critical to
were present in the anterior and lateral hypothalamic restore dopaminergic tone as quickly as possible. Thus, if a
nuclei (Horn et al. 1988). neuroleptic agent is at fault it should be discontinued, and
p 22.qxd 3/10/08 10:01 AM Page 685
if a dopaminergic agent has been stopped it should be bucco-lingual-masticatory movements. Less commonly,
restarted. Another strategy includes the use of bromocrip- one encounters dystonic and akathetic forms, and rarely
tine and/or dantrolene (Granato et al. 1983; Guze and Baxter one may see tics or pain. Although some authors treat these
1985; May et al. 1983; Mueller et al. 1983). Although these less common forms as separate entities, this distinction
agents have not been assessed in controlled trials, anecdotal appears unwarranted. Another nosologic dispute centers
reports support their use. Bromocriptine is given orally, by on the question of whether there is any fundamental differ-
nasogastric tube if necessary, in doses ranging from 2.5 to ence between those cases that are permanent and those
20 mg t.i.d., and dantrolene is given intravenously in a dose in which the abnormal movements remit spontaneously
of 1–2 mg/kg, which is repeated as necessary to a maximum within a few months of the discontinuation of the antipsy-
of 10 mg/kg/24 hours. Recent double-blind work in cases chotic. Some have referred to the latter form as ‘withdrawal
secondary to withdrawal of dopaminergic agents in patients dyskinesia’, but this distinction too may be unwarranted; in
with Parkinson’s disease demonstrated that the addition of all likelihood, tardive dyskinesia, like many disorders,
intravenous methylprednisolone (1000 mg daily) to com- varies in severity, with some cases demonstrating perma-
bined treatment with bromocriptine (7.5 mg daily) and nent symptomatology and others displaying a spontaneous
dantrolene (75 mg daily) for a 3-day course not only fur- remission.
ther reduced the severity of the syndrome but also short- The overall prevalence of tardive dyskinesia in those
ened its overall course (Sato et al. 2003). Finally, there are treated chronically with first-generation antipsychotics is
case reports (Lattanzi et al. 2006; Wang and Hsieh 2001) of in the order of 20 percent (Woerner et al. 1991); the preva-
the successful use of subcutaneous apomorphine, which may lence in those treated with second-generation agents is far
be given in a dose of 2 mg every 3 hours for 2 days, then less (Beasley et al. 1999; Tenback et al. 2005).
every 6 hours for an additional 2 days (Lattanzi et al. 2006).
Another very important treatment option is electrocon-
vulsive therapy (ECT) (Caroff et al. 2000; Davis et al. 1991; Clinical features
Hermesh et al. 1987; Troller and Sachdev 1999), which
appears to be safe and effective in the treatment of antipsy- Although some cases of tardive dyskinesia have been
chotic-induced neuroleptic malignant syndrome. reported after only a month of treatment with an antipsy-
In many cases of the neuroleptic malignant syndrome chotic, this is quite rare; in general, at least 6 months are
occurring secondary to an antipsychotic, patients require required, and often 1 or more years pass before the abnor-
ongoing treatment. In such cases it has been found possible mal movements appear. An exception to this rule is seen in
to reinstitute treatment with an antipsychotic (Rosebush the elderly, in whom the latency between initiation of treat-
et al. 1989) provided that one waits for at least 2 weeks after ment and the appearance of abnormal movements may be
the neuroleptic malignant syndrome has entirely cleared much shorter (Kane and Smith 1982; Saltz et al. 1991).
and then reintroduces the antipsychotic cautiously, start- The mode of onset may be either acute or gradual. An
ing with a low dose and increasing very gradually. Although acute onset may occur when the antipsychotic is discontin-
there are case reports of the successful reinstitution of ued or the dose rapidly decreased, in which case an abrupt
treatment with the same agent that caused the syndrome, ‘unmasking’ occurs with an equally abrupt appearance of
prudence dictates using a different antipsychotic. Thus, if abnormal movements. Conversely, if the dose is maintained,
a high-potency first-generation agent was used, one should or decreased only slightly, the abnormal movements may
probably choose either a low-potency first-generation agent make their appearance gradually or insidiously.
or a second-generation one. If the syndrome has occurred As noted earlier, tardive dyskinesia may manifest with
secondary to a second-generation agent, then one might chorea, dystonia, akathisia, tics, or pain, and each of these
consider an alternate second-generation agent with a presentations is considered in turn.
statistically lower chance of producing extrapyramidal Choreiform movements in tardive dyskinesia are most
side-effects commonly found in the lower part of the face (Burke et al.
1982; Kang et al. 1986), less so in the extremities, and only
rarely in the trunk, and range in severity from mild to dis-
22.2 TARDIVE DYSKINESIA abling (Kennedy 1969). Classically, one sees buccolinguo-
masticatory movements in the face, with pursing or
Tardive dyskinesia is a movement disorder occurring as a puckering of the lips, chewing motions, and repetitive
side-effect of chronic treatment with antipsychotic drugs. tongue protrusions. Facial grimacing may also be seen, but
In contrast to the more common typical ‘extrapyramidal’ this, importantly, spares the forehead. Extremity involve-
side-effects seen with these agents, however, tardive dyski- ment may present with shoulder-shrugging or a restless
nesia does not remit promptly when the offending medica- piano-playing movement of the fingers and hands; in
tion is discontinued, but rather persists for prolonged the lower extremities there may be foot-tapping. Truncal
periods and may be permanent. involvement may manifest with axial to-and-fro rocking or
The most typical, and by far the most common, form with pelvic thrusting. Uncommonly, respiratory dyskinesias
of tardive dyskinesia is a choreiform one, often with may occur, with irregular, grunting respirations (Chiang
p 22.qxd 3/10/08 10:01 AM Page 686
et al. 1985; Ivanovitch et al. 1993; Rich and Radwany 1994; movements continue to lessen and, after many months or
Yassa and Lal 1986a). Critically, the choreiform movements a year or more, they go into a spontaneous remission. In
of tardive dyskinesia tend to be repetitive and stereotyped the remainder, however, only a partial remission occurs,
(Stacy et al. 1993); furthermore, they tend to wax and wane after which the abnormal movements persist indefinitely.
in severity throughout the day, and they disappear in sleep. This chronic course is more likely in the elderly and in
Some patients are able to suppress them voluntarily, but those who have been treated with very high doses.
such suppression is at best temporary and they inevitably Interestingly, choreiform movements in tardive dyski-
reappear. nesia are worsened by anticholinergics (Greil et al. 1984),
Dystonic movements (Burke et al. 1982; Kang et al. such as benztropine (Reunanen et al. 1982), and also
1986; Kiriakakis et al. 1998; Sachdev 1993a; Wojcik et al. may vary with mood. Patients who develop a depressive
1991; Yassa et al. 1986) typically appear focally and most syndrome typically experience a worsening of symptoms
commonly involve the face or neck, followed by the upper (Sachdev 1989), whereas during mania there may be a
extremity, the trunk, and the lower extremity. Over a long partial remission (de Potter et al. 1983; Yazici et al. 1991);
period of time, segmental spread to adjacent body parts symptom improvement has also been noted during
may occur, and, rarely, the dystonia may become general- catatonic stupor (Assmann and van Woerkom 1987).
ized (Burke et al. 1982; Wojcik et al. 1991). Facial involve-
ment may manifest with blepharospasm (Ananth et al.
1988; Glazer et al. 1983; Weiner et al. 1981), oromandibular Etiology
dystonia (Tan and Jankovic 2000), or oculogyric crises
(FitzGerald and Jankovic 1989; Sachdev 1993b). As with Although the vast majority of cases of tardive dyskinesia
chorea, the severity of tardive dystonia ranges from mild to occur secondary to treatment with antipsychotics, cases have
disabling (Yadalam et al. 1990). Importantly, many patients also been reported with other dopamine blockers, such as
with tardive dystonia will also have choreiform movements metoclopramide (Sewell and Jeste 1992; Sewell et al. 1994),
(Sachdev 1993a; Wojcik et al. 1991). and secondary to chronic treatment with the antidepres-
Akathisia occurring on a tardive basis is symptomatically sant amoxapine (Huang 1986; Thornton and Stahl 1984);
very similar to that occurring as an acute extrapyramidal in this latter case, however, it is probably not amoxapine
side-effect of an antipsychotic, with restlessness, marching that is at fault but rather one of its metabolites, loxapine,
in place, and ‘restless’ thoughts (Burke et al. 1989; Dufresne which is an antipsychotic.
and Wagner 1988; Lang 1994; Sachdev and Loneragan 1991). Given that all of the drugs capable of causing tardive
Tics may be either focal or multifocal, and at times are dyskinesia have one thing in common, namely a blockade
so extensive as to mimic the picture seen in Tourette’s syn- of post-synaptic dopamine receptors, and given that the
drome (Bharucha and Sethi 1995; Stahl 1980), thus prompt- risk of tardive dyskinesia increases with higher doses
ing the term ‘tardive tourettism’. (Morganstern and Glazer 1993) and a longer duration of
Pain represents the rarest expression of tardive dyskine- treatment (Glazer et al. 1993; Kane et al. 1988), it seems
sia, and patients may complain of burning pain in the mouth reasonable to suppose that it is some effect of the chronic
or genital area; this typically occurs in the setting of dopamine blockade that is etiologic in this disorder, and,
choreiform movements or akathisia (Ford et al. 1994). indeed, this is the basis for the dopamine up-regulation
hypothesis. According to this hypothesis, with chronic
dopamine blockade there is a gradually worsening com-
Course pensatory up-regulation of the post-synaptic receptors to
the point at which, if the dose of the dopamine blocker is
The course of tardive dyskinesia has been most thoroughly reduced, the ‘unmasking’ of these up-regulated receptors
studied with reference to the choreiform type. In situations leads to a hyperdopaminergic state and the production of
in which the antipsychotic is continued at a constant dose, the abnormal movements. Further support for a distur-
there is a gradual worsening of symptoms; although in most bance in dopamine transmission is provided by the response
cases the severity eventually reaches and stays at a plateau, to anticholinergics in tardive dyskinesia. Dopaminergic and
in a minority one sees a relentless progression (Gardos et al. cholinergic systems exist in a balance in the basal ganglia,
1988, 1994; Glazer et al. 1984; Yagi and Itoh 1987). Should such that an increase in dopaminergic tone may be mim-
the dose of the antipsychotic be substantially increased, icked by a reduction in cholinergic tone and vice versa.
there is a ‘masking’ of symptoms; however, this is tempo- Given this one would predict that, in patients with tardive
rary and they eventually reappear. Conversely, if the dose is dyskinesia, a reduction in cholinergic tone, as might occur
decreased, symptoms worsen. If the antipsychotic is dis- with the administration of an anticholinergic medication,
continued there is typically a pronounced worsening of would increase the abnormal movements, and this is
symptoms, which is followed, however, over the succeed- generally what happens (Klawans and Rubovits 1974).
ing weeks or months, by at least some diminution of symp- As attractive as this dopamine theory is, it does not
toms, after which one of two eventualities may ensue (Glazer account for several important findings. First, the fact that
et al. 1990). In some cases, perhaps one-third, abnormal acute antipsychotic-induced parkinsonism can co-exist with
p 22.qxd 3/10/08 10:01 AM Page 687
tardive dyskinesia (Richardson and Craig 1982) argues course: acute side-effects occur shortly after the initiation
against any generalized hyperdopaminergic state, as theo- or dose increase of an antipsychotic and subside with a
retically this should bring a relief of the parkinsonism. dose decrease or discontinuation; by contrast, tardive dys-
Second, some cases of the dystonic subtype of tardive dystonia and akathisia come on only after a long period of
kinesia may, as noted below, be relieved by, rather than treatment and worsen when the dose is decreased or the
worsened by, anticholinergic agents. Finally, if it were sim- antipsychotic is discontinued.
ply a matter of the compensatory up-regulation of the post- Tourette’s syndrome typically has an onset in childhood,
synaptic dopamine receptors, then providing that the dose and the presence of tics before treatment with antipsy-
of a neuroleptic were held constant, with no dose decrease, chotics makes the diagnosis straightforward. As noted in
one should not see any abnormal movements as there would Section 8.25, however, after a full or partial remission in
be no ‘unmasking’ and thus no hyperdopaminergic state. late adolescence, there may be a relapse decades later, and
Unfortunately for the theory, however, tardive dyskinesia if this relapse should occur in a patient being treated with
does in fact emerge while patients continue at the same an antipsychotic for another reason, diagnostic confusion
dose, a fact strongly suggesting that some other process, in may ensue; in such cases it is critical to obtain a childhood
addition perhaps to a progressive up-regulation, is at work. history, with special reference to the symptomatology of
The nature of this other process is not clear. Theories the prior tics to allow a comparison with the current ones.
include disturbances in GABAergic transmission, gluta-
mate toxicity, and progressive neuronal destruction by free
radicals produced in the course of neuroleptic treatment. Treatment
This last theory is of some interest given the evidence,
noted below, for the treatment efficacy of vitamin E, an The best ‘treatment’ is prevention, and chronic antipsy-
antioxidant. chotic treatment should not be undertaken for those dis-
orders for which other medications with better side-effect
profiles would be as effective.
Differential diagnosis When tardive dyskinesia does first appear, a decision
must be made as to whether ongoing treatment with a neu-
In evaluating a patient with abnormal movements the diag- roleptic is required, carefully weighing the risk of worsen-
nosis of tardive dyskinesia cannot be considered unless the ing dyskinesia against the risk of relapse. In the case of
patient has undergone chronic treatment with an antipsy- schizophrenia, the balance often tips towards continuing
chotic. The overall differential diagnoses of chorea, dystonia, neuroleptic treatment. If treatment is continued, efforts, if
akathisia, and tics are discussed in Sections 3.4, 3.7, 3.10, not already in place, should be made to keep the dose as low
and 3.3 respectively; of the disorders discussed in these as possible, consistent with adequate symptomatic control.
sections, several deserve special consideration. In the past it was felt that intermittent ‘drug holidays’ for
Choreiform movements may occur in both Huntington’s patients with schizophrenia might reduce the risk of
disease and schizophrenia, and both of these disorders tardive dyskinesia, but subsequent studies have suggested
are typically treated with antipsychotics. With regard to that drug holidays may actually increase the risk (Goldman
Huntington’s disease, genetic testing is of course diagnos- and Luchins 1984; van Harten et al. 1998; Jeste et al. 1979).
tic; however, certain clinical features may also allow a dif- In cases due to treatment with a first-generation antipsy-
ferentiation to be made, including the presence of forehead chotic, consideration should be given to switching to a
chorea and a ‘dancing and prancing’ gait, both of which second-generation agent; with such a switch, adequate
may be seen in Huntington’s disease but not in tardive symptom control is maintained or improved and the risk
dyskinesia. The nature of the chorea itself provides another of worsening tardive dyskinesia with further treatment is
differential point: in Huntington’s disease it is extremely lessened.
transient, flickering from one part of the body to another In cases in which treatment cannot be discontinued, or
in an almost random pattern, whereas in tardive dyskinesia in cases in which discontinuation is possible but symptoms
the chorea tends to be stereotyped, repetitive, and persist- fail to go into remission, various medical treatments may
ently recurring in the same area. Schizophrenia may at be considered, including vitamin E, vitamin B6, melatonin,
times be characterized by choreiform movements, as pointed branched chain amino acids, piracetam, and dopamine
out by Kraepelin in the early part of the twentieth century depletors, such as tetrabenazine, alpha-methyldopa or
(Kraepelin 1971) and confirmed by subsequent investiga- reserpine. In selected cases botulinum toxin may be con-
tors (Farran-Ridge 1926; Mettler and Crandall 1959; Owens sidered, and in severe, treatment-resistant cases both ECT
et al. 1982; Yarden and Discipio 1971); these choreiform and deep brain stimulation constitute options.
movements, however, are mild, generally involve the face, Vitamin E, in doses ranging from 1200 to 1600 IU daily
and are present before any treatment with antipsychotics. (divided into three doses), has been shown to be effective
Both dystonia and akathisia may occur as acute extrapyra- in most (Adler et al. 1993, 1998; Akhtar et al. 1993; Dabiri
midal side-effects of antipsychotics but are readily distin- et al. 1994; Egan et al. 1992; Elkashef et al. 1990; Lohr and
guished from tardive dystonia or tardive akathisia by their Caligiuri 1996; Lohr et al. 1988; Zhang et al. 2004), but not
p 22.qxd 3/10/08 10:01 AM Page 688
all (Adler et al. 1999; Shriqui et al. 1992), studies; weeks or of schizophrenia, and indeed some observers have
months may be required to see a treatment response. held that all reported cases of supersensitivity psychosis
Vitamin B6 may be given in a dose of 300 mg (Lerner et al. represent merely such exacerbations. However, the occur-
2001), and melatonin in a dose of 10 mg (Shamir et al. rence of this supersensitivity psychosis in patients treated
2001). From a pharmacologic viewpoint branched chain with antipsychotics who have never had symptoms of
amino acids constitute an interesting option (Richardson schizophrenia, or any other psychosis, clearly indicates that
et al. 2003). Administration of a combination of valine, the syndrome, although rare, does exist (Moore 1986).
isoleucine, and leucine (given in a ratio of 3:3:4 at a dose of
222 mg/kg three times daily) is followed by a fall in the
plasma levels of the aromatic amino acids tyrosine and Clinical features
tryptophan, with presumably a fall in central nervous sys-
tem levels of dopamine and serotonin, and it is this change After a year or more of treatment with an antipsychotic,
that presumably accounts for the improvement in the the syndrome emerges. This emergence may be fairly
tardive dyskinesia. Piracetam (not available in the United abrupt if the antipsychotic is discontinued or there is a
States), in a dose of 4800 mg/day, was recently found to be rapid dose reduction; in other cases a more gradual onset
effective (Libov et al. 2007). The dopamine depleters tetra- may occur, for example when the dose of the antipsychotic
benazine (Ondo et al. 1999) (not available in the United is held constant or only gradually and modestly decreased.
States), alpha-methyldopa, and reserpine (Huang et al. 1981) Clinically (Chouinard and Jones 1980; Kirkpatrick
are likewise effective, presumably because of the reduction et al. 1992; Moncrieff 2006; Steiner et al. 1990), patients
in dopaminergic tone. develop a psychosis characterized by delusions and halluci-
Of these options, the vitamins and melatonin are the nations. Tardive dyskinesia may or may not accompany
most benign, and one of these should probably be tried this development.
first; vitamin E has by far the most support and is a reason-
able starting point. In some cases combination treatment
with two or more of these agents may be appropriate. Course
Branched chain amino acid treatment is also generally
benign, but should not be used in diabetics. The dopamine Although the course has not been well-studied, it appears
depleters, given their unfavorable side-effect profile, that, in cases in which the antipsychotic is discontinued,
should generally be held in reserve. symptoms very gradually lessen; the percentage of cases that
Botulinum toxin may be considered in cases in which go on to full remission or a stable chronicity is not known.
the abnormal movement is well-localized, as may be seen
with certain choreiform movements or, more especially, Etiology
dystonia.
Anecdotally, ECT is effective for tardive dyskinesia Although the etiology is not known, it is speculated that
(Adityanjee 1990), especially in cases in which the patient with chronic treatment with antipsychotics there is an
is depressed (Hay et al. 1990). Deep brain stimulation of up-regulation of post-synaptic dopamine receptors within
the globus pallidus is effective (Damier et al. 2007) but for the limbic system leading to a chronic hyperdopaminergic
obvious reasons constitutes a last option. state. Of note, cases have also been described secondary to
Other options exist for tardive dystonia and for tardive chronic treatment with the dopamine-blocker metoclo-
akathisia. In the case of tardive dystonia, anecdotal reports pramide (Lu et al. 2002).
support treatment with high-dose anticholinergic agents
(Burke et al. 1982), such as 20 mg trihexyphenidyl (Fahn
1983); however, in cases in which the dystonia is accom- Differential diagnosis
panied by choreiform movements, these may worsen.
Anecdotally, tardive akathisia may respond to propranolol The diagnosis should only be entertained in patients who
(Yassa et al. 1988); however, high doses may be required. have been treated chronically with an antipsychotic or
other dopamine blocker.
As most patients treated chronically with antipsychotics
22.3 SUPERSENSITIVITY PSYCHOSIS have schizophrenia, the main differential for supersensitiv-
ity psychosis is an exacerbation of the schizophrenia. For
Supersensitivity psychosis represents a very rare side-effect example, consider the case of a patient with schizophrenia
of chronic treatment with antipsychotic drugs. As such, it who had been doing well and whose antipsychotic dose
bears a strong etiologic relationship to tardive dyskinesia, had been substantially reduced, after which there was a
and indeed this syndrome is also referred to as ‘tardive psy- reappearance of hallucinations or delusions. The question
chosis’. This is, for some, a controversial diagnosis. As noted here is whether this appearance of hallucinations and delu-
below (see Differential diagnosis) it may be difficult to dis- sions represents merely the schizophrenia or whether the
tinguish supersensitivity psychosis from an exacerbation patient now has two disorders, namely schizophrenia and
p 22.qxd 3/10/08 10:01 AM Page 689
22.5 Serotonin syndrome 689
supersensitivity psychosis. One helpful differential point Course

here lies in the course of the development of the hallucina-
tions and delusions: exacerbations of schizophrenia are With continued antipsychotic treatment the tremor becomes
generally leisurely affairs, spanning weeks or months; by more pronounced; with discontinuation of the antipsy-
contrast, supersensitivity psychosis appears fairly promptly, chotic the tremor gradually decreases in amplitude over
often within days. weeks or months and, in most, but not all, cases, eventually
Patients with major depression or with bipolar disorder remits.
may also be treated chronically with antipsychotics, and the
emergence of delusions and hallucinations in such patients
may or may not represent a supersensitivity psychosis. The Etiology
guiding differential point here is whether the delusions and
hallucinations emerge in the context of a severe depression Apart from the fact that this disorder generally occurs
or mania. If they do then they may well be simply part of secondary to antipsychotic treatment, the etiology is not
the expression of the underlying mood disorder; if, how- known. Whether it represents a kind of acute, antipsychotic-
ever, the patient was euthymic during the emergence of the induced parkinsonism, or rather a form of tardive dyskine-
psychosis, then the diagnosis of supersensitivity psychosis sia, is simply not clear. To complicate matters further there
is more likely. are rare reports of the rabbit syndrome occurring secondary
to treatment with antidepressants, such as imipramine
(Fornazzari et al. 1991) and citalopram (Parvin and Swartz
Treatment 2005).
The best treatment is prevention, and antipsychotics should
not be used chronically in conditions that may respond to Differential diagnosis
other agents.
In cases in which it is possible to discontinue the antipsy- Essential tremor can produce a tremor of the jaw and chin;
chotic, this should be carried out, in the hope of achieving however, the tremor here is generally more rapid than the
a gradual spontaneous remission. In cases in which ongo- ‘rabbit chewing’ movement seen in the rabbit syndrome;
ing treatment is required, or when discontinuation is not furthermore in essential tremor one also finds a tremor in
followed by a spontaneous remission, consideration may be the hands, something that is absent in the rabbit syndrome.
given to increasing the dose of the antipsychotic to suppress Parkinsonism may also cause a jaw tremor; however, in
symptoms; in such instances, if a first-generation agent has parkinsonism this is accompanied by tremor of the hands
been at fault it is probably appropriate to switch to a second- and, at some point, rigidity and bradykinesia, findings absent
generation one. Whether or not some of the treatments in the rabbit syndrome.
effective for tardive dyskinesia, such as vitamin E, are effec- Tardive dyskinesia may be considered, but the
tive here is not certain; however, given the benign nature of bucco-lingual-masticatory movement with repetitive tongue
these treatments a trial would be appropriate. protrusion is fundamentally different from the chewing
motion of the rabbit syndrome, in which the tongue is
spared. Furthermore, anticholinergics worsen tardive dysk-
22.4 RABBIT SYNDROME inesia, whereas, as noted below, they are of benefit in the
rabbit syndrome.
The rabbit syndrome is an uncommon movement disorder
that generally occurs secondary to chronic treatment with
an antipsychotic (Chiu et al. 1993; Yassa and Lal 1986b); Treatment
although first-generation agents are the most common
causes, cases have been reported with second-generation If possible, the antipsychotic should be discontinued to
agents. allow for a spontaneous resolution of the syndrome. If this
is not possible, or if symptoms fail to fully remit, treatment
Clinical features with an anticholinergic agent, such as benztropine (Todd
et al. 1983), is effective.
The onset is gradual, usually after a year or more of antipsy-
chotic treatment. Clinically (Decina et al. 1990; Deshmukh
et al. 1990; Todd et al. 1983), the syndrome is characterized 22.5 SEROTONIN SYNDROME
by a rhythmic rest tremor of the jaw, with a frequency and
amplitude such that the appearance is that of a rabbit The serotonin syndrome, characterized classically by delir-
chewing. Importantly, there is no involvement of the tongue ium and myoclonus, is a potentially fatal complication arising
or tremor elsewhere, nor is there any associated rigidity or from any pharmacologic maneuver that abruptly increases
bradykinesia. serotoninergic tone within the central nervous system.
p 22.qxd 3/10/08 10:01 AM Page 690
Clinical features Monotherapy with serotoninergic agents at therapeutic

doses can cause the syndrome, but this is quite rare; it has
The onset occurs within hours or days of one of the phar- been reported for SSRIs, tricyclics, venlafaxine, mirtazap-
macologic maneuvers noted below (see Etiology). ine, and trazodone. With overdoses of SSRIs, however, the
Clinically (Bodner et al. 1995; Boyer and Shannon 2005; syndrome is not uncommon.
Feighner et al. 1990; Mason et al. 2000; Sternbach 1991), Before leaving this discussion, mention should be made
patients present with varying admixtures of delirium, of tryptophan and of a relatively new antibiotic, linezolid.
myoclonus, dysarthria or ataxia, and hyper-reflexia (espe- Tryptophan, a serotonin precursor, has been banned in the
cially in the lower extremities). Other signs and symptoms United States but may be found in various ‘supplements’,
may include extensor plantar responses, coarse tremor, shiv- some of which may not be labelled as such, and the syn-
ering, and diaphoresis. In severe cases one may see hyper- drome has occurred with the combination of tryptophan
thermia, seizures, rhabdomyolysis, renal failure, cardiac and an MAOI, an SSRI or a tricyclic. Linezolid, in addition
arrhythmias, and disseminated intravascular coagulation. to being an antibiotic, also inhibits MAO, and there has
been some concern that it could have the same ability to
cause the serotonin syndrome as do the other MAOIs. As it
Course turns out, however, these fears are generally unfounded;
although cases have been reported with the combination of
Although potentially fatal, most patients recover, and if linezolid and an SSRI, they appear to be rare.
nothing else is done besides discontinuing the offending
medications, the syndrome gradually remits within any-
where from a day to a week. Differential diagnosis
The occurrence of delirium in the setting of any of the

Etiology pharmacologic maneuvers noted above, under Etiology,
should suggest the serotonin syndrome. In some cases,
This syndrome occurs secondary to any of a large number however, the medication history may not be available, and
of pharmacologic maneuvers, all of which have in com- here consideration must be given to other causes of the
mon the effect of abruptly increasing serontoninergic tone combination of delirium and myoclonus, including uremic
within the central nervous system. Although, as noted encephalopathy, hepatic encephalopathy, hyperosmolar
below, the syndrome has been reported after monotherapy non-ketotic hyperglycemia, Hashimoto’s encephalopathy,
with serotoninergic agents, this is very rare (except in the baclofen withdrawal, complex partial status epilepticus,
case of overdose) and the vast majority of cases occur sec- and encephalopathic pellagra.
ondary to combinations of agents. Of these combinations,
the one with by far the highest risk is an monamine oxidase Treatment
inhibitor (MAOI) and a selective serotonin reuptake
inhibitor (SSRI), and this combination should not be used. The offending medications must be discontinued and
Other combinations of some concern include the fol- vigorous supportive care should be provided; in cases of
lowing: an MAOI with a tricyclic or with venlafaxine; and severe hyperthermia, consideration should be given to
an SSRI with a tricyclic. With regard to the tricyclics, special paralysis with a non-depolarizing agent. Agitation may be
attention should be paid to the use of clomipramine, as it treated with lorazepam; however, specific treatment with
has strong serotoninergic effects. Although these combina- cyproheptadine, a serotonin antagonist, should be under-
tions can cause the syndrome, this is quite uncommon, and taken. Cyproheptadine may be given in a dose of 4–8 mg
indeed the combination of an MAOI and a tricylic is one of every 2 hours, or in a loading dose of 12 mg followed by 2 mg
the recommended treatments for resistant depression. every 2 hours, until symptoms are controlled or a maximum
Various other combinations have also been reported to dose of 32 mg is reached. Most patients respond within a
cause the syndrome, but in general these combinations are day; additional doses may or may not be required, depend-
quite safe. They include an MAOI with duloxetine, cycloben- ing, in part, on the half-lives of the medications at fault.
zaprine or meperidine; an SSRI in combination with any
one of the following: a triptan (e.g., sumatriptan), a second-
generation antipsychotic (e.g., risperidone, olanzapine or 22.6 ANTICHOLINERGIC DELIRIUM
quetiapine), an opioid (e.g., tramadol, fentanyl, hydro-
morphone, meperidine or pentazocine), carbamazepine, In sufficient dosage, any drug with anticholinergic properties
trazodone, mirtazapine, bupropion, buspirone, and, finally, that crosses the blood–brain barrier may cause a delirium.
levodopa; and lithium with a tricyclic, venlafaxine or a Old age and medical frailty increase the risk, and anticholin-
triptan. Unusual combinations include trazodone with ergic toxicity is a prominent cause of delirium in hospitalized
venlafaxine, buspirone or bupropion; buspirone and bupro- patients (Han et al. 2001), especially in post-operative cases
pion; and cyclobenzaprine and duloxetine. (Tune et al. 1981).
p 22.qxd 3/10/08 10:01 AM Page 691
Of some literary interest is the possibility that the (106°F), whereas in simple anticholinergic delirium it
Reverend Dimmesdale, of Nathaniel Hawthorne’s The rarely rises above 40°C (104°F). Certainly, the diagnosis of
Scarlet Letter, may himself have succumbed to an herbal heat stroke should not be considered unless the ambient
preparation with anticholinergic properties, administered temperature is quite high; however, in some cases of high
by the good Doctor Chillingworth (Khan 1984). ambient temperature when patients are taking anticholin-
ergics, one may be confronted with an etiologically mixed
picture in which the anticholinergic, by reducing sweating,
Clinical features sets the stage for the dramatic temperature increases seen
in heat stroke.
Clinically (Itil and Fink 1966), there is delirium and rest-
lessness or agitation, often accompanied by visual halluci-
nations. On examination, the temperature and pulse are Treatment
elevated, the skin is typically dry and flushed (at times to a
scarlet hue), the pupils are dilated, and the deep tendon The anticholinergic should be stopped and, if ingestion is
reflexes are brisk. Urinary retention may occur and, in recent, consideration may be given to gastric lavage or acti-
severe cases, there may be seizures, coma, respiratory depres- vated charcoal. General supportive measures include intra-
sion, and death. venous fluids and, if the temperature is significantly elevated,
cooling blankets. Seizures may be treated with lorazepam.
In emergent situations, treatment with physostigmine
Course (Beaver and Gavin 1998; Burns et al. 2000; Duvoisin and
Katz 1968; Stern 1983) may be considered; however, as noted
In the natural course of events, provided that the offending below, this carries some risk. Physostigmine may be given
medication is discontinued, there is a gradual remission of intravenously in a dose of 0.5–2 mg, at a rate no faster than
symptoms, consistent with the half-life of the anticholinergic 1 mg/min, with repeat doses every 5–10 minutes until
in question. the patient is out of danger. Given the half-life of most
anticholinergics, repeat doses of physostigmine are often
required, initially every 30–60 minutes. A failure to respond
Etiology to physostigmine essentially rules out a diagnosis of anti-
cholinergic delirium. Physostigmine is not a benign treat-
Any of a large number of drugs with anticholinergic prop-
ment and patients may develop bradycardia, asystole or
erties may, if given in sufficient dose, cause a delirium (Tune
seizures; furthermore, in cases of tricyclic overdose, physo-
et al. 1981); although in most cases relatively high doses are
stigmine has no effect on the development of arrhythmia,
required, individual sensitivity varies widely, and in some
which is the main concern in this situation. Consequently,
patients, especially the elderly, seemingly innocuous doses
many clinicians will opt for conservative treatment and
can have devastating results. Anticholinergically active drugs
simply let the offending agent ‘wash out’, allowing the
to consider include the following: atropine, scopolamine
delirium to resolve on its own. In severe cases, however,
(Vonderahe 1929; Ziskind 1988), and homatropine oph-
with significant temperature elevations, seizures, coma or
thalmic drops (Tune et al. 1992); anticholinergic anti-
respiratory depression, treatment is justified.
parkinsonian agents (De Smet et al. 1982) such as
benztropine, biperidin, and trihexyphenidyl (Porteous
and Ross 1956); tricyclic antidepressants (Goodwin 1983;
Preskorn and Simpson 1982); antihistamines such as 22.7 CHOLINERGIC REBOUND
diphenhydramine (Tejera et al. 1994) and hydroxyzine; low-
potency first-generation antipsychotics; cyclobenzaprine The abrupt discontinuation of medications with signifi-
(Engel and Chapron 1993); and oxybutynin and tolteri- cant anticholinergic properties may, in about one-third of
done (Tsao and Heilman 2003). Delirium has also been cases, be followed by a syndrome known as cholinergic
noted with ‘recreational’ intoxication with Angel’s trumpet rebound, or cholinergic overdrive.
(Datura stramonium) (Hall et al. 1977; Oberndorfer et al.
2002). Of all of these agents, diphenhydramine stands out
(Agostino et al. 2001), not so much because of its inherent Clinical features
toxicity but because of the frequency with which it is used
in hospitalized patients. The onset of cholinergic rebound is in large part deter-
mined by the half-life of the drug that has just undergone
abrupt discontinuation; thus, in the case of most tricyclic
Differential diagnosis antidepressants, the onset may be anticipated within 36–48
hours.
Heat stroke is clinically similar to anticholinergic delirium; Clinically (Dilsaver 1989; Dilsaver et al. 1983a; Petti and
however, in heat stroke the temperature is often at 41.1°C Law 1981), patients present with depressed mood, anxiety,
p 22.qxd 3/10/08 10:01 AM Page 692
malaise, and insomnia; typically, there is also nausea and Clinical features
abdominal cramping, with, at times, vomiting and diarrhea.
Alcoholic dementia presents insidiously, generally after
decades of alcoholism. Clinically (Lee et al. 1979; Lishman
Course 1981), patients typically present with a personality change,
with frontal lobe features: there is a general coarsening of
In the natural course of events, symptoms subside over personality and a heedless disregard for social conventions;
1–3 days. judgment becomes poor and some patients may become
apathetic. Over time cognitive deficits gradually accrue,
including short-term memory loss and concreteness; some
Etiology patients may also develop minor ‘cortical’ signs such as
apraxia, agnosia, and a minor degree of aphasia, but these
With chronic treatment with any drug possessing anti-
signs are often almost subclinical and never play a major
cholinergic properties there is a compensatory up-regulation
role in the overall clinical picture.
of post-synaptic acetylcholine receptors; if the drug is
Computed tomography (CT) (Carlen et al. 1981; Gurling
abruptly discontinued and there is insufficient time for a
et al. 1984; Harper et al. 1985) and magnetic resonance
gradual ‘down-regulation’, the increased number of recep-
(MR) (Jernigan et al. 1991; Schroth et al. 1988) scanning
tors is ‘unmasked’, resulting in an increase in cholinergic
reveal both cortical atrophy and ventricular dilation, and
transmission and the symptoms seen in this disorder
there is a correlation between the extent of atrophy and the
(Dilsaver et al. 1983b; Luchins et al. 1980). This has been
severity of the dementia (Carlen et al. 1981; Carlsson et al.
noted with tricyclic antidepressants (Dilsaver et al. 1983a;
1979).
Wolfe 1997), low-potency first-generation antipsychotics,
the second-generation antipsychotic clozapine (Delassus-
Guenault et al. 1999), and anti-parkinsonian anticholiner- Course
gics, such as benztropine, atropine, and scopolamine.
With continued drinking the dementia progresses and may
become profound; with abstinence a variable degree of
Differential diagnosis recovery may be expected over about a 6-month period
(Grant et al. 1984; Hambidge 1990), after which any remain-
The appearance of depressed mood and insomnia shortly ing deficits tend to persist indefinitely.
after stopping a tricyclic antidepressant may suggest a
relapse of depression; however, the abruptness of the onset
of symptoms is inconsistent with a relapse of depression, Etiology
which would not be expected for at least a matter of weeks
after stopping an antidepressant. Alcohol, in all likelihood, is directly toxic to the white mat-
ter and perhaps also to cortical neurons. Autopsy studies
have demonstrated a reduction in brain weight (Harper
Treatment and Blumbergs 1982; Torvik et al. 1982) with overall cere-
bral atrophy (Harper and Krill 1985; Lynch 1960; Neuberger
The best treatment is prevention, and medications with 1957), due primarily to loss of white matter (Harper et al.
strong anticholinergic effects should be tapered over 3 or 4 1985; Jensen and Pakkenberg 1993); there is also some evi-
days. In cases in which rebound does occur, some patients dence for neuronal loss, particularly in the superior frontal
may elect to simply wait it out. When symptoms are severe, cortex (Krill et al. 1997). Of note, it appears that some of
however, one may restart the original medication, or, if these changes may be reversible: with sobriety, MR scan-
this is not feasible, use another anticholinergic medication ning has revealed re-expansion of the brain (Pfefferbaum
(e.g., benztropine in a dose of 1–2 mg), and adjust the dose et al. 1995; Schroth et al. 1988; Zipursky et al. 1989),
to suppress symptoms, after which a gradual tapering may primarily as a result of enlargement of the white matter
be undertaken (Wolfe 1997). (Agartz et al. 2003).
22.8 ALCOHOLIC DEMENTIA Differential diagnosis

Alcoholic dementia is one of the most common causes of Given the denial seen in alcoholism, at times this critical
dementia and indeed may account for approximately one- historical fact will be obscured, and in such cases the
fifth of all cases among the institutionalized elderly (Carlen differential, as discussed in Section 5.1, is fairly wide,
et al. 1994). Among chronic alcoholics, approximately encompassing various dementias of gradual or subacute
10 percent will develop this dreaded complication. onset, often lacking in distinctive features, such as
p 22.qxd 3/10/08 10:01 AM Page 693
22.9 Alcohol hallucinosis 693
Alzheimer’s disease, Pick’s disease, frontotemporal demen- Course

tia, Binswanger’s disease, etc.; given the propensity of alco-
holics for falling, chronic subdural hematoma should also With continued drinking, symptoms persist and may
be considered. In cases in which the history of alcoholism worsen. With abstinence, a gradual remission of symptoms
is clear, one should also bear in mind that cognitive deficits of variable extent may occur over the following weeks or
associated with withdrawal may persist for some time; months. Should patients commence drinking again, symp-
hence, the diagnosis of alcoholic dementia should proba- toms typically recur, and, with another period of abstinence,
bly be only tentative until a month or more of sobriety has the remission is generally not as substantial. Eventually, with
been maintained. repeated relapses, there may be a chronic persistence of
Alcoholic dementia must also be distinguished from symptoms, even with long-sustained sobriety.
Korsakoff’s syndrome; however, this should not be diffi-
cult. As discussed in Section 13.5, Korsakoff’s syndrome is
one of the amnestic syndromes, characterized by short- Etiology
term memory loss and lacking the personality change and
concreteness seen in alcoholic dementia. Although the etiology of alcohol hallucinosis is not clear, it
does appear that the risk for developing this disorder rises in
direct proportion to the severity of the alcoholism and, more
importantly, to the frequency with which alcohol withdrawal
Treatment
and delirium tremens occurs. With this in mind, some inves-
tigators have proposed that alcohol hallucinosis is the end
Adequate nutrition, including thiamine and niacin, and,
result of repeated ‘kindling’ within the temporal lobes.
above all, abstinence are essential. The overall treatment of
Importantly, alcohol hallucinosis is not etiologically related
alcoholism is discussed in Section 21.5. In cases in which
to paranoid schizophrenia (Schuckit and Winokur 1971).
patients are unable to participate successfully in rehabilita-
tive efforts, institutionalization may be required.
22.9 ALCOHOL HALLUCINOSIS Delirium tremens may cause auditory hallucinations, and
the fact that alcohol hallucinosis often has an onset in the
Alcohol hallucinosis, also known as alcohol-induced psy- course of delirium tremens sets the stage for some diagnostic
chotic disorder with hallucinations, is seen only in chronic difficulty. The question, however, may be resolved by observ-
alcoholics, typically after one or more decades of severe, ing the patient during enforced abstinence: in cases in
heavy drinking. This psychosis is an uncommon disorder which delirium tremens alone are present, all symptoms,
and may be more common in men than women. including auditory hallucinations, gradually resolve; in cases,
however, in which alcohol hallucinosis has appeared, the
auditory hallucinations will persist despite resolution of
other symptoms of delirium tremens, such as confusion,
Clinical features disorientation, tremor, etc.
Alcoholic paranoia, discussed in the next section, is dis-
The onset is typically abrupt, over a matter of days, and tinguished by the prominence of delusions of persecution
generally occurs in the context of either alcohol withdrawal in the relative absence of any hallucinations.
or delirium tremens. Clinically (Victor and Hope 1958; Of the other causes of psychosis discussed in Section 7.1,
Soyka 1990), the principal symptom of alcohol halluci- the one that occasions the most diagnostic difficulty is para-
nosis is auditory hallucinations. These are often extremely noid schizophrenia. Patients with schizophrenia may also
vivid and clear, and the patient has no doubt as to their develop alcoholism; however, in these cases the psychosis
reality. For the most part they are critical, deprecatory, and generally occurs either before the onset of the alcoholism
often persecutory. Generally, more than one voice is heard, or relatively early on, in contrast to alcohol hallucinosis,
and, curiously, the voices often talk among themselves. which occurs only after a decade or more of heavy drink-
Visual hallucinations may also occur, but these are far less ing. Certain symptoms may also enable a differential diag-
prominent than auditory hallucinations. Delusions of nosis to be made: loosening of associations, bizarre delusions,
persecution and reference often accompany the auditory and bizarre behavior, although common in paranoid
hallucinations, and are generally congruent with them. schizophrenia, are not seen in alcohol hallucinosis.
Patients may believe that others are plotting against them,
or that the police are following them. Occasionally there
may be Schneiderian first rank delusions, such as thought- Treatment
broadcasting or delusions of influence (Soyka 1990).
Patients are often constrained and very watchful, and tend Abstinence is essential, and the overall treatment of alco-
to be irritable and querulous. holism is discussed in Section 21.5. Unfortunately, the very
p 22.qxd 3/10/08 10:01 AM Page 694
symptoms that are characteristic of alcohol hallucinosis Differential diagnosis

often make it impossible for patients to participate in reha-
bilitative efforts, and hence treatment with antipsychotics Alcohol hallucinosis, discussed in the preceding section, is
is generally required. The choice of which of these agents to distinguished by its abrupt onset during alcohol with-
use may be made following the same principles given in drawal or delirium tremens, and by the prominence of hal-
Section 20.1 for the treatment of schizophrenia. Given the lucinations.
natural course of alcohol hallucinosis, an attempt should Of the other causes of psychosis discussed in Section 7.1,
be made to gradually taper the dose of the antipsychotic delusional disorder most closely resembles alcoholic para-
after the patient has been sober and free of symptoms for a noia. In delusional disorder, however, the history of chronic
matter of months. alcoholism is lacking.
22.10 ALCOHOLIC PARANOIA Treatment
Alcoholic paranoia, also known as alcohol-induced psy- Abstinence is essential, and the overall treatment of alco-
chotic disorder with delusions, like alcohol hallucinosis, is holism is discussed in Section 21.5. Treatment with
seen only in chronic alcoholics, after many years of severe, antipsychotics should be considered, especially in cases in
heavy drinking. Although the prevalence of this disorder which delusions of persecution hinder the patient’s efforts
has not been clearly determined, I have found it to be rela- to engage in rehabilitation. The choice of antipsychotic is
tively common amongst chronic alcoholics. based on the same principles as outlined for schizophrenia
in Section 20.1; given the natural history of alcoholic para-
noia, attempts should eventually be made to taper the dose
Clinical features after the patient has been symptom free and sober for at
least a few months.
The onset is gradual, and symptoms appear without any
direct connection with either alcohol withdrawal or delir-
ium tremens. Clinically (Albert et al. 1995), patients grad- 22.11 MARCHIAFAVA–BIGNAMI DISEASE
ually develop either delusions of persecution or of jealousy.
Those with delusions of persecution may believe that the Marchiafava–Bignami disease is a very rare disorder that
police are following them or that intruders are hiding in was first described by Drs Marchiafava and Bignami (1903)
the house; patients may peek out of windows to try and in Italian alcoholics. It may present in one of two fashions,
catch a glimpse of the police they are sure are ‘staking out’ either acutely, with a delirium, or chronically, with a
the house, or they may feel compelled to go from room to dementia.
room, perhaps with a weapon, looking for intruders. Those
with delusions of jealousy typically suspect their spouse or
lover of infidelity, and they may follow them or look for Clinical features
clues of the suspected romantic encounters. Occasionally
there may be some hallucinations but these never domi- Acute onsets are marked by delirium, stupor, or coma,
nate the clinical picture; indeed, if they do occur they typi- often accompanied by seizures, either focal or generalized,
cally play a very minor role, for example the persecuted long-tract signs, aphasia, or ataxia (Bohrod 1942; Ironside
patient may hear footsteps outside or the jealous patient et al. 1961; Kamaki et al. 1993; Koeppen and Barron 1978;
may smell an unaccustomed cologne or perfume. Rosa et al. 1991).
Chronic cases present gradually with a dementia that
may be accompanied by a frontal lobe syndrome and, clas-
Course sically, signs of callosal disconnection, such as left-sided
apraxia or agnosia (Lechevalier et al. 1977; Lhermitte et al.
In general, with continued drinking there is a gradual wors- 1977; Mayer et al. 1987).
ening of symptoms until eventually a ‘plateau’ of severity is Magnetic resonance scanning (Johkura et al. 2005;
reached, after which symptoms remain stable, despite Kamaki et al. 1993; Kawamura et al. 1985; Menegon et al.
ongoing drinking. With abstinence, symptoms gradually 2005) reveals distinctive changes. In acute cases, increased
lessen over months to up to 2 years, and then either go into signal intensity on T2-weighted, fluid-attenuated inversion
remission or settle into a stable, low-level chronicity. recovery (FLAIR), and diffusion-weighted imaging is seen
in the corpus callosum and, in some cases, the adjacent
white matter of the cerebral hemispheres; in severe cases,
Etiology similar changes have also been noted in the frontal and
parietal cortices. In chronic cases, atrophy and cystic changes
The mechanism by which this disorder occurs is not clear. may be noted in the same areas. One remarkable MRI
p 22.qxd 3/10/08 10:01 AM Page 695
References 695
study captured the entire evolution of these MRI changes Clinical features
(Chang et al. 1992).
The onset of dementia is gradual in the setting of ongoing,
Course chronic inhalent use. Clinically (Fornazzari et al. 1983;
Grabski 1961; Hormes et al. 1986; Knox and Nelson 1966;
Those with acute onsets generally progress to coma and Lazar et al. 1983; Lewis et al. 1981; Rosenberg et al. 1988),
death within days to weeks; recovery, although uncommon, patients become apathetic and concrete, and have difficulty
has been reported (Helenius et al. 2001). In chronic cases, with memory; in general, ‘cortical’ signs, such as aphasia,
should alcohol use persist, there is a steady progression to are lacking. In concert with the dementia, cerebellar signs are
death within 3–8 years; with abstinence there may be a very common, including ataxia, dysarthria, titubation, inten-
variable, but not complete, degree of recovery. tion tremor, and ocular abnormalities such as nystagmus
or opsoclonus; a minority of patient may also have spasticity.
In some cases there may also be a peripheral neuropathy
Etiology (Korobkin et al. 1975).
Computed tomography scanning reveals cerebral and
Pathologically (Bohrod 1942; Ironside et al. 1961; Poser
cerebellar cortical atrophy (Fornazzari et al. 1983; Hormes
1973), demyelinization with relative axonal sparing is found
et al. 1986; Lazar et al. 1983); in addition to the atrophy,
in the central portion of the corpus callosum, sparing the
T2-weighted MR imaging also reveals diffuse, increased
dorsal and ventral areas, and this may extend laterally in a
signal intensity in the cerebral and cerebellar white matter,
symmetric fashion to involve adjacent areas of the centrum
with, in some cases, decreased signal intensity in the thalami
semiovale. Demyelinization may also be seen in the ante-
or basal ganglia (Aydin et al. 2002; Filley et al. 1990; Rosenberg
rior and posterior commisures and the middle cerebellar
et al. 1988).
peduncles. In severe cases, cystic changes may occur.
The cause of this demyelinization is not clear. Originally
it was believed that there was an association with the con-
sumption of cheap red wine by Italian men, as most of the Course
original cases fit this description; however, it has become
quite clear that this disease may occur in alcoholics who With continued use a progression occurs; with abstinence
consume whiskey, beer, or white wine, and also in non- there may be a gradual, but generally only partial, remission.
Italians (Ironside et al. 1961). Indeed, there are also rare
reports of the disease occurring in association with severe
malnutrition in non-alcoholics (Leong 1979). Presumably, Etiology
the demyelinization occurs secondary to a vitamin defi-
ciency; however, the nature of this deficiency is not clear, Autopsy studies have revealed both cerebral and cerebellar
nor is it clear if a genetic susceptibility is involved. atrophy, with widespread demyelinization (Escobar and
Aruffo 1980; Kornfeld et al. 1994; Rosenberg et al. 1988).
Marchiafava–Bignami disease must be distinguished from
other disorders typically seen in chronic alcoholism. Acute
Consideration may be given to other disorders capable of
cases may be mimicked clinically by delirium tremens,
causing dementia in combination with ataxia, as discussed
Wernicke’s encephalopathy, hepatic encephalopathy, and
in Section 5.1; however, the history of chronic inhalent use
encephalopathic pellagra, whereas chronic cases may be
is hard to miss.
mistaken for alcoholic dementia. In practice, the diagnosis
is generally only suspected when MR scanning reveals the
distinctive findings noted above.
Treatment
Treatment Abstinence is essential and may require institutionaliza-
tion. There is no specific treatment.
Abstinence and adequate nutrition are critical, and it is
appropriate to give thiamine, niacin, and folic acid.
REFERENCES
22.12 INHALENT-INDUCED DEMENTIA
Addonizio G, Susman VL, Roth SD. Neuroleptic malignant
Inhalent intoxication (discussed in Section 21.7), if chronic syndrome: review and analysis of 115 cases. Biol Psychiatry
and repeated, may cause a dementia. 1987; 22:1004–20.
p 22.qxd 3/10/08 10:01 AM Page 696
Adityanjee, Jayaswal SK, Chan TM et al. Temporary remission of anticholinergic poisoning. Ann Emerg Med 2000;
tardive dystonia following electroconvulsive therapy. Br J 35:374–81.
Psychiatry 1990; 156:433–5. Carlen PL, Wilkinson DA, Wotzman G et al. Cerebral atrophy and
Adler LA, Peselow E, Rotrosen J et al. Vitamin E in the treatment functional deficits in alcoholics without clinically apparent
of tardive dyskinesia. Am J Psychiatry 1993; 150:1405–7. liver disease. Neurology 1981; 31:377–85.
Adler LA, Edson R, Lavori P et al. Long-term treatment effects of Carlen PL, McAndrews MP, Weiss RT et al. Alcohol-related
vitamin E for tardive dyskinesia. Biol Psychiatry 1998; dementia in the institutionalized elderly. Alcohol Clin Exp Res
43:868–72. 1994; 18:1330–4.
Adler LA, Rotrosen J, Edson R et al. Vitamin E treatment for Carlsson C, Claeson L-E, Karlsson K-I et al. Clinical, psychometric
tardive dyskinesia. Arch Gen Psychiatry 1999; 56:863–41. and radiological signs of brain damage in chronic alcoholism.
Agartz I, Brag S, Franck J et al. MR volumetry during acute Acta Neurol Scand 1979; 60:85–92.
alcohol withdrawal and abstinence: a descriptive study. Caroff SN. The neuroleptic malignant syndrome. J Clin Psychiatry
Alcohol Alcohol 2003; 38:71–8. 1980; 41:79–83.
Agostino JV, Leo-Summers LS, Inouye SK. Cognitive and other Caroff SN, Massa SC, Keck PE et al. Residual catatonic state
adverse effects of diphenhydramine use in hospitalized older following neuroleptic malignant syndrome. J Clin
patients. Arch Int Med 2001; 161:2091–7. Psychopharmacol 2000; 2:257–9.
Akhtar S, Jajor TR, Kumar S. Vitamin E in the treatment of tardive Castillo E, Rubin RT, Holsboer-Trachsler E. Clinical differentiation
dyskinesia. J Postgrad Med 1993; 39:124–6. between lethal catatonia and neuroleptic malignant
Albert A, Mirza S, Mirza KAH et al. Morbid jealousy in alcoholics. syndrome. Am J Psychiatry 1989; 146:324–8.
Br J Psychiatry 1995; 167:668–72. Chang KH, Cha SH, Han MH et al. Marchiafava–Bignami disease:
Ananth J, Edelmuth E, Dargan B. Meige’s syndrome associated serial changes in corpus callosum on MRI. Neuroradiology
with neuroleptic treatment. Am J Psychiatry 1988; 1992; 34:480–2.
145:513–15. Chiang E, Pitts WM, Rodriguez-Garcia M. Respiratory dyskinesia:
Anderson ES, Powers PS. Neuroleptic malignant syndrome review and case reports. J Clin Psychiatry 1985; 46:232–4.
associated with clozapine use. J Clin Psychiatry 1991; Chiu HFK, Lan LCW, Chung DWS. Prevalence of the rabbit
52:102–4. syndrome in Hong Kong. J Nerv Ment Dis 1993; 181:264–5.
Assmann VCCA, van Woerkom TCAM. Disappearance of tardive Chouinard G, Jones BD. Neuroleptic-induced supersensitivity
dyskinesia during catatonic stupor. Acta Psychiatr Scand psychosis: clinical and pharmacologic characteristics. Am J
1987; 76:217–18. Psychiatry 1980; 137:16–21.
Aydin K, Sencer S, Demir T et al. Cranial MR findings in chronic Coffey RJ, Edgar TS, Francsco GE et al. Abrupt withdrawal from
toluene abuse by inhalation. AJNR 2002; 23:1173–9. intrathecal baclofen: recognition and management of a
Beasley CM, Dellva MA, Tamura RN et al. Randomized double- potentially life-threatening syndrome. Arch Phys Med Rehabil
blind comparison of the incidence of tardive dyskinesia in 2002; 83:1479.
patients with schizophrenia during long-term treatment with Cunningham MA, Darby DG, Donnan GA. Controlled-release
olanzapine or haloperidol. Br J Psychiatry 1999; 174:23–30. delivery of L-dopa associated with nonfatal hyperthermia,
Beaver KM, Gavin TJ. Treatment of acute anticholinergic rigidity and autonomic dysfunction. Neurology 1991;
poisoning with physostigmine. Am J Emerg Med 1998; 41:942–3.
16:505–7. Dabiri LM, Pasta D, Darby JK et al. Effectiveness of vitamin E for
Bharucha KJ, Sethi KD. Tardive Tourettism after exposure to the treatment of long-term tardive dyskinesia. Am J Psychiatry
neuroleptic therapy. Mov Disord 1995; 10:791–3. 1994; 151:925–6.
Bodner RA, Lynch T, Lewis L et al. Serotonin syndrome. Neurology Damier P, Thobois S, Witjas T et al. Bilateral deep brain
1995; 45:219–23. stimulation of the globus pallidus to treat tardive dyskinesia.
Bohrod MG. Primary degeneration of the corpus callosum Arch Gen Psychiatry 2007; 64:170–6.
(Marchiafava’s disease): report of the second American case. Daras M, Kakkouras L, Tuchman AJ et al. Rhabdomyolysis and
Arch Neurol Psychiatry 1942; 47:465–73. hyperthermia after cocaine abuse: a variant of the
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med neuroleptic malignant syndrome? Acta Neurol Scand 1995;
2005; 352:1112–20. 92:161–5.
Brunelle J, Guigueno S, Gouin P et al. Aripiprazole and neuroleptic Das Gupta K, Young A. Clozapine-induced neuroleptic malignant
malignant syndrome. J Clin Psychopharmacol 2007; 27:212–14. syndrome. J Clin Psychiatry 1991; 52:105–7.
Burke RE, Fahn S, Jankovic J et al. Tardive dyskinesia: late-onset Davis JM, Janicak PG, Sakkas P et al. Electroconvulsive therapy in
and persistent dystonia caused by antipsychotic drugs. the treatment of the neuroleptic malignant syndrome.
Neurology 1982; 32:1335–46. Convulsive Ther 1991; 7:111–20.
Burke RE, Kang UK, Jankovic J et al. Tardive akathisia: an analysis Decina P, Caracci G, Spichio PL. The rabbit syndrome. Mov Disord
of clinical features and response to open therapeutic trials. 1990; 5:263–6.
Mov Disord 1989; 4:157–75. Delassus-Guenault N, Jegouzo A, Odou P et al. Clozapine-
Burns MJ, Linden CH, Graudins A et al. A comparison of olanzapine: a potentially dangerous switch. A report of two
physostigmine and benzodiazepines for the treatment of cases. J Clin Pharmacol Ther 1999; 24:191–5.
p 22.qxd 3/10/08 10:01 AM Page 697
References 697
Deshmukh DK, Joshi VS, Agarwal MR. Rabbit syndrome – a rare Friedman J, Feinberg SS, Feldman RG. A neuroleptic malignant-
complication of long-term neuroleptic medication. Br J like syndrome due to L-dopa withdrawal. Ann Neurol 1984;
Psychiatry 1990; 157:293. 16:126–7.
De Smet Y, Ruberg M, Serdaru M et al. Confusion, dementia and Freidman LS, Weinrauch LA, D’Elia JA. Metoclopramide-induced
anticholinergics in Parkinson’s disease. J Neurol Neurosurg neuroleptic malignant syndrome. Arch Int Med 1987;
Psychiatry 1982; 45:1161–4. 147:1495–7.
Dilsaver SC. Antidepressant withdrawal syndromes: Gardos G, Cole JO, Haskell D et al. The natural history of tardive
phenomenonology and pathophysiology. Acta Psychiatr Scand dyskinesia. J Clin Psychopharmacol 1988; 8(suppl. 4):31–3.
1989; 79:113. Gardos G, Casey D, Cole JO et al. Ten year outcome of tardive
Dilsaver SC, Feinberg M, Greden JF. Antidepressant withdrawal dyskinesia. Am J Psychiatry 1994; 151:836–41.
symptoms treated with anticholinergic agents. Am J Psychiatry Gibb W, Griffith D. Levodopa withdrawal syndrome identical to
1983a; 140:249–51. neuroleptic malignant syndrome. Postgrad Med J 1986;
Dilsaver SC, Kronfol Z, Sackellares JC et al. Antidepressant 62:59–60.
withdrawal syndrome: evidence supporting the cholinergic Glazer WM, Moore DC, Hansen TC et al. Meige syndrome and
overdrive hypothesis. J Clin Psychopharmacol 1983b; tardive dyskinesia. Am J Psychiatry 1983; 140:798–9.
3:157–64. Glazer WM, Moore DC, Schooler NR et al. Tardive dyskinesia:
Dufresne RL, Wagner RL. Antipsychotic-withdrawal akathisia a discontinuation study. Arch Gen Psychiatry 1984;
versus antipsychotic-induced akathisia: further evidence for 41:623–7.
the existence of tardive akathisia. J Clin Psychiatry 1988; Glazer WM, Morgenstern H, Schooler N et al. Predictors of
49:435–8. improvement in tardive dyskinesia following discontinuation
Duvoisin RC, Katz R. Reversal of central anticholinergic syndrome of neuroleptic medication. Br J Psychiatry 1990; 157:585–92.
in man by physostigmine. JAMA 1968; 206:1963–5. Glazer WM, Morgenstern H, Doucette JT. Predicting the long-term
Egan MF, Hyde TM, Albers GW et al. Treatment of tardive risk of tardive dyskinesia in outpatients maintained on
dyskinesia with vitamin E. Am J Psychiatry 1992; neuroleptic medication. J Clin Psychiatry 1993; 54:133–9.
149:773–7. Goldman MB, Luchins DJ. Intermittent neuroleptic therapy and
Elkashef AM, Ruskin PE, Bacher N et al. Vitamin E in the tardive dyskinesia: a literature review. Hosp Comm Psychiatry
treatment of tardive dyskinesia. Am J Psychiatry 1990; 1984; 35:1215–19.
147:505–6. Goodwin CD. Case report of tricyclic-induced delirium at a
Engel PA, Chapron D. Cyclobenzaprine-induced delirium in two therapeutic drug concentration. Am J Psychiatry 1983;
octogenarians. J Clin Psychiatry 1993; 54:39. 140:1517–18.
Escobar A, Aruffo C. Chronic thinner intoxication: clinico- Grabski DA. Toluene sniffing producing cerebellar degeneration.
pathologic report of a human case. J Neurol Neurosurg Am J Psychiatry 1961; 118:461–2.
Psychiatry 1980; 43:986–94. Granato JE, Stern BJ, Ringel J et al. Neuroleptic malignant
Fahn S. High dosage anticholinergic therapy in dystonia. syndrome: successful treatment with dantrolene and
Neurology 1983; 33:1255–61. bromocriptine. Ann Neurol 1983; 14:89–90.
Farran-Ridge C. Some syndromes referable to the basal ganglia Grant I, Adams KM, Reed R. Aging, abstinence, and medical risk
occurring in dementia praecox and epidemic encephalitis. factors in the prediction of neuropsychologic deficit among
J Ment Sci 1926; 72:513–23. long-term alcoholics. Arch Gen Psychiatry 1984; 41:710–18.
Feighner JP, Boyer WF, Tyler DL et al. Adverse consequences of Greil W, Haag H, Rossnagl G et al. Effect of anticholinergics on
fluoxetine–MAOI combination therapy. J Clin Psychiatry 1990; tardive dyskinesia: a controlled discontinuation study. Br J
51:222–5. Psychiatry 1984; 145:304–10.
Figa-Talamanca L, Gualandi C, Di Meo L et al. Hyperthermia after Gurling HMD, Reveley MA, Murray RM. Increased cerebral
discontinuance of levodopa and bromocriptine therapy: ventricular volume in monozygotic twins discordant for
impaired dopamine receptors a possible cause. Neurology alcoholism. Lancet 1984; 1:986–8.
1985; 35:258–61. Guze BH, Baxter LR. Current concepts: neuroleptic malignant
Filley CM, Heaton RK, Rosenberg NL. White matter dementia in syndrome. N Engl J Med 1985; 313:163–6.
chronic toluene abuse. Neurology 1990; 40:532–4. Hall RCW, Popkin MK, McHenry LE. Angel’s trumpet psychosis: a
FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neurology central nervous system anticholinergic syndrome. Am J
1989; 39:1434–7. Psychiatry 1977; 134:312–14.
Ford B, Greene P, Fahn S. Oral and genital tardive pain syndromes. Hambidge DM. Intellectual impairment in male alcoholics. Alcohol
Neurology 1994; 44:2115–19. Alcoholism 1990; 25:555–9.
Fornazzari L, Wilkinson DA, Kapur BM et al. Cerebellar, cortical Han L, McCusker J, Cole M et al. Use of medications with
and functional impairment in toluene abusers. Acta Neurol anticholinergic effect predicts clinical severity of delirium
Scand 1983; 67:319–29. symptoms in older medical inpatients. Arch Int Med 2001;
Fornazzari L, Ichise M, Remington G et al. Rabbit syndrome, 161:1099–105.
antidepressant use, and cerebral perfusion SPECT scan Harper CG, Blumbergs PC. Brain weights in alcoholics. J Neurol
findings. J Psychiatry Neurosci 1991; 16:227–9. Neurosurg Psychiatry 1982; 45:838–40.
p 22.qxd 3/10/08 10:01 AM Page 698
Harper CG, Krill JJ. Brain atrophy in chronic alcoholic patients – a Kane JM, Smith JM. Tardive dyskinesia: prevalence and risk
quantitative pathological study. J Neurol Neurosurg Psychiatry factors, 1959–1979. Arch Gen Psychiatry 1982; 39:473–81.
1985; 48:211–17. Kane JM, Woerner M, Lieberman J. Tardive dyskinesia: prevalence,
Harper CG, Krill JJ, Holloway RL. Brain shrinkage in chronic incidence and risk factors. J Clin Psychopharmacol 1988;
alcoholics: a pathological study. BMJ 1985; 290:501–4. 8:52S–56S.
Harsch HH. Neuroleptic malignant syndrome: physiological and Kang UJ, Burke RE, Fahn S. Natural history and treatment of
laboratory findings in a series of nine cases. J Clin Psychiatry tardive dystonia. Mov Disord 1986; 1:193–208.
1987; 48:328–33. Kawamura M, Shiota J, Yagishita T et al. Marchiafava–Bignami
van Harten PN, Hoek HW, Matroos GE et al. Intermittent disease: computed tomographic scan and magnetic resonance
neuroleptic treatment and risk of tardive dyskinesia: Curacao imaging. Ann Neurol 1985; 18:103–4.
extrapyramidal syndromes study III. Am J Psychiatry 1998; Keck PE, Pope HG, McElroy SL. Frequency and presentation of
155:565–7. neuroleptic malignant syndrome: a prospective study. Am J
Hay DP, Hay L, Blackwell B et al. ECT and tardive dyskinesia. Psychiatry 1987; 144:1344–6.
J Geriatr Psychiatr Neurol 1990; 3:106–9. Kellam AMP. Neuroleptic malignant syndrome, so-called. A survey
Helenius J, Tatlisumak T, Soinne L et al. Marchiafava–Bignami of the world literature. Br J Psychiatry 1987; 150:752–9.
disease: two cases with favorable outcome. Eur J Neurol Kellam AMP. The (frequently) neuroleptic malignant syndrome.
2001; 8:269–72. Br J Psychiatry 1990; 157:169–73.
Hermesh H, Aizenburg D, Weizman A. A successful Kennedy PF. Chorea and phenothiazines. Br J Psychiatry 1969;
electroconvulsive treatment of neuroleptic malignant 115:103–4.
syndrome. Acta Psychiatr Scand 1987; 75:237–9. Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in
Hormes JT, Filley CM, Rosenberg NL. Neurologic sequelae Parkinson’s disease after withdrawal or alteration of
of chronic solvent vapor abuse. Neurology 1986; dopaminergic therapy. Arch Int Med 1991; 151:794–6.
36:698–702. Khan JA. Occasional notes: atropine poisoning in Hawthorne’s The
Horn E, Lach B, Lapierre Y et al. Hypothalamic pathology in the Scarlet Letter. N Engl J Med 1984; 311:414–17.
neuroleptic malignant syndrome. Am J Psychiatry 1988; Kiriakakis V, Bhatia K, Quinn NP et al. The natural history of
145:617–20. tardive dystonia: a long-term follow-up study of 107 cases.
Huang CC. Persistent tardive dyskinesia associated with Brain 1998; 121:2053–66.
amoxapine therapy. Am J Psychiatry 1986; 143:1069–70. Kirkpatrick B, Alphs L, Buchanen RW. The concept of
Huang CC, Wang RI, Haegawa A et al. Reserpine and alpha- supersensitivity psychosis. J Nerv Ment Dis 1992; 180:265.
methyldopa in the treatment of tardive dyskinesia. Klawans HL, Rubovits R. Effect of cholinergic and anticholinergic
Psychopharmacology 1981; 73:359–62. agents on tardive dyskinesia. J Neurol Neurosurg Psychiatry
Ironside R, Bosanquet FD, McMenemy WH. Central demyelination 1974; 37:941–7.
of the corpus callosum (Marchiafava–Bignami disease): with Knox JW, Nelson JR. Permanent encephalopathy from toluene
report of a second case in Great Britain. Brain 1961; inhalation. N Engl J Med 1966; 275:1494–6.
84:212–30. Koch M, Chandragiri S, Rizvi S et al. Catatonic signs in neuroleptic
Itil T, Fink M. Anticholinergic drug-induced delirium: experimental malignant syndrome. Compr Psychiatry 2000; 41:73–5.
modification, quantitative EEG, and behavioral correlations. Koeppen AH, Barron KD. Marchiafava–Bignami disease. Neurology
J Nerv Ment Dis 1966; 143:492–507. 1978; 28:290–4.
Ivanovitch M, Glantz R, Bone RC et al. Respiratory dyskinesia Kontaxakis VP, Havaki-Kontaxaki BJ, Pappa DA et al. Neuroleptic
presenting as acute respiratory distress. Chest 1993; malignant syndrome after addition of paroxetine to
103:314–16. olanzapine. J Clin Psychopharmacol 2003; 23:671–2.
Jensen GB, Pakkenberg B. Do alcoholics drink their neurons away? Kornfeld M, Moser AB, Moser HW et al. Solvent vapor abuse
Lancet 1993; 342:1201–4. leukoencephalopathy. Comparison to adrenoleukodystrophy.
Jernigan TL, Butters N, Ditraglia G et al. Reduced cerebral grey J Neuropathol Exp Neurol 1994; 53:389–98.
matter in alcoholics using MRI. Alcoholism Clin Exp Res 1991; Korobkin R, Asbury AK, Sumner AJ et al. Glue-sniffing neuropathy.
15:418–27. Arch Neurol 1975; 32:158–62.
Jeste DV, Potkin SG, Sinha S et al. Tardive dyskinesia – reversible Kraepelin E. Dementia praecox and paraphrenia. Huntington, NY:
and persistent. Arch Gen Psychiatry 1979; 36:585–90. Robert E. Krieger, 1971.
Johkura K, Naito M, Naka T. Cortical involvement in Krill JJ, Halliday GM, Svoboda MD et al. The cerebral cortex is
Marchiafava–Bignami disease. AJNR 2005; 26:670–3. damaged in chronic alcoholics. Neuroscience 1997;
Jones EM, Dawson A. Neuroleptic malignant syndrome: a case 79:983–98.
report with post-mortem brain and muscle pathology. J Neurol Lang AE. Withdrawal akathisia: case reports and a proposed
Neurosurg Psychiatry 1989; 52:1006–9. classification of chronic akathisia. Mov Disord 1994;
Kamaki M, Kawamura M, Moriya H et al. ‘Crossed homonymous 9:188–92.
hemianopia’ and a ‘crossed left hemispatial neglect’ in a case Lattanzi L, Mungai F, Romano A et al. Subcutaneous apomorphine
of Marchiafava–Bignami disease. J Neurol Neurosurg for neuroleptic malignant syndrome. Am J Psychiatry 2006;
Psychiatry 1993; 56:1027–32. 163:1450–1.
p 22.qxd 3/10/08 10:01 AM Page 699
References 699
Lazar RB, Ho SU, Melen O et al. Multifocal central nervous system Mendhekar DN, Andrade CR. Neuroleptic malignant syndrome
damage caused by toluene abuse. Neurology 1983; with promethazine. Aust N Z J Psychiatry 2005; 39:310.
33:1337–40. Menegon P, Sibon I, Pachia C et al. Marchiafava–Bignami
Lechevalier B, Anderson JC, Morin P. Hemispheric disconnection disease: diffusion-weighted MRI in corpus callosum and
syndrome with a ‘crossed avoiding’ reaction in a case of cortical lesions. Neurology 2005; 65:475–7.
Marchiafava–Bignami disease. J Neurol Neurosurg Psychiatry Meterissian GB. Risperidone-induced neuroleptic malignant
1977; 40:483–97. syndrome: a case report and review. Can J Psychiatry 1996;
Lee K, Moller L, Hardt F et al. Alcohol induced brain damage and 41:52–4.
liver damage in young males. Lancet 1979; 2:759–61. Mettler FA, Crandall A. Neurologic disorders in psychiatric
Leong ASV. Marchiafava–Bignami disease in a non-alcoholic institutions. J Nerv Ment Dis 1959; 128:148–59.
Indian male. Pathology 1979; 11:241–9. Miller DD, Sharafuddin MJA, Kathol RG. A case of clozapine-
Lerner V, Miodownik C, Kapstan A et al. Vitamin B6 in the induced neuroleptic malignant syndrome. J Clin Psychiatry
treatment of tardive dyskinesia: a double-blind, placebo- 1991; 52:99–101.
controlled, crossover study. Am J Psychiatry 2001; Moncrieff J. Does antipsychotic withdrawal provoke psychosis?
158:1511–14. Review of the literature on rapid onset psychosis
Levenson JL. Neuroleptic malignant syndrome after the initiation (supersensitivity psychosis) and withdrawal-related relapse.
of olanzapine. J Clin Psychopharmacol 1999; 19:477–8. Acta Psychiatr Scand 2006; 114:3–13.
Levin GM, Lazowick AL, Powell HS. Neuroleptic malignant syndrome Moore DP. Tardive psychosis. J Ky Med Assoc 1986; 84:351–3.
with risperidone. J Clin Psychopharmacol 1996; 16:192–3. Morganstern H, Glazer WM. Identifying risk factors for tardive
Lewis JD, Moritz D, Mellis LP. Long-term toluene abuse. Am J dyskinesia among the long-term outpatients maintained
Psychiatry 1981; 138:368–70. with neuroleptic medications. Arch Gen Psychiatry 1993;
Lhermitte F, Marteau R, Serdaru M et al. Signs of interhemispheric 50:723–33.
disconnection in Marchiafava–Bignami disease. Arch Neurol Mueller PS, Vester JW, Fermaglich J. Neuroleptic malignant
1977; 34:254–7. syndrome – successful treatment with bromocriptine. JAMA
Libov I, Miodowni C, Bersudsky Y et al. Efficacy of piracetam in 1983; 249:386–8.
the treatment of tardive dyskinesia in schizophrenic patients: Neuberger KT. The changing neuropathological picture of chronic
a randomized, double-blind, placebo-controlled crossover alcoholism. Arch Pathol 1957; 63:1–6.
study. J Clin Psychiatry 2007; 68:1031–7. Nimmagadda SR, Ryan DH, Atkin SL. Neuroleptic malignant
Lishman WA. Cerebral disorder in alcoholism: syndromes of syndrome after venlafaxine. Lancet 2000; 354:289–90.
impairment. Brain 1981; 104:373–410. Oberndorfer S, Grisold W, Hinterholzer G et al. Coma with focal
Lohr JB, Caligiuri MP. A double-blind placebo-controlled study of neurological signs caused by Datura stramonium intoxication
vitamin E in the treatment of tardive dyskinesia. J Clin in a young man. J Neurol Neurosurg Psychiatry 2002; 73:458–9.
Psychiatry 1996; 57:167–73. Ondo WG, Hanna PA, Jankovi J. Tetrabenazine treatment for
Lohr JB, Cadet JL, Lohr MA et al. Vitamin E in the treatment of tardive dyskinesia: assessment by randomized videotape
tardive dyskinesia: the possible involvement of free radical protocol. Am J Psychiatry 1999; 156:1279–81.
mechanisms. Schizophr Bull 1988; 14:291–6. Ossemann M, Sindic CJM, Laterre C. Tetrabenazine as a cause of
Lu ML, Pan JJ, Teng HW et al. Metoclopramide-induced neuroleptic malignant syndrome. Mov Disord 1996; 11:95.
supersensitivity psychosis. Ann Pharmacother 2002; Owens DGC, Johnstone EC, Frith CD. Spontaneous involuntary
36:1387–90. disorders of movement: their prevalence, severity and
Luchins DJ, Freed WJ, Wyatt RJ. The role of cholinergic distribution in chronic schizophrenics with and without
supersensitivity in the medical symptoms associated with treatment with neuroleptics. Arch Gen Psychiatry 1982;
withdrawal of antipsychotic drugs. Am J Psychiatry 1980; 39:452–61.
137:1395–8. Ozen ME, Yumru M, Savas HA et al. Neuroleptic malignant
Lynch MJG. Brain lesions in chronic alcoholism. Arch Pathol 1960; syndrome induced by ziprasidone on the second day of
69:342–53. treatment: a case report. World J Biol Psychiatry 2007;
Marchiafava E, Bignami A. Sopra un alterazione del corpo callsos 8:133–4.
osservata in sogetti alcoolisti. Riv Patol Nerv Mentale 1903; Parvin MM, Swartz CM. Dystonic rabbit syndrome from
8:544–9. citalopram. Clin Neuropharmacol 2005; 28:289–91.
Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Peiris DTS, Kuruppuarachchi KALA, Weeasena LP et al. Neuroleptic
Presentation of 2 cases and review of the literature. Medicine malignant syndrome without fever: a report of three cases.
May EDC, Morris SW, Stewart RM et al. Neuroleptic malignant Petti TA, Law W. Abrupt cessation of high-dose imipramine
syndrome: response to dantrolene sodium. Ann Intern Med treatment in children. JAMA 1981; 246:768–9.
1983; 98:183–4. Pfefferbaum A, Sullivan EV, Mathalon DH et al. Longitudinal
Mayer JM, De Liege P, Netter JM et al. Computerized tomography changes in magnetic resonance imaging brain volumes in
and nuclear magnetic resonance imaging in Marchiafava– abstinent and relapsed alcoholics. Alcohol Clin Exp Res 1995;
Bignami disease. J Neuroradiol 1987; 14:152–8. 19:1177–91.
p 22.qxd 3/10/08 10:01 AM Page 700
Pope HG, Keck PE, McElroy SL. Frequency and presentation of Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;
neuroleptic malignant syndrome in a large psychiatric 74:574–6.
hospital. Am J Psychiatry 1986; 143:1227–33. Schroth G, Naegele T, Klose U et al. Reversible brain shrinkage in
Porteous HB, Ross DN. Mental symptoms in parkinsonism abstinent alcoholics, measured by MRI. Neuroradiology 1988;
following benzhexol hydrochloride therapy. BMJ 1956; 30:385–9.
2:138–40. Schuckitt MA, Winokur G. Alcohol hallucinosis and schizophrenia:
Poser CM. Demyelinization in the central nervous system in a negative study. Br J Psychiatry 1971; 119:549–53.
chronic alcoholism, central pontine myelinolysis, and Sechi GP, Tanda F, Mutani R. Fatal hyperpyrexia after withdrawal
Marchiafava–Bignami’s disease. Ann NY Acad Sci 1973; of levodopa. Neurology 1984; 34:249–51.
215:373–81. Sewell DD, Jeste DV. Metoclopramide-associated tardive
de Potter RW, Linkowski P, Mendelwicz J. State-dependent tardive dyskinesia: an analysis of 67 cases. Arch Fam Med 1992;
dyskinesia in manic-depressive illness. J Neurol Neurosurg 1:271–8.
Psychiatry 1983; 46:666–8. Sewell DD, Kodsi AB, Caligiuri MP et al. Metoclopramide and
Preskorn SH, Simpson S. Tricyclic-antidepressant-induced delirium tardive dyskinesia. Biol Psychiatry 1994; 36:630–2.
and plasma drug concentrations. Am J Psychiatry 1982; Shamir E, Varak Y, Shalman I et al. Melatonin treatment for
139:822–3. tardive dyskinesia. A double-blind, placebo-controlled,
Reunanen M, Kaarnen P, Vaisanen E. The influence of crossover study. Arch Gen Psychiatry 2001; 58:1049–52.
anticholinergic treatment on tardive dyskinesia caused Shriqui CL, Bradwejn J, Annable L et al. Vitamin E in the treatment
by neuroleptic drugs. Acta Psychiatr Scand 1982; of tardive dyskinesia: a double-blind placebo-controlled study.
65(suppl. 90):278–9. Am J Psychiatry 1992; 149:391–3.
Rich MW, Radwany SM. Respiratory dyskinesia: an Sing KJ, Ramaekers GMGI, van Harten PN. Neuroleptic malignant
underrecognized phenomenon. Chest 1994; 105:1826–32. syndrome and quetiapine. Am J Psychiatry 2002; 159:149–50.
Richardson MA, Craig TJ. The coexistence of Parkinsonism-like Soyka M. Psychopathological characteristics in alcohol
symptoms and tardive dyskinesia. Am J Psychiatry 1982; hallucinosis and paranoid schizophrenia. Acta Psychiatr Scand
139:341–3. 1990; 81:255–9.
Richardson MA, Vevans ML, Read LL et al. Efficacy of branched- Stacy M, Cardoso F, Jankovic J. Tardive stereotypy and other
chain amino acids in the treatment of tardive dyskinesia. movement disorders in tardive dyskinesias. Neurology 1993;
Am J Psychiatry 2003; 160:1117–24. 43:937–41.
Rosa A, Demiati M, Cartz L et al. Marchiafava–Bignami Stahl SM. Tardive Tourette syndrome in an autistic patient after
disease, syndrome of interhemispheric disconnection, and long-term neuroleptic administration. Am J Psychiatry 1980;
right-handed agraphia in a left-hander. Arch Neurol 1991; 137:1267–9.
48:986–8. Steiner W, Laporta M, Chouinard G. Neuroleptic-induced
Rosebush P, Stewart T. A prospective analysis of 24 episodes of supersensitivity psychosis in patients with bipolar affective
neuroleptic malignant syndrome. Am J Psychiatry 1989; disorder. Acta Psychiatr Scand 1990; 81:437–40.
146:717–25. Stern TA. Continuous infusion of physostigmine in anticholinergic
Rosebush PI, Stewart TED, Gelelberg AJ. Twenty neuroleptic delirium: case report. J Clin Psychiatry 1983; 44:463–4.
rechallenges after neuroleptic malignant syndrome in Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;
15 patients. J Clin Psychiatry 1989; 50:295–8. 148:705–13.
Rosenberg NL, Kleineschmidt-DeMasters BK, Davis KA et al. Suh H, Bronson B, Martin R. Neuroleptic malignant syndrome and
Toluene abuse causes diffuse central nervous system white low-dose olanzapine. Am J Psychiatry 2003; 160:796.
matter changes. Ann Neurol 1988; 23:611–14. Tan E-K, Jankovic J. Tardive and idiopathic oromandibular
Sachdev PS. Depression-dependent exacerbation of tardive dystonia: a clinical comparison. J Neurol Neurosurg Psychiatry
dyskinesia. Br J Psychiatry 1989; 155:253–5. 2000; 68:186–90.
Sachdev P. Clinical characteristics of 15 patients with tardive Taylor NE, Schwartz HI. Neuroleptic malignant syndrome
dystonia. Am J Psychiatry 1993a; 150:498–500. following amoxapine overdose. J Nerv Ment Dis 1988;
Sachdev P. Tardive and chronically recurrent oculogyric crises. 176:249–51.
Mov Disord 1993b; 8:93–7. Tejera CA, Saravay SM, Goldman E et al. Diphenhydramine-
Sachdev P, Loneragan C. The present status of akathisia. J Nerv induced delirium in elderly hospitalized patients with mild
Ment Dis 1991; 179:381–91. dementia. Psychosomatics 1994; 35:399–402.
Sachdev P, Kruk J, Kneebone M et al. Clozapine-induced Tenback DE, van Harten PN, Slooff CJ et al. Effects of
neuroleptic malignant syndrome: review and report of new antipsychotic treatment on tardive dyskinesia: a 6-month
case. J Clin Psychopharmacol 1995; 15:365–71. evaluation of patients from the European Schizophrenia
Saltz BL, Woerner MG, Kane JM et al. Prospective study of Outpaient Health Outcomes (SOHO) Study. J Clin Psychiatry
tardive dyskinesia incidence in the elderly. JAMA 1991; 2005; 66:1130–3.
266:2402–6. Thornton NE, Stahl SM. Case report of tardive dyskinesia and
Sato Y, Asoh T, Metoki N et al. Efficacy of methylprednisolone parkinsonism associated with amoxapine therapy. Am J
pulse therapy on neuroleptic malignant syndrome in Psychiatry 1984; 141:704–5.
p 22.qxd 3/10/08 10:01 AM Page 701
References 701
Todd R, Lippmann S, Manshadi M et al. Recognition and Woerner M, Kane JM, Lieberman JA et al. The prevalence of
treatment of rabbit syndrome, an uncommon complication of tardive dyskinesia. J Clin Psychopharmacol 1991; 11:34–42.
neuroleptic therapies. Am J Psychiatry 1983; 140:1519–20. Wojcik JD, Falk WE, Fink JS et al. A review of 32 cases of tardive
Toru M, Matsuda O, Makiguchi K et al. Single case study: dystonia. Am J Psychiatry 1991; 148:1055–9.
neuroleptic malignant syndrome-like state following Wolfe RM. Antidepressant withdrawal reactions. Am Fam
withdrawal of antiparkinsonian drugs. J Nerv Ment Dis 1981; Physician 1997; 56:455–62.
169:324–7. Yadalam KG, Korn ML, Simpson GM. Tardive dystonia: four case
Torvik A, Lindboe CF, Rogde S. Brain lesions in alcoholics. A histories. J Clin Psychiatry 1990; 51:17–20.
neuropathological study with clinical correlations. J Neurol Sci Yagi G, Itoh H. Follow-up study of 11 patients with potentially
1982; 56:233–48. reversible tardive dyskinesia. Am J Psychiatry 1987;
Troller JN, Sachdev PS. Electroconvulsive treatment of neuroleptic 144:1596–8.
malignant syndrome: a review and report of cases. Aust N Z J Yarden PE, Discipio WJ. Abnormal movements and prognosis in
Psychiatry 1999; 33:650–9. schizophrenia. Am J Psychiatry 1971; 128:317–23.
Tsao JW, Heilman KM. Transient memory impairment and Yassa R, Lal S. Respiratory irregularity and tardive dyskinesia: a
hallucination associated with tolteridone use. N Engl J Med prevalence study. Acta Psychiatr Scand 1986a; 73:506–10.
2003; 349:2274–5. Yassa R, Lal S. Prevalence of the rabbit syndrome. Am J Psychiatry
Tune LE, Dainloth NF, Holland A et al. Association of postoperative 1986b; 143:656–7.
delirium with raised serum levels of anticholinergic drugs. Yassa R, Nair V, Dimitry A. Prevalence of tardive dystonia. Acta
Lancet 1981; 2:651–3. Psychiatr Scand 1986; 73:629–33.
Tune LE, Bylsma FW, Hilt DC. Anticholinergic delirium caused Yassa R, Iskander H, Nastase C. Propranolol in the treatment of
by topical homatropine ophthalmic solution: confirmation tardive akathisia: a report of two cases. J Clin Psychopharmacol
by anticholinergic radioreceptor assay in two cases. 1988; 8;283–5.
J Neuropsychiatry Clin Neurosci 1992; 4:195–7. Yazici O, Kantemir E, Tastaban Y et al. Spontaneous improvement
Turner MR, Gainsborough N. Neuroleptic malignant-like syndrome of tardive dystonia during mania. Br J Psychiatry 1991;
after abrupt withdrawal of baclofen. J Psychopharmacol 2001; 158:847–50.
15:61–3. Zhang XY, Zhou DF, Cao LY et al. The effect of vitamin E treatment
Velamoor VR, Norman RMG, Caroff SN et al. Progression of on tardive dyskinesia and blood superoxide dismutase: a
symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis double-blind, placebo-controlled trial. J Clin Psychopharmacol
1994; 182:168–73. 2004; 24:83–6.
Victor M, Hope JM. The phenomenon of auditory hallucinations in Zipursky RB. Lim KC, Pfefferbaum A. MRI study of brain changes
chronic alcoholism. J Nerv Ment Dis 1958; 126:451–8. with short-term abstinence from alcohol. Alcohol Clin Exp Res
Vonderahe AR. Lilliputian hallucinations: report of a case of 1989; 13:664–6.
hyoscine poisoning. Arch Neurol Psychiatry 1929; 22:585–8. Ziskind AA. Transdermal scopolamine-induced psychosis. Postgrad
Wang H-C, Hsieh Y. Treatment of neuroleptic malignant syndrome Med 1988; 84:73–6.
with subcutaneous apomorphine therapy. Mov Disord 2001;
16:765–7.
Weiner WJ, Nausieda PA, Glantz RH. Meige syndrome
(blepharospasm–oromandibular dystonia) after long-term
neuroleptic therapy. Neurology 1981; 31:1555–6.
ex.qxd 3/10/08 10:01 AM Page 703
Index
Indexer: Dr Laurence Errington

Note: ‘vs’ indicates the differential diagnosis of various conditions.
abducens nerve testing 11 ADH see antidiuretic hormone affective disturbances (mood disturbances)
abscess, cerebral adhesiveness of thought in interictal 208–14, 618–31
fungal 516 personality syndrome 245 in Alzheimer’s disease 336
seizures with 264 adolescence and juveniles in frontal lobe syndrome 244
absence seizures see petit mal attention-deficit/hyperactivity disorder idiopathic 618–31
abstinence (as treatment) progression into 419 in Kleine–Levin syndrome 580
alcohol 666–7 disease-onset personality change vs 248–9
benzodiazepines 669 absence epilepsy 262 in simple partial seizures 252
cannabis 671 adrenoleukodystrophy 376 in substance abuse
cocaine 658 chorea 79, 80 hallucinogens 659
nicotine/smoking 674 Huntington’s disease 168, 169, 356 phencylidine and ketamine 661
opioid 673 metachromatic leukodystrophy 374, see also schizoaffective disorder
abstracting ability 375 age of onset
assessing 10, 162 myoclonic epilepsy 262 childhood see childhood onset
in dementia 162 seizures 268 juvenile see adolescence
abulia (pure psychic akinesia; adrenocortical insufficiency 536–7 schizophrenia 606
athymormia) 125–6 clinical features 536 agitation 222–5
differential diagnosis 126 depression 212 clinical features 222
apathy 214 psychosis 241 differential diagnosis 223
catatonic stupor 96, 126 primary 536, 536–7 akathisia 93, 223
mutism 119, 126 secondary 536, 537 excited catatonia 96
acalculia and dyscalculia (calulating in adrenoleukodystrophy 376, 377 sympathetic storms 291
inability) 51, 423 adrenocorticotrophic hormone (ACTH) etiology 222–3
acquired/new-onset 51 levels dementias 173, 223–4, 340
child 423 elevated 534, 535 depression 209, 225, 625
in dementia 162 with pituitary tumors 534, 535, traumatic brain injury 224, 291
developmental 51, 423 599 treatment 223–5, 291
acamprosate, alcoholism 667 reduced 536 agnosia 57–62
acanthocytosis 358 adrenoleukodystrophy 376–7 differential diagnosis 56, 57–62
acceleration/deceleration injury 171, 289, clinical features 376 tests 16
294, 455, 456 dementia 172 types 16, 57–62
accessory nerve testing 12 mania 221 agoraphobia 634–5
acetylcholinesterase inhibitors, Alzheimer’s personality change 246 differential diagnosis 635
disease 339 differential diagnosis 377 social phobia 635, 637
achromatopsia, central, color agnosia vs multiple sclerosis 547 agraphesthesia 12–13
60 advanced sleep phase disorder 584, 585 agraphia (acquired writing inabilities)
acoustic neuroma 598 affect 208–14 50–1
acquired immunodeficiency syndrome see assessing 6–7 alexia with 49
AIDS bizarre, in schizophrenia 608 differential diagnosis 49, 51
ACTH see adrenocorticotrophic hormone flattened see flattened affect testing 16
activation procedures, EEG 29–30 inappropriate 139–40 see also dysgraphia, developmental
Addison’s disease, ambiguous definition vs sensory aprosodia 55, 140 AIDS 493–5
536 lability, vs emotional incontinence of clinical features (in general) 493–4
see also adrenocortical insufficiency pseudobulbar palsy 124 course 494
adenoma, pituitary see pituitary tumor affective deafness, pure 54 dementia 166, 169, 493, 495
ex.qxd 3/10/08 10:01 AM Page 704
704 Index
AIDS (continued) management 224–5, 665–6 differential diagnosis 271, 448

imaging 20, 494 panic attacks 632 etiology 184–6
and seizures 266, 493 seizures see seizures brain tumors 185, 186, 596–7
differential diagnosis 494–5 tremor 73–4 dementia 162, 335–6
etiology 494 Alcoholics Anonymous 666 epilepsy, see subheading above
neurosyphilis and 590 ALD mutation 376 Korsakoff’s syndrome 185, 470, 471
psychosis 243 aldosteronism, depression 212 post-anoxic encephalopathy 462
treatment 495 alexia (acquired reading inability) 49–50 traumatic brain injury 186, 291
akathisia 14–15, 92–3 differential diagnosis 49, 50 transient global see transient global
clinical features 14–15, 92 testing 16 amnesia
differential diagnosis 93 see also dyslexia, developmental see also dysmnesia; paramnesia
agitation 93, 223 alien hand syndrome/sign 129–31 amphetamine 656
restless legs syndrome 93, 582 clinical features 129–30 psychosis with 240
etiology 92–3 differential diagnosis 130–1 amputation, phantom limb 131–2
antipsychotics 92, 614, 686, 687 asomatognosia 62, 130 amusia 136–7
Parkinson’s disease 93, 345 environmental dependency syndrome β-amyloid (beta-amyloid; amyloid-beta),
tardive 92, 686, 687 127, 131 Alzheimer’s disease 336–7, 338
akinesia (and bradykinesia) 91–2 grope reflex 122, 130 amyloid angiopathy, cerebral see cerebral
differential diagnosis etiology 130 amyloid angiopathy
apathy 214 alpha rhythm 23 amyloid precursor protein gene and
depression 91, 213 alpha-1 antagonists, post-traumatic stress Alzheimer’s disease 338
etiology 91 disorder 641 amyotrophic lateral sclerosis (European
antipsychotics 91, 614 alpha-2 agonists term ⫽ motor neuron disease)
pure psychic see abulia attention-deficit/hyperactivity disorder 166, 167, 342–4
akinetic mutism 96, 118–19 420 clinical features 342–3
differential diagnosis 119 Tourette’s syndrome 371 dementia 166, 167, 342, 343, 344
abulia 119, 126 Alstrom–Hallgren syndrome vs course 343
alcohol (ethanol) abuse/overconsumption Bardet–Biedl syndrome 412 differential diagnosis 343–4
661–7, 692–5 aluminium intoxication in dialysis patients etiology 343
clinical features 662–3, 692–5 (dialysis dementia) 169, 171, 222, frontal lobe syndrome 247
dementia see dementia 476–7 frontotemporal lobar dementia with
depression 211 Alzheimer’s disease 163, 335–40 342
paranoia see paranoia (subheading clinical features 335–7 treatment 344
below) depression 212, 336 anabolic steroids
parkinsonism 89–90 mania 221 depression 212
psychosis see subheading below course 337 mania 219
course 663–4 differential diagnosis 338–9 psychosis 240
differential diagnosis 664 Binswanger’s disease 339, 437 anemia, pernicious 466, 467
AIDS dementia 495 Pick’s disease 339, 341 anergia 208, 625
delusional disorder 617, 694 etiology 337–8 anesthesia, conversion 297
isopropanol intoxication 664, 677 Down’s syndrome 407, 408 angiitis
methanol intoxication 664, 676 multi-infarct dementia and, mixed granulomatous see granulomatous
etiology 664 434 angiitis
fetal alcohol syndrome 189 treatment 339–40 isolated, seizures 266
maternal, fetal effects see fetus amantadine see also cranial arteritis; polyarteritis
paranoia (⫽alcohol-induced psychotic Huntington’s disease 357 nodosa; vasculitis
disorder with delusions) 617, 693 Parkinson’s disease 348 angina vs panic attack causing chest pain
differential diagnosis 693, 694 amelodia 136–7 633
psychosis of 240 amine theory of depression 626 angiomatosis, encephalotrigeminal, see also
with delusions see paranoia δ-aminolevulinic acid dehydratase Sturge–Weber syndrome
(subheading above) deficiency 483 angiopathy, cerebral amyloid see cerebral
with hallucinations (⫽alcohol amnesia (memory impairment) 183–7 amyloid angiopathy
hallucinosis) 693–4, 694 clinical features 183–4 angular gyrus lesions 49–50
schizophrenia vs 612 confabulation 136 anhedonia 208, 625
treatment 665–7 differential diagnosis 186–7 anomic aphasia 47
of complications/associated disorders delirium 182, 186–7 anomic aphasia vs 59
693, 693–4, 694, 695 dementia 173, 186–7 tactile agnosia vs 58
Wernicke’s encephalopathy vs other mild cognitive impairment 174 visual agnosia vs 58
conditions caused by 471 topographical agnosia 60 anosognosia 16, 61
withdrawal symptoms 179, 224–5, epileptic, pure 184, 256–7 diagnostic tests 16
662–3 continuous/closely spaced (amnestic in traumatic brain injury 291
agitation 224–5 status epilepticus) 186, 259 anoxia see post-anoxic encephalopathy
ex.qxd 3/10/08 10:01 AM Page 705
Index 705
anterograde amnesias 183–4, 184–5, post-traumatic stress disorder 641 delirium 182–3, 224
185–6 premenstrual syndrome 630 delusional disorder 617
in Korsakoff syndrome 471 social phobia 637 diffuse Lewy body disease 352
with retrograde component see Tourette’s syndrome 371 mania (incl. bipolar disorder) 222,
retrograde amnesia antidiuretic hormone (ADH; vasopressin) 225, 622, 689
seizures 256 analog (desmopressin), in nocturnal obsessive–compulsive disorder 639
transient global 184, 447 enuresis 575 post-partum psychosis 618
antibiotics syndrome of inappropriate secretion, in post-traumatic stress disorder 641
Lyme disease 511, 512 subarachnoid hemorrhage 281 psychosis (in general) 244
streptococcal pharyngitis/rheumatic anti-epileptic drugs (AEDs) 272–5 schizoaffective disorder 615
fever 558, 560 prenatal exposure causing mental schizophrenia 613–14
syphilis 510 retardation 189 stuttering 424
tuberculosis 512–13 therapeutic use 272–5 Tourette’s syndrome 370–1
Whipple’s disease 513 alcohol withdrawal 665–6 antiretroviral agents, AIDS 495
antibodies brain tumors 600 anti-thyroid antibodies see thyroid gland
in autoimmune disorders status epilepticus 274–5 antituberculous agents 512–13
(autoantibodies) stroke patients 288 antiviral agents
anti-phospholipid syndrome 552 traumatic brain injury 293 AIDS 495
Hashimoto’s encephalopathy 541, tuberous sclerosis patients 405 cytomegalovirus 496
557, 558 antifungal drugs 516 herpes simplex virus 499
Hashimoto’s thyroiditis 540, 541, antihypertensive drugs, hypertensive Anton’s syndrome 61
556 encephalopathy 444 anxiety (and fear) 225–7
limbic encephalitis 554 anti-nuclear antibodies see nuclear acute see panic attacks
Sjögren’s syndrome 551 components anticipatory 632
Sneddon’s syndrome 552 anti-phospholipid antibodies clinical features 6, 225
systemic lupus erythematosus 549 in anti-phospholipid syndrome 552, differential diagnosis 227
detection in CSF 34 553 agitation 223
in Sydenham’s chorea 559 in Sneddon’s syndrome 552 normal fears vs social phobia 637
see also monoclonal antibody therapy anti-phospholipid syndrome 552–3 simple partial seizures 270
anticholinergics chorea gravidarum associated with etiology 225–6, 538
delirium with 690–1 560 cannabis 670
in Parkinson’s disease 348 clinical features Cushing’s syndrome 534
rebound following discontinuation dementia 172 drug-related 225, 282, 350
691–2 thrombotic infarctions 283 hyperthyroidism 226, 537, 538
anticholinesterases, Alzheimer’s disease differential diagnosis 553 seizures 252, 259
339 Sneddon’s syndrome 552 stroke 282
anticipation anti-platelet agents, ischemic stroke 287 observing for 6
in myotonic dystrophy 372 antiprotozoals in toxoplasmosis 516 persistent 225, 225–6
in panic attacks 632 antipsychotics (neuroleptics) 613–14, treatment 227, 282
anticonvulsants see anti-epileptic drugs 683–9 tremor and 73, 74
antidepressants 1st generation 613, 684 anxiety disorders 631–42
adverse/side-effects 627 2nd generation 613, 684 generalized 641–2
delirium 177 adverse effects 614, 683–9 anxiolytics see benzodiazepines;
serotonin syndrome 690 akathisia 92, 614, 686, 687 sedative–hypnotics
attention-deficit/hyperactivity disorder akinesia 91, 614 apathy 214–15
420 dystonia 85, 686 Alzheimer’s disease 340
autism 418 mannerisms 140 frontal lobe syndrome 214, 244, 245
in depression 214, 281–2, 627–8 rabbit syndrome 689 hyperthyroidism 538
in Alzheimer’s disease 339–40 seizures 262–3 traumatic brain injury 292
in bipolar disorder 623 supersensitivity psychosis 240, aphasia 45–9
in diffuse Lewy body disease 352 688–9 atypical 47–8
major depression 627–8 tardive dyskinesia see tardive clinical features 45–8
in multiple sclerosis 548 dyskinesia (antipsychotic-induced) differential diagnosis 48–9
in Parkinson’s disease 350 see also neuroleptic malignant apraxia 56
in post-concussion syndrome 458 syndrome aprosodia 55
resistance to 628 therapeutic use 613–14 delirium 48–9, 182
in traumatic brain injury 292 agitation 173, 223–5 foreign accent syndrome 137
generalized anxiety disorder 642 Alzheimer’s disease 340 stuttering 120
interactions with other drugs 627 autism 418 visual agnosia 58
mechanism of action 626 ballism 83 etiology 48
obsessive–compulsive disorder 639 cannnabis users 671 progressive, dementia presenting with
panic disorder 634 chorea 81 163, 164, 167
ex.qxd 3/10/08 10:01 AM Page 706
706 Index
aphasia (continued) conversion 297 autoimmune disorder(s) 544–68

testing 15–16 dementia with 163, 164, 169–70 acute disseminated encephalomyelitis as
treatment 49 etiology 169–70 504
types 15–16, 46–8 Wernicke’s encephalopathy 470–1 adrenal glands 536–7
see also specific types hemiparesis with, in lacunar infarction delirium in 178, 181
see also dysphasia 279 encephalitis lethargica as 500
aphemia 117 optic 131 see also antibodies
apnea, sleep see sleep apnea spinocerebellar see spinocerebellar autoimmune neuropsychiatric disorders
apolipoprotein E gene, Alzheimer’s disease ataxia associated with streptococcal
338 see also fragile X-associated infections, pediatric see PANDAS
appearance, assessing tremor/ataxia syndrome automatic behavior in narcolepsy 575–6
facial appearance 10–11 atherosclerotic occlusions 283 automatisms
grooming/dress 5 athetosis 14, 81–2 in catatonic stupor 94
apperceptive visual agnosia 57, 57–8 differential diagnosis 82 in seizures 254–5, 259
appetite problems in depression 208, 625 chorea 81, 82 autonomic symptoms
apraxia 16, 55–7 dystonia 86–7 hypoglycemia 478, 479
clinical features 55–6 athymormia see abulia simple partial seizures with 251
diagnostic tests 16 atonic seizures (astatic seizures; drop autoscopy 142
differential diagnosis 56–7 attacks) 256 depersonalization vs 133
acalculia 51 differential diagnosis 271 avolition in schizophrenia 609
alexia 51 cataplexy 138, 271 axonal injury, diffuse 293–4, 455–6
neglect 57, 64 ATP7B mutations 362 clinical features 455–6
etiology 56–7 atrial tachycardia, paroxysmal 227 dementia 171
optic 131 atrophin-1 gene mutation 361
treatment 58 atrophy Babinski sign 15
aprosodia 53–5 dentatorubropallidoluysian see post-ictal 272, 279
differential diagnosis 55 dentatorubropallidoluysian baby blues see post-partum period
amusia 137 atrophy baclofen
flattened affect 55, 139 hippocampal, and post-traumatic stress psychosis induced by 241
inappropriate affect 55, 140 disorder 641 withdrawal symptoms, vs neuroleptic
testing for 16 multiple system see multiple system malignant syndrome 684
aqueductal stenosis, psychosis 242 atrophy bacterial infections incl. encephalitis 295,
arboviral encephalitis/meninogencephalitis posterior cortical 131 508–13
295, 497–8 spinal muscular (X-linked), vs Balint’s syndrome 131
arithmetic skills see acalculia; calculating amyotrophic lateral sclerosis 344 ballismus 14, 82–3
ability in spinocerebellar ataxia 363–4 clinical features 14, 82
arsenic intoxication 170, 473–4 attention-deficit/hyperactivity disorder barbiturates 667–9
arterial supply to brain 275–7 (ADHD; hyperkinetic disorder) withdrawal 668
arteriosclerotic encephalopathy, 418–20 delirium 179
subcortical see Binswanger’s disease clinical features 418–19 Bardet–Biedl syndrome 412
arteriosclerotic parkinsonism see vascular course 419 clinical features 412
parkinsonism differential diagnosis 419–20 mental retardation 188–9
arteritis see cranial arteritis; polyarteritis etiology 419 differential diagnosis 412
nodosa mental retardation 189 Prader–Willi syndrome 412, 413
arylsulfatase A mutations 375 Tourette’s syndrome 369, 371 basilar artery see vertebral and/or basilar
asomatognosia 61–2 treatment 371, 420 artery
differential diagnosis 62 see also hyperactivity basilar meningitis, fungal 516
alien hand sign 62, 130 auditory agnosia 58–9 BBS1 and BBS2 412
Asperger’s syndrome 417 auditory hallucinations 142–3 bedwetting 574–5
aspirin, ischemic stroke 287 etiology 144, 146 behavioral abnormalities
associations, loosening of 608 alcohol hallucinosis 693 autistic children 416
sensory aphasia vs 48 depression 626 Kleine–Levin syndrome 580
associative visual agnosia 57, 58 schizophrenia 607 schizophrenia 608–9
astatic seizures see atonic seizures as Schneiderian first rank symptoms see also specific types of behavior
asterixis 15, 98–9 147 behavioral assessment 5–6
clinical features 15, 98–9 aura behavioral therapy/modification
differential diagnosis 97 epileptic 249, 253 agoraphobia 635
myoclonus 77 migrainous (vs epileptic aura) 270 autism 418
tremor 74, 97 autism 416–18 nocturnal enuresis 574–5
asterognosia, differential diagnosis 58 differential diagnosis 417 see also cognitive–behavioral therapy
astrocytomas 597–8 developmental dysphasia 417, 421 Behçet’s syndrome/disease 442–3
ataxia 169–70 schizophrenia 417, 419 clinical features 443
ex.qxd 3/10/08 10:01 AM Page 707
Index 707
dementia 170 blood, CSF 33 intracranial, imaging 20

multiple sclerosis vs 443, 547 blood cell counts, CSF 33 calculating ability
benzodiazepines 667–9 blood-injury phobia 635, 636 assessing 10, 162
intoxication, clinical features 667–8 blues, post-partum see post-partum period impaired see acalculia
therapeutic use blunted affect see flattened affect callosal lesions, alien hand sign 130
alcohol withdrawal 665 body dysmorphic disorder cancer, pancreatic, depression 211
generalized anxiety disorder 642 psychosis in 239, 240 cannabis 670–1
panic disorder 634 social phobia vs 637 clinical features 670
primary insomnia 586 borderline personality disorder psychosis 240, 670, 671
specific phobias 636 psychosis 239, 240 Capragas syndrome 143
withdrawal of 668 schizophrenia vs 612–13 carbamazepine
delirium 179 borreliosis see Lyme disease alcohol withdrawal 665
panic attacks 632 botulinum toxin bipolar disorder 622, 623
treatment 669 primary cervical dystonia 367 carbidopa, Parkinson’s disease 348
benztropine, akinesia 91–2 spasmodic dysphonia 369 carbon monoxide intoxication 463–4
beta-amyloid, Alzheimer’s disease 336–7, tardive dyskinesia 688 clinical features 463–4
338 Bourneville’s disease see tuberous sclerosis delirium 181
beta-blocker, circumscribed social phobia bovine spongiform encephalopathy and dementia 168
638 new-variant Creutzveldt–Jakob carcinomatosis, leptomeningeal 599–600
beta rhythm 23 disease 527, 527–8 cardiopulmonary conditions, anxiety 227
bicycling movements, complex partial bradykinesia see akinesia carotid artery (CA)
seizures 254 bradyphrenia vs apathy 214 anatomy 275
bilateral independent periodic lateralized brain trauma/tumors etc. see intracranial; dissection and embolus 283
epileptiform discharges (BIPLEDS) trauma; tumors etc. and entries occlusion
29 under cerebral bilateral 172
Binswanger’s disease (subcortical brainstem and major depression 626 internal CA in cranial arteritis 438
arteriosclerotic encephalopathy) branched chain amino acids, tardive stenosis, surgery 287
163, 166, 167, 436–7 dyskinesia 688 cataplexy 137–8
differential diagnosis 437 brief psychotic disorder/reactive psychosis differential diagnosis 138
Alzheimer’s disease 339, 437 vs schizophrenia 613 atonic seizures 138, 271
cerebral amyloid angiopathy 437, 439 Briquet’s syndrome see somatization narcolepsy with 575, 576
imaging 19–20, 436–7 disorder sleep attacks with 576
bipolar (manic–depressive) disorder 210, Broca’s aphasia see motor aphasia treatment 138, 577
218–19, 618–20 bromocriptine catastrophic reaction 139
clinical distinction from major abulia 126 in dementia 162
depression 624 alexia 49 in stroke 282
clinical features 618–19 mutism 119 catatonia 15, 93–6
course 620–1 neuroleptic malignant syndrome 685 clinical features 15, 94
differential diagnosis 621–2 Brueghel’s syndrome 368 differential diagnosis 96
post-partum depression 630 buprenorphine 672 abulia 96, 126
post-partum psychosis 618, 621–2 maintenance use 673 akinetic mutism 96, 119
schizoaffective disorder 615, 621 bupropion 674, 675 mania 96, 222
schizophrenia 611 burst-suppression 29 neuroleptic malignant syndrome
etiology 621 buspirone, opioid withdrawal 673 684
treatment 622–4, 689 in schizophrenia 93, 95, 608
bismuth intoxication 474 cabergoline, Parkinson’s disease 349 as dominant symptom 609
blackouts 184 CADASIL (cerebral autosomal dominant caudate lacunes 279
alcohol-induced 662 arteriopathy with subcortical cavernous sinuses
differential diagnosis 664 infarcts and leukoencephalopathy) anatomy 277
treatment 665 167, 285, 439–40 thrombosis 281
sedative–hypnotic-induced 667–8 differential diagnosis 440 central achromatopsia vs color agnosia
differential diagnosis 668 Binswanger’s disease 437 60
treatment 669 MELAS 440, 445 central nervous system complaints,
transient global amnesia vs 449 caffeine 675 somatization disorder 299
blepharospasm, essential/primary 368 CAG repeats central pontine myelinolysis 479–81
blindness dentatorubropallidoluysian atrophy clinical features 479–80
conversion 297 361 delirium 181
delusions and hallucinations in 145 Huntington’s disease 357 parkinsonism 90
see also color blindness; cortical calcarine artery anatomy 276 course 480
blindness; hemianopia; occipital calcification differential diagnosis 480
spikes of blind persons; word cortical, in Sturge–Weber syndrome etiology 480
blindness, pure 403 treatment 480–1
ex.qxd 3/10/08 10:01 AM Page 708
708 Index
central sleep apnea 577 Sjögren’s syndrome 551 phobias 635

clinical features 577 systemic lupus erythematosus 549 seizures/epilepsies 262, 268
etiology 578 infectious and post-infectious disorders somnambulism 569
treatment 578–9 acute disseminated encephalomyelitis see also adolescence; congenital
cerebellar arteries 505 infections; developmental and/or
anatomy 276 AIDS 495 congenital disorders
occlusion 278 arboviral meningoencephalitis 497 cholesterol emboli syndrome 180, 447
thrombotic see thrombosis CMV encephalitis 495 cholinergic inhibitors see anticholinergics
cerebellar ataxia, autosomal dominant see Creutzveldt–Jakob disease 525 cholinesterase inhibitors, Alzheimer’s
spinocerebellar ataxia Creutzveldt–Jakob disease, new- disease 339
cerebellar hemorrhage 280 variant 527 chorea (choreic/choreiform movements)
cerebellar testing 13 encephalitis lethargica 499–500 14, 78–81, 687
cerebral abscess see abscess fungal infections 516 benign hereditary 360
cerebral amyloid angiopathy 438–9 herpes zoster 502 clinical features 78–9
clinical features 348–9 HSV encephalitis 498 dementia with 163, 164, 169
dementia 166, 167, 438 Lyme disease 511 differential diagnosis 81, 687
seizures 266 progressive multifocal athetosis 81, 82
differential diagnosis 439 leukoencephalopathy 496 myoclonic jerks 77, 81
Alzheimer’s disease 339 progressive rubella panencephalitis tics 78, 81
Binswanger’s disease 437, 439 507 etiology 79–81
CADASIL 440 rabies 504 systemic lupus erythematosus 549
cerebral artery Rocky Mountain spotted fever 514 tardive dyskinesia 685–6, 686
anterior (ACA) subacute measles encephalitis 507 in Huntington’s disease see
anatomy 275–6 subacute sclerosing panencephalitis Huntington’s disease
infarction 278 506 senile 359–60
middle (MCA) syphilis 509 Sydenham’s see Sydenham’s chorea
anatomy 276 toxoplasmosis 515 tics in disorders with 77–8, 78
infarction 277–8 Whipple’s disease 513 treatment 81
posterior (PCA) see also lumbar puncture chorea gravidarum 560–1
anatomy 276 cerebrotendinous xanthomatosis 373–4 clinical features 560–1
infarction 278 clinical features 373 mania 221
see also watershed infarctions dementia 170 psychosis 243
cerebral autosomal dominant arteriopathy seizures 266 choreoacanthocytosis 80
with subcortical infarcts and cerebrovascular system clinical features 358
leukoencephalopathy see CADASIL anatomy 275–7 dementia 169
cerebral edema in head injury 293, 294 disorders, seizures 264 choreoathetosis, paroxysmal dystonic 86
cerebral hemorrhage 280, 284, 288 see also hemorrhage; infarction; stroke choroidal artery
in cerebral amyloid angiopathy 438, ceroid lipofuscinosis, neuronal, adult form anterior
439 (Kufs’ disease) 172, 377 anatomy 277
diagnostic work-up 286 cervical dystonia, idiopathic 366–7 infarction 278
differential diagnosis 286, 439 CGG repeats, fragile X mental retardation posterior, anatomy 276–7
imaging 19 1 gene 359, 409–10 chromosomal disorders, mental
traumatic 294 Charles Bonnet syndrome 145, 146 retardation 188–9
treatment 288 chelating therapy circadian rhythm sleep disorder 584–5
cerebral infarction see infarction aluminium intoxication in dialysis 477 circumstantiality 7
cerebral lesions (in general), delusions and lead intoxication 475 clock-drawing test 63
hallucinations in 144, 145, 146 Wilson’s disease 362 clonazepam, restless legs syndrome 582
cerebral salt wasting in subarachnoid chemotherapy, brain tumors 600 clonic movements, postural tremor vs 74
hemorrhage 281 chest pain with panic attacks 632 clonidine
cerebral veins vs heart disease 633 autism 418
superficial and deep, anatomy 277 chickenpox 502 opioid withdrawal 673
thrombosis 281, 284 chief complaint, establishing 3–4 Tourette’s syndrome 371
treatment 288 childhood onset 403–32 clozapine, seizures 262
cerebrospinal fluid, production and adrenoleukodystrophy 376 CMV see cytomegalovirus
circulation 600 chorea 79, 80 cobalamin see vitamin B12 deficiency
cerebrospinal fluid tests 33–4 dopa-responsive dystonia 365 cocaine 657–9
Alzheimer’s disease 336–7 lead intoxication 475 clinical features 657–8
immune-related disorders metachromatic leukodystrophy 374, psychosis 240, 658
Hashimoto’s encephalopathy 557 375 cognitive–behavioral therapy
limbic encephalitis 554 obsessive–compulsive disorder 639 agoraphobia 635
multiple sclerosis 545 pantothenate kinase-associated alcoholism 666
sarcoidosis 556 neurodegeneration 364 primary insomnia 586
ex.qxd 3/10/08 10:01 AM Page 709
Index 709
cognitive deficits/impairment tumors 20, 21, 597 parkinsonism 89, 168, 354
anosognosia for 61 concentration difficulties, major course 354
fragile X-associated tremor/ataxia depression 625 differential diagnosis
syndrome 359 concussion (and post-concussion diffuse Lewy body disease 352
Kleine–Levin syndrome 580 syndrome) 457–8 Parkinson’s disease 348
mild 173–4 clinical features 457 progressive supranuclear palsy 353
differential diagnosis 172–3, 174, amnesia 184–5 corticospinal tract and fibers
187 differential diagnosis 458 emotional facial palsy and 124–5
in simple partial seizures 251 post-traumatic stress disorder 641 pseudobulbar palsy and 123
sleep apnea 578 transient global amnesia 448 corticosteroid therapy
syndromes of 162–207 traumatic brain injury 294 Cushing’s syndrome due to 535
traumatic brain injury 290–1 conduction aphasia 47 therapeutic use
treatment 290–1 conduction aprosodia 54 acute disseminated encephalomyelitis
see also dementia confabulation 136 505–6
coherence of speech in aphasia 45 confusion brain tumors 600
‘cold turkey’ 672, 673 in delirium 174 cranial arteritis 438
colloid cysts, third ventricle 599 in diffuse Lewy body disease 351 Hashimoto’s encephalopathy 558
color agnosia 60 episodic, vs complex partial seizures multiple sclerosis 457
color blindness, acquired, color agnosia vs 270–1, 271 radiation encephalopathy 459
60 observing for presence or absence 9 Sydenham’s chorea 560
coma congenital disorders see developmental systemic lupus erythematosus
conversion 297 and/or congenital disorders and 550–1
myxedema 539, 541 specific disorders see also dexamethasone; prednisone
phencylidine and ketamine-induced congenital infections corticotrophin-releasing hormone (CRH)
660 rubella see rubella stimulation test 535
see also Glasgow Coma Scale syphilis 509 cortisol, elevated 534, 535
comprehension consciousness, level counselling see family counselling; genetic
in aphasia 45 impaired, seizures 249–50, 253–4 counselling
in aprosodia 53 observing 9 cranial arteritis (temporal/giant cell
compulsions 9, 133–5, 638 see also coma arteritis) 437–8
clinical features (in general) 9, 134 constructional apraxia 16, 56 clinical features 437–8
differential diagnosis 135 neglect vs 57, 64 dementia 167
stereotypies 141 ‘continuation’ reactive automatisms 255 stroke 285
etiology 134–5 control, delusion of 608 cranial fractures 294
Sydenham’s chorea 558 contusions, cerebral 294 cranial nerves
Tourette’s syndrome 369 conversion disorder (hysteria) 296–9 disorders in sarcoidosis 555
treatment 135 clinical features 296–8 examination 11–12
see also obsessive–compulsive disorder mutism 118 craniopharyngioma 599
computed tomography 17 seizures 271–2, 297–8 ‘crash’ with cocaine 658
alcoholic dementia 692 course 298 creatine phospokinase (CPK) levels and
Binswanger’s disease 19–20, 436 differential diagnosis 298–9 seizures vs pseudoseizures 272
clinical indications (in general) 18–21 Briquet’s syndrome 298, 299, 300 Creutzveldt–Jakob disease 525–8
Fahr’s syndrome 485 hypochondriasis 301 clinical features 525
HSV encephalitis 20, 498 etiology 298 alien hand sign 130
hydrocephalus 601 treatment 299 ataxia 170
normal-pressure 603 convulsions see seizures dementia 166, 169, 170
hypertensive encephalopathy 444 copper chelating agents, Wilson’s disease depression 213
inhalent-induced dementia 695 362 EEG see electroencephalography
multi-infarct dementia 433 coproporphyria, hereditary 483, 484 mania 221
neurodegenerative and movement coronary heart disease vs panic attack myoclonus 169
disorders causing chest pain 633 personality change 246
adrenoleukodystrophy 376 corpus callosum lesions, alien hand sign psychosis 242
Alzheimer’s disease 336 130 seizures 266
Huntington’s disease 356 cortical atrophy, posterior 131 course 525–6
Pick’s disease 340 cortical blindness, anosognosia for 61 differential diagnosis 526–7
seizures 269 cortical calcification in Sturge–Weber 14–3-3 protein see 14–3-3 protein
stroke 285 syndrome 403 new-variant 527–8
trauma cortical signs and symptoms 45–71 treatment 527
dementia pugilistica 456 corticobasal ganglionic degeneration 354 CRH stimulation test 535
diffuse axonal injury 455 clinical features 354 crying (dacrystic) seizures 252, 254
subdural hematoma 454 dementia 168, 169, 354 ctendoids 30
tuberous sclerosis 405 dystonia 169 CTG triplet, myotonic dystrophy 372
ex.qxd 3/10/08 10:01 AM Page 710
710 Index
culture, microbial, CSF 33–4 mania 222 course 617

culture-bound syndromes vs pathologic mild cognitive impairment 174 differential diagnosis 617
startle 98 psychosis 182, 243 alcoholism 617, 694
Cushing’s disease (ACTH-secreting etiology 175–82 schizophrenia 612, 617
pituitary tumor) 534, 535, 599 adrenocortical insufficiency 537 etiology 617
Cushing’s syndrome 534–6 brain trauma 181, 283 dementia 162–73, 335–40
clinical features 534–5 brain tumors 596 AIDS see AIDS
depression 212, 534, 536 cannabis 670 alcoholic 171, 692–4
mania 219, 534 CMV encephalitis 495 in Marchiafava–Bignami disease
psychosis 241, 534 Cushing’s syndrome 534 694–5
course 535 drugs (therapeutic) 175, 175–6, 177, clinical features 162–3
differential diagnosis 535–6 350, 690–1 agitation 173, 223–4, 340
etiology 535 Hashimoto’s encephalopathy 181, apathy 214
cyanocobalamin administration 467–8 557 delusions and hallucinations 143,
cyclophosphamide, systemic lupus hepatic encephalopathy 176, 481 162–3
erythematosus 550, 551 Korsakoff’s syndrome 471 depression 173, 209, 210, 210
cyclothymia 219 phencylidine and ketamine 661 mania 218, 221
bipolar disorder vs 621 sedative–hypnotic withdrawal 668, perseveration 121
CYP27 and cerebrotendinous 669 personality change 162, 246
xanthomatosis 373 Sydenham’s chorea 559 seizures 260–1, 261, 266
cysts, colloid, third ventricle 599 systemic lupus erythematosus 181, dialysis 169, 171, 222, 476–7
cytomegalovirus encephalitis/ 549, 550 differential diagnosis 172–3, 351–2
ventriculoencephalitis 471, 495–6 Wernicke’s encephalopathy 179, agraphias 51
differential diagnosis 496 470 alexia 50
Wernicke’s encephalopathy 471 myoclonus with 75, 76 amnesia 173, 186–7
treatment 182–3, 224, 289 aphasia 48–9
D-cycloserine, Alzheimer’s disease 339 tremor and 73, 73–4 delirium 173, 182
dacrystic seizures 252, 254 see also delirium tremens mental retardation 173, 189
dantrolene, neuroleptic malignant delirium tremens (delirium ⫹ tremor of mild cognitive impairment 172–3,
syndrome 685 alcoholism) 240, 263 174
daytime enuresis (awake wetting) 574 differential diagnosis 664 personality change 248
daytime sleepiness, excessive see alcohol hallucinosis 693 psychosis 243
hypersomnia treatment 666 etiology 163–72, 335–40
de Clerambault’s syndrome see erotomanic delirium tremens sine tremore 663 alcohol, see subheading above
delusions delta activity 24 amyotrophic lateral sclerosis 166,
deafness intermittent rhythmic and frontal 167, 342, 343, 344
conversion 297 intermittent rhythmic 25 brain tumors 165, 167, 596
delusions and hallucinations in 146 delusion(s) 8, 142–6 cerebral amyloid angiopathy 166,
developmental dysphasia vs 421 clinical features 143 167, 438
pure word deafness vs 49 in delusional disorder 615, 616–17 corticobasal ganglionic degeneration
see also affective deafness; word deafness differential diagnosis 146 168, 169, 354
deep brain stimulation confabulation 136 diffuse Lewy body disease 163, 168,
Lesch–Nyhan syndrome 412 etiology 143–4 351
Parkinson’s disease 349 cocaine 657, 658 Down’s syndrome 171, 407
deep tendon reflexes, assessing 15 delirium 143–4, 175 folate deficiency see folate deficiency
defect symptoms of schizophrenia 608 dementia 143, 162–3 Huntington’s disease 166, 168, 169,
déjà vu and déjà entendu 251 depression 144, 625–6, 689 356, 357
delayed sleep phase disorder 584, 585 Kleine–Levin syndrome 580 hydrocephalus 601, 602, 602–3
delirious mania 215, 217, 619–20 psychosis see subheading below hyperthyroidism 165, 538
delirium 174–83, 224 stimulants 656 hypothyroidism 165, 540
agraphia vs 51 of orientation (⫽reduplicative inhalants 170, 171, 695
clinical features 174–5 paramnesia) 135–6 Lyme disease 166, 511
agitation 224 in psychosis 144, 238 manganese intoxication 168, 472
delusions and hallucinations 143–4, alcohol-related see alcohol mercury intoxication 170, 476
174–5 schizophrenia 607 metachromatic leukodystrophy 170,
differential diagnosis 182 as Schneiderian first rank symptoms 172, 375
amnesia 182, 186–7 147 multiple sclerosis 166, 544–5, 548
anxiety 227 treatment 146 multiple system atrophy 355
aphasia 48–9, 182 delusional disorder (paranoia) 615–17 Parkinson’s disease 168, 345, 350
dementia 173, 182 alcoholic see alcohol, paranoia pellagra 170, 468, 469
environmental dependency syndrome clinical features 616–17 phencylidine and ketamine 661
127 psychosis 238–9 Pick’s disease 166, 167, 340
ex.qxd 3/10/08 10:01 AM Page 711
Index 711
post-anoxic encephalopathy 169, flattened affect 139 dysgraphia 51, 422

171, 462 hypochondriasis 301 dysphasia see dysphasia
post-concussion syndrome 458 insomnia (primary) 586 seizures 261, 266–7
progressive supranuclear palsy 168, mutism 119 stuttering 119–20, 120, 423–4
353 psychosis 243 see also childhood onset and specific
sarcoidosis 172, 555 schizophrenia 612 disorders
spinocerebellar ataxia 363 etiology 209–13, 538, 626–7 dexamethasone, brain tumors 600
stroke 163, 164, 166–7, 281 adrenocortical insufficiency 537 dexamethasone suppression test 535
subdural hematoma (traumatic) bipolar disorder 620, 623 dextroamphetamine 656
455 brain tumors 213, 597 diagnostic assessment 3–42
syphilis 166, 509 concussion 457, 458 dialysis dementia 169, 171, 222, 476–7
systemic lupus erythematosus 166, Cushing’s syndrome 212, 534, 536 dialysis dysequilibrium syndrome 477
168, 172, 549, 550 dementia see subheading above dietary deficiency
Whipple’s disease 169, 172 diffuse Lewy body disease 212, 351, folate 468
lacunar see lacunar dementia 352 niacin 469
multi-infarct see multi-infarct dementia Down’s syndrome 213, 407 thiamine 470
myoclonus with 75, 76, 163, 164, 169 hyperthyroidism 211, 538 diffuse axonal injury see axonal injury
parkinsonism with 89, 163, 164, 167–8 hypothyroidism 212, 539, 539 diffuse Lewy body disease see Lewy body
treatment 173, 434 Kleine–Levin syndrome 580–1 disease
pharmacological see drug therapy multiple sclerosis 212–13, 545, 548 diffusion-weighted MRI 18
vascular, definition 433 Parkinson’s disease 212, 345, 350 disconnection syndrome, apraxia as part of
dementia pugilistica 168, 170, 456–7 post-psychotic depression 614 56
demyelinization post-partum depression see post- disinhibition in frontal lobe syndrome
central pontine myelinolysis 479, 480 partum period 244, 245
Marchiafava–Bignami disease 695 schizoaffective disorder 211, 615 disorganized schizophrenia 608–9
radiation encephalopathy 458, 459 simple partial seizures 252 disorientation 9
vitamin B12 deficiency 466, 467 sleep apnea 211, 578 delusional (⫽reduplicative paramnesia)
denial, emotionally-motivated, stroke 212, 281–2 135–6
anosognosia for vs 61 systemic lupus erythematosus 213, of place see topographical disorientation
dentatorubropallidoluysian atrophy 549, 550 disseminated intravascular coagulation vs
360–1 traumatic brain injury 292 thrombotic thrombocytopenic
clinical features 360 major see depressive disorder, major purpura 446
dementia 169, 170 observing for 6 dissociative amnesia 186
psychosis 241 recurrence with nicotine abstinence distractibility 216
differential diagnosis 361 675 disulfiram
spinocerebellar ataxia 364 resistant 628 alcoholism 667
depersonalization 132–3 treatment 213–14, 225, 281–2, 292, dementia associated with 171
observing for 8–9 350, 627–9, 689 divalproex see valproic acid and sodium
in simple partial seizures 251 in bipolar disorder 623 valproate
depression (depressed mood) 208–14, tremor and 73, 74 domoic acid intoxication 263
624–9 depressive disorder, major 624–9 donepezil, Alzheimer’s disease 339
clinical features 208–9, 624–6 clinical features 624–6 dopa (L-dopa) see levodopa
agitation 209, 225, 625 course 208 dopamine blockers-induced conditions
apathy 214 differential diagnosis 627 neuroleptic malignant syndrome 684
delusions and hallucinations in 144, generalized anxiety disorder 642 tardive dyskinesia 686
625–6, 689 post-partum 630 dopaminergic drugs (incl. dopamine
depersonalization 133 post-traumatic stress disorder 641 agonists)
Schneiderian first rank symptoms schizoaffective disorder 615 adverse effects 349–50
147–8 schizophrenia 611, 612 psychosis 240
sleep disturbances 208–9, 586, 625 etiology 636–7 therapeutic use
in dementia 173, 209 recurrence with nicotine abstinence neuroleptic malignant syndrome
Alzheimer’s disease 212, 336 675 684–5
dementia in 165 treatment 627–9 Parkinson’s disease 348–9, 349
differential diagnosis 213, 627 deprivation, severe, vs developmental restless legs syndrome 582
akinesia 91, 213 dysphasia 421 double orientation (⫽reduplicative
Alzheimer’s disease 339 desipramine, Tourette’s syndrome 371 paramnesia) 135–6
amnesia 187 desmopressin, nocturnal enuresis 575 Down’s syndrome (trisomy 21) 188, 407,
anxiety 227 detoxification, rapid/ultra-rapid, opioid 407–8
apathy 214–15 673 clinical features 407
attention-deficit/hyperactivity developmental and/or congenital disorders dementia 171, 407
disorder 419 and factors 403–32 depression 213, 407
Briquet’s syndrome 300 amusia 137 seizures 266, 407
ex.qxd 3/10/08 10:01 AM Page 712
712 Index
doxepin, primary insomnia 586 delusional disorder 617 nocturnal enuresis 575
dreams, acting out during sleep see REM delusions and hallucinations 146 periodic limb movements 583
sleep behavior disorder dementias REM sleep behavior disorder 571–2
dress, assessing 5 for agitation 173, 223 restless legs syndrome 582
dressing apraxia 16, 56 in AIDS patients 495 stroke 287, 288
neglect vs 57 Alzheimer’s disease 339–40 stuttering 424
drip artifact 30 in Binswanger’s disease 437 subacute sclerosing panencephalitis
drop attacks see atonic seizures diffuse Lewy body disease 352 506
drug abuse see substance abuse frontotemporal dementia 342 substance abuse
drug-induced conditions 683–92 Huntington’s disease 347 alcohol 665–7
akathisia 92, 614, 686, 687 multi-infarct dementia 434 cocaine 658–9
akinesia 91, 614 in multiple sclerosis 548 hallucinogens 661
anxiety 225, 282, 350 Parkinson’s disease 350 methanol 676
asterixis 97 depression 214, 281–2, 292, 339–40 nicotine incl. smoking 674–5
catatonia 95 major 627–8 sedative–hypnotic withdrawal 669
chorea 79 post-partum 631 Susac’s syndrome 553
delirium 175, 175–6, 177, 350, 690–1 see also antidepressants Sydenham’s chorea 560
delusions and hallucinations 144, 145, epilepsy see anti-epileptic drugs systemic lupus erythematosus 550–1
146 generalized anxiety disorder 642 tardive dyskinesia 688
dementia 171 Hashimoto’s encephalopathy 558 Tourette’s syndrome 370–1
depersonalization 133 hyperekplexia 379 traumatic brain injury
depression 209, 210, 211 hypertensive encephalopathy 444 in acute phase 289
dystonia 84, 85, 686 hyperthyroidism 538–9 in chronic phase 290–2
emotional incontinence 124 Kluver–Bucy syndrome 128–9 tremor 75
folate deficiency 468 Korsakoff’s syndrome 472 essential 378
lupus 550 limbic encephalitis 555 Wegener’s granulomatosis 442
mania 218, 219, 621 mania 222, 622–3 see also specific (types of) drugs
myoclonus 75–6, 76 MELAS 445 drug withdrawal symptoms see withdrawal
obsessions and compulsions 134 multiple sclerosis 547 symptoms
parkinsonism 88, 89, 686–7 mutism 119 dumb rabies 503
psychosis 240, 350 neurodegenerative and movement dural metastases 600
supersensitivity 240, 688–9 disorders dural venous sinuses
Schneiderian first rank symptoms 148 amyotrophic lateral sclerosis 344 anatomy 277
seizures 260, 261–2 dementias see subheading above thrombosis 281
sleep attacks 576 Huntington’s disease 357 dysarthria 13
sleepwalking 570 multiple system atrophy 355 differential diagnosis 48
startle 98 Parkinson’s disease 348–50 dysarthria–clumsy hand 279
tics 77, 78, 686 progressive supranuclear palsy 353 dyscalculia see acalculia
tremor 73 Wilson’s disease 362 dysexecutive syndrome in frontal lobe
see also intoxicants and specific (types of) neuroleptic malignant syndrome syndrome 244
drugs 684–5 dysgraphia, developmental 51, 422
drug therapy obsessive–compulsive disorder 639 see also agraphia
abulia 126 panic disorder 633 dyskinesia, tardive see tardive dyskinesia
agitation 223–5, 291 parkinsonism 91, 473 dyslexia, developmental 421–2
in dementia 173, 223 personality change 249, 473 dysmenorrhea vs premenstrual syndrome
akathisia 93 phantom limb pain 132 630
akinesia 91–2 phobias dysmnesia, simple partial seizures 251
anxiety 227 simple/specific 636 dysmorphic disorder, body see body
apathy 215 social 637–8 dysmorphic disorder
aphasia 49 polyarteritis nodosa 442 dysmorphic features
attention-deficit/hyperactivity disorder post-traumatic stress disorder 641 Down’s syndrome 407
371, 420 psychosis 244 fetal alcohol syndrome 414
autism 418 post-partum 618 Prader–Willi syndrome 412
ballism 83 radiation encephalopathy 459 velocardiofacial syndrome 410
Behçet’s disease 443 sarcoidosis 556 dysphasia, acquired 421
bipolar disorder 622–3 schizophrenia 613–14 dysphasia, developmental (specific
cerebrotendinous xanthomatosis Sjögren’s syndrome 551 language impairment) 48, 420–1
373–4 sleep disorders differential diagnosis 421
chorea 81 cataplexy 577 autism 417, 421
Creutzveldt–Jakob disease 527 Kleine–Levin syndrome 581 see also aphasia
delirium 182–3, 289 narcolepsy 576–7 dysphonia, spasmodic 368–9
anticholinergic-induced 691 nightmare disorder 572 dysthymia 210–11
ex.qxd 3/10/08 10:01 AM Page 713
Index 713
dystonia 14, 83–7, 365–8 new-variant 527 acute encephalitis 295

cervical, idiopathic 366–7 decreased amplitude 24–5 multiple sclerosis 457
clinical features 14, 83, 365, 366, 367 artifacts resembling 31 etiology 505
dementia with 163, 169 decreased amplitude see subheading below treatment 505–6
differential diagnosis 86–7, 687 developmental dysphasia 421 encephalopathy
dopa-responsive 365 epilepsy see seizures dialysis (⫽dialysis dementia) 169, 171,
etiology 83–6 Hashimoto’s encephalopathy 557 222, 476–7
drugs 84, 85, 686 instrumentation 21–2 Hashimoto’s/steroid-responsive see
pantothenate kinase-associated Kleine–Levin syndrome 580 Hashimoto’s encephalopathy
neurodegeneration 169, 364 limbic encephalitis 554 hepatic 481–2
ictal 86 MELAS 445 asterixis 97
laryngeal (spasmodic dysphonia) normal patterns 23–4 ataxia 170
368–9 variants 30 course 482
nocturnal paroxysmal 86 pseudoseizures 272 delirium 176, 481
tardive 687 Sydenham’s chorea 559 dementia 169, 170
task-specific 367–8 systemic lupus erythematosus 549 differential diagnosis 482
torsion, primary 366 embolus etiology 482
treatment 87 cardiac and artery-to-artery, infarction mania 219
see also myoclonus–dystonia syndrome due to 282–3 parkinsonism 90
dystonia plus syndrome 83, 85 pulmonary, anxiety 227 treatment 482
dystonic tremor 74 see also microembolism syndromes hypertensive see hypertensive
emotional facial palsy 124–5 encephalopathy
eating-induced complex partial seizures emotional incontinence lead see lead intoxication
258 in multiple sclerosis 545, 548 metabolic (in general)
EBV 501 post-stroke 282 delirium 176
ECG artifacts on EEG 31 in pseudobulbar palsy 123, 124 parkinsonism 90
echolalia 8, 141–2 sensory aprosodia vs 55 in uremia see uremia
in catatonic stupor 94 in traumatic brain injury 292 pellagrous 468–9
clinical features 8, 141 emotionalism post-anoxic see post-anoxic
echopraxia (imitation behavior) emotional incontinence of encephalopathy
in catatonic stupor 94 pseudobulbar palsy vs 124 radiation 171, 458–9
clinical features 8, 141 in traumatic brain injury 292 subcortical arteriosclerotic see
differential diagnosis 141 encephalitis Binswanger’s disease
environmental dependency syndrome limbic see limbic encephalitis transmissible spongiform 525–8
127, 141 Rasmussen’s 268 Wernicke’s see Wernicke’s
eclampsia vs post-partum psychosis 618 in Sydenham’s chorea 559 encephalopathy
ecstasy 659 see also encephalomyelitis; see also leukoencephalopathy
ECT see electroconvulsive therapy meningoencephalitis; encephalotrigeminal angiomatosis, see also
edema, cerebral, in head injury 293, 294 panencephalitis; post-encephalitic Sturge–Weber syndrome
edentulous patients, oromandibular patients endocrinologic disorders 534–43
movements 81 encephalitis, acute 180, 294–5 clinical features (or as cause)
educational classes, special, autism 418 clinical features 294–5 anxiety 225, 226, 227
EEG see electroencephalography amnesia 186 bipolar disorder 621
Ekbom’s syndrome see restless legs delirium 180, 181 delirium 178, 182
syndrome psychosis 238, 242 depression 209, 210, 212, 626
electrocardiography artifacts on EEG 31 differential diagnosis 295 mania 219
electroconvulsive therapy (ECT) treatment 295 psychosis 238, 239, 241
catatonia 96 viral see viral encephalitis tremor 73
major depression 628, 629 encephalitis lethargica (von Economo’s in radiation encephalopathy 458–9
neuroleptic malignant syndrome 685 disease) 499–500 in sarcoidosis 555–6
Parkinson’s disease clinical features 499–500 energy
for depression 350 mania 221 decreased (anergia) 208, 625
for motor symptoms 349 obsessions and compulsions 134 increased 216
tardive dyskinesia 688 encephalomyelitis, acute disseminated enuresis
electrodes, EEG 21–2 (post-infectious/post-vaccinial) awake/daytime 574
pop artifacts 31 221–2, 504–6 nocturnal 574–5
electroencephalography (EEG) 21–31 clinical features 504–5 environmental dependency syndrome
abnormal patterns (in general) 24–9 delirium 180 (utilization behavior) 126–7
activation procedures 29–30 mania 221–2 differential diagnosis 127
acute encephalitis 295 seizures 266 alien hand sign 127, 131
artifacts 30–1 course 505 personality change 249
Creutzveldt–Jakob disease 28, 525, 527 differential diagnosis 505 echopraxia vs 127, 141
ex.qxd 3/10/08 10:01 AM Page 714
714 Index
ependymomas 597 face folie à deux 243

epilepsy 249–75 appearance, assessing 10–11 forced normalization, psychosis of 95, 242
clinical features 249–60 dysmorphism in velocardiofacial foreign accent syndrome 137
amnesia see amnesia syndrome 410 le fou rire prodromique 124, 125
catatonia 95 facial nerve testing 12 14- and 6-cps positive bursts 30
delirium 178, 182 facial palsy 14–3-3 protein in CSF
depression 213 emotional 124–5 Creutzveldt–Jakob disease 34, 525, 527
mania 221 voluntary 124 measurements 34
psychosis 95, 238, 239, 242 facial recognition inability 59 fractures, cranial 294
diagnostic work-up 268–70 factitious illness/disorder 302–3 fragile X-associated tremor/ataxia
differential diagnosis 270–2 differential diagnosis syndrome (FXTAS) 170, 359
etiology 260–8 Briquet’s syndrome 300 fragile X mental retardation 1 protein and
hypergraphia and 52, 245 hypochondriasis 301 gene 359, 409–10
myoclonic see myoclonic epilepsy post-traumatic stress disorder 641 fragile X syndrome 359, 409–10
seizures in see seizures psychosis 243 clinical features 409
startle 99 Fahr’s syndrome 484–5 seizures 266
treatment 272–5 clinical features 484–5 with mental retardation 188, 359, 409
see also post-ictal period; status dementia 168 freezing phenomenon, Parkinson’s disease
epilepticus and entries under ictal; depression 213 344–5
interictal mania 222 Fregoli syndrome 143
episodic anterograde amnesia 183, movement disorder 80, 485 frontal intermittent rhythmic delta activity
184–5, 186 psychosis 242 25
episodic confusion vs complex partial familial occurrence of phobias 635 frontal lobe pathology
seizures 270–1, 271 family counselling, autism 418 primitive reflexes in 122
episodic hypersomnolence 587 ‘fascinations’, autism 416 tumors, dementia 165, 167
Epstein–Barr virus 501 fat embolism syndrome 180, 446 frontal lobe syndromes 244–5, 247–8
erotomanic delusions (de Clerambault’s fatal familial insomnia, psychosis in 242 clinical features 244–5
syndrome) 143 fatigue in traumatic brain injury 292 apathy 214, 244, 245
in delusional disorder 616 fear see anxiety differential diagnosis
erythrophobia 637 feeding difficulties, mental retardation 188 anosognosia for cognitive deficits 61
essential blepharospasm 368 fetus Kluver–Bucy syndrome 129
essential hypersomnia 587 alcohol syndrome 414 etiology 247–8
essential myoclonus 76 differential diagnosis 414, 419 brain tumors 247, 248, 596
essential tremor 74, 377–8 mental retardation-causing insults 189 dementia 163, 164, 167
differential diagnosis 388 rubella see rubella stroke 247, 282
rabbit syndrome 689 fibrinolytics in ischemic stroke 287 traumatic brain injury 248, 292
estrogens and Alzheimer’s disease finger-to-nose test 13, 72 localizing and lateralizing value 248
prevention 339 first rank symptoms see Schneiderian first frontal variant frontotemporal dementia
ethanol see alcohol rank symptoms 341
ethylene glycol intoxication vs other fits see seizures frontotemporal dementia 167, 341–2
alcohols 664, 676, 677 FLAIR sequences (MRI) 18 chromosome 17-linked (FTDP-17)
euphoria flashbacks, hallucinogen 659 168, 342
antiparkinsonian drug-induced 350 flattened/blunted affect 139 parkinsonism 89, 168
in mania 216 differential diagnosis 139 clinical features 341–2
personality change vs 248–9 motor aprosodia 55, 139 personality change 246, 341
in multiple sclerosis 545, 548 observing for 7 course 342
in simple partial seizures 252 schizophrenia 609 differential diagnosis 342
stimulant-induced 657 flight of ideas 7, 216 Alzheimer’s disease 339, 341
evoked potentials, multiple sclerosis 545 fluency of speech in aphasia 45 etiology 342
excited catatonia 94, 95, 96 fluorescent treponemal antibody test 509 treatment 342
mania vs 96, 222 FMR1 (fragile X mental retardation 1) frontotemporal lobar dementia-
executive dysfunction in frontal lobe gene and its protein 359, 409–10 ubiquinated 342
syndrome 244 focal seizures see partial seizures frontotemporal lobar dementia with
exercise-induced paroxysmal dystonic focal signs and symptoms motor neuron disease 342
choreoathetosis 86 brain trauma 291 fungal infections 516–17
explosive disorder, intermittent 271 brain tumors 596 furious rabies 503
expressive amusia 136, 137 focal slowing of EEG 25 FXTAS (fragile X-associated tremor/ataxia
expressive aphasia see motor aphasia folate (folic acid) deficiency 468 syndrome) 170, 359
extinction, types and tests 17 dementia of 165, 468
eye involvement, zoster 502 Alzheimer’s disease vs 339 GABAergic pathways
eye movements inducing artifacts on differential diagnosis 468 alcoholism and 664
EEG 31 vitamin B12 deficiency 467, 468 panic disorder 632, 633
ex.qxd 3/10/08 10:01 AM Page 715
Index 715
gabapentin dystonia global aphasia 16, 47

multiple sclerosis 547 dopa-responsive 365 global aprosodia 54
restless legs syndrome 582 primary torsion 366 global hypoxic–ischemic disorders see
Gage, Phineas 244–5 Fahr’s syndrome 485 hypoxic–ischemic disorders
gait fragile X-associated tremor/ataxia glossokinetic artifact 31
assessment 13 syndrome 359, 410 glossopharyngeal nerve testing 12
disturbances fragile X syndrome 359, 409–10 GLRA1 mutations and startle disease 379
hydrocephalus 601, 602 frontotemporal dementia 168, 342 glucose, CSF measurements 33
parkinsonism 87, 91 generalized anxiety disorder 642 glycine receptor and startle disease 379
galantamine, diffuse Lewy body disease hepatic porphyria 483, 484 grand mal (generalized tonic–clonic)
352 Huntington’s disease 357 seizures 256
gamma-hydroxybutyrate (GHB; sodium Klinefelter’s syndrome 409 continuous/closely spaced (petit mal
oxybate) Kufs’ disease 172, 377 status epilepticus) 259, 260
in narcolepsy 577 Lesch–Nyhan syndrome 411 conversion 297–8
withdrawal delirium 179–80 MELAS 445 differential diagnosis 271
gangliocytoma 598 multiple sclerosis 546 in idiopathic generalized epilepsy 262
Ganser syndrome 302 myotonic dystrophy 372 lateralizing and localizing symptoms
gastrointestinal symptoms, somatization nocturnal enuresis 574 and signs 270
disorder 299 panic disorder 632 pseudo- 271
GCH1 (guanosine triphosphate pantothenate kinase-associated grandiose delusions 143
cyclohydrolase 1 gene) and dopa- neurodegeneration 364 in delusional disorder 616
responsive dystonia 365 Parkinson’s disease 347 in schizophrenia 607
gelastic seizures 252 Pick’s disease 341 granuloma, fungal 516
le fou rire prodromique vs 125 Prader–Willi syndrome 413 granulomatosis, Wegener’s 442
general paresis (of the insane) 508, premenstrual syndrome 629 granulomatous angiitis 440–1
508–9, 510 prion diseases clinical features 440–1
generalized anxiety disorder 641–2 Creutzveldt–Jakob disease 526 dementia 166
generalized seizures Creutzveldt–Jakob disease, new- seizures 266
idiopathic 260, 260–1, 262 variant 528 graphesthesia, assessing 12–13
EEG 268 familial fatal insomnia 529 grasp reflex 15, 122
treatment 272–3 Gerstmann–Sträusller–Scheinker environmental dependency syndrome vs
tonic–clonic see grand mal disease 528 127
generalized social phobia see social phobia progressive supranuclear palsy 353 grasping, instinctive see grope reflex
genetic counselling restless legs syndrome 581 Graves’ disease 537
tuberous sclerosis 405 Rett’s syndrome 415 grooming, assessing 5
von Recklinghausen’s disease 407 schizoaffective disorder 615 grope reflex (instinctive grasping)
genetic disorders schizophrenia 611 clinical features and tests 15, 122
mental retardation 188–9 spinocerebellar ataxia 363 differential diagnosis 122
neurodegenerative, psychosis 241–2 stuttering 423 alien hand sign 122, 130
partial epilepsies 267–8 Tourette’s syndrome 370 guanosine triphosphate cyclohydrolase 1
genetic testing tuberous sclerosis 405 gene and dopa-responsive dystonia
Huntington’s disease 357, 357–8 velocardiofacial syndrome 410 365
Lesch–Nyhan syndrome 411 Wilson’s disease 362 gummas 508, 509
spinocerebellar ataxia 363 geniculate zoster 502 gustatory hallucinations 143
genetics (incl. genes and genetic factors) genitourinary complaints, somatization etiology 144, 146
adrenoleukodystrophy 376 disorder 299 schizophrenia 607
Alzheimer’s disease 338 Gerstmann–Sträussler–Scheinker disease
amyotrophic lateral sclerosis 343 170, 528–9 Hallervorden–Spatz syndrome see
attention-deficit/hyperactivity disorder Gerstmann syndrome 51–2 pantothenate kinase-associated
419 Geschwind (interictal personality) neurodegeneration
autism 417 syndrome 52, 245–6, 248, 249 hallucinations and delusions 8, 142–6
Bardet–Biedl syndrome 412 giant cell arteritis see cranial arteritis clinical features 8, 142–3
benign hereditary chorea 360 giant lacune 279 differential diagnosis 146
bipolar disorder 621 glandular fever (infectious mononucleosis) simple partial seizures 270
cerebrotendinous xanthomatosis 373 295, 500–1 etiology 143–4
choreoacanthocytosis 358 Glasgow Coma Scale, traumatic brain antiparkinsonian drugs 349–50
dentatorubropallidoluysian atrophy injury 290 cocaine 658, 675
361 glatiramer, multiple sclerosis 547 delirium 143–4, 174
depression 626 gliomas 597–8 delusional disorder 617
Down’s syndrome 407–8 global amnesia, transient see transient dementia 143, 163
dyslexia (developmental) 422 global amnesia depression 144, 625–6, 689
dysphasia (developmental) 421 global amusia (acquired) 137 diffuse Lewy body disease 168, 351
ex.qxd 3/10/08 10:01 AM Page 716
716 Index
hallucinations and delusions (continued) hemorrhage and hematoma, intracranial parkinsonism 168
epilepsy 252, 259 280–1, 284 personality change 246, 356
hallucinogen-related flashbacks 659 asterixis in 97 psychosis 241–2
narcolepsy 575 in cerebral amyloid angiopathy 438 course 356–7
psychosis, see subheading below differential diagnosis 286, 439 differential diagnosis 357
stimulants 656 imaging 19, 285 tardive dyskinesia 357, 687
in psychosis 144, 238 seizures 264 etiology 357
alcoholism (⫽alcohol hallucinosis) stroke 280–1, 284, 286 juvenile/adolescent-onset 168, 169,
693–4, 694 subdural, dementia 171 356
schizophrenia 606–7 traumatic 294 treatment 357–8
treatment 146 treatment 288 Huntington’s disease-like 2 vs
hallucinogens 659–60 see also cerebellar hemorrhage; cerebral choreoacanthocytosis 358
clinical features 659 hemorrhage; subarachnoid hydrocephalus 600–3
psychosis 240, 659 hemorrhage; ventricles acute 601
hamartoma, hypothalamic 264–5 heparin, ischemic stroke 287 chronic 601
hand hepatic disorders see liver disorders and dementia 165–6
alien see alien hand syndrome entries below clinical features 601, 602–3
clumsiness, dysarthria and 279 hepatocerebral degeneration, acquired depression 213
handedness, assessing 11 482–3 communicating 601, 602
Hashimoto’s encephalopathy (steroid- clinical features 482–3 course 601–2, 603
responsive encephalopathy) ataxia 170 differential diagnosis 602, 603
556–8 chorea 80, 169 etiology 602, 603
clinical features 557 dementia 169, 170 sarcoidosis 555
delirium 181, 557 hepatolenticular degeneration see Wilson’s ex vacuo vs true 502
seizures 267 disease non-communicating 601, 602
course 557 heredity see entries under genetic normal pressure, vs Binswanger’s
differential diagnosis 557–8 heroin vapour, dementia 171 disease 437
etiology 557 herpes simplex virus encephalitis 295, obstructive 601
Hashimoto’s thyroiditis and 498–9 in tuberous sclerosis 405
clinical distinction 541, 556–7 clinical features 498 5-hydroxytryptamine see selective
co-existing 558 amnesia 186 serotonin re-uptake inhibitors;
treatment 558 imaging 20, 498, 499 serotonin
Hashimoto’s thyroiditis 537, 539, 540 herpes zoster (shingles) 502–3 hyperactivity 217
Hashimoto’s encephalopathy and see encephalitis 295, 502 observing 6
Hashimoto’s encephalopathy Heubner’s recurrent artery, anatomy 277 see also attention-deficit/hyperactivity
head banging, nocturnal 573–4 hippocampal atrophy and post-traumatic hyperaldosteronism, depression 212
head injury, closed see trauma stress disorder 641 hypercalcemia
headache history-taking 3, 4 delirium 179
brain tumor 596 collateral 5 depression 211
in cranial arteritis 437 HIV infection, pathogenesis 494 hypercortisolemia 534, 535
migraine see migraine see also AIDS hyperekplexia (hyperexplekia) 98, 378–9
post-lumbar puncture 32–3 HLA-DQB1 and narcolepsy 575 hyperglycemia
heart disease Holmes’ tremor 14, 72–3 delirium in 179
congenital, diagnostic work-up 407 etiology 64, 73 seizures in 262
coronary, vs panic attack causing chest treatment 75 transient ischemic attacks vs 286–7
pain 633 hormone-secreting tumors hypergraphia 52–3
heat stroke ACTH 534, 535, 599 interictal personality syndrome and
vs anticholinergic delirium 691 pituitary tumors see pituitary tumors 52, 245
vs neuroleptic malignant syndrome 684 hospitalization hypermagnesemia, delirium 179
hebephrenic schizophrenia 608–9 post-partum psychosis 618 hypernatremia
hemangioblastoma 599 schizophrenia 614 delirium 179
hemianopia HSV encephalitis see herpes simplex virus seizures 262
anosognosia for 61 encephalitis hyperorality in Kluver–Bucy syndrome
visual neglect vs 64 Huntington’s disease 80, 356–8 127, 128
hemifacial spasm vs tics 78 chorea 169, 356, 357 hyperparathyroidism 168, 172
hemiparesis anosognosia for 61 hyperphagia
anosognosia for 61 clinical features 356 Kleine–Levin syndrome 579, 580
ataxic, in lacunar infarction 279 chorea see subheading above Prader–Willi syndrome 412
motor neglect vs 64 dementia 166, 168, 169, 356, 357 hyperprolactinemia
hemiplegia, conversion 296–7 depression 212 depression 212
hemochromatosis, idiopathic 169 mania 221 pituitary tumor-related (prolactinoma)
hemodialysis see dialysis myoclonus 169 599, 600
ex.qxd 3/10/08 10:01 AM Page 717
Index 717
hypersexuality see sexual behavior delirium 179 immunosuppressant drugs, multiple

hypersomnia (excessive daytime seizures 262 sclerosis 547
sleepiness) 587 in subarachnoid hemorrhage 281 impulsive behavior
differential diagnosis 587 hypoparathyroidism, Fahr’s syndrome antiparkinsonian drug-induced 350
Kleine–Levin syndrome 580 485 attention-deficit/hyperactivity disorder
myotonic dystrophy 372 hypothalamus 419
Prader–Willi syndrome 413 in bipolar disorder etiology 621 inattentiveness see attention-
primary/essential 587 in depression etiology 626 deficit/hyperactivity disorder
traumatic brain injury 292, 587 hamartoma 264–5 incoherence
hypertensive encephalopathy 443–4 tumors, symptoms 597 observing for 7
clinical features 443–4 hypothyroidism 539–41 sensory aphasia vs 48
delirium 181 clinical features 539–40 infantile-onset metachromatic
seizures 267 dementia 165, 540 leukodystrophy 374
differential diagnosis 444 depression 212, 539 infarction 277–80
reversible posterior psychosis 241, 539–40 clinical features
leukoencephalopathy 444, 445 differential diagnosis 540–1 abulia 126
hyperthermia, malignant, vs neuroleptic post-partum depression 630 asterixis 97
malignant syndrome 684 in Down’s syndrome 407 emotional incontinence in 123
hyperthyroidism and thyrotoxicosis 537–9 etiology 540 hallucinations in pontine infarction
clinical features 538–9 primary 240, 240–1 146
anxiety 226, 537, 538 subclinical 540 mania in 218, 220
dementia 165, 538 secondary 240, 241 seizures 264
depression 211, 538 tertiary 240, 241 imaging 18–19
mania 219, 538 hypoventilation in Pickwickian syndrome ischemic see ischemic infarction
psychosis 241, 538 579 lacunar see lacunar infarction
course 538 hypoxanthine-guanine phosphoribosyl occipital, vs reversible posterior
differential diagnosis 538–9 transferase deficiency 411 leukoencephalopathy 445
etiology 538 hypoxic–ischemic disorders, global silent 280
treatment 538–9 462–5 subcortical see CADASIL
hyperventilation, EEG 29 amnesia 186 in systemic lupus erythematosus 549,
hyperviscosity syndrome 479 delirium 178, 180–1 550
hypnagogic hallucinations 142 encephalopathy following see posttraumatic etiology 294
narcolepsy 575 anoxic encephalopathy watershed/low-flow 277, 278, 284
hypnic jerks vs myoclonus 77 hysteria see conversion disorder see also multi-infarct dementia;
hypnopompic hallucinations 142 stroke
narcolepsy 575 ictal depressions 252 infections 493–524
hypnotics see sedative–hypnotics ictal dystonia 86 congenital see congenital infections
hypocalcemia ictal EEG 26–8 delirium 175, 177–8, 179, 180
delirium 179 see also seizures multiple sclerosis etiology 546
seizures 262 ictal psychosis 242 opportunistic see immunocompromized
hypochondriasis 300–1 ideational apraxia 16, 51, 55–6 persons
differential diagnosis 301 differential diagnosis 56 see also specific (types of) pathogens
Briquet’s syndrome 300, 301 etiology 56 influence, delusions of 147
delusional disorder 617 ideomotor apraxia 16, 55–6 schizophrenia 608
hypoglossal nerve testing 12 etiology 56 inhalant abuse 669–70
hypoglycemia 478–9 illusions see hallucinations clinical features 695
clinical features 478 imaging see neuroimaging ataxia 170
delirium 179 imipramine, nocturnal enuresis 575 dementia 170, 171, 695
dementia 171 imitation inheritance see entries under genetic
seizures 262 of behavior see echopraxia injury, head/brain see trauma
differential diagnosis 478–9 of movements see mirror movements inositol in panic disorder 634
transient ischemic attacks 287 or words/speech of others see echopraxia insight 145
hypomagnesemia immediate recall, testing 9 assessing 10
delirium 179 immobility insomnia 585–6
seizures 262 in akinetic mutism 118 etiology
hypomania (stage I mania) 215, 215–17, in catatonic stupor 94 dementia 173, 340
619 immune-related disorder see autoimmune depression 208–9, 625
differential diagnosis 222 disorders primary insomnia 585–6
hyponatremia immunocompromized persons, traumatic brain injury 293
chronic, overly rapid correction causing opportunistic infections 494–5 fatal familial 528–9
central pontine myelinolysis 479, CMV 495 psychosis in 242
480 immunoglobulin G index, CSF 34 primary 585–6
ex.qxd 3/10/08 10:01 AM Page 718
718 Index
intellectual impairment see mental irregular sleep-wake syndrome 584, 585 laboratory screen, delirium 175
retardation irritability lactic acidosis in MELAS 445
intentional tremor 14, 72 manic patients 216 lacunar dementia 163–5, 167
etiology 73, 74 observing for 6 differential diagnosis 435
interferon therapy, multiple sclerosis ischemic attacks, transient see transient Alzheimer’s disease 339
547, 548 ischemic attacks multi-infarct dementia 434
interictal EEG 28 ischemic infarction 277–80, 286, 287–8 lacunar infarction and syndromes 278–9
artifacts resembling 30–1 diagnostic work-up 285, 286 imaging 18–19
interictal personality syndrome 52, differential diagnosis 286 lambda waves 30
245–6, 248, 249 etiology 282–4 Landau–Kleffner syndrome 268
interictal psychosis, catatonia 95 treatment 287–8 landmark agnosia 59, 60
intermittent explosive disorder 271 ischemic injury, global see language disturbances, autism 416
intermittent porphyria, acute 483, 484 hypoxic–ischemic disorders see also dysphasia, developmental
intermittent rhythmic delta activity 25 isopropanol 676–7 large vessel syndromes 277–8
International League Against Epilepsy, differential diagnosis 677 laryngeal dystonia (spasmodic dysphonia)
classification scheme 249 alcohol intoxication 664, 677 368–9
interview, diagnostic 3–5 methanol intoxication 676, 677 lateral sclerosis
concluding 5 amyotrophic see amyotrophic lateral
directive portion 4–5 jactatio nocturnal capitis 573–4 sclerosis
non-directive portion 4 jamais vu and jamais entendu 251 primary
setting 3 JC virus 496 in amyotrophic lateral sclerosis 343
intoxicants (toxic substances) 472–6 jealousy delusions 143 mimicking conditions 343
anxiety 225 in delusional disorder 616 laughter
ataxia 170, 226, 226–7 jerks in complex partial seizures 254
chorea 79 myoclonic see myoclonus see also gelastic seizures
delirium 175, 176 in sleep mirthless 254
delusions and hallucinations in 144, 145 hypnic, vs myoclonus 77 in le fou rire prodromique 124, 125
dementia 168, 170, 172 isolated 583 nervous, vs inappropriate affect 140
depersonalization 133 of periodic limb movements 582, Laurence–Moon–Biedl syndrome see
depression 209, 210, 211 583 Bardet–Biedl syndrome
encephalitis (acute) vs 295 jet lag 584, 585 le fou rire prodromique 124, 125
mania 218, 219 judgement, assessing 10 lead intoxication and encephalopathy
parkinsonism 88, 89–90, 168

Textbook of Clinical Neuropsychiatry

Uploaded by

Copyright:

Available Formats

Textbook of Clinical Neuropsychiatry

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Textbook of Clinical Neuropsychiatry

Uploaded by

Copyright:

Available Formats

qxd 3/10/08 5:51 PM Page i

Textbook of Clinical Neuropsychiatry

PART OF HACHETTE LIVRE UK

First published in Great Britain in 2001 by Arnold

Copyright © 2008 David P Moore

British Library Cataloguing in Publication Data

Library of Congress Cataloging-in-Publication Data

ISBN-13 978 0 340 93953 6

Commissioning Editor: Philip Shaw

Typeset in 10/12 pt Minion by Charon Tec Ltd

‘Scribere actum fidei est’

PART I DIAGNOSTIC ASSESSMENT 1

PART II SIGNS, SYMPTOMS, AND SYNDROMES 43

4.3 Stuttering 119

PART III SPECIFIC DISORDERS 333

8 Neurodegenerative and movement disorders 335

8.4 Amyotrophic lateral sclerosis 342

10.6 Cerebral amyloid angiopathy 438

14.11 Acute disseminated encephalomyelitis 504

20 Idiopathic psychotic, mood, and anxiety disorders 606

1.1 Diagnostic interview 3 1.5 Electroencephalography 21

1.2 Mental status examination 5

1.2 Mental status examination 7

1.2 Mental status examination 9

Presence or absence of confusion

1.3 Neurologic examination 11

1.3 Neurologic examination 13

Drift patient carries out an intended action, as, for example,

1.3 Neurologic examination 15

Multiple sclerosis is characterized by plaques of demyelin- HERPES SIMPLEX VIRAL ENCEPHALITIS

should include at least 20 minutes of artifact-free record-

Electrodes are attached to the scalp and are connected via

sample the medial aspect of the temporal lobe (MacLean

F3⫺C3 show a downward or negative pen deflection. What PERIODIC COMPLEXES

1.6 Lumbar puncture 31

1.6 Lumbar puncture 33

2 ‘Cortical’ signs and symptoms 45

2.1 Aphasia 45 2.7 Aprosodia 53

2.1 APHASIA Comprehension, or its lack, becomes apparent during

46 ‘Cortical’ signs and symptoms

Transcortical sensory aphasia resembles sensory aphasia, PURE WORD DEAFNESS

CONDUCTION APHASIA ATYPICAL APHASIA

48 ‘Cortical’ signs and symptoms

50 ‘Cortical’ signs and symptoms

2.5 Gerstmann’s syndrome 51

Apraxia may lead to disturbed handwriting; however, Etiology

In addition, if possible, to treatment of the underlying

52 ‘Cortical’ signs and symptoms

54 ‘Cortical’ signs and symptoms

In this condition, spontaneous speech shows a normal range

Speech therapy may be helpful in addition to treatment, if

Motor aprosodia must be distinguished from flattened

56 ‘Cortical’ signs and symptoms

Etiology Dressing apraxia may be seen with lesions, again generally

Both ideomotor and ideational apraxia may occur in a

58 ‘Cortical’ signs and symptoms

visual cortex prevents, as it were, the ‘working-up’ of the ETIOLOGY

Astereognosia is similar clinically to tactile agnosia in that

Tactile agnosia is characterized by an inability to recognize CLINICAL FEATURES