Neuropsychological Neurology The Neurocognitive Impairments of Neurological Disorders PDF

This page intentionally left blank
Neuropsychological Neurology
The Neurocognitive Impairments of
Neurological Disorders
Neuropsychological
Neurology
The Neurocognitive
Impairments of Neurological
Disorders
A. J. Larner
Consultant Neurologist, Cognitive Function Clinic,
Walton Centre for Neurology and Neurosurgery, Liverpool, UK
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo
Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521717922
© A. J. Larner 2008
This publication is in copyright. Subject to statutory exception and to the

provision of relevant collective licensing agreements, no reproduction of any part
may take place without the written permission of Cambridge University Press.
First published in print format 2008
ISBN-13 978-0-511-45520-9 eBook (EBL)
ISBN-13 978-0-521-71792-2 paperback
Cambridge University Press has no responsibility for the persistence or accuracy

of urls for external or third-party internet websites referred to in this publication,
and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every effort has been made in preparing this publication to provide accurate and
up-to-date information which is in accord with accepted standards and practice at
the time of publication. Although case histories are drawn from actual cases, every
effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors and publishers can make no warranties that the
information contained herein is totally free from error, not least because clinical
standards are constantly changing through research and regulation. The authors,
editors and publishers therefore disclaim all liability for direct or consequential
damages resulting from the use of material contained in this publication. Readers
are strongly advised to pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
To Jo – because no one has dedicated a book
to you before
Disorders of intellect . . . happen much more

often than superficial observers will easily
believe.
Samuel Johnson, The History of Rasselas, Prince
of Abyssinia (1759)
Contents
Acknowledgements page ix
Introduction 1
1 Cognitive function,
neuropsychological evaluation,
and syndromes of cognitive
impairment 6
1.1 Attention 8
1.2 General intelligence, IQ 10
1.3 Memory 11
1.4 Language 15
1.5 Perception 16
1.6 Praxis 19
1.7 Executive function, ‘frontal
function’ 20
1.8 ‘Bedside’ neuropsychological
test instruments 22
1.9 Normal aging 32
1.10 Dementia, delirium, depression 33
1.11 Cortical versus subcortical
dementias, thalamic dementia 35
1.12 Disconnection syndromes 37
2 Neurodegenerative disorders 39
2.1 Alzheimer’s disease (AD) 40
2.2 Frontotemporal lobar
degenerations (FTLD) 49
2.3 Motor neurone disease (MND),
amyotrophic lateral sclerosis (ALS) 63
2.4 Parkinson’s disease dementia
(PDD) and dementia with
Lewy bodies (DLB) 69
vii
viii Contents
2.5 Prion diseases 82 6.3 Sarcoidosis 165

2.6 Mild cognitive impairment (MCI) 87 6.4 Systemic lupus erythematosus
(SLE) 166
3 Cerebrovascular disease: vascular
6.5 Sjögren’s syndrome 168
dementia and vascular cognitive
6.6 Behçet’s disease 169
impairment 90
6.7 Rheumatoid arthritis (RhA) 170
3.1 Cortical vascular dementia,
6.8 Scleroderma, systemic sclerosis 170
multi-infarct dementia (MID),
6.9 Relapsing polychondritis 171
post-stroke dementia 93
6.10 Cerebral vasculitides 171
3.2 Subcortical vascular dementia,
6.11 Sydenham’s chorea, paediatric
Binswanger’s disease, lacunar
autoimmune neuropsychiatric
state, subcortical ischaemic
disorders associated with
vascular disease (SIVD) 95
streptococcal infections
3.3 Strategic infarct dementia,
(PANDAS) 173
strategic strokes 97
6.12 Limbic encephalitis 174
3.4 Subarachnoid haemorrhage (SAH) 101
6.13 Hashimoto’s encephalopathy
3.5 Intracranial vascular
(HE) 176
malformations 104
6.14 Erdheim–Chester disease 176
3.6 Vasculopathies 106
6.15 Bilateral vestibulopathy 177
3.7 Other cerebrovascular disorders 112
7 Structural brain lesions 178
4 The epilepsies 115
7.1 Brain tumours and their treatment 178
4.1 Epilepsy and cognitive impairment 115
7.2 Hydrocephalic dementias 182
4.2 Cognitive decline and epilepsy:
7.3 Other structural lesions 186
shared aetiology 116
4.3 Seizures causing acquired 8 Endocrine, metabolic, and toxin-related
cognitive impairment 120 disorders 188
4.4 Antiepileptic drug therapy 8.1 Endocrine disorders 188
causing cognitive impairment 122 8.2 Metabolic disorders 193
4.5 Treatment of cognitive problems 8.3 Toxin-related disorders 200
in epilepsy 123
9 Infective disorders 204
5 Neurogenetic disorders 125 9.1 Encephalitides and
5.1 Hereditary dementias 126 meningoencephalitides 205
5.2 Hereditary ataxias 135 9.2 Meningitides 209
5.3 Hereditary spastic paraplegia 140 9.3 Human immunodeficiency virus
5.4 Hereditary movement disorders 141 (HIV) and related conditions 210
5.5 Hereditary metabolic disorders 146 9.4 Other disorders of infective
5.6 Hereditary neurocutaneous aetiology 211
syndromes (phakomatoses) 155
10 Neuromuscular disorders 215
6 Inflammatory, immune-mediated, and 10.1 Myotonic dystrophy
systemic disorders 157 (Steinert disease) 215
6.1 Multiple sclerosis (MS) 157 10.2 Myasthenia gravis (MG) 216
6.2 Acute disseminated
encephalomyelitis (ADEM) 165 Index 218
Acknowledgements
First and foremost I thank my wife Philippa, and

children Thomas and Elizabeth, for their forbear-
ance and moral support (perhaps involuntary) in
allowing me to write another book.
I thank the many colleagues with whom I have
worked and from whom I have learned much: Mark
Doran, Eric Ghadiali, Daniel du Plessis, and Pavla
Hancock in Liverpool; Alex Leff, Jonathan Schott,
Nick Fox, Angus Kennedy, John Janssen, Lisa
Cipolotti, Gail Robinson, Richard Wise, and Martin
Rossor in London; and John Hodges in Cambridge.
I thank also the colleagues and friends who have
offered advice on particular topics in this book:
Rustam Al-Shahi, Alasdair Coles, Kalvinder Gahir,
Desmond Kidd, Michael and Sally Mansfield, and
Sivakumar Sathasivam.
All errors or misconceptions which remain are
entirely my own work. I shall be pleased to hear
from readers who detect errors or omissions.
ix
Introduction
The aim of this book is to review what is known There is a perception in some quarters that
about the neuropsychological or neurocognitive neuropsychology is something rather separate from
impairments which occur in neurological dis- clinical neurology. The case may perhaps be per-
orders, and in some general medical conditions suasively made for academic cognitive neuro-
which may be seen by neurologists. Such neuropsychology, which aims to infer mental structure
psychological deficits are of course relatively well from neuropsychological test performance, often in
defined in those disorders which present with, or single case studies of highly unusual but instructive
whose clinical features are largely restricted to, patients (Shallice, 1988; Ellis & Young, 1996), and
cognitive impairment, specifically the dementia even ‘clinical’ neuropsychology texts (e.g. McCarthy
syndromes, of both neurodegenerative and vascu- & Warrington, 1990; Groth-Marnat, 2001; Halligan
lar aetiology, and these account for a fair propor- et al., 2003; Devinsky & D’Esposito, 2004) may con-
tion of this book. However, cognitive dysfunction tain more than a practising clinician would require,
may also occur in other neurological disorders, an or possibly desire. Nonetheless, clinical neurologists
observation which may have implications for both neglect cognitive function at their peril. It should not
clinical diagnosis and case management. Few texts be forgotten that cognitive neuroscience has neuro-
have, to my knowledge, specifically addressed this logical foundations (D’Esposito 2003; Panegyres,
area (e.g. Grant & Adams, 1996; Green, 2000; Harrison 2004).
& Owen, 2002), and some only in passing. To be It is well recognized that the standard neuro-
sure, there are a number of excellent texts which logical examination is focused predominantly on
tackle the classical neuropsychological syndromes functions mediated by the parietal and occipital
such as amnesia, aphasia, alexia, agraphia, apraxia, lobes, with frontal and temporal lobe functions
agnosia, and executive dysfunction (e.g. Baddeley being relatively untested. Since, in the context of the
et al., 1995; Benson & Ardila, 1996; Kirshner, 2002; clinical history, neurological signs help to focus on
Heilman & Valenstein, 2003). The case-study the likely locale of pathology (Larner, 2006), it would
approach to the neuropsychological features of seem desirable to be able to tap the functions of
neurological disorders (e.g. Kapur, 1996; Ogden, these areas of the brain as well.
2005) has even spilled over into populist texts, but A neuropsychological examination provides the
though such in-depth case studies are informative, opportunity to do this; such assessment permits a
they may not immediately correspond to the case more fine-grained analysis of cognitive function, a
mix seen by clinical neurologists. Textbooks of refinement which may have localizing and diag-
neurology may mention dementia as a feature of nostic value. Just as one would not contemplate
certain neurological diseases, often in a rather omitting the visual field examination or the plantar
diffuse way. responses when examining a patient suspected of
1
2 Introduction
harbouring neurological disease, so some form of but the aim has been entirely pragmatic, for the
higher cognitive testing should also be undertaken benefit of clinical practitioners. In the chapters
whenever the clinical history suggests possible which follow, the neuropsychological impairments
cognitive impairment. The requirement is for a of neurological and general medical disorders are
manual of ‘neuropsychology in clinical practice’. considered. Detailed discussions of neurological
Professor John Hodges’ book on cognitive testing features of the disorders covered are not included,
has pointed the way for clinical neurologists to do although brief notes are given and, where possible,
this without the need for highly specialized equip- references to diagnostic criteria are cited. For more
ment or training (Hodges, 1994). information on the clinical features of neurological
Not only are neuropsychological tests essential in disease, the reader is referred to other textbooks of
the diagnosis of dementia disorders, but they may neurology (for one of which the current author has a
also be helpful in differential diagnosis, for example particular, and perhaps forgivable, predilection:
of movement disorders (Pillon et al., 1996). Neuro- Barker et al., 2005). A few comments on the treat-
psychological features may contribute to disease ment of cognitive impairments are given as a gentle
morbidity even where outcome is judged good or rebuff to those who imagine neuropsychological
excellent on neurological grounds, e.g. in multiple neurology to be a purely descriptive undertaking.
sclerosis (Feinstein, 1999) or subarachnoid haem- This overview is no small undertaking (I have
orrhage (Hütter, 2000). Neuropsychological par- amongst my papers a draft plan of the book, not too
ameters may therefore be as appropriate as motor, dissimilar from the current contents, dated 27 August
sensory, or functional scales as outcome measures 1998), for which reason certain omissions have
in the conduct of clinical trials. Early identification proved necessary. Perhaps the most important of
and treatment of cognitive impairments would these is the lack of coverage of neuropsychiatric
seem the most likely time point at which interven- features of neurological disease (mood disorders,
tions might show therapeutic efficacy. Part of the delusions, hallucinations, depression, euphoria, etc.)
desire here, of course, is to identify conditions with which often coexist with, and may confound the
neuropsychological deficits that may reverse with examination of, neuropsychological deficits. (Pain is
appropriate treatment of the underlying condition. also a potential confounder of neuropsychological
Much has been written on the subject of ‘reversible testing, as in mild traumatic brain injury or headache:
dementias’, no less than 65 such conditions being Nicholson et al., 2001.) It seems to me that the domain
alluded to in one review (Cummings et al., 1980), of neuropsychiatry, or behavioural neurology, the
although it seems that the overall frequency of such overlap between neurological disorders and psychi-
reversible conditions is low, and falling (Barry & atric features, has been relatively well addressed, both
Moskovitz, 1988; Waldemar, 2002; Clarfield, 2003). in general texts (e.g. Lishman, 1987; Trimble, 1996;
Part of the problem, of course, is the sophistica- Moore, 2001; Pincus & Tucker, 2002; Cummings &
tion of neuropsychological testing, the plethora of Mega, 2003; Feinberg & Farah, 2003) and in texts
possible tests available to bewilder the uninitiated devoted to specific diseases (e.g. stroke: Robinson,
(Lezak et al., 2004; Mitrushina et al., 2005; Strauss 2006; multiple sclerosis: Feinstein, 1999; Parkinson’s
et al., 2006), and the lack of time devoted in clinical disease: Starkstein & Merello, 2002; Alzheimer’s dis-
training to this subject. For this reason, a brief ease: Ballard et al., 2001). As a corollary to this, the
overview of cognitive function and neuropsycho- grey area of depression-related dementia or depres-
logical evaluation prefaces the chapters devoted to sive pseudodementia (Roose & Devanand, 1999;
the neuropsychological profiles of specific disease Kanner, 2005) has been referred to only briefly.
entities. This modest excursion into applied Given my personal clinical training and experi-
neuropsychology will in all probability horrify those ence, the perspective is entirely that of adult
trained in the art and science of neuropsychology, neurological practice. For childhood disorders
Introduction 3
causing cognitive decline, standard texts are avail- occupational therapy, speech and language ther-
able (e.g. Lyon et al., 1996; Brett, 1997; Clarke, 2002; apy) may also find material of interest and use.
Panteliadis & Korinthenberg, 2005). Learning dis-
ability (mental retardation), of which over 2000 dif-
REFERENCES
ferent syndromes are described, is entirely
eschewed. However, those ‘childhood’ neurodegen-
Baddeley A, Wilson BA, Watts FN (eds.). Handbook of
erative disorders that may on occasion present as
Memory Disorders. Chichester: Wiley, 1995.
dementia in adults (e.g. Coker, 1991; Doran, 1997; Baldwin R, Murray M (eds.). Younger People with
Panegyres, 2001; Sampson et al., 2004) have been Dementia: a Multidisciplinary Approach. London: Mar-
included. Some specific topics have not been tin Dunitz, 2003.
tackled, again for lack of personal training and Ballard CG, O’Brien J, James I, Swann A. Dementia:
experience, most notably head injury and drug- Management of Behavioural and Psychological Symp-
induced cognitive problems (for the latter see Farlow toms. Oxford: Oxford University Press, 2001.
& Hake, 1998; Moore & O’Keefe, 1999), with the Barker R, Rowe D, Scolding N, Larner AJ. The A–Z of
exception of antiepileptic drugs, radiotherapy and Neurological Practice: a Guide to Clinical Neurology.
Cambridge: Cambridge University Press, 2005.
chemotherapy treatment of brain tumours, and a
Barry P, Moskovitz MA. The diagnosis of reversible
passing mention of solvent exposure (Berent &
dementia in the elderly: a critical review. Arch Intern
Albers, 2005). Neither the management of dementia
Med 1988; 148: 1914–18.
(e.g. Qizilbash et al., 2002; Baldwin & Murray, 2003; Benson DF, Ardila A. Aphasia: a Clinical Perspective. New
Brown & Hillam, 2004; Curran & Wattis, 2004; Rabins York: Oxford University Press, 1996.
et al., 2006) nor neuropsychological rehabilitation Berent S, Albers JW. Neurobehavioral Toxicology: Neuro-
(e.g. Wilson, 1999; Greenwood et al., 2003; Halligan & logical and Neuropsychological Perspectives. Volume I:
Wade, 2005; Selzer et al., 2006) is discussed. Since Foundations and Methods. London: Taylor & Francis,
dementia syndromes have been relatively well 2005: 101–33.
covered, collectively (e.g. Parks et al., 1993; Hodges, Brett EM. Paediatric Neurology (3rd edition). Edinburgh:
2001; Mendez & Cummings, 2003; Burns et al., 2005) Churchill Livingstone, 1997.
Brown J, Hillam J. Dementia: Your Questions Answered.
and individually, the text is slightly weighted towards
Edinburgh: Churchill Livingstone, 2004.
other neurological disorders. The arrangement of the
Burns A, O’Brien J, Ames D (eds.). Dementia (3rd edition).
chapters is somewhat arbitrary, with certain condi-
London: Hodder Arnold, 2005.
tions potentially relevant to more than one, but Clarfield AM. The decreasing prevalence of reversible
hopefully those scanning rather than reading sys- dementias: an updated meta-analysis. Arch Intern Med
tematically will find what they are seeking without 2003; 163: 2219–29.
too much difficulty. Unavoidably, the author’s own Clarke JTR. A Clinical Guide to Inherited Metabolic Disease
interests may appear overemphasized. (2nd edition). Cambridge: Cambridge University Press,
This book is envisaged as a reference text relevant 2002.
to all neurologists, not only those with a declared Coker SB. The diagnosis of childhood neurodegenerative
interest in cognitive disorders; to old age psych- disorders presenting as dementia in adults. Neurology
1991; 41: 794–8.
iatrists and geriatricians who have to assess patients
Cummings JL, Benson DF, LoVerme S Jr. Reversible
with cognitive decline; and also as a resource for
dementia: illustrative cases, definition, and review.
general physicians and specialists who deal with
JAMA 1980; 243: 2434–9.
any endocrine, metabolic, vascular, or infective Cummings JL, Mega MS. Neuropsychiatry and Behavioral
disorders that may compromise cognitive function. Neuroscience. Oxford: Oxford University Press, 2003.
Practitioners of professions allied to medicine Curran S, Wattis JP (eds.). Practical Management of
which involve contact with cognitively impaired Dementia: a Multi-Professional Approach. Oxford:
patients (mental health nursing, physiotherapy, Radcliffe, 2004.
4 Introduction
D’Esposito M (ed.). Neurological Foundations of Cognitive Kirshner HS. Behavioral Neurology: Practical Science of
Neuroscience. Cambridge, MA: MIT Press, 2003. Mind and Brain (2nd edition). Boston: Butterworth-
Devinsky O, D’Esposito M. Neurology of Cognitive and Heinemann, 2002.
Behavioral Disorders. Oxford: Oxford University Press, Larner AJ. A Dictionary of Neurological Signs (2nd edition).
2004. New York: Springer, 2006.
Doran M. Diagnosis of presenile dementia. Br J Hosp Med Lezak MD, Howieson DB, Loring DW. Neuropsychological
1997; 58: 105–10. Assessment (4th edition). New York: Oxford University
Ellis AW, Young AW. Human Cognitive Neuropsychology: a Press, 2004.
Textbook with Readings. Hove: Psychology Press, 1996. Lishman WA. Organic Psychiatry (2nd edition). Oxford:
Farlow MR, Hake AM. Drug-induced cognitive impair- Blackwell Science, 1987.
ment. In: Biller J (ed.), Iatrogenic Neurology. Boston: Lyon G, Adams RD, Kolodny EH. Neurology of Hereditary
Butterworth-Heinemann, 1998: 203–14. Metabolic Diseases of Children (2nd edition). New York:
Feinberg TE, Farah MJ (eds.). Behavioral Neurology and McGraw-Hill, 1996.
Neuropsychology (2nd edition). New York: McGraw-Hill, McCarthy RA, Warrington EK. Cognitive Neuropsychology: a
2003. Clinical Introduction. San Diego: Academic Press, 1990.
Feinstein A. The Clinical Neuropsychiatry of Multiple Mendez MF, Cummings JL. Dementia: a Clinical Approach
Sclerosis. Cambridge: Cambridge University Press, 1999. (3rd edition). Philadelphia: Butterworth-Heinemann, 2003.
Grant I, Adams KM (eds.). Neuropsychological Assessment Mitrushina M, Boone KB, Razani J, D’Elia LF. Handbook of
of Neuropsychiatric Disorders (2nd edition). Oxford: Normative Data for Neuropsychological Assessment (2nd
Oxford University Press, 1996. edition). Oxford: Oxford University Press, 2005.
Green J. Neuropsychological Evaluation of the Older Adult: a Moore AR, O’Keefe ST. Drug-induced cognitive impair-
Clinician’s Guidebook. San Diego: Academic Press, 2000. ment in the elderly. Drugs Aging 1999; 15: 15–28.
Greenwood RJ, Barnes MP, McMillan TM, Ward CD (eds.). Moore DP. Textbook of Clinical Neuropsychiatry. London:
Handbook of Neurological Rehabilitation (2nd edition). Arnold, 2001.
Hove: Psychology Press, 2003: 363–415. Nicholson K, Martelli MF, Zasler ND. Does pain confound
Groth-Marnat G (ed.). Neuropsychological Assessment in interpretation of neuropsychological test results? Neuro
Clinical Practice: a Guide to Test Interpretation and Rehabilitation 2001; 16: 225–30.
Integration. New York: Wiley, 2001. Ogden JA. Fractured Minds: a Case-Study Approach to
Halligan PW, Kischka U, Marshall JC (eds.). Handbook of Clinical Neuropsychology (2nd edition). Oxford: Oxford
Clinical Neuropsychology. Oxford: Oxford University University Press, 2005.
Press, 2003. Panegyres PK. Dementia in young adults. In: Hodges JR
Halligan PW, Wade DT (eds.). Effectiveness of Rehabili- (ed.), Early-Onset Dementia: a Multidisciplinary
tation for Cognitive Deficits. Oxford: Oxford University Approach. Oxford: Oxford University Press, 2001: 404–21.
Press, 2005. Panegyres PK. The contribution of the study of neurode-
Harrison JE, Owen AM (eds.). Cognitive Deficits in Brain generative disorders to the understanding of human
Disorders. London: Martin Dunitz, 2002. memory. Q J Med 2004; 97: 555–67.
Heilman KM, Valenstein E (eds.). Clinical Neuropsycho- Panteliadis CP, Korinthenberg R (eds.). Paediatric
logy (4th edition). Oxford: Oxford University Press, 2003. Neurology: Theory and Practice. Stuttgart: Thieme, 2005.
Hodges JR. Cognitive Assessment for Clinicians. Oxford: Parks RW, Zec RF, Wilson RS (eds.). Neuropsychology of
Oxford University Press, 1994. Alzheimer’s Disease and Other Dementias. New York:
Hodges JR (ed.). Early-Onset Dementia: a Multidisciplinary Oxford University Press, 1993.
Approach. Oxford: Oxford University Press, 2001. Pillon B, Dubois B, Agid Y. Testing cognition may
Hütter BO. Neuropsychological Sequelae of Subarachnoid contribute to the diagnosis of movement disorders.
Hemorrhage and its Treatment. Berlin: Springer, 2000. Neurology 1996; 46: 329–34.
Kanner AM. Depression in Neurological Disorders. Cam- Pincus JH, Tucker GJ. Behavioral Neurology (4th edition),
bridge: Lundbeck Institute, 2005. Oxford: Oxford University Press, 2002.
Kapur N. Injured Brains of Medical Minds: Views from Qizilbash N, Schneider LS, Chui H, et al. (eds.). Evidence-
Within. Oxford: Oxford University Press, 1996. Based Dementia Practice. Oxford: Blackwell, 2002.
Introduction 5
Rabins PV, Lyketsos CG, Steele CD. Practical Dementia Shallice T. From Neuropsychology to Mental Structure.
Care (2nd edition). Oxford: Oxford University Press, Cambridge: Cambridge University Press, 1988.
2006. Starkstein SE, Merello M. Psychiatric and Cognitive Dis-
Robinson RG. The Clinical Neuropsychiatry of Stroke: orders in Parkinson’s Disease. Cambridge: Cambridge
Cognitive, Behavioral and Emotional Disorders Follow- University Press, 2002.
ing Vascular Brain Injury (2nd edition). Cambridge: Strauss E, Sherman EMS, Spreen O. A Compendium of
Cambridge University Press, 2006. Neuropsychological Tests: Administration, Norms,
Roose SP, Devanand DP. The Interface Between Dementia Commentary (3rd edition). Oxford: Oxford University
and Depression. London: Martin Dunitz, 1999. Press, 2006.
Sampson EL, Warren JD, Rossor MN. Young onset Trimble MR. Biological Psychiatry (2nd edition). Chichester:
dementia. Postgrad Med J 2004; 80: 125–39. Wiley, 1996.
Selzer ME, Clarke S, Cohen LG, Duncan PW, Gage FH Waldemar G. Reversible dementias: do they exist? Pract
(eds.). Textbook of Neural Repair and Rehabilitation. Neurol 2002; 2: 138–43.
Volume II: Medical Neurorehabilitation. Cambridge: Wilson B. Case Studies in Neuropsychological Rehabili-
Cambridge University Press, 2006: 411–511. tation. Oxford: Oxford University Press, 1999.
1
Cognitive function, neuropsychological evaluation,

and syndromes of cognitive impairment
1.1 Attention 8
1.2 General intelligence, IQ 10
1.3 Memory 11
1.4 Language 15
1.5 Perception 16
1.6 Praxis 19
1.7 Executive function, ‘frontal function’ 20
1.8 ‘Bedside’ neuropsychological test instruments 22
1.8.1 Mini-Mental State Examination (MMSE) 26
1.8.2 Clock drawing 28
1.8.3 Queen Square Screening Test for Cognitive Deficits 28
1.8.4 Addenbrooke’s Cognitive Examination (ACE) and Addenbrooke’s Cognitive
Examination–Revised (ACE-R) 28
1.8.5 DemTect 30
1.8.6 Dementia Rating Scale (DRS) 30
1.8.7 ADAS-Cog 31
1.8.8 CERAD battery 31
1.8.9 Clinical Dementia Rating (CDR) 31
1.8.10 Global Deterioration Scale (GDS) 31
1.8.11 Instrumental Activities of Daily Living (IADL) scale 32
1.9 Normal aging 32
1.11 Cortical versus subcortical dementias, thalamic dementia 35
This chapter seeks to elucidate briefly the various attention, memory, language, perception, praxis,
domains of cognitive function, their neuropsycho- and executive function. These subdivisions, all
logical evaluation, and syndromes of cognitive (hopefully) working in concert, not in isolation, to
impairment. It is aimed at the practising neurologist produce in sum what we understand by con-
rather than the academic neuropsychologist. sciousness, may direct a structured approach to
Without necessarily subscribing to an explicitly the clinical assessment of cognitive function. Now-
modular concept of cerebral function, it is none- adays, a model of distributed neural networks with
theless convenient to think in terms of cognitive nodal points more specialized for certain functions
domains or functional systems (‘a congeries has supplanted the idea of particular brain centres
of mental faculties’) in the brain, specifically (Mesulam, 1990).
6
Cognitive function 7
The neurocognitive domains may be described as shortcomings that neurologists need to bear in
either localized, implying lateralization to one mind: a raw score derived from a series of tests is not
hemisphere of part thereof, focal damage to which necessarily ‘diagnostic’, although it may increase
may impair that specific function; or distributed, the likelihood of a particular diagnosis. The poten-
implying a non-localized function often involving tial for incongruous or anomalous performance of
both hemispheres and/or subhemispheric struc- tests in a medicolegal setting has been noted
tures (basal ganglia, brainstem), widespread dam- (Trimble, 2004).
age being required to impair these functions It is also important to note that when evaluating
(Hodges, 1994). Moreover, particular domains may cognitive disorders, particularly those involving
be subdivided, or fractionated, into subsystems or memory impairment, obtaining some collateral
specific functions which may be selectively history from a relative, friend, or carer familiar with
impaired, suggesting the existence of functionally the subject is a vital part of the evaluation (Tierney
distinct neuropsychological substrates. et al., 1996; Jorm, 1997; Carr et al., 2000; Shulman &
There are many tests available to the neuro- Feinstein, 2003), even for early stages of disease
psychologist for the evaluation of cognitive func- (Isella et al., 2006). Even the simple observation that
tion, either global function or individual domains a patient attends the clinic alone despite having
(Lezak et al., 2004; Mitrushina et al., 2005, Strauss been instructed to bring a relative or friend is of
et al., 2006). The variety of tests available may diagnostic relevance, arguing strongly against the
bewilder the non-specialist. Moreover, the choice of presence of a cognitive disorder (Larner, 2005).
different test instruments in different studies may
make direct comparisons difficult. Of course, it must
be remembered that any neuropsychological test REFERENCES
may have multiple sensory, motor, perceptual, and
cognitive demands, and hence ‘pure’ tests of any Burns A, Lawlor B, Craig S. Assessment Scales in Old Age
single cognitive domain are the exception, rather Psychiatry. London: Martin Dunitz, 1999.
Burns A, Lawlor B, Craig S. Assessment Scales in Old
than the rule.
Age Psychiatry (2nd edition). London: Martin Dunitz,
Neuropsychologists insist, rightly, that special
2004.
training is required in the administration and
Carr DB, Gray S, Baty J, Morris JC. The value of informant
interpretation of neuropsychological tests. Clinical versus individual’s complaints of memory impairment
neurologists will therefore rely on their neu- in early dementia. Neurology 2000; 55: 1724–6.
ropsychologist colleagues for the performance and Griffiths TD, Welch JL. How to do it: use a diagnostic
interpretation of these ‘formal’ tests, since they fall neuropsychology service properly. Pract Neurol 2003; 3:
outwith neurologists’ expertise, and may take sub- 170–5.
stantial time to administer, incompatible with Hodges JR. Cognitive Assessment for Clinicians. Oxford:
clinical schedules. Nonetheless, some form of Oxford University Press, 1994.
neuropsychological testing, often labelled as ‘bedside’ Isella V, Villa L, Russo A, et al. Discriminative and
predictive power of an informant report in mild
to distinguish it from ‘formal’ testing, is within
cognitive impairment. J Neurol Neurosurg Psychiatry
the scope of neurologists and may be of diagnostic
2006; 77: 166–71.
use (Griffiths & Welch, 2003). Numerous test bat-
Jorm AF. Methods of screening for dementia: a meta-
teries which may be applied within 10–30 minutes analysis of studies comparing an informant question-
are available, encompassing not only cognitive naire with a brief cognitive test. Alzheimer Dis Assoc
function but also functional, behavioural, and Disord 1997; 11: 158–62.
global assessment (Burns et al., 1999, 2004). Because Larner AJ. ‘Who came with you?’ A diagnostic observation
of the brevity which makes them clinically applic- in patients with memory problems? J Neurol Neurosurg
able, these instruments often have certain Psychiatry 2005; 76: 1739.
8 Cognitive function
Lezak MD, Howieson DB, Loring DW. Neuropsychological Disturbance of consciousness may encompass
Assessment (4th edition). New York: Oxford University both a quantitative and a qualitative dimension.
Press, 2004. Hence one may speak of a ‘level’ of consciousness,
Mesulam MM. Large-scale neurocognitive networks and perhaps in terms of arousal, alertness, or vigilance,
distributed processing for attention, language, and
forming a continuum from coma to the awake state;
memory. Ann Neurol 1990; 28: 597–613.
and an ‘intensity’ or quality of consciousness, in
Mitrushina M, Boone KB, Razani J, D’Elia LF. Handbook of
terms of clarity of awareness of the environment,
Normative Data for Neuropsychological Assessment (2nd
edition). Oxford: Oxford University Press, 2005.
and ability to focus, sustain, or shift attention. Coma
Shulman K, Feinstein A. Quick Cognitive Screening for obviously implies a state of unresponsiveness from
Clinicians: Mini Mental, Clock Drawing and Other Brief which a patient cannot be roused by verbal or
Tests. London: Martin Dunitz, 2003: 125–39. mechanical stimuli. Lesser degrees of impaired
Strauss E, Sherman EMS, Spreen O. A Compendium of consciousness, sometimes labelled clinically as
Neuropsychological Tests: Administration, Norms, and stupor, torpor, or obtundation (although these
Commentary (3rd edition). New York: Oxford University terms lack precision, their meaning often varying
Press, 2006. between different observers) may also interfere with
Tierney MC, Szalai JP, Snow WG, Fisher RH. The
cognitive assessment. There are many causes of
prediction of Alzheimer disease: the role of patient
coma (Plum & Posner, 1980; Young et al., 1998).
and informant perceptions of cognitive deficits. Arch
These states may be obvious clinically, such as
Neurol 1996; 53: 423–7.
Trimble M. Somatoform Disorders: a Medicolegal Guide.
drowsiness, or difficulty rousing the patient, but
Cambridge: Cambridge University Press, 2004: 109–39. may also be occult, perhaps manifesting as
increased distractibility. Impairments in level of
consciousness are a sine qua non for the diagnosis of
1.1 Attention delirium (see Section 1.10), as enshrined in the
diagnostic criteria of DSM-IV and ICD10, although
It is perhaps redundant to point out that before any these deficits may be subtle and not immediately
meaningful assessment of ‘higher cognitive func- obvious at the bedside though yet sufficient to
tion’ can be made, it should be ascertained that impair attentional mechanisms. These attentional
‘lower cognitive function’ is intact, assuming that deficits may be responsible for the impaired cogni-
the workings of the nervous system are hierarchical tive function that is also a diagnostic feature of
in their operation. To indulge in reductio ad absur- delirium (Burns et al., 2004; Larner 2004; Inouye,
dum, it would not be reasonable to expect a coma- 2006).
tose patient, or a sleeping subject, to perform well Attention, or concentration, is a non-uniform,
on tests of memory, although that memory function distributed cognitive function. It may be defined as
may be intact or impaired on recovery from coma or that component of consciousness which distributes
awakening from sleep. The nature of consciousness awareness to particular sensory stimuli. Bombarded
is an area of great interest to both neuroscientists as the nervous system is with stimuli in multiple
and philosophers (e.g. Dennett, 1993; Penrose, 1995; sensory domains, only some reach awareness or
Zeman, 2001, 2002; Libet, 2004), but other than to salience, whilst many percepts are not consciously
assume that it is an emergent property of brain taken notice of. Attentional resources, which are
function, nothing further about its possible neuro- finite, are devoted to some channels but not others.
anatomical and neurophysiological basis will be Attention is thus effortful, selective, and closely
considered here. Dissociation between apparent linked to intention. Distinction may be made
preservation of consciousness and absence of cog- between different types of attentional mechanism:
nitive function may occur, for example in vegetative sustained attention implies devotion of most
states (Jennett, 2002). attentional resources to one particular stimulus;
1.1 Attention 9
selective attention is the directing of attentional that could explain such behaviour. Extinction, the
resources to one stimulus amongst many (‘cocktail failure to respond to a novel or meaningful sensory
party phenomenon’); divided attention implies a stimulus on one side when a homologous stimulus
division of attentional resources between compet- is given simultaneously to the contralateral side
ing stimuli. Neuroanatomical structures thought to (i.e. double simultaneous stimulation), sometimes
be important in mediating attention include the called ‘suppression’, may be a lesser degree of neg-
reticular activating system in the brainstem, the lect. In the visual domain, neglect may be categor-
thalamus, and prefrontal cerebral cortex of multi- ized as a disorder of spatial attention, which is more
modal association type, particularly in the right common after right rather than left brain damage,
hemisphere, since damage to any of these areas may usually of vascular origin, an observation accounted
result in impairments of attention. Dopaminergic for by the ability of the right hemisphere to attend to
and cholinergic pathways are thought to be the both sides of space whereas the left hemisphere
important neurotransmitters mediating attention attends to the right side of space only (i.e. there is
(Perry et al., 2002). some lateralization of function). The angular gyrus
The term ‘working memory’ is used by neu- and parahippocampal gyrus may be the critical
ropsychologists to describe a limited-capacity store neuroanatomical substrates underpinning the devel-
for retaining information over a short term, 1–2 opment of visual neglect (Husain, 2002; Chatterjee,
minutes, and for ‘online’ manipulation of that 2003; Heilman et al., 2003).
information. This system has a limited capacity The Glasgow Coma Scale (GCS) is the instrument
wherein information rapidly degrades unless con- most commonly used for monitoring level of con-
tinuously rehearsed (hence ‘unstable’, compared to sciousness (Teasdale & Jennett, 1974). Introduced to
longer-term memory). Working memory may be assess the severity of traumatic head injuries, it has
fractionated into verbal (phonological or articula- subsequently been applied in other clinical situa-
tory loop) and visual (visuospatial sketch pad) tions (e.g. delirium, stroke) although its validity in
components, governed by a supervisory central some of these circumstances remains to be con-
executive (Baddeley, 1986). Working memory func- firmed. In the individual patient, use of the indi-
tion is dissociable from ‘long-term memory’ func- vidual components of the GCS (eye, verbal, motor
tion (see Section 1.3): for example, in patients with response ¼ EVM) is more useful than the summed
amnesia as a consequence of Wernicke–Korsakoff score (out of 15), although for demographic research
syndrome working memory is preserved (Section use of the summed score is preferable. A GCS score
8.3.1). Working memory is perhaps better envisaged of 15/15 does not guarantee intact attention, since
as a component of the selective attention system deficits may be subtle, and it may therefore be
(the ‘specious present’ of William James), and is necessary to undertake tests of attentional function
certainly not congruent with the term ‘short-term before any other neuropsychological instruments
memory’ often used by patients, which refers to are administered.
recent long-term memory. Grammatical complex- Many tests of attention are available (Strauss
ity, for example in sentence construction, is asso- et al., 2006), such as the Trail Making Test, the
ciated with working memory capacity, which Continuous Performance Test, the Paced Auditory
mediates the need to keep many elements in play Serial Addition Test (PASAT: Gronwall, 1977), and
and not lose the train of thought before completing the Symbol Digit Modalities Test. Simple bedside
the sentence. tests which tap attentional mechanisms include
Neglect, sometimes known as inattention, is a orientation in time and place, digit span forwards
failure to orient to, respond to, or report novel or and/or backwards (also WAIS-R Digit Span subtest),
meaningful stimuli in the absence of sensory or reciting the months of the year or the days of the
motor deficits such as hemiparesis or hemianopia week backwards, or counting back from 30 down to
1. Distractibility may be evident if the patient loses Libet B. Mind Time: the Temporal Factor in Conscious-
his or her way, or starts the more automatic forward ness. Cambridge, MA: Harvard University Press, 2004.
recital. In the Mini-Mental State Examination (see Penrose R. Shadows of the Mind. London: Vintage, 1995.
Section 1.8), performing serial sevens (subtracting 7 Perry E, Ashton H, Young A (eds.). Neurochemistry of
Consciousness: Neurotransmitters in Mind. Amsterdam:
from 100 repeatedly ¼ 93, 86, 79, 72, 65, etc.) or
John Benjamins, 2002.
spelling the word WORLD backwards are labelled as
Plum F, Posner JB. The Diagnosis of Stupor and Coma (3rd
tests of attention or concentration, but it should be
edition). Philadelphia: Davis, 1980.
realized that failure in these tests may be for reasons Strauss E, Sherman EMS, Spreen O. A Compendium of
other than impaired attention (e.g. poor mental Neuropsychological Tests: Administration, Norms,
arithmetic abilities in serial sevens). Commentary (3rd edition). Oxford: Oxford University
Neglect may be clinically obvious, for example if a Press, 2006: 546–677.
patient fails to dress one side of the body, but is Teasdale G, Jennett B. Assessment of coma and impaired
sometimes more subtle, in which case its presence consciousness: a practical scale. Lancet 1974; 2: 81–4.
may be sought using cancellation tests (e.g. stars in Young GB, Ropper AH, Bolton CF (eds.). Coma and
an unstructured array, or letters in a structured Impaired Consciousness: a Clinical Perspective. New
York: McGraw-Hill, 1998.
array), figure copying (e.g. the Rey–Osterreith
Zeman A. Consciousness. Brain 2001: 124: 1263–89.
figure), line bisection tasks, numbering a clock face,
Zeman A. Consciousness: a User’s Guide. New Haven: Yale
or drawing from memory.
University Press, 2002.
REFERENCES 1.2 General intelligence, IQ
Baddeley AD. Working Memory. Oxford: Oxford University Formal neuropsychological assessment often
Press, 1986. involves testing of general intelligence, before any
Burns A, Gallagley A, Byrne J. Delirium. J Neurol specific assessment of the individual domains of
Neurosurg Psychiatry 2004; 75: 362–7. cognitive function. This is legitimate since a general
Chatterjee A. Neglect: a disorder of spatial attention. In:
intelligence factor, g, seems to account for a sig-
D’Esposito M (ed.), Neurological Foundations of Cogni-
nificant proportion of the individual differences
tive Neuroscience. Cambridge, MA: MIT Press, 2003: 1–26.
among test scores for groups of people (Deary,
Dennett DC. Consciousness Explained. London: Penguin,
1993. 2001). General intellectual function is most often
Gronwall DMA. Paced Auditory Serial-Addition Task: a measured by administration of one of the Wechsler
measure of recovery from concussion. Percept Motor Intelligence Scales, most often the Wechsler Adult
Skills 1977; 44: 367–73. Intelligence Scale–Revised (WAIS-R: Wechsler,
Heilman KM, Watson RT, Valenstein E. Neglect and 1981) or the Wechsler Adult Intelligence Scale–III
related disorders. In: Heilman KM, Valenstein E (eds.), (WAIS-III: Wechsler, 1997). (There is a separate scale
Clinical Neuropsychology (4th edition). Oxford: Oxford for children, the Wechsler Intelligence Scale for
University Press, 2003: 296–346. Children, WISC.) Updating of these tests is required
Husain M. Cognitive neuroscience of hemispatial neglect.
periodically because of changes in the abilities of the
Cognit Neuropsychiatry 2002; 7: 195–209.
normative group from which standardized scores
Inouye SK. Current concepts: delirium in older persons. N
are derived (Deary, 2001).
Engl J Med 2006; 354: 1157–65.
Jennett B. The Vegetative State: Medical Facts, Ethical and Administration of these tests may take anything
Legal Dilemmas. Cambridge: Cambridge University up to 2 hours or more, sometimes necessitating
Press, 2002. more than one testing session to avoid patient
Larner AJ. Delirium: diagnosis, aetiopathogenesis and fatigue. Subtests in these batteries fall into two
treatment. Adv Clin Neurosci Rehabil 2004; 4 (2): 28–9. categories, verbal and performance, the former
1.3 Memory 11
including tests of general knowledge, vocabulary, Non-verbal tests of general intelligence are also
comprehension, and verbal abstract thinking (e.g. available, such as the Progressive Matrices described
Digit Span, Arithmetic, Similarities), and the latter by Raven (1938, 1958). Other tests examining general
including tests of perceptual organization, complex cognitive functioning by means of neuropsycho-
visuospatial function, and psychomotor speed (e.g. logical batteries and assessment of premorbid intel-
Digit Symbol, Picture Completion and Arrange- ligence are available (Strauss et al., 2006).
ment, Block Design, Object Assembly). These
subtests yield an index of verbal intelligence, verbal
IQ (VIQ), and of performance intelligence, per- REFERENCES
formance IQ (PIQ), as well as an overall full-scale IQ
(FSIQ). Based on extensive normative data from Deary IJ. Intelligence: a Very Short Introduction. Oxford:
healthy North Americans and Europeans, these Oxford University Press, 2001.
Iverson GL, Mendrek A, Adams RL. The persistent belief
measures have a mean score of 100 with a standard
that VIQ–PIQ splits suggest lateralized brain damage.
deviation of 15 such that 95% of the population will
Appl Neuropsychol 2004; 11: 85–90.
fall within the range 70–130. Generally VIQ and PIQ
Nelson HE, Willison J. National Adult Reading Test (NART)
are correlated, but occasional discrepancies may be (2nd edition). Windsor: NFER-Nelson, 1991.
seen in normal individuals. The belief that VIQ–PIQ Raven JC. Progressive Matrices: a Perceptual Test of Intel-
split can be reliably used to infer the lateralization of ligence. London: HK Lewis, 1938.
brain pathology (VIQ more impaired in left-sided Raven JC. Advanced Progressive Matrices, Set 1. London:
lesions, PIQ with right-sided lesions) should be HK Lewis, 1958.
viewed with caution (Iverson et al., 2004). Strauss E, Sherman EMS, Spreen O. A Compendium of
For the assessment of individuals complaining of Neuropsychological Tests: Administration, Norms,
cognitive disorders, especially memory disorders, an Commentary (3rd edition). Oxford: Oxford University
Press, 2006: 98–362.
IQ score per se may not be particularly helpful.
Wechsler D. Weschler Adult Intelligence Scale-Revised
Change in IQ, possibly reflecting cognitive decline, is
(WAIS-R). San Antonio: Psychological Corporation, 1981.
more helpful, but it is seldom the case that an indi-
Wechsler D. Weschler Adult Intelligence Scale, 3rd edition
vidual patient will have undergone previous testing (WAIS-III). San Antonio: Psychological Corporation, 1997.
with which to make comparison. Previous educa-
tional and occupational history may give clues to
premorbid intelligence, as may performance on 1.3 Memory
verbal subtests of the WAIS batteries. This difficulty
may also be partially circumvented by administering Memory is a non-uniform, distributed cognitive
a test specifically designed to estimate premorbid function. In other words, subdivisions in memory
intellectual abilities, such as the National Adult function may be discriminated, which involve vari-
Reading Test (NART: Nelson & Willison, 1991), since ous neuroanatomical substrates.
the overlearned ability to read a series of words with Current taxonomies of memory propose a dis-
irregular spelling-to-sound correspondences is rela- tinction between declarative (also known as explicit
tively preserved in a number of neurodegenerative or conscious memory) and non-declarative memory
disorders (there are exceptions, e.g. frontotemporal (implicit, procedural, unconscious memory).
lobar degenerations causing linguistic syndromes, Declarative or explicit memories are intentional or
Sections 2.2.2 and 2.2.3). The NART IQ may then be conscious recollections of previous experience.
compared with the Wechsler FSIQ to give some Declarative memory may be further subdivided into
indication of whether general intellectual function is episodic memory and semantic memory. Episodic
stable or has declined. A difference of 20 points is memories are particular personal events, sometimes
probably significant, of 40 points certainly so. known as autobiographical memories, specific to
time and place (context-specific), whereas semantic neuropsychology and, more recently, neuroima-
memories are facts, a database of culturally ging. The literature makes reference to hippo-
approved knowledge independent of any specific campal, diencephalic, frontal, and basal forebrain
context (Schacter & Tulving, 1994; Hodges & Greene, amnesia, largely based on lesion and neuropatho-
1995). Many tests are available to probe the specific logical studies. Structures in the medial temporal
areas of episodic and semantic long-term memory. lobe, centred on the hippocampus, and in the
A distinction may also be drawn between ante- diencephalon surrounding the third ventricle,
rograde memory, the laying down of new memories, are thought to be crucial to episodic memory
and retrograde memory, the store of previously (O’Keefe & Nadel, 1978; Cohen & Eichenbaum, 1993;
encoded material. An autobiographical–semantic Zola-Morgan & Squire, 1993). Lesions anywhere
dissociation of retrograde memory loss may be along the circuit described by Papez (entorhinal
noted (Kapur, 1993, 1997). area of the parahippocampal gyrus, perforant and
In contrast to explicit memory, implicit memories alvear pathways, hippocampus, fimbria and fornix,
refer to a heterogeneous collection of faculties, such mammillary bodies, mammillothalamic tract,
as skill learning, priming, and conditioning, which are anterior thalamic nuclei, internal capsule, cingulate
not available to conscious thought or report (Schacter gyrus, and cingulum) may lead to anterograde and
et al., 1993). Generally, clinical examination of retrograde amnesia. The experience of the patient
implicit memory functions is not undertaken. known as HM was a key indicator of the importance
In clinical practice, lay observers and primary care of these structures. Because of his medically
physicians frequently distinguish between prob- refractory epilepsy, HM underwent bilateral medial
lems with ‘short-term memory’ and ‘long-term temporal lobectomy, encompassing the amygdala,
memory’, most usually referring to material learned entorhinal cortex, anterior dentate gyrus, hippo-
recently or in the more distant past, respectively. campus, and subiculum, which operation was fol-
Such a division persists in professional terminology, lowed by a dense anterograde amnesia, and
although the meanings are different. Professional retrograde amnesia covering about a decade prior to
‘short-term memory’ is analogous to ‘working the surgery (Scoville & Milner, 1957). HM has been
memory’, best conceptualized as an attentional followed up for many years with essentially no
function (see Section 1.1). Patient ‘short-term improvement in his neuropsychological deficits,
memory’ is in fact one component of professional such that he is ‘marooned in the moment’ (Ogden,
‘long-term memory’ (which encompasses all the 2005). Similar outcomes have been seen on occasion
subdivisions previously mentioned), specifically with unilateral surgery (Kapur & Prevett, 2003).
that for the learning of new information. Amnesia is Lesions confined to the hippocampus may be
the syndrome of impaired memory and new learn- particularly associated with retrograde amnesia
ing, which may be characterized as anterograde or (Cipolotti et al., 2001). Amnesia has been described
retrograde, acute/transient or chronic/persistent. in association with basal forebrain (Damasio et al.,
Anterograde amnesia may be clinically manifest as 1985) and frontal lesions, the latter with a defect in
repeated questioning about day-to-day matters, memory encoding (Parkin, 1997a).
inability to carry out simple chores, or repeating the There are many causes of memory disorder (Kapur,
same information. A better distinction may be 1994; Baddeley et al., 1995; Hodges & Greene,
between ‘recent’ and ‘remote’ memory. 1995; Parkin, 1997b; Kopelman, 2002; Mega, 2003;
The neuroanatomical substrates of explicit Papanicolaou, 2006). Impairment of episodic
memory are partially understood, based on studies memory is the most common presenting feature of
of experimental animals and of patients developing Alzheimer’s disease (AD: see Section 2.1), sometimes
memory problems as a consequence of focal brain occurring in isolation, although other deficits may
lesions which may be examined by means of be apparent on clinical or neuropsychological
1.3 Memory 13
assessment. For this reason, and because AD is the which covers both personal semantic information
most common cause of dementia, neuropsycho- and autobiographical incidents, although this may
logical test batteries, particularly ‘bedside’ tests, are underestimate the true extent of retrograde amnesia,
often weighted toward memory testing to the relative missing ‘islands’ of memory loss unique to the indi-
exclusion of other cognitive domains such as execu- vidual. The Famous Faces Test may be used to study
tive function, leading to difficulty identifying other remote memory (Hodges et al., 1993). Integrity of the
neurocognitive disorders in which memory is not semantic network, including semantic memory, may
the principal domain affected. Anterograde amnesia be tested using category (or semantic) fluency tests
may also occur as a consequence of open or closed (see Section 1.7). Reading words with irregular
head injury (post-traumatic amnesia), Wernicke– sound-to-spelling correspondence may produce
Korsakoff syndrome (see Section 8.3.1), herpes sim- surface dyslexia (regularization errors) in patients
plex encephalitis (Section 9.1.1), limbic encephalitis of with impaired access to or breakdown of semantic
paraneoplastic or non-paraneoplastic origin (Sections networks. Other tests accessing associative semantic
6.12.1 and 6.12.2, respectively), strategic brain infarcts networks include the Pyramids and Palm Trees Test
(Section 3.4), and surgery to remove temporal lobe or (Howard & Patterson, 1992). A semantic memory test
third ventricle lesions (Section 7.2.3). Transient battery involving subtests of category fluency, nam-
amnesias may be of epileptic origin (transient epi- ing, naming to description, and picture–word
leptic amnesia: Section 4.3.1) or, in transient global matching in response to spoken word has also been
amnesia, of probable vascular aetiology (Section described (Hodges et al., 1992a,b).
3.7.3). Psychogenic amnesia may also enter the dif- Of the frequently used ‘bedside’ neuropsycho-
ferential diagnosis of transient amnesias (Pujol & logical test instruments (see Section 1.8), the Mini-
Kopelman, 2003; Butler & Zeman, 2006). A temporal Mental State Examination has only perfunctory
gradient of retrograde amnesia may also be present in examination of memory function (registration and
some of these conditions, but rare cases of focal recall after distractor items of the names of three
retrograde amnesia with relative sparing of ante- objects, e.g. ball, flag, tree). Longer (supraspan)
rograde memory have been described, sometimes word lists are used in the DemTect and the Hopkins
following head injury or an encephalitic illness (e.g. Verbal Learning Test, and the latter includes both
Stuss & Guzman, 1988; Kapur, 1993; Hunkin, 1997; recall and recognition paradigms to try to ascertain
Mackenzie-Ross, 2000; Larner et al., 2004). whether failures result from encoding or retrieval
Many tests of memory are available (Strauss et al., defects. The Addenbrooke’s Cognitive Examination
2006). The Wechsler Memory Scale, now in its third (ACE) and its revision (ACE-R) add recall of a seven-
edition (WMS-III), is a battery testing auditory and item name and address, with a recognition para-
visual declarative (and working) memory. Other digm in the ACE-R, and also a test of category
specific tests of episodic memory sometimes fluency. The Queen Square Screening Test for
deployed include the Buschke Selective Reminding Cognitive Deficits has a qualitative story recall test,
Test (Buschke & Fuld, 1974), the California Verbal and also picture recall to test visual memory.
Learning Test (Delis et al., 2000), the Hopkins Verbal
Learning Test (Brandt, 1991; Shapiro et al., 1999), the
Camden Recognition Memory Test and the Topo- REFERENCES
graphical Recognition Memory Test (Warrington,
1984, 1996), and the Rey Auditory Verbal Learning Baddeley AD, Wilson BA, Watts FN (eds.). Handbook of
Test. Recall of the Rey–Osterrieth Complex Figure Memory Disorders. Chichester: Wiley, 1995.
may be used as a test of visual memory. Retrograde Brandt J. The Hopkins Verbal Learning Test: development
memory may be investigated using the Autobio- of a new memory test with six equivalent forms. Clin
graphical Memory Interview (Kopelman et al., 1989), Neuropsychol 1991; 5: 125–42.
Buschke H, Fuld PA. Evaluating storage, retention, and Kopelman MD. Disorders of memory. Brain 2002; 125:
retrieval in disordered memory and learning. Neurology 2152–90.
1974; 24: 1019–25. Kopelman MD, Wilson BA, Baddeley AD. The Autobio-
Butler C, Zeman A. Syndromes of transient amnesia. Adv graphical Memory Interview: a new assessment of
Clin Neurosci Rehabil 2006; 6 (4): 13–14. autobiographical and personal semantic memory in
Cipolotti L, Shallice T, Chan D, et al. Long-term retrograde amnesic patients. J Clin Exp Neuropsychol 1989; 11:
amnesia: the crucial role of the hippocampus. Neuro- 724–44.
psychologia 2001; 39: 151–72. Larner AJ, Ghadiali EJ, Doran M. Focal retrograde
Cohen NJ, Eichenbaum H. Memory, Amnesia, and the amnesia: clinical, neuropsychological and neuroima-
Hippocampal System. Cambridge, MA: MIT Press, 1993. ging study. Neurobiol Aging 2004; 25: S128 (abstract
Damasio AR, Graff-Radford NR, Eslinger PJ, Damasio H, P1–116).
Kassell N. Amnesia following basal forebrain lesions. Mackenzie-Ross S. Profound retrograde amnesia
Arch Neurol 1985; 42: 263–71. following mild head injury: organic or functional?
Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Cortex 2000; 36: 521–37.
Learning Test (2nd edition, adult version). San Antonio: Mega MS. Amnesia: a disorder of episodic memory. In:
Psychological Corporation, 2000. D’Esposito M (ed.), Neurological Foundations of Cog-
Hodges JR, Greene JDW. Disorders of memory. In: nitive Neuroscience. Cambridge, MA: MIT Press, 2003:
Kennard C (ed.). Recent advances in clinical neurology 8. 41–66.
Edinburgh: Churchill Livingstone, 1995: 151–69. Ogden JA. Fractured Minds: a Case-Study Approach to
Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic Clinical Neuropsychology (2nd edition). Oxford: Oxford
dementia: progressive fluent aphasia with temporal University Press, 2005: 46–63.
lobe atrophy. Brain 1992a; 115: 1783–806. O’Keefe J, Nadel L. The Hippocampus as a Cognitive Map.
Hodges JR, Salmon DP, Butters N. Semantic memory Oxford: Clarendon Press, 1978.
impairment in Alzheimer’s disease: failure of access or Papanicolaou AC. The Amnesias: a Clinical Textbook of
degraded knowledge? Neuropsychologia 1992b; 30: Memory Disorders. Oxford: Oxford University Press,
301–14. 2006.
Hodges JR, Salmon DP, Butters NA. Recognition and Parkin AJ. The long and winding road: twelve years of
naming of famous faces in Alzheimer’s disease: a frontal amnesia. In: Parkin AJ (ed.), Case Studies in the
cognitive analysis. Neuropsychologia 1993; 31: 775–88. Neuropsychology of Memory. Hove: Psychology Press,
Howard D, Patterson K. Pyramids and Palm Trees: a Test 1997a: 127–40.
of Semantic Access From Pictures and Words. Bury St Parkin AJ (ed.). Case Studies in the Neuropsychology of
Edmunds: Thames Valley Test Company, 1992. Memory. Hove: Psychology Press, 1997b.
Hunkin N. Focal retrograde amnesia: implications for the Pujol M, Kopelman MD. Psychogenic amnesia. Pract
organisation of memory. In: Parkin AJ (ed.), Case Studies Neurol 2003; 3: 292–9.
in the Neuropsychology of Memory. Hove: Psychology Schacter DL, Chiu CYP, Ochsner KN. Implicit memory: a
Press, 1997: 63–82. selective review. Annu Rev Neurosci 1993; 16: 159–82.
Kapur N. Focal retrograde amnesia in neurological Schacter DL, Tulving E. Memory Systems. Cambridge, MA:
disease: a critical review. Cortex 1993; 29: 219–34. MIT Press, 1994.
Kapur N. Memory Disorders in Clinical Practice. Hove: Scoville W, Milner B. Loss of recent memory after bilateral
Lawrence Erlbaum, 1994. hippocampal lesions. J Neurol Neurosurg Psychiatry
Kapur N. Autobiographical amnesia and temporal lobe 1957; 20: 11–21.
pathology. In: Parkin AJ (ed.), Case Studies in the Shapiro AM, Benedict RH, Schretlen D, Brandt J. Construct
Neuropsychology of Memory. Hove: Psychology Press, and concurrent validity of the Hopkins Verbal Learning
1997: 37–62. Test-revised. Clin Neuropsychol 1999; 13: 348–58.
Kapur N, Prevett M. Unexpected amnesia: are there Strauss E, Sherman EMS, Spreen O. A Compendium of
lessons to be learned from cases of amnesia following Neuropsychological Tests: Administration, Norms,
unilateral temporal lobe surgery? Brain 2003; 126: Commentary (3rd edition). Oxford: Oxford University
2573–85. Press, 2006: 678–890.
1.4 Language 15
Stuss DT, Guzman DA. Severe remote memory loss with testing of language, for example using the Token Test
minimal anterograde amnesia: a clinical note. Brain (De Renzi & Faglioni, 1978), in which commands of
Cogn 1988; 8: 21–30. increasing length and complexity are given for
Warrington EK. Recognition Memory Test. Windsor: NFER- manipulating a deck of coloured tokens of differing
Nelson, 1984.
size and shape (some have objected to the word
Warrington EK. The Camden Memory Tests Manual. Hove:
‘token’, preferring ‘item’: Critchley, 1979). Sentence
Psychology Press, 1996.
comprehension skills may be ascertained by per-
Zola-Morgan S, Squire LR. Neuroanatomy of memory.
Annu Rev Neurosci 1993; 16: 547–63.
formance of the Test for the Reception of Grammar
(Bishop, 1983). Wernicke type aphasia typically has
marked comprehension impairments, with fluent
1.4 Language speech output but often with poverty of content,
sometimes reduced to a meaningless jumble of
Historically, language disorder provided the first words (jargon aphasia). Although Broca type aphasia
unequivocal evidence that loss of a higher brain is often characterized as having preserved compre-
function could be ascribed to damage to a specific hension, this may in fact be impaired for more
brain region, based on the work of Broca and, pos- complex syntax.
sibly, Marc Dax in the mid nineteenth century There are many tests of language available (Lezak
(Schiller, 1993). The work of Wernicke was also et al., 2004; Strauss et al., 2006). Comprehensive
seminal in establishing the neural substrates of batteries include the Boston Diagnostic Aphasia
language function, indicating that language is a Examination (BDAE: Goodglass & Kaplan, 1983), the
localized function. Every medical student now Western Aphasia Battery (WAB: Shewan & Kertesz,
knows that most individuals, whether left- or right- 1980), the Psycholinguistic Assessment of Language
handed, have language in the dominant hemi- Processing in Aphasia (PALPA: Kay et al., 1992), and
sphere, although around 30% of left-handers and the Comprehensive Aphasia Test (Swinburn et al.,
< 1% of right-handers have language in the non- 2004). Specific tests of naming often deployed
dominant hemisphere. include the Graded Naming Test (McKenna &
Aphasia, a primary disorder of language, is often Warrington, 1980, 1983) and the Boston Naming
mirrored by similar defects in reading (alexia) and Test (Kaplan et al., 2001).
writing (agraphia), all of which are amenable, within At the bedside, listening to speech output will
certain limitations (Willmes & Poeck, 1993), to permit a simple classification of aphasia as fluent or
clinical localization, often on the basis of simple non-fluent, and also detect paraphasias (phonemic
bedside examination. In addition to the Broca (non- or semantic) and neologisms. From questioning
fluent, anterior, motor, expressive) and Wernicke or instructing the patient during history taking
(fluent, posterior, sensory, receptive) types of and clinical examination, comprehension difficul-
aphasia, clinical distinctions may also be drawn ties may be evident. Testing of repetition may
between conduction aphasia (impaired repetition) differentiate aphasias in which this ability is rela-
and transcortical aphasias (preserved repetition). A tively preserved (transcortical aphasias) or impaired
classification of aphasias as perisylvian (Broca, (conduction aphasia). Naming skills have less
Wernicke, conduction) and extrasylvian has also localizing value, although marked anomia should
been proposed. There are many texts and reviews raise the suspicion of semantic problems, either
devoted to the subject (e.g. Benson & Ardila, 1996; degradation of or access to semantic stores. Reading
Brown & Hagoort, 2000; Basso, 2003; Caplan, 2003; and writing function should also be examined, even
Spreen & Risser, 2003). if spoken language function seems intact, since
It may be necessary to test auditory comprehension various syndromes of alexia and agraphia are
before undertaking any other neuropsychological described (Benson & Ardila, 1996; Saver, 2002; Leff,
2004; Larner 2006). Idea density in written material Saver JL. Approach to the patient with aphasia. In: Biller J
reflects language processing ability. (ed.), Practical Neurology (2nd edition). Philadelphia:
Of the frequently used ‘bedside’ neuropsycho- Lippincott Williams & Wilkins, 2002: 27–39.
logical test instruments (see Section 1.8), most are Schiller F. Paul Broca: Founder of French Anthropology,
Explorer of the Brain. Oxford: Oxford University Press,
heavily weighted for language function, such
1993.
that patients with primarily linguistic disorders (e.g.
Shewan CM, Kertesz A. Reliability and validity character-
semantic dementia, aphasic presentations of
istics of the Western Aphasia Battery (WAB). J Speech
Alzheimer’s disease) may find it difficult or impos- Hear Disord 1980; 45: 308–24.
sible to complete them. Spreen O, Risser AH. Assessment of Aphasia. Oxford:
Oxford University Press, 2003.
Strauss E, Sherman EMS, Spreen O. A Compendium of
REFERENCES Neuropsychological Tests: Administration, Norms,
Commentary (3rd edition). Oxford: Oxford University
Basso A. Aphasia and its Therapy. Oxford: Oxford Uni- Press, 2006: 891–962.
versity Press, 2003. Swinburn K, Porter G, Howard D. Comprehensive Aphasia
Benson DF, Ardila A. Aphasia: a Clinical Perspective. Test. Hove: Psychology Press, 2004.
New York: Oxford University Press, 1996. Willmes K, Poeck K. To what extent can aphasic
Bishop DVM. Test for the Reception of Grammar. syndromes be localized? Brain 1993; 116: 1527–40.
Manchester: Chapel Press, 1983.
Brown CM, Hagoort P (eds.). The Neurocognition of Lan-
guage. Oxford: Oxford University Press, 2000.
Caplan D. Aphasic syndromes. In: Heilman KM, Valenstein 1.5 Perception
E (eds.), Clinical Neuropsychology (4th edition). Oxford:
Oxford University Press, 2003: 14–34. Higher-order deficits of sensory processing, not
Critchley M. The Divine Banquet of the Brain and Other explicable in terms of a disorder of attention, intel-
Essays. New York: Raven Press, 1979: 68. lectual decline, or a failure to name the stimulus
De Renzi E, Faglioni P. Normative data and screening (anomia), are known as agnosias, a term coined by
power of a shortened version of the Token Test. Cortex Sigmund Freud (1891) and meaning literally ‘not
1978; 14: 41–9.
knowing’ or ‘without knowledge’. Lissauer (1890;
Goodglass H, Kaplan E. Boston Diagnostic Aphasia
abridged translation by Shallice & Jackson, 1988),
Examination (BDAE). Philadelphia: Lea & Febiger, 1983.
speaking of Seelenblindheit, literally ‘soul-blindness’
Kaplan EF, Goodglass H, Weintraub S. The Boston Naming
Test (2nd edition). Philadelphia: Lippincott Williams &
or technically ‘psychic blindness’, drew a distinction
Wilkins, 2001. between apperceptive deficits and associative defi-
Kay J, Lesser R, Coltheart M. Psycholinguistic Assessment of cits: in the former a defect of higher-order complex
Language Processing in Aphasia. Hove: Psychology perceptual processing was deemed to be present,
Press, 1992. whereas in the latter perception was held to be intact
Larner AJ. A Dictionary of Neurological Signs (2nd edition). but a defect in giving meaning to the percept was
New York: Springer, 2006: 10–1, 14–6, 32–3. present. Earlier descriptions probably reporting
Leff A. Alexia. Adv Clin Neurosci Rehabil 2004; 4 (3): 18, agnosic defects had appeared (Meyer, 1974). The
20, 22.
debate continues as to whether all agnosias, although
Lezak MD, Howieson DB, Loring DW. Neuropsychological
clinically distinguishable as apperceptive or asso-
Assessment (4th edition). New York: Oxford University
ciative, are in fact attributable to faulty perception
Press, 2004: 501–30.
McKenna P, Warrington EK. Testing for nominal aphasia. J
(Farah, 1995).
Neurol Neurosurg Psychiatry 1980; 43: 781–8. Although auditory and tactile agnosias are
McKenna P, Warrington EK. The Graded Naming Test. described, they seem to be relatively rare in com-
Windsor: NFER-Nelson, 1983. parison with visual agnosia, which has certainly
1.5 Perception 17
been more extensively studied (Farah, 1995; Bauer & in dorsal stream lesions. The workings of the
Demery, 2003; Ghadiali, 2004). The visual agnosias visuomotor control system are not available to
may be relatively selective, for example an inability consciousness (‘unconscious vision’), unlike the
to recognize previously known human faces or visual identification of objects.
equivalent stimuli, known as prosopagnosia. This A specific inability to see objects in motion, aki-
may be developmental (Nunn et al., 2001; Larner netopsia or cerebral visual motion blindness, despite
et al., 2003) or acquired in origin, the latter usually a preserved perception of other visual attributes such
consequence of cerebrovascular disease causing as colour, form, and depth, has been described in
bilateral occipitotemporal lesions, but occasionally association with selective lesions to area V5 of the
it occurs as a feature of neurodegenerative disease, visual cortex (Zihl et al., 1983; Zeki, 1991). Although
sometimes in relative isolation associated with focal exceptionally rare, such cases suggest a distinct
right temporal lobe atrophy (progressive proso- neuroanatomical substrate for movement vision, as
pagnosia: Evans et al., 1995). Pure alexia is an agnosia do cases in which motion vision is selectively spared
for words which results in a laborious letter-by-letter in a scotomatous area (Riddoch’s syndrome: Zeki &
reading strategy to arrive at a word’s identity, con- ffytche, 1998). Perception within a ‘blind’ visual field
ceptualized as a consequence of damage to a brain without conscious awareness has been termed
region mediating whole-word recognition, which blindsight (Weiskrantz, 1986). Visual neglect is con-
may be located in the medial left occipital lobe and sidered as a disorder of attention (see Section 1.1).
posterior fusiform gyrus (Leff et al., 2006). The rare Cases of isolated progressive visual agnosia were
syndrome of pure word deafness may be a form of presented by De Renzi (1986). Benson et al. (1988)
auditory agnosia. Finger agnosia, the inability to drew attention to a disorder comprising alexia,
identify which finger has been touched despite agraphia, visual agnosia, with or without compon-
knowing that a finger has been touched, is a form of ents of Balint and Gerstmann syndromes, trans-
tactile agnosia, which may be seen as one feature of cortical sensory aphasia, but with relative
Gerstmann syndrome although it may occur in isol- preservation of memory until late in the course, a
ation (Della Sala & Spinnler, 1994). Likewise, Braille disorder they named posterior cortical atrophy
alexia may in some instances be a form of tactile (PCA) in the absence of neuropathological data. It is
agnosia (Larner, 2007). now believed that most such cases have Alzheimer’s
The existence of two visual processing pathways disease pathology, hence the ‘visual variant of Alz-
within the brain was first proposed by Ungerlieder heimer’s disease’ (Levine et al., 1993), although this
and Mishkin (1982): an occipitoparietal dorsolateral might also be characterized, at least in its early
(‘where’) visual processing stream, and an occipi- stages, as focal onset AD or a non-amnestic form of
totemporal ventromedial (‘what’) stream. In rare mild cognitive impairment (MCI: Larner, 2004).
cases, these pathways may be selectively affected: Other pathologies have sometimes been found in
for instance the ventral stream, specifically the lat- PCA cases (Pantel & Schröder, 1996). Diagnostic
eral occipital area, in a famous patient with ‘visual criteria for PCA have been developed (Mendez
form agnosia’ following carbon monoxide poison- et al., 2002). Visual agnosic problems are a common
ing. Her perceptual identification of shape and form finding in Alzheimer’s disease, though usually less
was lost, although she could still perceive colour and apparent than the mnemonic difficulties. Various
the fine detail of surfaces (visual texture), and her visual processing disorders may occur in AD
visuomotor (‘vision for action’) skills were strikingly (Cronin-Golomb & Hof, 2004).
preserved (Milner & Goodale, 1995; Goodale & Various means may be used specifically to test
Milner, 2004). Optic ataxia, impaired voluntary visual perceptual and visuoconstructive functions
reaching for a visually presented target with mis- (Strauss et al., 2006). These may be individual tests
direction and dysmetria, is the sign typically evident such as Judgment of Line Orientation (thought to
tap right occipital lobe function); copy of the Rey– Farah MJ. Visual Agnosia: Disorders of Object Recognition
Osterrieth Complex Figure (Rey, 1941; Osterrieth, and What They Tell Us About Normal Vision. Cambridge,
1944; translation by Corwin & Bylsma, 1993) or the MA: MIT Press, 1995.
Taylor Figure (Taylor, 1969); decoding embedded Freud S. Zur Auffassung der Aphasien, eine Kritische Stu-
die. Leipizig: Deuticke, 1891.
(Poppelreuter) figures; parts of test batteries, such as
Ghadiali E. Agnosia. Adv Clin Neurosci Rehabil 2004; 4 (5):
the WAIS-R Block Design (visuospatial construc-
18–20.
tion); or dedicated batteries such as the Visual
Goodale MA, Milner AD. Sight Unseen: an Exploration of
Object and Space Perception Battery (VOSP: Conscious and Unconscious Vision. Oxford: Oxford
Warrington & James, 1991). University Press, 2004.
Of the frequently used ‘bedside’ neuropsycho- Larner AJ. ‘Posterior cortical atrophy’ or ‘focal-onset
logical test instruments (see Section 1.8), the Mini- Alzheimer’s disease’? A clinical, neuropsychological
Mental State Examination has only perfunctory and neuroimaging study. J Neurol 2004; 251 (suppl 3):
examination of visuospatial function, requiring III102 (abstract P385).
copying a drawing of intersecting pentagons. Clock Larner AJ. Braille alexia: an apperceptive tactile agnosia?
Drawing is, at least in part, a visuospatial test, but J Neurol Neurosurg Psychiatry 2007; 78: 907–8.
Larner AJ, Downes JJ, Hanley JR, Tsivilis D, Doran M.
requires other skills. The Queen Square Screening
Developmental prosopagnosia: a clinical and neuro-
Test for Cognitive Deficits calls for the identification
psychological study. J Neurol 2003; 250 (suppl 2): II156
of fragmented letters and pictures. The Adden-
(abstract P591).
brooke’s Cognitive Examination (ACE) adds copying Leff AP, Spitsyna G, Plant GT, Wise RJS. Structural
a wire cube and clock drawing, and ACE-R adds anatomy of pure and hemianopic alexia. J Neurol
counting dots and identifying fragmented letters. Neurosurg Psychiatry 2006; 77: 1004–7.
DemTect eschews specific visuoperceptual testing, Levine DN, Lee JM, Fisher CM. The visual variant of
other than in a number transcoding task. Alzheimer’s disease: a clinicopathologic case study.
Neurology 1993; 43: 305–13.
Lissauer H. Ein Fall von Seelenblindheit nebst einem
REFERENCES Beitrag zur Theorie derselben. Arch Psychiatr Nervenkr
1890; 21: 222–70.
Bauer RM, Demery JA. Agnosia. In: Heilman KM, Valenstein Mendez MF, Ghajarania M, Perryman KM. Posterior
E (eds.), Clinical Neuropsychology (4th edition). Oxford: cortical atrophy: clinical characteristics and differences
Oxford University Press, 2003: 236–95. compared to Alzheimer’s disease. Dement Geriatr Cogn
Benson DF, Davis RJ, Snyder BD. Posterior cortical Disord 2002; 14: 33–40.
atrophy. Arch Neurol 1988; 45: 789–93. Meyer A. The frontal lobe syndrome, the aphasias and
Corwin J, Bylsma FW. ‘Psychological examination of related conditions. Brain 1974; 97: 565–600.
traumatic encephalopathy’ by A. Rey and ‘The complex Milner AD, Goodale MA. The Visual Brain in Action.
figure copy test’ by P.A. Osterrieth. Clin Neuropsychol Oxford: Oxford University Press, 1995.
1993; 7: 3–21. Nunn JA, Postma P, Pearson R. Developmental prosopag-
Cronin-Golomb A, Hof PR (eds.). Vision in Alzheimer’s nosia: should it be taken at face value? Neurocase 2001;
Disease. Basel: Karger, 2004. 7: 15–27.
Della Sala S, Spinnler H. Finger agnosia: fiction or reality? Osterrieth PA. Le test de copie d’une figure complex:
Arch Neurol 1994; 51: 448–50. contribution à l’étude de la perception et de la
De Renzi E. Slowly progressive visual agnosia or apraxia mémoire. Arch Psychol 1944; 30: 286–356.
without dementia. Cortex 1986; 22: 171–80. Pantel J, Schröder J. Posterior cortical atrophy: a new
Evans JJ, Heggs AJ, Antoun N, Hodges JR. Progressive dementia syndrome or a form of Alzheimer’s disease [in
prosopagnosia associated with selective right tem- German]. Fortschr Neurol Psychiatr 1996; 64: 492–508.
poral lobe atrophy: a new syndrome? Brain 1995; 118: Rey A. L’examen psychologique dans les cas d’encépha-
1–13. lopathie traumatique. Arch Psychol 1941; 28: 286–340.
1.6 Praxis 19
Shallice T, Jackson M. Lissauer on agnosia. Cogn Neuro- damage (De Renzi et al., 1968). Ideomotor apraxia in
psychol 1988; 5: 153–92. Broca’s aphasia may be conceptualized as a
Strauss E, Sherman EMS, Spreen O. A Compendium of disconnection syndrome (see Section 1.12).
Neuropsychological Tests: Administration, Norms, Cases of isolated progressive apraxia were pre-
Commentary (3rd edition). Oxford: Oxford University
sented by De Renzi (1986). Apraxia may be a feature
Press, 2006: 963–1011.
of neurodegenerative disease, classically corticoba-
Taylor LB. Localization of cerebral lesions by psycho-
sal degeneration (see Section 2.4.3), although
logical testing. Clin Neurosurg 1969; 16: 269–87.
Ungerlieder LG, Mishkin M. Two cortical visual systems.
Alzheimer’s disease can on occasion present with a
In: Ingle DJ, Goodale MA, Mansfield RJW (eds.), Analysis similar phenotype (biparietal atrophy: Section 2.1),
of Visual Behavior. Cambridge, MA: MIT Press, 1982: even with alien limb behaviour.
549–86. Praxic difficulties may be tested for in various
Warrington EK, James M. The Visual Object and Space ways (Crutch, 2005), including gesture naming,
Perception Battery. Bury St Edmunds: Thames Valley decision and recognition; gesture to verbal command,
Test Company, 1991. to visual or tactile tool; imitation of real or
Weiskrantz L. Blindsight: a Case Study and Implications. nonsense gestures; and tool selection. There are
Oxford: Clarendon Press, 1986.
test batteries, including the Florida Apraxia
Zeki S. Cerebral akinetopsia (cerebral visual motion
Screening Test-Revised (FAST-R: Gonzalez Rothi
blindness). Brain 1991; 114: 811–24.
et al., 1997).
Zeki S, ffytche DH. The Riddoch syndrome: insights into
the neurobiology of conscious vision. Brain 1998; 121:
25–45.
Zihl J, Von Cramon D, Mai N. Selective disturbance of REFERENCES
movement vision after bilateral brain damage. Brain
1983; 106: 313–40. Crutch S. Apraxia. Adv Clin Neurosci Rehabil 2005; 5 (1):
16, 18.
De Renzi E. Slowly progressive visual agnosia or apraxia
1.6 Praxis without dementia. Cortex 1986; 22: 171–80.
De Renzi E, Pieczuro A, Vignolo LA. Ideational apraxia: a
quantitative study. Neuropsychologia 1968; 6: 41–52.
Apraxia, impairment of praxis, is an acquired dis-
Gonzalez Rothi LJ, Raymer AM, Heilman KM. Limb praxis
order of higher-level motor control causing
assessment. In: Gonzalez Rothi LJ, Heilman KM (eds.),
impaired purposeful voluntary motor skill (Grafton, Apraxia: the Neuropsychology of Action. Hove: Psychol-
2003; Heilman & Gonzalez Rothi, 2003; Leiguarda, ogy Press, 1997: 61–74.
2005), first defined as such and associated with left- Grafton S. Apraxia: a disorder of motor control. In:
sided lesions by Liepmann (1900). The disorder D’Esposito M (ed.), Neurological Foundations of Cog-
should not be explicable in terms of lower-motor nitive Neuroscience. Cambridge, MA: MIT Press, 2003:
deficits, such as pyramidal, extrapyramidal, cere- 239–58.
bellar, or sensory dysfunction, nor in terms of other Heilman KM, Gonzalez Rothi LJ. Apraxia. In: Heilman
cognitive deficits such as language or perception. KM, Valenstein E (eds.), Clinical Neuropsychology
(4th edition). Oxford: Oxford University Press, 2003:
For example, deficits labelled as ‘constructional
215–35.
apraxia’ or ‘dressing apraxia’ are better explained as
Leiguarda R. Apraxias as traditionally defined. In: Freund
visuoperceptual and/or visuospatial deficits, as is
HJ, Jeannerod M, Hallett M, Leiguarda R (eds.), Higher-
the misdirected reaching for visual targets typical of Order Motor Disorders: from Neuroanatomy and
optic ataxia. Neurobiology to Clinical Neurology. Oxford: Oxford
Traditionally a distinction has been drawn University Press, 2005: 303–38.
between ideational and ideomotor apraxias, Liepmann H. Das Krankheitsbild der Apraxie (‘motorischen
although both are often present in left hemisphere Asymbolie’). Berlin: Karger, 1900.
1.7 Executive function, ‘frontal function’ Oral tests of verbal fluency, or controlled oral
word association tests (COWAT), may be divided
The term ‘executive function’ is used to encompass into those testing phonological, letter, or lexical
various abilities, including the formulation of goals; fluency, such as the FAS test (in one minute name as
organization, planning, execution, and monitoring of many words as possible beginning with the letter F,
a sequence of actions; problem solving; and abstract then another minute to name words beginning with
thinking. It also overlaps with sustained attention. A, then another minute to name words beginning
The term ‘dysexecutive syndrome’ may be used to with S), and those testing semantic or category flu-
describe dysfunction in any or all of these areas, ency (in one minute name as many animals, or
which is most often associated with pathological fruits, or musical instruments, or whatever category
processes in the frontal lobes (Filley, 2000; Chayer & is chosen, as possible). Letter fluency has been
Freedman, 2001; Miller & Cummings, 2007). Because characterized as a test of mental flexibility probing
of the heterogeneity of these functions, some authors executive function, which is particularly impaired
dislike the umbrella term of ‘executive function’, and (‘defective exemplification’: Critchley, 1979) with
prefer to describe the specific function impaired. left frontal lesions (without aphasia), whereas cat-
Moreover, frontal lobe damage may result in various egory fluency examines the integrity of the semantic
clinical phenotypes, in which behavioural change is network. Design fluency, a visual analogue of verbal
often the most salient feature. Orbitofrontal injury fluency, may be more impaired with right frontal
may result in disinhibition, as described in Phineas lesions (Jones-Gotman & Milner, 1977). Verbal flu-
Gage, one of the most famous patients in the annals ency tasks are attractive because they are brief
of clinical neuropsychology, who exhibited behav- (1 minute each) and require no special equipment,
ioural change following frontal lobe injury (Damasio but account may need to be taken of patient age
et al., 1994; Macmillan, 2000; Larner & Leach, 2002), and education when considering test norms
although other patterns of clinical and cognitive (Mathuranath et al., 2003). Verbal fluency tests are
change may be observed with frontal lobe injury incorporated into test batteries such as the
(Loring & Meador, 2006): for example, apathetic Dementia Rating Scale and the CERAD Battery, as
(frontal convexity) and akinetic (medial frontal) well as the Addenbrooke’s Cognitive Examination
syndromes are also described (Trimble, 1996). (see Section 1.8), and may be of diagnostic utility in
Because of the overarching nature of the con- Alzheimer’s disease and vascular dementia (Cerhan
struct ‘executive function’, no single test is adequate et al., 2002; Duff Canning et al., 2004).
to assess its integrity (Goldberg & Bougakov, 2005). Perhaps the most frequently used tests probing
A wide variety of tests known to be sensitive to executive functions are the Stroop Test (Stroop, 1935)
aspects of executive dysfunction is available. At the and the Wisconsin Card Sorting Test (WCST) and the
bedside or in the clinic, ‘Go–No Go’ tests may be Modified Wisconsin Card Sorting Test (MWCST:
applied to assess failure of inhibitory responses, Nelson, 1976). In the Stroop Test, patients are
or stimulus-boundedness, for example asking the required to read a list of colour names, printed in
patient to tap twice in response to a single tap given colours which differ from the name, followed by
by the examiner, and once in response to two taps. naming the colours in which each name is printed,
Repeating alternating sequences, for example of thus having to inhibit the reading of each colour
hand gestures (fist–palm) or of writing (m n m n m n), name (i.e. inhibition of inappropriate responses).
may be used to similar purpose. The Trails A and B MWCST uses a set of cards marked with symbols of
test also requires a sequence, of letters or numbers, different shape, colour, and number which may be
to be followed. Interpretation of proverbs is a sorted in various ways. Sorting rules are changed by
popular bedside test, ‘concrete’ interpretation sug- the examiner without informing the subject, requir-
gesting frontal lobe problems. ing problem-solving skills. Difficulty switching
1.7 Executive function, ‘frontal function’ 21
category is typical of frontal lobe damage, leading to variant frontotemporal dementia, may complete
perseveration with previous categories. Clearly these tests without conspicuous errors.
MWCST, unlike the Stroop Test, calls for novel Of the ‘bedside’ neuropsychological test instru-
responses. MWCST may not be specific to frontal ments (see Section 1.8), the Mini-Mental State
lobe dysfunction, since patients with hippocampal Examination has been criticized for its lack of
lesions may commit perseverative errors (Corcoran & assessment of executive function, one shortcoming
Upton, 1993). which the Addenbrooke’s Cognitive Examination
There are many other tests probing executive seeks to address by using letter and category verbal
functions, sometimes along with other domains fluency tests. Moreover, a test subscore, the VLOM
(Strauss et al., 2006). These include Raven’s Pro- ratio, has been reported to distinguish fronto-
gressive Matrices, the Porteus Mazes, the Tower of temporal dementia from Alzheimer’s disease
London Test (Shallice, 1982), the Tower of Hanoi (Mathuranath et al., 2000), although evidence to the
Test, the Trail Making Test (especially Part B), the contrary has been presented for some of these
Halstead–Reitan Category Test, the Weigl Colour parameters (Bier et al., 2004; Larner, 2005; Cas-
Form Sorting Test (Weigl, 1941), the Cognitive tiglioni et al., 2006). Other batteries which tap
Estimates Test (Shallice & Evans, 1978), and the executive function include the Frontal Assessment
Verbal Switching Test (Warrington, 2000). The Battery (Dubois et al., 2000; Slachevsky et al., 2004),
Hayling and Brixton Tests for sentence completion the Frontal Behavioural Inventory (Kertesz et al.,
and spatial anticipation are tests of rule following 2000), and the Middelheim Frontality Score (De
and verbal suppression of a familiar response Deyn et al., 2005). Clock drawing may also dis-
(Burgess & Shallice, 1996, 1997). Certain WAIS-R criminate FTD from AD, more errors being made in
subtests are sensitive to aspects of executive/frontal the latter (Blair et al., 2006).
lobe function, such as the Similarities test of verbal
abstraction and the Digit Symbol test of psycho-
motor speed. Tests of decision making and risk REFERENCES
taking, faculties which may also be encompassed
under the rubric of executive function (Lehto & Bechara A, Damasio AR, Damasio H, Anderson SW.
Elorinne, 2003) and mediated by the prefrontal Insensitivity to future consequences following damage
cortex and amygdala, include the Iowa Gambling to human prefrontal cortex. Cognition 1994; 50: 7–15.
Test (Bechara et al., 1994) and the Cambridge Bier JC, Ventura M, Donckels V, et al. Is the Adden-
Gamble Task (Rogers et al., 1999). brooke’s Cognitive Examination effective to detect
There are also batteries of tests such as the Beha- frontotemporal dementia? J Neurol 2004; 251: 428–31.
vioural Assessment of the Dysexecutive Syndrome Blair M, Kertesz A, McMonagle P, Davidson W, Bodi N.
(BADS: Wilson et al., 1996) and the Delis–Kaplan Quantitative and qualitative analyses of clock drawing
in frontotemporal dementia and Alzheimer’s disease.
Executive Function System (D-KEFS: Delis et al.,
J Int Neuropsychol Soc 2006; 12: 159–65.
2001), but since these take some time to administer
Burgess PW, Shallice T. Bizarre responses, rule detection
they are best reserved for specific investigation of
and frontal lobe lesions. Cortex 1996; 32: 241–59.
known frontal problems. The Frontal Lobe Persona- Burgess PW, Shallice T. The Hayling and Brixton Tests.
lity Change Questionnaire (FLOPS) may be used to Thurston: Thames Valley Test Company, 1997.
assess behavioural change and includes a carer Castiglioni S, Pelati O, Zuffi M, et al. The Frontal
version, useful for gaining collateral information. Assessment Battery does not differentiate frontotem-
Since most tests of executive function probe poral dementia from Alzheimer’s disease. Dement
planning and strategy, mediated by dorsolateral Geriatr Cogn Disord 2006; 22: 125–31.
prefrontal cortex, some patients with exclusive Cerhan JH, Ivnik RJ, Smith GE, et al. Diagnostic utility of
orbitofrontal damage, for example with frontal letter fluency, category fluency, and fluency difference
scores in Alzheimer’s disease. Clin Neuropsychol 2002; Mathuranath P, George A, Cherian P, et al. Effects of age,
16: 35–42. education and gender on verbal fluency. J Clin Exp
Chayer C, Freedman M. Frontal lobe functions. Curr Neuropsychol 2003; 25: 1057–64.
Neurol Neurosci Rep 2001; 1: 547–52. Miller BL, Cummings JL (eds.). The Human Frontal Lobes:
Corcoran R, Upton D. A role for the hippocampus in card Functions and Disorders (2nd edition). London: Guilford
sorting? Cortex 1993; 29: 293–304. Press, 2007.
Critchley M. The Divine Banquet of the Brain and Other Nelson HE. A modified card sorting test sensitive to
Essays. New York: Raven Press, 1979: 54. frontal lobe defects. Cortex 1976; 12: 313–24.
Damasio H, Grabowski T, Frank R, Galaburda AM, Rogers RD, Everitt BD, Baldacchino A, et al. Dissociable
Damasio AR. The return of Phineas Gage: clues about deficits in the decision-making cognition of chronic
the brain from the skull of a famous patient. Science amphetamine abusers, opiate abusers, patients with
1994; 264: 1102–5. focal damage to prefrontal cortex, and tryptophan-
De Deyn PP, Engelborghs S, Saerens J, et al. The Middelheim depleted normal volunteers: evidence for monoaminer-
Frontality Score: a behavioural assessment scale that gic mechanisms. Neuropsychopharmacology 1999; 20:
discriminates frontotemporal dementia from Alzheimer’s 322–39.
disease. Int J Geriatr Psychiatry 2005; 20: 70–9. Shallice T. Specific impairments of planning. Phil Trans R
Delis D, Kaplan E, Kramer J. Delis–Kaplan Executive Func- Soc Lond B Biol Sci 1982; 298: 199–209.
tion System. New York: Psychological Corporation, 2001. Shallice T, Evans ME. The involvement of the frontal lobes
Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal in cognitive estimation. Cortex 1978; 14: 294–303.
Assessment Battery at bedside. Neurology 2000; 55: 1621–6. Slachevsky A, Villalpando JM, Sarazin M, Hahn BV, Pillon
Duff Canning SJ, Leach L, Stuss D, Ngo L, Black SE. B, Dubois B. Frontal assessment battery and differential
Diagnostic utility of abbreviated fluency measures in diagnosis of frontotemporal dementia and Alzheimer
Alzheimer disease and vascular dementia. Neurology disease. Neurology 2004; 61: 1104–7
2004; 62: 556–62. Strauss E, Sherman EMS, Spreen O. A Compendium of
Filley CM. Clinical neurology and executive function. Neuropsychological Tests: Administration, Norms,
Semin Speech Lang 2000; 21: 95–108. Commentary (3rd edition). Oxford: Oxford University
Goldberg E, Bougakov D. Neuropsychologic assessment of Press, 2006: 401–545.
frontal lobe dysfunction. Psychiatr Clin North Am 2005; Stroop J. Studies of interference in serial verbal reaction.
28: 567–80. J Exp Psychol 1935; 18: 643–62.
Jones-Gotman M, Milner B. Design fluency: the invention Trimble MR. Biological Psychiatry (2nd edition). Chi-
of nonsense drawings after focal cortical lesions. chester: Wiley, 1996: 147–56.
Neuropsychologia 1977; 15: 653–74. Warrington EK. Homophone meaning generation: a new
Kertesz A, Nadkarni N, Davidson W, Thomas AW. The test of verbal switching for the detection of frontal lobe
Frontal Behavioural Inventory in the differential diag- dysfunction. J Int Neuropsychol Soc 2000; 6: 643–8.
nosis of frontotemporal dementia. J Int Neuropsychol Weigl E. On the psychology of so-called processes of
Soc 2000; 6: 460–8. abstraction. J Norm Soc Psychol 1941; 36: 3–33.
Larner AJ. An audit of the Addenbrooke’s Cognitive Wilson BA, Alderman N, Burgess PW, Emslie H, Evans JJ.
Examination (ACE) in clinical practice. Int J Geriatr Behavioural Assessment of the Dysexecutive Syndrome.
Psychiatry 2005; 20: 593–4. Bury St Edmunds: Thames Valley Test Company, 1996.
Larner AJ, Leach JP. Phineas Gage and the beginnings of
neuropsychology. Adv Clin Neurosci Rehabil 2002; 2 (3): 26.
Lehto JE, Elorinne E. Gambling as an executive function
1.8 ‘Bedside’ neuropsychological test
task. Appl Neuropsychol 2003; 10: 234–8.
Loring DW, Meador KJ. Case studies of focal prefrontal
instruments
lesions in man. In: Risberg J, Grafman J (eds.), The
Frontal Lobes: Development, Function and Pathology. How should the practising clinician, perhaps
Cambridge: Cambridge University Press, 2006: 163–77. untrained in the nuances of neuropsychology, and
Macmillan M. An Odd Kind of Fame: Stories of Phineas pressed for time, assess cognitive function at the
Gage. Cambridge, MA: MIT Press, 2000. bedside when the complaint of the patient and/or
relatives suggests the possibility of cognitive dis- (Deeks & Altman, 2004). Construction of a receiver
order? Primary care practitioners may use simple operating characteristic (ROC) curve (Hanley &
clinical observations to give pointers to, or raise McNeil, 1982, 1983) is also desirable, with area
suspicion of, a diagnosis of dementia: patient age under the curve (AUC), a measure of diagnostic
and suggestive collateral history are probably the accuracy, > 0.80, where AUC ¼ 0.5 indicates a test
most important factors (Fisher & Larner, 2006). providing no added information and AUC ¼ 1 indi-
Practitioners in secondary care settings will, in cates a test providing perfect discrimination. Diag-
addition, use brief ‘bedside’ tests in the initial nostic odds ratio, a summary measure of test
assessment of patients with cognitive complaints. diagnostic performance, should be high. Such data
(‘Bedside’ is a misnomer, since the bedside may be a are not available for all bedside tests.
far from ideal location in which to administer such Many bedside tests are available, all of which have
tests, surrounded by the noise of a ward, spectators, their adherents. In primary care, where time is of the
and the imminent possibility of interruption.) There essence, guidelines have been published which
are many such instruments (Burns et al., 1999, recommend the use of formal cognitive testing as
2006), some of the most widely used of which are well as clinical judgment (Eccles et al., 1998). Very
briefly discussed here. These may be broadly cate- brief screens such as the Abbreviated Mental Test
gorized as ‘simple’ or ‘complex’; or as ‘mini’, Score (AMTS: Hodkinson, 1972), the 6 Item Cogni-
implying a performance time of 10 minutes or tive Impairment Test (6CIT, also sometimes known
under, or ‘midi’, taking perhaps 15–30 minutes to as the Kingshill Test: Brooke & Bullock, 1999),
perform. Batteries requiring 45–60 minutes or more GPCOG (Brodaty et al., 2002), Memory Alteration
are not discussed, as their use will in all likelihood be Test (Rami et al., 2007), or some form of clock
reserved to specialist clinics wherein the time factor drawing task might be used. However, a recent
is less of an issue. These tests have focused largely survey suggested that cognitive test instruments
on identifying Alzheimer’s disease (AD), since this is were seldom used by general practitioners (c. 20%)
the commonest cause of dementia, and hence are prior to referral of patients to a dedicated cognitive
weighted towards detecting memory deficits. Hence function clinic, and that the Mini-Mental State
these instruments may be suboptimal for detecting Examination (MMSE; see below) was the instrument
disorders with prominent non-memory cognitive most commonly used (Fisher & Larner, 2007).
and/or behavioural symptoms. However, in the primary care setting, Wind et al.
Methodological standards to evaluate screening (1997) found the MMSE to be of limited value in
and diagnostic tests for dementia have been diagnosing dementia (sensitivity 0.65, specificity
outlined, specifically their reliability and validity 0.93).
(Gifford & Cummings, 1999), and the principles of Both AMTS and 6CIT are derived from the Blessed
evidence-based diagnosis are well established Information Memory Concentration Test (BIMC:
(Qizilbash, 2002). Test sensitivity and specificity not Blessed et al., 1968), one of a large number of tests
less than 0.8 and positive predictive value available for clinical use. These include:
approaching 0.9, the recommended criteria for Cognitive Capacity Screening Examination
molecular biomarkers for AD (Ronald and Nancy (CCSE: Jacobs et al., 1977)
Reagan Research Institute of the Alzheimer’s Asso- Telephone Interview for Cognitive Status (TICS:
ciation and the National Institute on Aging, 1998), Brandt et al., 1988)
would seem to be desirable attributes of bedside Short Test of Mental Status (Kokmen et al., 1991)
tests for dementia. Likelihood ratios, the ratio of pre- Structured Interview for the diagnosis of Demen-
test to post-test odds and hence a measure of tia of the Alzheimer type, Multi-infarct dementia
‘diagnostic gain’, should desirably have values > 10 and dementias of other aetiology (SIDAM: Zaudig
or < 0.1, meaning the test has a large diagnostic gain et al., 1991)
Cognitive Abilities Screening Instrument (CASI: Activities of Daily Living Questionnaire (Johnson
Teng et al., 1994) et al., 2004). Inclusion of global, behavioural, and
Hasegawa Dementia Scale–Revised (HDS-R: Imai ADL scales is now mandatory in clinical drug trials
& Hasegawa, 1994; Kim et al., 2005) in dementia, whilst pharmacoeconomic assess-
Cambridge Cognitive Examination (CAMCOG: ments and quality of life scales are also thought
Huppert et al., 1995) desirable.
7-minute screen (Solomon et al., 1998) Informant questionnaires may also be used to
Memory Impairment Screen (Buschke et al., 1999) gather collateral information not available from
Mini-Cog (Borson et al., 2000) patient history (lone patient attendance in the clinic
Visual Association Test (Lindeboom et al., 2002) despite a request to bring a relative, carer, or friend
Kingston Standardized Cognitive Assessment is a strong indicator of the absence of dementia:
(Hopkins et al., 2004) Larner, 2004, 2005), particularly examining change
TE4D-Cog (Mahoney et al., 2005). from a premorbid level of functioning (Jorm, 1997).
For dementia that has already progressed to a severe The Informant Questionnaire on Cognitive Decline
stage, the following instruments are available: in the Elderly (IQCODE: Jorm & Jacomb, 1989) is one
Severe Impairment Battery (SIB: Saxton & Swihart, such instrument, which has also been reported
1989) useful in the diagnosis of MCI (Isella et al., 2006).
Middlesex Elderly Assessment of Mental State
(MEAMS: Golding, 1989)
Severe MMSE (Harrell et al., 2000) REFERENCES
mini-SIB (Qazi et al., 2005).
Computerized test batteries are also available, such Blessed G, Tomlinson BE, Roth M. The association
as the Cambridge Neuropsychological Test Auto- between quantitative measures of dementia and of
mated Battery, from which the Paired Associates senile change in the cerebral grey matter of elderly
Learning test (CANTAB-PAL) may be useful for the subjects. Br J Psychiatry 1968; 114: 797–811.
Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog:
early detection and diagnosis of dementia (Swain-
a cognitive ‘vital signs’ measure for dementia screening
son et al., 2001).
in multi-lingual elderly. Int J Geriatr Psychiatry 2000; 15:
Tests measuring global function, behaviour, and
1021–7.
activities of daily living (ADL) may also be under- Brandt J, Spencer M, Folstein M. The Telephone Interview
taken in the assessment of patients with cognitive for Cognitive Status. Neuropsychiatry Neuropsychol
disorders (Burns et al., 1999, 2006; McKeith, 1999). Behav Neurol 1988; 1: 111–17.
Popular global measures, not further discussed Brodaty H, Pond D, Kemp NM, et al. The GPCOG: a new
here, include the Functional Assessment Staging screening test for dementia designed for general
(FAST: Reisberg, 1988) and the Clinicians Interview- practice. J Am Geriatr Soc 2002; 50: 530–4.
Based Impression of Change (CIBIC, or CIBICþ if Brooke P, Bullock R. Validation of a 6 item Cognitive
caregiver input is included). The Neuropsychiatric Impairment Test with a view to primary care usage. Int J
Geriatr Psychiatry 1999; 14: 936–40.
Inventory (NPI) is perhaps the most widely used
Bucks RS, Ashworth DL, Wilcock GK, Siegfried K.
measure of behaviour in dementia (Cummings
Assessment of activities of daily living in dementia:
et al., 1994). Popular ADL scales include the Alz-
development of the Bristol Activities of Daily Living
heimer’s Disease Cooperative Study Activities of Scale. Age Ageing 1996; 25: 113–20.
Daily Living Scale (ADCS-ADL), the Instrumental Burns A, Lawlor B, Craig S. Assessment Scales in Old Age
Activities of Daily Living (IADL) Scale (Lawton & Psychiatry. London: Martin Dunitz, 1999.
Brody, 1969), the Functional Activities Question- Burns A, Lawlor B, Craig S. Assessment Scales in Old
naire (FAQ: Pfeffer et al., 1982), the Bristol Activities Age Psychiatry (2nd edition). London: Martin Dunitz,
of Daily Living Scale (Bucks et al., 1996), and the 2006.
Buschke H, Kuslansky G, Katz M, et al. Screening Isella V, Villa L, Russo A, et al. Discriminative and
for dementia with the Memory Impairment Screen. predictive power of an informant report in mild
Neurology 1999; 52: 231–8. cognitive impairment. J Neurol Neurosurg Psychiatry
Cummings JL, Mega MS, Gray K, et al. The Neuropsychia- 2006; 77: 166–71.
tric Inventory: comprehensive assessment of psycho- Jacobs JW, Bernhard MR, Delgado A, Strain JJ. Screening
pathology in dementia. Neurology 1994; 44: 2308–14. for organic mental symptoms in the medically ill. Ann
Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. Intern Med 1977; 86: 40–6.
BMJ 2004; 329: 168–9. Johnson N, Barion A, Rademaker A, Rehkemper G,
Eccles M, Clarke J, Livingston M, Freemantle N, Mason J. Weintraub S. The Activities of Daily Living Question-
North of England evidence based guidelines develop- naire: a validation study in patients with dementia.
ment project: guideline for the primary care manage- Alzheimer Dis Assoc Disord 2004; 18: 223–30.
ment of dementia. BMJ 1998; 317: 802–8. Jorm AF. Methods of screening for dementia: a meta-
Fisher CAH, Larner AJ. FAQs: memory loss. Practitioner analysis of studies comparing an informant question-
2006; 250 (1683): 14–16, 19, 21. naire with a brief cognitive test. Alzheimer Dis Assoc
Fisher CAH, Larner AJ. Frequency and diagnostic utility of Disord 1997; 11: 158–62.
cognitive test instrument use by GPs prior to memory Jorm AF, Jacomb PA. The Informant Questionnaire on
clinic referral. Fam Pract 2007; 24: 495–7. Cognitive Decline in the Elderly (IQCODE): socio-
Gifford DR, Cummings JL. Evaluating dementia screening demographic correlates, reliability, validity and some
tests: methodologic standards to rate their perform- norms. Psychol Med 1989; 19: 1015–22.
ance. Neurology 1999; 52: 224–7. Kim KW, Lee DY, Jhoo JH, et al. Diagnostic accuracy of
Golding E. The Middlesex Elderly Assessment of Mental mini-mental status examination and revised Hasegawa
State. Bury St Edmunds, Thames Valley Test Company, dementia scale for Alzheimer’s disease. Dement Geriatr
1989. Cogn Disord 2005; 19: 324–30.
Hanley JA, McNeil BJ. The meaning and use of the area Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RC.
under a receiver operating characteristic (ROC) curve. The Short Test of Mental Status: correlations with
Radiology 1982; 143: 29–36. standardized psychometric testing. Arch Neurol 1991;
Hanley JA, McNeil BJ. A method of comparing the areas 48: 725–8.
under a receiver operating characteristic curves derived Larner AJ. Getting it wrong: the clinical misdiagnosis of
from the same cases. Radiology 1983; 148: 839–43. Alzheimer’s disease. Int J Clin Pract 2004; 58: 1092–4.
Harrell LE, Marson D, Chatterjee A, Parrish JA. The Severe Larner AJ. ‘Who came with you?’ A diagnostic observation
Mini-Mental State Examination: a new neuropsycho- in patients with memory problems? J Neurol Neurosurg
logical instrument for the bedside assessment of Psychiatry 2005; 76: 1739.
severely impaired patients with Alzheimer’s disease. Lawton MP, Brody EM. Assessment of older people: self-
Alzheimer Dis Assoc Disord 2000; 14: 168–75. maintaining and instrumental activities of daily living.
Hodkinson HM. Evaluation of a mental test score for Gerontologist 1969; 9: 176–85.
assessment of mental impairment in the elderly. Age Lindeboom J, Schmand B, Tulner L, Walstra G, Jonker C.
Ageing 1972; 1: 233–8. Visual association test to detect early dementia of the
Hopkins R, Kilik L, Day D, Rows C, Hamilton P. The Alzheimer type. J Neurol Neurosurg Psychiatry 2002; 73:
Revised Kingston Standardized Cognitive Assessment. 126–33.
Int J Geriatr Psychiatry 2004; 19: 320–6. McKeith IG (ed.). Outcome Measures in Alzheimer’s Dis-
Huppert FA, Brayne CA, Gill C, et al. CAMCOG: a concise ease. London: Martin Dunitz, 1999.
neuropsychological test to assist dementia diagnosis. Mahoney R, Johnston K, Katona C, Maxmin K, Livingston G.
Sociodemographic determinants in an elderly popula- The TE4D-Cog: a new test for detecting early dementia
tion sample. Br J Clin Psychol 1995; 34: 529–41. in English-speaking populations. Int J Geriatr Psychiatry
Imai Y, Hasegawa K. The revised Hasegawa Dementia 2005; 20: 1172–9.
Scale (HDS-R): evaluation of its usefulness as a Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S.
screening test for dementia. J Hong Kong Coll Psychiatr Measurement of functional activities in older adults in
1994; 4 (2): 20–4. the community. J Gerontol 1982; 37: 323–9.
Qazi A, Richardson B, Simmons P, et al. The Mini-SIB: a useful in monitoring change, but not primarily as a
short scale for measuring cognitive function in severe diagnostic tool (Folstein et al., 1975). However, it has
dementia. Int J Geriatr Psychiatry 2005; 20: 1001–2. proved acceptable and useful in the assessment of
Qizilbash N. Evidence-based diagnosis. In: Qizilbash N, cognitive status in general medical and neurological
Schneider LS, Chui H, et al. (eds.), Evidence-Based
patients (Dick et al., 1984; Tangalos et al., 1996) and
Dementia Practice. Oxford: Blackwell, 2002: 18–25.
has become the most widely used brief cognitive
Rami L, Molinuevo JL, Sanchez-Valle R, Bosch B, Villar A.
assessment. (Surely no other medical investigation
Screening for amnestic mild cognitive impairment and
early Alzheimer’s disease with M@T (Memory Alteration
can claim to have been memorialized, at least in
Test) in the primary care population. Int J Geriatr part, in a sonnet – by Rafael Campo: see Levin, 2001).
Psychiatry 2007; 22: 294–304. The MMSE has good intra- and inter-rater reliability
Reisberg B. Functional assessment staging (FAST). Psy- and internal consistency, although there has
chopharmacol Bull 1988; 24: 653–9. been debate about appropriate cutoff scores
Ronald and Nancy Reagan Research Institute of the (Tombaugh & McIntyre, 1992). There are two dem-
Alzheimer’s Association and the National Institute on onstrable normative influences on MMSE scores,
Aging. Consensus report of the Working Group on namely patient age and years of education, norms
molecular and biochemical markers of Alzheimer’s
for which may be factored into the cutoffs (Crum
disease. Neurobiol Aging 1998; 19: 109–16.
et al., 1993). MMSE may be useful in tracking cog-
Saxton J, Swihart AA. Neuropsychological assessment of
nitive decline in AD (Han et al., 2000), falling on
the severely impaired elderly patient. Clin Geriatr Med
1989; 5: 531–43.
average 3 points per year, although there is vari-
Solomon PR, Hirschoff A, Kelly B, et al. A 7-minute ability, some patients remaining stable and some
neurocognitive screening battery highly sensitive to even improving (Holmes & Lovestone, 2003),
Alzheimer’s disease. Arch Neurol 1998; 55: 349–55. meaning that this may be a less than ideal instru-
Swainson R, Hodges JR, Galton CJ, et al. Early detection ment on which to base therapeutic decisions, for
and differential diagnosis of Alzheimer’s disease and example on the efficacy of cholinesterase inhibitors
depression with neuropsychological tests. Dement (even aside from the patient anxiety which fore-
Geriatr Cogn Disord 2001; 12: 265–80. knowledge of those judgments may engender, the
Teng EL, Hasegawa K, Homma, A, et al. The Cognitive
‘Godot syndrome’, which itself may influence test
Abilities Screening Instrument (CASI): a practical test
performance: Larner & Doran, 2002). It has also
for cross-cultural epidemiological studies of dementia.
sometimes been objected that the MMSE takes too
Int Psychogeriatr 1994; 6: 45–58.
Wind AW, Schellevis FG, Van Staveren G, et al. Limitations
long to administer (c. 10 minutes: Tangalos et al.,
of the Mini-Mental State Examination in diagnosing 1996). Both expanded (Standardized MMSE, SMMSE:
dementia in general practice. Int J Geriatr Psychiatry Molloy et al., 1991; Modified MMSE, 3MS: Teng &
1997; 12: 101–8. Chui, 1987) and shortened (Galasko et al., 1990)
Zaudig M, Mittelhammer J, Hiller W, et al. SIDAM: a versions have been developed, as well as a version for
structured interview for the diagnosis of dementia of severe disease (Harrell et al., 2000).
the Alzheimer type, multi-infarct dementia and demen- One of the difficulties with the MMSE is deter-
tias of other aetiology according to ICD-10 and DSM- mining where the cutoff(s) should be. For a cutoff
III-R. Psychol Med 1991; 21: 225–36.
< 24, Kukull et al. (1994) found a sensitivity of 0.63
and a specificity of 0.96 for the diagnosis of AD in a
1.8.1 Mini-Mental State Examination (MMSE) cohort of 133 patients (80 dementia, 53 no demen-
tia); sensitivity increased at higher cutoff scores,
The Mini-Mental State Examination (MMSE) was unsurprisingly, leading to a recommendation that
originally designed to differentiate organic from MMSE score of 26 or 27 should be used in symp-
functional disorders in psychiatric practice, and as a tomatic populations if the aim is to miss few true
quantitative measure of cognitive impairment cases. Tangalos et al. (1996) found a sensitivity and
specificity of 0.69 and 0.99 for a cutoff of 23 or less; Dick JPR, Guiloff RJ, Stewart A, et al. Mini-mental state
use of age- and education-specific cutoff scores examination in neurological patients. J Neurol Neuro-
improved the sensitivity to 0.82 with no loss of surg Psychiatry 1984; 47: 496–9.
specificity. In the author’s clinic, in 154 consecutive Folstein MF, Folstein SE, McHugh PR. ‘Mini-Mental State’:
a practical method for grading the cognitive state of
patients, of whom 51% had a dementia syndrome,
patients for the clinician. J Psychiatr Res 1975; 12: 189–98.
sensitivity and specificity for MMSE cutoff scores of
Galasko D, Klauber MR, Hofstetter CR, et al. The Mini-
27 and 24 for a diagnosis of dementia were 0.91 and
Mental State Examination in the early diagnosis of
0.70, and 0.73 and 0.86, respectively, giving positive Alzheimer’s disease. Arch Neurol 1990; 47: 49–52.
and negative likelihood ratios (with 95% confidence Han L, Cole M, Bellevance F, McCusker J, Primeau F.
intervals, log method) of 3.04 (2.14–4.31) and 0.13 Tracking cognitive decline in Alzheimer’s disease using
(0.09–0.18), and 5.09 (2.90–8.95) and 0.32 (0.18–0.56), the Mini-Mental State Examination: a meta-analysis. Int
respectively, hence moderate values for MMSE > 27 Psychogeriatr 2000; 12: 231–47.
excluding dementia and MMSE < 24 diagnosing Harrell LE, Marson D, Chatterjee A, Parrish JA. The Severe
dementia (Larner, 2005). Diagnostic odds ratio, a Mini-Mental State Examination: a new neuropsycho-
summary measure of test diagnostic performance, logical instrument for the bedside assessment of
severely impaired patients with Alzheimer’s disease.
for MMSE cutoff of 27 was 23.5.
Alzheimer Dis Assoc Disord 2000; 14: 168–75.
A subscore from the MMSE has been suggested to
Holmes C, Lovestone S. Long-term cognitive and func-
be helpful in the differential diagnosis of dementia,
tional decline in late onset Alzheimer’s disease: thera-
specifically of AD from dementia with Lewy bodies peutic implications. Age Ageing 2003; 32: 200–4.
(DLB), based on the greater impairment of atten- Kukull WA, Larson EB, Teri L, et al. The Mini-Mental State
tional and visuospatial function and the relative Examination score and the clinical diagnosis of demen-
preservation of memory in DLB as compared to tia. J Clin Epidemiol 1994; 47: 1061–7.
AD, calculated using the equation [attention – Larner AJ. MMSE subscores and the diagnosis of dementia
5/3 · memory þ 5 · construction]. A subscore of < 5 with Lewy bodies. Int J Geriatr Psychiatry 2003; 18: 855–6.
was reported in a small retrospective series of Larner AJ. Use of MMSE to differentiate Alzheimer’s
pathologically confirmed cases of AD and DLB disease from dementia with Lewy bodies. Int J Geriatr
Psychiatry 2004; 19: 1209–10.
to have sensitivity of 0.82 and specificity of 0.81 for
Larner AJ. An audit of the Addenbrooke’s Cognitive
DLB (Ala et al., 2002), hence positive likelihood ratio
Examination (ACE) in clinical practice. Int J Geriatr
(LRþ) ¼ 4.45 (small) and negative likelihood ratio
Psychiatry 2005; 20: 593–4.
(LR) ¼ 0.22 (small). This subscore has not been Larner AJ, Doran M. Broader assessment needed for
found helpful for differential diagnosis in a pro- treatment decisions in AD. Prog Neurol Psych 2002; 6
spective study of a large (n ¼ 285) clinically diag- (3): 5–6.
nosed cohort (Larner, 2003, 2004). Levin P (ed.). The Penguin Book of the Sonnet: 500 years of a
classic tradition in English. London: Penguin, 2001: 334.
Molloy DW, Alemayehu E, Roberts R. Reliability of a
Standardized Mini-Mental State Examination compared
REFERENCES with the traditional Mini-Mental State Examination. Am
J Psych 1991; 148: 102–5.
Ala T, Hughes LF, Kyrouac GA, Ghobrial MW, Elble RJ. The Tangalos EG, Smith GE, Ivnik RJ, et al. The Mini-Mental
Mini-Mental State exam may help in the differentiation State Examination in general medical practice: clinical
of dementia with Lewy bodies and Alzheimer’s disease. utility and acceptance. Mayo Clin Proc 1996; 71: 829–37.
Int J Geriatr Psychiatry 2002; 17: 503–9. Teng EL, Chui HC. The modified Mini-Mental State (3MS)
Crum RM, Anthony JC, Bassett SS, Folstein MF. Popula- Examination. J Clin Psychiatry 1987; 48: 314–18.
tion-based norms for the Mini-Mental State Examina- Tombaugh TN, McIntyre NJ. The Mini-Mental State
tion by age and educational level. JAMA 1993; 269: Examination: a comprehensive review. J Am Geriatr
2386–91. Soc 1992; 40: 922–35.
1.8.2 Clock drawing Sociodemographic determinants in an elderly popula-

tion sample. Br J Clin Psychol 1995; 34: 529–41.
Clock drawing has a long history as a test for cognitive Larner AJ. Of clocks and mirrors: the Backward Clock Test.
impairment and remains popular (Freedman et al., Eur J Neurol 2007; 14 (suppl 1): 100 (abstract P1265).
1994; Shulman & Feinstein, 2003). It has the advan- Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W,
tage of being quick and simple, and tests a wide range Hodges JR. A brief cognitive test battery to differentiate
of cognitive domains (a ‘diffuse’ screening test) Alzheimer’s disease and frontotemporal dementia.
including auditory comprehension, memory, execu- Neurology 2000; 55: 1613–20.
tive control (planning), and visuospatial abilities, as Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The
well as motor skills. However, this very breadth poses Addenbrooke’s Cognitive Examination Revised (ACE-R):
a brief cognitive test battery for dementia screening. Int
problems when interpreting and scoring clock
J Geriatr Psychiatry 2006; 21: 1078–85.
drawing, to encompass both quantitative and quali-
Morris J, Heyman A, Mohs R, et al. The Consortium to
tative features. Nonetheless, most scoring systems
Establish a Registry for Alzheimer’s Disease (CERAD).
are reported to achieve a sensitivity and specificity of Part I. Clinical and neuropsychological assessment of
around 0.85. Clock drawing has been incorporated in Alzheimer’s disease. Neurology 1989; 39: 1159–65.
other screening and diagnostic tests such as the Royall DR, Cordes JA, Polk M. CLOX: an executive clock
CERAD (Morris et al., 1989), CAMCOG (Huppert drawing task. J Neurol Neurosurg Psychiatry 1998; 64:
et al., 1995), Mini-Cog (Borson et al., 2000), and the 588–94.
ACE (Mathuranath et al., 2000) and ACE-R (Mioshi Shulman K, Feinstein A. Quick Cognitive Screening for
et al., 2006). It may address a deficiency in many Clinicians: Mini Mental, Clock Drawing and Other Brief
other brief cognitive tests through its probing of Tests. London: Martin Dunitz, 2003: 43–78.
executive function (Royall et al., 1998), but it may
have limitations in detecting mild dementia or MCI. 1.8.3 Queen Square Screening Test for
A Backward Clock Test, using the mirror image of Cognitive Deficits
a normal analogue clock, in which patients are
For generations of neurological trainees at the
required to read strings of times shown either
National Hospital for Neurology and Neurosurgery in
backward ( ¼ backward clock, or normal analogue
London, the Queen Square Screening Test for Cog-
clock viewed, Alice Through the Looking Glass style,
nitive Deficits (QSSTCD), often known as the ‘green
in a mirror) or forward (¼ normal analogue clock, or
book’, has been the standard bedside neuropsycho-
backward clock viewed in a mirror), may likewise be
logy test instrument (Warrington, 1989). Although
useful as a ‘diffuse’ test, differentiating patients with
entirely qualitative, it is useful in giving pointers to
focal cognitive deficits from those with global
the localization of any cognitive deficits.
impairments (i.e. dementia: Larner, 2007).
REFERENCES
REFERENCES
Warrington EK. The Queen Square Screening Test for

Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog:
Cognitive Deficits. London: Institute of Neurology, 1989.
a cognitive ‘vital signs’ measure for dementia screening
in multi-lingual elderly. Int J Geriatr Psychiatry 2000; 15:
1021–7. 1.8.4 Addenbrooke’s Cognitive Examination
Freedman M, Leach L, Kaplan E, et al. Clock Drawing: a (ACE) and Addenbrooke’s Cognitive
Neuropsychological Analysis. New York: Oxford Univer-
Examination–Revised (ACE-R)
sity Press, 1994.
Huppert FA, Brayne CA, Gill C, et al. CAMCOG: a concise This theoretically motivated development of the
neuropsychological test to assist dementia diagnosis. MMSE incorporates more material to address the
acknowledged shortcomings of the MMSE, sensitivity and specificity in a selected university

particularly with respect to testing of memory, hospital clinic population. These results were
visuospatial function, and executive function largely replicated in a pragmatic study in an
(Mathuranath et al., 2000; Nestor & Hodges, 2001). unselected clinic population (AUC ¼ 0.95; 95% CI
The ACE has been widely adopted and translated 0.90–0.99), but with the suggestion that a lower
into various languages (Mathuranath et al., 2004; cutoff may be required, since day-to-day clinical
Bier et al., 2005; Larner, 2005, 2006, 2007a; Garcia- practice permits no exclusion criteria and has no
Caballero et al., 2006). The ACE is also reported to be population preselected as ‘normal’ (Larner, 2007b).
useful in detecting the cognitive features of atypical
parkinsonian syndromes (Bak et al., 2005a,b) and in
differentiating dementia from affective disorder REFERENCES
(Dudas et al., 2005).
For an ACE cutoff score of 88 the index paper Bak TH, Crawford LM, Hearn VC, Mathuranath PS,
reported sensitivity of 0.93 and specificity of 0.71, Hodges JR. Subcortical dementia revisited: similarities
and differences in cognitive function between progres-
while for a cutoff score of 83 sensitivity was 0.82 and
sive supranuclear palsy (PSP), corticobasal degenera-
specificity 0.96, in a cohort of 139 patients
tion (CBD) and multiple system atrophy (MSA).
(Mathuranath et al., 2000). The study by Bier et al.
Neurocase 2005b; 11: 268–73.
(2004) (n ¼ 79) also found high sensitivities (1.0 and Bak TH, Rogers TT, Crawford LM, et al. Cognitive bedside
0.9 for cutoffs of 88 and 83, respectively) but lower assessment in atypical parkinsonian syndromes.
specificities (0.46 and 0.64). In the author’s clinic, in J Neurol Neurosurg Psychiatry 2005a; 76: 420–2.
154 consecutive patients, of whom 51% had a Bier JC, Ventura M, Donckels V, et al. Is the Adden-
dementia syndrome, sensitivity and specificity for brooke’s Cognitive Examination effective to detect
an ACE cutoff score of 88 were 0.97 and 0.47, with frontotemporal dementia? J Neurol 2004; 251: 428–31.
0.92 and 0.62 for a cutoff score of 83, giving positive Bier JC, Donckels V, Van Eyll E, et al. The French
and negative likelihood ratios (with 95% confidence Addenbrooke’s Cognitive Examination is effective in
detecting dementia in a French-speaking population.
intervals, log method) of 1.83 (1.48–2.26) and 0.06
Dement Geriatr Cogn Disord 2005; 19: 15–17.
(0.05–0.07), and 2.45 (1.82–3.29) and 0.13 (0.10–0.17),
Dudas RB, Berrios GE, Hodges JR. The Addenbrooke’s
respectively, hence large values for ACE > 88
Cognitive Examination (ACE) in the differential diagno-
excluding dementia (Larner, 2005). Diagnostic odds sis of early dementias versus affective disorder. Am J
ratio for ACE cutoff of 88 was 32.9. Geriatr Psychiatry 2005; 13: 218–26.
As well as proving useful for the early diagnosis of Garcia-Caballero A, Garcia-Lado I, Gonzalez-Hermida J,
dementia, a subscore derived from the ACE, the et al. Validation of the Spanish version of the Adden-
VLOM ratio, may be calculated from the scores of the brooke’s Cognitive Examination in a rural community
subtests [verbal fluency þ language] / [orientation þ in Spain. Int J Geriatr Psychiatry 2006; 21: 239–45.
delayed recall], to differentiate AD (VLOM ratio > 3.2) Larner AJ. An audit of the Addenbrooke’s Cognitive
from FTD (VLOM ratio < 2.2). In the index paper Examination (ACE) in clinical practice. Int J Geriatr
Psychiatry 2005; 20: 593–4.
(Mathuranath et al., 2000), VLOM ratio > 3.2 showed
Larner AJ. An audit of the Addenbrooke’s Cognitive
sensitivity of 0.75 and specificity of 0.84 for the diag-
Examination (ACE) in clinical practice. 2. Longitudinal
nosis of AD. Figures for the diagnostic utility of VLOM
change. Int J Geriatr Psychiatry 2006; 21: 698–9.
ratio > 3.2 for the diagnosis of AD were confirmed in Larner AJ. Addenbrooke’s Cognitive Examination (ACE)
independent cohorts but these studies also found low for the diagnosis and differential diagnosis of dementia.
sensitivity of VLOM < 2.2 for the diagnosis of FTD Clin Neurol Neurosurg 2007a; 109: 491–4.
(Bier et al., 2004; Larner, 2005, 2007a). Larner AJ. Addenbrooke’s Cognitive Examination-Revised
Recently, a revised version of the ACE, ACE-R, has (ACE-R) in day-to-day clinical practice. Age Ageing
been published (Mioshi et al., 2006), with excellent 2007b; 36: 685–6.
Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Kalbe E, Kessler J, Calabrese P, et al. DemTect: a new,
Hodges JR. A brief cognitive test battery to differentiate sensitive cognitive screening test to support the diag-
Alzheimer’s disease and frontotemporal dementia. nosis of mild cognitive impairment and early dementia.
Neurology 2000; 55: 1613–20. Int J Geriatr Psychiatry 2004; 19: 136–43.
Mathuranath PS, Hodges JR, Mathew R, et al. Adaptation of Larner AJ. DemTect in the diagnosis of dementia: first 100
the ACE for a Malayalam speaking population in patients. Alzheimers Dement 2006; 2 (suppl 1): S375
southern India. Int J Geriatr Psychiatry 2004; 19: 1188–94. (abstract P3–012).
Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Larner AJ. DemTect: 1-year experience of a neuropsycho-
Addenbrooke’s Cognitive Examination Revised (ACE-R): logical screening test for dementia. Age Ageing 2007; 36:
a brief cognitive test battery for dementia screening. Int 326–7.
J Geriatr Psychiatry 2006; 21: 1078–85. Scheurich A, Muller MJ, Slessmeier T, et al. Validating the
Nestor P, Hodges JR. The clinical approach to assessing DemTect with 18-fluoro-2-deoxy-glucose positron
patients with early onset dementia. In: Hodges JR (ed.), emission tomography as a sensitive neuropsychological
Early-Onset Dementia: a Multidisciplinary Approach. scree-ning test for early Alzheimer disease in patients of
Oxford: Oxford University Press, 2001: 23–46. a memory clinic. Dement Geriatr Cogn Disord 2005; 20:
271–7.
1.8.5 DemTect
1.8.6 Dementia Rating Scale (DRS)
DemTect is a brief screening test for dementia
comprising five subtests: repetition of 10-word list, The Mattis Dementia Rating Scale (DRS: Mattis,
number transcoding, semantic word fluency task, 1976, 1992), and its successor DRS-2, comprise a
backward digit span, and delayed recall of the initial number of subtests (attention, initiation, construc-
10-word list. Raw scores are transformed to give a tion, conceptualization, memory) to give a global
final score, maximum 18, which is independent of measure of dementia (score 0–144) and take about
age and educational level, with classification as 30 minutes to perform. Normative data are available
‘suspected dementia’ (score 8), ‘mild cognitive (Lucas et al., 1998). DRS is useful in detecting cog-
impairment’ (9–12), and ‘appropriate for age’ (13–18) nitive impairment and is sensitive to the early stages
(Kalbe et al., 2004). In the index study the sensitivity of dementia. The assessment of a range of cognitive
and specificity for AD were reported to be 100% and abilities suggests that the DRS may be useful in
92% respectively, and in a validation study (n ¼ 38) longitudinal tracking of cognitive change. More-
with 18FDG-PET imaging area under the ROC curve over, DRS was designed to assist in the differential
(AUC) was 0.85 (95% CI 0.73–0.97: Scheurich et al., diagnosis of dementia syndromes (e.g. Rosser &
2005). In the author’s clinic, a study of 111 con- Hodges, 1994; Donnelly & Grohman, 1999; Lukatela
secutive referrals, of whom 52% had a dementia et al., 2000). It is reported to be able to distinguish
syndrome, found sensitivity and specificity for subcortical diseases from AD (Bak et al., 2005).
dementia of 85% and 72% respectively, with AUC of
0.87 (95% CI 0.80–0.93: Larner 2006, 2007). Use of
DemTect has also been reported in CADASIL, a REFERENCES
subcortical dementia (Hennerici et al., 2006).
Bak TH, Crawford LM, Hearn VC, Mathuranath PS,
Hodges JR. Subcortical dementia revisited: similarities
REFERENCES sive supranuclear palsy (PSP), corticobasal degener-
ation (CBD) and multiple system atrophy (MSA).
Hennerici MG, Daffertshofer M, Caplan LR, Szabo K. Case Neurocase 2005; 11: 268–73.
Studies in Stroke: Common and Uncommon Presenta- Donnelly K, Grohman K. Can the Mattis Dementia Rating
tions. Cambridge: Cambridge University Press, 2006: Scale differentiate Alzheimer’s disease, vascular dementia,
137 [Case 31]. and depression in the elderly? Brain Cogn 1999; 39: 60–3.
Lucas JA, Ivnik RJ, Smith GE, et al. Normative data for the 1989) incorporates the MMSE and other subtests of
Mattis Dementia Rating Scale. J Clin Exp Neuropsychol memory, naming, and verbal fluency.
1998; 20: 536–47.
Lukatela K, Cohen RA, Kessler H, et al. Dementia Rating
Scale performance: a comparison of vascular and REFERENCES
Alzheimer’s dementia. J Clin Exp Neuropsychol 2000;
22: 445–54. Morris J, Heyman A, Mohs R, et al. The Consortium to
Mattis S. Mental status examination for organic mental syn- Establish a Registry for Alzheimer’s Disease (CERAD).
drome in the elderly. In: Bellack R, Karasu B (eds.), Geriatric Part I. Clinical and neuropsychological assessment of
Psychiatry. New York: Grune & Stratton, 1976: 77–121. Alzheimer’s disease. Neurology 1989; 39: 1159–65.
Mattis S. Dementia Rating Scale. Windsor: NFER-Nelson,
1992.
1.8.9 Clinical Dementia Rating (CDR)
Rosser AE, Hodges JR. The Dementia Rating Scale in
Alzheimer’s disease, Huntington’s disease and progres- Although this is a global staging measure, rather than
sive supranuclear palsy. J Neurol 1994; 241: 531–6. a purely neuropsychological test instrument (Hughes
et al., 1982; Morris, 1993), it is included here because
of the prominence which it has gained in the defini-
1.8.7 ADAS-Cog tion of mild cognitive impairment (MCI: see Section
The Alzheimer’s Disease Assessment Scale–Cognitive 2.6). It is based on both patient assessment and
Section (ADAS-Cog: Rosen et al., 1984) has become a caregiver interview, rating memory, orientation,
widely used reference measure, for example as an judgment and problem solving, community affairs,
outcome measure of drug efficacy in clinical trials home and hobbies, and personal care. About 40
practice. Memory, attention, learning, and orienta- minutes is needed to gather the required infor-
tion are among the domains examined, the final mation. Ratings range from 0 to 3. A CDR score of 0.5
score (0–70) being higher for more severe impair- (questionable dementia) correlates, although is not
ment. Since the ADAS-Cog takes significantly longer necessarily synonymous, with MCI. A CDR score of
to perform than the MMSE (30–45 minutes) it may 1 has a good sensitivity and specificity in screening
not be practical for use in day-to-day clinical prac- for dementia (Juva et al., 1995), and the test is reliably
tice. A ‘calculator’ to convert MMSE scores to and consistently scored (Schafer et al., 2004).
equivalent ADAS-Cog scores is available, reflecting
the strong correlation between ADAS-Cog and REFERENCES
MMSE scores (Doraiswamy et al., 1997).
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A
new clinical scale for the staging of dementia. Br J
REFERENCES Psychiatry 1982; 140: 566–72.
Juva K, Sulkava R, Erkinjuntti T, et al. Usefulness of the
Clinical Dementia Rating scale in screening for demen-
Doraiswamy PM, Bieber F, Kaiser L, et al. The Alzheimer’s
tia. Int Psychogeriatr 1995; 7: 17–24.
Disease Assessment Scale: patterns and predictors of
Morris J. The CDR: current version and scoring rules.
baseline cognitive performance in multicenter Alzhei-
Neurology 1993; 43: 2412–14.
mer’s disease trials. Neurology 1997; 48: 1511–7.
Schafer KA, Tractenberg RE, Sano M, et al. Reliability of
Rosen WG, Mohs RC, Davis KL. A new rating scale for
monitoring the clinical dementia rating in multicenter
Alzheimer’s disease. Am J Psych 1984; 141: 1356–64.
clinical trials. Alzheimer Dis Assoc Disord 2004; 18: 219–22.
1.8.8 CERAD battery 1.8.10 Global Deterioration Scale (GDS)

The Consortium to Establish a Registry for Like CDR, the Global Deterioration Scale (GDS) is a
Alzheimer’s Disease (CERAD) battery (Morris et al., staging instrument for cognitive and functional
capacity over a seven-point scale (Reisberg et al., Hancock P, Larner AJ. The diagnosis of dementia:
1982). A GDS score of 3 has been used in some diagnostic accuracy of an instrument measuring activi-
centres to define MCI, but similar caveats apply as ties of daily living in a clinic-based population. Dement
with CDR ¼ 0.5. Geriatr Cogn Disord 2007; 23: 133–9.
Lawton MP, Brody EM. Assessment of older people: self-
maintaining and instrumental activities of daily living.
REFERENCES Gerontologist 1969; 9: 176–85.
Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global

Deterioration Scale (GDS) for assessment of primary
degenerative dementia. Am J Psych 1982; 139: 1136–9. 1.9 Normal aging
Various changes in neurological function occur with

1.8.11 Instrumental Activities of Daily Living increasing age, motor, sensory, and cognitive (Larner,
(IADL) scale 2006; Peters, 2006). To what extent these changes
Since the canonical definition of dementia (see reflect ‘normal aging’, however that may be defined,
Section 1.10) encompasses not only cognitive or to what extent they reflect an increasing burden of
impairment but also impairments in social and age-related neurological disease, remains uncertain.
occupational function as a consequence of the cog- In consequence, the inevitable physiological changes
nitive decline, it might be argued that ADL scales that occur in cognition with increasing age may be
could serve as independent diagnostic tests for difficult to distinguish from the earliest stages of
dementia equally as well as cognitive tests. Certainly pathological brain disorders causing cognitive
in epidemiological studies, loss of certain instru- impairments.
mental activities of daily living (such as independent A distinction may be drawn between ‘crystallized
use of the telephone, ability to travel alone on per- intelligence’, characterized by practical problem-
sonal or public transport, and responsibility for solving skills, knowledge gained from experience, and
supervising medications and finances) have proven vocabulary, and ‘fluid intelligence’, characterized by
predictive of a diagnosis of dementia (Barberger- the ability to acquire and use new information, as
Gateau et al., 1992; De Lepeleire et al., 2004). In a measured by the solution of abstract problems and
clinic-based population, however, use of the physical speeded performance (Horn & Cattell, 1967). Crys-
self-maintenance and instrumental activities of daily tallized intelligence is assumed to be cumulative:
living scale of Lawton and Brody (1969), or parts longitudinal studies of vocabulary, for example, show
thereof, had a low diagnostic accuracy for the diagno decline through old age. By contrast, fluid intelli-
nosis of dementia (AUC ¼ 0.75), principally because gence does change with age: performance on tests
many people adjudged demented by DSM-IV criteria such as Raven’s Progressive Matrices and Digit
were at ceiling on this scale (Hancock & Larner, 2007). Symbol substitution declines marginally up to the age
of 40 years and then more rapidly (Salthouse, 1982).
There is general consensus that typical cognitive aging
REFERENCES
involves losses in processing speed, cognitive flexi-
bility, and the efficiency of working memory (sus-
Barberger-Gateau P, Commenges D, Gagnon M, et al.
tained attention). In other words, it may take more
Instrumental activities of daily living as a screening tool
time and/or more trials to learn new information.
for cognitive impairment and dementia in elderly
community dwellers. J Am Geriatr Soc 1992; 40: 1129–34. Cognitive domains such as access to remotely learned
De Lepeleire J, Aertgeerts B, Umbach I, et al. The diagnostic information, including semantic networks, and
value of IADL evaluation in the detection of dementia in retention of well-encoded new information are spared
general practice. Aging Ment Health 2004; 8: 52–7. with typical aging; this may permit testing of these
domains to be used as sensitive indicators of disease Larner AJ. Neurological signs of aging. In: Pathy MSJ,
processes (Smith & Ivnik, 2003). It may be that Sinclair AJ, Morley JE (eds.), Principles and Practice of
memory decline in healthy aging is secondary to Geriatric Medicine (4th edition). Chichester: Wiley,
decline in processing speed and efficiency, since 2006: 743–50.
Nicholson K, Martelli MF, Zasler ND. Does pain confound
controlling for processing speed may attenuate or
interpretation of neuropsychological test results? Neuro
eliminate age-related differences in memory per-
Rehabilitation 2001; 16: 225–30.
formance, unlike the situation with memory impair-
Peters R. Ageing and the brain. Postgrad Med J 2006; 82:
ment in dementia (Sliwinski et al., 2003). 84–8.
Longitudinal studies of neuropsychological func- Salthouse TA. Adult Cognition. New York: Springer, 1982.
tion in older Americans indicate that there is con- Sliwinski M, Lipton R, Buschke H, Wasylyshyn C. Opti-
siderable variability in normal older adults across mizing cognitive test norms for detection. In: Petersen
different skills, and consistency across different RC (ed.), Mild Cognitive Impairment: Aging to Alzheimer’s
domains may not necessarily be observed (Smith & Disease. Oxford: Oxford University Press, 2003: 89–104.
Ivnik, 2003). Clearly this needs to be taken into Smith GE, Ivnik RJ. Normative neuropsychology. In:
account when assessing whether perceived cognitive Petersen RC (ed.), Mild Cognitive Impairment: Aging to
Alzheimer’s Disease. Oxford: Oxford University Press,
decline is pathological or normal, that is in defining
2003: 63–88.
neuropsychological norms for aging. Furthermore,
norms for IQ are increasing over time (Deary, 2001).
Likewise, norms may need to be age-weighted rather 1.10 Dementia, delirium, depression
than age-corrected to detect cognitive impairment
related to Alzheimer’s disease (Sliwinski et al., 2003), The diagnosis of dementia is currently based on
the prevalence of which increases exponentially with fulfilment of clinical diagnostic criteria, for example
increasing age. Many other situational influences those in the generic Diagnostic and Statistical
may also impact on testing of cognitive skills, such as Manual (DSM), the International Classification of
fatigue, emotional status, medication use, pain Diseases (ICD), or dedicated criteria for specific
(Nicholson et al., 2001), and stress. These also need to dementia subtypes. DSM-IV (American Psychiatric
be taken into account when considering the results of Association, 1994), for example, requires the devel-
cognitive testing, as may factors such as educational opment of multiple cognitive deficits that include
and background experience. Many norms are also memory impairment, of gradual onset and pro-
culturally weighted. gressive course, sufficiently severe to cause impair-
Notwithstanding these difficulties, the definition ment in occupational or social functioning, not
of a syndrome or syndromes of cognitive impairment better accounted for by another diagnosis. However,
greater than expected for age, which are the harbin- application of such criteria to large cohorts of
gers of progressive cognitive decline, the prodromal patients may classify different numbers of patients
phases of neurodegenerative disorder, may now be as having dementia, with differences up to a factor
identifiable, with all the consequent ramifications for of 10 found in one study (Erkinjuntti et al., 1997).
potential therapeutic intervention (see Section 2.6). One reason for this variability is that many of these
criteria are heavily weighted toward memory
impairment. Because memory impairment is the
REFERENCES most salient feature in Alzheimer’s disease, the most
common cause of dementia, many diagnostic cri-
Deary IJ. Intelligence: a Very Short Introduction. Oxford: teria, for example those for vascular dementia, have
Oxford University Press, 2001: 102–13. been inadvertently ‘Alzheimerized’, with undue
Horn JL, Cattell RB. Age difference in fluid and crystallized emphasis placed on memory loss at the expense of
intelligence. Acta Psychol 1967; 26: 107–29. other clinical features (Bowler & Hachinski, 2003).
A ‘type 2 dementia’, which unlike ‘type 1 dementia’ imagined that attentional mechanisms in dementia
is lacking cortical features such as amnesia, has are normal, thereby permitting a clear-cut distinc-
been proposed, in which demonstrable executive tion between delirium and dementia. This is not the
control function impairments are sufficient to cause case: attentional mechanisms may not be normal in
disability (Royall, 2006). Another potentially con- dementia syndromes (e.g. divided and selective
fusing outcome of the emphasis of diagnostic cri- attention in Alzheimer’s disease); indeed in some
teria on memory is that syndromes with a diagnostic (e.g. dementia with Lewy bodies), attentional
label of dementia, such as frontotemporal demen- dysfunction is central to the diagnosis.
tia, may not fulfil diagnostic crtieria for dementia in Affective disorder, principally in the form of major
their early stages because the initial features are depression, may be associated with impairment of
executive (frontal) dysfunction and non-cognitive cognitive functions. Terms used to describe this
behavioural change (Mendez et al., 2006). Tautology clinical entity have included pseudodementia,
may also occur simply as a reflection of the fact that dementia syndrome of depression, and depression-
unequivocal cognitive deficits may not be sufficient related cognitive dysfunction (Kiloh, 1961; Wells, 1979;
to meet criteria for dementia (e.g. in mild cognitive Roose & Devanand, 1999; Shanmugham & Alex-
impairment: see Section 2.6). opoulos, 2005). To ascertain with certainty whether
Other diagnoses may also be confused with manifest cognitive decline, particularly in elderly
dementia, necessitating consideration in the dif- patients, results from depression or from an under-
ferential diagnosis, most particularly delirium and lying neurodegenerative disorder is one of the greatest
depression. Cognitive deficits, particularly those of challenges facing the clinician in the memory clinic
acute onset in an elderly person, should not (Christensen et al., 1997). Moreover, depression may
immediately lead to a diagnosis of dementia unless be an integral part of many neurological disorders,
delirium has been excluded, since a degree of including dementia syndromes, not simply a reaction
reversibility of cognitive deficits may be possible to diagnosis and neurological impairment (Kanner,
with correction of the precipitating factors of delir- 2005). Neuropsychological test results may not reliably
ium. Impairments of consciousness, a sine qua non discriminate, although some have been claimed to
for the diagnosis of delirium (see Section 1.1), may do so (e.g. ACE: Dudas et al., 2005; CANTAB-PAL:
be subtle. Furthermore, delirium may be the pre- Swainson et al., 2001). An empirical trial of anti-
senting feature of an underlying dementia syn- depressant medication may be given, but even clinical
drome (Robertsson et al., 1998; Rockwood et al., improvement may not absolutely establish the diag-
1999). In other words, dementia may be a predis- nosis; prolonged follow-up may be required. Pro-
posing factor for delirium, presumably because gressive cognitive decline may also be a feature of the
cerebral reserve is reduced and hence the brain is natural history of schizophrenia (Almeida & Howard,
less able to cope with additional precipitating fac- 2005; Al-Uzri et al., 2006; Morrison et al., 2006).
tors, of which infection or metabolic derangement
are the most common (Lindesay et al., 2002; Larner,
2004). One study found that around one quarter of
REFERENCES
AD patients had an episode of delirium during the
course of their illness (Baker et al., 1999). Guidelines
Almeida OP, Howard R. Schizophrenia, cognitive impair-
for the prevention, diagnosis, and treatment of ment and dementia. In: Burns A, O’Brien J, Ames D
delirium have been published (e.g. Royal College of (eds.), Dementia (3rd edition). London: Hodder Arnold,
Physicians, 2006). 2005: 750–3.
It may also be pointed out that since dementia Al-Uzri MM, Reveley MA, Owen L, et al. Measuring
may be defined as an acquired syndrome of cogni- memory impairment in community-based patients
tive impairment in a clear sensorium, it might be with schizophrenia. Br J Psychiatry 2006; 189: 132–6.
1.11 Cortical versus subcortical dementias 35
American Psychiatric Association. Diagnostic and Statis- and Related Disorders Annual 5. London: Taylor &
tical Manual of Mental Disorders. Washington, DC: Francis, 2006: 35–62.
American Psychiatric Association, 1994. Shanmugham B, Alexopoulos G. Depression with cogni-
Baker FM, Wiley C, Kokmen E, Chandra V, Schoenberg BS. tive impairment. In: Burns A, O’Brien J, Ames D (eds.),
Delirium episodes during the course of clinically Dementia (3rd edition). London: Hodder Arnold, 2005:
diagnosed Alzheimer’s disease. J Natl Med Assoc 1999; 731–7.
91: 625–30. Swainson R, Hodges JR., Galton CJ, et al. Early detection
Bowler JV, Hachinski V. Current criteria for vascular and differential diagnosis of Alzheimer’s disease and
dementia: a critical appraisal. In: Bowler JV, Hachinski V depression with neuropsychological tests. Dement
(eds.), Vascular Cognitive Impairment: Reversible Geriatr Cogn Disord 2001; 12: 265–80.
Dementia. Oxford: Oxford University Press, 2003: 1–11. Wells CE. Pseudodementia. Am J Psych 1979; 136: 895–900.
Christensen H, Griffiths K, MacKinnon A. A quantitative
review of cognitive deficits in depression and Alzheimer-
type dementia. J Int Neuropsychol Soc 1997; 3: 631–51.
1.11 Cortical versus subcortical dementias,
Dudas RB, Berrios GE, Hodges JR. The Addenbrooke’s
thalamic dementia
Cognitive Examination (ACE) in the differential diagno-
sis of early dementias versus affective disorder. Am J
Geriatr Psychiatry 2005; 13: 218–26.
Albert et al. (1974) first used the term ‘subcortical
Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The dementia’ to describe the cognitive impairments
effect of different diagnostic criteria on the prevalence seen in progressive supranuclear palsy: forgetful-
of dementia. N Engl J Med 1997; 337: 1667–74. ness, slowness of thought processes (bradyphrenia),
Kanner AM. Depression in Neurological Disorders. Cam- alteration of personality with marked apathy and
bridge: Lundbeck, 2005. depression, and an impaired ability to manipulate
Kiloh L. Pseudodementia. Acta Psychiatr Scand 1961; 37: acquired knowledge. These deficits were felt to be
336–51. qualitatively distinct from those seen in cortical
Larner AJ. Delirium: diagnosis, aetiopathogenesis and
dementias, typically Alzheimer’s disease, which
treatment. Adv Clin Neurosci Rehabil 2004; 4 (2): 28–9.
include impairments in language (aphasia), mem-
Lindesay J, Rockwood K, Macdonald A (eds.). Delirium in
ory (amnesia), perception (agnosia), and skilled
Old Age. Oxford: Oxford University Press, 2002.
Mendez MF, McMurtray A, Licht EA, Saul RE, Miller BL. Is
learned movements (apraxia). The term ‘limbic
early frontotemporal dementia a dementia? Alzheimers dementia’ has sometimes been used for syndromes
Dement 2006; 2 (suppl 1): S548 (abstract P4–112). with marked amnesia and evidence for limbic sys-
Morrison G, O’Carroll R, McCreadie R. Long-term course tem pathology such as Alzheimer’s disease.
of cognitive impairment in schizophrenia. Br J Psych- Whereas cueing or recognition paradigms could
iatry 2006; 189: 556–7. improve performance in delayed recall memory
Robertsson B, Blennow K, Gottfries CG, Wallin A. Delirium tests in subcortical dementias, suggesting ineffect-
in dementia. Int J Geriatr Psychiatry 1998; 13: 49–56. ive retrieval but with relatively preserved encoding
Rockwood K, Cosway S, Carver D, et al. The risk of
of material, in cortical dementias such strategies
dementia and death following delirium. Age Ageing
were ineffective, suggesting impaired encoding as
1999; 28: 551–6.
well as retrieval. The term ‘subcortical’ was selected
Roose SP, Devanand DP. The Interface Between Dementia
and Depression. London: Martin Dunitz, 1999.
because of the resemblance of the deficits to those
Royal College of Physicians. The Prevention, Diagnosis seen with bifrontal lobe disease, also reflected in the
and Management of Delirium in Older People. London: concurrent emotional and movement deficits in
Royal College of Physicians, 2006. the two types: subcortical dementias tended to be
Royall DR. Executive control function in ‘mild’ cognitive associated with apathy and depression and promi-
impairment and Alzheimer’s disease. In: Gauthier S, nent disorders of muscle tone, posture, and gait,
Scheltens P, Cummings JL (eds.), Alzheimer’s Disease whereas cortical dementias were attended with
cognitive anosognosia and disinhibition and an integrative function, reciprocally linking cortical
absence of movement disorder (Cummings, 1990). and subcortical structures, white matter pathology
Prototypical subcortical dementias were said to might be expected to result in functional discon-
occur in Huntington’s disease (McHugh & Folstein, nection of brain areas, and disordered brain func-
1975) and Parkinson’s disease (Starkstein & Merello, tion at a site distant from a lesion (diaschisis) is a
2002). It has been hypothesized that the basal ganglia, well-recognized phenomenon (see Section 1.12).
in addition to their role in movement, support a basic This may be seen with frontal lobe dysfunction in
attentional mechanism, facilitating the synchroniza- multiple sclerosis (Foong et al., 1997) and has also
tion of cortical activity underlying the selection and been suggested in X-linked adrenoleukodystrophy
promulgation of an appropriate sequence of (Larner, 2003a). Identical or similar clinical pheno-
thoughts; this ‘focused attention’ differs from arousal, types may result from pathologies affecting either
vigilance, or alertness. Basal ganglia damage thus grey matter or subjacent white matter (e.g. sub-
results in a failure of synchronization, manifest as cortical aphasias: Benson & Ardila, 1996). Against
abulia and bradyphrenia (Brown & Marsden, 1998). this argument, however, false localization of
The ‘white matter’ dementia occurring in, for neurological signs usually deemed indicative of
example, some patients with multiple sclerosis may higher, cortical cognitive function (e.g. agnosia,
have similar neuropsychological features (Rao, 1996). neglect) is rarely reported (Larner, 2003b, 2005).
White matter cognitive impairments have been Whatever the precise physiological relationship,
extensively documented by Filley (2001). nonetheless, the cortical/subcortical terminology
An entity called thalamic dementia is also men- may still have some clinical utility in the differential
tioned in the literature (Stern, 1939), referring to diagnosis of dementia syndromes (e.g. Neary &
cognitive impairments in conditions with relatively Snowden, 2002; Bak et al., 2005).
selective thalamic damage. Most commonly this is
due to vascular lesions (see Section 3.3.3) or neo-
plasia, but in addition relatively selective degenera-
REFERENCES
tion of the thalamus may occur. This may mostly be
due to prion disease (Petersen et al., 1992) such as
Albert ML, Feldman RG, Willis AL. The ‘subcortical
fatal familial insomnia (Gallassi et al., 1996), although
dementia’ of progressive supranuclear palsy. J Neurol
cases of selective thalamic degeneration with the Neurosurg Psychiatry 1974; 37: 121–30.
pathology of multiple system atrophy (Petersen et al., Bak TH, Crawford LM, Hearn VC, Mathuranath PS,
1992) or motor neurone disease (Deymeer et al., Hodges JR. Subcortical dementia revisited: similarities
1989), or without evidence of prion disease (Janssen and differences in cognitive function between progres-
et al., 2000), have been reported. The neuropsycho- sive supranuclear palsy (PSP), corticobasal degenera-
logical features may include forgetfulness, apathy, tion (CBD) and multiple system atrophy (MSA).
and hypersomnia. Cognitive impairment may also Neurocase 2005; 11: 268–73.
occur in patients with isolated brainstem lesions of Benson DF, Ardila A. Aphasia: a Clinical Perspective.
New York: Oxford University Press, 1996: 166–79.
vascular, inflammatory, infective, or metabolic origin
Brown P, Marsden CD. What do the basal ganglia do?
(Garrard et al., 2002; for examples, see Sections 3.3.8,
Lancet 1998; 351: 1801–4.
8.2.1, 9.4.2).
Brown RG, Marsden CD. ‘Subcortical dementia’: the neuro-
Evidence for and against the cortical/subcortical psychological evidence. Neuroscience 1988; 25: 363–87.
dichotomy has been debated (Brown & Marsden, Cummings JL. Subcortical Dementias. London: Oxford
1988), and objections have been raised to the con- University Press, 1990.
cept of subcortical dementia. Cortical and subcort- Deymeer F, Smith TW, De Girolami U, Drachman DA.
ical areas are not functionally independent, but Thalamic dementia and motor neuron disease. Neuro-
overlapping. Since white matter has an essentially logy 1989; 39: 58–61.
Filley CM. The Behavioral Neurology of White Matter. New was originally advanced in the 1890s, but was
York: Oxford University Press, 2001. revived and developed by Norman Geschwind in the
Foong J, Rozewicz L, Quaghebeur G, et al. Executive 1960s (Geschwind, 1965; Absher & Benson, 1993;
function in multiple sclerosis: the role of frontal lobe Catani & ffytche, 2005). Disconnection syndromes
pathology. Brain 1997; 120: 15–26.
essentially result either from interruption of fibres
Gallassi R, Morreale A, Montagna P, et al. Fatal familial
within the corpus callosum or commissures (inter-
insomnia: behavioral and cognitive features. Neurology
hemispheric disconnection syndromes), or of fibres
1996; 46: 935–9.
Garrard P, Bradshaw D, Jäger HR, et al. Cognitive
within a hemisphere (intrahemispheric disconnec-
dysfunction after isolated brainstem insult: an under- tion syndromes). The former is most graphically
diagnosed cause of long-term morbidity. J Neurol seen in patients who have undergone surgical
Neurosurg Psychiatry 2002; 73: 191–4. commissurotomy for intractable seizure disorders
Janssen JC, Lantos PL, Al Sarraj S, Rossor MN. Thalamic (‘split-brain’ patients: Sperry, 1982; Zaidel et al.,
degeneration with negative prion protein immunostain- 2003), whilst the latter syndromes are best described
ing. J Neurol 2000; 247: 48–51. in the domain of language. Although mass lesions
Larner AJ. Adult-onset dementia with prominent frontal and iatrogenesis (surgery) are obvious causes of
lobe dysfunction in X-linked adrenoleukodystrophy
disconnection, functional disconnection may also
with R152C mutation in ABCD1 gene. J Neurol 2003a;
result from inflammatory disorders of white matter
250: 1253–4.
(see Section 1.11). A ‘callosal dementia’ has been
Larner AJ. False localising signs. J Neurol Neurosurg
Psychiatry 2003b; 74: 415–8.
postulated, characterized by callosal disconnection,
Larner AJ. A topographical anatomy of false-localising Balint syndrome, gaze apraxia, and neurobeha-
signs. Adv Clin Neurosci Rehabil 2005; 5 (1): 20–1. vioural features such as alternating apathy and
McHugh PR, Folstein MF. Psychiatric symptoms of Hun- agitation (Ghika Schmid et al., 1999).
tington’s chorea: a clinical and phenomenological With complete interhemispheric disconnection,
study. In: Benson DF, Blumer D (eds.), Psychiatric for example with a tumour or following surgical
Aspects of Neurological Disease. New York: Raven Press, section of the corpus callosum, a blindfolded patient
1975: 267–85. can correctly name objects placed in the right hand,
Neary D, Snowden JS. Sorting out the dementias. Pract
but not those in the left, and objects in the left visual
Neurol 2002; 2: 328–39.
hemifield cannot be named or matched to a similar
Petersen RB, Tabaton M, Berg L, et al. Analysis of the
object in the right hemifield. With posterior callosal
prion protein gene in thalamic dementia. Neurology
1992; 42: 1859–63.
section at the splenium, for example following left
Rao SM. White matter disease and dementia. Brain Cogn posterior cerebral artery occlusion, patients cannot
1996; 31: 250–68. read or name colours, since information cannot pass
Starkstein SE, Merello M. Psychiatric and Cognitive Dis- to the left hemispheric language areas. Copying of
orders in Parkinson’s Disease. Cambridge: Cambridge words and writing, both spontaneously and to dic-
University Press, 2002: 59–66. tation, is intact, as information may pass to the left
Stern K. Severe dementia associated with bilateral hemisphere anterior to the site of damage (aphasia
symmetrical degeneration of the thalamus. Brain without agraphia).
1939; 62: 157–71.
Various intrahemispheric disconnection syn-
dromes have been described. In conduction apha-
sia, the patient has fluent but paraphasic speech
1.12 Disconnection syndromes and writing, with greatly impaired repetition
despite relatively normal comprehension of the
Disconnection syndromes may be defined as con- spoken and written word. This has traditionally
ditions in which there is an interruption of inter- been explained as due to a lesion in the arcuate
and/or intra-hemispheric fibre tracts. The concept fasciculus/supramarginal gyrus disconnecting the
sensory (Wernicke) and motor (Broca) language Yamauchi H, Fukuyama H, Nagahama Y, et al. Atrophy of
areas. Ideomotor apraxia in Broca’s aphasia, an the corpus callosum associated with cognitive impair-
apraxia of left hand movements to command, is ment and widespread cortical hypometabolism in carotid
ascribed to lesions disconnecting the cortical motor artery occlusive disease. Arch Neurol 1996; 53: 1103–9.
Zaidel E, Iacoboni M, Zaidel DW, Bogen JE. The callosal
areas anterior to the primary motor cortex. In pure
syndromes. In: Heilman KM, Valenstein E (eds.), Clini-
word deafness, patients are able to hear and identify
cal Neuropsychology (4th edition). Oxford: Oxford
non-verbal sounds but unable to understand
University Press, 2003: 347–403.
spoken language, due to lesions in the white matter
of the left temporal lobe which isolate Wernicke’s
area from the auditory cortex. Postscript
Alzheimer’s disease may be viewed as a discon-
nection syndrome (Lakmache et al., 1998; Delbeuck In the chapters which follow, the deficits in the
et al., 2003). AD pathology isolates the hippocampus various cognitive domains discussed in this chapter
from association cortices, basal forebrain, thalamus, which have been observed in neurological disorders
and hypothalamus (Hyman et al., 1984). Disconnec- are discussed. These may be localized or discrete
tion of cortical regions caused by white matter lesions deficits, or part of more widespread impairments
and cerebral atrophy due to internal carotid artery which add up to a diagnosis of dementia. It should,
occlusive disease has been suggested (Yamauchi et al., however, be added that many attending memory
1996). Speculations that unusual delusional syn- clinics with a complaint of impaired memory prove,
dromes (e.g. Capgras’, Cotard’s) might also represent after careful clinical, neuropsychological, and
disconnection syndromes have been advanced. imaging evaluation, to have no evidence for under-
lying neurological disorder. Such individuals, who
may account for up to 50% of patients seen in the
REFERENCES
clinic (Larner, 2005), sometimes labelled as ‘mem-
ory complainers’ or ‘worried well’, but perhaps
Absher JR, Benson DF. Disconnection syndromes: an
better described as those with ‘purely subjective
overview of Geschwind’s contributions. Neurology 1993;
43: 862–7.
memory impairment’, pose a significant diagnostic
Catani M, ffytche DH. The rises and falls of disconnection challenge. Some, to be sure, may represent missed
syndromes. Brain 2005; 128: 2224–39. diagnoses of incipient neurodegenerative disease
Delbeuck X, van der Linden M, Collette F. Alzheimer’s (‘mild cognitive impairment’: see Section 2.6);
disease as a disconnection syndrome? Neuropsychol Rev others may have primary affective disorders, sleep-
2003; 13: 79–92. related disorders, problems with drug misuse (pre-
Geschwind N. Disconnexion syndromes in animals and scription or recreational), or any combination
man. Brain 1965; 88: 237–94, 585–644. thereof to account for their complaints. Others may
Ghika Schmid F, Ghika J, Assal G, Bogousslavsky J.
perhaps have intuited their physiological age-
Callosal dementia: behavioural disorders related to
related decline in cognitive function (see Section
central and extrapontine myelinolysis [in French]. Rev
1.9). If doubt persists, such patients should ideally
Neurol Paris 1999; 155: 367–73.
Hyman BT, van Hoesen GW, Damasio AR, Barnes CL.
be followed up for longitudinal assessment.
Alzheimer’s disease: cell-specific pathology isolates the
hippocampal formation. Science 1984; 225: 1168–70.
Lakmache Y, Lassonde M, Gauthier S, Frigon JY, Lepore F. REFERENCES
Interhemispheric disconnection syndrome in Alzhei-
mer’s disease. Proc Natl Acad Sci USA 1998; 95: 9042–6. Larner AJ. An audit of the Addenbrooke’s Cognitive
Sperry RW. Some effects of disconnecting the cerebral Examination (ACE) in clinical practice. Int J Geriatr
hemispheres. Science 1982; 217: 1223–6. Psychiatry 2005; 20: 593–4.
2
Neurodegenerative disorders
2.1 Alzheimer’s disease (AD) 40

2.2 Frontotemporal lobar degenerations (FTLD) 49
2.2.1 Frontotemporal dementia (FTD), dementia of frontal type (DFT),
frontal variant of frontotemporal dementia (fvFTD), behavioural variant of
frontotemporal dementia (bvFTD) 51
2.2.2 Semantic dementia (SD), progressive fluent aphasia, temporal variant of
frontotemporal dementia (tvFTD) 54
2.2.3 Progressive non-fluent aphasia (PNFA), primary progressive aphasia (PPA) 56
2.2.4 Frontotemporal dementia with parkinsonism linked to chromosome 17
(FTDP-17) 58
2.2.5 Progressive subcortical gliosis (of Neumann) 60
2.2.6 Argyrophilic grain disease (AGD) 61
2.2.7 Neurofibrillary tangle dementia (NTD), diffuse neurofibrillary tangles with
calcification (DNTC, Kosaka–Shibayama disease) 61
2.2.8 Neuronal intermediate filament inclusion disease (NIFID) 62
2.2.9 Basophilic inclusion body disease (BIBD) 62
2.3 Motor neurone disease (MND), amyotrophic lateral sclerosis (ALS) 63
2.3.1 Primary lateral sclerosis (PLS), progressive symmetric spinobulbar spasticity 67
2.3.2 Mills’ syndrome 67
2.3.3 Hippocampal sclerosis, pure hippocampal sclerosis 68
2.3.4 Progressive muscular atrophy (PMA) 68
2.4 Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) 69
2.4.1 Other (‘atypical’) parkinsonian syndromes 76
2.4.2 Progressive supranuclear palsy (PSP), Steele–Richardson–Olszewski (SRO)
syndrome 76
2.4.3 Corticobasal degeneration (CBD) 78
2.4.4 Multiple system atrophy (MSA) 80
2.4.5 Dementia pugilistica 81
2.4.6 Amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) of
Guam, Lytico-Bodig, Marianas dementia 81
2.5 Prion diseases 82
2.5.1 Sporadic prion disease: sporadic Creutzfeldt–Jakob disease (sCJD) 83
2.5.2 Iatrogenic prion disease: variant Creutzfeldt–Jakob disease (vCJD), kuru 84
2.5.3 Inherited prion disease: familial CJD, Gerstmann–Straussler–Scheinker disease
(GSS), fatal familial insomnia (FFI) 86
2.6 Mild cognitive impairment (MCI) 87
39
40 Neurodegenerative disorders
2.1 Alzheimer’s disease (AD) least one first-degree family relative is affected, and
autosomal dominant AD, where at least three
Alzheimer’s disease (AD) is the archetypal neuro- family members are affected in at least two gen-
degenerative cognitive disorder (Larner, 2008). erations. Autosomal dominant AD is most usually of
Alois Alzheimer’s critical contribution, which later early-onset type, sometimes manifesting as early as
prompted Emil Kraepelin to bestow the eponym the third or fourth decade of life. To date, muta-
upon the condition, was to link the clinical tions deterministic for AD have been discovered in
phenotype of cognitive decline with specific neu- three genes, encoding the amyloid precursor pro-
ropathological findings, namely neurofibrillary tein (APP), presenilin-1 (PS1), and presenilin-2
tangles (Hodges, 2006; Larner 2006a). (PS2). Multiple mutations have been identified in
Initially conceived of as a rare disease of the each gene (Alzheimer Disease and Frontotemporal
presenium, it was not until the 1960s that neuro- Dementia Mutation Database, www.molgen.ua.ac.
psychological (Blessed et al., 1968) and neurobe/Admutations), around 150 in PS1 (Larner &
pathological (Tomlinson et al., 1968, 1970) studies Doran, 2006), which is the commonest site for
showed that most cases of ‘senile dementia’ were genetic mutations causing AD (Cruts et al., 1998).
identical to AD. Clinical diagnostic criteria for AD Virtually all of these mutations appear to alter the
have been developed by the National Institute of metabolism of APP such that production of the
Neurologic and Communicative Disorders and amyloid b-peptide, the major protein component
Stroke, and the Alzheimer’s Disease and Related of amyloid plaques, is increased. These findings
Disorders Association (NINCDS-ADRDA) work- have raised hopes for the development of disease-
group, with definite, probable, and possible cate- modifying therapy for AD, particularly if cases can
gories (McKhann et al., 1984). Clinical criteria are be identified early in the disease course. To date,
also available from the American Psychiatric however, only symptomatic treatments for AD are
Association’s (1994) Diagnostic and Statistical available, namely cholinesterase inhibitors and
Manual (DSM-IV). Generally these criteria perform memantine.
well, with >80% accuracy of clinical diagnosis, Diagnosis hinges on appropriate clinical features
hence highly sensitive for an antemortem diagnosis aided by ancillary investigations (Waldemar et al.,
of AD, although specificity is poorer such that other 2000, 2006; Knopman et al., 2001). Structural brain
dementias may erroneously be identified as AD. imaging may show generalized brain atrophy, but
Neuropathological criteria are also available for this finding is non-specific, and over-reliance on it
AD, based on the quantitation and distribution of may lead to incorrect diagnosis of AD (Larner,
the hallmark features, senile plaques and neurofi- 2004). Volumetric magnetic resonance imaging
brillary tangles (Mirra et al., 1991; Braak & Braak, showing hippocampal atrophy, progressing with
1991; National Institute on Aging, 1997). longitudinal follow-up, may be a more secure sign
Epidemiological studies have shown that the (Fox et al., 1996). Imaging of amyloid deposits
prevalence of AD increases steeply with increasing themselves has been demonstrated and may soon
age, with over 50% of over-85-year-olds being be applicable clinically (Klunk et al., 2004). EEG
affected. Early-onset AD, that is presenting at or changes of background slowing and loss of signal
before 65 years of age, may be differentiated from synchronization between different brain regions
late-onset disease (McKhann et al., 1984), although may be seen (Hegerl & Möller, 1997; Stam, 2006).
this distinction is probably arbitrary since the The neuropsychological features of AD have
underlying pathobiology is identical. More useful, been extensively studied (Parks et al., 1993; Morris
in terms of elucidating aetiology, has been the & Becker, 2004). Disturbance of memory, particu-
distinction of sporadic AD, where there is no family larly recent memory, is the commonest presenting
history of the condition, from familial AD, where at symptom, often manifested as repeating the same
2.1 Alzheimer’s disease 41
information or questions within a short space of neurofibrillary tangle (NFT) load in frontal cortex.
time, accompanied by difficulty learning new Behavioural variants of AD with a clinical phenotype
information, for example use of new household overlapping frontal variant frontotemporal demen-
appliances. Although this may be an isolated tia (fvFTD) have also been recorded in association
amnesic syndrome, usually with a temporal gradi- with certain PS1 mutations (Larner & Doran, 2006),
ent with more recent information more signifi- cases which might be labelled as fvAD. Whether
cantly affected, more often than not other cognitive such a phenotype ever occurs in sporadic AD is
domains are found to be affected when formally uncertain, although possible cases have been pre-
tested, particularly language and visuospatial sented (Brun & Gustafson, 2006; Larner, 2006b). The
function. frequency of these clinical variants is uncertain, but
On occasion, AD may present with complaints may constitute up to 10% of AD presentations in a
other than memory decline, representing other specialist cognitive disorders clinic with a particular
variants – not subtypes (Jorm, 1985) – of AD. Pre- interest in early-onset cases, the agnosic (PCA) and
sentation with primarily visuoperceptual dysfunc- aphasic presentations being the most common
tion is well recognized, described as posterior (Larner, 2006c). However, even in this selected
cortical atrophy (PCA) or the visual variant of AD population, amnesic presentations greatly outnum-
(Benson et al., 1988; Levine et al., 1993), although ber variant cases.
other pathologies can on occasion be the substrate Although cognitive decline is the dominant
of PCA (Pantel & Schröder, 1996). Diagnostic cri- phenotypic manifestation of AD, other neurological
teria for PCA have been suggested (Mendez et al., features may occur such as epileptic seizures
2002). Slowly progressive apraxia has been (Mendez & Lim, 2003; Lozsadi & Larner, 2006)
described as a presentation of AD, either bilateral and movement disorders, particularly myoclonus
with biparietal atrophy (Mackenzie Ross et al., (Kurlan et al., 2000), most often in the later stages
1996; Galton et al., 2000) or, rarely, unilateral of the disease. Extrapyramidal signs such as par-
(Crystal et al., 1982). AD cases which overlap clini- kinsonism are reported (Tsolaki et al., 2001;
cally with corticobasal degeneration are described Scarmeas et al., 2004), though confounding by con-
(Doran et al., 2003), even with the alien limb phe- current Lewy body pathology (see Section 2.4) or use
nomenon (Ball et al., 1993). Slowly progressive of neuroleptic medications is possible. Sleep-related
aphasia has been reported on occasion to be the disorders may likewise become more common with
presentation of AD, rather than one of the focal disease progression. Although behavioural and psy-
frontotemporal lobar degeneration syndromes chological symptoms are common in AD, presenta-
(see Section 2.2), often with non-fluent aphasia tion with prominent features of this kind has been
(Section 2.2.3) but sometimes fluent aphasia with reported only occasionally (Rippon et al., 2003;
the characteristics approximating a transcortical Doran & Larner, 2004).
sensory aphasia (Pogacar & Williams, 1984; Men-
dez & Zander, 1991; Galton et al., 2000; Godbolt
Neuropsychological profile
et al., 2004a; Hodges et al., 2004). Acute, post-
operative, presentation of isolated aphasia resem- The neuropsychological deficits of AD are sum-
bling a cerebrovascular event but subsequently marized in Table 2.1 and are discussed in more
evolving to AD has also been reported (Larner, detail below.
2005). A frontal variant of AD has been postulated
(Johnson et al., 1999), based on the retrospective Attention
finding of early and disproportionately severe Attentional mechanisms are impaired in AD (Perry
impairments on tests of frontal lobe functioning & Hodges, 1999; Parasuraman, 2004). Tests of
in a subset of definite AD cases with higher selective attention such as the Stroop Test are
Table 2.1. Neuropsychological deficits in Alzheimer’s disease (AD).
Attention # Selective, divided; sustained attention relatively preserved

General intelligence, IQ # FSIQ vs. premorbid IQ; PIQ typically more impaired than VIQ
Memory # Episodic memory (encoding, storage) with temporal gradient; þ/ semantic memory
impairment (category verbal fluency)
Language Semantic naming errors, circumlocutions; phonology, syntax relatively spared. Aphasic
presentations rare
Perception Agnosic presentations may occur (PCA): Balint syndrome, topographical agnosia,
dressing apraxia; object agnosia, pure alexia, prosopagnosia
Praxis Ideomotor, ideational apraxia: modest. Apraxic presentations rare
Executive function May be early impairments of judgment, abstract reasoning, problem solving
impaired early in the disease course, possibly words memories with an autobiographical refer-
reflecting pathological involvement of the cingulate rent (Overman & Becker, 2004). Tests requiring the
gyrus and/or the basal forebrain cholinergic system learning and recall of supraspan word lists are very
(Lawrence & Sahakian, 1995). Tests of divided sensitive to the episodic memory impairment in
attention such as dual-task performance tests also early AD; examples include the Buschke Selective
show impairment (Baddeley et al., 2001). In con- Reminding Test, the Rey Auditory Verbal Learning
trast, sustained attention is relatively preserved in Test, the California Verbal Learning Test, and the
the early stages, as evidenced by preserved per- Hopkins Verbal Learning Test. (It is of note that the
formance on tests of ‘working memory’ (Cherry MMSE word list contains only three items and is
et al., 2002), although these may show progressive therefore a less stringent test; this has been
decline. The greater preservation of attentional addressed in other bedside instruments such as the
functions may be one feature assisting in the dif- CERAD, ACE, and DemTect.) The learning curve is
ferential diagnosis of AD from dementia with Lewy virtually flat (i.e. many trials are required to learn
bodies (see Section 2.4). the new information), intrusion errors are common
(i.e. reporting words which were not on the list to
General intelligence, IQ be remembered, although these may be semantic-
Typically patients with AD show disparity between ally related), and recognition paradigms are little
their current full-scale IQ scores and estimates of better than recall. There may be an accelerated rate
premorbid IQ based on the NART or educational/ of forgetting (Christensen et al., 1998). In other
occupational achievement, especially for perform- words, the findings are typical of a cortical, as
ance IQ, indicating a decline in intellectual function- opposed to subcortical, disorder: encoding and
ing. Estimates of premorbid IQ using the NART may storage deficits are paramount, rather than a pri-
be difficult or impossible if there is marked aphasia. mary deficit of memory retrieval.
Although it is a common clinical observation that
Memory patients’ distant, long-term, (remote) memory is
Memory decline is the commonest complaint of spared, evaluation of retrograde memory is not
patients and, more often, of their caregivers in AD. entirely normal, with a temporal gradient such that
This is most commonly seen in the domain of more distant memories are most intact (Bright &
anterograde episodic memory, that is the encoding, Kopelman, 2004).
storage, retention, and recall of new information The deficits of episodic memory reflect patho-
about day-to-day personal experiences, in other logical change in the mesial temporal regions,
particularly the hippocampal formation, which is Progressive loss of the richness of language may
also evident on volumetric brain imaging (Fox be evident to the point that speech production may
et al., 1996). That these are typically the earliest be described as ‘empty’, lacking in specific content
changes in AD is confirmed by their observation in and impoverished in both conveying and obtaining
individuals carrying deterministic genetic muta- information. Some semantic information about
tions for AD who are tracked from the pre- items which cannot be named may be generated,
symptomatic stages (Fox et al., 1998). This is also for example ‘a beautiful thing which jumps’ for
the area earliest affected by neurofibrillary patho- kangaroo (Garrard et al., 2005). As previously
logical change (Braak & Braak, 1991; Delacourte mentioned, verbal fluency is typically more
et al., 1999). impaired in the category (semantic) than in the
Semantic memory impairments may also be letter (phonological) paradigm (Henry et al., 2004).
detected in AD (Hodges et al., 1992; Garrard et al., In comparison with the semantic aspects of lan-
2004). On tests of verbal fluency, category fluency guage, phonological and syntactic abilities are
is more impaired than letter fluency, indicating relatively preserved early in AD, although they may
difficulty accessing the semantic lexicon of word break down as the disease progresses (Croot et al.,
meanings (Cerhan et al., 2002; Henry et al., 2004). 2001). Repetition and motor speech may be rela-
Naming difficulties may also be semantic in their tively intact whilst increasingly impaired compre-
origin. hension of the spoken or written word is evident.
The pattern of implicit memory impairments in Attempts have been made to fit the language dis-
AD differs from that in Huntington’s disease, with turbance of AD into established aphasia categories
verbal priming severely impaired but motor (pur- (e.g. anomic aphasia in the early stages, extra-
suit rotor) skill normally acquired (Salmon & sylvian or transcortical sensory aphasia in the later
Fennema-Notestine, 2004). stages) but the implication that AD-related lan-
guage dysfunction is congruent with one of these
Language ‘typical’ aphasia syndromes may not be justified.
Language deficits in AD have been extensively Slowly progressive aphasia has occasionally been
studied (Kertesz, 2004). The language disorder of reported as the presenting symptom of AD. Such
AD varies with the stage of the disease, initially aphasia at onset may lead to confusion with the
remaining fluent with lexicosemantic deficits pre- linguistic variants of frontotemporal lobar degener-
dominating, but ultimately evolving to global ation (see Section 2.2). Presence or absence of
aphasia (Cummings et al., 1985; Faber-Langendoen deficits in other cognitive domains may give clues
et al., 1988; Emery, 2000). to the correct diagnosis, as may structural and
Word-finding difficulties are common in the functional brain imaging. Sometimes, however,
early stages of AD. The tip-of-the-tongue phe- only with the passage of time and the evolution of
nomenon may be evident: for example, on picture symptoms does diagnostic clarity emerge, or even
naming the first letter or phoneme may be gen- only at postmortem.
erated but not the rest of the word, sometimes with
the use of circumlocutions (anomia). Naming Perception
errors are largely semantic, rarely phonological or Visuoperceptual and visuospatial deficits are sel-
visual (Huff et al., 1986; Hodges et al., 1991). dom clinically evident in the early stages of AD,
Naming may be relatively preserved in some PS1 with the notable exception of those patients who
mutations (e.g. M139V: Fox et al., 1997; Warrington present with visual agnosia, the visual variant of AD
et al., 2001; Larner & du Plessis 2003), whereas (Levine et al., 1993), or posterior cortical atrophy
other PS1 mutations may present with aphasia (PCA: Mendez et al., 2002), with evidence from
(Godbolt et al., 2004a). functional imaging of visual cortical hypoperfusion
and hypometabolism (Nestor et al., 2003). to show impairment; imitation of meaningless

Impaired naming is not thought to result from gestures may be a sensitive early measure of
perceptual deficits. Tests which tap aspects of vis- apraxia. Apraxia as the earliest symptom of AD is
ual cognition, such as drawing the Rey–Osterrieth rare (Green et al., 1995; Galton et al., 2000). How-
Complex Figure, overlapping pentagons (from the ever, apraxia sufficient to cause diagnostic confu-
MMSE), the Necker cube, and clock drawing, may sion with corticobasal degeneration does rarely
be impaired early in AD, although performance occur (Boeve et al., 1999; Doran et al., 2003). Con-
may also be degraded by concurrent apraxia and/ ceptual apraxia, defined by Ochipa et al. (1992) as
or planning difficulties. impaired knowledge of what tools and objects are
Various visual processing disorders may occur in needed to perform a skilled movement, is said to be
AD (Mendez et al., 2002; Cronin-Golomb & Hof, common in AD.
2004), their exact nature depending upon the
relative involvement of right or left hemisphere, Executive function
and the two streams of visual processing (Unger- Executive abilities may be impaired in AD, produ-
lieder & Mishkin, 1982; see Section 1.5), namely cing impairments of judgment, abstract reasoning,
dorsal (occipitoparietal, ‘where’) or ventral (occi- and problem solving, as evidenced by difficulties
pitotemporal, ‘what’: Mackenzie Ross et al., 1996). with verbal fluency, the Wisconsin Card Sorting
These may occur with relative preservation of Test (WCST), and trail-making tests. These changes
memory and language in posterior cortical atrophy. may occur early in the disease course in some
Dorsal stream involvement, the most commonly patients, and are commonly observed when spe-
observed pattern in one series of PCA patients cifically sought (Lafleche & Albert, 1995; Binetti
(Nestor et al., 2003), results in Balint syndrome and et al., 1996; Collette et al., 1999; Royall, 2000; Chen
dressing apraxia, whereas ventral stream involve- et al., 2000, 2001; Swanberg et al., 2004). Verbal
ment may produce object agnosia, pure alexia, fluency measures have sometimes been proposed
and prosopagnosia. However, segregation of cases as diagnostic tests for AD (Cerhan et al., 2002; Duff
into dorsal and ventral stream involvement may Canning et al., 2004). The possible impact of
be clinically difficult (Mendez et al., 2002). Pre- executive dysfunction on tests which also tap lan-
dominant right hemisphere involvement may guage and perceptual functions has already been
produce left visual hemineglect, whereas predom- noted. Very prominent executive dysfunction, suf-
inant left hemisphere involvement is associated ficient to prompt a clinical diagnostic label of
with Gerstmann syndrome, pure alexia, and right ‘frontotemporal dementia’, has been reported in
hemiachromatopsia. Cortical blindness and Anton’s some familial AD cases with certain PS1 gene
syndrome (visual anosognosia) have also been mutations, but whether this phenotype ever occurs
recorded. in sporadic AD is doubtful.
Praxis
Presymptomatic Alzheimer’s disease
Both ideomotor and ideational apraxia may occur
in AD, prevalence increasing with disease severity Patients with mild cognitive impairment (MCI: see
(Edwards et al., 1991; Derouesne et al., 2000). Section 2.6) may be in the prodromal phase of AD,
However, this is usually inapparent or of modest but to examine presymptomatic AD patients one
severity, rarely producing symptoms (Rapcsak needs either to test large numbers of normal indi-
et al., 1989), in comparison with cognitive impair- viduals, ideally in a community sample, follow
ments in other areas. Limb transitive actions (e.g. them up over a period of years until some develop
asking the patient to show how he/she would use a a diagnosis of AD, and then look back at their
comb/toothbrush/pair of scissors) are most likely pre-diagnosis cognitive profile; or, perhaps easier,
to study asymptomatic individuals known to be receptors, has also been shown to benefit cognitive
carrying highly penetrant genetic mutations domains (Reisberg et al., 2003, 2006) and is
deterministic for AD. In individuals harbouring licensed for use in moderate to severe AD, although
genetic mutations, episodic memory deficit was the not reimbursed in some jurisdictions.
earliest change detected, along with decline in
general intelligence, whilst perceptual, naming,
and spelling skills were relatively preserved REFERENCES
(Newman et al., 1994; Fox et al., 1998; Godbolt
et al., 2004b). American Psychiatric Association. Diagnostic and Statistical
Community-based studies have suggested that Manual of Mental Disorders. Washington, DC: American
tests of both memory and executive function, and Psychiatric Association, 1994.
possibly perceptual speed, show the greatest Amieva H, Jacqmin-Gadda H, Orgogozo JM, et al. The 9
declines over time in individuals destined to year cognitive decline before dementia of the Alzheimer
manifest AD, and these may be apparent several type: a prospective population-based study. Brain 2005;
128: 1093–101.
years prior to diagnosis (Chen et al., 2000, 2001;
Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ.
Bäckman et al., 2001, 2004; Amieva et al., 2005).
Multiple cognitive deficits during the transition to
These domains are similar to those which decline
Alzheimer’s disease. J Intern Med 2004; 256: 195–204.
in ‘normal’ cognitive aging (see Section 1.9). Bäckman L, Small BJ, Fratiglioni L. Stability of the
preclinical episodic memory deficit in Alzheimer’s
disease. Brain 2001; 124: 96–102.
Treatment of neuropsychological deficits
Baddeley AD, Baddeley HA, Bucks RS, Wilcock GK.
Cholinesterase inhibitors (ChEIs) are licensed for Attentional control in Alzheimer’s disease. Brain 2001;
the symptomatic treatment of mild to moderate AD 124: 1492–508.
in many jurisdictions, the rationale being that they Ball JA, Lantos PL, Jackson M, et al. Alien hand sign in
help to restore the cholinergic deficits that are a association with Alzheimer’s histopathology. J Neurol
Neurosurg Psychiatry 1993; 56: 1020–3.
neurochemical feature of AD brain. The evidence
Benson DF, Davis RJ, Snyder BD. Posterior cortical
base for their modest efficacy is relatively strong, as
atrophy. Arch Neurol 1988; 45: 789–93.
evidenced by meta-analyses (Lanctôt et al., 2003;
Binetti G, Magni E, Padovani A, et al. Executive dysfunc-
Ritchie et al., 2004; Whitehead et al., 2004). These tion in early Alzheimer’s disease. J Neurol Neurosurg
show stability or even improvement in cognitive Psychiatry 1996; 60: 91–3.
scales such as the MMSE and ADAS-Cog as com- Blessed G, Tomlinson BE, Roth M. The association
pared with placebo-treated patients over periods of between quantitative measures of dementia and of
6–12 months. Whether this reflects genuine mne- senile change in the cerebral grey matter of elderly
monic improvement, or simply better attentional subjects. Br J Psychiatry 1968; 114: 797–811.
function, is debatable. Behavioural improvements Boeve BF, Maraganore MD, Parisi JE, et al. Pathologic
are also noted with ChEIs, but cognitive domains heterogeneity in clinically diagnosed corticobasal
degeneration. Neurology 1999; 53: 795–800.
other than attention and memory are little affected.
Braak H, Braak E. Neuropathological stageing [sic] of
A report of improved visuospatial function follow-
Alzheimer-related changes. Acta Neuropathol (Berl)
ing ChEI treatment in a case of PCA (Kim et al.,
1991; 82: 239–59.
2005) would seem to be exceptional. Whether Bright P, Kopelman MD. Remote memory in Alzheimer’s
ChEIs have disease-modifying effects, or alter the disease. In: Morris RG, Becker JT (eds.), Cognitive
natural history of AD, for example by reducing the Neuropsychology of Alzheimer’s Disease (2nd edition).
rate of nursing home placement, remains debat- Oxford: Oxford University Press, 2004: 141–51.
able (Lopez et al., 2002; Larner, 2007). Memantine, Brun A, Gustafson L. Clinical symptoms and neuropatho-
an antagonist at the NMDA type of glutamate logy in organic dementing disorders affecting the frontal
lobes. In: Risberg J, Grafman J (eds.), The Frontal Lobes: Doran M, Larner AJ. Prominent behavioural and psychi-
Development, Function and Pathology. Cambridge: atric symptoms in early-onset Alzheimer’s disease in a
Cambridge University Press, 2006: 199–221 [at 212–13]. sib pair with the presenilin-1 gene R269G mutation. Eur
Cerhan JH, Ivnik RJ, Smith GE, et al. Diagnostic utility of Arch Psychiatry Clin Neurosci 2004; 254: 187–9.
letter fluency, category fluency, and fluency difference Duff Canning SJ, Leach L, Stuss D, Ngo L, Black SE.
scores in Alzheimer’s disease. Clin Neuropsychol 2002; Diagnostic utility of abbreviated fluency measures in
16: 35–42. Alzheimer disease and vascular dementia. Neurology
Chen P, Ratcliff G, Belle SH, et al. Cognitive tests that best 2004; 62: 556–62.
discriminate between presymptomatic AD and those Edwards DF, Deuel RK, Baum CM, Morris JC. A quantita-
who remain nondemented. Neurology 2000; 55: 1847–53. tive analysis of apraxia in senile dementia of Alzheimer
Chen P, Ratcliff G, Belle SH, et al. Patterns of cognitive type: stage-related differences in prevalence and type.
decline in presymptomatic Alzheimer disease: a pro- Dementia 1991; 2: 142–9.
spective community study. Arch Gen Psychiatry 2001; Emery VO. Language impairment in dementia of the
58: 853–8. Alzheimer type: a hierarchical decline? Int J Psychiatry
Cherry BJ, Buckwalter JG, Henderson VW. Better preser- Med 2000; 30: 145–64.
vation of memory span relative to supraspan immediate Faber-Langendoen K, Morris JC, Knesevich JW, et al.
recall in Alzheimer’s disease. Neuropsychologia 2002; Aphasia in senile dementia of the Alzheimer type. Ann
40: 846–52. Neurol 1988; 23: 365–70.
Christensen H, Kopelman MD, Stanhope N, Lorentz I, Fox NC, Kennedy AM, Harvey RJ, et al. Clinicopathological
Owen P. Rates of forgetting in Alzheimer dementia. features of familial Alzheimer’s disease associated with
Neuropsychologia 1998; 36: 547–57. the M139V mutation in the presenilin 1 gene. Pedigree
Collette F, van der Linden M, Salmon E. Executive dysfunc- but not mutation specific age at onset provides
tion in Alzheimer’s disease. Cortex 1999; 35: 57–72. evidence for a further genetic factor. Brain 1997; 120:
Cronin-Golomb A, Hof PR (eds.). Vision in Alzheimer’s 491–501.
Disease. Basel: Karger, 2004. Fox NC, Warrington EK, Freeborough PA, et al. Presymp-
Croot K, Hodges JR, Xuereb JH, Patterson K. Phonological tomatic hippocampal atrophy in Alzheimer’s disease: a
and articulatory impairment in Alzheimer’s disease: a longitudinal MRI study. Brain 1996; 119: 2001–7.
single case series. Brain Lang 2001; 75: 277–309. Fox NC, Warrington EK, Seiffer AL, Agnew SK, Rossor MN.
Cruts M, van Duijn CM, Backhovens H, et al. Estimation of Presymptomatic cognitive deficits in individuals at risk
the genetic contribution of presenilin-1 and -2 muta- of familial Alzheimer’s disease: a longitudinal prospect-
tions in a population-based study of presenile Alzhei- ive study. Brain 1998; 121: 1631–9.
mer disease. Hum Mol Genet 1998; 7: 43–51. Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical
Crystal HA, Horoupian DS, Katzman R, Jotkowicz S. and typical presentations of Alzheimer’s disease: a
Biopsy-proved Alzheimer disease presenting as a right clinical, neuropsychological, neuroimaging and patho-
parietal lobe syndrome. Ann Neurol 1982; 12: 186–8. logical study of 13 cases. Brain 2000; 123: 484–98.
Cummings JL, Benson DF, Hill MA, Read S. Aphasia in Garrard P, Maloney LM, Hodges JR, Patterson K. The
dementia of the Alzheimer type. Neurology 1985; 35: effects of very early Alzheimer’s disease on the
394–7. characteristics of writing by a renowned author. Brain
Delacourte A, David JP, Sergeant N, et al. The biochemical 2005; 128: 250–60.
pathway of neurofibrillary degeneration in aging and Garrard P, Patterson K, Hodges JR. Semantic processing in
Alzheimer’s disease. Neurology 1999; 52: 1158–65. Alzheimer’s disease. In: Morris RG, Becker JT (eds.),
Derouesne C, Lagha-Pierucci S, Thibault S, Baudouin- Cognitive Neuropsychology of Alzheimer’s Disease (2nd
Madec V, Lacomblez L. Apraxic disturbances in patients edition). Oxford: Oxford University Press, 2004: 179–96.
with mild to moderate Alzheimer’s disease. Neuropsy- Godbolt AK, Beck JA, Collinge J, et al. A presenilin 1 R278I
chologia 2000; 38: 1760–9. mutation presenting with language impairment.
Doran M, du Plessis DG, Enevoldson TP, et al. Patho- Neurology 2004a; 63: 1702–4.
logical heterogeneity of clinically diagnosed corticoba- Godbolt AK, Cipolotti L, Watt H, et al. The natural history
sal degeneration. J Neurol Sci 2003; 216: 127–34. of Alzheimer disease: a longitudinal presymptomatic
and symptomatic study of a familial cohort. Arch Neurol Lafleche G, Albert MS. Executive function deficits in mild
2004b; 61: 1743–8. Alzheimer’s disease. Neuropsychology 1995; 9: 313–20.
Green RC, Goldstein FC, Mirra SS, et al. Slowly progressive Lanctôt KL, Hermann N, Yau KK, et al. Efficacy and safety
apraxia in Alzheimer’s disease. J Neurol Neurosurg of cholinesterase inhibitors in Alzheimer’s disease: a
Psychiatry 1995; 59: 312–15. meta-analysis. CMAJ 2003; 169: 557–64.
Hegerl U, Möller HJ. Electroencephalography as a diag- Larner AJ. Getting it wrong: the clinical misdiagnosis of
nostic instrument in Alzheimer’s disease: reviews and Alzheimer’s disease. Int J Clin Pract 2004; 58: 1092–4.
perspectives. Int Psychogeriatr 1997; 9 (suppl 1): 237–46. Larner AJ. ‘Dementia unmasked’: atypical, acute aphasic,
Henry JD, Crawford JR, Phillips LH. Verbal fluency presentations of neurodegenerative dementing disease.
performance in dementia of the Alzheimer type: a Clin Neurol Neurosurg 2005; 108: 8–10.
meta-analysis. Neuropsychologia 2004; 42: 1212–22. Larner AJ. Alzheimer 100. Adv Clin Neurosci Rehabil
Hodges JR. Alzheimer’s centennial legacy: origins, land- 2006a; 6 (5): 24.
marks and the current status of knowledge concerning Larner AJ. ‘Frontal variant Alzheimer’s disease’: a
cognitive aspects. Brain 2006; 129: 2811–22. reappraisal. Clin Neurol Neurosurg 2006b; 108: 705–8.
Hodges JR, Davies RR, Xuereb JH, et al. Clinicopatholo- Larner AJ. Frequency of agnosic, apraxic and aphasic
gical correlates in frontotemporal dementia. Ann Neurol presentations of Alzheimer’s disease. Eur J Neurol
2004; 56: 399–406. 2006c; 13 (suppl 2): 193 (abstract P2098).
Hodges JR, Salmon DP, Butters N. The nature of the Larner AJ. Do cholinesterase inhibitors alter the course of
naming deficit in Alzheimer’s and Huntington’s disease. dementia? Prog Neurol Psych 2007; 11 (5): 26–8.
Brain 1991; 114: 1547–58. Larner AJ. Alzheimer’s disease. In: Cappa S, Abutalebi J,
Hodges JR, Salmon DP, Butters N. Semantic memory Demonet JF, Fletcher P, Garrard P (eds.), Cognitive
impairment in Alzheimer’s disease: failure of access or Neurology: a Clinical Textbook. Oxford: Oxford Univer-
degraded knowledge? Neuropsychologia 1992; 30: 301–14. sity Press, 2008: in press.
Huff FJ, Corkin S, Growden JH. Semantic impairment and Larner AJ, Doran M. Clinical phenotypic heterogeneity of
anomia in Alzheimer’s disease. Brain Lang 1986; 28: Alzheimer’s disease associated with mutations of the
235–49. presenilin-1 gene. J Neurol 2006; 253: 139–58.
Johnson JK, Head E, Kim R, Starr A, Cotman CW. Clinical Larner AJ, du Plessis DG. Early-onset Alzheimer’s disease
and pathological evidence for a frontal variant of with presenilin-1 M139V mutation: clinical, neuro-
Alzheimer disease. Arch Neurol 1999; 56: 1233–9. psychological and neuropathological study. Eur J
Jorm AF. Subtypes of Alzheimer’s disease: a conceptual Neurol 2003; 10: 319–23.
analysis. Psychol Med 1985; 15: 543–53. Lawrence AD, Sahakian BJ. Alzheimer’s disease, attention,
Kertesz A. Language in Alzheimer’s disease. In: Morris RG, and the cholinergic system. Alzheimer Dis Assoc Disord
Becker JT (eds.), Cognitive Neuropsychology of Alzheimer’s 1995; 9 (suppl 2): 43–9.
Disease (2nd edition). Oxford: Oxford University Press, Levine DN, Lee JM, Fisher CM. The visual variant of
2004: 197–218. Alzheimer’s disease: a clinicopathologic case study.
Kim E, Lee Y, Lee J, Han SH. A case with cholinesterase Neurology 1993; 43: 305–13.
inhibitor responsive asymmetric posterior cortical atro- Lopez OL, Becker JT, Wisniewski S, et al. Cholinesterase
phy. Clin Neurol Neurosurg 2005; 108: 97–101. inhibitor treatment alters the natural history of
Klunk WE, Engler H, Nordberg A, et al. Imaging brain Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002;
amyloid in Alzheimer’s disease with Pittsburgh 72: 310–14.
Compound-B. Ann Neurol 2004; 55: 306–19. Lozsadi DA, Larner AJ. Prevalence and causes of seizures
Knopman DS, DeKosky ST, Cummings JL, et al. Practice at the time of diagnosis of probable Alzheimer’s disease.
parameter: diagnosis of dementia (an evidence-based Dement Geriatr Cogn Disord 2006; 22: 121–4.
review). Report of the Quality Standards Subcommittee McKhann G, Drachman D, Folstein M, et al. Clinical
of the American Academy of Neurology. Neurology diagnosis of Alzheimer’s disease. Report of the
2001; 56: 1143–53. NINCDS-ADRDA work group under the auspices of
Kurlan R, Richard IH, Papka M, Marshall F. Movement the Department of Health and Human Service Task
disorders in Alzheimer’s disease: more rigidity of forces on Alzheimer’s disease. Neurology 1984; 34:
definitions is needed. Mov Disord 2000; 15: 24–9. 939–44.
Mackenzie Ross SJ, Graham N, Stuart-Green L, et al. Parasuraman R. Attentional functioning in Alzheimer’s
Progressive biparietal atrophy: an atypical presentation disease. In: Morris RG, Becker JT (eds.), Cognitive
of Alzheimer’s disease. J Neurol Neurosurg Psychiatry Neuropsychology of Alzheimer’s Disease (2nd edition).
1996; 61: 388–95. Oxford: Oxford University Press, 2004: 81–102.
Mendez MF, Ghajarania M, Perryman KM. Posterior Parks RW, Zec RF, Wilson RS (eds.). Neuropsychology of
cortical atrophy: clinical characteristics and differences Alzheimer’s Disease and Other Dementias. New York:
compared to Alzheimer’s disease. Dement Geriatr Cogn Oxford University Press, 1993.
Disord 2002; 14: 33–40. Perry RJ, Hodges JR. Attention and executive deficits in
Mendez MF, Lim GTH. Seizures in elderly patients with Alzheimer’s disease: a critical review. Brain 1999; 122:
dementia: epidemiology and management. Drugs Aging 383–404.
2003; 20: 791–803. Pogacar S, Williams RS. Alzheimer’s disease presenting
Mendez MF, Zander BA. Dementia presenting with as slowly progressive aphasia. R I Med J 1984; 67:
aphasia: clinical characteristics. J Neurol Neurosurg 181–5.
Psychiatry 1991; 54: 542–5. Rapcsak SZ, Croswell SC, Rubens A. Apraxia in Alzheimer’s
Mirra SS, Heyman A, McKeel D, et al. The Consortium to disease. Neurology 1989; 39: 664–8.
Establish a Registry for Alzheimer’s Disease (CERAD). Reisberg B, Doody R, Stöffler A, et al., for the Memantine
Part II. Standardization of the neuropathologic assess- Study Group. Memantine in moderate-to-severe
ment of Alzheimer’s disease. Neurology 1991; 41: 479–86. Alzheimer’s disease. N Engl J Med 2003; 348: 1333–41.
Morris RG, Becker JT (eds.). Cognitive Neuropsychology of Reisberg B, Doody R, Stöffler A, et al. A 24-week open-
Alzheimer’s Disease (2nd edition). Oxford: Oxford Uni- label extension study of memantine in moderate
versity Press, 2004. to severe Alzheimer disease. Arch Neurol 2006; 63:
National Institute on Aging and Reagan Institute Working 49–54.
Group on Diagnostic Criteria for the Neuropathological Rippon GA, Crook R, Baker M, et al. Presenilin 1 mutation
Assessment of Alzheimer Disease. Consensus recom- in an African American family presenting with atypical
mendations for the post-mortem diagnosis of Alzhei- Alzheimer dementia. Arch Neurol 2003; 60: 884–8.
mer’s disease. Neurobiol Aging 1997; 18 (suppl 4): Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of
S1–2. randomized trials of the efficacy and safety of donepe-
Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. The zil, galantamine and rivastigmine for the treatment of
topography of metabolic deficits in posterior cortical Alzheimer disease. Am J Geriatr Psychiatry 2004; 12:
atrophy (the visual variant of Alzheimer’s disease) 358–69.
with FDG-PET. J Neurol Neurosurg Psychiatry 2003; Royall DR. Executive cognitive impairment: a novel per-
74: 1521–9. spective on dementia. Neuroepidemiol 2000; 19: 293–9.
Newman SK, Warrington EK, Kennedy AM, Rossor MN. Salmon DP, Fennema-Notestine C. Implicit memory in
The earliest cognitive change in a person with familial Alzheimer’s disease: priming and skill learning. In:
Alzheimer’s disease: presymptomatic neuropsycho- Morris RG, Becker JT (eds.), Cognitive Neuropsychology
logical features in a pedigree with familial Alzheimer’s of Alzheimer’s Disease (2nd edition). Oxford: Oxford
disease confirmed at necropsy. J Neurol Neurosurg University Press, 2004: 153–78.
Psychiatry 1994; 57: 967–72. Scarmeas N. Hadjigeorgiou GM, Papadimitriou A, et al.
Ochipa C, Rothi LJG, Heilman KM. Conceptual apraxia in Motor signs during the course of Alzheimer disease.
Alzheimer’s disease. Brain 1992; 115: 1061–71. Neurology 2004; 63: 975–82.
Overman AA, Becker JT. Information processing defects in Stam CJ. Modern applications of electroencephalography
episodic memory in Alzheimer’s disease. In: Morris RG, in dementia diagnosis. In: Gauthier S, Scheltens P,
Becker JT (eds.), Cognitive Neuropsychology of Alzhei- Cummings JL (eds.), Alzheimer’s Disease and Related
mer’s Disease (2nd edition). Oxford: Oxford University Disorders Annual 5. London: Taylor & Francis, 2006:
Press, 2004: 121–40. 191–206.
Pantel J, Schröder J. Posterior cortical atrophy: a new Swanberg MM, Tractenberg RE, Mohs R, Thal LJ,
dementia syndrome or a form of Alzheimer’s disease [in Cummings JL. Executive dysfunction in Alzheimer
German]. Fortschr Neurol Psychiatr 1996; 64: 492–508. disease. Arch Neurol 2004; 61: 556–60.
2.2 Frontotemporal lobar degenerations 49
Tomlinson BE, Blessed G, Roth M. Observations on the A potentially bewildering profusion of names has
brains of non-demented old people. J Neurol Sci 1968; 7: become attached to these focal degenerative dis-
331–56. orders, based on clinical, pathological, and clin-
Tomlinson BE, Blessed G, Roth M. Observations on the icopathological observations. Although some
brains of demented old people. J Neurol Sci 1970; 11:
investigators have tried to label these, and related,
205–42.
conditions as ‘Pick’s complex’ (Kertesz & Munoz,
Tsolaki M, Kokarida K, Iakovidou V, et al. Extrapyramidal
1998), the term ‘frontotemporal lobar degenera-
symptoms and signs in Alzheimer’s disease: prevalence
and correlation with the first symptom. Am J Alzheimers
tions’ (FTLD) seems preferable (Snowden et al.,
Dis Other Demen 2001; 16: 268–78. 1996), of which frontotemporal dementia (FTD) is
Ungerlieder LG, Mishkin M. Two cortical visual systems. In: one specific type. Clinical and neuropathological
Ingle DJ, Goodale MA, Mansfield RJW (eds.), Analysis of diagnostic criteria have been suggested (Gregory &
Visual Behavior. Cambridge, MA: MIT Press, 1982: 549–86. Hodges, 1993; Brun et al., 1994; Neary et al., 1998;
Waldemar G, Dubois B, Emre M, et al. Diagnosis and McKhann et al., 2001), but not all have been
management of Alzheimer’s disease and other disorders evaluated for their validity and reliability (Miller
associated with dementia: the role of neurologists in et al., 1997). Moreover, it has been suggested that
Europe. European Federation of Neurological Societies.
most cases of FTD also meet diagnostic criteria for
Eur J Neurol 2000; 7: 133–44.
AD (Varma et al., 1999): it is known that AD criteria
Waldemar G, Dubois B, Emre M, et al. Alzheimer’s disease
have good sensitivity but poor specificity, hence
and other disorders associated with dementia. In:
Hughes R, Brainin M, Gilhus NE (eds.), European
misidentifying other dementias as AD. If so, FTLD
Handbook of Neurological Management. Oxford: cases may be misdiagnosed, and incidence and
Blackwell, 2006: 266–98 [also Eur J Neurol 2007; 14: e1–26]. prevalence underestimated. Reported prevalence
Warrington EK, Agnew SK, Kennedy AM, Rossor MN. rates of FTLD are around 15/100 000 (Ratnavalli
Neuropsychological profiles of familial Alzheimer’s et al., 2002; Rosso et al., 2003).
disease associated with mutations in the presenilin 1 Besides the clinical phenotype of primary
and amyloid precursor protein genes. J Neurol 2001; behavioural (frontal) or linguistic (temporal)
248: 45–50. decline, neuropsychological findings may be help-
Whitehead A, Perdomo C, Pratt RD, et al. Donepezil for
ful in differentiating FTD from AD (Hodges et al.,
the symptomatic treatment of patients with mild to
1999; Bozeat et al., 2000; Perry & Hodges, 2000).
moderate Alzheimer’s disease: a meta-analysis of
Subscores from the Addenbrooke’s Cognitive
individual patient data from randomised controlled
trials. Int J Geriatr Psychiatry 2004; 19: 624–33.
Examination (ACE), a bedside test of neuro-
psychological function, are claimed to facilitate the
distinction (Mathuranath et al., 2000; see Section
2.2 Frontotemporal lobar degenerations 1.8). Neuropsychiatric features may also help to
(FTLD) differentiate FTD from AD, such as stereotypic
behaviours, changes in eating preference, disin-
Arnold Pick, in the 1890s, was the first clinician to hibition, and poor social awareness (Bozeat et al.,
describe syndromes related to focal lobar degener- 2000; Bathgate et al., 2001).
ation of the brain, both frontal degeneration asso- Other investigations may help with the diagnosis:
ciated with behavioural change and temporal structural brain imaging (CT, MRI) may show focal
degeneration associated with linguistic decline frontal and/or temporal atrophy, often asymmetric,
(Graham & Hodges, 2005). The term ‘Pick’s disease’ and functional neuroimaging (SPECT, PET) may
came later, based on the neuropathological finding show frontotemporal hypoperfusion or hypometa-
(by Alzheimer) of ballooned achromatic neurones bolism. The EEG has been said to be normal, des-
(Pick cells) and neuronal inclusions (Pick bodies) in pite clinically evident dementia (this is one of the
some, but not all, cases of lobar degeneration. investigational diagnostic criteria of Neary et al.,
1998), in contrast to the situation in AD, although a Since this text is oriented to clinical practice,
recent study suggested that EEG abnormalities FTLDs will be considered according to clinical
were in fact present in more than 60% of FTLD presentation (behavioural, linguistic: Snowden
patients, increasing with dementia severity (Chan et al., 1996), followed by some additional notes
et al., 2004). about specific neuropathological entities. Cortico-
Although a universally acceptable nomenclature basal degeneration and progressive supranuclear
and taxonomy is not currently available, perhaps the palsy are considered under atypical parkinsonian
most significant distinction (at time of writing) is syndromes (Section 2.4.2 and 2.4.3, respectively).
between those FTLDs with neuropathological
appearances characterized by inclusions immuno-
positive for tau protein, and those without tau REFERENCES
inclusions but with ubiquitin immunopositive
inclusions (FTLD-U: Hodges et al., 2004; Cairns, Bathgate D, Snowden JS, Varma A, Blackshaw A, Neary D.
2006). Amongst the former group may be included Behaviour in frontotemporal dementia, Alzheimer’s
disease and vascular dementia. Acta Neurol Scand
‘true’ Pick’s disease (European Concerted Action on
2001; 103: 367–78.
Pick’s (ECAPD) Consortium, 1998), and fronto-
Bozeat S, Gregory CA, Lambon Ralph MA, Hodges JR.
temporal dementia with parkinsonism linked to
Which neuropsychiatric and behavioural features dis-
chromosome 17 (FTDP-17), associated with muta- tinguish frontal and temporal variants of frontotem-
tions in the tau gene. In the FTLD-U group may be poral dementia from Alzheimer’s disease? J Neurol
included some sporadic FTLD cases, FTD associ- Neurosurg Psychiatry 2000; 69: 178–86.
ated with or without clinical evidence of motor Brown J, Ashworth A, Gydesen S, et al. Familial non-
neurone disease (FTLD-MND and motor neurone specific dementia maps to chromosome 3. Hum Mol
disease inclusion dementia, MNDID, respectively: Genet 1995; 4: 1625–8.
see Section 2.3), and rare entities such as pure hip- Brun A, Englund B, Gustafson L, et al. Clinical and
pocampal sclerosis (Section 2.3.3) and FTD with neuropathological criteria for frontotemporal dementia.
J Neurol Neurosurg Psychiatry 1994; 57: 416–18.
inclusion body myopathy and Paget’s disease (Sec-
Cairns NJ. Neuropathology of frontotemporal lobar
tion 5.1.8). Some cases lack either tau or ubiquitin
degenerations. In: Strong MJ (ed.), Dementia and Motor
pathology and are labelled as ‘dementia lacking
Neuron Disease. Abingdon: Informa Healthcare, 2006:
distinctive histology’ (Knopman et al., 1990). Corti- 147–66.
cobasal degeneration and progressive supranuclear Chan D, Walters RJ, Sampson EL, et al. EEG abnormalities
palsy may also be subsumed under the rubric of in frontotemporal lobar degeneration. Neurology 2004;
FTLDs with tau inclusions (Kertesz & Munoz, 1998; 62: 1628–30.
Hodges et al., 2004; Cairns, 2006). European Concerted Action on Pick’s (ECAPD) Consor-
Neurogenetic studies also confirm the hetero- tium. Provisional clinical and neuroradiological criteria
geneity of FTLDs. FTDP-17 may be associated with for the diagnosis of Pick’s disease. Eur J Neurol 1998; 5:
mutations of either the tau or progranulin genes 519–20.
Graham A, Hodges J. Pick’s disease: its relationship to
(see Section 2.2.4). Besides FTDP-17, familial
progressive aphasia, semantic dementia and fronto-
FTLDs have also been described linked to
temporal dementia. In: Burns A, O’Brien J, Ames D
chromosomes 3 and 9. The former, in a Danish
(eds.), Dementia (3rd edition). London: Hodder Arnold,
kindred (Brown et al., 1995), was eventually found 2005: 678–88.
to have mutations in the charged multivesicular Gregory CA, Hodges JR. Dementia of frontal type and the
body protein 2B gene (CHMP2B: Skibinski et al., focal lobar atrophies. Int Rev Psychiatry 1993; 5: 397–406.
2005); the latter, in a family with FTLD and motor Hodges JR, Davies RR, Xuereb JH, et al. Clinicopatholo-
neurone disease (MND), in the dynactin gene gical correlates in frontotemporal dementia. Ann Neurol
(Munch et al., 2005). 2004; 56: 399–406.
Hodges JR, Patterson K, Ward R, et al. The differentiation of 2.2.1 Frontotemporal dementia (FTD),
semantic dementia and frontal lobe dementia (temporal dementia of frontal type (DFT),
and frontal variants of frontotemporal dementia) from frontal variant of frontotemporal dementia
early Alzheimer’s disease: a comparative neuropsycho- (fvFTD), behavioural variant of
logical study. Neuropsychology 1999; 13: 31–40.
frontotemporal dementia (bvFTD)
Kertesz A, Munoz DG (eds.). Pick’s Disease and Pick
Complex. New York: Wiley-Liss, 1998. This syndrome, variously known as FTD, DFT,
Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T. fvFTD, or bvFTD, is defined on the basis of a
Dementia lacking distinctive histologic features: a com- behavioural disorder, featuring declines in social
mon non-Alzheimer degenerative dementia. Neurology interpersonal conduct and the regulation of per-
1990; 40: 251–6.
sonal conduct, emotional blunting, and loss of
McKhann GM, Albert MS, Grossman M, et al. Clinical and
insight (Neary et al., 1998). Characteristics may
pathological diagnosis of frontotemporal dementia.
include neglect of personal hygiene, transgression
Report of the Work Group on Frontotemporal Dementia
and Pick’s disease. Arch Neurol 2001; 58: 1803–9.
of social mores, mental rigidity and inflexibility
Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, (increased adherence to routines, rituals, clock-
Hodges JR. A brief cognitive test battery to differentiate watching), changes in dietary habits with a predi-
Alzheimer’s disease and frontotemporal dementia. lection for sweet foods, motor and verbal perse-
Neurology 2000; 55: 1613–20. verations, disinhibition, or inertia. The syndrome is
Miller BL, Ikonte C, Ponton M, et al. A study of the Lund– not homogeneous, and clinical subtypes may be
Manchester research criteria for frontotemporal defined on the basis of the most prominent
dementia: clinical and single-photon emission CT behavioural and motor features: disinhibited type,
correlations. Neurology 1997; 48: 937–42.
with predominant orbitofrontal lobe involvement,
Munch C, Rosenbohm A, Sperfeld AD, et al. Heterozygous
apathetic type, with predominant dorsolateral
R1101K mutation of the DCTN1 gene in a family with
convexity involvement, and stereotypic type, with
ALS and FTD. Ann Neurol 2005; 58: 777–80.
Neary D, Snowden JS, Gustafson L, et al. Frontotemporal
predominant striatal involvement (Snowden et al.,
lobar degeneration: a consensus on clinical diagnostic 1996). Early diagnosis may be difficult, since
criteria. Neurology 1998; 51: 1546–54. neuropsychological tests and structural and func-
Perry RJ, Hodges JR. Differentiating frontal and temporal tional neuroimaging may not be sensitive to the
variant frontotemporal dementia from Alzheimer’s early changes in fvFTD (Gregory et al., 1999), which
disease. Neurology 2000; 54: 2277–84. may be associated with various pathologies
Ratnavalli E, Brayne C, Dawson K, Hodges JR. The (Hodges et al., 2004).
prevalence of frontotemporal dementia. Neurology
2002; 58: 1615–21.
Rosso SM, Donker KL, Baks T, et al. Frontotemporal Neuropsychological profile
dementia in the Netherlands: patient characteristics
and prevalence estimates from a population-based The neuropsychological deficits of fvFTD are
study. Brain 2003; 126: 2016–22. summarized in Table 2.2 and discussed in more
Skibinski G, Parkinson NJ, Brown J, et al. Mutations in the detail below.
endosomal ESCRTIII complex subunit CHMP2B in
frontotemporal dementia. Nat Genet 2005; 37: 806–8. Attention
Snowden JS, Neary D, Mann DMA. Fronto-Temporal Poor sustained attention, manifest as distractibility
Lobar Degeneration: Fronto-Temporal Dementia, Pro- or motor restlessness, may be an evident behav-
gressive Aphasia, Semantic Dementia. New York:
ioural feature in fvFTD (cf. AD). ‘Don’t know’
Churchill Livingstone, 1996.
responses may be frequent, especially for effortful
Varma AR, Snowden JS, Lloyd JJ, et al. Evaluation of
tasks, one feature of the lack of mental application,
the NINCDS-ADRDA criteria in the differentiation of
Alzheimer’s disease and frontotemporal dementia. or economy of effort, evident on clinical testing.
J Neurol Neurosurg Psychiatry 1999; 66: 184–8. Responses may be rapid and impulsive, with lack
Table 2.2. Neuropsychological deficits in frontal variant frontotemporal dementia (fvFTD).
Attention # Sustained attention; distractibility, apathy, economy of effort, poor self-monitoring,

impulsive
General intelligence, IQ FSIQ may be normal or # due to lack of mental effort
Memory Absence of amnesia may be a requirement for diagnosis; amnesia generally not
prominent but reported in some cases; better performance with cueing, and specific
as opposed to open-ended questions
Language # Verbal fluency (letter and category)
Perception Typically normal
Praxis Generally preserved; imitation and utilization behaviour may be seen
Executive function Lack of insight; impaired planning, judgment, abstraction, organization, and problem
solving; perseveration, failure to inhibit inappropriate responses
of attention to accuracy, or slowed in apathetic economy of effort in performing tests and poor
patients. sustained attention.
General intelligence, IQ Language

Performance may be normal on test batteries such In conversation, spontaneous speech output may
as the WAIS-R or MMSE, despite the change in be reduced, brief, and concrete in character.
behaviour. More usually, however, performance is Stereotyped words or phrases (‘catchphrases’) and
impaired. This may sometimes affect all areas, verbal perseverations may be evident; repetition is
reflecting lack of mental application to tests, or may relatively preserved. Output is fluent although
sometimes favour performance over verbal subtests. prosody may be lost. Comprehension is preserved
at the individual word level but may be impaired
Memory on tests of more complex items, perhaps related to
Some clinical diagnostic criteria require no lack of mental effort or self-monitoring, and
amnesia (Neary et al., 1998). However, severe rap- impulsive responding. Object naming is generally
idly progressive anterograde amnesia has been preserved, in contrast to difficulties with verbal
recorded on occasion in pathologically confirmed fluency, both letter and category. Progression to
FTD with prominent involvement of the hippo- eventual mutism may occur. Preservation of cal-
campi (Caine et al., 2001), and marked amnesia at culation skills despite dissolution of language has
presentation has been noted in other pathologic- been reported (Rossor et al., 1995). Acute aphasic
ally confirmed cases (Hodges et al., 2004; Graham presentation of clinically diagnosed frontal variant
et al., 2005). Semantic memory is stable in fvFTD FTD, following cardiac surgery, has been reported
(Perry & Hodges, 2000). (Larner, 2005).
Performance on memory tests is, however, often
impaired for both recall and recognition, despite Perception
patients, ability to provide autobiographical infor- Some clinical diagnostic criteria require no per-
mation and orientation in time (i.e. not evidently ceptual deficit (Neary et al., 1998). Visual agnosia is
amnesic clinically; cf. AD). Memory performance not apparent, and spatial skills are intact. Patients
may benefit from cues and from the use of specific may take long walks without becoming lost.
as opposed to open-ended questions. Poor per- Impaired performance on tests such as drawing the
formance may be related to the generalized Rey–Osterrieth Complex Figure may reflect cursory
performance with lack of attention to detail. Dot Treatment of neuropsychological deficits

counting and line orientation, undemanding tasks
Currently there are no licensed treatments for the
of visuospatial function, are typically normal.
neuropsychological deficits of fvFTD, although
Enhancement of artistic ability has been noted in
empirical treatments for behavioural features (e.g.
FTD (Miller et al., 1998).
mood stabilizers for disinhibition) might tempor-
arily improve some aspects of cognitive function. A
Praxis
trial of the serotonin reuptake inhibitor paroxetine
Manual skills are generally well preserved. Tests of
impaired cognition in fvFTD (Deakin et al., 2004).
praxis may reveal perseveration of gestures, writ-
ing, and alternating hand movements or motor
sequences, although copying of hand postures is
generally performed better. Use of body part as REFERENCES
object is typical when pantomiming actions. Con-
textually inappropriate use of objects, utilization Caine D, Patterson K, Hodges JR, Heard R, Halliday G.
behaviour, may occur. Dependent upon the topo- Severe anterograde amnesia with extensive hippocam-
pal degeneration in a case of rapidly progressive
graphical distribution of pathology, a phenotype
frontotemporal dementia. Neurocase 2001; 7: 57–64.
resembling corticobasal degeneration may occur
Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ.
occasionally (Doran et al., 2003).
Paroxetine does not improve symptoms and impairs
cognition in frontotemporal dementia: a double-blind
Executive function randomized controlled trial. Psychopharmacol 2004;
A dysexecutive syndrome is typical of fvFTD, 172: 400–8.
manifest as lack of insight and impaired planning, Doran M, du Plessis DG, Enevoldson TP, et al. Patho-
judgment, abstraction, organization, and problem logical heterogeneity of clinically diagnosed corticoba-
solving. Tests deemed sensitive to frontal lobe sal degeneration. J Neurol Sci 2003; 216: 127–34.
function are performed poorly. For example, in the Graham A, Davies R, Xuereb J, et al. Pathologically proven
WAIS-R, the Similarities subtest may be impaired frontotemporal dementia presenting with severe
amnesia. Brain 2005; 128: 597–605.
due to difficulties in abstracting similarities between
Gregory CA, Serra Mestres J, Hodges JR. Early diagnosis of
objects, and Picture Arrangement to tell a story may
the frontal variant of frontotemporal dementia: how
not be completed, although individual elements can
sensitive are standard neuroimaging and neuropsycho-
be identified and described. Proverb interpretation logic tests? Neuropsychiatry Neuropsychol Behav Neurol
is concrete and cognitive estimates may be wildly 1999; 12: 128–35.
inaccurate. As previously mentioned, verbal fluency Hodges JR, Davies RR, Xuereb JH, et al. Clinicopatholo-
is impaired for both letter and category; design flu- gical correlates in frontotemporal dementia. Ann Neurol
ency, the visual analogue of verbal fluency, is also 2004; 56: 399–406.
impaired, with multiple rule violations. Sorting rules Larner AJ. ‘Dementia unmasked’: atypical, acute aphasic,
are not identified and perseverative errors common presentations of neurodegenerative dementing disease.
in both the Weigl and the Wisconsin Card Sorting Clin Neurol Neurosurg 2005; 108: 8–10.
Lo Coco D, Nacci P. Frontotemporal dementia presenting
Test. Failure to inhibit inappropriate responses may
with pathological gambling. J Neuropsychiatry Clin
be encountered on the Stroop Colour Word Test. In
Neurosci 2004; 16: 117–18.
mild fvFTD, however, risk-taking behaviour with
Miller BL, Cummings J, Mishkin F, et al. Emergence of
increased deliberation time may be the only finding, artistic talent in frontotemporal dementia. Neurology
with other tests sensitive to frontal lobe function 1998; 51: 978–82.
remaining normal (Rahman et al., 1999). FvFTD Neary D, Snowden JS, Gustafson L, et al. Frontotemporal
presenting with pathological gambling has been lobar degeneration: a consensus on clinical diagnostic
reported (Lo Coco & Nacci, 2004). criteria. Neurology 1998; 51: 1546–54.
Perry RJ, Hodges JR. Differentiating frontal and temporal Pick’s disease and Alzheimer’s disease may also be
variant frontotemporal dementia from Alzheimer’s seen (Davies et al., 2005; Godbolt et al., 2005).
disease. Neurology 2000; 54: 2277–84.
Rahman S, Sahakian BJ, Hodges JR, Rogers RD, Robbins
TW. Specific cognitive deficits in mild frontal variant Neuropsychological profile
frontotemporal dementia. Brain 1999; 122: 1469–93.
The neuropsychological deficits of semantic demen-
Rossor M, Warrington EK, Cipolotti L. The isolation of
tia are shown in Table 2.3.
calculation skills. J Neurol 1995; 242: 78–81.
Snowden JS, Neary D, Mann DMA. Fronto-Temporal
Lobar Degeneration: Fronto-Temporal Dementia, Pro- Attention
gressive Aphasia, Semantic Dementia. New York: In contrast to fvFTD, sustained attention to tasks is
Churchill Livingstone, 1996: 9–58. good in semantic dementia. Working memory is
intact as assessed by digit span and by Corsi span,
at least until the very late stages of the disease.
2.2.2 Semantic dementia (SD), progressive
fluent aphasia, temporal variant of
General intelligence, IQ
frontotemporal dementia (tvFTD)
Performance on the WAIS-R is typically impaired.
Warrington (1975) was the first to report patients For patients with a disorder of word meaning, a
with selective impairment of semantic memory verbal–performance discrepancy favouring per-
causing a progressive anomia. The linguistic vari- formance is evident, with subtest scores reflecting
ant of FTD now generally known as semantic the semantic component of each task, the most
dementia is characterized by a loss of the know- impaired being Vocabulary, Comprehension, Infor-
ledge about items and their meanings. It affects mation, Similarities, Picture Completion, and Picture
naming, word comprehension, and object recog- Arrangement, whilst Block Design remains intact.
nition, with relatively stable attention and pre-
served executive function (Poeck & Luzzatti, 1988; Memory
Hodges et al., 1992; Snowden et al., 1996; Garrard & Episodic memory is relatively preserved. Patients are
Hodges, 2000; Perry & Hodges, 2000). Activities of not amnesic, since they can relate details about recent
daily living are relatively well preserved. activities. However, autobiographical memory for
The neuroradiological signature of SD is asym- remote events is more impaired (Graham & Hodges,
metric focal atrophy of all anterior temporal lobe 1997; Larner et al., 2005), a reversal of the temporal
structures, especially entorhinal cortex, amygdala, gradient effect seen in Alzheimer’s disease. Semantic
anterior medial and inferior temporal gyri, and memory is severely impaired; there is a breakdown in
anterior fusiform gyrus, with an anteroposterior factual knowledge. Depending on the lateralization of
gradient of atrophy (cf. AD: symmetrical atrophy, brain atrophy, this may be more evident for verbal or
especially medial temporal lobe structures includ- visual material. Cued recall shows no advantage over
ing hippocampus, with no anteroposterior gradi- free recall, indicating breakdown or impaired access
ent; Chan et al., 2001). Left-sided cases of semantic to semantic knowledge.
dementia are apparently more common than right-
sided (Thompson et al., 2003), but this may be Language
artefactual, the profound anomia drawing atten- There is a selective breakdown in the lexicosemantic
tion to the former cases whereas progressive pro- aspects of language. ‘Loss of memory for words’ is
sopagnosia associated with right-sided cases may often the main presenting complaint, with relatives
not come to clinical attention. The commonest and carers providing examples of the patient’s loss of
neuropathological substrate is MND-type ubiquitin- word meaning (‘What’s Coca-Cola?’, ‘What’s a
positive tau-negative inclusions, although true hobby?’). Marked anomia is evident on testing;
Table 2.3. Neuropsychological deficits in semantic dementia (SD).
Attention Essentially intact

General intelligence, IQ # FSIQ; VIQ typically more impaired than PIQ due to semantic deficit
Memory Absence of amnesia for recent events; remote autobiographical memory may be
impaired; semantic memory severely impaired
Language Marked anomia; # verbal fluency (category > letter). Comprehension impaired; syntax,
grammar preserved; surface dyslexia (regularization errors)
Perception Essentially intact
Praxis Essentially intact
Executive function # Verbal fluency; frontal features may gradually emerge
moreover, unlike the situation in AD, patients are Rey–Osterrieth Complex Figure, and object
often unable to provide any contextual information matching are intact. Object recognition failure
about objects they cannot name: a patient with AD reflects the breakdown in semantics.
unable to name a picture of a kangaroo may none-
theless be able to say that it jumps and is found in Praxis
Australia, but such details are not available to the Praxis is generally intact in semantic dementia,
patient with SD with degradation of, or loss of access although motor skills with a symbolic basis may be
to, semantic memory. Providing semantically related impaired.
multiple choice alternatives is not helpful. Repetition
is common, for example of overlearned words and Executive function
phrases or of the examiner’s questions, although As previously mentioned, tests of sustained attention
there may be inability to understand what is being are intact but tests thought sensitive in part to
repeated. Verbal fluency tasks are severely impaired, frontal lobe function such as verbal fluency are
letter generally being superior to category since the impaired. The Weigl may be completed but patients
latter is reliant upon access to semantic knowledge. may fail to understand the instructions for the Wis-
There may also be difficulty recognizing familiar consin Card Sorting Test. Behavioural features rem-
faces (progressive prosopagnosia: Evans et al., 1995). iniscent of fvFTD may occasionally be present in
Conversational speech is fluent, syntactically and semantic dementia, such as apathy, irritability, and
grammatically correct, but may demonstrate disinhibition. However, in contrast to the impul-
anomia, and use of superordinate categories (e.g. siveness which compromises fvFTD patients’ per-
all animals are called dogs). Reading often dem- formance on gambling tasks, we have seen a patient
onstrates regularization errors when reading words with SD who was still able to bet regularly on horse
with irregular sound–spelling correspondence, for racing with moderate, better than break-even, suc-
example ‘pint’ read to rhyme with ‘mint’, the cess, despite being essentially mute (Larner, 2007).
phenomenon of surface dyslexia. As the disease
progresses, utterances may become increasingly
REFERENCES
brief and stereotyped.
Chan D, Fox NC, Scahill RI, et al. Patterns of temporal lobe

Perception atrophy in semantic dementia and Alzheimer’s disease.
Visuoperceptual and visuospatial function is pre- Ann Neurol 2001: 49: 433–42.
served. Tests such as Raven’s Progressive Matrices, Davies RR, Hodges JR, Kril JJ, et al. The pathological basis
Judgment of Line Orientation, copy of the of semantic dementia. Brain 2005; 128: 1984–95.
Evans JJ, Heggs AJ, Antoun N, Hodges JR. Progressive living until late in the illness. It is probably the
prosopagnosia associated with selective right tem- rarest of the FTLD syndromes.
poral lobe atrophy: a new syndrome? Brain 1995; 118: Diagnostic criteria have been suggested (Mesulam,
1–13. 2001), in part to exclude cases of AD with linguistic
Garrard P, Hodges JR. Semantic dementia: clinical,
presentation. Clinical heterogeneity is apparent
radiological and pathological perspectives. J Neurol
(Duffy & Petersen, 1992; Mesulam & Weintraub,
2000; 247: 409–22.
1992; Snowden et al., 1996; Westbury & Bub, 1997;
Godbolt AK, Josephs KA, Revesz T, et al. Sporadic and
familial dementia with ubiquitin-positive tau-negative
Kertesz, 1998; Amici et al., 2006), as is also the case
inclusions: clinical features of one histopathological for the pathological substrate, although non-fluent
abnormality underlying frontotemporal lobar degener- aphasia more reliably predicts Pick body pathology
ation. Arch Neurol 2005; 62: 1097–101. (Hodges et al., 2004). Most cases are sporadic;
Graham KS, Hodges JR. Differentiating the roles of the although some familial cases have been reported
hippocampal complex and the neocortex in long-term (Krefft et al., 2003), discordance in monozygotic
memory storage: evidence from the study of semantic twins has also been recorded (Doran & Larner,
dementia and Alzheimer’s disease. Neuropsychology 2004), suggesting genetic heterogeneity. Cases of
1997; 11: 77–89.
primary progressive aphasia which evolve over time
Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic
to the phenotype of corticobasal degeneration
dementia: progressive fluent aphasia with temporal
(Sakurai et al., 1996; Mimura et al., 2001; Ferrer et al.,
lobe atrophy. Brain 1992; 115: 1783–806.
Larner AJ. Gambling. Adv Clin Neurosci Rehabil 2007; 7
2003; Le Rhun et al., 2005) or progressive supra-
(1): 26. nuclear palsy (Boeve et al., 2003; Mochizuki et al.,
Larner AJ, Brookfield K, Flynn A, et al. The cerebral 2003) have been reported.
metabolic topography of semantic dementia. J Neurol
2005; 252 (suppl 2): II106 (abstract P399).
Perry RJ, Hodges JR. Differentiating frontal and temporal
variant frontotemporal dementia from Alzheimer’s The description (Table 2.4) is for a ‘pure’ case,
disease. Neurology 2000; 54: 2277–84. without features of any other underlying neuro-
Poeck K, Luzzatti C. Slowly progressive aphasia in three
pathological entity such as AD, corticobasal
patients: the problem of accompanying neuropsycho-
degeneration, or progressive supranuclear palsy.
logical deficit. Brain 1988; 111: 151–68.
Snowden JS, Neary D, Mann DMA. Fronto-Temporal
Lobar Degeneration: Fronto-Temporal Dementia, Pro-
Attention
gressive Aphasia, Semantic Dementia. New York: Attentional functions are preserved in progressive
Churchill Livingstone, 1996: 91–114. non-fluent aphasia.
Thompson SA, Patterson K, Hodges JR. Left/right asym-
metry of atrophy in semantic dementia: behavioural– General intelligence, IQ
cognitive implications. Neurology 2003; 61: 1196–203. A verbal–performance discrepancy on the WAIS-R
Warrington EK. The selective impairment of semantic in favour of non-verbal tasks is found.
memory. Q J Exp Psychol 1975; 27: 635–57.
Memory
Functional memory skills appear intact, although
2.2.3 Progressive non-fluent aphasia (PNFA),
scores on memory tests may be impaired because
primary progressive aphasia (PPA)
of the language disorder, especially for verbal tests.
This syndrome was first described as such by Recognition memory for faces is typically well
Mesulam (1982). It is characterized by progressive preserved. Likewise, impaired category verbal flu-
non-fluent aphasia with relative preservation of ency is due to language deficits rather than
other cognitive functions and activities of daily impaired semantic memory.
Table 2.4. Neuropsychological deficits in progressive non-fluent aphasia (PNFA).
Attention Essentially intact

General Intelligence, IQ # FSIQ; VIQ typically more impaired than PIQ due to linguistic impairment
Memory Essentially intact; impaired scores may reflect linguistic impairment
Language Phonological and syntactic breakdown; comprehension preserved; # verbal fluency
(letter > category)
Praxis Essentially intact
Executive Function # Verbal fluency, otherwise intact
Language REFERENCES
There is progressive breakdown of phonological and
syntactic processes resulting in progressive non- Amici S, Gorno-Tempini ML, Ogar JM, Dronkers NF,
fluent aphasia. Speech output is hesitant and effort- Miller BL. An overview on primary progressive aphasia
ful, with phonemic paraphasias and transpositional and its variants. Behav Neurol 2006; 17: 77–87.
errors (‘Spoonerisms’). Comprehension is largely Boeve BF, Dickson D, Duffy J, et al. Progressive nonfluent
intact, at least initially, for example in word–picture aphasia and subsequent aphasic dementia associated
with atypical progressive supranuclear palsy pathology.
matching tasks, although complex syntax may prove
Eur Neurol 2003; 49: 72–8.
difficult. Increasing comprehension problems
Doran M, Larner AJ. Monozygotic twins discordant for
develop with disease progression. Repetition is
primary progressive aphasia. Alzheimer Dis Assoc Disord
severely impaired, as is naming to confrontation or 2004; 18: 48–9.
description, although semantic information about Duffy JR, Petersen RC. Primary progressive aphasia.
the item which cannot be named may be provided Aphasiology 1992; 6: 1–15.
and the correct word can be selected from alterna- Ferrer I, Hernandez I, Boada M, et al. Primary progressive
tives: hence this is a problem of lexical access or aphasia as the initial manifestation of corticobasal
phonological selection. Verbal fluency is typically degeneration and unusual tauopathies. Acta Neuro-
better for category than for letter. Reading and writing pathol (Berl) 2003; 106: 419–35.
deficits mirror those in spoken language. Loss of Hodges JR, Davies RR, Xuereb JH, et al. Clinicopatholo-
gical correlates in frontotemporal dementia. Ann Neurol
prosody, a telegraphic quality to speech output, and
2004; 56: 399–406.
diminution to the point of mutism occur over time.
Kertesz A. Primary progressive aphasia. In: Kertesz A,
Munoz DG (eds.), Pick’s Disease and Pick Complex. New
Perception York: Wiley-Liss, 1998: 69–81.
Visuoperceptual and visuospatial function is Krefft TA, Graff-Radford NR, Dickson DW, Baker M,
essentially preserved, any errors resulting from Castellani RJ. Familial primary progressive aphasia.
linguistic rather than perceptual dysfunction. Alzheimer Dis Assoc Disord 2003; 17: 106–12.
Le Rhun E, Richard F, Pasquier F. Natural history of
Praxis primary progressive aphasia. Neurology 2005; 65: 887–91.
Mesulam MM. Slowly progressive aphasia without gener-
Praxis is generally intact. Apraxia for symbolic
alized dementia. Ann Neurol 1982; 11: 592–8.
action may emerge in the later stages.
Mesulam MM. Primary progressive aphasia. Ann Neurol
2001; 49: 425–32.
Executive function Mesulam MM, Weintraub S. Spectrum of primary pro-
Any deficits on tests of executive function may be gressive aphasia. In: Rossor MN (ed.), Unusual
explicable in terms of language deficits. Dementias. London: Bailliere Tindall, 1992: 583–609.
Mimura M, Oda T, Tsuchiya K, et al. Corticobasal www.molgen.ua.ac.be/Admutations). More recently,

degeneration presenting with nonfluent primary pro- a further genetic mutation has been defined in
gressive aphasia: a clinicopathological study. J Neurol FTDP families linked to chromosome 17q21 but
Sci 2001; 183: 19–26. with normal tau gene sequence, in the gene
Mochizuki A, Ueda Y, Komatsuzaki Y, et al. Progressive
encoding progranulin (Baker et al., 2006; Cruts
supranuclear palsy presenting with primary progressive
et al., 2006)
aphasia: clinicopathological report of an autopsy case.
Clinical and pathological heterogeneity of FTDP-
Acta Neuropathol (Berl) 2003; 105: 610–14.
Sakurai Y, Hashida H, Uesugi H, et al. A clinical profile of
17 cases has become increasingly apparent: in
corticobasal degeneration presenting as primary pro- addition to the prototypical behavioural FTD
gressive aphasia. Eur Neurol 1996; 36: 134–7. phenotype, cases are also described with the clinical
Snowden JS, Neary D, Mann DMA. Fronto-Temporal features of progressive supranuclear palsy (PSP:
Lobar Degeneration: Fronto-Temporal Dementia, Pro- Delisle et al., 1999; Pastor et al., 2001; Wszolek et al.,
gressive Aphasia, Semantic Dementia. New York: 2001; Morris et al., 2003; Ros et al., 2005), cortico-
Churchill Livingstone, 1996: 73–90. basal degeneration (CBD: Bugiani et al., 1999),
Westbury C, Bub D. Primary progressive aphasia: a review idiopathic Parkinson’s disease (Pastor et al., 2001),
of 112 cases. Brain Lang 1997; 60: 381–406.
Alzheimer’s disease (van Swieten et al., 1999; Mirra
et al., 1999; Doran et al., 2007), and respiratory
2.2.4 Frontotemporal dementia with failure (Nicholl et al., 2003), and with the neuro-
parkinsonism linked to chromosome 17 pathological features of PSP and CBD (Bird et al.,
(FTDP-17) 1999; Nasreddine et al., 1999). Clinical heterogeneity
may be observed with the same tau mutation, with
Frontotemporal dementia with parkinsonism linked presentation as prototypical FTD or with memory
to chromosome 17 (FTDP-17) was the umbrella deficits mistaken for AD reported with the R406W
term coined by Foster et al. (1997) to describe (van Swieten et al., 1999; Saito et al., 2002) and
autosomal dominant kindreds linked to chromo- 10þ16 (Janssen et al., 2002; Pickering-Brown et al.,
some 17q21–22 with a highly penetrant clinical 2002; Doran et al., 2007) mutations.
phenotype of frontotemporal dementia and par- Identification of tau mutation carriers has per-
kinsonism (Wilhelmsen et al., 1994). Prior to this, mitted presymptomatic testing of neuropsycho-
various clinical and clinicopathological labels logical function, many years before expected
had been used, including disinhibition–dementia– disease onset. Asymptomatic members of a large
parkinsonism–amyotrophy complex (DDPAC: Lynch French-Canadian kindred known to carry the
et al., 1994), hereditary dysphasic disinhibition P301L tau mutation (Nasreddine et al., 1999)
dementia (HDDD: Lendon et al., 1998), pallido- underwent neuropsychological evaluation and
ponto-nigral degeneration (PPND: Wszolek et al., mutation screening. Despite similar mean age, age
1992), progressive subcortical gliosis (Lanska et al., range, gender, and educational level, mutation
1994), and multiple system tauopathy with pre- carriers were impaired in tasks testing frontal
senile dementia (MSTD: Spillantini et al., 1997). executive and attentional functions, such as verbal
Pathogenic mutations in the gene encoding the fluency, Wisconsin Card Sorting Test categories
microtubule-associated protein tau deterministic completed, Stroop interference test, WAIS-R simi-
for FTDP-17 were first described in 1998 (Hutton larities and digit span subtests, and Trails B, com-
et al., 1998; Poorkaj et al., 1998; Spillantini et al., pared to those without tau mutations. However,
1998), since when around 30 different mutations verbal and spatial memory, language, and visuo-
have been described (Forman et al., 2004; motor constructive abilities were preserved in the
Mann, 2005; see also the Alzheimer Disease and mutation carriers. Hence the deficits in the muta-
Frontotemporal Dementia Mutation Database, tion carriers mirrored those seen at the onset of
clinical disease, but many years before the Hutton M, Lendon CL, Rizzu P, et al. Association of
expected age of onset. This observation has raised missense and 50 splice site mutations in tau with
the possibility that certain brain areas are more the inherited dementia FTDP-17. Nature 1998; 393:
vulnerable due to reduced reserve, hence explain- 702–5.
Janssen JC, Warrington EK, Morris HR, et al. Clinical
ing the focal clinical presentation, perhaps indi-
features of frontotemporal dementia due to the intronic
cating a neurodevelopmental component to
tau 10+16 mutation. Neurology 2002; 58: 1161–8.
disease phenotype (Geschwind et al., 2001).
Lanska DJ, Currier RD, Cohen M, et al. Familial progres-
sive subcortical gliosis. Neurology 1994; 44: 1633–43.
Lendon CL, Lynch T, Norton J, et al. Hereditary dysphasic
REFERENCES disinhibition dementia: a frontotemporal dementia
linked to 17q21–22. Neurology 1998; 50: 1546–55.
Baker M, Mackenzie IR, Pickering-Brown SM, et al. Lynch T, Sano M, Marder KS, et al. Clinical characteristics
Mutations in progranulin cause tau-negative fronto- of a family with chromosome 17-linked disinhibition–
temporal dementia linked to chromosome 17. Nature dementia–parkinsonism–amyotrophy complex. Neurol-
2006; 442: 916–19. ogy 1994; 44: 1878–84.
Bird TD, Nochlin D, Poorkaj P, et al. A clinical pathological Mann DMA. The genetics and molecular pathology of
comparison of three families with frontotemporal frontotemporal lobar degeneration. In: Burns A, O’Brien
dementia and identical mutations in the tau gene J, Ames D (eds.), Dementia (3rd edition). London:
(P301L). Brain 1999; 122: 741–56. Hodder Arnold, 2005: 689–701.
Bugiani O, Murrell JR, Giaccone G, et al. Frontotemporal Mirra SS, Murrell JR, Gearing M, et al. Tau pathology in a
dementia and corticobasal degeneration in a family family with dementia and a P301L mutation in tau. J
with a P301S mutation in tau. J Neuropathol Exp Neurol Neuropathol Exp Neurol 1999; 58: 335–45.
1999; 58: 667–77. Morris HR, Osaki Y, Holton J, et al. Tau exon 10þ16
Cruts M, Gijselinck I, van der Zee J, et al. Null mutations in mutation FTDP-17 presenting clinically as sporadic
progranulin cause ubiquitin-positive frontotemporal young onset PSP. Neurology 2003; 61: 102–4.
dementia linked to chromosome 17q21. Nature 2006; Nasreddine ZS, Loginov M, Clark LN, et al. From genotype
442: 920–4. to phenotype: a clinical, pathological and biochemical
Delisle MB, Murrell JR, Richardson R, et al. A mutation at investigation of frontotemporal dementia and parkin-
codon 279 (N279K) in exon 10 of the tau gene causes a sonism (FTDP-17) caused by the P301L tau mutation.
tauopathy with dementia and supranuclear palsy. Acta Ann Neurol 1999; 45: 704–15.
Neuropathol (Berl) 1999; 98: 62–77. Nicholl DJ, Greenstone MA, Clarke CE, et al. An English
Doran M, du Plessis DG, Ghadiali EJ, et al. Familial early- kindred with a novel recessive tauopathy and respira-
onset dementia with tau intron 10þ16 mutation with tory failure. Ann Neurol 2003; 54: 682–6.
clinical features similar to those of Alzheimer disease. Pastor P, Pastor E, Carnero C, et al. Familial atypical
Arch Neurol 2007; 64: 1535–9. progressive supranuclear palsy associated with homo-
Forman MS, Trojanowski JQ, Lee VMY. Hereditary tauo- zygosity for the delN296 mutation in the tau gene. Ann
pathies and idiopathic frontotemporal dementias. In: Neurol 2001; 49: 263–7.
Esiri MM, Trojanowski JQ, Lee VMY (eds.), The Neuro- Pickering-Brown SM, Richardson AMT, Snowden JS, et al.
pathology of Dementia (2nd edition). Cambridge: Inherited frontotemporal dementia in nine British
Cambridge University Press, 2004: 257–88. families associated with intronic mutations in the tau
Foster NL, Wilhelmsen K, Sima AAF, et al. Frontotemporal gene. Brain 2002; 125: 732–51.
dementia and parkinsonism linked to chromosome 17: Poorkaj P, Bird T, Wijsman E, et al. Tau is a candidate gene
a consensus conference. Ann Neurol 1997; 41: 706–15. for chromosome 17 frontotemporal dementia. Ann
Geschwind DH, Robidoux J, Alarcón M, et al. Dementia Neurol 1998; 43: 815–25.
and neurodevelopmental predisposition: cognitive dys- Ros R, Thobois S, Streichenberger N, et al. A new
function in presymptomatic subjects precedes demen- mutation of the s gene, G303V, in early-onset familial
tia by decades in frontotemporal dementia. Ann Neurol progressive supranuclear palsy. Arch Neurol 2005; 62:
2001; 50: 741–6. 1444–50.
Saito Y, Geyer A, Sasaki R, et al. Early-onset, rapidly be classified as FTDP-17. Cases with the pheno-
progressive familial tauopathy with R406W mutation. type of Alzheimer’s disease (Neumann & Cohn,
Neurology 2002; 58: 811–13. 1967; Lanska et al., 1994, 1998), Creutzfeldt–Jakob
Spillantini MG, Goedert M, Crowther RA, et al. Familial disease (Seitelberger, 1968; Bergmann et al., 1991),
multiple system tauopathy with presenile dementia: a
and progressive supranuclear palsy (Will et al.,
disease with abundant neuronal and glial tau filaments.
1988) have also been reported. The profile of
Proc Natl Acad Sci USA 1997; 94: 4113–18.
neuropsychological deficits might be anticipated
Spillantini MG, Murrell JR, Goedert M, et al. Mutation in
the tau gene in familial multiple system tauopathy with
to vary accordingly. Two reports have appeared
presenile dementia. Proc Natl Acad Sci USA 1998; 95: claiming that PSG is a prion disorder (Petersen
7737–41. et al., 1995; Revesz et al., 1995), one later retracted
van Swieten JC, Stevens M, Rosso SM, et al. Phenotypic (Gambetti, 1997).
variation in hereditary frontotemporal dementia with
tau mutations. Ann Neurol 1999; 46: 617–26.
Wilhelmsen KC, Lynch T, Pavlov E, Higgins M, Nygaard TG.
REFERENCES
Localization of disinhibition–dementia–parkinsonism–
amyotrophy complex to 17q21–22. Am J Hum Genet
1994; 55: 1159–65. Bergmann M, Gullotta F, Weitbrecht WU. Progressive
Wszolek ZK, Pfeiffer RF, Bhatt MH, et al. Rapidly subkortikale Gliose. Fortschr Neurol Psychiatr 1991; 59:
progressive autosomal dominant parkinsonism and 328–34.
dementia with pallido-ponto-nigral degeneration. Ann Gambetti P. Prion in progressive subcortical gliosis
Neurol 1992; 32: 312–20. revisited. Neurology 1997; 49: 309–10.
Wszolek ZK, Tsuboi Y, Uitti RJ, et al. Progressive supra- Goedert M, Spillantini MG, Crowther RA, et al. Tau gene
nuclear palsy as a disease phenotype caused by the mutation in familial progressive subcortical gliosis.
S305S tau gene mutation. Brain 2001; 124: 1666–70. Nature Med 1999; 5: 454–7.
Lanska DJ, Currier RD, Cohen M, et al. Familial progres-
sive subcortical gliosis. Neurology 1994; 44: 1633–43.
2.2.5 Progressive subcortical gliosis Lanska DJ, Markesbery WR, Cochran E, et al. Late-onset
(of Neumann) sporadic progressive subcortical gliosis. J Neurol Sci
1998; 157: 143–7.
The term progressive subcortical gliosis (PSG) was Larner AJ, Smith ETS, Doran M. Does MRI/MRS permit
first suggested by Neumann and Cohn (1967) to ante mortem diagnosis of progressive subcortical gliosis
describe a rare dementing disorder with typical of Neumann? J Neurol Neurosurg Psychiatry 2003; 74:
histopathological findings, namely frontotemporal 404 (abstract 29).
atrophy with a distinctive distribution of fibrillary Neumann MA, Cohn R. Progressive subcortical gliosis, a
astrogliosis in the superficial and deep cerebral rare form of presenile dementia. Brain 1967; 90: 405–18.
cortical layers, as well as in the subcortical white Petersen RB, Tabaton M, Chen SG, et al. Familial
matter, the latter sometimes extending to the basal progressive subcortical gliosis: presence of prions and
linkage to chromosome 17. Neurology 1995; 45: 1062–7.
ganglia, thalamus, brainstem, and even to the
Revesz T, Daniel SE, Lees AJ, Will RG. A case of progressive
ventral horns of the spinal cord. Amyloid plaques,
subcortical gliosis associated with deposition of abnor-
neurofibrillary tangles, Pick cells, and Pick bodies
mal prion protein (PrP). J Neurol Neurosurg Psychiatry
were not seen. The clinical correlate of these neu- 1995; 58: 759–60.
ropathological findings is variable. Some reported Seitelberger F. Präsenile gliale Dystrophie. Acta Neuro-
cases have the clinical features of prototypical pathol (Berl) 1968; Suppl 4: 109–18.
FTD (Neumann & Cohn, 1967; Vermersch et al., Vermersch P, Daems-Monpeurt C, Parent M, et al.
1994; Larner et al., 2003), including one family Démence sous-corticale type Neumann. Apport de
with an underlying tau gene mutation (Petersen l’imagérie morphologique et fonctionnelle. Rev Neurol
et al., 1995; Goedert et al., 1999) which would now (Paris) 1994; 150: 354–8.
Will RG, Lees AJ, Gibb W, Barnard RO. A case of progressive Tolnay M, Clavaguera F. Argyrophilic grain disease: a late-
subcortical gliosis presenting clinically as Steele– onset dementia with distinctive features among tauo-
Richardson–Olszewski syndrome. J Neurol Neurosurg pathies. Neuropathology 2004; 24: 269–83.
Psychiatry 1988; 51: 1224–7.
2.2.7 Neurofibrillary tangle dementia (NTD),

2.2.6 Argyrophilic grain disease (AGD) diffuse neurofibrillary tangles with
calcification (DNTC, Kosaka–Shibayama
This condition is defined neuropathologically
disease)
(Braak & Braak, 1998) by the presence of spindle-
shaped argyrophilic grains in neuronal processes Neurofibrillary tangle dementia (NTD; senile
and coiled bodies in oligodendrocytes composed dementia with tangles) is a form of late-life dementia
of tau protein, mainly in limbic regions (hippo- characterized by medial temporal lobe neurofibrillary
campus, entorhinal and transentorhinal cortices, tangles and neuropil threads but without amyloid
amygdala). Immunohistochemical and biochem- deposits. The clinical correlate is Alzheimer’s disease
ical studies have shown AGD to be a four-repeat (Ulrich et al., 1992; Bancher & Jellinger, 1994) or
(4R) tauopathy, like PSP and CBD and unlike AD frontotemporal dementia (McKhann et al., 2001).
(Togo et al., 2002). Macroscopically there is atro- Diffuse neurofibrillary tangles with calcification
phy of frontal and temporal lobes with little or no (DNTC; Kosaka–Shibayama disease), a condition
atrophy of the hippocampus and amygdala, but which pathologically resembles NTD, is mostly
the clinical phenotype is similar to the limbic reported from Japan. It is characterized radio-
dementias such as AD (Tolnay & Clavaguera, logically by temporal or temporofrontal atrophy,
2004). AGD is said to affect 5% of all patients with with pallidal and cerebellar calcification typical of
dementia, particularly the elderly. No, or only that seen in Fahr’s syndrome (see Section 5.1.7),
sparse, AD pathology is the norm, but concur- and pathologically by neuronal loss, astrocytosis,
rence of AD and AGD may lower the threshold for and neurofibrillary tangles but without senile
AD-related cognitive deficits (Thal et al., 2005). plaques, features which may be attended by the
Because of the tau inclusions and frontotemporal clinical correlate of a presenile, cortical, dementia
atrophy, AGD may be classified with the FTLDs (Kosaka, 1994). Cases without dementia have also
with tau inclusions. been reported (Langlois et al., 1995; Kosaka &
Ikeda, 1996). The tau pathology seems to comprise
a mixture of 3 and 4 repeat isoforms as in AD
REFERENCES (Tanabe et al., 2000). Increased brain lead content
has also been noted, suggesting the possibility of
Braak H, Braak E. Argyrophilic grain disease: frequency of lead neurotoxicity (Haraguchi et al., 2001).
occurrence in different age categories and neuropatho- Neuropsychological assessments show decline in
logical diagnostic criteria. J Neural Transm 1998; 105: memory retention and intelligence, and anomic
801–19. aphasia (Ito et al., 2003). Reduced blood flow and
Thal DR, Schultz C, Botez G, et al. The impact of metabolism in the temporal lobes has been
argyrophilic grain disease on the development of observed on functional imaging, without change
dementia and its relationship to concurrent Alzheimer’s
in the basal ganglia or cerebellum, suggesting that
disease-related pathology. Neuropath Appl Neurobiol
the calcification and neurodegeneration occur
2005; 31: 270–9.
independently (Ito et al., 2003). However, Fahr’s
Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease
is a sporadic 4-repeat tauopathy. J Neuropathol Exp
syndrome presenting with a pure and progressive
Neurol 2002; 61: 547–56. dementia has been reported (Modrego et al.,
2005), suggesting that brain calcification per se such as personality change, apathy, disinhibition,
may not be innocuous to cognitive function. blunted affect, memory and language impairments.
Neurological features may also be present, includ-
ing extrapyramidal signs, hyperreflexia, orofacial
REFERENCES apraxia, and supranuclear ophthalmoplegia. Neu-
roimaging and macroscopic pathological examin-
Bancher C, Jellinger KA. Neurofibrillary tangle predominant ation show frontotemporal atrophy, also involving
form of senile dementia of Alzheimer type: a rare subtype in the caudate nucleus. Neuropathology is typical of
very old subjects. Acta Neuropathol (Berl) 1994; 88: 565–70.
FTLDs, with neuronal loss, status spongiosus and
Haraguchi T, Ishizu H, Takehisa Y, et al. Lead content of
gliosis in frontal and temporal cortex, but in add-
brain tissue in diffuse neurofibrillary tangles with
ition there are neuronal inclusions of variable
calcification (DNTC): the possibility of lead neurotoxi-
city. Neuroreport 2001; 12: 3887–90.
morphology containing intermediate filament (IF)
Ito Y, Kato T, Suzuki T, et al. Neuroradiologic and clinical proteins, specifically the neurofilament (NF) pro-
abnormalities in dementia of diffuse neurofibrillary teins NF-H, NF-M, and NF-L, and a-internexin,
tangles with calcification (Kosaka–Shibayama disease). which may also stain with ubiquitin (Bigio et al.,
J Neurol Sci 2003; 209: 105–9. 2003; Josephs et al., 2003; Cairns et al., 2004).
Kosaka K. Diffuse neurofibrillary tangles with calcifica-
tion: a new presenile dementia. J Neurol Neurosurg
Psychiatry 1994; 57: 594–6. REFERENCES
Kosaka K, Ikeda K. Diffuse neurofibrillary tangles with
calcification in a non-demented woman. J Neurol
Bigio EH, Lipton AM, White CL III, et al. Frontotemporal
Neurosurg Psychiatry 1996; 61: 116.
and motor neurone degeneration with neurofilament
Langlois NEI, Grieve JHK, Best PV. Changes of diffuse
inclusion bodies: additional evidence for overlap
neurofibrillary tangles with calcification (DNTC) in a
between FTD and ALS. Neuropath Appl Neurobiol
woman without evidence of dementia. J Neurol Neuro-
2003; 29: 239–53.
surg Psychiatry 1995; 59: 103.
Cairns NJ, Grossman M, Arnold SE, et al. Clinical and
McKhann GM, Albert MS, Grossman M, et al. Clinical and
neuropathologic variation in neuronal intermediate
pathological diagnosis of frontotemporal dementia.
filament inclusion disease. Neurology 2004; 63: 1376–84.
Josephs KA, Holton JL, Rossor MN, et al. Neurofilament
inclusion body disease: a new proteinopathy? Brain
Modrego PJ, Mojonero J, Serrano M, Fayed N. Fahr’s
2003; 126: 2291–303.
syndrome presenting with pure and progressive pre-
senile dementia. Neurol Sci 2005; 26: 367–9.
Tanabe Y, Ishizu H, Ishiguro K, et al. Tau pathology in 2.2.9 Basophilic inclusion body disease
diffuse neurofibrillary tangles with calcification (BIBD)
(DNTC): biochemical and immunohistochemical inves-
tigation. Neuroreport 2000; 11: 2473–7. Cases with basophilic inclusion bodies may present
Ulrich J, Spillantini MG, Goedert M, et al. Abundant as juvenile or adult cases of FTD or MND or a
neurofibrillary tangles without senile plaques in a subset combination of both. There is frontotemporal
of patients with senile dementia. Neurodegeneration atrophy, with otherwise typical histopathological
1992; 1: 257–84. findings of FTLDs (neuronal loss, status spongio-
sus, gliosis). The inclusions, which do not stain for
tau, a-synuclein, or neuronal intermediate filament
2.2.8 Neuronal intermediate filament
proteins, involve not only the superficial laminae of
inclusion disease (NIFID)
the neocortex but also subcortical nuclei and
This young-onset dementia has a heterogeneous anterior horns of the spinal cord, but with sparing
phenotype including features resembling FTD, of the hippocampus and dentate gyrus. Typical
2.3 Motor neurone disease 63
pathological findings of MND are not seen extensive overlap (Bak & Hodges, 2001; Yoshida,
(Hamada et al., 1995). 2004; Mackenzie & Feldman, 2005; Strong, 2006).
Clinical diagnostic criteria (McKhann et al., 2001)
recognize a syndrome of frontotemporal lobar
REFERENCES degeneration with motor neurone disease (FTLD-
MND), also known as FTD-MND, MND dementia,
Hamada K, Fukuzawa T, Yanagihara T, et al. Dementia or ALS dementia, defined by the neuropathological
with ALS features and diffuse Pick body-like inclusions appearances of frontotemporal neuronal loss and
(atypical Pick’s disease?). Clin Neuropathol 1995; 14: gliosis with ubiquitin-positive tau-negative (MND-
1–6. type) inclusions without detectable amounts of
insoluble tau and with the clinical correlate of
MND. Similar neuropathological findings may
2.3 Motor neurone disease (MND), occur without the clinical correlate of MND, a
amyotrophic lateral sclerosis (ALS) syndrome known as frontotemporal lobar degen-
eration with MND-type inclusions but without
Traditionally it was taught that motor neurone MND (McKhann et al., 2001) or motor neurone
disease (MND) or amyotrophic lateral sclerosis disease inclusion dementia (MNDID: Jackson et al.,
(ALS) was a disorder confined to the motor system, 1995), or FTD-U. This may be the commonest
in which the intellect was preserved, and hence neuropathological correlate of FTD, accounting for
patients were all too horribly aware of their pro- 38% of cases (25/76) in the largest consecutive
gressive neurological predicament. Certainly the series of pathologically confirmed FTD cases
earliest description, by Charcot and Joffroy (1869), reported to date (Lipton et al., 2004). Alzheimer
has no mention of cognitive changes. Alzheimer type pathology, principally plaques, has been
may have reported a case of MND with dementia in reported in some cases of MND both with and
1891, but it was not until the later part of the without dementia (Hamilton & Bowser, 2004),
twentieth century that definitive cases of MND whilst both neuritic plaques and neurofibrillary
with concurrent dementia of frontal type were tangles typical of AD but sparing the hippocampus
presented (Hudson, 1981; Mitsuyama, 1984; Neary and entorhinal cortex were found in one patient
et al., 1990; Snowden et al., 1996). with a clinical presentation of bulbar MND with
The view of MND as an exclusively motor disorder rapidly progressive aphasia, another patient having
has been increasingly eroded, initially by occasional numerous cortical Lewy bodies in addition to
clinical reports both of cognitive impairment in frontotemporal neuronal loss and spongiosus
MND patients and of frontotemporal dementia (Doran et al., 1995).
(FTD) complicated by the development of MND, Clinical heterogeneity is noted in these cases,
and latterly by more systematic studies suggesting with presentations encompassing isolated cogni-
that significant numbers of MND patients, up to tive disorder, contemporaneous cognitive and
50%, have cognitive deficits when tested, sometimes motor disorder, and isolated motor disorder. In
sufficient to meet diagnostic criteria for FTD (Strong series reported from cognitive neurology clinics,
et al., 1999; Lomen-Hoerth et al., 2003; Ringholz cognitive impairment is noted to precede or coin-
et al., 2005), whilst neurophysiological investigation cide with the onset of motor symptoms, but this
of FTD patients has found evidence for subclinical may of course reflect selection bias (Bak & Hodges,
anterior horn cell disease in some (Lomen-Hoerth 2001; Sathasivam et al., 2007). Dementia preceding
et al., 2002). Now FTD and MND are thought to motor disorder has been reported (Vercelletto
represent a spectrum condition, with pure cognitive et al., 1999). The clinical phenotype may also
and pure motor cases at the boundaries but with encompass cases fulfilling diagnostic criteria for
frontal variant FTD (Godbolt et al., 2005), semantic Language

dementia (Davies et al., 2005; Godbolt et al., 2005), The frequency of language disorder in MND is
corticobasal degeneration (Grimes et al., 1999), and uncertain, since concurrent dysarthria may mask
progressive supranuclear palsy (Morris et al., 2005; language dysfunction unless appropriate tests are
Sathasivam et al., 2007), diagnosis only becoming used. Bulbar MND with rapidly progressive
apparent at postmortem in some of these cases. aphasia has been reported (Kirshner et al., 1987;
Thalamic dementia complicating MND has been Caselli et al., 1993; Doran et al., 1995). Marked
reported (Deymeer et al., 1989). anomia on picture naming, naming from verbal
Genetic linkage of familial FTD-MND to chromo- descriptions, and letter and category verbal flu-
some 9q21–22 has been reported (Hosler et al., ency may be observed, indicating a disorder of
2000), and in one family with cases of both FTD and language production, but with additional impair-
MND a missense mutation has been identified in the ments on syntactically based tasks of language
dynactin gene located on chromosome 9q (Munch comprehension (Token Test, Test for the Recep-
et al., 2005), although other families are described tion of Grammar) and picture–word matching
without linkage to this locus (Ostojic et al., 2003). tests of semantic comprehension (Doran et al.,
Pathogenetic mechanisms remain uncertain, but a 1995). Rakowicz & Hodges (1998) found a sub-
role for apoptosis, as suggested in MND (Sathasivam group of MND patients with language dysfunction
& Shaw, 2005), is possible. characterized by word-finding difficulties and
Other conditions potentially relevant to the cog- decreased verbal fluency, and Bak and Hodges
nitive disorder of MND/ALS include the amyo- (1997) found greater difficulty in confrontation
trophic lateral sclerosis/parkinsonism–dementia naming of verbs than nouns.
complex of Guam (see Section 2.4.6).
Perception
Neuropsychological profile As in FTD, there is no evidence for visual percep-
tual disorder in MND, with preserved spatial
The neuropsychological deficits of MND are sum- navigational skills, spatial localization, and orien-
marized in Table 2.5. tation, which may be confirmed on tests such as
dot counting and maze tracking. Poor performance
Attention on tests of drawing may result from lack of plan-
As in fvFTD, economy of effort, impulsiveness, and ning or strategy or motor deficits rather than from
distractibility may characterize test performance, visual perceptual impairment.
poor sustained attention compromising test results
(Neary et al., 1990; Snowden et al., 1996). Praxis
Impaired temporal sequencing of motor skills may
General intelligence, IQ be apparent, reflecting executive dysfunction.
Performance may be impaired on the WAIS-R,
sometimes in all areas, due to underlying executive Executive function
dysfunction. Frontal lobe dysfunction is evident on neuropsycho-
logical testing, without which it may be overlooked
Memory clinically (David & Gillham, 1986; Gallassi et al., 1989;
Formal tests of memory, both verbal and visual, Ludolph et al., 1992; Kew et al., 1993; Talbot et al.,
may show impaired scores but patients are not 1995; Abrahams et al., 1997; Evdokimidis et al., 2002),
amnesic, as reflected in their knowledge of auto- in between one-fifth and one-third of non-demented
biographical events and orientation in time and MND patients (Massman et al., 1996; Lomen-Hoerth
place, as in FTD. et al., 2003; Ringholz et al., 2005). There are
Table 2.5. Neuropsychological deficits in motor neurone disease (MND).
Attention # Sustained attention; economy of effort, impulsiveness, distractibility

General intelligence, IQ FSIQ may be normal or # due to executive dysfunction
Memory Not amnesic, but scores may be down due to executive dysfunction
Language þ/– aphasia (may be masked by dysarthria); anomia, # verbal fluency
Praxis Impaired temporal sequencing secondary to executive dysfunction
Executive function Impaired; # verbal fluency, card sorting
impairments on the Wisconsin Card Sorting Test with Davies RR, Hodges JR, Kril JJ, et al. The pathological basis
perseverations, Weigl’s Block Test, verbal and design of semantic dementia. Brain 2005; 128: 1984–95.
fluency, and WAIS-R Picture Arrangement. These Deymeer F, Smith TW, De Girolami U, Drachman DA.
deficits may be more common in patients with pre- Thalamic dementia and motor neuron disease. Neurol-
ogy 1989; 39: 58–61.
dominantly upper motor neurone signs (Iwasaki
Doran M, Xuereb J, Hodges JR. Rapidly progressive aphasia
et al., 1990), including primary lateral sclerosis (see
with bulbar motor neurone disease: a clinical and
Section 2.3.1), and in patients with predominantly
neuropsychological study. Behav Neurol 1995; 9: 169–80.
bulbar involvement (Talbot et al., 1995; Abrahams Evdokimidis I, Constantinidis TS, Gourtzelidis P, et al.
et al., 1997; Schreiber et al., 2005). Frontal lobe dysfunction in amyotrophic lateral scler-
osis. J Neurol Sci 2002; 195: 25–33.
Gallassi R, Montagna P, Morreale A, et al. Neuropsycho-
logical, electroencephalogram and brain computed
REFERENCES tomography findings in motor neuron disease. Eur
Neurol 1989; 29: 115–20.
Abrahams S, Goldstein LH, Al-Chalabi A, et al. Relation Godbolt AK, Josephs KA, Revesz T, et al. Sporadic and
between cognitive dysfunction and pseudobulbar palsy familial dementia with ubiquitin-positive tau-negative
in amyotrophic lateral sclerosis. J Neurol Neurosurg inclusions: clinical features of one histopathological
Psychiatry 1997; 62: 464–72. abnormality underlying frontotemporal lobar degener-
Alzheimer A. On a case of spinal progressive muscle ation. Arch Neurol 2005; 62: 1097–101.
atrophy with accessory disease of bulbar nuclei and the Grimes DA, Bergeron CB, Lang AE. Motor neuron disease-
cortex [in German]. Arch Psychiatr 1891; 23: 459–85. inclusion dementia presenting as cortical-basal gangli-
Bak T, Hodges JR. Noun–verb dissociation in three onic degeneration. Mov Disord 1999; 14: 674–80.
patients with motor neurone disease and aphasia. Hamilton RL, Bowser R. Alzheimer disease pathology in
Brain Lang 1997; 60: 38–41. amyotrophic lateral sclerosis. Acta Neuropathol 2004;
Bak TH, Hodges JR. Motor neurone disease, dementia and 107: 515–22.
aphasia: coincidence, co-occurrence or continuum? J Hosler BA, Siddique T, Sapp PC, et al. Linkage of familial
Neurol 2001; 248: 260–70. amyotrophic lateral sclerosis with frontotemporal
Caselli RJ, Windebank AJ, Petersen RC, et al. Rapidly dementia to chromosome 9q21–q22. JAMA 2000; 284:
progressive aphasic dementia and motor neuron dis- 1664–9.
ease. Ann Neurol 1993; 33: 200–7. Hudson AJ. Amyotrophic lateral sclerosis and its associ-
Charcot JM, Joffroy A. Deux cas d’atrophie musculaire ation with dementia, parkinsonism and other neuro-
progressive avec lésions de la substance grise et des logical disorders: a review. Brain 1981; 104: 217–47.
faisceaux antérolatéraux de la moelle épinière. Arch Iwasaki K, Kinoshita M, Ikeda K, et al. Cognitive
Physiol Norm 1869; 2: 354–67. impairment in amyotrophic lateral sclerosis and its
David AS, Gillham RA. Neuropsychological study of motor relation to motor disabilities. Acta Neurol Scand 1990;
neuron disease. Psychosomatics 1986; 27: 441–5. 81: 141–3.
Jackson M, Lennox G, Lowe J. Motor neurone disease- Munch C, Rosenbohm A, Sperfeld AD, et al. Heterozygous
inclusion dementia. Neurodegeneration 1995; 5: R1101K mutation of the DCTN1 gene in a family with
339–50. ALS and FTD. Ann Neurol 2005; 58: 777–80.
Kew JJM, Goldstein LH, Leigh PN, et al. The relationship Neary D, Snowden JS, Mann DMA, et al. Frontal lobe
between abnormalities of cognitive function and cere- dementia and motor neuron disease. J Neurol Neuro-
bral activation in amyotrophic lateral sclerosis: a surg Psychiatry 1990; 53: 23–32.
neuropsychological and positron emission tomography Ostojic J, Axelman K, Lannfelt L, Froelich-Fabre S. No
study. Brain 1993; 116: 1399–423. evidence of linkage to chromosome 9q21–22 in a Swedish
Kirshner HS, Tanridag O, Thurman L, Whetsell WO. family with frontotemporal dementia and amyotrophic
Progressive aphasia without dementia: two cases with lateral sclerosis. Neurosci Lett 2003; 340: 245–7.
focal spongiform degeneration. Ann Neurol 1987; 22: Rakowicz WP, Hodges JR. Dementia and aphasia in motor
527–32. neuron disease: an underrecognised association?
Lipton AM, White CL III, Bigio EH. Frontotemporal lobar J Neurol Neurosurg Psychiatry 1998; 65: 881–9.
degeneration with motor neuron disease-type inclu- Ringholz GM, Appel SH, Bradshaw M, et al. Prevalence
sions predominates in 76 cases of frontotemporal and patterns of cognitive impairment in sporadic ALS.
degeneration. Acta Neuropathol (Berl) 2004; 108: 379–85. Neurology 2005; 65: 586–90.
Lomen-Hoerth C, Anderson T, Miller B. The overlap of Sathasivam S, Doran M, Hancock P, Larner AJ. Fronto-
amyotrophic lateral sclerosis and frontotemporal temporal lobar degeneration with motor neuron disease
dementia. Neurology 2002; 59: 1077–9. (FTLD/MND): experience at a cognitive function clinic.
Lomen-Hoerth C, Murphy J, Langmore S, et al. Are J Neurol Neurosurg Psychiatry 2007; 78: 211 (abstract 027).
amyotrophic lateral sclerosis patients cognitively nor- Sathasivam S, Shaw PJ. Apoptosis in amyotrophic lateral
mal? Neurology 2003; 60: 1094–7. sclerosis: what is the evidence? Lancet Neurol 2005; 4:
Ludolph AC, Langen KJ, Regard M, et al. Frontal lobe 500–9.
function in amyotrophic lateral sclerosis: a neuropsy- Schreiber H, Gaigalat T, Wiedemuth-Catrinescu U, et al.
chologic and positron emission tomography study. Acta Cognitive function in bulbar- and spinal-onset amyo-
Neurol Scand 1992; 85: 81–9. trophic lateral sclerosis: a longitudinal study in 52
McKhann GM, Albert MS, Grossman M, et al. Clinical and patients. J Neurol 2005; 252: 772–81.
pathological diagnosis of frontotemporal dementia. Snowden JS, Neary D, Mann DMA. Fronto-Temporal
Report of the Work Group on Frontotemporal Dementia Lobar Degeneration: Fronto-Temporal Dementia, Pro-
and Pick’s disease. Arch Neurol 2001; 58: 1803–9. gressive Aphasia, Semantic Dementia. New York:
Mackenzie IRA, Feldman HH. Ubiquitin immunohisto- Churchill Livingstone, 1996: 59–72.
chemistry suggests classic motor neuron disease, motor Strong MJ (ed.). Dementia and Motor Neuron Disease.
neuron disease with dementia, and frontotemporal Abingdon: Informa Healthcare, 2006.
dementia of the motor neuron disease type represent Strong MJ, Grace GM, Orange JB, et al. A prospective study
a clinicopathologic spectrum. J Neuropathol Exp Neurol of cognitive impairment in ALS. Neurology 1999; 53:
2005; 64: 730–9. 1665–70.
Massman PJ, Sims J, Cooke N, et al. Prevalence and Talbot PR, Goulding PJ, Lloyd JJ, et al. Interrelation
correlates of neuropsychological deficits in amyo- between ‘classic’ motor neuron disease and frontotem-
trophic lateral sclerosis. J Neurol Neurosurg Psychiatry poral dementia: neuropsychological and single photon
1996; 61: 450–5. emission computed tomography study. J Neurol
Mitsuyama Y. Presenile dementia with motor neuron Neurosurg Psychiatry 1995; 58: 541–7.
disease in Japan: a clinico-pathological review of 26 Vercelletto M, Ronin M, Huvet M, Magne C, Feve JR.
cases. J Neurol Neurosurg Psychiatry 1984; 47: Frontal type dementia preceding amyotrophic lateral
953–9. sclerosis: a neuropsychological and SPECT study of five
Morris HR, Bronstein AM, Shaw CE, Lees AJ, Love S. clinical cases. Eur J Neurol 1999; 6: 295–9.
Clinical grand round: a rapidly progressive pyramidal Yoshida M. Amyotrophic lateral sclerosis with dementia:
and extrapyramidal syndrome with a supranuclear gaze the clinicopathological spectrum. Neuropathology 2004;
palsy. Mov Disord 2005; 20: 826–31. 24: 87–102.
2.3.1 Primary lateral sclerosis (PLS), Grace GM, Orange JB, Murphy MJ, et al. Primary lateral
progressive symmetric spinobulbar spasticity sclerosis: cognitive, language, and cerebral hemodynamic
findings. In: Strong MJ (ed.), Dementia and Motor Neuron
Primary lateral sclerosis (PLS) is a rare variant of Disease. Abingdon: Informa Healthcare, 2006: 87–97.
MND characterized by progressive spinobulbar Le Forestier N, Maisonobe T, Piquard A, et al. Does
spasticity. This is thought to result from isolated primary lateral sclerosis exist? A study of 20 patients and
involvement of upper motor neurones in the pre- a review of the literature. Brain 2001; 124: 1989–99.
central gyrus with secondary pyramidal tract Piquard A, Le Forestier N, Baudoin-Madec V, et al.
degeneration, without either clinical or neuro- Neuropsychological changes in patients with primary
physiological evidence of lower motor neurone lateral sclerosis. Amyotroph Lateral Scler 2006; 7: 150–60.
Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral
involvement (Pringle et al., 1992; Grace et al., 2006).
sclerosis: clinical features, neuropathology and diag-
Suggested diagnostic criteria require such isolated
nostic criteria. Brain 1992; 115: 495–520.
involvement to persist over a period of at least 3
years (Pringle et al., 1992), PLS tending to pursue a
more benign course than typical MND. 2.3.2 Mills’ syndrome
Studies of PLS in which cognitive testing was not
A syndrome of progressive ascending or descending
undertaken concluded that the intellect was pre-
hemiplegia without significant sensory involvement
served (Pringle et al., 1992). However more sys-
was first reported by Mills (1900). Its nosological
tematic, albeit retrospective, studies in small
status has been uncertain, but some cases may be
cohorts have suggested that mild cognitive dys-
hemiplegic forms of motor neurone disease with
function of frontal lobe type is present in PLS, with
exclusively upper motor neurone signs (Malin et al.,
deficits in executive function, psychomotor speed,
1986; Gastaut & Bartolomei, 1994), although this
and memory, but with normal orientation, spatial
clinical picture falls outwith proposed diagnostic
skills, and language (Caselli et al., 1995; Le Forestier
criteria for primary lateral sclerosis (Pringle et al.,
et al., 2001; Piquard et al., 2006). A prospective
1992). A case of progressive spastic hemiplegia
study of neuropsychological function using a broad
conforming to the description of Mills’ syndrome
battery of tests in 18 PLS patients found hetero-
with concurrent dementia of frontotemporal
geneity, but cognitive impairment according to the
type, with pathological confirmation of ubiquitin-
definitions of the study was present in 11 patients
positive motor neurone disease type inclusions in
(61%). Verbal fluency was the most sensitive test,
layer II cortical neurones, hippocampal dentate
but impairment was also noted on tests of auditory
granule cells, and hypoglossal nerve nucleus
verbal learning, visual (but not verbal) recognition
neurones, has been reported (Doran et al., 2005).
memory, and the Wisconsin Card Sorting Test.
Language testing showed impaired category verbal
fluency, specifically for non-living as opposed to
living items. These findings overlap with those REFERENCES
documented in MND, whereas others do not, such
as the finding that confrontation naming of nouns Doran M, Enevoldson TP, Ghadiali EJ, Larner AJ. Mills
and verbs was relatively intact (Grace et al., 2006). syndrome with dementia: broadening the phenotype of
FTD/MND. J Neurol 2005; 252: 846–7.
Gastaut JL, Bartolomei F. Mills’ syndrome: ascending (or
REFERENCES descending) progressive hemiplegia. A hemiplegic form
of primary lateral sclerosis? J Neurol Neurosurg Psychiatry
1994; 57: 1280–1.
Caselli RJ, Smith BE, Osborne D. Primary lateral sclerosis:
Malin JP, Poburski R, Reusche E. Clinical variants of
a neuropsychological study. Neurology 1995; 45:
amyotrophic lateral sclerosis: hemiplegic type of ALS
2005–9.
and Mills syndrome. A critical review [in German]. Hatanpaa KJ, Blass DM, Pletnikova O, et al. Most cases of
Fortschr Neurol Psychiatr 1986; 54: 101–5. dementia with hippocampal sclerosis may represent
Mills CK. A case of unilateral progressive ascending frontotemporal dementia. Neurology 2004; 63: 538–42.
paralysis probably presenting a new form of degenera- Leverenz JB, Agustin CM, Tsuang D, et al. Clinical and
tive disease. J Nerv Ment Dis 1900; 27: 195–200. neuropathological characteristics of hippocampal scler-
Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral osis: a community-based study. Arch Neurol 2002; 59:
sclerosis: clinical features, neuropathology and diag- 1099–106.
nostic criteria. Brain 1992; 115: 495–520. McKeel DW Jr, Burns JM, Meuser TM, Morris JC. An Atlas
of Investigation and Diagnosis: Dementia. Oxford:
Clinical Publishing, 2007: 172.
2.3.3 Hippocampal sclerosis, pure McKhann GM, Albert MS, Grossman M, et al. Clinical and
hippocampal sclerosis pathological diagnosis of frontotemporal dementia.
This condition was initially defined on neuropatho-
logical grounds, specifically by neuronal loss in the
CA1 region of the hippocampus, in association with
the neuroradiological signature of hippocampal 2.3.4 Progressive muscular atrophy (PMA)
atrophy and the clinical correlate of dementia
Variants of MND with a clinical phenotype of
(Corey-Bloom et al., 1997; Ala et al., 2000; Leverenz
exclusively lower motor neurone involvement, pro-
et al., 2002). Clinical overlap with AD was initially
gressive muscular atrophy (PMA), are rare, and may
emphasized, but more recently many cases have
be even rarer if neuropathological findings are taken
been reclassified as a subtype of FTD based on the
into account. One study of 12 PMA patients found
neuropathological finding of tau-negative ubiquitin-
no significant difference between subjects and
positive inclusions typical of MND-inclusion
healthy controls on any measure of cognitive,
dementia (Hatanpaa et al., 2004), and the overlap of
behavioural, or emotional function (Wicks et al.,
clinical and neuropsychological features with FTD
2006). Further support for the contention that
(Blass et al., 2004). Specifically, decreased grooming,
exclusively or predominantly lower motor neurone
inappropriate behaviour, decreased interest, and
involvement is not associated with cognitive decline
hyperorality were observed, with most patients
comes from a patient with the flail arm syndrome,
meeting diagnostic criteria (McKhann et al., 2001) for
symmetrical wasting and weakness of the arms with
FTD. However, other authors have not found the core
minimal leg or bulbar involvement at clinical pre-
neuropathological features of FTD (prefrontal neur-
sentation (Hu et al., 1998), also known as the
onal loss, microvacuolation, gliosis) in hippocampal
Vulpian–Bernhardt syndrome. A 73-year-old man
sclerosis brains (McKeel et al., 2007).
with flail arm syndrome had no complaints of
memory problems 4 years into his illness, and scored
79 on the ACE-R (see Section 1.8.4) out of a possible
REFERENCES
88, omitting those sections dependent on upper limb
function (90%), above the test cutoff excluding
Ala T, Beh GO, Frey WM II. Pure hippocampal sclerosis: a
dementia (Larner, unpublished observations).
rare cause of dementia mimicking Alzheimer’s disease.
Neurology 2000; 54: 843–8.
Blass DM, Hatanpaa KJ, Brandt J, et al. Dementia in
hippocampal sclerosis resembles frontotemporal demen- REFERENCES
tia more than Alzheimer disease. Neurology 2004; 63: 492–7.
Corey-Bloom J, Sabbagh MN, Bondi MW, et al. Hippo- Hu MTM, Ellis CM, Al-Chalabi A, Leigh PN, Shaw CE. Flail
campal sclerosis contributes to dementia in the elderly. arm syndrome: a distinctive variant of amyotrophic lateral
Neurology 1997; 48: 154–60. sclerosis. J Neurol Neurosurg Psychiatry 1998; 65: 950–1.
2.4 Parkinson’s disease dementia 69
Wicks P, Abrahams S, Leigh PN, Williams T, Goldstein LH. time-limited or which require motor skills may be
Absence of cognitive, behavioural, or emotional dys- impaired in PD because of the motor disorder rather
function in progressive muscular atrophy. Neurology than cognitive impairment per se.
2006; 67: 1718–19. Age, rather than age at onset, is a risk factor for
PDD, and symptoms such as rigidity, speech, gait,
and postural disorders are related to subsequent
2.4 Parkinson’s disease dementia (PDD) development of dementia whereas tremor-dominant
and dementia with Lewy bodies (DLB) disease is not (Starkstein & Merello, 2002; Emre,
2003; Aarsland, 2006). Classically, PDD has been
In his 1817 account of the disease which later, labelled as a subcortical dementia in distinction to
courtesy of Charcot, would bear his name, James the cortical dementia of AD. Cognitive deficits may
Parkinson stated that intellect was uninjured (a be found in non-demented PD patients, intermedi-
facsimile of Parkinson’s book on the shaking palsy ate between normal and PDD (Goldman et al., 1998),
is included in Gardner-Thorpe, 1987). Charcot and indeed these may be present in as many as one-
(1875) pointed out that this was not, in fact, the third of newly diagnosed PD patients (Foltynie
case, and that ‘psychic faculties are definitely et al., 2004).
impaired’ and that ‘the mind becomes clouded and The pathological hallmark of PD is the finding of
the memory is lost.’ Lewy bodies, intracytoplasmic rounded eosino-
It is now generally recognized that Parkinson’s philic inclusions in brainstem monoaminergic
disease (PD) is more than simply a motor disorder, and cholinergic neurones. The finding of similar
and that cognitive impairments are common, pro- structures in the neocortex of patients with
gressing in some patients to dementia (Starkstein & dementia and parkinsonism, often with concur-
Merello, 2002). Although this was not reflected in rent AD-type pathology, led to the delineation of a
the staging scale for PD developed by Hoehn and syndrome under a variety of names, such as cor-
Yahr (1967), which referred to motor symptoms tical Lewy body disease, senile dementia of the
only, the broader Unified Parkinson’s Disease Lewy body type, and the Lewy body variant of
Rating Scale (UPDRS) does encompass intellec- Alzheimer’s disease. All these entities are now
tual function. The motor stages of PD do not subsumed under the rubric of dementia with Lewy
correlate well with cognitive symptoms (Mortimer bodies (DLB: O’Brien et al., 2006). A distinction is
et al., 1982). sometimes drawn between cases with patho-
The exact frequency of Parkinson’s disease logical evidence of concurrent AD and Lewy body
dementia (PDD) is still debated, with widely diver- pathology, labelled Lewy body variant (LBV), and
gent figures being reported in different populations those without significant concomitant AD path-
and using different criteria for dementia diagnosis ology, labelled diffuse Lewy body disease (DLBD:
(Brown & Marsden, 1984). (There is a possibility that Hansen et al., 1990). The positive immunostaining
other parkinsonian disorders, which may also be of Lewy bodies in both PD and DLB with a-synu-
accompanied by cognitive decline, may be mistaken clein indicates that both disorders fall into the
for PD: Stocchi & Brusa, 2000; see Section 2.4.1.) As category of synucleinopathies. Lewy body path-
the prevalence of PD increases with age, the possi- ology is also common, if sought, in AD caused by
bility that cognitive impairment reflects concurrent mutations in the presenilin-1 gene, suggesting
Alzheimer’s disease (AD) must also be taken into other possible genetic influences on the develop-
account, as must concurrent depression and the ment of synuclein-related pathology (Leverenz
effects of drugs used in PD treatment (dopaminergic et al., 2006). Lewy body pathology may also be
agonists, anticholinergic medications). Further- found in some cases of Gaucher’s disease (see
more, performance on cognitive tests which are Section 5.5.3).
Clinical and pathological diagnostic criteria for Lewy bodies (Fleisher & Olichney, 2005; Galvin
DLB have been developed and validated (McKeith et al., 2006). Cognitive status seems to correlate with
et al., 1996, 1999, 2000a, 2005). The central clinical neuropathological staging (Braak et al., 2005).
feature is progressive cognitive decline with Cases fulfilling diagnostic criteria for DLB have
prominent deficits in attention, visuospatial abil- been reported in patients carrying point mutations
ities, and executive function, along with a number in the a-synuclein gene (E46K: Zarranz et al., 2004),
of other core features which are essential for a recognized but rare cause of genetically deter-
diagnosis of probable (two features) or possible mined PD, and in some patients with triplication of
(one feature) DLB, namely fluctuating cognition the a-synuclein gene (Singleton et al., 2003). Like-
with pronounced variations in attention (the wise, DLB has been reported in occasional patients
‘unstable platform of attention’), recurrent visual with mutations in the presenilin-1 gene (DT440:
hallucinations, and spontaneous motor features of Ishikawa et al., 2005) and the prion protein gene
parkinsonism. A number of other features may (PRNP M232R: Koide et al., 2002). Other disorders
support the diagnosis, including marked neuro- which may mimic or be confused with DLB, and
leptic sensitivity (McKeith et al., 1992) and synco- hence lead to confounding in defining the neuro-
pal episodes. Autonomic dysfunction when sought psychological profile, include CJD (Doran & Larner,
is reported to be common (Horimoto et al., 2003), 2004; Kraemer et al., 2005; du Plessis & Larner,
and cases of DLB ‘evolving’ from pure autonomic 2008) and vascular dementia.
failure have been reported (Larner et al., 2000;
Kaufmann et al., 2004). Greater impairment of
attentional and visuospatial function and relative
preservation of memory function is seen in DLB as Table 2.6 summarizes the neuropsychological def-
compared to AD (Salmon et al., 1996; Downes et al., icits typical of DLB, described in more detail below.
1998; Ballard et al., 1999; Calderon et al., 2001).
What is the relationship between PDD and DLB? Attention
A number of possibilities exist (Aarsland, 2006), The basal ganglia are implicated in the regulation of
including distinct diseases, part of a spectrum of attention (Brown & Marsden, 1998). There is evi-
dementia related to cortical Lewy body disease, or dence that PD patients disengage from attended
part of a spectrum of Lewy body and AD pathology. locations more readily, have less effective mechan-
Examination of many PD cases has demonstrated isms for resisting interference, and have difficulties
a characteristic pattern of topographical progression establishing a new target of attention (Dujardin
of Lewy body changes extending from brainstem to et al., 1999a). Tests of working memory in PD have
cortex (Braak et al., 2003), supporting the notion of a shown deficits, with spatial working memory
spectrum disorder, which may also extend to Lewy apparently more vulnerable than verbal or visual
body involvement of spinal autonomic ganglia (Ince working memory, which are affected later in the
et al., 1998). An arbitrary 1-year rule is sometimes disease course (Owen et al., 1997). Bradyphrenia, a
used to distinguish PDD from DLB, i.e. onset of slowness of thought or prolonged information pro-
dementia within 1 year of parkinsonism is labelled cessing time, is said to be a cardinal feature of
DLB, whilst more than 1 year of parkinsonism subcortical dementias, in PD perhaps paralleling the
before dementia develops equals PDD. Since there motor slowing (bradykinesia). However, if motor
is no clear neuropathological distinction between slowing is controlled for, then cognitive slowing
PDD and DLB, and the clinical boundaries may be does not seem to be a feature of PD (Rafal et al.,
blurred, both are dealt with here, assuming them to 1984; Smith et al., 1998). Concurrent depression or
reflect similar biological processes, both being mild dementia may also account, perhaps in part,
neurodegenerative disorders with diffuse cortical for bradyphrenia.
Table 2.6. Neuropsychological deficits in dementia with Lewy bodies (DLB).
Attention Prominent deficits: ‘unstable platform of attention’; difficulty establishing attentional

focus, easy disengagement; bradyphrenia; impaired spatial working memory;
fluctuating consciousness
General intelligence, IQ FSIQ #, PIQ worse than VIQ, possibly related to executive dysfunction
Memory Subcortical pattern of impairment, recognition better than recall
Language Relatively intact; verbal fluency may be impaired (?phonemic > category)
Perception Prominent deficits of visuoperceptual and visuospatial function
Praxis Possible ideomotor apraxia
Executive function Prominent deficits: impaired; # verbal fluency, card sorting
Fluctuating consciousness, clinically distinguish- Memory

able from delirium, is one of the core features of There is relatively less impairment of memory in
DLB, as noted in early clinical descriptions (e.g. PD/PDD/DLB than of visuospatial and executive
Gibb et al., 1987; Burkhardt et al., 1988; Byrne et al., functions (Ala et al., 2002), but nonetheless memory
1989) and enshrined in diagnostic criteria (McKeith is not normal. There is impairment of both recent
et al., 1996, 1999). This may lead to marked vari- and remote memory in PD, with recognition better
ability in performance on cognitive testing both than recall consistent with a retrieval deficit typical
within and between testing sessions. The clinical of impaired subcortical processes. Retrieval diffi-
diagnosis of fluctuating consciousness correlates culties may reflect the prominent executive dys-
with psychophysiological measures of variable function, with impaired allocation of attentional
attentional performance (Walker et al., 2000). This resources for effortful free recall tasks and the for-
‘unstable platform of attention’ may account for mulation of retrieval strategies (Ivory et al., 1999).
the observed impairments in attentional, mne- Registration, storage, and consolidation of memory
monic, and executive functions. Impairments of may be intact (Pillon et al., 1993). Semantic memory
attention may be demonstrated using the WAIS-R is also impaired (Portin et al., 2000).
Digit Span subtest (Hansen et al., 1990) and on In DLB, episodic memory deficits are less severe
complex set-shifting tasks examining shifts of than those of AD patients with an equal degree of
attention (Saghal et al., 1992). Subtypes of fluctu- dementia (Salmon et al., 1996; Downes et al., 1998;
ating cognition which differentiate DLB from AD Ballard et al., 1999; Calderon et al., 2001) due to
include daytime drowsiness and lethargy, daytime better retention and recognition memory, although
sleep > 2 hours, staring into space for long periods, learning and delayed recall in the free recall para-
and episodes of disorganized speech (Ferman digm showed similarly severe impairment. The dif-
et al., 2004). ferences are even more apparent when patients with
DLBD (i.e. without concomitant AD pathology) are
General intelligence, IQ compared to LBV and AD patients (Hamilton et al.,
Performance may be impaired on the WAIS-R, for 2004). Semantic memory is impaired (Lambon
example in Digit Span and Similarities subtests. Ralph et al., 2001).
There may be better verbal IQ than performance
IQ. On the MMSE, visuospatial and attentional Language
tests may be more impaired and memory relatively There is relatively less impairment of language in
preserved (Ala et al., 2002). PD/PDD/DLB than of visuospatial and executive
functions. There is no aphasia, and naming Executive function

remains intact until late stages, but hypophonia, As with attention, executive function impairments
monotonia, and aprosodia may be evident. Some are prominent in PD, PDD, and DLB, those dis-
groups have found reduced information content of proportionately affected in DLB being mildly
spontaneous speech, and impaired comprehension impaired in non-demented PD patients.
of complex commands and verbal reasoning skills Executive dysfunction in PD may be manifest as
(Cummings et al., 1988; Lewis et al., 1998). Poor psychomotor slowing, impairments in abstract rea-
verbal fluency is evident, perhaps more so for soning on WAIS-R Similarities subtest and Raven’s
phonemic than category fluency (Troyer et al., 1998), Progressive Matrices, and impaired performance on
and this may be an early indicator of developing the Stroop Test and Wisconsin Card Sorting Test
dementia. (Lees & Smith, 1983; Brown & Marsden, 1991;
Graham & Sagar, 1999). Executive dysfunction has
Perception also been reported in some first-degree relatives of
Visuoperceptual and visuospatial deficits are patients with familial PD, possibly representing a
reported in PD, PDD, and DLB, those in DLB being preclinical form of disease (Dujardin et al., 1999b).
disproportionate to AD. Recorded deficits in PD Pathological gambling, an executive dysfunction or
include prism adaptation (Canavan et al., 1990), impulse control disorder, has been reported in some
facial recognition (Levin et al., 1991), and complex PD patients following treatment with dopamine
figure drawing. In DLB, visuoperceptual and agonist drugs (Dodd et al., 2005; Larner, 2006).
visuospatial impairment is evident in tests of frag- A study of the qualitative performance charac-
mented letter identification and overlapping figures teristics of DLB patients on neuropsychological
(Calderon et al., 2001; Lambon Ralph et al., 2001), testing as compared to AD found evidence of
the Judgment of Line Orientation (Simard et al., inattention, visual distractibility, and persever-
2003), drawing simple and complex figures (Hansen ation. Externally cued intrusions from the visual
et al., 1990; Gnanalingham et al., 1996; Salmon et al., environment were common in DLB but never seen
1996; Cormack et al., 2004a), and in tests of visual in AD (Doubleday et al., 2002).
search (Cormack et al., 2004b). These deficits may
reflect the underlying attentional problems and/or
executive dysfunction, affecting planning and
strategy formation, and/or may be related to Since the cholinergic deficit in DLB is greater than
occipital cortical hypoperfusion observed in func- that observed in AD, a possible role for cholines-
tional imaging studies (Lobotesis et al., 2001). terase inhibitors (ChEIs) was anticipated in DLB.
Pentagon drawing in DLB and PDD is worse than in An international randomized double-blind pla-
AD or PD, apparently related in DLB to deficits in cebo-controlled trial demonstrated efficacy of
perception and praxis (Cormack et al., 2004a). rivastigmine for both cognitive and psychiatric
features (McKeith et al. 2000b), benefits main-
Praxis tained apparently up to 2 years (Grace et al., 2001).
Praxis may be difficult to evaluate meaningfully in ChEIs have also been reported beneficial for cog-
the context of the motor disorder of PD. However, nitive impairment in PD (Aarsland et al., 2002;
ideomotor apraxia for transitive movements has Leroi et al., 2004) and in PDD (Emre et al., 2004;
been documented in some PD patients, correlating Emre, 2006). However, clinical guidelines have
with deficits in tests sensitive to frontal lobe function suggested that further research is required to
(verbal fluency, Trail Making, Tower of Hanoi) and identify those patients who will benefit from ChEIs
suggesting corticostriatal dysfunction (Leiguarda (National Collaborating Centre for Chronic Condi-
et al., 1997; Zadikoff & Lang, 2005). tions, 2006).
The importance of dopaminergic mechanisms in to Alzheimer’s disease (AD). J Neurol Neurosurg Psych-
cognition may be demonstrated by the impair- iatry 2001; 70: 157–64.
ments in working memory and attentional set- Canavan AGM, Passingham RE, Marsden CD. Prism
shifting tasks seen in PD patients off their regular adaptation and other tasks involving spatial abilities in
patients with Parkinson’s disease, patients with frontal
dopaminergic therapy (Lange et al., 1992).
lobe lesions and patients with unilateral temporal
lobectomies. Neuropsychologia 1990; 28: 969–84.
Charcot JM. Leçons sur les maladies du système nerveux.
REFERENCES Paris: Delahaye, 1985 [1875]: 179.
Cormack F, Aarsland D, Ballard C, Tovée MJ. Pentagon
Aarsland D. Dementia in Parkinson’s disease. In: O’Brien drawing and neuropsychological performance in
J, McKeith I, Ames D, Chiu E (eds.), Dementia with Lewy dementia with Lewy bodies, Alzheimer’s disease, Par-
Bodies and Parkinson’s Disease Dementia. London: kinson’s disease and Parkinson’s disease with dementia.
Taylor & Francis, 2006: 221–39. Int J Geriatr Psychiatry 2004a; 19: 371–7.
Aarsland D, Laake K, Larsen JP, et al. Donepezil for Cormack F, Gray A, Ballard C, Tovée MJ. A failure of ‘pop-
cognitive impairment in Parkinson’s disease: a random- out’ in visual search tasks in dementia with Lewy bodies
ised controlled study. J Neurol Neurosurg Psychiatry as compared to Alzheimer’s and Parkinson’s disease. Int
2002; 72: 708–12. J Geriatr Psychiatry 2004b; 19: 763–72.
Ala T, Hughes LF, Kyrouac GA, Ghobrial MW, Elble RJ. The Cummings JL, Darkins A, Mendez M, Hill MA, Benson DF.
Mini-Mental State exam may help in the differentiation Alzheimer’s disease and Parkinson’s disease: compari-
of dementia with Lewy bodies and Alzheimer’s disease. son of speech and language alterations. Neurology 1988;
Int J Geriatr Psychiatry 2002; 17: 503–9. 38: 680–4.
Ballard CG, Ayre G, O’Brien J, et al. Simple standardised Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling
neuropsychological assessments aid in the differential caused by drugs used to treat Parkinson disease. Arch
diagnosis of dementia with Lewy bodies from Alzhei- Neurol 2005; 62: 1377–81.
mer’s disease and vascular dementia. Dement Geriatr Doran M, Larner AJ. EEG findings in dementia with Lewy
Cogn Disord 1999; 10: 104–8. bodies causing diagnostic confusion with sporadic
Braak H, Del Tredici K, Rüb U, et al. Staging of brain Creutzfeldt–Jakob disease. Eur J Neurol 2004; 11:
pathology related to sporadic Parkinson’s disease. 838–41.
Neurobiol Aging 2003; 24: 197–211. Doubleday EK, Snowden JS, Varma A, Neary D. Qualitative
Braak H, Rüb U, Jansen-Steur ENH, Del Tredici K, de Vos performance characteristics differentiate dementia with
RAI. Cognitive status correlates with neuropathologic Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg
stage in Parkinson disease. Neurology 2005; 64: 1404–10. Psychiatry 2002; 72: 602–7.
Brown P, Marsden CD. What do the basal ganglia do? Downes JJ, Priestley NM, Doran M, et al. Intellectual,
Lancet 1998; 351: 1801–4. mnemonic and frontal functions in dementia with Lewy
Brown RG, Marsden CD. How common is dementia in bodies: a comparison with early and advanced Parkin-
Parkinson’s disease? Lancet 1984; 2: 1262–5. son’s disease. Behav Neurol 1998; 11: 173–83.
Brown RG, Marsden CD. Dual task performance and Dujardin K, Degreef JF, Rogelet P, Defebvre L, Destee A.
processing resources in normal subjects and patients Impairment of the supervisory attentional system in
with Parkinson’s disease. Brain 1991; 114: 215–31. early untreated patients with Parkinson’s disease. J
Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, Neurol 1999a; 246: 783–8.
et al. Diffuse Lewy body disease and progressive Dujardin K, Duhamel A, Becquet E, et al. Neuropsycho-
dementia. Neurology 1988; 38: 1520–8. logical abnormalities in first degree relatives of patients
Byrne EJ, Lennox G, Lowe J, Godwin-Austen RB. Diffuse with familial Parkinson’s disease. J Neurol Neurosurg
Lewy body disease: clinical features in 15 cases. J Neurol Psychiatry 1999b; 67: 323–8.
Neurosurg Psychiatry 1989; 52: 709–17. du Plessis DG, Larner AJ. Phenotypic similarities causing
Calderon J, Perry R, Erzinclioglu S, et al. Perception, clinical misdiagnosis of pathologically confirmed spor-
attention and working memory are disproportionately adic Creutzfeldt–Jakob disease as dementia with Lewy
impaired in dementia with Lewy body (LBD) compared bodies. Clin Neurol Neurosurg 2008; 110: 194–7.
Emre M. Dementia associated with Parkinson’s disease. Hoehn MM, Yahr MD. Parkinsonism: onset, progression,
Lancet Neurol 2003; 2: 229–37. and mortality. Neurology 1967; 17: 427–42.
Emre M. Cholinesterase inhibitors in the treatment of Horimoto Y, Matsumoto M, Akatsu H, et al. Autonomic
dementia associated with Parkinson’s disease. In: Gau- dysfunctions in dementia with Lewy bodies. J Neurol
thier S, Scheltens P, Cummings JL (eds.), Alzheimer’s 2003; 250: 530–3.
Disease and Related Disorders Annual 5. London: Taylor Ince PG, Perry EK, Morris CM. Dementia with Lewy
& Francis, 2006: 181–90. bodies: a distinct non-Alzheimer dementia syndrome?
Emre M, Aarsland D, Albanese A, et al. Rivastigmine for Brain Pathol 1998; 8: 299–324.
dementia associated with Parkinson’s disease. N Engl J Ishikawa A, Piao YS, Miyashita A, et al. A mutant PSEN1
Med 2004; 351: 2509–18. causes dementia with Lewy bodies and variant Alzheimer’s
Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: disease. Ann Neurol, 2005; 57: 429–34.
specific features that reliably differentiate DLB from AD Ivory SJ, Knight RG, Longmore BE, Caradoc-Davies T.
and normal aging. Neurology 2004; 62: 181–7. Verbal memory in non-demented patients with idio-
Fleisher AS, Olichney JM. Neurodegenerative disorders pathic Parkinson’s disease. Neuropsychologia 1999; 37:
with diffuse cortical Lewy bodies. Adv Neurol 2005; 96: 817–28.
148–65. Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic
Foltynie T, Brayne CEG, Robbins TW, Barker RA. The failure as the initial presentation of Parkinson disease
cognitive ability of an incident cohort of Parkinson’s and dementia with Lewy bodies. Neurology 2004; 63:
patients in the UK. The CamPaIGN study. Brain 2004; 1093–5.
127: 550–60. Koide T, Ohtake H, Nakajima T, et al. A patient with
Galvin JE, Pollack J, Morris JC. Clinical phenotype of dementia with Lewy bodies and codon 232 mutation of
Parkinson disease dementia. Neurology 2006; 67: 1605–11. PRNP. Neurology 2002; 59: 1619–21.
Gardner-Thorpe C. James Parkinson 1755–1824. Exeter: Kraemer C, Lang K, Weckesser M, Evers S. Creutzfeldt–
Wheaton, 1987. Jacob [sic] disease misdiagnosed as dementia with Lewy
Gibb WR, Esiri MM, Lees AJ. Clinical and pathological bodies. J Neurol 2005; 252: 861–2.
features of diffuse Lewy body disease (Lewy body Lambon Ralph MA, Powell J, Howard D, et al. Semantic
dementia). Brain 1987; 110: 1131–53. memory is impaired in both dementia with Lewy bodies
Gnanalingham KK, Byrne EJ, Thornton A. Clock-face and dementia of Alzheimer’s type: a comparative
drawing to differentiate Lewy body and Alzheimer neuropsychological study and literature review. J Neurol
type dementia syndromes. Lancet 1996; 347: 696–7. Neurosurg Psychiatry 2001; 70: 149–56.
Goldman WP, Baty JD, Buckles VD, Sahrmann S, Morris JC. Lange KW, Robbins TW, Marsden CD, et al. L-dopa
Cognitive and motor functioning in Parkinson disease. withdrawal in Parkinson’s disease selectively impairs
Arch Neurol 1998; 55: 674–80. cognitive performance in tests sensitive to frontal
Grace J, Daniel S, Stevens T, et al. Long-term use of lobe dysfunction. Psychopharmacol (Berl) 1992; 107:
rivastigmine in patients with dementia with Lewy 394–404.
bodies: an open-label trial. Int Psychogeriatrics 2001; Larner AJ. Medical hazards of the internet: gambling in
13: 199–205. Parkinson’s disease. Mov Disord 2006; 21: 1789.
Graham JM, Sagar HJ. A data-driven approach to the study Larner AJ, Mathias CJ, Rossor MN. Autonomic failure
of heterogeneity in idiopathic Parkinson’s disease: preceding dementia with Lewy bodies. J Neurol 2000;
identification of three distinct subtypes. Mov Disord 247: 229–31.
1999; 14: 10–20. Lees AJ, Smith E. Cognitive deficits in the early stages of
Hamilton JM, Salmon DP, Galasko D, et al. A comparison Parkinson’s disease. Brain 1983; 106: 257–70.
of episodic memory deficits in neuropathologically- Leiguarda RC, Pramstaller PP, Merello M, et al. Apraxia in
confirmed dementia with Lewy bodies and Alzheimer’s Parkinson’s disease, progressive supranuclear palsy,
disease. J Int Neuropsychol Soc 2004; 10: 689–97. multiple system atrophy and neuroleptic-induced par-
Hansen L, Salmon D, Galasko D, et al. The Lewy body kinsonism. Brain 1997; 120: 75–90.
variant of Alzheimer’s disease: a clinical and pathologic Leroi I, Brandt J, Reich SG, et al. Randomized placebo-
entity. Neurology 1990; 40: 1–8. controlled trial of donepezil in cognitive impairment in
Parkinson’s disease. Int J Geriatr Psychiatry 2004; 19: Owen AM, Iddon JL, Hodges JR, Summers BA, Robbins TW.
1–8. Spatial and non-spatial working memory at different
Leverenz JB, Fishel MA, Peskind ER, et al. Lewy body stages of Parkinson’s disease. Neuropsychologia 1997; 35:
pathology in familial Alzheimer disease: evidence for 519–32.
disease- and mutation-specific pathologic phenotype. Pillon B, Deweer B, Agid Y, Dubois B. Explicit memory in
Arch Neurol 2006; 63: 370–6. Alzheimer’s, Huntington’s, and Parkinson’s diseases.
Levin BE, Llabre MM, Reisman S, et al. Visuospatial Arch Neurol 1993; 50: 374–9.
impairment in Parkinson’s disease. Neurology 1991; 41: Portin R, Laatu S, Revonsuo A, Rinne UK. Impairment of
365–9. semantic knowledge in Parkinson disease. Arch Neurol
Lewis FM, Lapointe L, Murdoch BE, Chenery HJ. Lan- 2000; 57: 1338–43.
guage impairment in Parkinson’s disease. Aphasiology Rafal RD, Posner MJ, Walker JA, Friedrich FJ. Cognition
1998; 12: 193–206. and the basal ganglia: separating mental and motor
Lobotesis K, Fenwick JD, Phipps A, et al. Occipital components of performance in Parkinson’s disease.
hypoperfusion on SPECT in dementia with Lewy bodies Brain 1984; 107: 1083–94.
but not AD. Neurology 2001; 56: 643–9. Saghal A, Galloway PH, McKeith IG, et al. A comparative
McKeith IG, Ballard CG, Perry RH, et al. Prospective study of attentional deficits in senile dementias of
validation of consensus criteria for the diagnosis of Alzheimer and Lewy body types. Dementia 1992; 3:
dementia with Lewy bodies. Neurology 2000a; 54: 1050–8. 350–4.
McKeith I, Del Ser T, Spano P, et al. Efficacy of Salmon DP, Galasko D, Hansen LA, et al. Neuropsycho-
rivastigmine in dementia with Lewy bodies: a random- logical deficits associated with diffuse Lewy body
ised, double-blind, placebo-controlled international disease. Brain Cogn 1996; 31: 148–65.
study. Lancet 2000b; 356: 2031–6. Simard M, van Reekum R, Myran D. Visuospatial impair-
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and ment in dementia with Lewy bodies and Alzheimer’s
management of dementia with Lewy bodies: third disease: a process analysis approach. Int J Geriatr
report of the DLB Consortium. Neurology 2005; 65: Psychiatry 2003; 18: 387–91.
1863–72. Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein
McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. locus triplication causes Parkinson’s disease. Science
Neuroleptic sensitivity in patients with senile dementia 2003; 302: 841.
of Lewy body type. BMJ 1992; 305: 673–8. Smith MC, Goldman WP, Janer KW, Baty JD, Morris JC.
McKeith IG, Galasko D, Kosaka K, et al. Consensus Cognitive speed in nondemented Parkinson’s disease.
guidelines for the clinical and pathologic diagnosis of J Int Neuropsychol Soc 1998; 4: 584–92.
dementia with Lewy bodies (DLB): report of the Starkstein SE, Merello M. Psychiatric and Cognitive Dis-
consortium on DLB international workshop. Neurology orders in Parkinson’s Disease. Cambridge: Cambridge
1996; 47: 1113–24. University Press, 2002: 55–87, 100–103.
McKeith IG, Perry EK, Perry RH, for the Consortium on Stocchi F, Brusa L. Cognition and emotion in different
Dementia with Lewy Bodies. Report of the second stages and subtypes of Parkinson’s disease. J Neurol
dementia with Lewy body international workshop. 2000; 247 (suppl 2): II/114–21.
Neurology 1999; 53: 902–5. Troyer AK, Moscovitch M, Winocur G, Leach L, Freedman
Mortimer JA, Pirozzola FJ, Hansch EC, Webster DD. M. Clustering and switching on verbal fluency tests in
Relationship of motor symptoms to intellectual deficits Alzheimer’s and Parkinson’s disease. J Int Neuropsychol
in Parkinson’s disease. Neurology 1982; 32: 133–7. Soc 1998; 4: 137–43.
National Collaborating Centre for Chronic Conditions. Walker MP, Ayre GA, Cummings JL, et al. The clinical
Parkinson’s Disease: National Clinical Guideline for assessment of fluctuation and the one day fluctuation
Diagnosis and Management in Primary and Secondary assessment scale: two methods to assess fluctuating
Care. London: Royal College of Physicians, 2006: 121–4. confusion in dementia. Br J Psychiatry 2000; 177:
O’Brien J, McKeith I, Ames D, Chiu E (eds.). Dementia 252–6.
with Lewy Bodies and Parkinson’s Disease Dementia. Zadikoff C, Lang AE. Apraxia in movement disorders.
London: Taylor & Francis, 2006. Brain 2005; 128: 1480–97.
Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new pressure hydrocephalus (Section 7.2.1), post-
mutation, E46K, of alpha-synuclein causes Parkinson encephalitic parkinsonism (encephalitis lethargica:
and Lewy body dementia. Ann Neurol 2004; 55: 164–73. Section 9.1.10), and some cases of Creutzfeldt–
Jakob disease (Section 2.5).
2.4.1 Other (‘atypical’) parkinsonian

syndromes
REFERENCES
Disorders which clinically may superficially
resemble idiopathic Parkinson’s disease (PD) but Bak TH, Crawford LM, Hearn VC, Mathuranath PS, Hodges
which in fact have different clinical features, JR. Subcortical dementia revisited: similarities and
course, and pathogenesis have sometimes been differences in cognitive function between progressive
labelled as ‘atypical’ parkinsonian syndromes, or supranuclear palsy (PSP), corticobasal degeneration
sometimes as ‘parkinsonism plus’. The most (CBD) and multiple system atrophy (MSA). Neurocase
2005; 11: 268–73.
common of these syndromes are progressive
Quinn N. Other atypical parkinsonian disorders and their
supranuclear palsy (PSP), corticobasal degener-
differentiation from dementia with Lewy bodies. In:
ation (CBD), and multiple system atrophy (MSA).
O’Brien J, McKeith I, Ames D, Chiu E (eds.), Dementia
The terminology raises the question as to what is with Lewy Bodies and Parkinson’s Disease Dementia.
‘atypical’ for PD, but features which should dis- London: Taylor & Francis, 2006a: 241–53.
suade one from a diagnosis of idiopathic PD Quinn NP. Atypical parkinsonian syndromes. Eur J Neurol
include early freezing and falls, rapid disease pro- 2006b; 13 (suppl2): 3 (abstract MT 4–1).
gression, early dysautonomia, early speech or
swallowing problems, levodopa unresponsiveness,
2.4.2 Progressive supranuclear palsy
and early dementia (Quinn, 2006a, b). It is reported
(PSP), Steele–Richardson–Olszewski (SRO)
that simple bedside cognitive screening tests such
syndrome
as the Dementia Rating Scale and the Adden-
brooke’s Cognitive Examination can differentiate Progressive supranuclear palsy (PSP) is an akinetic-
the commonest ‘atypical’ parkinsonian disorders rigid syndrome, the clinical phenotype of which was
(Bak et al., 2005) first described as such by Steele and colleagues
The disorders considered here include progres- (1964), although possible earlier cases, even dating
sive supranuclear palsy and corticobasal degener- to the nineteenth century, have been noted retro-
ation, tauopathies which some authorities regard spectively (Larner, 2002). Bradykinesia and axial
as falling within the rubric of frontotemporal lobar rigidity without tremor, postural instability with
degenerations; multiple system atrophy, a synu- early falls, supranuclear gaze palsy, and bulbar
cleinopathy; dementia pugilistica; and the parkin- symptoms are typical of PSP (Rehman, 2000),
sonism–dementia complex of Guam. Other although the characteristic eye movement disorder
disorders with clinical features that might cause is not always present, since cases with the typical
them to be regarded as ‘atypical’ parkinsonian pathological findings but without supranuclear gaze
syndromes but which are covered elsewhere palsy are described. It has been suggested that the
include frontotemporal dementia with parkinson- typical phenotype be called ‘Richardson’s syn-
ism linked to chromosome 17 (FTDP-17: Section drome’, and the atypical form, which is often con-
2.2.4), Huntington’s disease (Section 5.1.1), Wil- fused with idiopathic Parkinson’s disease because of
son’s disease (Section 5.4.1), neurodegeneration asymmetric onset, tremor, and modest response to
with brain iron accumulation (Hallervorden–Spatz levodopa, be called ‘PSP-P’ (Williams et al., 2005).
disease: Section 5.4.2), neuroacanthocytosis (Sec- Pathologically, neurofibrillary tangles and neuropil
tion 5.4.3), Fahr’s disease (Section 5.1.7), normal threads are seen using tau immunohistochemistry.
White matter astrocytes containing tangles (‘tufted 1994). Ideomotor apraxia may occur, which may
astrocytes’) may be seen, an appearance which may cause clinical confusion with corticobasal degen-
be unique to PSP. Cases with tau gene mutations eration, but it is usually bilateral (Leiguarda et al.,
have been reported (i.e. FTDP-17: see Section 2.2.4), 1997).
as have cases with ubiquitin-positive inclusions
typical of the MND type (Paviour et al., 2004),
observations which prompt some authors to cat- REFERENCES
egorize PSP as a frontotemporal lobar degeneration
(FTLD: Section 2.2). Clinical diagnostic criteria for Albert ML, Feldman RG, Willis AL. The ‘subcortical
PSP have been published (Litvan et al., 1996). dementia’ of progressive supranuclear palsy. J Neurol
Dementia as a component of PSP was explicit in Neurosurg Psychiatry 1974; 37: 121–30.
the first descriptions (Richardson et al., 1963; Steele Bak TH, Crawford LM, Hearn VC, Mathuranath PS,
et al., 1964). The term ‘subcortical dementia’ was Hodges JR. Subcortical dementia revisited: similarities
first used to describe the neuropsychological deficits
sive supranuclear palsy (PSP), corticobasal degener-
observed in PSP: forgetfulness, slowing of thought
processes, emotional or personality change (apathy,
Neurocase 2005; 11: 268–73.
depression with outbursts of irritability), and Bak TH, Hodges JR. The neuropsychology of progressive
impaired ability to manipulate acquired knowledge supranuclear palsy. Neurocase 1998; 4: 89–98.
(Albert et al., 1974). Notwithstanding the contro- Brown RG, Pillon B, Uttner I, Payan C, Lacomblez L,
versies engendered by the term ‘subcortical’ (Sec- Members of the Neuropsychology Working Group and
tion 1.11), cognitive deficits are common in PSP NNIPPS Consortium. Cognitive function in patients
(Bak & Hodges, 1998; Brown et al., 2002). Cases of with progressive supranuclear palsy (PSP) and multiple
PSP presenting with isolated dementia have been system atrophy (MSA). Mov Disord 2002; 17 (suppl 5):
reported (Davis et al., 1985; Masliah et al., 1991). S221 (abstract P706).
Davis PH, Bergeron C, McLachlan DR. Atypical presenta-
Cognitive slowing and executive dysfunction are
tion of progressive supranuclear palsy. Ann Neurol
the key findings, with relative preservation of
1985; 17: 337–43.
instrumental functions (Robbins et al., 1994). This
Larner AJ. Did Charles Dickens describe progressive
is manifested as slowed responses to questions or supranuclear palsy in 1857? Mov Disord 2002; 17:
problem solving, impaired verbal fluency, more so 832–3.
for phonological than for semantic categories Leiguarda RC, Pramstaller PP, Merello M, et al. Apraxia in
(Rosser & Hodges, 1994a; Bak et al., 2005), and Parkinson’s disease, progressive supranuclear palsy,
perseveration, as in the ‘applause test’ or ‘clapping multiple system atrophy and neuroleptic-induced par-
test’ (asked to clap three times, the patient often kinsonism. Brain 1997; 120: 75–90.
claps more than three times). On the Dementia Litvan I, Agid Y, Calne D, et al. Clinical research criteria for
Rating Scale, PSP patients are more impaired on the diagnosis of progressive supranuclear palsy (Steele–
Richardson–Olszewski syndrome): report of the NINDS-
the initiation/perseveration subtest and less
SPSP International Workshop. Neurology 1996; 47: 1–9.
impaired on the memory subtest than AD patients
Masliah E, Hansen LA, Quijada S, et al. Late onset
(Rosser & Hodges, 1994b). Nonetheless, memory
dementia with argyrophilic grains and subcortical
for long- and short-term material is also impaired, tangles or atypical progressive supranuclear palsy?
for both immediate and delayed recall, but unlike Ann Neurol 1991; 29: 389–96.
the situation in AD or other ‘cortical dementias’ Paviour DC, Lees AJ, Josephs KA, et al. Frontotemporal
memory performance is significantly improved by lobar degeneration with ubiquitin-only-immunoreac-
cueing and recognition, methods believed to tive neuronal changes: broadening the clinical picture
facilitate the retrieval process, itself thought to be to include progressive supranuclear palsy. Brain 2004;
related to the frontostriatal system (Pillon et al., 127: 2441–51.
Pillon B, Deweer B, Michon A, et al. Are explicit memory PSP are present in the substantia nigra. There are
disorders of progressive supranuclear palsy related to no cortical NFTs, Pick bodies or Pick cells, senile
damage to striatofrontal circuits? Comparison with plaques, Lewy bodies, granulovacuolar change, or
Alzheimer’s, Parkinson’s and Huntington’s diseases. amyloid deposits (Mahapatra et al., 2004). Neuro-
Neurology 1994; 44: 1264–70.
pathological diagnostic criteria for CBD have been
Rehman HU. Progressive supranuclear palsy. Postgrad
published (Dickson et al., 2002).
Med J 2000; 76: 333–6.
The clinical phenotype is variable: initial reports
Richardson JC, Steele J, Olszewski J. Supranuclear
ophthalmoplegia, pseudobulbar palsy, nuchal dystonia
emphasized a movement disorder, chronic pro-
and dementia: a clinical report on eight cases of gressive akinetic-rigid syndrome with asymmetric
heterogeneous system degeneration. Trans Am Neurol onset, limb apraxia sometimes with the alien limb
Assoc 1963; 88: 25–9. phenomenon, cortical sensory dysfunction, dysto-
Robbins TW, James M, Lange KW, et al. Cognitive deficits nia, and myoclonus, sometimes with eye move-
in progressive supranuclear palsy, Parkinson’s disease, ment disorder (Thompson & Marsden, 1992).
and multiple system atrophy in tests sensitive to frontal However, increasingly it has been recognized that
lobe dysfunction. J Neurol Neurosurg Psychiatry 1994; CBD is also a cognitive disorder (Grimes et al.,
57: 79–88.
1999b; Graham et al., 2003a). Initial clin-
Rosser AE, Hodges JR. Initial letter and semantic category
icopathological diagnostic criteria for CBD (Lang
fluency in Alzheimer’s disease, Huntington’s disease
et al., 1994) did not include cognitive decline, but
and progressive supranuclear palsy. J Neurol Neurosurg
Psychiatry 1994a; 57: 1389–94.
this has been rectified in more recently proposed
Rosser AE, Hodges JR. The Dementia Rating Scale in criteria, which include variable degrees of focal or
Alzheimer’s disease, Huntington’s disease and progres- lateralized cognitive dysfunction, with relative
sive supranuclear palsy. J Neurol 1994b; 241: 531–6. preservation of learning and memory, on neu-
Steele JC, Richardson JC, Olszewski J. Progressive supra- ropsychometric testing as a supportive investi-
nuclear palsy: a heterogeneous degeneration involving gation (Boeve et al., 2003). Brief ‘bedside’
the brainstem, basal ganglia and cerebellum with neuropsychological tests such as the Adden-
vertical gaze and pseudobulbar palsy, nuchal dystonia brooke’s Cognitive Examination are reported to be
and dementia. Arch Neurol 1964; 10: 333–58.
able to detect cognitive deficits in CBD (Bak et al.,
Williams DR, de Silva R, Paviour DC, et al. Characteristics of
2005b).
two distinct clinical phenotypes in pathologically proven
Care needs to be taken in defining the cognitive
progressive supranuclear palsy: Richardson’s syndrome
and PSP-parkinsonism. Brain 2005; 128: 1247–58.
profile of CBD since phenocopies are relatively
common (Boeve et al., 1999), with AD and Pick’s
disease being the commonest neuropathological
substrates of ‘corticobasal degeneration syndrome’
2.4.3 Corticobasal degeneration (CBD)
(CBDS: Doran et al., 2003; Larner & Doran, 2004).
Corticobasal degeneration (CBD), also known as Motor neurone disease inclusion dementia has also
cortical-basal ganglionic degeneration, was first been reported to present as ‘CBD’ (Grimes et al.,
defined neuropathologically (Rebeiz et al., 1967). It 1999a). Hence studies without neuropathological
is characterized by nerve cell loss and gliosis in the confirmation remain open to possible confounding
cortex, especially frontal and anterior parietal with CBDS phenocopies.
lobes, underlying white matter, thalamus, lenti- Neuropsychological studies in CBD have
form nucleus, subthalamic nucleus, substantia reported deficits of sustained attention and verbal
nigra, and locus caeruleus, with swollen and fluency as in AD (but more so for letter than for
chromatolysed residual nerve cells with eccentric category fluency: Bak et al., 2005a), and deficits of
nuclei (achromasia). Neuronal inclusions resem- praxis, finger tapping and motor programming not
bling the globose neurofibrillary tangles (NFTs) of seen in AD. These latter changes are thought to
reflect basal ganglia and posterior frontal lobe Boeve BF, Maraganore MD, Parisi JE, et al. Pathologic
involvement in CBD (Pillon et al., 1995; Massman heterogeneity in clinically diagnosed corticobasal
et al., 1996). Apraxia affecting limb function is one of degeneration. Neurology 1999; 53: 795–800.
the most typical features of CBD, which may be Boeve B, Parisi J, Petersen R, et al. Familial dementia/
parkinsonism/motor neuron disease with corticobasal
ideomotor and limb-kinetic (Zadikoff & Lang, 2005).
degeneration pathology but absence of a tau mutation.
Early and prominent language impairments have
Neurobiol Aging 2002; 23 (1S): S269 (abstract 1008).
also been noted (Lippa et al., 1991), specifically
Dickson DW, Bergeron C, Chin SS, et al. Office of Rare
phonological impairments overlapping with those Diseases neuropathologic criteria for corticobasal degen-
observed in the progressive non-fluent aphasia eration. J Neuropathol Exp Neurol 2002; 61: 935–46.
variant of FTD (Graham et al., 2003b; see Section Doran M, du Plessis DG, Enevoldson TP, et al. Patho-
2.2.3). Learning and episodic memory are mildly logical heterogeneity of clinically diagnosed corticoba-
impaired, if at all, particularly in the early stages. sal degeneration. J Neurol Sci 2003; 216: 127–34.
Cases presenting with features of frontotemporal Graham NL, Bak TH, Hodges JR. Corticobasal degener-
dementia (FTD) without a motor disorder have also ation as a cognitive disorder. Mov Disord 2003a; 18:
been reported (Lennox et al., 1994; Kertesz & 1224–32.
Graham NL, Bak T, Patterson K, Hodges JR. Language
Martinez-Lange, 1998; Kertesz & Munoz, 1998;
function and dysfunction in corticobasal degeneration.
Mathuranath et al., 2000), as have occasional
Neurology 2003b; 61: 493–9.
patients with parieto-occipital, Balint-like, cortical
Grimes DA, Bergeron CB, Lang AE. Motor neuron disease-
dysfunction (Tang-Wai et al., 2003), and a com- inclusion dementia presenting as cortical-basal gangli-
bination of dementia, parkinsonism, and motor onic degeneration. Mov Disord 1999a; 14: 674–80.
neurone disease (Boeve et al., 2002). These findings Grimes DA, Lang AE, Bergeron CB. Dementia as the most
presumably reflect the regional distribution of common presentation of cortical-basal ganglionic
pathological change. Some authors categorize CBD degeneration. Neurology 1999b; 53: 1969–74.
as a frontotemporal lobar degeneration (FTLD) Kertesz A, Martinez-Lange P. Cognitive changes in corti-
with tau inclusions (e.g. Kertesz & Martinez-Lage, cobasal degeneration. In: Kertesz A, Munoz DG (eds.),
1998), and this phenotype may on occasion be seen Pick’s Disease and Pick Complex. New York: Wiley-Liss,
1998: 121–8.
in patients harbouring mutations in the tau gene
Kertesz A, Munoz DG. Clinical and pathological overlap in
(see Section 2.2.4).
Pick complex. In: Kertesz A, Munoz DG (eds.), Pick’s
Disease and Pick Complex. New York: Wiley-Liss, 1998:
281–6.
REFERENCES
Lang AE, Riley DE, Bergeron C. Cortical-basal ganglionic
degeneration. In: Calne DB (ed.), Neurodegenerative
Bak TH, Crawford LM, Hearn VC, Mathuranath PS, Diseases. Philadelphia: Saunders, 1994: 877–94.
Hodges JR. Subcortical dementia revisited: similarities Larner AJ, Doran M. Language function and dysfunction
and differences in cognitive function between progres- in corticobasal degeneration. Neurology 2004; 62: 1238.
sive supranuclear palsy (PSP), corticobasal degener- Lennox G, Jackson M, Lowe J. Corticobasal degeneration
ation (CBD) and multiple system atrophy (MSA). manifesting as a frontal lobe dementia. Ann Neurol
Neurocase 2005a; 11: 268–73. 1994; 36: 273–4 (abstract P52).
Bak TH, Rogers TT, Crawford LM, et al. Cognitive bedside Lippa CF, Cohen R, Smith TW, Drachman DA. Primary
assessment in atypical parkinsonian syndromes. J Neurol progressive aphasia with focal neuronal achromasia.
Neurosurg Psychiatry 2005b; 76: 420–2. Neurology 1991; 41: 882–6.
Boeve BF, Lang AE, Litvan I. Corticobasal degeneration Mahapatra RK, Edwards MJ, Schott JM, Bhatia KP.
and its relationship to progressive supranuclear palsy Corticobasal degeneration. Lancet Neurol 2004; 3: 736–43.
and frontotemporal dementia. Ann Neurol 2003; 54 Massman PJ, Kreiter KT, Jankovic J, Doody RS. Neuro-
(suppl 5): S15–19. psychological functioning in cortical-basal ganglionic
degeneration: differentiation from Alzheimer’s disease. Of the various parkinsonian syndromes, MSA is
Neurology 1996; 46: 720–6. probably the one least associated with cognitive
Mathuranath PS, Xuereb JH, Bak T, Hodges JR. Cortico- impairments (Bak et al., 2005a, b). Intelligence is
basal ganglionic degeneration and/or frontotemporal generally normal, but there may be neuropsycho-
dementia? A report of two overlap cases and review of
logical impairments. Frontal lobe dysfunction has
literature. J Neurol Neurosurg Psychiatry 2000; 68:
been a fairly consistent finding when sought, with
304–12.
difficulties in attentional mechanisms and set-
Pillon B, Blin J, Vidailhet M, et al. The neuropsychological
pattern of corticobasal degeneration: comparison with
shifting, impinging on working memory and speed
progressive supranuclear palsy and Alzheimer’s disease. of thinking (Sullivan et al., 1991; Robbins et al.,
Neurology 1995; 45: 1477–83. 1992, 1994; Meco et al., 1996; Brown et al., 2002). In
Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatoni- MSA-P, verbal fluency (phonemic and category)
gral degeneration with neuronal achromasia: a progres- deficits have been noted despite normality on the
sive disorder of late adult life. Trans Am Neurol Assoc WAIS, Wisconsin Card Sorting Test, and Stroop
1967; 92: 23–6. Test (Pillon et al., 1995). Apraxia is not a feature of
Tang-Wai DF, Josephs KA, Boeve BF, et al. Pathologically MSA (Leiguarda et al., 1997).
confirmed corticobasal degeneration presenting with
visuospatial dysfunction. Neurology 2003; 61: 1134–5.
Thompson PD, Marsden CD. Corticobasal degeneration.
In: Rossor MN (ed.), Unusual Dementias. London: REFERENCES
Bailliere Tindall, 1992: 677–86.
Zadikoff C, Lang AE. Apraxia in movement disorders. Bak TH, Crawford LM, Hearn VC, Mathuranath PS,
Brain 2005; 128: 1480–97. Hodges JR. Subcortical dementia revisited: similarities
sive supranuclear palsy (PSP), corticobasal degener-
2.4.4 Multiple system atrophy (MSA)
Multiple system atrophy (MSA) is a neurodegener- Neurocase 2005a; 11: 268–73.
ative disorder characterized as a synucleinopathy on Bak TH, Rogers TT, Crawford LM, et al. Cognitive bedside
the basis of the signature neuropathological finding assessment in atypical parkinsonian syndromes. J Neurol
of glial cytoplasmic inclusions in basal ganglia, sub- Neurosurg Psychiatry 2005b; 76: 420–2.
Brown RG, Pillon B, Uttner I, Payan C, Lacomblez L,
stantia nigra, pontine nuclei, medulla, cerebellum,
Members of the Neuropsychology Working Group and
and white matter, composed of fibrils of polymerized
NNIPPS Consortium. Cognitive function in patients
a-synuclein. The clinical phenotype is variable. Ini-
with progressive supranuclear palsy (PSP) and multiple
tially three syndromes were defined – olivoponto- system atrophy (MSA). Mov Disord 2002; 17 (suppl 5):
cerebellar atrophy (OPCA), striatonigral degeneration S221 (abstract P706).
(SND), and Shy–Drager syndrome (Graham & Geser F, Colosimo C, Wenning GK. Multiple system atro-
Oppenheimer, 1969) – but the current classification, phy. In: Beal MF, Lang AE, Ludolph A (eds.), Neurode-
based on the relative predominance of clinical (and generative Diseases: Neurobiology, Pathogenesis and
pathological) changes, encompasses MSA-C (cere- Therapeutics. Cambridge: Cambridge University Press,
bellar ataxia), roughly equivalent to OPCA, and MSA- 2005: 623–62.
P (parkinsonism), roughly equivalent to SND. All Gilman S, Low PA, Quinn N, et al. Consensus statement
on the diagnosis of multiple system atrophy. J Neurol
cases have autonomic dysfunction, which was the
Sci 1999; 163: 94–8.
prominent feature of Shy–Drager syndrome. The
Graham JG, Oppenheimer DR. Orthostatic hypotension
phenotype of MSA is broad, with many other neuro-
and nicotine sensitivity in a case of multiple system
logical features sometimes encountered (Geser et al., atrophy. J Neurol Neurosurg Psychiatry 1969; 32: 28–34.
2005). Clinicopathological diagnostic criteria for MSA Leiguarda RC, Pramstaller PP, Merello M, et al. Apraxia in
have been proposed (Gilman et al., 1999). Parkinson’s disease, progressive supranuclear palsy,
multiple system atrophy and neuroleptic-induced par- injury (Erlanger et al., 1999). In assessing these
kinsonism. Brain 1997; 120: 75–90. impairments, allowance may need to be made for
Meco G, Gasparini M, Doricchi F. Attentional functions premorbid intellectual level and for concurrent
in multiple system atrophy and Parkinson’s disease. alcohol misuse. The neuropsychological sequelae
of mild traumatic brain injury have been reviewed
Pillon B, Gouider-Khouja N, Deweer B, et al. Neuro-
(Kapur, 1994; Echemendia & Julian, 2001).
psychological pattern of striatonigral degeneration:
comparison with Parkinson’s disease and progressive
supranuclear palsy. J Neurol Neurosurg Psychiatry 1995;
58: 174–9. REFERENCES
Robbins TW, James M, Lange KW, et al. Cognitive
performance in multiple system atrophy. Brain 1992; Corsellis JAN, Bruton CJ, Freeman-Browne D. The
115: 271–91. aftermath of boxing. Psychol Med 1973; 3: 270–303.
Robbins TW, James M, Lange KW, et al. Cognitive deficits Echemendia RJ, Julian LJ. Mild traumatic brain injury in
in progressive supranuclear palsy, Parkinson’s disease, sports: neuropsychology’s contribution to a developing
and multiple system atrophy in tests sensitive to frontal field. Neuropsychol Rev 2001; 11: 69–88.
lobe dysfunction. J Neurol Neurosurg Psychiatry 1994; Erlanger DM, Kutner KC, Barth JT, Barnes R. Neuro-
57: 79–88. psychology of sports-related head injury: dementia
Sullivan EV, De La Paz R, Zipursky RB, Pfefferbaum A. pugilistica to post concussion syndrome. Clin Neuro-
Neuropsychological deficits accompanying striatonigral psychol 1999; 13: 193–209.
degeneration. J Clin Exp Neuropsychol 1991; 13: 773–88. Kapur N. Memory Disorders in Clinical Practice. Hove:
Lawrence Erlbaum, 1994: 97–113.
Nicoll JAR, Roberts GW, Graham DI. Apolipoprotein E
2.4.5 Dementia pugilistica epsilon-4 allele is associated with deposition of amyloid
beta-protein following head injury. Nat Med 1995; 1: 135–7.
A syndrome of cognitive impairment following Roberts GW, Gentleman SM, Lynch A, et al. b-amyloid
repeated blunt head trauma has been described, protein deposition in the brain following severe head
originally in boxers (hence dementia pugilistica, injury: implications for the pathogenesis of Alzheimer’s
boxer’s dementia, or ‘punch drunk syndrome’: disease. J Neurol Neurosurg Psychiatry 1994; 57: 419–25.
Corsellis et al., 1973), although other professions
may also be at risk of sports-related head injury (e.g.
2.4.6 Amyotrophic lateral sclerosis/
steeplechase jockeys after repeated falls). In add-
parkinsonism–dementia complex (ALS/PDC) of
ition to cognitive impairment, there may be a par-
Guam, Lytico-Bodig, Marianas dementia
kinsonian syndrome dominated by akinesia and
variably responsive to levodopa, as well as dysar- The Chamorro people of the island of Guam have
thria. Brain imaging may show ventricular dilatation been recognized to suffer a high prevalence of
and a cavum septum pellucidum. Pathologically the neurodegenerative disorders, known locally as
condition is reminiscent of Alzheimer’s disease, Lytico-Bodig, encompassing varying degrees of the
with neurofibrillary tangles, deposition of amyloid clinical features of MND/ALS, Parkinson’s disease,
b-peptide and diffuse neuronal loss. Brain trauma is and Alzheimer’s disease (Perl, 2006). The ALS and
known to increase expression of amyloid b (Roberts parkinsonism–dementia complex (PDC) were ini-
et al., 1994) and epidemiological studies have sug- tially described separately, but few pure cases of
gested head injury may be a risk factor for Alzhei- either condition exist, and both have severe neu-
mer’s disease, particularly in the presence of the rofibrillary neuropathology with little amyloid,
ApoE e4 genotype (Nicoll et al., 1995). suggesting that there may be shared pathogenetic
Dementia pugilistica lies at one end of a spec- mechanisms, for which various aetiological con-
trum of neuropsychological deficits following head cepts have been suggested (Perl, 2006).
The neuropsychological impairments of PDC drome (Brownell–Oppenheimer (ataxic) variant),

encompass recent memory loss, disorientation, cortical blindness (Heidenhain variant), or enceph-
and impairments of language, visuospatial, and alopathy (Nevin–Jones syndrome), but these terms
executive function (Galasko et al., 2002), a global are now seldom used, classification being based on
pattern similar to that seen in Alzheimer’s disease. PRNP codon 129 genotype and PrP isotype as
Very occasionally Chamorros may present with a detected by Western blotting, resulting in six vari-
pure dementing illness without extrapyramidal ants (Parchi et al., 1999).
symptoms or signs, referred to as ‘Marianas Inherited prion disorders, accounting for
dementia’ (Perl et al., 1994). approximately 10–15% of the total, are associated
with mutations in the PRNP gene which encodes
PrP (Kovacs et al., 2002). These have a broad
REFERENCES phenotype, including familial CJD, Gerstmann–
Straussler–Scheinker syndrome (GSS), and fatal
Galasko D, Salmon DP, Craig UK, et al. Clinical features familial insomnia (FFI).
and changing patterns of neurodegenerative disorders Acquired, iatrogenic, or transmissible forms of
on Guam, 1997–2000. Neurology 2002; 58: 90–7. prion disease account for <1% of the total. These
Perl DP. Amyotrophic lateral sclerosis/parkinsonism–
include kuru, a disorder of the Fore people of the
dementia complex of Guam. In: Strong MJ (ed.),
eastern highlands of New Guinea transmitted by
Dementia and Motor Neuron Disease. Abingdon:
ritual endocannibalism of brain tissue, a practice
Informa Healthcare, 2006: 177–91.
Perl DP, Hof PR, Steele JC, et al. Neuropathologic studies
which is now outlawed. Iatrogenic disease may
of a pure dementing syndrome (Marianas dementia) result from exposure to contaminated instrumen-
among the inhabitants of Guam, a form of ALS/ tation (depth EEG electrodes), grafts (cornea, dura
parkinsonism dementia complex. Brain Pathol 1994; mater), exogenous human pituitary hormones
4: 529 (abstract P31-13). (growth hormone, gonadotrophins), and possibly
blood transfusion (Peden et al., 2004). Variant CJD
(vCJD) is caused by the same prion strain respon-
2.5 Prion diseases sible for the epidemic of bovine spongiform
encephalopathy (BSE) in cattle, presumably
The aetiological agents for the prion group of dis- reaching humans through the food chain, and
orders are conformationally altered proteins, or hence is sometimes also known as ‘human BSE’
prions, which autocatalytically convert normal (Collinge, 1999). Progressive dementia, often rapid,
cellular prion protein (PrP), encoded by the PRNP is common to many of these prion disorders. Brain
gene on chromosome 20, to an abnormal form that tissue (biopsy, autopsy) typically shows spongiform
is highly resistant to degradation (Prusiner, 1982, vacuolation affecting any part of the cerebral grey
2001; Collinge, 2001). matter (hence these disorders are sometimes called
Prion diseases (or prionoses) may afflict both ‘spongiform encephalopathies’), with astrocytic
humans and animals (Collinge & Palmer, 1997; proliferation, gliosis, neuronal loss, synaptic
Prusiner, 1999). Human disease takes a number of degeneration, and variable frequencies of PrP-
clinicopathological forms, namely sporadic, gen- immunopositive amyloid plaques (Ironside &
etic, or iatrogenic. Sporadic Creutzfeldt–Jakob dis- Head, 2004). Prion disease cases without spongi-
ease (sCJD) is the commonest prion disease, form change have also been described (Collinge
occurring with an incidence of around one case per et al., 1990).
million population throughout the world. The older The pathogenesis of neurodegeneration in the
literature defined a number of clinical variants of various prion disorders is thought to be common
sCJD, presenting with prominent cerebellar syn- to the different aetiologies (Hegde et al., 1999).
Polymorphism at codon 129 of the PRNP gene, and phenotypic analysis of 300 subjects. Ann Neurol
which may encode either valine or methionine, 1999; 46: 224–33.
may have a dramatic effect on disease phenotype, Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW.
including susceptibility to disease, the incubation Preclinical vCJD after blood transfusion in a PRNP codon
129 heterozygous patient. Lancet 2004; 364: 527–9.
period of the disease, and the duration of illness
Prusiner SB. Novel proteinaceous particles cause scrapie.
(Palmer et al., 1991; Parchi et al., 1999).
Science 1982; 216: 136–44.
Prion disorders are rare. Only a handful of cases
Prusiner SB (ed.). Prion Biology and Diseases. Cold Spring
is seen each year in regional neuroscience centres Harbor: Cold Spring Harbor Laboratory Press, 1999.
(Larner & Doran, 2004). No treatment, curative, Prusiner SB. Shattuck lecture: neurodegenerative diseases
symptomatic, or palliative, is yet described but and prions. N Engl J Med 2001; 344: 1516–26.
research into possible therapeutic interventions Trevitt CR, Collinge J. A systematic review of prion
continues (Larner & Doran, 2003; Trevitt & Collinge, therapeutics in experimental models. Brain 2006; 129:
2006). 2241–65.
2.5.1 Sporadic prion disease: sporadic

REFERENCES Creutzfeldt–Jakob disease (sCJD)
Collinge J. Variant Creutzfeldt–Jakob disease. Lancet 1999; CJD occurs in sporadic, familial, and iatrogenic
354: 317–23. forms. CSF proteins which are markers of neuronal
Collinge J. Prion diseases of humans and animals: their injury may be elevated; although these are not
causes and molecular basis. Annu Rev Neurosci 2001; disease-specific, estimations of the 14-3-3 protein
24: 519–50. have a high degree of sensitivity and specificity for
Collinge J, Owen F, Poulter M, et al. Prion dementia the diagnosis of sCJD (Zerr et al., 2000). EEG may
without characteristic pathology. Lancet 1990; 336: 7–9. show periodic sharp wave complexes (PSWCs) at a
Collinge J, Palmer MS (eds.). Prion diseases. Oxford: frequency of around 2–3 Hz in a markedly abnor-
Oxford University Press, 1997.
mal background in sCJD, again a highly specific
Hegde RS, Tremblay P, Groth D, et al. Transmissible and
and sensitive finding (Zerr et al., 2000), especially if
genetic prion diseases share a common pathway of
strict criteria for the definition of PSWC are used
neurodegeneration. Nature 1999; 402: 822–6.
Ironside JW, Head MW. Human prion diseases. In: Esiri (Steinhoff et al., 2004). Other disorders which may
MM, Lee VM-Y, Trojanowski JQ (eds.), The Neuropath- mimic or be clinically confused with CJD, and
ology of Dementia (2nd edition). Cambridge: Cambridge hence may lead to confounding in defining the
University Press, 2004: 402–26. neuropsychological profile, include AD (Tschampa
Kovacs GG, Trabattoni G, Hainfellner JA, et al. Mutations of et al., 2001; Reinwald et al., 2004), DLB (Tschampa
the prion protein gene: phenotypic spectrum. J Neurol et al., 2001; Doran & Larner 2004; Kraemer et al.,
2002; 249: 1567–82. 2005), progressive subcortical gliosis of Neumann
Larner AJ, Doran M. Prion diseases: update on therapeutic (Seitelberger, 1968; Bergmann et al., 1991), Wer-
patents, 1999–2002. Exp Opin Ther Patents 2003; 13:
nicke–Korsakoff syndrome (Pietrini, 1992; Mona-
67–78.
ghan et al., 2006), nonconvulsive status epilepticus
Larner AJ, Doran M. Prion disease at a regional neurosci-
(Cohen et al., 2004; Vaz et al., 2005), angioen-
ence centre: retrospective audit. J Neurol Neurosurg
Psychiatry 2004; 75: 1789–90. dotheliomatosis (Drlicek et al., 1991), Hashimoto’s
Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozy- encephalopathy (Schott et al., 2003), pellagra
gous prion protein genotype predisposes to sporadic encephalopathy (Pellisé et al., 2002), and glioma-
Creutzfeldt–Jakob disease. Nature 1991; 352: 340–2. tosis cerebri (Slee et al., 2006).
Parchi P, Giese A, Capellari S, et al. Classification of Because of the rapid progression of the disease,
sporadic Creutzfeldt–Jakob disease based on molecular profound cognitive deficits amounting to dementia
may be present before clinical presentation. When with an atypical presentation of Creutzfeldt–Jakob
assessment has been possible, a subcortical pattern disease. Med Sci Monit 2001; 7: 1307–15.
has generally been reported in familial CJD, and Pellisé A, Navarro O, Rey M, Cardozo A, Ferrer I. Protein
both sporadic and familial cases have been found 14-3-3 in pellagra encephalopathy. Neurologia 2002; 17:
655–6.
to have episodic unresponsiveness, interference
Pietrini V. Creutzfeldt–Jakob disease presenting as Wer-
effects, and verbal and motor perseverations, per-
nicke–Korsakoff syndrome. J Neurol Sci 1992; 108:
haps reflecting thalamic involvement (Snowden
149–53.
et al., 2002). Presentation with isolated aphasia has Reinwald S, Westner IM, Niedermaier N. Rapidly progres-
been reported (Mandell et al., 1989). In a patient sive Alzheimer’s disease mimicking Creutzfeldt–Jakob
undergoing neuropsychological testing in a pre- disease. J Neurol 2004; 251: 1020–2.
dementia stage, deficits resembling progressive Schott JM, Warren JD, Rossor MN. The uncertain nosology
supranuclear palsy were reported (Zarei et al., of Hashimoto encephalopathy. Arch Neurol 2003; 60:
2002). A patient with the Heidenhain variant has 1812.
been reported whose initial symptom was agra- Seitelberger F. Präsenile gliale Dystrophie. Acta Neuro-
phia, followed by hemianopsia and visual hallu- pathol (Berl) 1968; Suppl 4: 109–18.
Slee M, Pretorius P, Ansorge O, Stacey R, Butterworth R.
cinations, and evolving to dementia over a 3-
Parkinsonism and dementia due to gliomatosis cerebri
month period (Pachalska et al., 2001).
mimicking sporadic Creutzfeldt–Jakob disease (CJD).
Snowden JA, Mann DMA, Neary D. Distinct neuropsycho-
REFERENCES logical characteristics in Creutzfeldt–Jakob disease.
Bergmann M, Gullotta F, Weitbrecht WU. Progressive Steinhoff B, Zerr I, Glatting M, et al. Diagnostic value of
subkortikale Gliose. Fortschr Neurol Psychiat 1991; 59: periodic complexes in Creutzfeldt–Jakob disease. Ann
328–34. Neurol 2004; 56: 702–8.
Cohen D, Kutluay E, Edwards J, Peltier A, Beydoun A. Tschampa HJ, Neumann M, Zerr I, et al. Patients with
Sporadic Creutzfeldt–Jakob disease presenting with Alzheimer’s disease and dementia with Lewy bodies
nonconvulsive status epilepticus. Epilepsy Behav 2004; mistaken for Creutzfeldt–Jakob disease. J Neurol
5: 792–6. Neurosurg Psychiatry 2001; 71: 33–9.
Doran M, Larner AJ. EEG findings in dementia with Lewy Vaz J, Sierazdan K, Kane N. Non convulsive status
bodies causing diagnostic confusion with sporadic epilepticus in Creutzfeldt–Jakob disease: a short report.
Creutzfeldt–Jakob disease. Eur J Neurol 2004; 11: 838–41. J Neurol Neurosurg Psychiatry 2005; 76: 1318 (abstract
Drlicek M, Grisold W, Liszka U, Hitzenberger P, Machacek 030).
E. Angiotropic lymphoma (malignant angioendothelio- Zarei M, Nouraei SA, Caine D, Hodges JR, Carpenter RH.
matosis) presenting with rapidly progressive dementia. Neuropsychological and quantitative oculometric study
Acta Neuropathol (Berl) 1991; 82: 533–5. of a case of sporadic Creutzfeldt–Jakob disease at
Kraemer C, Lang K, Weckesser M, Evers S. Creutzfeldt– predementia stage. J Neurol Neurosurg Psychiatry
Jacob [sic] disease misdiagnosed as dementia with Lewy 2002; 73: 56–8.
bodies. J Neurol 2005; 252: 861–2. Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and
Mandell AM, Alexander MP, Carpenter S. Creutzfeldt– CSF 14-3-3 proteins as aids to the diagnosis of
Jakob disease presenting as isolated aphasia. Neurology Creutzfeldt–Jakob disease. Neurology 2000; 55: 811–5.
1989; 39: 55–8.
Monaghan TS, Murphy DT, Tubridy N, Hutchinson M.
The woman who mistook the past for the present. Adv 2.5.2 Iatrogenic prion disease: variant
Clin Neurosci Rehabil 2006; 6 (3); 27–8. Creutzfeldt–Jakob disease (vCJD), kuru
Pachalska M, Kurzbauer H, MacQueen BD, Forminska-
Kapuscik M, Herman-Sucharska I. Neuropsychological Since its first description in 1996, vCJD has
features of rapidly progressive dementia in a patient attracted much attention despite its clinical rarity
because of its probable aetiology, namely trans- Kuru, an epidemic disorder transmitted by
mission of bovine spongiform encephalopathy endocannibalism amongst the Fore people of Papua
across the species barrier from cattle to humans New Guinea, was the first human prion disease to
through the consumption of infected meat prod- be extensively described (Gajdusek, 1977; Zigas,
ucts (Collinge, 1999). Transmission by blood 1990). It has become less common since the cessa-
transfusion is also a possibility (Wroe et al., 2006). tion of endocannibalism, although some new cases
Unlike sporadic CJD, vCJD tends to affect younger are still reported, reflecting extremely long incuba-
individuals, and the presentation is often with non- tion periods of 40–50 years (Collinge et al., 2006).
specific sensory and psychiatric features (Spencer The profile of cognitive deficits is not reported, since
et al., 2002), although presentation with epilepsy common neuropsychological testing methods are
has been reported (Silverdale et al., 2000). Magnetic not culturally appropriate.
resonance imaging may show high signal intensity
in the posterior thalamus (pulvinar sign) in vCJD
REFERENCES
(Zeidler et al., 2000), although this is not unique to
vCJD (Monaghan et al., 2006). EEG PSWCs are
Collinge J. Variant Creutzfeldt–Jakob disease. Lancet 1999;
absent in vCJD. PrP-immunopositive staining may
354: 317–23.
be present in lymphoreticular tissues, even pre-
Collinge J, Whitfield J, McKintosh E, et al. Kuru in the
symptomatically (Hilton et al., 1998, 2002). In the
21st century: an acquired human prion disease
appropriate clinical setting, tonsil biopsy is helpful with very long incubation periods. Lancet 2006; 367:
in the diagnosis of vCJD (Hill et al., 1999). 2068–74.
Reports of neuropsychological assessment in Cordery RJ, Alner K, Cipolotti L, et al. The neuropsycho-
vCJD are rare. Kapur et al. (2001) reported early logy of variant CJD: a comparative study with inherited
deficits in episodic memory, semantic memory, and sporadic forms of prion disease. J Neurol Neurosurg
retrieval and executive tasks but with relative Psychiatry 2005; 76: 330–6.
sparing of recognition memory, autobiographical Cordery RJ, Hall M, Cipolotti L, et al. Early cognitive
memory, and face perception. In a larger cohort, decline in Creutzfeldt–Jakob disease associated with
human growth hormone treatment. J Neurol Neurosurg
findings were of low performance IQ, with
Psychiatry 2003; 74: 1412–16.
impairments on tests of memory, executive func-
Gajdusek DC. Unconventional viruses and the origin and
tion, attention speed, and visuoperceptual reason-
disappearance of kuru. Science 1977; 197: 943–60.
ing, with relative preservation of digit span, verbal Hill AF, Butterworth RJ, Joiner S, et al. Investigation of
reasoning, long-term autobiographical memory, variant Creutzfeldt–Jakob disease and other human
and face perception. The profile was one of com- prion disease with tonsil biopsy samples. Lancet 1999;
bined cortical and subcortical dementia (Kapur 353: 183–9.
et al., 2003). A study of ten vCJD patients, com- Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J.
paring them with sCJD and inherited prion disease, Prion immunoreactivity in appendix before clinical
found evidence for generalized cognitive decline onset of variant Creutzfeldt–Jakob disease. Lancet
but with the suggestion that visual perception 1998; 352: 703–4.
Hilton D, Ghani AC, Conyers L, et al. Accumulation of
might be spared (Cordery et al., 2005).
prion protein in tonsil and appendix: review of tissue
In a series of five patients with iatrogenic prion
samples. BMJ 2002; 325: 633–4.
disease resulting from exposure to cadaveric
Kapur N, Abbott P, Lowman A, Will RG. The neuropsycho-
human growth hormone, only one had a complaint logical profile associated with variant Creutzfeldt–Jakob
of mild memory problems but four had evidence disease. Brain 2003; 126: 2693–702.
for mild intellectual decline on the WAIS-R and one Kapur N, Ironside J, Abbott P, et al. A neuropsychological–
had selective visual memory and frontal executive neuropathological case study of variant Creutzfeldt–
impairments (Cordery et al., 2003). Jakob disease. Neurocase 2001; 7: 261–7.
Monaghan TS, Murphy DT, Tubridy N, Hutchinson M. disturbance (depression, psychosis) is also reported.
The woman who mistook the past for the present. Adv Deficits seem to vary amongst the different reports,
Clin Neurosci Rehabil 2006; 6 (3); 27–8. including focal abnormalities suggestive of cortical
Silverdale M, Leach JP, Chadwick DW. New variant involvement (acalculia, agnosia, apraxia), and more
Creutzfeldt–Jakob disease presenting as localization-
global impairment including attention and execu-
related epilepsy. Neurology 2000; 54: 2188.
tive functions suggesting possible subcortical
Spencer MS, Knight RSG, Will RG. First hundred cases of
involvement (Farlow et al., 1989; Unverzagt et al.,
variant Creutzfeldt–Jakob disease: retrospective case
note review of early psychiatric and neurological
1997). This would be in keeping with the multi-
features. BMJ 2002; 324: 1479–82. focal nature of brain involvement in prion
Wroe SJ, Pal S, Siddique D, et al. Clinical presentation and disorders.
pre-mortem diagnosis of variant Creutzfeldt–Jakob FFI, a rare inherited prion disorder linked to
disease associated with blood transfusion: a case report. mutations of the PrP gene and a particular poly-
Lancet 2006; 368: 2061–7. morphism at codon 129, is characterized clinically
Zeidler M, Sellar RJ, Collie DA, et al. The pulvinar sign on by sleep, autonomic, and motor disturbances and
magnetic resonance imaging in variant Creutzfeldt– pathologically by marked atrophy of the anterior
Jakob disease. Lancet 2000; 355: 1412–8.
and dorsomedial nuclei of the thalamus. A rare
Zigas V. Laughing death: the untold story of kuru. Clifton
sporadic form of the latter has also been described
NJ: Humana, 1990.
(Scaravilli et al., 2000). Neuropsychological studies
(Gallassi et al., 1992, 1996) have shown early
2.5.3 Inherited prion disease: familial CJD, impairments of attention and vigilance, working
Gerstmann–Straussler–Scheinker disease memory deficits with a particular difficulty in the
(GSS), fatal familial insomnia (FFI) ordering of events, and a progressive confusional
state. The pattern seems to be distinct from that of
Inherited prion disease results from mutations in the cortical and subcortical dementias and reflective of
PrP gene on chromosome 20, with various pheno- a thalamic dementia.
types (Kovacs et al., 2002), described as familial CJD,
Gerstmann–Straussler–Scheinker disease (GSS), and
fatal familial insomnia (FFI). One study found gen- REFERENCES
eralized cognitive decline in inherited prion disease
with relative preservation of nominal function in Cordery RJ, Alner K, Cipolotti L, et al. The neuropsycho-
some cases (Cordery et al., 2005). logy of variant CJD: a comparative study with inherited
In a single case study of familial CJD, verbal and sporadic forms of prion disease. J Neurol Neurosurg
memory, word finding, and dominant hand tactual Psychiatry 2005; 76: 330–6.
performance were impaired, with other functions Farlow MR, Yee RD, Dlouhy SR, et al. Gerstmann–
relatively intact (Gass et al., 2000). A family with a Straussler–Scheinker disease. I. Extending the clinical
novel mutation, T183A, in the PRNP gene has been spectrum. Neurology 1989; 39: 1446–52.
reported with clinical features resembling fronto- Gallassi R, Morreale A, Montagna P, Gambetti P, Lugaresi
E. Fatal familial insomnia: neuropsychological study of
temporal dementia and parkinsonism linked to
a disease with thalamic degeneration. Cortex 1992; 28:
chromosome 17 (FTDP-17: see Section 2.2.4; Nitrini
175–87.
et al., 1997, 2001).
Gallassi R, Morreale A, Montagna P, et al. Fatal familial
GSS is an autosomal dominant disorder due to insomnia: behavioral and cognitive features. Neurology
mutations in the PrP gene with cerebellar ataxia as 1996; 46: 935–9.
an early feature, along with dysarthria and eye Gass CS, Luis CA, Meyers TL, Kuljis RO. Familial
movement disorders. Extrapyramidal signs may Creutzfeldt–Jakob disease: a neuropsychological case
evolve. Progressive dementia with behavioural study. Arch Clin Neuropsychol 2000; 15: 165–75.
2.6 Mild cognitive impairment 87
Kovacs GG, Trabattoni G, Hainfellner JA, et al. Mutations of 1993) score of 0.5 or a Global Deterioration Scale
the prion protein gene: phenotypic spectrum. J Neurol (GDS: Reisberg et al., 1982) score of 3, but Petersen
2002; 249: 1567–82. has been at pains to point out that MCI remains a
Nitrini R, Rosemberg S, Passos-Bueno MR, et al. Familial clinical diagnosis (Petersen, 2003). A Preclinical AD
spongiform encephalopathy associated with a novel
Scale to identify cases has been published (Visser
prion protein gene mutation. Ann Neurol 1997; 42:
et al., 2002). Complex ADL may be impaired in MCI
138–46.
(Perneczky et al., 2006).
Nitrini R, Teixeira-da-Silva LS, Rosemberg S, et al. Prion
disease resembling frontotemporal dementia and par-
MCI may be clinically and aetiologically hetero-
kinsonism linked to chromosome 17. Arq Neuropsi- geneous. At the time of clinical presentation, a
quiatr 2001; 59: 161–4. memory complaint is the most common feature, so
Scaravilli F, Cordery RJ, Kretschmar H, et al. Sporadic fatal called amnestic MCI. Other variants have been
insomnia: a case study. Ann Neurol 2000; 48: 665–8. described, specifically single non-memory-domain
Unverzagt FW, Farlow MR, Norton J, et al. Neuropsycho- MCI and multiple-domain MCI. The former may be
logical function in patients with Gerstmann–Straussler the harbinger of AD – for example a focal deficit
disease from the Indiana kindred (F198S). J Int such as visual agnosia may be due to the ‘visual
Neuropsychol Soc 1997; 3: 169–78.
variant of Alzheimer’s disease’ (Levine et al., 1993;
Larner, 2004a) – but might also reflect the path-
ology of another disorder such as frontotemporal
2.6 Mild cognitive impairment (MCI) dementia, dementia with Lewy bodies, or vascular
dementia. Multiple-domain MCI might reflect
It has been increasingly recognized in recent times single or multiple aetiologies (Petersen, 2003;
that a degree of age-related cognitive decline may Petersen & Morris, 2005). The possibility that ‘MCI’
exist in individuals who do not fulfil validated cri- may reflect conditions such as dysphoria, vascular
teria for the diagnosis of Alzheimer’s disease (AD: disease, and miscellaneous disorders which may
McKhann et al., 1984). Various terms have been cause cognitive impairment such as obstructive
used to describe this state, including benign senes- sleep apnoea, alcohol misuse, head injury, and
cent forgetfulness, age-associated memory impair- metabolic or nutritional deficiencies, some of them
ment (AAMI), age-associated cognitive decline treatable, has been emphasized by some authors
(AACD), cognitive decline no dementia (CIND), and (Gauthier & Touchon, 2005).
mild cognitive impairment (MCI). The neuroanatomical and neuropathological
A degree of consensus has developed around the substrates for the changes characterized as MCI
concept of MCI (Golomb et al., 2001; Petersen, have been examined. Structural neuroimaging
2003, 2007; Winblad et al., 2004; Petersen & Morris, techniques such as computed tomography (CT)
2005; Portet et al., 2006; Tuokko & Hultsch, 2006), and, particularly, magnetic resonance imaging
though not unanimity (Ritchie & Touchon, 2000; (MRI) have shown reduced volume of brain tissue
Gauthier & Touchon, 2005). MCI may be defined by and an increased volume of cerebrospinal fluid with
the presence of a subjective memory complaint, increasing age, the former consisting predominantly
preferably corroborated by an informant; evidence of a decline in white matter (Albert, 1998). Hence,
of objective memory impairment for age and level brain atrophy per se is not specific for the diagnosis
of education; largely normal general cognitive of pathological change, an assumption which may
function; essentially intact activities of daily living lead to clinical misdiagnosis of AD if undue weight
(ADL); and failure to fulfil criteria for dementia is placed on imaging findings (Larner, 2004b). In
(Petersen et al., 1999). Global rating scales have MCI which is destined to become AD, hippocampal
been used to define MCI, such as a Clinical and entorhinal cortex volume are reduced and there
Dementia Rating (CDR: Hughes et al., 1982; Morris, may be a higher rate of hippocampal volume loss
(Jack et al., 1999; de Leon et al., 2004; Karas et al., (Salloway et al., 2004). In the future, drugs targeting
2004; Korf et al., 2004). specific pathogenetic processes in AD may find a
Neuropathological studies of the aging brain have role in MCI. Since the amyloid hypothesis remains
examined both positive and negative phenomena the most tenable explanation of AD pathogenesis,
(Gómez-Isla & Hyman, 2003; DeKosky et al., 2006). targeting the Ab protein, by means of immuno-
Of the former, neurofibrillary pathology (neurofi- therapy (‘vaccine’: Schenk et al., 1999; Gilman et al.,
brillary tangles, neuropil threads) and senile neuritic 2005) or secretase inhibitors (Larner, 2004c), and the
plaques, hallmarks of the AD brain, may be seen in consequences of its overproduction such as oxida-
cognitively normal older individuals. The develop- tive stress, would seem logical. However, vitamin E
ment of neurofibrillary pathology follows a relatively (a-tocopherol), which is believed to act as an
stereotyped hierarchical pattern with age, appearing antioxidant, failed to slow conversion rate of MCI to
first in the transentorhinal cortex (Arnold et al., AD (Petersen et al., 2005).
1991; Braak & Braak, 1991). Spread to hippocampal
and association cortex is associated with progressive
appearance of cognitive decline. Senile plaques have REFERENCES
a broader and more variable distribution; a signifi-
cant burden may be associated with normal cogni- Albert MS. Normal and abnormal memory: aging and
tion. Negative phenomena include neuronal and Alzheimer’s disease. In: Wang E, Snyder DS (eds.),
synaptic loss. In normal aging, there is relative Handbook of the Aging Brain. San Diego: Academic
preservation of cortical and hippocampal neuronal Press, 1998: 1–17.
populations, although subcortical structures such as Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen
the basal forebrain, locus caeruleus, and substantia GW. The topographical and neuroanatomical distribu-
nigra do show losses. In contrast, marked cell loss tion of neurofibrillary tangles and neuritic plaques in
has been observed in entorhinal cortex in MCI, cerebral cortex of patients with Alzheimer’s disease.
Cerebral Cortex 1991; 1: 103–16.
followed later by involvement of association cortex,
Braak H, Braak E. Neuropathological stageing [sic] of
changes which increase in severity with increasing
Alzheimer-related changes. Acta Neuropathol (Berl)
severity of illness. In other words, preclinical AD
1991; 82: 239–59.
(MCI) and normal aging may be differentiated on a DeKosky ST, Ikonomovic MD, Hamilton RL, Bennett DA,
pathological basis, the changes in the former falling Mufson EJ. Neuropathology of mild cognitive impair-
midway between those seen in normal aging and in ment in the elderly. In: Gauthier S, Scheltens P, Cum-
AD (Kordower et al., 2001; DeKosky et al., 2006; mings JL (eds.), Alzheimer’s Disease and Related Disorders
Markesbery et al., 2006). Annual 5. London: Taylor & Francis, 2006: 1–16.
Longitudinal studies have shown a conversion de leon MJ, Desanti S, Zinkowski R, et al. MRI and CSF
rate from MCI to AD of around 10–15% per year. studies in the early diagnosis of Alzheimer’s disease.
Clearly, if some MCI, mostly amnestic MCI, is pro- J Intern Med 2004; 256: 205–23.
Gauthier S, Touchon J. Mild cognitive impairment is not a
dromal AD, or early-stage AD (Morris, 2006), then a
clinical entity and should not be treated. Arch Neurol
disease-modifying therapeutic intervention at this
2005; 62: 1164–6.
stage might be anticipated to delay progression to,
Gilman S, Koller M, Black RS, et al. Clinical effects of
and hence reduce the incidence of, AD. A double- Abeta immunization (AN1792) in patients with AD in an
blind placebo-controlled trial of the cholinesterase interrupted trial. Neurology 2005; 64: 1553–62.
inhibitor donepezil in MCI suggested initial delay in Golomb J, Kluger A, Garrard P, Ferris S. Clinician’s Manual
conversion rate in the treated group but with on Mild Cognitive Impairment. London: Science Press,
equalization of conversion rates by 3 years (Petersen 2001.
et al., 2005), confirming the lack of effect seen in Gómez-Isla T, Hyman BT. Neuropathological changes
an earlier trial of donepezil of shorter duration in normal aging, mild cognitive impairment, and
2.6 Mild cognitive impairment 89
Alzheimer’s disease. In: Petersen RC (ed.), Mild Cogni- Perneczky R, Pohl C, Sorg C, et al. Impairment of activities
tive Impairment: Aging to Alzheimer’s Disease. Oxford: of daily living requiring memory of complex reasoning
Oxford University Press, 2003: 191–204. as part of the MCI syndrome. Int J Geriatr Psychiatry
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A 2006; 21: 158–62.
new clinical scale for the staging of dementia. Br J Petersen RC (ed.). Mild Cognitive Impairment: Aging to
Psychiatry 1982; 140: 566–72. Alzheimer’s Disease. Oxford: Oxford University Press,
Jack CR Jr, Petersen RC, Xu YC, et al. Prediction of AD with 2003.
MRI-based hippocampal volume in mild cognitive Petersen RC. Mild cognitive impairment: current research
impairment. Neurology 1999; 52: 1397–403. and clinical implications. Semin Neurol 2007; 27: 22–31.
Karas GB, Scheltens P, Rombouts SARB, et al. Global and Petersen RC, Morris JC. Mild cognitive impairment as a
local gray matter loss in mild cognitive impairment clinical entity and treatment target. Arch Neurol 2005;
and Alzheimer’s disease. Neuroimage 2004; 23: 62: 1160–3.
708–16. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive
Kordower JH, Chu Y, Stebbins GT, et al. Loss and atrophy impairment: clinical characterization and outcome.
of layer II entorhinal cortex neurons in elderly people Arch Neurol 1999; 56: 303–8.
with mild cognitive impairment. Ann Neurol 2001; 49: Petersen RC, Thomas RG, Grundman M, et al. Vitamin E
202–13. and donepezil for the treatment of mild cognitive
Korf ESC, Wahlund LO, Visser PJ, Scheltens P. Medial impairment. N Engl J Med 2005; 352: 2379–88.
temporal lobe atrophy on MRI predicts dementia in Portet F, Ousset PJ, Visser PJ, et al. Mild cognitive
patients with mild cognitive impairment. Neurology impairment (MCI) in medical practice: a critical review
2004; 63: 94–100. of the concept and new diagnostic procedure. Report of
Larner AJ. ‘Posterior cortical atrophy’ or ‘focal-onset the MCI Working Group of the European Consortium
Alzheimer’s disease’? A clinical, neuropsychological and on Alzheimer’s Disease. J Neurol Neurosurg Psychiatry
neuroimaging study. J Neurol 2004a; 251 (suppl 3): III102 2006; 77: 714–18.
(abstract P385). Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global
Larner AJ. Getting it wrong: the clinical misdiagnosis of Deterioration Scale (GDS) for assessment of primary
Alzheimer’s disease. Int J Clin Pract 2004b; 58: 1092–4. degenerative dementia. Am J Psych 1982; 139: 1136–9.
Larner AJ. Secretases as therapeutic targets in Alzheimer’s Ritchie K, Touchon J. Mild cognitive impairment: concep-
disease: patents 2000–2004. Exp Opin Therap Patents tual basis and current nosological status. Lancet 2000;
2004c; 14: 1403–20. 355: 225–8.
Levine DN, Lee JM, Fisher CM. The visual variant of Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in
Alzheimer’s disease: a clinicopathologic case study. mild cognitive impairment: a randomized placebo-
Neurology 1993; 43: 305–13. controlled trial. Neurology 2004; 63: 651–7.
McKhann G, Drachman D, Folstein M, et al. Clinical Schenk D, Barbour R, Dunn W, et al. Immunization with
diagnosis of Alzheimer’s disease. Report of the NINCDS- amyloid-b attenuates Alzheimer-disease-like pathology
ADRDA work group under the auspices of the Depart- in the PDAPP mouse. Nature 1999; 400: 173–7.
ment of Health and Human Service Task forces on Tuokko HA, Hultsch DF (eds.). Mild Cognitive Impair-
Alzheimer’s disease. Neurology 1984; 34: 939–44. ment: International Perspectives. London: Taylor &
Markesbery WR, Schmitt FA, Kryscio RJ, et al. Neuro- Francis, 2006.
pathologic substrate of mild cognitive impairment. Arch Visser PJ, Verhey FRJ, Scheltens P, et al. Diagnostic
Neurol 2006; 63: 38–46. accuracy of the Preclinical AD Scale (PAS) in cognitively
Morris J. The CDR: current version and scoring rules. mildly impaired subjects. J Neurol 2002; 249: 312–19.
Neurology 1993; 43: 2412–4. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive
Morris JC. Mild cognitive impairment is early-stage impairment: beyond controversies, towards a consen-
Alzheimer disease: time to revise diagnostic criteria. sus. Report of the International Working Group on Mild
Arch Neurol 2006; 63: 15–16. Cognitive Impairment. J Int Med 2004; 256: 240–6.
3
Cerebrovascular disease: vascular dementia and

vascular cognitive impairment
3.1 Cortical vascular dementia, multi-infarct dementia (MID), post-stroke

dementia 93
3.2 Subcortical vascular dementia, Binswanger’s disease, lacunar state,
subcortical ischaemic vascular disease (SIVD) 95
3.3 Strategic infarct dementia, strategic strokes 97
3.3.1 Angular gyrus 97
3.3.2 Corpus callosum, fornix 97
3.3.3 Thalamus 97
3.3.4 Genu of the internal capsule 99
3.3.5 Caudate nucleus, globus pallidus 99
3.3.6 Hippocampus 100
3.3.7 Basal forebrain 100
3.3.8 Brainstem and cerebellum 100
3.4 Subarachnoid haemorrhage (SAH) 101
3.4.1 Aneurysmal SAH, unruptured aneurysms 102
3.4.2 Perimesencephalic (non-aneurysmal) SAH 103
3.4.3 Superficial siderosis of the nervous system 103
3.5 Intracranial vascular malformations 104
3.5.1 Arteriovenous malformations (AVMs) 104
3.5.2 Cavernous haemangiomas 105
3.6.1 Angioendotheliomatosis, intravascular lymphomatosis 106
3.6.2 CADASIL 106
3.6.3 Cerebral amyloid angiopathies (CAA) 107
3.6.4 Familial young-adult-onset arteriosclerotic leukoencephalopathy
with alopecia and lumbago without arterial hypertension 109
3.6.5 Familial occipital calcifications, haemorrhagic strokes, leukoencephalopathy,
dementia and external carotid dysplasia (FOCHS-LADD) 109
3.6.6 Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) 109
3.6.7 Hereditary multi-infarct dementia of Swedish type 109
3.6.8 Hughes’ syndrome (primary antiphospholipid antibody syndrome) 110
3.6.9 Polycythaemia rubra vera 111
3.6.10 Sickle cell disease 111
3.6.11 Sneddon’s syndrome 111
3.6.12 Spatz–Lindenberg disease (von Winiwarter–Buerger’s disease) 112
3.6.13 Susac syndrome 112
90
Cerebrovascular disease 91

3.7.1 Cortical venous sinus thrombosis (CVST) 112
3.7.2 Migraine 112
3.7.3 Transient global amnesia (TGA) 114
Cognitive impairment and dementia associated with community-based study most patients with
cerebrovascular disease is not a unitary entity, but dementia coming to autopsy had mixed AD/cere-
one typified by clinical, pathological, and aetiological brovascular disease (MRC CFAS, 2001). Consid-
heterogeneity. Different variants or subtypes have ering the shared vascular risk factors for AD and
been noted for over a century but still the classifi- VaD (Stewart, 2005) this observation is perhaps not
cation and categorization of vascular dementia (VaD) surprising. Conversely, there have been reports of
and vascular cognitive impairment is evolving, cur- series of patients clinically diagnosed as VaD who
rent taxonomies incorporating combinations of at postmortem proved to have either AD alone or
lesion aetiology, pathological type, neuroanatomical mixed disease (Nolan et al., 1998). Double patho-
location, and clinical syndrome (e.g. Amar & Wilcock, logy may lower the threshold for clinical mani-
1996; Chiu et al., 2000; Erkinjuntti & Gauthier, 2002; festation of cognitive deficits (Snowdon et al., 1997;
Bowler & Hachinski, 2003; De Leeuw & van Gijn, Snowdon, 2001). Pure VaD may be a rare cause of
2003; O’Brien et al., 2003; Rockwood et al., 2003; dementia (Hulette et al., 1997).
Godefroy & Bogousslavsky, 2007). Various consensus Clinically the distinction between AD and VaD is
diagnostic criteria for VaD have been proposed, not always clear-cut. The Hachinski Ischaemic
including the State of California Alzheimer’s Disease Score (HIS) has been suggested to differentiate
Diagnostic and Treatment Centers (ADDTC) criteria patients with VaD from those with AD (Hachinski
(Chui et al., 1992) and the National Institute of et al., 1975) but is recognized to have shortcom-
Neurological Disorders and Stroke and the Associ- ings. In a neuropathologically confirmed series of
ation Internationale pour la Recherche et dementia patients, items from the HIS showing
l’Enseignement en Neurosciences (NINDS-AIREN) independent correlation with VaD were stepwise
criteria (Román et al., 1993), as well as the general deterioration, fluctuating course, and a history of
criteria of DSM and ICD. NINDS-AIREN recognizes hypertension, stroke, and focal neurological
the need to establish a causal relationship between symptoms (Moroney et al., 1997).
cerebrovascular lesions and cognitive deficit both The definition of vascular cognitive impairment
spatially and temporally, emphasizing the import- (VCI: Bowler & Hachinski, 1995), a new conceptual
ance of neuroimaging to corroborate clinical findings approach, stemmed in part from the realization
(Román et al., 1993). However, because memory that older concepts were unduly influenced by
impairment is the most salient feature in Alzheimer’s thinking on AD, and in part from the realization
disease (AD), the most common cause of dementia, it that cognitive decline due to vascular disease is
has been noted that many of these diagnostic criteria amenable to prevention. VCI might be envisaged as
have been inadvertently ‘Alzheimerized’, with undue one form of mild cognitive impairment (MCI: see
emphasis placed on memory loss at the expense of Section 2.6). To detect VCI may require new, spe-
other neuropsychological features (Bowler & cifically designed, neuropsychological test instru-
Hachinski, 2003). This may account for the low sen- ments, rather than those typically used for AD, for
sitivity, but high specificity, of these criteria (Holmes example a vascular equivalent of the ADAS-Cog,
et al., 1999). ‘VaDAS-Cog’.
Perhaps one of the reasons for this is that cere- Attempts to define the neuropsychological
brovascular disease is very common in AD. In one profile of VaD have often been undertaken in
92 Cerebrovascular disease
comparison with AD, but this has proved difficult and may potentially include any cause of intra-
because of diagnostic and methodological incon- parenchymal or subarachnoid haemorrhage (see
sistencies, and no reliable profile has emerged. Section 3.4). The hereditary causes of vascular dis-
Nonetheless, reviewing such studies and using ease are increasingly defined (Markus, 2003), some
strict inclusion and exclusion criteria, such as of which may be associated with dementia such as
matching for level of overall cognitive decline, CADASIL (Section 3.6.2), MELAS and other mito-
Sachdev and Looi (2003) found relative preservation chondrial disorders (Section 5.5.1), and Anderson–
of long-term memory and greater deficits in Fabry disease (Section 5.5.3). Other brain vascular
executive function in VaD patients, corroborating disorders considered here include arteriovenous
previous qualitative reviews (e.g. Hodges & Graham, malformations, certain vasculopathies (cerebral
2001). Cognitive domains not permitting discrim- vasculitides are discussed in the chapter on
ination of VaD from AD included digit span, atten- inflammatory and systemic disorders: Section 6.10),
tion, visuoconstructive, and conceptual tasks, whilst concluding with a miscellaneous group of condi-
language was thought to be an area in which AD tions in which vascular mechanisms may be sus-
would be predicted to be superior to VaD (Sachdev pected rather than proved.
& Looi, 2003). Verbal fluency for letter is more
affected in VaD (Duff Canning et al., 2004) whilst
category fluency is equally impaired in VaD and AD REFERENCES
(Bentham et al., 1997). The heterogeneity of the VaD
group may mandate subdivision in order to find Amar K, Wilcock G. Vascular dementia. BMJ 1996; 312:
diagnostically meaningful cognitive profiles. 227–31.
Pending the development of empirically derived, Bentham PW, Jones S, Hodges JR. A comparison of
rather than consensus, criteria which are oper- semantic memory in vascular dementia and dementia
ationalized and have undergone validation, classi- of Alzheimer’s type. Int J Geriatr Psychiatry 1997; 12:
fication of vascular dementia remains somewhat 575–80.
Bowler JV, Hachinski V. Vascular cognitive impairment: a
arbitrary. NINDS-AIREN suggested a pathogenetic
new approach to vascular dementia. In: Hachinski V (ed.),
classification based on hypoxia–ischaemia and
Cerebrovascular Disease. London: Bailliere Tindall, 1995:
infarction (encompassing multi-infarct, small ves-
357–76.
sel, and strategic infarct dementia), hypoperfusion Bowler JV, Hachinski V (eds.). Vascular Cognitive
(incomplete infarctions), and intracerebral haem- Impairment: Reversible Dementia. Oxford: Oxford Uni-
orrhage dementia (Román et al., 1993). These versity Press, 2003.
mechanisms are not necessarily mutually exclu- Chiu E, Gustafson L, Ames D, Folstein MF (eds.). Cerebro-
sive, and similarly the neuropathological substrates vascular Disease and Dementia: Pathology, Neuropsychiatry
of vascular dementia are heterogeneous and may and Management. London: Martin Dunitz, 2000.
overlap (Vinters et al., 2000; Morris et al., 2004). For Chui HC, Victoroff JI, Margolin D, et al. Criteria for the
the purposes of this chapter, classification is largely diagnosis of ischemic vascular dementia proposed by
the State of California Alzheimer’s Disease Diagnostic
clinical, examining cortical, subcortical, and stra-
and Treatment Centers. Neurology 1992; 42: 473–80.
tegic infarct subtypes. Haemodynamic or hypo-
De Leeuw FE, van Gijn J. Vascular dementia. Pract Neurol
perfusion dementia, associated with occlusive
2003; 3: 86–91.
carotid artery disease or watershed infarcts (also Duff Canning SJ, Leach L, Stuss D, Ngo L, Black SE.
known as distal field or borderzone infarcts), is Diagnostic utility of abbreviated fluency measures in
included with cortical VaD. The entity of ‘cardiogenic Alzheimer disease and vascular dementia. Neurology
dementia’ discussed in the older literature (Lane, 2004; 62: 556–62.
1991) is also assumed to fall within this rubric. Erkinjuntti T, Gauthier S (eds.). Vascular Cognitive
The category of haemorrhagic dementia is broad, Impairment. London: Martin Dunitz, 2002.
3.1 Cortical vascular dementia 93
Godefroy O, Bogousslavsky J. The Behavioral and Cogni- Snowdon D. Aging with Grace: the Nun Study and the
tive Neurology of Stroke. Cambridge: Cambridge Science of Old Age. How We Can All Live Longer,
University Press, 2007. Healthier and More Vital Lives. London: Fourth Estate,
Hachinski VC, Iliff LD, Zilkha E, et al. Cerebral blood flow 2001.
in dementia. Arch Neurol 1975; 32: 632–7. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain
Hodges JR, Graham NL. Vascular dementias. In: Hodges JR, infarction and the clinical expression of Alzheimer’s
(ed.), Early-Onset Dementia: a Multidisciplinary disease. The Nun Study. JAMA 1997; 277: 813–17.
Approach. Oxford: Oxford University Press, 2001: 319–37. Stewart R. Vascular factors in Alzheimer’s disease. In:
Holmes C, Cairns N, Lantos P, et al. Validity of current Burns A, O’Brien J, Ames D (eds.), Dementia (3rd edi-
clinical criteria for Alzheimer’s disease, vascular tion). London: Hodder Arnold, 2005: 436–43.
dementia and dementia with Lewy bodies. Br J Vinters HV, Ellis WG, Zarow C, et al. Neuropathologic
Psychiatry 1999; 174: 45–50. substrates of vascular dementia. J Neuropath Exp
Hulette C, Nochlin D, McKeel DW, et al. Clinical– Neurol 2000; 59: 931–45.
neuropathologic findings in multi-infarct dementia: a
report of six autopsied cases. Neurology 1997; 48: 668–72.
Lane RJM. ‘Cardiogenic dementia’ revisited. J R Soc Med
3.1 Cortical vascular dementia,
1991; 84: 577–9.
multi-infarct dementia (MID), post-stroke
Markus HS (ed.). Stroke Genetics. Oxford: Oxford Univer-
sity Press, 2003.
dementia
Moroney JT, Bagiella E, Desmond DW, et al. Meta-analysis
of the Hachinski Ischemic Score in pathologically Originally conceived of as multi-infarct dementia
verified dementias. Neurology 1997; 49: 1096–105. (MID: Hachinski et al., 1974), cortical vascular
Morris JH, Kalimo H, Viitanen M. Vascular dementias. In: dementia refers to cognitive impairment following
Esiri MM, Trojanowski JQ, Lee VMY (eds.), The Neuro- large vessel disease, cardiac and carotid embolic
pathology of Dementia (2nd edition). Cambridge; events, and hence also post-stroke dementia
Cambridge University Press, 2004: 289–329. (Leys et al., 2005), resulting in large cortical and
MRC CFAS. Pathological correlates of late-onset dementia corticosubcortical complete infarcts in arterial
in a multicentre, community-based population in
territory distribution. Within this category may
England and Wales. Neuropathology Group of the
also be included haemodynamic or hypoperfusion
Medical Research Council Cognitive Function and
dementia, for example related to occlusive carotid
Ageing Study. Lancet 2001; 357: 169–75.
Nolan KA, Lino MM, Seligmann AW, et al. Absence of artery disease or watershed (distal field, border-
vascular dementia in an autopsy series from a dementia zone) infarction between the territories of anterior,
clinic. J Am Geriatr Soc 1998; 46: 597–604. middle, and posterior cerebral arteries, and
O’Brien J, Ames D, Gustafson L, Folstein MF, Chiu E incomplete infarctions related to global cerebral
(eds.). Cerebrovascular Disease, Cognitive Impairment ischaemia following profound and prolonged
and Dementia. London: Martin Dunitz, 2003. hypotension, for example associated with cardiac
Rockwood K, Burns A, Gauthier S, DeKosky ST. Vascular arrest, cardiac arrhythmias, or hypovolaemic shock.
cognitive impairment. Lancet Neurol 2003; 2: 89–98. The studies of Tomlinson et al. (1970) suggested
Román GC, Tatemichi TK, Erkinjuntti T, et al. Vascular
that dementia correlated with increasing volume of
dementia: diagnostic criteria for research studies.
infarcted tissue, above a threshold of 100 ml. Clas-
Report of the NINDS-AIREN international workshop.
sically cortical VaD is characterized as having an
Neurology 1993; 43: 250–60.
Sachdev PC, Looi JCL. Neuropsychological differentiation abrupt onset and stepwise deterioration, and it is
of Alzheimer’s disease and vascular dementia. In: associated with focal neurological signs (e.g. hemi-
Bowler JV, Hachinski V (eds.), Vascular Cognitive paresis, hemianopia, gait impairment, pseudo-
Impairment: Reversible Dementia. Oxford: Oxford Uni- bulbar palsy), as expected with stroke (Hachinski
versity Press, 2003: 153–75. et al., 1975).
The cognitive profile of cortical VaD is depend- occlusions who underwent extracranial–intracranial
ent upon the precise arterial territory affected, but bypass surgery has been reported (Tatemichi
is said to include memory impairment, cortical et al., 1995). Hypoperfusion may be the cause of
signs such as aphasia, apraxia, or agnosia, visuos- cognitive impairments sometimes encountered in
patial and/or visuoconstructive difficulties, and patients with dural arteriovenous fistulae (see
executive dysfunction, although the latter is not as Section 3.5.1),
marked as in subcortical VaD. The fact that around Watershed infarction has on occasion been
10% or more of stroke patients have pre-existing reported to be associated with dementia (Hashi-
dementia (‘pre-stroke dementia’: Hénon et al., guchi et al., 2000).
1997; Klimkowicz et al., 2002), which may result Cognitive recovery may occur after stroke, for
from vascular lesions and/or concurrent Alzhei- example in aphasia, visual neglect, attention span,
mer’s disease, may potentially confound these and verbal recall, but this is variable (Wade et al.,
observations. 1988).
Occlusive carotid artery disease is a well-
recognized risk factor for the development of
transient ischaemic attacks (TIA) and stroke. REFERENCES
Studies have been undertaken to assess whether
occlusive carotid artery disease is also associated Antonelli Incalzi R, Gemma A, Landi F, et al. Neuropsy-
with cognitive impairment. A systematic review of chologic effects of carotid endarterectomy. J Clin Exp
such studies (Bakker et al., 2000) found marked Neuropsychol 1997; 19: 785–94.
heterogeneity in terms of study design, neuro- Bakker FC, Klijn CJM, Jennekens-Schinkel A, Kappelle LJ.
psychological assessment procedures, and inter- Cognitive disorder in patients with occlusive disease of
pretation, making it difficult to draw meaningful the carotid artery: a systematic review of the literature.
conclusions. Accepting a degree of case selection J Neurol 2000; 247: 669–76.
Hachinski VC, Iliff LD, Zilkha E, et al. Cerebral blood flow
bias (i.e. those likely to undergo surgery), the
in dementia. Arch Neurol 1975; 32: 632–7.
majority of studies found evidence of cognitive
Hachinski VC, Lassen NA, Marshall J. Multi-infarct
impairment, generally mild, in both symptomatic
dementia: a cause of mental deterioration in the elderly.
and asymptomatic patients. This was associated Lancet 1974; 2: 207–10.
with either generalized cognitive impairment or Hashiguchi S, Mine H, Ide M, Kawachi Y. Watershed
with specific deficits in memory, reasoning, and infarction associated with dementia and cerebral
psychomotor skills. Hence, cognitive impairment atrophy. Psychiatry Clin Neurosci 2000; 54: 163–8.
may be the sole symptom of carotid artery sten- Hénon H, Pasquier F, Durieu I, et al. Preexisting dementia
osis (Lehrner et al., 2005). in stroke patients : baseline frequency, associated
Similarly, the data on the effects on cognition of factors, and outcome. Stroke 1997; 28: 2429–36.
carotid endarterectomy for carotid artery occlusive Klimkowicz A, Dziedzic T, Slowik A, et al. Incidence of
pre- and poststroke dementia: Cracow Stroke Registry.
disease are difficult to interpret because of meth-
Dement Geriatr Cogn Disord 2002; 14: 137–40.
odological issues (Lunn et al., 1999). Although
Lehrner J, Willfort A, Mlekusch I, et al. Neuropsychological
the majority of studies suggest postoperative
outcome 6 months after unilateral carotid stenting.
improvement, for example in verbal memory, con- J Clin Exp Neuropsychol 2005; 27: 859–66.
structive abilities, and visual attention (Antonelli Leys D, Henon H, Mackowiak Cordoliani MA, Pasquier F.
Incalzi et al., 1997), others suggest no change, mak- Poststroke dementia. Lancet Neurol 2005; 4: 752–9.
ing it impossible to draw clear conclusions about Lunn S, Crawley F, Harrison MJG, Brown MM, Newman
the efficacy of this procedure for the treatment of SP. Impact of carotid endarterectomy upon cognitive
cognitive problems (Lunn et al., 1999). Cognitive functioning: a systematic review of the literature.
improvement in a patient with bilateral carotid Cerebrovasc Dis 1999; 9: 74–81.
3.2 Subcortical vascular dementia 95
Tatemichi TK, Desmond DW, Prohovnik I, Eidelberg D. cognitive impairment and the risk of cognitive
Dementia associated with bilateral carotid occlusions: impairment (Pantoni & Inzitari, 2005)
neuropsychological and haemodynamic course after The état lacunaire, or lacunar state, as described
extracranial to intracranial bypass surgery. J Neurol by Pierre Marie in 1901, comprised small cavitary
lesions in the brain parenchyma, particularly in
Tomlinson BE, Blessed G, Roth M. Observations on the
deep grey matter, internal capsule, basis pontis,
brains of demented old people. J Neurol Sci 1970; 11:
and deep hemispheric white matter, reflecting
205–42.
Wade DT, Wood VA, Hewer RL. Recovery of cognitive
small vessel disease, which occurs frequently in
function soon after stroke: a study of visual neglect, patients with hypertension. Lacunar infarcts, also
attention span and verbal recall. J Neurol Neurosurg known as small deep infarcts, are readily seen on
Psychiatry 1988; 51: 10–13. neuroimaging, and may be associated with a var-
iety of clinical syndromes, originally described by
Fisher (1982), such as pure motor stroke, pure
3.2 Subcortical vascular dementia, sensory stroke, sensorimotor stroke, and ataxic
Binswanger’s disease, lacunar state, hemiparesis. In addition, lacunar strokes may be
subcortical ischaemic vascular associated with cognitive impairment which, in
disease (SIVD) contrast to cortical VaD, is often of insidious, rather
than abrupt, onset, and has a progressive, rather
Diffuse damage to subcortical structures is prob- than stepwise, course.
ably the commonest cause of vascular dementia or In epidemiological studies of independently liv-
vascular cognitive impairment, due to small vessel ing elderly individuals, increasing severity of white
disease in individuals with hypertension. Subcort- matter changes and lacunes on MR imaging has
ical forms of VaD and VCI encompass both the been associated with deteriorating cognition,
leukoencephalopathy originally described by independent of vascular risk factors and stroke, the
Binswanger and the état lacunaire originally more so if there is concurrent medial temporal lobe
described by Marie. atrophy (van der Flier et al., 2005a,b).
In 1894 Otto Binswanger reported subcortical The cognitive profile of subcortical VaD is typ-
obliteration of small cerebral arteries and arteri- ically that of executive dysfunction, as may be
oles, often in association with systemic hyperten- anticipated with lesions affecting subcortical cir-
sion, leading to pathological periventricular cuits, with slowed information processing and
demyelination and the clinical correlate of impairments of initiation, planning, sequencing,
dementia (translation by Blass et al., 1991). The and abstracting (Kramer et al., 2002). Certainly MR
condition, subsequently known as Binswanger’s imaging has indicated that infarcts and white
disease, Binswanger’s encephalopathy, or subcort- matter lesions increase the risk of executive dys-
ical arteriosclerotic encephalopathy (SAE), was function (Vataja et al., 2003). Episodic memory
judged relatively rare until the advent of structural impairment may, or may not, be present, and is
neuroimaging showed radiological evidence of typically milder than in AD, with impaired recall
basal ganglia infarcts and periventricular white but better recognition and with benefit from cueing
matter disease often with sparing of subcortical U (Desmond et al., 1999). There may be additional
fibres (the white matter changes sometimes known neuropsychiatric signs (depression, inertia, emo-
as leukoaraiosis: Hachinski, 1987), sometimes tional lability) and neurological signs, although the
associated with cognitive impairment, leading to latter are fewer than in cortical VaD, including gait
increased use of this diagnostic category (Babikian disorder of frontal type (broad-based, short-
& Ropper, 1987; Fisher, 1989; Bennett et al., 1990; stepped), subtle upper motor neurone signs, dys-
Caplan, 1995). Leukoaraiosis is associated with arthria, urinary incontinence, and extrapyramidal
signs. Although there is overlap, mild subcortical Blass JP, Hoyer S, Nitsch R. A translation of Otto
vascular dementia may be differentiated from AD Binswanger’s article, ‘The delineation of the generalized
on the basis of greater impairment in tests of progressive paralyses’, 1894. Arch Neurol 1991; 48:
semantic memory, executive function, and visuo- 961–72.
Caplan LR. Binswanger’s disease revisited. Neurology
spatial and perceptual skills (Graham et al., 2004).
1995; 45: 626–33.
More recently, cases which might previously have
Desmond DW, Erkinjuntti T, Sano M, et al. The cognitive
been labelled as Binswanger’s disease and/or lacu-
syndrome of vascular dementia: implications for clin-
nar infarctions have been incorporated under the ical trials. Alzheimer Dis Assoc Disord 1999; 13 (suppl 3):
rubric of subcortical ischaemic vascular disease S21–9.
(SIVD: Román et al., 2002). Research criteria have Erkinjuntti T, Inzitari D, Pantoni L, et al. Research criteria
been suggested (Erkinjuntti et al., 2000), with diag- for subcortical vascular dementia in clinical trials.
nosis based on the relationship between clinical and J Neural Transm Suppl 2000; 59: 23–30.
radiological findings, specifically the presence of Erkinjuntti T, Roman G, Gauthier S, Feldman H, Rock-
extensive white matter lesions and multiple lacunar wood K. Emerging therapies for vascular dementia and
infarcts due to small vessel disease. Progressive vascular cognitive impairment. Stroke 2004; 35: 1010–7.
Fisher CM. Lacunar strokes and infarcts: a review.
cognitive decline may be the clinical correlate. In a
Neurology 1982; 32: 871–6.
series of radiologically (MRI) defined cases of SIVD,
Fisher CM. Binswanger’s encephalopathy: a review.
executive deficits and subtle delayed memory def-
J Neurol 1989; 236: 65–79.
icits were found, thought to reflect disruption of Graham NL, Emery T, Hodges JR. Distinctive cognitive
frontal-subcortical circuits and medial temporal profiles in Alzheimer’s disease and subcortical vascular
lobe atrophy respectively (Jokinen et al., 2006). dementia. J Neurol Neurosurg Psychiatry 2004; 75: 61–71.
Hachinski VC. Leukoaraiosis. Arch Neurol 1987; 44: 21–3.
Jokinen H, Kalska H, Mäntylä R, et al. Cognitive profile of
subcortical ischaemic vascular disease. J Neurol Neuro-
in vascular dementia
surg Psychiatry 2006; 77: 28–33.
Since VaD is associated with cholinergic deficits, Kramer JH, Reed BR, Mungas D, Weiner MW, Chui HC.
the use of cholinesterase inhibitors in the treat- Executive dysfunction in subcortical ischaemic vascular
ment of VaD has been explored in a number of disease. J Neurol Neurosurg Psychiatry 2002; 72: 217–20.
Marie P. Des foyers lacunaires de désintégration de
studies, overviews of which suggest that modest
différents autres états cavitaires du cerveau. Rev Méd
benefits in cognitive function may accrue (Erkin-
1901; 21: 281–98.
juntti et al., 2004). Memantine may also improve
Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F.
cognition in vascular dementia (Orgogozo et al., Efficacy and safety of memantine in patients with mild
2002; Wilcock et al., 2002). to moderate vascular dementia: a randomized, placebo-
controlled trial (MMM 300). Stroke 2002; 33: 1834–9.
Pantoni L, Inzitari D. Leukoaraiosis and cognitive
REFERENCES impairment. In: Burns A, O’Brien J, Ames D (eds.),
Dementia (3rd edition). London: Hodder Arnold, 2005:
Babikian V, Ropper AH. Binswanger’s disease: a review. 546–64.
Stroke 1987; 18: 2–12. Román GC, Erkinjuntti T, Pantoni L, Wallin A, Chui HC.
Bennett DA, Wilson RS, Gilley DW, Fox JH. Clinical Subcortical ischaemic vascular dementia. Lancet Neurol
diagnosis of Binswanger’s disease. J Neurol Neurosurg 2002; 1: 426–36.
Psychiatry 1990; 53: 961–5. van der Flier WM, van Straaten ECW, Barkhof F, et al.
Binswanger O. Die Abgrenzung der allgemeinen progres- Small vessel disease and general cognitive function in
siven paralyse. Berl Klin Wochenschr 1894; 31: 1102–5, nondisabled elderly: the LADIS study. Stroke 2005a; 36:
1137–9, 1180–6. 2116–20.
van der Flier WM, van Straaten ECW, Barkhof F et al. disorientation, finger agnosia), sometimes in the
Medial temporal lobe atrophy and white matter hyper- absence of focal sensorimotor deficit and some-
intensities are associated with mild cognitive deficits in times simulating Alzheimer’s disease (Benson
non-disabled elderly people: the LADIS study. J Neurol et al., 1982; Roeltgen et al., 1983).
Neurosurg Psychiatry 2005b; 76: 1497–500.
Vataja R, Pohjasvaara T, Mäntylä R, et al. MRI correlates of
executive dysfunction in patients with ischaemic stroke.
REFERENCES
Eur J Neurol 2003; 10: 625–31.
Wilcock GK, Möbius HJ, Stöffler A. A double-blind
placebo-controlled multicentre study of memantine in Benson DF, Cummings JL, Tsai SY. Angular gyrus
mild to moderate vascular dementia (MMM500). Int syndrome simulating Alzheimer’s disease. Arch Neurol
Clin Psychopharmacol 2002; 17: 297–305. 1982; 39: 616–20.
Roeltgen DP, Sevush S, Heilman KM. Pure Gerstmann’s
syndrome from a focal lesion. Arch Neurol 1983; 40: 46–7.
3.3 Strategic infarct dementia, strategic
strokes
3.3.2 Corpus callosum, fornix
Strategic infarct dementia refers to focal ischaemic Acute anterograde amnesia following ischaemic
lesions in regions eloquent for cognitive processes, infarct of the genu of the corpus callosum and both
although they may not cause dementia in the strict columns and the body of the fornix has been reported,
sense of the DSM or ICD criteria, and hence stra- with subjective improvement in memory on follow-
tegic strokes may be a better term. The possibility up (Moudgil et al., 2000). Such a strategic infarct must
that other subclinical lesions may contribute to the be exceedingly rare. Selective damage to the fornix is
clinical picture cannot be entirely excluded. more commonly seen after surgery for third ventricle
Nonetheless, a variety of locations have been lesions such as colloid cyst (see Section 7.2.3).
associated with cognitive deficits (Katz et al., 1987;
Tatemichi et al., 1995).
REFERENCES
REFERENCES Moudgil SS, Azzouz M, Al-Azzaz A, Haut M, Gutmann L.

Amnesia due to fornix infarction. Stroke 2000; 31: 1418–19.
Katz DI, Alexander MP, Mandell AM. Dementia following
strokes in the mesencephalon and diencephalon. Arch
Neurol 1987; 44: 1127–33. 3.3.3 Thalamus
Tatemichi TK, Desmond DW, Prohovnik I. Strategic
Several types of thalamic infarct have been described,
infarcts in vascular dementia: a clinical and brain
involving differing thalamic vascular territories and
imaging experience. Arzneimittelforschung 1995; 45:
371–85.
damaging differing nuclei (Schmahmann, 2003).
Various neuropsychological deficits have been
described with thalamic infarctions, particularly
3.3.1 Angular gyrus paramedian or polar infarcts, including aphasia,
Infarction of the angular gyrus in the posterior hemineglect, amnesia, and dementia (Van Der Werf
parietotemporal region of the dominant hemi- et al., 2000; de Freitas & Bogousslavsky, 2002).
sphere in the territory of the posterior branch of the A single branch of the posterior cerebral artery
middle cerebral artery may be associated with may supply the medial thalamic nuclei bilaterally.
combinations of aphasia, alexia with agraphia, Occlusion of this paramedian thalamic artery
and Gerstmann syndrome (acalculia, right–left may therefore cause bilateral medial thalamic
infarction, with acute onset of confusion followed case of bilateral paramedian thalamic infarction. Neuro-
by a persistent amnesia, so-called diencephalic case 1996; 2: 405–12.
amnesia. This amnesia may be global, or may de Freitas GR, Bogousslavsky J. Thalamic infarcts. In:
resemble Wernicke–Korsakoff syndrome (see Sec- Donnan G, Norrving B, Bamford J, Bogousslavsky J
(eds.), Subcortical Stroke (2nd edition). Oxford: Oxford
tion 8.3.1; Parkin et al., 1994), or cause principally
autobiographical amnesia (e.g. Graff-Radford et al.,
Eslinger PJ, Warner GC, Grattan LM, Easton JD. Frontal
1990; Tatemichi et al., 1992; Hodges & McCarthy,
lobe utilization behavior associated with paramedian
1993; Crews et al., 1996). thalamic infarction. Neurology 1991; 41: 450–2.
The topographical correlates of amnesia are Graff-Radford NR, Tranel D, Van Hoesen GW, Brandt JP.
involvement of either the dorsomedial thalamic Diencephalic amnesia. Brain 1990; 113: 1–25.
nucleus or the mammillothalamic tract and internal Hodges JR, McCarthy RA. Autobiographical amnesia
medullary lamina. Anterograde memory impairment resulting from bilateral paramedian thalamic infarction.
for verbal material has been reported after left dor- Brain 1993; 116: 921–40.
somedial thalamic infarct, and for visuospatial Kalashnikova LA, Gulevskaya TS, Kashina EM. Disorders
material after right dorsomedial thalamic infarct of higher mental function due to single infarctions in
the thalamus and in the area of the thalamofrontal
(Speedie & Heilman, 1982, 1983). Functional imaging
tracts. Neurosci Behav Physiol 1999; 29: 397–403.
may also show frontal cortical hypoperfusion or
Karussis D, Leker RR, Abramsky O. Cognitive dysfunction
hypometabolism. Selective verbal memory impair-
following thalamic stroke: a study of 16 cases and
ment after a left thalamic infarct involving the review of the literature. J Neurol Sci 2000; 172: 25–9.
mammillothalamic tract has been reported (Schott Larner AJ. Post-stroke mutism. Pract Neurol 2006; 6:
et al., 2003). Long-lasting amnesia is more often 192–4.
associated with bilateral lesions, as is dementia (see Nadeau SE, Roeltgen DP, Sevush S, Ballinger WE, Watson
Section 1.11). Associated features include impaired RT. Apraxia due to a pathologically documented
attention, apathy, slow verbal and motor responses, thalamic infarction. Neurology 1994; 44: 2133–7.
and amnesia, with athymhormia (psychic akinesia) or Parkin AJ, Rees JE, Hunkin NM, Rose PE. Impairment of
akinetic mutism (Kalashnikova et al., 1999). memory following discrete thalamic infarction. Neu-
ropsychologia 1994; 32: 39–51.
Aphasia, usually of non-fluent type, may occur with
Rudd R, Maruff P, MacCupsie-Moore C, et al. Stimulus
left-sided thalamic lesions, and neglect and anosog-
relevance in eliciting utilisation behaviour: case study in
nosia with right-sided lesions, (Karussis et al., 2000).
a patient with a caudate lesion. Cogn Neuropsychiatry
Thalamic involvement may also have contributed to 1998; 3: 287–98.
an unusual case of prolonged post-stroke mutism Schmahmann JD. Vascular syndromes of the thalamus.
(Larner, 2006). Apraxia has also been reported with Stroke 2003; 34: 2264–78.
thalamic infarction (Nadeau et al., 1994). Schott JM, Crutch SJ, Fox NC, Warrington EK. Develop-
Executive impairment and attentional deficit ment of selective verbal memory impairment secondary
may contribute to cognitive dysfunction after to a left thalamic infarct: a longitudinal case study.
thalamic infarction (Van Der Werf et al., 1999), and J Neurol Neurosurg Psychiatry 2003; 74: 255–7.
utilization behaviour may be seen (Eslinger et al., Speedie LJ, Heilman KM. Amnestic disturbance following
infarction of the left dorsomedial nucleus of the
1991), although the latter has also been recorded
thalamus. Neuropsychologia 1982; 20: 597–604.
with caudate lesions (Rudd et al., 1998).
Speedie LJ, Heilman KM. Anterograde memory deficits for
visuospatial material after infarction of the right
thalamus. Arch Neurol 1983; 40: 183–6.
REFERENCES Tatemichi TK, Steinke W, Duncan C, et al. Paramedian
thalamopeduncular infarction: clinical syndromes and
Crews WD, Manning CA, Skalabrin E. Neuropsychological magnetic resonance imaging. Ann Neurol 1992; 32:
impairments of executive functions and memory in a 162–71.
Van Der Werf YD, Weerts JGE, Jolles J, et al. Neuropsycho- 3.3.5 Caudate nucleus, globus pallidus
logical correlates of a right unilateral lacunar thalamic
infarction. J Neurol Neurosurg Psychiatry 1999; 66: 36–42.
Cognitive and neurobehavioural problems are
Van Der Werf YD, Witter MP, Uylings HB, Jolles J. common with vascular lesions of the caudate
Neuropsychology of infarctions in the thalamus: a nucleus, which may also extend to involve the
review. Neuropsychologia 2000; 38: 613–27. anterior limb of the internal capsule and the
putamen. Mendez et al. (1989) found impaired
3.3.4 Genu of the internal capsule sustained attention and executive function, and
poor recall on tests of immediate and delayed
Infarction of the inferior genu of the internal capsule recall in a series of 12 patients with mostly uni-
may cause an acute confusional state with inatten- lateral caudate lesions: some were apathetic or
tion, memory loss, psychomotor retardation, apathy, abulic, others disinhibited and impulsive. Similar
and abulia (Tatemichi et al., 1992). Persistent deficits observations have been made in other series
associated with dominant hemisphere lesions (Caplan et al., 1990; Kumral et al., 1999), with
include verbal memory, naming, and verbal fluency, additional aphasia with left-sided lesions and neg-
reflecting damage to the limbic system (Kooistra & lect with right-sided lesions. Executive dysfunction
Heilman, 1988; Markowitsch et al., 1990; Schnider has also been noted (Kumral et al., 1999). Poor recall
et al., 1996; Madureira et al., 1999; van Zandvoort of long-term verbal memory was the principal fea-
et al., 2000; Pantoni et al., 2001). As with thalamic ture in an adolescent with an isolated infarct of
infarcts, these neuropsychological sequelae may the left caudate, internal capsule, and putamen
reflect disruption of thalamocortical pathways. (Markowitsch et al., 1990). A 2-year study of sub-
cortical strokes found that patients with caudate
lesions had lower scores on the MMSE (perhaps not
REFERENCES
a good test for subcortical deficits) on long-term
follow-up than other locations, with evidence of
Kooistra CA, Heilman KM. Memory loss from a subcort-
ical white matter infarct. J Neurol Neurosurg Psychiatry
deterioration despite no new strokes (Bokura &
1988; 51: 866–9. Robinson, 1997). These various cognitive changes
Madureira S, Guerriero M, Ferro JM. A follow-up study of have been ascribed to interruption of striatal effer-
cognitive impairment due to inferior capsular genu ents to the cortex.
infarction. J Neurol 1999; 246: 764–9. Isolated athymhormia (psychic akinesia) has
Markowitsch HJ, von Cramon DY, Hofmann E, Sick CD, been reported with ischaemic pallidal lesions (Mori
Kinzler P. Verbal memory deterioration after unilateral et al., 1996).
infarct of the internal capsule in an adolescent. Cortex
1990; 26: 597–609.
Pantoni L, Basile AM, Romanelli M, et al. Abulia and
cognitive impairment in two patients with capsular REFERENCES
genu infarct. Acta Neurol Scand 2001; 104: 185–90.
Schnider A, Gutbrod K, Hess CW, Schroth G. Memory Bokura H, Robinson RG. Long-term cognitive impair-
without context: amnesia with confabulations after ment associated with caudate stroke. Stroke 1997; 28:
infarction of the right capsular genu. J Neurol Neurosurg 970–5.
Psychiatry 1996; 61: 186–93. Caplan LR, Schmahmann JD, Kase CS, et al. Caudate
Tatemichi TK, Desmond DW, Prohovnik I, et al. Confusion infarcts. Arch Neurol 1990; 47: 133–43.
and memory loss from capsular genu infarction: a Kumral E, Evyapan D, Balkir K. Acute caudate vascular
thalamocortical disconnection syndrome? Neurology lesions. Stroke 1999; 30: 100–8.
1992; 42: 1966–79. Markowitsch HJ, von Cramon DY, Hofmann E, Sick CD,
van Zandvoort MJ, Aleman A, Kappelle LJ, De Haan EH. Kinzler P. Verbal memory deterioration after unilateral
Cognitive functioning before and after a lacunar infarct. infarct of the internal capsule in an adolescent. Cortex
Cerebrovasc Dis 2000; 10: 478–9. 1990; 26: 597–609.
Mendez MF, Adams NL, Lewandowski KS. Neurobeha- et al., 1985; Rajaram, 1997), presumably due to
vioral changes associated with caudate lesions. Neurol- disruption of the basal forebrain cholinergic
ogy 1989; 39: 349–54. projection to the hippocampus (which is also a key
Mori E, Yamashita H, Takauchi S, Kondo K. Isolated site of pathology in Alzheimer’s disease). Features
athymhormia following hypoxic bilateral pallidal
may be akin to the amnesia seen in Korsakoff
lesions. Behav Neurol 1996; 9: 17–23.
syndrome (see Section 8.3.1), although this is not
invariably so.
3.3.6 Hippocampus
Stroke limited to the hippocampus is a rare event;
REFERENCES
first-ever stroke confined to the hippocampus even
more so. One patient with possible hippocampal
Damasio AR, Graff-Radford NR, Eslinger PJ, Damasio H,
ischaemic infarcts causing bilateral hippocampal
Kassell N. Amnesia following basal forebrain lesions.
volume loss has been extensively studied, showing Arch Neurol 1985; 42: 263–71.
impaired recall but relatively preserved item rec- Rajaram S. Basal forebrain amnesia. Neurocase 1997; 3:
ognition memory (e.g. Mayes et al., 2002). In a 405–15.
41-year old right-handed man with first-ever stroke
affecting the left posterior choroidal artery territory
and involving the left posterior hippocampus, pre- 3.3.8 Brainstem and cerebellum
sentation was with an amnesic syndrome resem- Can isolated infratentorial ischaemic lesions cause
bling transient global amnesia (see Section 3.7.3) cognitive impairment? Transient amnesia has been
but with additional ‘amnestic aphasia.’. Improve- reported as a herald of brainstem infarction
ment over 24–48 hours was followed by a severe (Howard et al., 1992) and basilar artery thrombosis
deficit of episodic long-term memory, particularly in (Taylor et al., 2005), but these syndromes may
the verbal modality, with default of encoding and conceivably have involved memory-eloquent
semantic intrusions. This case suggested special- structures in the thalamus. The question may be
ization of the left hippocampus for encoding of addressed by examining patients with lesions
verbal material (Scacchi et al., 2006). confined to brainstem and cerebellum.
In a series of 17 patients with lacunar infarcts in
the brainstem, neuropsychological evaluation
REFERENCES showed impairments in naming, category fluency,
and trail making, a profile similar to that seen with
Mayes AR, Holdstock JS, Isaac CL, Hunkin NM, Roberts N.
supratentorial lacunar infarcts, prompting the
Relative sparing of item recognition memory in a
conclusion that small white matter infarcts affect
patient with adult-onset damage limited to the hippo-
cognitive function in a non-specific way (van
campus. Hippocampus 2002; 12: 325–40.
Scacchi F, Carota A, Morier J, Bogousslavsky J. Predomin-
Zandvoort et al., 2003). Occasional cases of cogni-
antly verbal deficit of encoding with stroke limited to tive impairment in patients with brainstem vascu-
the left posterior hippocampus. J Neurol 2006; 253 lar events complicated by peduncular hallucinosis
(suppl 2): II137 (abstract P543). have been reported (Benke, 2006).
In a series of 15 patients with isolated cerebellar
infarcts, confirmed by MR imaging, neuropsycho-
3.3.7 Basal forebrain
logical testing showed changes consistent with a
‘Basal forebrain amnesia’ has been reported fol- frontal deficit in comparison with controls (Neau
lowing surgery for ruptured anterior communi- et al., 2000). A study of 26 patients with exclusively
cating artery aneurysm (see Section 3.4.1; Damasio cerebellar infarcts found slow performance on
3.4 Subarachnoid haemorrhage 101
visuospatial tasks with left-sided lesions and in reasons. A careful reckoning of risk–benefit ratio
verbal memory with right-sided lesions. The subtle must be undertaken before deciding on treatment
deficits were interpreted as being mediated by the of such asymptomatic lesions.
contralateral cortical hemisphere (Hokkanen et al., SAH patients are heterogeneous with respect to
2006). bleeding source (aneurysms may be on the internal
Hence, from the limited information currently carotid, anterior communicating, middle cerebral,
available, it would seem likely that isolated posterior cerebral, or basilar artery), the severity of
ischaemic infratentorial lesions may have subtle the initial bleed (which may be graded, for example
effects on cognition. using the Hunt & Hess classification, or the World
Federation of Neurological Surgeons scale based
on the Glasgow Coma Scale), degree of brain
REFERENCES injury, occurrence of complications such as
vasospasm or hydrocephalus, and treatment
Benke T. Peduncular hallucinosis: a syndrome of impaired method used. Ruptured aneurysms may be treated
reality monitoring. J Neurol 2006; 253: 1561–71. by open surgical clipping or, increasingly fre-
Hokkanen LS, Kauranen V, Roine RO, Salonen O, Kotila M. quently, by intravascular embolization (‘coiling’),
Subtle cognitive deficits after cerebellar infarcts. Eur J both procedures isolating the aneurysm from the
Neurol 2006; 13: 161–70.
circulation (Molyneux et al., 2002, 2005). Add to
Howard RS, Festenstein R, Mellers J, Kartsounis LD, Ron
this the significant psychological sequelae of SAH,
M. Transient amnesia heralding brain stem infarction.
including fatigue and anxiety, and the difficulty of
J Neurol Neurosurg Psychiatry 1992; 55: 977.
Neau JP, Arroyo-Anllo E, Bonnaud V, Ingrand P, Gil R.
defining the neuropsychological profile associated
Neuropsychological disturbances in cerebellar infarcts. with SAH becomes apparent.
Acta Neurol Scand 2000; 102: 363–70.
Taylor RA, Wu GF, Hurst RW, Kasner SE, Cucchiara BL.
Transient global amnesia heralding basilar artery REFERENCES
thrombosis. Clin Neurol Neurosurg 2005; 108: 60–2.
van Zandvoort M, de Haan E, van Gijn J, Kappelle LJ. Crawley F, Clifton A, Brown MM. Should we screen
Cognitive functioning in patients with a small infarct in for familial intracranial aneurysm? Stroke 1999; 30:
the brainstem. J Int Neuropsychol Soc 2003; 9: 490–4. 312–16.
Molyneux A, Kerr R, Stratton I, et al. International
Subarachnoid Aneurysm Trial (ISAT) of neurosurgical
3.4 Subarachnoid haemorrhage (SAH) clipping versus endovascular coiling in 2143 patients
with ruptured intracranial aneurysms: a randomised
Subarachnoid haemorrhage (SAH), bleeding into trial. Lancet 2002; 360: 1267–74.
the space between pia and arachnoid mater, is the Molyneux A, Kerr R, Yu LM, et al. International Subar-
least common form of stroke, accounting for per- achnoid Aneurysm Trial (ISAT) of neurosurgical clip-
ping versus endovascular coiling in 2143 patients with
haps 5% of the total. Bleeding may originate from a
ruptured intracranial aneurysms: a randomised com-
ruptured intracranial aneurysm, or from an arter-
parison of effects on survival, dependency, seizures,
iovenous malformation (see Section 3.5.1), but in
rebleeding, subgroups, and aneurysm occlusion. Lancet
some cases no specific bleeding source is identified 2005; 366: 809–17.
(van Gijn & Rinkel, 2001). Unruptured intracranial Teasdale GM, Wardlaw JM, White PM, et al. The familial
aneurysms may be discovered as a result of risk of subarachnoid haemorrhage. Brain 2005; 128:
screening in families with a history of SAH (Crawley 1677–85.
et al., 1999; Teasdale et al., 2005) or incidentally van Gijn J, Rinkel GJE. Sub-arachnoid haemorrhage: diagno-
when neuroimaging is undertaken for other sis, causes and management. Brain 2001; 124: 249–78.
been noted. An apraxic, alien hand, syndrome has

3.4.1 Aneurysmal SAH, unruptured
on occasion been reported after anterior commu-
aneurysms
nicating artery (AcoA) aneurysm rupture (Banks
The large literature on the neuropsychological et al., 1989).
sequelae of subarachnoid haemorrhage (SAH), Although older studies suggested that cognitive
most often following aneurysm rupture, has been deficits were greatest with ruptured AcoA aneur-
reviewed by Hütter (2000) and DeLuca & Chiar- ysms, even suggesting the existence of an ‘AcoA
avalloti (2002). syndrome’ characterized by severe memory deficit,
It has become increasingly recognized that confabulation, and personality change (Talland
patients who survive the acute phase of SAH may et al., 1967), more systematic studies have found
be left with significant neuropsychological deficits the pattern of deficits to be unrelated to the loca-
despite an apparently excellent neurological out- tion of the ruptured aneurysm, and to be persistent
come. For example, in a retrospective survey over time (Maurice-Williams et al., 1991; Ogden
Hütter et al. (1995) found that significant cognitive et al., 1993; Tidswell et al., 1995). The profile may
performance deficits were present in between one- be aggravated by concurrent infarction in the vas-
third and two-thirds of patients adjudged to have a cular territory of the ruptured aneurysm. Left-sided
good neurological outcome after SAH. Similar infarcts and global cerebral oedema were reported
findings are reported from other studies, including to be predictors of post-SAH cognitive dysfunction
those with a prospective design (Ogden et al., 1993; in one study (Kreiter et al., 2002).
Tidswell et al., 1995). Cognitive impairments impact on functional
The pattern of cognitive impairments is global in status and quality of life (Mayer et al., 2002).
some patients, even amounting to dementia, Comparison of cognitive outcome between aneur-
whereas in others general intelligence as measured ysm coiling and clipping showed a trend toward
by conventional IQ tests remains intact but there poorer outcome in the surgical, clipping group, who
may be specific impairments of psychomotor also had a significantly higher incidence of infarcts
speed, language function, and verbal memory in the vascular territory of the aneurysm, suggesting
(DeLuca & Diamond, 1995). Working memory and that the complications of SAH are the principal
verbal short-term memory seem most affected, determinants of cognitive outcome (Hadjivassiliou
with features sometimes reported to resemble the et al., 2001). These findings add to the argument in
amnesia of Korsakoff syndrome, with or without favour of coiling rather than clipping of aneurysms
confabulation. Basal forebrain injury, damaging (Molyneux et al., 2005).
the septo-hippocampal system, may be responsible The detection and management of unruptured
for amnesia (Damasio et al., 1985). Concurrent intracranial aneurysms remains an area of investi-
frontal lobe injury may be required for the pres- gation (Wardlaw & White, 2001). Neuropsycho-
ence of confabulation (Downes & Mayes, 1995; logical sequelae of treatment of unruptured
DeLuca & Chiaravalloti, 2002). In addition there aneurysms are not unknown, and are an important
may be deficits in perceptual speed and accuracy, consideration, since most patients are healthy at
visuospatial and visuoconstructive function, and the time of treatment (Towgood et al., 2004).
abstraction and cognitive flexibility, for example
in the Wisconsin Card Sorting Test, the latter
suggesting frontocortical cognitive dysfunction REFERENCES
(Stenhouse et al., 1991). Executive dysfunction may
significantly affect anterograde memory (Diamond Banks G, Short P, Martinez J, et al. The alien hand
et al., 1997). The similarity of this profile to that syndrome: clinical and postmortem findings. Arch
seen following mild traumatic brain injury has Neurol 1989; 46: 456–9.
3.4 Subarachnoid haemorrhage 103
Damasio AR, Graff-Radford NR, Eslinger PJ, Damasio H, Tidswell P, Dias PS, Sagar HJ, Mayes AR, Battersby RD.
Kassell N. Amnesia following basal forebrain lesions. Cognitive outcome after aneurysm rupture: relationship
Arch Neurol 1985; 42: 263–71. to aneurysm site and perioperative complications.
DeLuca J, Chiaravalloti ND. The neuropsychological Neurology 1995; 45: 875–82.
consequences of ruptured aneurysms of the anterior Towgood K, Ogden JA, Mee E. Neurological, neuropsycho-
communicating artery. In: Harrison JE, Owen AM (eds.), logical, and psychosocial outcome following treatment
Cognitive Deficits in Brain Disorders. London: Martin of unruptured intracranial aneurysms: a review and
Dunitz, 2002: 17–36. commentary. J Int Neuropsychol Soc 2004; 10: 1–21.
DeLuca J, Diamond BJ. Aneurysm of the anterior Wardlaw JM, White PM. The detection and management
communicating artery: a review of neuroanatomical of unruptured intracranial aneurysms. Brain 2001; 123:
and neuropsychological sequelae. J Clin Exp Neuropsy- 205–21.
chol 1995; 17: 100–21.
Diamond BJ, DeLuca J, Kelley SM. Memory and executive
3.4.2 Perimesencephalic (non-aneurysmal)
functions in amnesic and non-amnesic patients with
aneurysms of the anterior communicating artery. Brain
SAH
1997; 120: 1015–25. In perimesencephalic SAH (pSAH), no underlying
Downes JJ, Mayes AR. How bad memories can sometimes aneurysm(s) may be identified with conventional
lead to fantastic beliefs and strange visions. In: Campbell
angiography in 15–20% of cases. Hence, pSAH
R, Conway MA (eds.), Broken Memories: Case Studies in
differs from other types of SAH in its excellent
Memory Impairment. Oxford: Blackwell, 1995: 115–23.
prognosis, since there is a very low risk of re-
Hadjivassiliou M, Tooth CL, Romanowski CA, et al. Aneur-
ysmal SAH: cognitive outcome and structural damage bleeding (van Gijn et al., 1985). Only minor cogni-
after clipping or coiling. Neurology 2001; 56: 1672–7. tive deficits have been identified on follow-up of
Hütter BO. Neuropsychological Sequelae of Subarachnoid pSAH patients, but high scores on a depression
Hemorrhage and its Treatment. Berlin: Springer, 2000. scale, suggesting that vigorous reassurance and
Hütter BO, Gilsbach JM, Kreitschmann I. Quality of life treatment of depression might improve outcome in
and cognitive deficits in patients after subarachnoid this subgroup (Madureira et al., 2000).
haemorrhage. Br J Neurosurg 1995; 9: 465–75.
Kreiter KT, Copeland D, Bernardini GL, et al. Predictors of
cognitive dysfunction after subarachnoid haemorrhage. REFERENCES
Stroke 2002; 33: 200–8.
Maurice-Williams RS, Willison JR, Hatfield R. The cognitive
Madureira S, Canhao P, Guerreiro M, Ferro JM. Cognitive
and psychological sequelae of uncomplicated aneurysm
and emotional consequences of perimesencephalic
surgery. J Neurol Neurosurg Psychiatry 1991; 54: 335–40.
subarachnoid haemorrhage. J Neurol 2000: 247: 862–7.
Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-
van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A.
specific cognitive impairment and outcome after subar-
Perimesencephalic hemorrhage: a nonaneurysmal and
achnoid haemorrhage. Neurology 2002; 59: 1750–8.
benign form of subarachnoid hemorrhage. Neurology
Ogden JA, Mee EW, Henning M. A prospective study of
1985; 35: 493–7.
impairment of cognition and memory and recovery
after subarachnoid haemorrhage. Neurosurgery 1993;
33: 572–87. 3.4.3 Superficial siderosis of the nervous
Stenhouse LM, Knight RG, Longmore BE, Bishara SN. system
Long-term cognitive deficits in patients after surgery on
Deposition of ferritin in the superficial layers of the
aneurysms of the anterior communicating artery.
J Neurol Neurosurg Psychiatry 1991; 54: 909–14. CNS as a consequence of repeated or continuous
Talland GA, Sweet WH, Ballantine HT Jr. Amnesic leakage of blood into the CSF is the cause of this
syndrome with anterior communicating artery aneur- unusual condition, with subsequent gliosis and
ysm. J Nerv Ment Dis 1967; 145: 179–92. neuronal loss, particularly in the eighth cranial
nerve, the cerebellar vermis, and the inferior frontal approaches, lesions not always having been
cerebral cortex. Clinical features include sensori- described in a standardized way. Distinction may
neural hearing loss, cerebellar ataxia, dysarthria, be made between haemangiomas, in which endo-
anosmia, and pyramidal signs, with typical thelial hyperplasia occurs, and non-proliferating
appearances of signal void around affected areas of vascular anomalies in which there is no hyperpla-
brain on T2-weighted MR images, corresponding to sia. These latter include arterial malformations
deposition of haemosiderin (Fearnley et al., 1995). (angiodysplasia, aneurysms) and lesions in which
In a review of the literature, 14 cases with dementia there is arteriovenous shunting of blood, either
of variable severity were identified, with onset through a tangled anastomosis of vessels (‘arter-
between 1 and more than 30 years after disease onset iovenous malformation’, AVM) or a direct high flow
(Fearnley et al., 1995). Only one systematic study of connection between artery and vein (‘arterio-
the cognitive impairments in superficial siderosis has venous fistula’, AVF). AVMs and AVFs may be within
been reported (van Harskamp et al., 2005). In six the brain parenchyma or in the dura (Chaloupka &
patients tested, general intellectual function was well Huddle, 1998; Choi & Mohr, 2005).
preserved, but speech production difficulties,
impairment of visual recall, and executive impair-
ments formed the core neuropsychological deficits. REFERENCES
Impaired executive function was evident in tests of
both initiation (phonemic fluency, Hayling sentence Chaloupka JC, Huddle DC. Classification of vascular malfor-
completion part A) and inhibition (Stroop, Hayling mations of the central nervous system. Neuroimaging
sentence completion part B). Naming, literacy, cal- Clin North Am 1998; 8: 295–321.
culation, visual perceptual and visuospatial skills, Choi JH, Mohr JP. Brain arteriovenous malformations in
adults. Lancet Neurol 2005; 4: 299–308.
verbal and visual recognition memory, verbal recall
memory, and speed of information processing were
all relatively preserved. All patients also failed a the- 3.5.1 Arteriovenous malformations (AVMs)
ory of mind test, indicating a mentalizing impair-
ment. Overall the deficits were akin to the previously Whether AVMs cause cognitive deficits over and
described cerebellar cognitive affective syndrome above their haemorrhagic and epileptic compli-
(Schmahmann & Sherman, 1998). cations, which generally are what bring cases to
clinical attention, is uncertain (Al-Shahi & Warlow,
2001). Some early studies suggested ‘mental
REFERENCES changes’ in 50% of patients with ‘AVMs’ (Olivecrona
& Reeves, 1948) whereas others found normal full-
Fearnley JM, Stevens JM, Rudge P. Superficial siderosis of scale IQ and no lateralizing changes comparable
the central nervous system. Brain 1995; 118: 1051–66. with those seen with acute focal lesions (Waltimo &
Schmahmann JD, Sherman JC. The cerebellar cognitive Putkonen, 1974). Mahalick et al. (1991) reported a
affective syndrome. Brain 1998; 121: 561–79. series of 24 patients, 12 each with right and left
van Harskamp NJ, Rudge P, Cipolotti L. Cognitive and AVMs, and found compromised higher cortical
social impairments in patients with superficial side-
function (attention, memory, learning, fluency)
rosis. Brain 2005; 128: 1082–92.
both ipsilateral and contralateral to the lesion,
more so ipsilateral, prompting them to argue that a
3.5 Intracranial vascular malformations vascular ‘steal’ phenomenon accounted for con-
tralateral deficits. However, there were no con-
The classification of intracranial arteriovenous comitant vascular imaging studies. To answer the
vascular anomalies has been subject to various question of the neuropsychological effects of
3.5 Intracranial vascular malformations 105
AVMs, one ideally would wish to study asymp- Datta NN, Rehman SU, Kwok JC, Chan KY, Poon CY.
tomatic individuals, perhaps discovered by chance Reversible dementia due to arteriovenous fistula:
on brain imaging for other reasons. a simple surgical option. Neurosurg Rev 1998; 21:
Cases of higher cortical dysfunction have been 174–6.
Hirono N, Yamadori A, Komiyama M. Dural arteriovenous
reported in association with dural AVFs, sometimes
fistula: a cause of hypoperfusion-induced intellectual
amounting to dementia (Hirono et al., 1993; Nencini
impairment. Eur Neurol 1993; 33: 5–8.
et al., 1993). Five out of 40 cases in the series of
Hurst RW, Bagley LJ, Galetta S, et al. Dementia resulting
Hurst et al. (1998) had dementia or encephalopathy from dural arteriovenous fistulas: the pathologic find-
with remission after embolization. Detailed pre- and ings of venous hypertensive encephalopathy. AJNR Am J
post-ablation neuropsychological investigations of Neuroradiol 1998; 19: 1267–73.
such patients have not been identified. In a further Mahalick DM, Ruff RM, U HS. Neuropsychological
example, a man with a 12-month history of pro- sequelae of arteriovenous malformations. Neurosurgery
gressive cognitive decline, precluding occupational 1991; 29: 351–7.
function, who had profound psychomotor slowing, Nencini P, Inzitari D, Gibbs J, Mangiafico S. Dementia
returned to normal after endovascular embolization with leukoaraiosis and dural arteriovenous malforma-
tion: clinical and PET case study. J Neurol Neurosurg
of a dural AV fistula (Bernstein et al., 2003). Com-
Psychiatry 1993; 56: 929–31.
bined embolization/ligation and surgical ‘scalping’
Olivecrona H, Reeves J. Arteriovenous malformations of
has also been reported to reverse dementia (Datta
the brain: their diagnosis and treatment. Arch Neurol
et al., 1998). Psychiatr Chicago 1948; 59: 567–602.
It is argued that the mechanism of cognitive Tanaka K, Morooka Y, Nakagawa Y, Shimizu S. Dural
impairment in these patients is high flow through arteriovenous malformation manifesting as dementia
the AV shunt combined with venous outflow due to ischemia in bilateral thalami. A case report. Surg
obstruction causing impaired cerebral venous Neurol 1999; 51: 489–93.
drainage, and hence widespread venous hyper- Waltimo O, Putkonen AR. Intellectual performance of
tension and diffuse ischaemia (which may be patients with intracranial arteriovenous malformations.
manifest neuroradiologically as a leukoencephalo- Brain 1974; 97: 511–20.
Waragai M, Takeuchi H, Fukushima T, Haisa T, Yonemitsu
pathy: Waragai et al., 2006), and thus progressive
T. MRI and SPECT studies of dural arteriovenous
cognitive dysfunction, in the same way that spinal
fistulas presenting as pure progressive dementia with
dural AVFs cause a myelopathy in Foix–Alajoua-
leukoencephalopathy: a cause of treatable dementia.
nine syndrome (Hurst et al., 1998). Thalamic Eur J Neurol 2006; 13: 754–9.
ischaemia has also been implicated (Tanaka et al.,
1999). Hence it is reasoned that dural AVFs are a
cause of reversible vascular dementia. Newer neu- 3.5.2 Cavernous haemangiomas
roimaging modalities (PET, DWI) may help to
Cavernous haemangiomas or cavernomas are thin-
clarify some of the uncertainty around these issues.
walled vascular spaces lacking a shunt, hence not
arteriovenous malformations. They may present as
space-occupying lesions, with seizures or relaps-
REFERENCES
ing–remitting symptoms related to haemorrhage.
Multiple cavernous angiomas (cavernomatosis)
Al-Shahi R, Warlow CP. A systematic review of the
which undergo multiple and recurrent haemor-
frequency and prognosis of arteriovenous malforma-
tions of the brain in adults. Brain 2001; 124: 1900–26 rhages may rarely be associated with cognitive
[esp. 1913–14]. decline and dementia (Hayman et al., 1982;
Bernstein R, Dowd CF, Gress DR. Rapidly reversible Gil-Nagel et al., 1995; Kageyama et al., 2000; Kariya
dementia. Lancet 2003; 361: 392. et al., 2000).
REFERENCES with the vascular dementias (Reinglass et al., 1977;

Drlicek et al., 1991; Treves et al., 1995). Brain and/
Gil-Nagel A, Wilcox KJ, Stewart JM, et al. Familial cerebral or meningeal biopsy is usually required for diagno-
cavernous angioma: clinical analysis of a family and sis. A case associated with a reversible dementia
phenotypic classification. Epilepsy Res 1995; 21: 27–36. following immunosuppressive treatment in a
Hayman L, Evans R, Ferrell R, et al. Familial cavernous transplant recipient has been reported (Heafield
angiomas: natural history and genetic study over a et al., 1993).
5-year period. Am J Med Genet 1982; 11: 147–60.
Kageyama Y, Kodama Y, Yamamoto S, et al. A case of
multiple intracranial cavernous angiomas presented
REFERENCES
with dementia and parkinsonism: clinical and MRI
study for 10 years [in Japanese]. Rinsho Shinkeigaku
2000; 40: 1105–9. Drlicek M, Grisold W, Liszka U, Hitzenberger P, Machacek
Kariya S, Kawahara M, Suzumura A. A case of multiple E. Angiotropic lymphoma (malignant angioendothelio-
cavernous angioma with dementia [in Japanese]. Rinsho matosis) presenting with rapidly progressive dementia.
Shinkeigaku 2000; 40: 1003–7. Acta Neuropathol 1991; 82: 533–5.
Heafield MT, Carey M, Williams AC, Cullen M. Neoplastic
angioendotheliomatosis: a treatable ‘vascular dementia’
occurring in an immunosuppressed transplant recipi-
3.6 Vasculopathies
ent. Clin Neuropathol 1993; 12: 102–6.
Reinglass JL, Muller J, Wissman S, Wellman H. Central
Vasculopathy is a relatively non-specific term for
nervous system angioendotheliosis: a treatable multiple
blood vessel abnormalities, which is here inter- infarct dementia. Stroke 1977; 8: 218–21.
preted to encompass not only primary abnormal- Treves TA, Gadoth N, Blumen S, Korczyn AD. Intravas-
ities of blood vessel wall structure predisposing to cular malignant lymphomatosis: a cause of subacute
intraluminal thrombosis, but also rheologic dementia. Dementia 1995; 6: 286–93.
abnormalities promoting a thrombotic tendency.
Although there may be overlap at the level of
3.6.2 CADASIL
pathophysiology, inflammatory disorders of blood
vessels such as the primary and secondary cerebral Cerebral autosomal dominant arteriopathy with
vasculitides are considered elsewhere (Sections subcortical infarcts and leukoencephalopathy
6.10.1 and 6.10.2, respectively), as are primary (CADASIL) is an autosomal dominant vasculopathy
metabolic disorders affecting blood vessels such as resulting from mutations within the gene encoding
Anderson–Fabry disease (Section 5.5.3). the notch3 protein on chromosome 19q12 (Joutel
et al., 1996). It is characterized clinically by recur-
rent subcortical strokes, both symptomatic and
3.6.1 Angioendotheliomatosis,
silent, migraine, psychiatric disturbances, with late
intravascular lymphomatosis
pseudobulbar palsy, occasionally epilepsy, and a
Angioendotheliomatosis, also known as intravas- reversible encephalopathy (Schon et al., 2003). Skin
cular lymphomatosis and neoplastic angioen- biopsy may show granular osmiophilic material
dotheliomatosis, is a malignant intravascular adjacent to the basement membrane of smooth
proliferation of endothelial cells or lymphocytes muscle cells of dermal arterioles; similar deposits
defined as an angiotropic intravascular large-cell may be observed in the thickened arterial media in
lymphoma of B-cell type. The commonest clinical vessels on brain biopsy (Lammie et al., 1995). MR
presentation is with multifocal ischaemic events brain imaging shows confluent high signal in
due to vascular occlusion with neoplastic cells, but it periventricular and deep white matter, basal gan-
may also cause dementia, leading to classification glia lacunar infarcts, and characteristic high signal
in the anterior temporal pole and external capsule. ment of vascular dementia, as well as Alzheimer’s
The mechanism(s) by which mutations lead to disease (Erkinjuntti et al., 2004).
disease are not currently understood.
A subcortical-type, white matter, vascular
dementia may also occur, with both stepwise and REFERENCES
progressive course (Martin & Markus, 2001). This
dementia may occur in the absence of other Buffon F, Porcher R, Hernandez K, et al. Cognitive profile
neurological features other than migraine (Mellies in CADASIL. J Neurol Neurosurg Psychiatry 2006; 77:
175–80.
et al., 1998). The neuropsychological profile is
Dichgans M, Filippi M, Brüning R, et al. Quantitative MRI
characterized by a deficit in sustained attention,
in CADASIL: correlation with disability and cognitive
cognitive slowing, impaired learning with intact
performance. Neurology 1999; 52: 1361–7.
recognition, and perseveration, in other words a Erkinjuntti T, Roman G, Gauthier S, Feldman H, Rockwood
pattern resembling that in other white matter dis- K. Emerging therapies for vascular dementia and
orders (Filley et al., 1999). Executive and attentional vascular cognitive impairment. Stroke 2004; 35: 1010–17.
dysfunction has been identified in non-demented Filley CM, Thompson LL, Sze CI, et al. White matter
patients, some without a history of prior vascular demetia in CADASIL. J Neurol Sci 1999; 163: 163–7.
events (Taillia et al., 1998). In a cross-sectional Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations
study of 42 patients, Buffon et al. (2006) found a in CADASIL, a hereditary adult-onset condition causing
heterogeneous cognitive profile at disease onset, stroke and dementia. Nature 1996; 383: 707–10.
Lammie GA, Rakshi J, Rossor MN, Harding AE, Scaravilli F.
most often affecting executive skills leading to
Cerebral autosomal dominant arteriopathy with sub-
impaired memory and attention, evolving to a
cortical infarcts and leukoencephalopathy (CADASIL):
more homogeneous pattern affecting all domains
confirmation by cerebral biopsy in 2 cases. Clin
with increasing age, including language and Neuropathol 1995; 14: 201–6.
visuospatial function, although distinct from Martin R, Markus H. CADASIL: a genetic form of
Alzheimer’s disease. Retrieval was better with cue- subcortical vascular dementia. Dementia Rev 2001;
ing, suggesting that encoding was relatively spared, 4 (1): 1–6.
as were recognition and semantic memory. The Mellies JK, Bäumer T, Müller JA, et al. SPECT study of a
authors speculated that this pattern resulted from German CADASIL family: a phenotype with migraine
initial damage to frontal–subcortical networks with and progressive dementia only. Neurology 1998; 50:
sparing of the hippocampus, with diffuse cortical 1715–21.
Mesulam M, Siddique T, Cohen B. Cholinergic denerva-
dysfunction in later disease reflecting the accumu-
tion in a pure multi-infarct state: observations in
lation of subcortical ischaemic insults, although
CADASIL. Neurology 2003; 60: 1183–5.
since history of stroke was not associated with
Schon F, Martin RJ, Prevett M, et al. ‘CADASIL coma’: an
dementia most of these events must have been underdiagnosed acute encephalopathy. J Neurol Neu-
silent. In one series of 64 patients, not selected for rosurg Psychiatry 2003; 74: 249–52.
the presence or absence of dementia, a significant Taillia H, Chabriat H, Kurtz A, et al. Cognitive alterations
inverse correlation was noted between overall cog- in non-demented CADASIL patients. Cerebrovasc Dis
nitive performance, as assessed with the MMSE 1998; 8: 97–101.
score, and total MRI lesion volume (Dichgans et al.,
1999).
3.6.3 Cerebral amyloid angiopathies (CAA)
Cholinergic denervation has been shown in one
pathologically examined case of CADASIL, despite Cerebral amyloid angiopathy (CAA) refers to the
this being a pure vascular dementia (Mesulam deposition of amyloidogenic peptides in the walls
et al., 2003), adding weight to the argument in of small parenchymal and leptomeningeal arteries
favour of cholinesterase inhibitors for the treat- (congophilic angiopathy), sometimes extending
from around vessel walls into the brain paren- late-onset dementia as the only manifestation of
chyma (dyshoric angiopathy) (Vinters, 1987; Coria HCHWA-I has been reported, with cortical and
& Rubio, 1996; Yamada, 2000; Revesz et al., 2003). subcortical infarctions (Sveinbjörnsdóttir et al.,
CAA may be one feature of AD brain pathology, but 1996).
may also occur in relative isolation as either a Autosomal dominant familial CAA causing
sporadic or a familial condition, a classification dementia usually without strokes or haemorrhages,
system for which has been proposed (Greenberg of British and Danish types (Plant et al., 2004), is
et al., 1996). Cerebral haemorrhage in a lobar dis- also described (see Sections 5.1.3 and 5.1.4,
tribution is the commonest complication of CAA, respectively).
although other transient focal neurological features
may occur, including transient ischaemic attacks,
focal seizures, and multifocal cortical myoclonus REFERENCES
(Greenberg et al., 1993; Larner et al., 1998), as well
as a leukoencephalopathy (Gray et al., 1985). Coria F, Rubio I. Cerebral amyloid angiopathies. Neuro-
pathol Appl Neurobiol 1996; 22: 216–27.
Dementia without major lobar haemorrhage is also
Dermaut B, Kumar-Singh S, De Jonghe C, et al. Cerebral
reported (Greenberg et al., 1993).
amyloid angiopathy is a pathogenic lesion in Alzhei-
It has been suggested that CAA may contribute to
mer’s disease due to a novel presenilin 1 mutation.
neurodegeneration in Alzheimer’s disease associ- Brain 2001; 124: 2383–92.
ated with certain presenilin-1 gene mutations Gray F, Dubas F, Roullet E, Escourolle R. Leukoencepha-
(Dermaut et al., 2001). CAA in association with a lopathy in diffuse hemorrhagic cerebral amyloid angio-
granulomatous angiitis resembling primary angiitis pathy. Ann Neurol 1985; 18: 54–9.
of the CNS (PACNS), so-called Ab-related angiitis Greenberg SM, Edgar MA, Kunz DP, et al. Cerebral
(ABRA), has been reported to produce prominent hemorrhage in a 69-year-old woman receiving warfarin:
cognitive problems (Scolding et al., 2005; see cerebral amyloid angiopathy (MGH Case Records Case
Section 6.10.1). 22-1996). N Engl J Med 1996; 335: 189–96.
Greenberg SM, Vonsattel JP, Stekes JW, Gruber M,
Of the familial CAAs, hereditary cerebral haem-
Finklestein SP. The clinical spectrum of cerebral
orrhage with amyloidosis Dutch type (HCHWA-D)
amyloid angiopathy: presentations without lobar haem-
results from mutations at codon 693 of the amyloid
orrhage. Neurology 1993; 43: 2073–9.
precursor protein (APP) gene; other mutations Haan J, Lanser JB, Zijderveld I, van der Does IG, Roos RA.
within this gene are deterministic for autosomal Dementia in hereditary cerebral haemorrhage
dominant Alzheimer’s disease (see Section 2.1). with amyloidosis – Dutch type. Arch Neurol 1990; 47:
The phenotype is one of cerebral haemorrhages 965–7.
which may result in cognitive impairment of cor- Larner AJ, Elkington P, Mehta H, et al. Multifocal cortical
tical type (Haan et al., 1990), although dementia in myoclonus and cerebral amyloid b-peptide angiopathy.
the absence of a history of stroke or focal radio- J Neurol Neurosurg Psychiatry 1998; 65: 951–2.
logical change may occur. Dementia in HCHWA-D Natté R, Maat-Schieman MLC, Haan J, et al. Dementia in
hereditary cerebral hemorrhage with amyloidosis–
is independent of neurofibrillary pathology, plaque
Dutch type is associated with cerebral amyloid angio-
density, and age, but related to the CAA load in
pathy but is independent of plaques and neurofibrillary
frontal cortex, as quantified by computerized
tangles. Ann Neurol 2001; 50: 765–72.
morphometry, and vessel wall thickening, sug- Plant GT, Ghiso J, Holton JL, Frangione B, Revesz T.
gesting that CAA per se may cause dementia (Natté Familial and sporadic cerebral amyloid angiopathies
et al., 2001). Hereditary cerebral haemorrhage with associated with dementia and the BRI dementias. In:
amyloidosis Icelandic type (HCHWA-I), resulting Esiri MM, Lee VMY, Trojanowski JQ (eds.), The Neuro-
from mutations in the cystatin c gene, also causes pathology of Dementia (2nd edition). Cambridge:
intracerebral haemorrhages. One family with a Cambridge University Press, 2004: 330–52.
Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid The genetic defect remains unknown. Of the six
angiopathies: a pathologic, biochemical and genetic affected individuals in two generations, neuro-
view. J Neuropathol Exp Neurol 2003; 62: 885–98. psychological testing was only reported in one
Scolding NJ, Joseph F, Kirby PA, et al. Ab-related angiitis: patient, who developed progressive memory
primary angiitis of the central nervous system associ-
decline in the early 60s with additional evidence of
ated with cerebral amyloid angiopathy. Brain 2005; 128:
visuoconstructional problems, ‘ideokinetic’ apraxia,
500–15.
calculation and writing errors, and frontal lobe
Sveinbjörnsdóttir S, Blöndal H, Gudmundsson G, et al.
Progressive dementia and leucoencephalopathy as the
symptoms.
initial presentation of late onset hereditary cystatin-C
amyloidosis: clinicopathological presentation of two
cases. J Neurol Sci 1996; 140: 101–8.
REFERENCES
Vinters HV. Cerebral amyloid angiopathy: a critical review.
Stroke 1987; 18: 311–24. Iglesias S, Chapon F, Baron JC. Familial occipital
Yamada M. Cerebral amyloid angiopathy: an overview. calcifications, haemorrhagic strokes, leukoencephalo-
Neuropathology 2000; 20: 8–22. pathy, dementia and external carotid dysplasia. Neurol-
ogy 2000; 55: 1661–7.
3.6.4 Familial young-adult-onset

3.6.6 Hereditary endotheliopathy with
arteriosclerotic leukoencephalopathy
retinopathy, nephropathy, and stroke (HERNS)
with alopecia and lumbago without arterial
hypertension This microangiopathy of the brain and retina,
inherited as an autosomal dominant condition
In this rare syndrome, reported only in Japanese
linked to chromosome 3p21, is characterized clin-
families, progressive subcortical dementia is com-
ically by progressive visual loss, headache, seizures,
mon, with accompanying pseudobulbar palsy and
focal neurological deficits, and progressive cogni-
pyramidal signs. Lacunar strokes occurred in about
tive decline (Grand et al., 1988; Jen et al., 1997).
half of the patients (Fukutake & Hirayama, 1995).
REFERENCES
REFERENCES
Grand MG, Kaine J, Fulling K, et al. Cerebroretinal
Fukutake T, Hirayama K. Familial young-adult-onset vasculopathy: a new hereditary syndrome. Ophthalmol-
arteriosclerotic leukoencephalopathy with alopecia ogy 1988; 95: 649–59.
and lumbago without arterial hypertension. Eur Neurol Jen J, Cohen AH, Yue Q, et al. Hereditary endotheliopathy
1995; 35: 69–79. with retinopathy, nephropathy and stroke (HERNS).
Neurology 1997; 49: 1322–30.
3.6.5 Familial occipital calcifications,

haemorrhagic strokes, leukoencephalopathy, 3.6.7 Hereditary multi-infarct dementia
dementia and external carotid dysplasia of Swedish type
(FOCHS-LADD)
Sourander and Wålinder (1977) described a Swed-
Described in one family of Spanish descent, with ish pedigree with a hereditary disorder character-
presumed autosomal dominant transmission, this ized by multiple infarcts and cognitive decline.
syndrome featured dementia and cerebral haem- When CADASIL was described as such in 1993 (see
orrhages with radiological evidence of fine tram- Section 3.6.2) it was thought that this ‘hereditary
line occipital calcifications (Iglesias et al., 2000). multi-infarct dementia’ was in fact an example of
CADASIL. However, further clinical, neuro- criteria require both clinical (thrombotic) and
radiological, neuropathological, and neurogenetic laboratory features, and a ‘probable’ category has
examination of the Swedish pedigree refutes this also been suggested, in which the antibodies occur
suggestion. Patients from this kindred did not have without a history of large vessel thromboses
migraine, MR appearances did not show the typical (Asherson, 2006). There is also overlap between
anterior temporal pole or external capsule hyper- Hughes syndrome and Sneddon’s syndrome (see
intensities seen in CADASIL, skin biopsy did not Section 3.6.11).
show granular osmiophilic deposits, and neuroge- Cognitive impairment and dementia have been
netic testing found no pathogenic mutation in the recorded in primary antiphospholipid antibody
NOTCH3 gene. Hence Swedish multi-infarct syndrome. For example, in a young woman not
dementia is a novel small vessel disease (Low et al., meeting diagnostic criteria for SLE (Tan et al.,
2007). 1982), decline in intellect and occupational failure
were the presenting features, with MMSE score
28/30 (5-minute recall ¼ 1/3), poor right–left
REFERENCES orientation, right inattention, reduced motor
speed, mild impulsivity, and poor concentration.
Low WC, Junna M, Borjesson-Hanson A, et al. Hereditary MR brain imaging showed small high-signal lesions
multi-infarct dementia of the Swedish type is a novel in the right caudate and frontal–subcortical white
disorder different from NOTCH3 causing CADASIL. matter. The patient improved after treatment with
Brain 2007; 130: 357–67. corticosteroids, aspirin, and hydroxychloroquine
Sourander P, Wålinder J. Hereditary multi-infarct demen- (van Horn et al., 1996). Reviewing the literature
tia. Morphological and clinical studies of a new disease. over the period 1983–2003 and their own experi-
Acta Neuropathol (Berl) 1977; 39: 247–54.
ence, Gómez-Puerta et al. (2005) identified 30 cases
of dementia associated with antiphospholipid
3.6.8 Hughes’ syndrome (primary syndrome (primary : secondary ¼ 14 : 16, the latter
antiphospholipid antibody syndrome) having SLE or ‘lupus-like syndrome’). On brain
imaging, cortical infarcts were common (in more
Antiphospholipid antibodies (lupus anticoagulant, than half the cases), subcortical and basal ganglia
or anticardiolipin antibodies) may be associated infarcts less so (in less than one-third). Hence
with various neurological features including seiz- dementia would seem to be an unusual compli-
ures, chorea, transverse myelitis, depression, cation of antiphospholipid syndromes.
psychosis, and cognitive decline. Whether these
clinical features are linked to arterial and venous
thromboses or to immune-mediated mechanisms, REFERENCES
or both, remains uncertain, and hence whether
optimal treatment is with antiplatelet and anti- Asherson RA. New subsets of the antiphospholipid
coagulant therapy or immunosuppression or both syndrome in 2006: PRE-APS (probable APS) and micro-
(Brey & Escalante, 1998). Antiphospholipid anti- angiopathic antiphospholipid syndromes (MAPS). Auto-
bodies may occur in association with conditions immun Rev 2006; 6: 76–80.
Brey RL, Escalante A. Neurological manifestations of
such as SLE, rheumatoid arthritis, Sjögren’s syn-
antiphospholipid antibody syndrome. Lupus 1998; 7
drome, and scleroderma, known as secondary
(suppl 2): S67–74.
antiphospholipid antibody syndromes; or without
Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia
evidence of accompanying connective tissue dis- associated with the antiphospholipid syndrome: clinical
ease, known as primary antiphospholipid antibody and radiological characteristics of 30 patients. Rheuma-
syndrome, or Hughes’ syndrome. Diagnostic tology (Oxford) 2005; 44: 95–9.
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria relationship to MR imaging findings and hematocrit.
for the classification of systemic lupus erythematosus. AJNR Am J Neuroradiol 2003; 24: 382–9.
Arthritis Rheum 1982; 25: 1271–7.
van Horn G, Arnett FC, Dimachkie MM. Reversible
dementia and chorea in a young woman with the 3.6.11 Sneddon’s syndrome
lupus anticoagulant. Neurology 1996; 46: 1599–603.
Sneddon’s syndrome is a non-inflammatory,
thrombo-occlusive, arteriolar vasculopathy, affect-
3.6.9 Polycythaemia rubra vera ing skin and brain and often, but not invariably,
associated with antiphospholipid antibodies. The
Polycythaemia rubra vera is a myeloproliferative
disorder occurs primarily in young patients, with a
disease characterized by increased red cell mass
female preponderance. Clinical features include
and blood volume, resulting in erythrocytosis
livedo reticularis or livedo racemosa, recurrent
(raised haematocrit) and increased blood viscosity.
strokes in the absence of obvious risk factors, focal
Associated neurological features include transient
neurological signs, seizures, and sometimes cog-
ischaemic attacks and thrombotic strokes, less
nitive decline (Sneddon, 1965; Frances et al., 1999).
commonly with cerebral haemorrhage, and chorea.
Cases presenting with cognitive decline or
Cognitive decline, which partially reversed on
dementia without a clinical history of stroke, but
reduction of the haematocrit, has been reported
with imaging evidence of cortical and subcortical
(Di Pollina et al., 2000).
infarcts with brain atrophy, have been reported
(Wright & Kokmen, 1999; Adair et al., 2001). Of 30
patients with dementia and antiphospholipid
REFERENCES
antibody syndrome reported in a 20-year literature
review (Gómez-Puerta et al., 2005), 10 had Sned-
Di Pollina L, Mulligan R, Juillerat van der Linden A, Michel JP,
don’s syndrome.
Gold G. Cognitive impairment in polycythaemia
rubra vera: partial reversibility upon lowering of the
hematocrit. Eur Neurol 2000; 44: 57–9.
REFERENCES
3.6.10 Sickle cell disease
Adair JC, Digre KB, Swanda RM, et al. Sneddon’s
Dementia may be a feature of sickle cell disease as a syndrome: a cause of cognitive decline in young adults.
consequence of multiple ischaemic strokes, Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:
although diffuse brain injury, perhaps related to 197–204.
hypoxia, may also contribute (Steen et al., 2003). A Frances C, Papo T, Wechsler B, et al. Sneddon syndrome
with or without antiphospholipid antibodies: a com-
progressive encephalopathy related to small vessel
parative study in 46 patients. Medicine (Baltimore) 1999;
disease has also been reported (Pavlakis et al., 1989).
78: 209–19.
Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia
associated with the antiphospholipid syndrome: clinical
REFERENCES and radiological characteristics of 30 patients. Rheuma-
tology (Oxford) 2005; 44: 95–9.
Pavlakis S, Prohovnik I, Piomelli S, DeVivo DC. Neurologic Sneddon IB. Cerebrovascular lesions and livedo reticu-
complications of sickle cell disease. Adv Pediatr 1989; laris. Br J Dermatol 1965; 77: 180–5.
36: 247–76. Wright RA, Kokmen E. Gradually progressive dementia
Steen RG, Miles MA, Helton KJ, et al. Cognitive impair- without discrete cerebrovascular events in a patient with
ment in children with hemoglobin SS sickle cell disease: Sneddon’s syndrome. Mayo Clin Proc 1999; 74: 57–61.
3.6.12 Spatz–Lindenberg disease 3.7 Other cerebrovascular disorders

(von Winiwarter–Buerger’s disease)
3.7.1 Cortical venous sinus thrombosis (CVST)
This rarely described condition is characterized
pathologically by isolated cerebral non-inflammatory Cortical venous sinus thrombosis (CVST) is a rare
occlusive vasculopathy (‘thromboangiitis obliter- cause of stroke, with many possible causes (Bous-
ans’), hence Buerger’s disease confined to the brain ser & Ross Russell, 1997). Studies examining cog-
(Zhan et al., 1993). A vascular dementia with add- nitive outcomes have been small. De Bruijn et al.
itional upper motor neurone signs (hemiparesis, (2000) found cognitive impairments in around one-
aphasia) and seizures may result (Larner et al., 1999), third of survivors at 1 year, suggesting an
but no systematic exploration of the neuropsycho- unfavourable outcome, whereas Buccino et al.
logical deficits has been reported. (2003) found mild non-fluent aphasia in 9% and
working memory deficits in 18% of a cohort of 34
patients seen over a 10-year period, suggesting
REFERENCES good cognitive long-term outcome. The variable
results may relate to case mix and duration of fol-
Larner AJ, Kidd D, Elkington P, Rudge P, Scaravilli F. low-up. In children, lateral and sigmoid sinus
Spatz–Lindenberg disease: a rare cause of vascular involvement was reported to be a predictor of good
dementia. Stroke 1999; 30: 687–9. cognitive outcome (Sébire et al., 2003).
Zhan S-S, Beyreuther K, Schmitt HP. Vascular dementia in
Spatz–Lindenberg disease (SLD): cortical synaptophysin
immunoreactivity as compared with dementia of
Alzheimer type and non-demented controls. Acta
REFERENCES
Neuropathol (Berl) 1993; 86: 259–64.
Bousser MG, Ross Russell RW. Cerebral Venous Throm-
bosis. London: Saunders, 1997.
3.6.13 Susac syndrome Buccino G, Scoditti U, Patteri I, Bertolino C, Mancia D.
Neurological and cognitive long-term outcome in
Susac syndrome, or retinocochleocerebral vascu-
patients with cerebral venous sinus thrombosis. Acta
lopathy, is a rare, idiopathic, non-inflammatory Neurol Scand 2003; 107: 330–5.
vasculopathy affecting principally young women. It De Bruijn SF, Budde M, Teunisse S, de Haan RJ, Stam J.
usually follows a monophasic but fluctuating Long-term outcome of cognition and functional health
course, causing small infarcts in the cochlea, ret- after cerebral venous sinus thrombosis. Neurology 2000;
ina, and brain. Characteristic clinical features are 54: 1687–9.
sensorineural deafness, branch retinal arteriolar Sébire G, Tabarki B, Saunders DE, et al. Cerebral venous
occlusions, encephalopathy, acute psychiatric fea- sinus thrombosis in children: risk factors, presentation,
tures, upper motor neurone limb signs, cranial diagnosis and outcome. Brain 2005; 128: 477–89.
nerve palsies, and seizures. Cognitive dysfunction
is reported, specifically impaired short-term
3.7.2 Migraine
memory, and dementia is said to be a rare late
sequela (Papo et al., 1998). Migraine may be symptomatic of a neurological
disorder that may also cause cognitive impairment,
e.g. CADASIL (Section 3.6.2) or mitochondrial dis-
REFERENCES ease (Section 5.5.1), but it is more usually a primary
or idiopathic headache disorder which occurs with
Papo T, Biousse V, Lehoang P, et al. Susac syndrome. or without aura (MA, MO: International Headache
Medicine (Baltimore) 1998; 77: 3–11. Society Classification Subcommittee, 2004). Whether
migraine disorders are associated with cognitive Calandre EP, Bembibre J, Arnedo ML, Becerra D.
deficits, either between or within attacks, has been a Cognitive disturbances and regional cerebral blood
subject of ongoing debate. The rare entity of flow abnormalities in migraine patients: their relation-
migraine stroke may be associated with focal def- ship with the clinical manifestation of the illness.
Cephalalgia 2002; 22: 291–302.
icits, as with strokes of other aetiologies.
Evers S, Frese A, Sörös P, et al. Involvement of cognitive
Studies have been published showing subtle
processing in cluster headache. In: Olesen J, Goadsby PJ
changes in cognition in migraineurs examined
(eds.), Cluster Headache and Related Conditions (Fron-
either during or between migraine episodes tiers in headache research, volume 9). Oxford: Oxford
(O’Bryant et al., 2006). Interictal deficits have been University Press, 1999: 201–6.
reported, involving certain frontal lobe functions Farmer K, Cady R, Bleiberg J, Reeves D. A pilot study to
(Mongini et al., 2005), or associated with right- measure cognitive efficiency during migraine. Headache
sided pain (Le Pira et al., 2004), or with higher 2000; 40: 657–61.
frequency of attacks or length of migraine history Farmer K, Cady R, Bleiberg J, et al. Sumatriptan nasal
(Calandre et al., 2002). Certainly migraine patients spray and cognitive function during migraine: results of
show an interictal loss of normal cognitive an open-label study. Headache 2001; 41: 377–84.
International Headache Society Classification Subcom-
habituation, although this does not seem to occur
mittee. The international classification of headache
in cluster headache (Evers et al., 1999). Conversely,
disorders, second edition. Cephalalgia 2004; 24 (suppl 1):
case–control and group studies have been pub-
1–160.
lished that do not support a link between migraine Jelicic M, van Boxtel MP, Houx PJ, Jolles J. Does migraine
and cognitive impairment (Bell et al., 1999; Pearson headache affect cognitive function in the elderly?
et al., 2006). A 10-year study suggested impair- Report from the Maastricht Aging Study (MAAS).
ments of immediate and delayed memory in MA Headache 2000; 40: 715–19.
patients at baseline but less decline over time than Kalaydjian A, Zandi PP, Swartz KL, Eaton WW, Lyketsos C.
controls (Kalaydjian et al., 2007). How migraines impact cognitive function: findings
During migraine attacks, simple reaction time, from the Baltimore ECA. Neurology 2007; 68: 1417–24.
sustained attention, and visuospatial processing Le Pira F, Lanaia F, Zappala G, et al. Relationship between
clinical variables and cognitive performances in
may be adversely affected, changes which may be
migraineurs with and without aura. Funct Neurol
effectively reversed by triptans (Mulder et al., 1999;
2004; 19: 101–5.
Farmer et al., 2000, 2001) or sleep (Meyer et al.,
Meyer JS, Thornby J, Crawford K, Rauch GM. Reversible
2000). However, some of these studies were per- cognitive decline accompanies migraine and cluster
formed without control groups, so it is difficult to headaches. Headache 2000; 40: 638–46.
know whether these problems relate to concurrent Mongini F, Keller R, Deregibus A, Barbalonga E, Mongini
pain or the pathophysiology of the headache syn- T. Frontal lobe dysfunction in patients with chronic
drome per se. Moreover, information processing migraine: a clinical–neuropsychological study. Psych-
speed and memory may be influenced by age, iatry Res 2005; 133: 101–6.
independent of migraine (Jelicic et al., 2000). Mulder EJ, Linssen WH, Passchier J, Orlebeke JF, de Geus
EJ. Interictal and postictal cognitive changes in
migraine. Cephalalgia 1999; 19: 557–65.
O’Bryant SE, Marcus DA, Rains JC, Penzien DB. The
REFERENCES neuropsychology of recurrent headache. Headache
2006; 46: 1364–76.
Bell BD, Primeau M, Sweet JJ, Lofland KR. Neuropsycho- Pearson AJ, Chronicle EP, Maylor EA, Bruce LAM.
logical functioning in migraine headache, nonheadache Cognitive function is not impaired in people with a
chronic pain, and mild traumatic brain injury patients. long history of migraine: a blinded study. Cephalalgia
Arch Clin Neuropsychol 1999; 14: 389–99. 2006; 26: 74–80.
3.7.3 Transient global amnesia (TGA) attack has been reported (Roman-Campos et al.,
1980), although it is possible that this patient had
The aetiopathogenesis of transient global amnesia
epilepsy with a left temporal EEG focus (transient
(TGA) is imperfectly understood (Quinette et al.,
epileptic amnesia should be considered in the dif-
2006). Recent evidence of vascular involvement,
ferential diagnosis: Section 4.3.1). The majority of
specifically from diffusion-weighted MR imaging
attacks of TGA occur in isolation with a low
techniques (Sander & Sander, 2005), and the
recurrence rate (3% per year). It has been suggested
increased incidence of jugular vein valve insuffi-
that TGA may be a risk factor for the amnestic
ciency (Nedelmann et al., 2005), prompt its inclu-
variant of mild cognitive impairment (Borroni
sion in this chapter.
et al., 2004).
The syndrome of TGA consists of an abrupt
attack of impaired anterograde memory, often
manifest as repeated questioning, without clouding
REFERENCES
of consciousness or focal neurological signs (Fisher
& Adams, 1964; Caplan, 1985). Episodes are of brief
Borroni B, Agosti C, Brambilla C, et al. Is transient global
duration (< 24 hours), with no recollection of the
amnesia a risk factor for amnestic mild cognitive
amnesic period following resolution. Diagnostic impairment? J Neurol 2004; 251: 1125–7.
criteria for TGA have been suggested (Caplan 1985; Caplan LR. Transient Global Amnesia. Amsterdam: Else-
Hodges & Warlow, 1990). Subgroups have been vier, 1985.
suggested, with the suggestion of different pre- Fisher CM, Adams RD. Transient global amnesia. Acta
cipitating events in men (physical) and women Neurol Scand 1964; 40 (Suppl 9): 1–81.
(emotional), with headache being a risk factor in Hodges JR. Transient semantic amnesia. J Neurol Neuro-
younger individuals (Quinette et al., 2006). surg Psychiatry 1997; 63: 548–9.
As expected for an acute and transient syndrome, Hodges JR, Ward CD. Observations during transient global
amnesia: a behavioural and neuropsychological study
most cases which come to medical attention are
of five cases. Brain 1989; 112: 595–620.
seen by primary care physicians in the community
Hodges JR, Warlow CP. Syndromes of transient amnesia:
or district general hospitals (Larner, 2007) rather
towards a classification. A study of 153 cases. J Neurol
than by neurologists, let alone those with an Neurosurg Psychiatry 1990; 53: 834–43.
interest in neuropsychology. Nonetheless, occa- Larner AJ. Transient global amnesia in the district general
sionally it has been possible to undertake neuro- hospital. Int J Clin Pract 2007: 61: 255–8.
psychological assessment during an attack. This Nedelmann M, Eicke BM, Dieterich M. Increased inci-
shows a dense anterograde amnesia, with a vari- dence of jugular valve insufficiency in patients with
ably severe retrograde amnesia, but intact working transient global amnesia. J Neurol 2005; 252: 1482–6.
memory and semantic memory. Implicit memory Quinette P, Guillery-Girard B, Dayan J, et al. What does
functions (e.g. for driving) are usually intact transient global amnesia really mean? Review of the
literature and thorough study of 142 cases. Brain 2006;
(Hodges & Ward, 1989). A variant in which transi-
129: 1640–58.
ent impairment of semantic memory was present
Roman-Campos G, Poser CM, Wood F. Persistent retro-
has been described (Hodges, 1997).
grade memory deficit after transient global amnesia.
After an attack patients are usually normal, Cortex 1980; 16: 500–19.
although there may be subtle impairment of ante- Sander K, Sander D. New insights into transient global
rograde verbal memory on neuropsychological amnesia: recent imaging and clinical findings. Lancet
assessment. Prolonged retrograde amnesia after an Neurol 2005; 4: 437–44.
4
The epilepsies
4.1 Epilepsy and cognitive impairment 115

4.2 Cognitive decline and epilepsy: shared aetiology 116
4.2.1 Localization-related (partial) epilepsies 117
4.2.2 Rasmussen’s syndrome (chronic encephalitis and epilepsy) 119
4.2.3 Idiopathic generalized epilepsies 120
4.3 Seizures causing acquired cognitive impairment 120
4.3.1 Transient epileptic amnesia (TEA) 121
4.3.2 Epileptic aphasia, ictal speech arrest 121
4.4 Antiepileptic drug therapy causing cognitive impairment 122
4.5 Treatment of cognitive problems in epilepsy 123
4.1 Epilepsy and cognitive impairment (generalized versus partial, or localization-related),

aetiology (idiopathic versus symptomatic), and
As far back as the seventeenth century, Thomas pathology (Engel & Pedley, 1997; Panayiotopoulos,
Willis recognized that long-term epilepsy could 2002), means that definition of a specific profile of
bring on ‘stupidity’, a term roughly corresponding neuropsychological impairments is as untenable for
to our notion of dementia (Zimmer, 2004). epilepsy as it is for cerebrovascular disease. None-
Nineteenth-century authors such as Henry Maudsley theless certain common patterns may be identified
and William Gowers both regarded epileptics as in certain epilepsy syndromes.
prone to dementia or defective memory; Maudsley Historically, epilepsy surgery provided one of the
thought such decline inevitable (Brown & Vaughan, critical clues to the relevance of certain brain
1988). Their views may have been determined by structures in cognitive function through one of the
clinical practice amongst patients with very severe most remarkable cases in the history of neuro-
seizure disorders, and with the advent of effective psychology, Henry or HM, who developed pro-
antiepileptic drugs in the twentieth century a more found anterograde amnesia following surgical
optimistic outlook generally prevailed. Now, how- removal of the anterior temporal lobes, including
ever, cognitive impairment in epilepsy is once again the hippocampus, bilaterally for intractable seiz-
a subject of increasing concern. Rather than an ures of temporal lobe origin (Scoville & Milner,
‘epileptic dementia’, it is now thought better 1957; Ogden, 2005). Occasional cases of amnesia
to consider ‘dementia in people with epilepsy’, a following unilateral surgery have also been
syndrome with various possible causes. reported (Kapur & Prevett, 2003).
The marked heterogeneity of epilepsy syndromes, There are at least three possible reasons for an
with respect to factors such as site of seizure origin association between cognitive decline and epileptic
115
116 The epilepsies
seizures (Trimble & Reynolds, 1988; Kwan & Bro- Engel J, Pedley TA (eds.). Epilepsy: a Comprehensive
die, 2001; Trimble & Schmitz, 2002; Motamedi & Textbook. Philadelphia: Lippincott-Raven, 1997.
Meador, 2003; Elger et al., 2004): Kapur N, Prevett M. Unexpected amnesia: are there lessons
Cognitive decline and epilepsy may share an to be learned from cases of amnesia following unilateral
temporal lobe surgery? Brain 2003; 126: 2573–85.
underlying aetiology.
Kwan P, Brodie MJ. Neuropsychological effects of epilepsy
Seizures per se may lead to acquired cognitive
and antiepileptic drugs. Lancet 2001; 357: 216–22.
impairment.
Motamedi G, Meador K. Epilepsy and cognition. Epilepsy
Antiepileptic drug therapy may cause cognitive Behav 2003; 4: S25–38.
decline. Ogden JA. Fractured Minds: a Case-Study Approach to
These variables are not necessarily independent: Clinical Neuropsychology (2nd edition). Oxford: Oxford
specific brain diseases or brain injuries may be University Press, 2005: 46–63.
associated with longer duration of seizure disorder Panayiotopoulos CP. A Clinical Guide to Epileptic Syn-
and/or more frequent seizures, requiring poly- dromes and Their Treatment: Based on the New ILAE
therapy and/or higher doses of antiepileptic drugs. Diagnostic Scheme. Chipping Norton: Bladon, 2002.
Because of this potential confounding, it is difficult Scoville W, Milner B. Loss of recent memory after bilateral
hippocampal lesions. J Neurol Neurosurg Psychiatry
to dissect the various parameters apart. Indeed,
1957; 20: 11–21.
most cognitive problems in patients with epilepsy
Trimble MR, Reynolds EH (eds.). Epilepsy, Behaviour and
are of multifactorial origin. Psychiatric comorbidity
Cognitive Function. Chichester: Wiley, 1988.
may also need to be taken into account; depression Trimble M, Schmitz B (eds.). The Neuropsychiatry of Epilepsy.
may contribute more to subjective memory com- Cambridge: Cambridge University Press, 2002: 135–85.
plaints and poor quality of life in epilepsy than Zimmer C. Soul Made Flesh. The Discovery of the Brain –
seizures. Brain plasticity and epilepsy surgery may and How it Changed the World. London: Heinemann,
also have cognitive consequences, but are not 2004: 226.
considered further here (Elger et al., 2004).
Memory problems in epilepsy are a subject of
increasing concern in the management of epilepsy, 4.2 Cognitive decline and epilepsy:
over and above simple reduction in seizure fre- shared aetiology
quency and severity (Brookes & Baker, 2006). How
appropriate standard neuropsychological tests are in Cognitive decline and epilepsy may both be fea-
the detection of cognitive impairments in epilepsy tures of certain brain disorders. The symptomatic
patients is open to question (Baker & Marson, 2001), epilepsies include those due to brain tumour,
particularly in the assessment of executive functions. stroke (infarct or haemorrhage), demyelination,
infection (encephalitis, meningitis), and various
dementia syndromes (Larner, 2007). The concur-
REFERENCES rence of seizures and cognitive impairment does
not necessarily imply a causal link (i.e. seizures
Baker GA, Marson AG. Cognitive and behavioural assess- causing cognitive impairment) in these conditions.
ments in clinical trials: what type of measure? Epilepsy For example, seizures may sometimes be a feature
Res 2001; 45: 163–7.
of Huntington’s disease (HD; see Section 5.1.1),
Brookes JA, Baker GA. Epilepsy and memory. Epilepsy
particularly early-onset forms, but there is no
Professional 2006; 1 (2): 21–3.
suggestion that these seizures are responsible for,
Brown SW, Vaughan M. Dementia in epileptic patients. In:
Trimble MR, Reynolds EH (eds.), Epilepsy, Behaviour and or even contribute to, the cognitive deficits of HD.
Cognitive Function. Chichester: Wiley, 1988: 177–88. Likewise Alzheimer’s disease (AD) is recognized to
Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy be a risk factor for the development of late-onset
and cognition. Lancet Neurol 2004; 3: 663–72. seizures (Hauser et al., 1986; Romanelli et al., 1990),
of both partial and generalized onset (Hesdorffer Loiseau P, Strube E, Broustet D, et al. Evaluation of
et al., 1996), and seizures become increasingly memory function in a population of epileptic patients
common with the progression of AD (Mendez & and matched controls. Acta Neurol Scand Suppl 1980;
Lim, 2003), but they cannot be held responsible for 80: 58–61.
Lozsadi DA, Larner AJ. Prevalence and causes of seizures
progression of cognitive impairments, not even
at time of diagnosis of probable Alzheimer’s disease.
when present in the earliest stages of the disease
Dementia Geriatr Cogn Disord 2006; 22: 121–4.
(Lozsadi & Larner, 2006). More likely, cognitive
Mendez MF, Lim GTH. Seizures in elderly patients with
decline and seizures reflect a shared pathogenesis dementia: epidemiology and management. Drugs Aging
in terms of neuronal disconnection. Seizures may 2003; 20: 791–803.
be a symptomatic feature of various other patho- Mirsky AF, Primac DW, Marsan CA, Rosvold HE, Stevens
logies associated with cognitive decline (e.g. JR. A comparison of the psychological test performance
encephalitis, mitochondrial disease, progressive of patients with focal and non-focal epilepsy. Exp
myoclonic epilepsy syndromes). The corollary of Neurol 1960; 2: 75–89.
this observation is that treatment of the underlying Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced
disease, where possible, might ameliorate both Alzheimer’s disease is a risk factor for late-onset
seizures. Arch Neurol 1990; 47: 847–50.
cognitive decline and seizures.
In contrast to symptomatic epilepsies, many seiz-
ure disorders remain idiopathic despite extensive 4.2.1 Localization-related (partial) epilepsies
investigation. These idiopathic epilepsies may be
categorized according to whether the seizures are of Partial or focal seizures may be of temporal,
generalized or partial onset. Group studies have frontal, or occipital lobe onset, with or without
suggested that epilepsy patients have reduced speed secondary generalization. Cognitive features have
of mental processing, reaction and response times been most extensively investigated in temporal
(Bruhn & Parsons, 1977), as well as impairments in lobe epilepsy. Generally, cognitive deficits are
remembering lists of words and geometric patterns localized to the brain region affected. Thus partial
(Loiseau et al., 1980). Attention deficits may be more seizures with epileptic foci in the left temporal
common in generalized than in focal epilepsy (Mirsky region have generally been associated with
et al., 1960; Kimura, 1964), memory difficulties more impaired verbal long-term memory, whilst right
common in focal (temporal lobe) epilepsy. temporal lobe foci cause greater difficulty with
visual long-term memory, whereas early group
studies found patients with unilateral frontal lobe
REFERENCES foci to be no different from controls (Làdavas et al.,
1979; Delaney et al., 1980). These findings may in
Bruhn P, Parsons OA. Reaction time variability in epileptic part explain why even patients with well-controlled
and brain-damaged patients. Cortex 1977; 13: 373–84. partial seizures, doing a regular job or attending a
Hauser WA, Morris ML, Heston LL, Anderson VE. Seizures normal school, may be found on neuropsychological
and myoclonus in patients with Alzheimer’s disease. testing to have impaired cognition (Engelberts
Neurology 1986; 36: 1226–30. et al., 2002).
Hesdorffer DC, Hauser WA, Annegers JF, Kokmen E, Rocca
WA. Dementia and adult-onset unprovoked seizures.
Neurology 1996; 46: 727–30. Temporal lobe epilepsy
Kimura D. Cognitive deficit related to seizure patterns in
centrencephalic epilepsy. J Neurol Neurosurg Psychiatry Symptomatic temporal lobe epilepsy (TLE) with the
1964; 27: 291–5. neuroradiological signature of hippocampal scler-
Larner AJ. Epilepsy and dementia: confusion over osis or mesial temporal sclerosis (MTS) is thought to
seizures. Epilepsy Professional 2007; Issue 6: 21–3. be the commonest form of localization-related
118 The epilepsies
epilepsy (Wieser, 2004). Precipitating incidents such seizures with or without Jacksonian march, and
as febrile convulsions, brain trauma, ischaemia, tonic posturing in seizures of supplementary
or intracranial infection are common, and most motor-area origin (fencer’s posture, en garde,
individuals have seizure onset in childhood or salutatory seizures). FLE may be idiopathic or
adolescence. symptomatic.
Because of the involvement of structures There is evidence for frontal-type, executive,
important for memory processes, it has been nat- cognitive dysfunction in FLE, in terms of attention,
ural to examine cognitive function in TLE patients. working memory, planning, and psychomotor speed
Even at disease onset deficits may be apparent, (Helmstaedter et al., 1996; Upton & Thompson,
suggesting that these are symptoms of the disease 1997; Exner et al., 2002). Elements of social cogni-
and not simply consequences of frequent seizures tion, such as humour appreciation and ability to
or the effects of antiepileptic drug therapy (Aikia detect emotional expression, but not tests of theory
et al., 2001). Left-sided (dominant hemisphere) TLE of mind, may also be impaired (Farrant et al., 2005).
is characterized by deficits in material-specific ver- A nocturnal variant of FLE may be either sporadic
bal memory (Hermann et al., 1997), whereas right or inherited as an autosomal dominant disorder, the
TLE is associated with non-verbal/visual memory latter (ADNFLE) associated with mutations in at
deficit, albeit less consistently (Gleissner et al., least two genes, CHRNA4 and CHRNB2 (Combi
1998). Other profiles are sometimes encountered, et al., 2004). ADNFLE associated with one mutation
for example relatively selective autobiographical in CHRNB2, I312M, is reported to be associated with
amnesia (Kapur, 1997). Quantitative MR imaging distinct memory deficits involving the storage of
studies suggest that both the hippocampus and verbal information (Bertrand et al., 2005).
other related structures such as the fornix are atro-
phied in TLE patients (Kuzniecky et al., 1999).
Some studies have indicated that higher seizure
REFERENCES
frequency and duration of TLE are associated with
more severe cognitive decline (Jokheit & Ebner,
Aikia M, Salmenpera T, Partanen K, Kalviainen R. Verbal
1999), but in a report on patients with TLE under-
memory in newly diagnosed patients and patients with
going temporal lobe resection no correlation was
chronic left temporal lobe epilepsy. Epilepsy Behav
found between disease-related parameters, such as 2001; 2: 20–7.
cumulative number of seizures, and neuropsycho- Bertrand D, Elmslie F, Hughes E, et al. The CHRNB2
logical deficits, suggesting that factors other than mutation I312M is associated with epilepsy and distinct
repetitive seizures are responsible for cognitive memory deficits. Neurobiol Dis 2005; 20: 799–804.
dysfunction in TLE patients (Kramer et al., 2006). Combi R, Dalpra L, Tenchini ML, Ferini-Strambi L.
Longitudinal studies have suggested that there is Autosomal dominant nocturnal frontal lobe epilepsy: a
an early epilepsy-related memory deficit which critical review. J Neurol 2004; 251: 923–34.
then remains relatively stable over time, with any Delaney RC, Rosen AJ, Mattson RH, Novelly RA. Memory
function in focal epilepsy: a comparison of non-
additional changes typical of those related to aging.
surgical, unilateral temporal lobe and frontal lobe
samples. Cortex 1980; 16: 103–17.
Frontal lobe epilepsy Engelberts NHJ, Klein M, van der Ploeg HM, et al.
Cognition and health-related quality of life in a well-
The frontal lobe epilepsies (FLE), resulting from a defined subgroup of patients with partial epilepsy.
primary epileptic focus anywhere within the frontal J Neurol 2002; 249: 294–9.
lobe, have various seizure patterns. Motor mani- Exner C, Boucsein K, Lange C, et al. Neuropsychological
festations are more common than in seizures performance in frontal lobe epilepsy. Seizure 2002; 11:
arising elsewhere, for example simple focal motor 20–32.
Farrant A, Morris RG, Russell T, et al. Social cognition in viral infection and autoimmune mechanisms
frontal lobe epilepsy. Epilepsy Behav 2005; 7: 506–16. (Larner & Anderson, 1995; Bien et al., 2005).
Gleissner U, Helmstaedter C, Elger CE. Right hippocampal Although typically a disorder with childhood onset
contribution to visual memory: a presurgical and (Andermann, 1991), cases with adult onset have
postsurgical study in patients with temporal lobe
been described on occasion (e.g. McLachlan et al.,
epilepsy. J Neurol Neurosurg Psychiatry 1998; 65: 665–9.
1993; Nicholas et al., 2002). These appear to have a
Helmstaedter C, Kemper B, Elger CE. Neuropsychological
more protracted and milder clinical course with
aspects of frontal lobe epilepsy. Neuropsychologia 1996;
34: 399–406.
less in the way of residual functional deficits, lesser
Hermann BP, Seidenberg M, Schoenfeld J, Davies K. degrees of brain hemiatrophy, but with identical
Neuropsychological characteristics of the syndrome of clinical, EEG, neuroimaging, and histopathology
mesial temporal lobe epilepsy. Arch Neurol 1997; 54: findings (Bien et al., 2002).
369–76. Neuropsychological assessment of patients with
Jokheit H, Ebner A. Long term effects of refractory Rasmussen’s syndrome is subject to various biases,
temporal lobe epilepsy on cognitive abilities: a cross such as selected cohorts, ongoing seizures or even
sectional study. J Neurol Neurosurg Psychiatry 1999; 67: epilepsia partialis continua, and surgical interven-
44–50.
tions. Low IQ is typical in childhood-onset cases,
Kapur N. Autobiographical amnesia and temporal lobe
usually with little change after surgery, although
pathology. In: Parkin AJ (ed.), Case Studies in the
exceptionally improvement is noted (Taylor, 1991).
Neuropsychology of Memory. Hove: Psychology Press,
1997: 37–62.
In adult-onset cases, McLachlan et al. (1993) noted
Kramer U, Kipervasser S, Neufeld MY, et al. Is there any decline in IQ in two of their three patients, with
correlation between severity of epilepsy and cognitive greater left hemisphere dysfunction (PIQ > VIQ),
abilities in patients with temporal lobe epilepsy? Eur J consistent in one patient with exclusively left
Neurol 2006; 13: 130–4. hemisphere involvement. Over an 8-year period,
Kuzniecky R, Bilir E, Gilliam F, et al. Quantitative MRI in between the ages of 22 and 30 years, another adult-
temporal lobe epilepsy: evidence for fornix atrophy. onset patient developed IQ decline, impaired
Neurology 1999; 53: 496–501. auditory verbal memory, motor and sensory
Làdavas E, Umiltà C, Provinciali L. Hemisphere-dependent
aphasia in association with left temporo-occipital
cognitive performances in epileptic patients. Epilepsia
cortical MR imaging change and EEG multifocal
1979; 20: 493–502.
spike discharges in the left posterior quadrant
Upton D, Thompson PJ. Age at onset and neuropsycho-
logical function in frontal lobe epilepsy. Epilepsia 1997;
(Larner et al., 1995). However, cases with no
38: 1103–13. recorded cognitive deficit have been presented
Wieser HG. Mesial temporal lobe epilepsy with hippo- (Gawler, 2006). Improvements in neuropsycho-
campal sclerosis. Epilepsia 2004; 45: 695–714. logical function, as well as in seizure frequency,
have been recorded in adult-onset cases following
cycles of treatment with human intravenous
4.2.2 Rasmussen’s syndrome (chronic
immunoglobulin (Leach et al., 1999).
encephalitis and epilepsy)
A syndrome of chronic partial, often intractable,
epileptic seizures attended by progressive focal REFERENCES
sensorimotor neurological deficit and cognitive
decline was described by Rasmussen et al. (1958); a Andermann F (ed.). Chronic Encephalitis and Epilepsy:
similar syndrome was described by Kozhevnikov in Rasmussen’s Syndrome. Boston: Butterworth-Heinemann,
Russian in 1952. The pathogenesis of Rasmussen’s 1991.
syndrome, also known as chronic encephalitis and Bien CG, Granata T, Antozzi C, et al. Pathogenesis,
epilepsy, remains uncertain: possibilities include diagnosis and treatment of Rasmussen encephalitis: a
120 The epilepsies
European consensus statement. Brain 2005; 128: juvenile myoclonic epilepsy (JME), abstract rea-
454–71. soning, planning, and mental flexibility are
Bien CG, Widman G, Urbach H, et al. The natural history reported to be impaired, suggesting frontal type
of Rasmussen’s encephalitis. Brain 2002; 125: 1751–9. dysfunction (Devinsky et al., 1997).
Gawler J. A ‘glioma’ that was cured. Pract Neurol 2006; 6:
117–21.
Larner AJ, Anderson M. Rasmussen’s syndrome: patho-
genetic theories and therapeutic strategies. J Neurol REFERENCES
1995; 242: 355–8.
Larner AJ, Smith SJM, Duncan JS, Howard RS. Late-onset Devinsky O, Gershengorn J, Brown E, et al. Frontal
Rasmussen’s syndrome with first seizure during preg- functions in juvenile myoclonic epilepsy. Neuropsychia-
nancy. Eur Neurol 1995; 35: 172. try Neuropsychol Behav Neurol 1997; 10: 243–6.
Leach JP, Chadwick DW, Miles JB, Hart IK. Improvement Dickson JM, Wilkinson ID, Howell SJL, Griffiths PD,
in adult-onset Rasmussen’s encephalitis with long-term Grünewald RA. Idiopathic generalised epilepsy: a pilot
immunomodulatory therapy. Neurology 1999; 52: study of memory and neuronal dysfunction in the
738–42. temporal lobes, assessed by magnetic resonance
McLachlan RS, Girvin JP, Blume WT, Reichman H. spectroscopy. J Neurol Neurosurg Psychiatry 2006; 77:
Rasmussen’s chronic encephalitis in adults. Arch Neurol 834–40.
1993; 50: 269–74.
Nicholas RS, Scott AC, Hart IK. Two clinical presentations
of adult onset Rasmussen’s syndrome share common
immunological and pathological features. J Neurol 4.3 Seizures causing acquired cognitive
Neurosurg Psychiatry 2002; 72: 141 (abstract). impairment
Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures
due to chronic localized encephalitis. Neurology 1958; 8: Seizures may unequivocally lead to cognitive
435–45. impairment (Aldenkamp, 1997), as may frequent
Taylor LB. Neuropsychologic assessment of patients with interictal epileptiform discharges (Aldenkamp &
chronic encephalitis. In: Andermann F (ed.), Chronic Arends, 2004). Impairments have been noted in
Encephalitis and Epilepsy: Rasmussen’s Syndrome. Bos- psychomotor speed, attention, memory, and
ton: Butterworth-Heinemann, 1991: 111–21.
visuomotor tasks which cannot be ascribed to the
encephalopathy associated with status epilepticus,
postictal state, or antiepileptic drug toxicity, and
4.2.3 Idiopathic generalized epilepsies
which are reversible with good seizure control.
Idiopathic generalized epilepsies (IGE) are charac- Longitudinal studies suggest a link between
terized by primary generalized seizures which, adverse cognitive change and number of seizures
unlike localization-related epilepsies, occur in the or presence of tonic–clonic status epilepticus
absence of any macroscopic brain abnormalities. (Dodrill, 2004).
Hence, IGEs may facilitate the study of the effect of Amnesia is the norm for complex partial seizures,
seizures on cognitive function. However, controlled and for primary and secondary generalized seiz-
studies in homogeneous groups of IGE patients are ures. Sometimes the effects of frequent complex
in their infancy. IGE patients are reported to per- partial seizures are sufficient to manifest as a
form worse than controls on speed of information dementia syndrome that may even be confused
processing and in tests of memory encompassing with Alzheimer’s disease (Tatum et al., 1998; Høgh
word and face recognition and verbal and visual et al., 2002; Sinforiani et al., 2003). The frequency of
recall, with MR spectroscopy evidence that this such ‘epileptic pseudodementia’ is not known, but
may correlate with neuronal dysfunction second- clinically it merits consideration in light of the fact
ary to epileptic activity (Dickson et al., 2006). In that the incidence of complex partial seizures rises
4.3 Seizures causing acquired cognitive impairment 121
sharply after the age of 60 years. However, the REFERENCES

classic example of seizures causing cognitive
impairment is seen in the syndrome of transient Gallassi R, Morreale A, Di Sarro R, Lugaresi E. Epileptic
epileptic amnesia. amnesic syndrome. Epilepsia 1992; 33 (suppl 6): S21–5.
Kapur N. Transient epileptic amnesia: a clinical update
and a reformulation. J Neurol Neurosurg Psychiatry
REFERENCES 1993; 56: 1184–90.
Manes F, Graham KS, Zeman A, de Luján Calcagno M,
Hodges JR. Autobiographical amnesia and accelerated
Aldenkamp AP. Effect of seizures and epileptiform
forgetting in transient epileptic amnesia. J Neurol
discharges on cognitive function. Epilepsia 1997; 38
(suppl 1): S52–5.
Pritchard PB III, Holmstrom VL, Roitzsch JC, Giacinto J.
Aldenkamp AP, Arends J. Effects of epileptiform EEG
Epileptic amnesic attacks: benefit from antiepileptic
discharges on cognitive function: is the concept of
drugs. Neurology 1985; 35: 1188–9.
‘transient cognitive impairment’ still valid? Epilepsy
Zeman AZJ, Boniface SJ, Hodges JR. Transient epileptic
Behav 2004; 5 (suppl 1): S25–34.
amnesia: a description of the clinical and neuropsycho-
Dodrill CB. Neuropsychological effects of seizures. Epi-
logical features in 10 cases and a review of the literature.
lepsy Behav 2004; 5 (suppl 1): S21–4.
Høgh P, Smith SJ, Scahill RI, et al. Epilepsy presenting as
AD: neuroimaging, electroclinical features, and
response to treatment. Neurology 2002; 58: 298–301. 4.3.2 Epileptic aphasia, ictal speech arrest
Sinforiani E, Manni R, Bernasconi L, Banchieri LM,
Zucchella C. Memory disturbances and temporal lobe Aphasia is the principal symptom in the childhood
epilepsy simulating Alzheimer’s disease: a case report. epilepsy disorder of Landau–Kleffner syndrome
Funct Neurol 2003; 18: 39–41. (acquired epileptic aphasia), possibly reflecting a
Tatum WO, Ross J, Cole AJ. Epileptic pseudodementia. verbal auditory agnosia (Paquier et al., 1992). Isolated
Neurology 1998; 50: 1472–5. epileptic aphasia is uncommon, perhaps obscured in
some cases by ictal motor activity (Rosenbaum et al.,
4.3.1 Transient epileptic amnesia (TEA) 1986). Non-convulsive status epilepticus may mani-
fest with aphasia (‘status aphasicus’), usually with
Attacks of transient amnesia of epileptic origin are abrupt onset and rapid resolution with appropriate
usually brief, 1 hour or less in duration, often occur antiepileptic drug therapy, although persistent
on waking, and may be associated with clear-cut aphasia has also been reported (DeToledo et al., 2000;
EEG abnormalities. There may be a concurrent Chung et al., 2002). Aphasic status most often
history of other seizure types. Clinically this con- reflects left frontotemporal or temporoparietal
dition resembles transient global amnesia (TGA), pathology (Grimes & Guberman, 1997), although
but generally responds favourably to standard visual stimuli provoking an occipital lobe seizure
antiepileptic medications such as sodium valproate spreading to the left inferior frontal lobe has been
or carbamazepine (Pritchard et al., 1985; Gallassi reported (Kobayashi et al., 1999), as has a right-
et al., 1992; Kapur, 1993; Zeman et al., 1998). An sided focus (DeToledo et al., 2000). Parasagittal
accelerated loss of new information and impaired lesions confined to the left superior frontal gyrus
remote autobiographical memory has been dem- (supplementary motor area) may be sufficient to
onstrated in TEA patients, but the aetiology of cause the syndrome (Wieshmann et al., 1997). Other
these deficits remains uncertain, possibilities reported causes include non-ketotic hypergly-
including ongoing seizure activity, seizure-induced caemia (Carril et al., 1992), AIDS–toxoplasmosis
medial temporal lobe damage, or subtle ischaemic (Ozkaya et al., 2006), and multiple sclerosis (Trinka
pathology (Manes et al., 2005). et al., 2002; see Section 6.1).
122 The epilepsies
REFERENCES have long been a topic of research interest

(Devinsky, 1995; Vermeulen & Aldenkamp, 1995).
Carril JM, Guijarro C, Portocarrero JS, et al. Speech arrest The vexed questions of the effects of AEDs, par-
as manifestation of seizures in non-ketotic hypergly- ticularly sodium valproate, on the IQ of children
caemia. Lancet 1992; 340: 1227. exposed in utero (Vinten et al., 2005) and during
Chung PW, Seo DW, Kwon JC, Kim H, Na DL. Non- development (Kasteleijn-Nolst Trinité & de Saint-
convulsive status epilepticus presenting as a subacute Martin, 2004) remain highly topical but are not
progressive aphasia. Seizure 2002; 11: 449–54.
discussed here.
DeToledo JC, Minagar A, Lowe MR. Persisting aphasia as
Sedation may be an important factor in adults
the sole manifestation of partial status epilepticus. Clin
receiving AEDs, as judged by increased reaction
Neurol Neurosurg 2000; 102: 144–8.
Grimes DA, Guberman A. De novo aphasic status times and specific deficits in attention and working
epilepticus. Epilepsia 1997; 38: 945–9. memory observed in some, but not all, patients
Kobayashi M, Takayama H, Mihara B, Sugishita M. Partial taking drugs such as phenobarbitone, phenytoin,
seizure with aphasic speech arrest caused by watching a and benzodiazepines. Patients receiving mono-
popular animated TV program. Epilepsia 1999; 40: 652–4. therapy with phenytoin, sodium valproate, or car-
Ozkaya G, Kurne A, Unal S, et al. Aphasic status bamazepine who were tested before and after
epilepticus with periodic lateralized epileptiform dis- changes in drug dosage, either up or down, showed
charges in a bilingual patient as a presenting sign of deficits in cognitive performance in the high serum
AIDS–toxoplasmosis complex. Epilepsy Behav 2006; 9:
level group, especially those receiving phenytoin or
193–6.
sodium valproate, whereas the carbamazepine
Paquier PF, Van Dongen HR, Loonen CB. The Landau–
group showed no change or even a trend towards
Kleffner syndrome or ‘acquired aphasia with convulsive
disorder’: long-term follow-up of six children and a improvement in the high serum level group
review of the recent literature. Arch Neurol 1992; 49: (Thompson & Trimble, 1982, 1983). Volunteers
354–9. receiving phenytoin, carbamazepine, sodium
Rosenbaum DH, Siegel M, Barr WB, Rowan AJ. Epileptic valproate, clonazepam, and clobazam have shown
aphasia. Neurology 1986; 36: 822–5. significant deficits, most marked with phenytoin
Trinka E, Unterberger I, Spiegel M, et al. De novo aphasic and clonazepam. A large study in the USA com-
status epilepticus as presenting symptom of multiple paring efficacy and toxicity of monotherapy with
sclerosis. J Neurol 2002; 249: 782–3. four antiepileptic drugs (phenobarbitone, primi-
Wieshmann UC, Niehaus L, Meierkord H. Ictal speech
done, phenytoin, and carbamazepine) found that,
arrest and parasagittal lesions. Eur Neurol 1997; 38:
when controlling for age, education, and IQ, car-
123–7.
bamazaepine had fewer cognitive effects than the
other drugs (Mattson et al., 1985), confirming pre-
vious smaller studies. However, other studies have
4.4 Antiepileptic drug therapy causing not found a difference between carbamazepine and
cognitive impairment phenytoin when drug levels have been taken into
account (Dodrill & Troupin, 1991). Polypharmacy is
Although reduction in seizure frequency as a con- certainly associated with more severe adverse
sequence of prescribing antiepileptic drugs (AEDs) consequences for cognitive function (Trimble,
may unquestionably improve cognitive function, 1987).
nonetheless AEDs feature in any list of medicines Newer antiepileptic drugs generally have
which may cause cognitive decline or even improved side-effect profiles in comparison with
dementia (Farlow & Hake, 1998; Moore & O’Keefe, previously used medications, but the increased
1999). The cognitive side effects of chronic AED scrutiny to which these medications have been
therapy, to which the elderly are more susceptible, subject has unfortunately shown that they are not
4.5 Treatment of cognitive problems in epilepsy 123
exempt from cognitive side effects (Aldenkamp Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD
et al., 2003). Lamotrigine, probably the most study of effectiveness of carbamazepine, gabapentin,
extensively studied from the cognitive perspective, lamotrigine, oxcarbazepine, or topiramate for the
seems well tolerated (Aldenkamp & Baker, 2001), treatment of partial epilepsy: an unblinded randomised
controlled trial. Lancet 2007a; 369: 1000–15.
and the same is probably true of gabapentin
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD
(Dodrill et al., 1999) and oxcarbazepine. However,
study of effectiveness of valproate, lamotrigine, or
impaired attention, psychomotor slowing, and
topiramate for generalised and unclassifiable epilepsy:
memory deficits have been recorded with topir- an unblinded randomised controlled trial. Lancet 2007b;
amate, which seems more prone to cognitive side 369: 1016–26.
effects than lamotrigine or gabapentin (Martin et al., Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of
1999; Huppertz et al., 2001), although this may be topiramate, gabapentin, and lamotrigine in healthy
related to rapid drug titration in some studies. young adults. Neurology 1999; 52: 321–7.
Pragmatic comparative drug trials have shown that Mattson RH, Cramer JA, Collins JF, et al. Comparison of
memory disturbance is a common symptom and carbamazepine, phenobarbital, phenytoin and primi-
one of the most common adverse effects to result in done in partial and secondarily generalized tonic-clonic
seizures. N Engl J Med 1985; 313: 145–51.
treatment failure; this may be particularly the case
Moore AR, O’Keefe ST. Drug-induced cognitive impair-
with topiramate (Marson et al., 2007a, b). Currently
ment in the elderly. Drugs Aging 1999; 15: 15–28.
there are few studies evaluating cognitive side
Thompson PJ, Trimble MR. Anticonvulsant drugs and
effects of vigabatrin, levetiracetam, tiagabine, and cognitive functions. Epilepsia 1982; 23: 531–44.
zonisamide (Aldenkamp et al., 2003). Thompson PJ, Trimble MR. Anticonvulsant serum levels:
relationship to impairments of cognitive functioning.
REFERENCES Trimble MR. Anticonvulsant drugs and cognitive function:
a review of the literature. Epilepsia 1987; 28 (suppl 3):
Aldenkamp AP, Baker G. A systematic review of the effects 37–45.
of lamotrigine on cognitive function and quality of life. Vermeulen J, Aldenkamp AP. Cognitive side-effects of
Epilepsy Behav 2001; 2: 85–91. chronic antiepileptic drug treatment: a review of 25
Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic years of research. Epilepsy Res 1995; 22: 65–95.
drugs and cognitive issues. Epilepsia 2003; 44 (suppl): Vinten J, Adab N, Kini U, et al. Neuropsychological effects
21–9. of exposure to anticonvulsant medication in utero.
Devinsky O. Cognitive and behavioral effects of antiepi- Neurology 2005; 64: 949–54.
leptic drugs. Epilepsia 1995; 36 (suppl 2): 46–65.
Dodrill CB, Arnett JL, Hayes AG, et al. Cognitive abilities
and adjustment with gabapentin: results of multi-site 4.5 Treatment of cognitive problems in
study. Epilepsy Res 1999; 35: 109–21. epilepsy
Dodrill CB, Troupin AS. Neuropsychological effects of
carbamazepine and phenytoin: a reanalysis. Neurology Treatment of cognitive complaints needs to be
1991; 41: 141–3. individualized to each patient with epilepsy, but
Farlow MR, Hake AM. Drug-induced cognitive impair-
some general guidelines may be enunciated. Opti-
ment. In: Biller J (ed.), Iatrogenic Neurology. Boston:
mizing seizure control with AEDs that have a good
Butterworth-Heinemann, 1998: 203–14.
side-effect profile as far as cognitive function is
Huppertz HJ, Quiske A, Schulze Bonhage A. Cognitive
impairments due to add-on therapy with topiramate [in concerned, and avoiding polypharmacy, is para-
German]. Nervenarzt 2001; 72: 275–80. mount. Treating confounding factors such as
Kasteleijn-Nolst Trinité DGA, de Saint-Martin A. Cognitive depression and sleep disorders is mandatory.
aspects. In: Wallace SJ, Farrell K (eds.), Epilepsy in However, it must be recognized that the underlying
Children (2nd edition). London: Arnold, 2004: 433–46. aetiology of seizures is often a major contributing
124 The epilepsies
factor, and one that may not be amenable to spe- REFERENCES

cific treatment. Whether cognitive enhancers such
as cholinesterase inhibitors have anything to offer Fisher RS, Bortz JJ, Blum DE, Duncan B, Burke H. A pilot
in this circumstance requires further study (Fisher study of donepezil for memory problems in epilepsy.
et al., 2001). Epilepsy Behav 2001; 2: 330–4.
5
Neurogenetic disorders
5.1 Hereditary dementias 126

5.1.1 Huntington’s disease (HD) 126
5.1.2 Dentatorubropallidoluysian atrophy (DRPLA) 130
5.1.3 Familial British dementia (FBD) 131
5.1.4 Familial Danish dementia (FDD) 131
5.1.5 Familial encephalopathy with neuroserpin inclusion bodies (FENIB) 132
5.1.6 Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL),
Nasu–Hakola disease, presenile dementia with bone cysts 132
5.1.7 Fahr’s syndrome (striatopallidal calcification) 133
5.1.8 Inclusion body myopathy associated with Paget’s disease of bone and
frontotemporal dementia (IBMPFD) 133
5.1.9 Kufor–Rakeb syndrome (PARK9) 134
5.1.10 Urbach–Wiethe disease (lipoid proteinosis) 134
5.1.11 Fragile X syndrome (FRAX), fragile X tremor/ataxia syndrome (FXTAS) 135
5.2 Hereditary ataxias 135
5.2.1 Autosomal dominant hereditary ataxias, spinocerebellar ataxias (SCA) 136
5.2.2 Autosomal recessive hereditary ataxias 138
5.3 Hereditary spastic paraplegia 140
5.3.1 SPG4 140
5.3.2 SPG21, mast syndrome 141
5.4 Hereditary movement disorders 141
5.4.1 Wilson’s disease (hepatolenticular degeneration) 141
5.4.2 Neurodegeneration with brain accumulation of iron-1 (NBAI-1),
Hallervorden–Spatz disease 142
5.4.3 Neuroacanthocytosis 143
5.4.4 Neuroferritinopathy 144
5.4.5 Acaeruloplasminaemia 144
5.4.6 Essential tremor (ET) 145
5.4.7 Restless legs syndrome (RLS) 146
5.4.8 Tourette syndrome (TS), obsessive-compulsive disorder (OCD) 146
5.5 Hereditary metabolic disorders 146
5.5.1 Mitochondrial disorders 146
5.5.2 Leukodystrophies 147
5.5.3 Lysosomal storage disorders 151
5.5.4 Cerebrotendinous xanthomatosis (CTX) 153
5.5.5 Haemochromatosis 153
5.5.6 Lafora body disease 154
5.5.7 Polyglucosan body disease 154
125
126 Neurogenetic disorders
5.5.8 Porphyria 155

5.5.9 Unverricht–Lundborg disease (Baltic myoclonus) 155
5.6 Hereditary neurocutaneous syndromes (phakomatoses) 155
5.6.1 Neurofibromatosis 156
5.6.2 Tuberous sclerosis 156
Although great advances have been made in progressive impairment of the mind (Huntington,
elucidating the genetic basis of neurological dis- 1872). Cognition is one of the four characteristics,
orders in recent years, with profound implications along with motor function, behaviour, and func-
not only for diagnosis but also for beginning to tional abilities, assessed by the Unified Huntington’s
understand disease pathogenesis, nonetheless a Disease Rating Scale (UHDRS), which has now
clinical rather than a pathogenetic classification of become the universal scale for measuring HD func-
disorders is used here, in part because the patho- tion (Huntington’s Study Group, 1996).
genetic pathway from mutant gene to disease Collaborative studies have shown that HD results
phenotype remains uncertain in many instances. from a trinucleotide (CAG, polyglutamine, polyQ)
repeat expansion on the IT15 gene on chromosome
4 encoding the huntingtin protein (Huntington’s
5.1 Hereditary dementias Disease Collaborative Research Group, 1993). A
significant inverse relationship exists between
Under this rubric, dementia syndromes with con- CAG repeat length and age at clinical onset. Clin-
firmed genetic basis, with or without additional ical phenotype also varies with age of onset:
neurological features, are included. Autosomal juvenile disease (Westphal variant) has a promin-
dominant Alzheimer’s disease (see Section 2.1), ent parkinsonian syndrome, whereas very late-
frontotemporal dementia with parkinsonism linked onset disease may be associated with chorea and
to chromosome 17 (FTDP-17: Section 2.2.4) and little intellectual impairment. Neuropathologically,
hereditary forms of prion disease (Section 2.5.3) are there is a loss of medium spiny neurones and
discussed elsewhere, as are other genetic disorders gliosis in the caudate nucleus and putamen,
which may result in dementia such as CADASIL resulting in shrinkage of the caudate, which may be
(Section 3.6.2) and some of the hereditary cerebral observed on structural brain imaging, as well as
amyloid angiopathies (Section 3.6.3). degenerative change in the cortex and hippocam-
pus. Intranuclear inclusions immunopositive for
huntingtin and ubiquitin are found (Vonsattel &
5.1.1 Huntington’s disease (HD)
Lianski, 2004). The availability of a diagnostic
The archetypal hereditary dementia is Huntington’s neurogenetic test has made possible the detection
disease (HD), although a number of the common of presymptomatic cases in at-risk family mem-
neurodegenerative dementias may sometimes be bers. HD phenocopies, without trinucleotide repeat
inherited in an autosomal dominant manner (see in the huntingtin gene, do occur (Rosenblatt
Chapter 2). In his description of the disorder that et al., 1998). These cases may have insertions in
now bears his name, George Huntington not only the prion protein (PRNP) gene, or expansions in
delineated the movement disorder, most usually the genes encoding junctophilin-3 (JPH3) or
chorea (cortical myoclonus and parkinsonism may TATA binding protein gene (TBP), the latter
also occur), the neuropsychiatric features, and the allelic with spinocerebellar ataxia type 17 (Stevanin
mode of inheritance, but also alluded to the gradually et al., 2003). As yet, no curative treatment is
Table 5.1. Neuropsychological deficits in Huntington’s disease (HD).
Attention # divided, sustained attention; working memory

Memory ‘Subcortical pattern’: impaired encoding and retrieval, recognition better than recall;
impaired skill learning
Language Letter fluency worse than category fluency
Perception Visuoperceptual problems: defects in judging distance, spatial relationships
Praxis Ideomotor apraxia
Executive function Dysexecutive syndrome (impaired Stroop, Wisconsin Card Sorting); may contribute to
many of the neuropsychological deficits observed
available for HD, and symptomatic treatments are detected in low-level psychomotor tasks, object
limited in their effect. The natural history is one of recall, and verbal fluency, whereas executive
relentless progression (Kosinski & Landwehrmeyer, function (WCST) remained stable (Snowden et al.,
2005). 2001).
The cognitive disorder of HD has been exten-
sively investigated (Craufurd & Snowden, 2003;
Paulsen & Conybeare, 2005). Following the char-
acterization of ‘subcortical dementia’ in progres- The neuropsychological deficits typically seen in
sive supranuclear palsy (Albert et al., 1974; Section Huntington’s disease are summarized in Table 5.1.
2.4.2), the core deficits in HD have also been
labelled as subcortical (McHugh & Folstein, 1975) Attention
and subsequent investigations have confirmed a Impairments in attentional functions in HD are
pattern of deficits distinct from that in AD. Using attested to by poor performance on WAIS subtests
the MMSE, HD patients perform more poorly than such as Digit Span and Digit Symbol which probe
Alzheimer’s disease patients on the attention item attention and working memory. Shifting of atten-
(serial sevens) but better on the orientation in time tion to new information may be particularly
and memory items (Brandt et al., 1988). Likewise, impaired, whereas attention to previously learned
HD patients administered the Dementia Rating information is maintained with perseveration on
Scale show more impairment on the initiation/ previously correct responses (Lawrence et al.,
perseveration subtest and less impairment on the 1996). This may be reflected in the clinical obser-
memory subtest than AD patients (Rosser & vation that HD patients perform worse when
Hodges, 1994a). Reviewing a large number of required to divide attention between tasks or
studies of HD patients, Zakzanis (1998) reported stimuli. Selective and progressive attentional and
deficits in memory acquisition and delayed recall, executive dysfunctions are features of early HD (Ho
cognitive flexibility, abstraction, attention, and et al., 2003), and assessment of attentional tasks
concentration. It may be that a dysexecutive syn- may be used to monitor progression of disease
drome accounts for the poor performance in (Lemiere et al., 2004).
many areas, reflective of pathological involvement
of the basal ganglia and frontostriatal connec- Memory
tions. The natural history of cognitive function is Learning and memory difficulties are a common
one of decline, but the rate is variable, as are the complaint of HD patients and their relatives. There is
different domains affected. In one longitudinal a problem with encoding and retrieval, since verbal
study, over a 1-year period significant decline was recognition memory is preserved relative to recall
(Butters et al., 1986). This may relate to inefficient Perception

encoding strategies, reflective of executive dys- Visuospatial disorder may be evident on object
function. Retention of information over a delay assembly and block design tasks and tests of
period is relatively intact, hence there is no pattern and spatial recognition memory, but again
abnormal forgetting (Massman et al., 1990), and these deficits may reflect problems with other
on remote memory tests there is no temporal processes such as planning (Lawrence et al., 2000).
gradient. Compared to AD patients, HD patients A defect in the perception of personal (egocentric)
matched for overall level of dementia had less space has been consistently documented, with
impairment of delayed verbal and figural episodic difficulty judging distances and spatial relationship
memory but were worse on letter fluency, to other objects (Brouwers et al., 1984), the clinical
suggesting a double dissociation of semantic correlate of which is a tendency to bump into
and episodic memory impairment (Hodges et al., things; it may also contribute to falls. Visuospatial
1990). Semantic memory and delayed recall memory may be impaired early in HD (Lawrence
memory are relatively unaffected in early HD et al., 1996).
(Rohrer et al., 1999; Ho et al., 2003) but visuo-
spatial memory may be impaired (Lawrence et al., Praxis
1996). Although the assessment of praxis may be difficult
Implicit memory as tested by skill learning is in the context of the motor disorder of HD, none-
impaired, indicating a role for the basal ganglia in theless occasional studies have been undertaken.
such learning processes, particularly ‘open-loop’ Shelton and Knopman (1991) found ideomotor
skills, a finding which may possibly be related to apraxia to be common in a small cohort of patients
working memory deficits. with long-standing disease (mean duration > 10
years), particularly for imitation of non-symbolic
Language movements, whereas recognition of gestures was
Naming errors in HD seem to be largely visually preserved. These changes were thought to be pri-
based, reflecting disrupted perceptual analysis, marily subcortical in origin. Hamilton et al. (2003),
whilst phonemic processes remain relatively intact however, found apraxia to be more common
(Hodges et al., 1991). This contrasts with the in patients with greater neurological involvement
semantic breakdown observed in AD, and is cor- and longer disease duration, suggesting that
roborated by verbal fluency tests showing greater apraxia resulted from damage to corticostriate
impairment in letter fluency rather than semantic pathways rather than restricted basal ganglia
fluency in HD even early in the disease (Hodges involvement as in early disease, which fits better
et al., 1990; Randolph et al., 1993; Rosser & Hodges, with the notion of apraxia as a feature of cortical
1994b), presumably related to frontostriatal dys- dementias.
function. Late deficits in confrontation naming are
more likely due to visuoperceptual deficits and Executive function
retrieval slowing rather than a disintegration of Progressive impairment in executive function is
semantic knowledge (Rohrer et al., 1999). found in early HD (Lawrence et al., 1996; Ho et al.,
The motor disorder of HD may affect phonation, 2003) and is associated with bilateral striatal
speech output becoming increasingly limited as (caudate) and extrastriatal (insular) atrophy
the disease progresses. Apathy and psychomotor (Peinemann et al., 2005). Typical of patients with
slowing may also contribute to this loss of speech. executive deficits, verbal fluency tests show poor
There may also be impaired comprehension of category fluency but worse letter fluency, the
affective and propositional speech prosody (Speedie reverse of the pattern seen in AD (Rosser & Hodges,
et al., 1990). 1994b), plus impairments on the Stroop Test and
the WCST (Lemiere et al., 2004). This dysexecutive

REFERENCES
syndrome may account for many of the cognitive
impairments documented in HD, caused by striatal
Albert ML, Feldman RG, Willis AL. The ‘subcortical
and corticostriatal involvement. Assessment of
dementia’ of progressive supranuclear palsy. J Neurol
executive functions may be used to monitor pro-
gression of disease (Lemiere et al., 2004). Brandt J, Folstein SE, Folstein MF. Differential cognitive
impairment in Alzheimer’s disease and Huntington’s
Presymptomatic gene mutation carriers disease. Ann Neurol 1988; 23: 555–61.
Testing of presymptomatic carriers of the HD gene Brouwers P, Cox C, Martin A, Chase T, Fedio P. Differen-
mutation has become possible with the characteri- tial perceptual–spatial impairment in Huntington’s and
zation of the CAG trinucleotide repeat mutation on Alzheimer’s dementia. Arch Neurol 1984; 41: 1073–6.
chromosome 4 (Huntington’s Disease Collabora- Butters N, Wolfe J, Granholm E, Martone M. An assessment
tive Research Group, 1993), prior studies having of verbal recall, recognition, and fluency abilities in
patients with Huntington’s disease. Cortex 1986; 22: 11–32.
relied on linkage. Campodonico et al. (1996) found
Campodonico JR, Codori AM, Brandt J. Neuropsycho-
stability in neuropsychological tests over a 2-year
logical stability over two years in asymptomatic carriers
period in asymptomatic carriers, with a suggestion
of the Huntington’s disease mutation. J Neurol Neuro-
that patients nearing clinical onset showed def- surg Psychiatry 1996; 61: 621–4.
icits in sustained attention and mental processing Craufurd D, Snowden JS. Neuropsychological and neu-
speed. A larger study found that whereas some ropsychiatric aspects of Huntington’s disease. In: Bates
carriers were cognitively no different from con- G, Harper PS, Jones L (eds.), Huntington’s Disease (3rd
trols, others had poorer performance on learning edition). Oxford: Oxford University Press, 2003: 62–94.
and memory tests, significantly associated with Hahn-Barma V, Deweer B, Dürr A, et al. Are cognitive
CAG repeat length, suggesting that cognitive def- changes the first symptoms of Huntington’s disease? A
icits may be an early, subclinical, manifestation of study of gene carriers. J Neurol Neurosurg Psychiatry
1998; 64: 172–7.
disease (Hahn-Barma et al., 1998). These preclin-
Hamilton JM, Haaland KY, Adair JC, Brandt J. Ideomotor limb
ical deficits were suggested to be highly specific by
apraxia in Huntington’s disease: implications for corti-
Lawrence et al. (1998) for attentional set shifting
costriate involvement. Neuropsychologia 2003; 41: 614–21.
and semantic verbal fluency, reflecting impaired Ho AK, Sahakian BJ, Brown RG, et al. Profile of cognitive
striatofrontal mechanisms. In another study, car- progression in early Huntington’s disease. Neurology
riers performed worse on digit symbol, picture 2003; 61: 1702–6.
arrangement and arithmetic tests and also showed Hodges JR, Salmon DP, Butters N. Differential impairment
mild impairment on reaction time tasks (Kirk- of semantic and episodic memory in Alzheimer’s and
wood et al., 2000). A prospective study of genet- Huntington’s diseases: a controlled prospective study.
ically defined disease carriers found impairments J Neurol Neurosurg Psychiatry 1990; 53: 1089–95.
in attentional, visuoperceptual, and executive Hodges JR, Salmon DP, Butters N. The nature of the
naming deficit in Alzheimer’s and Huntington’s disease.
functions compared to controls (Lemiere et al.,
Brain 1991; 114: 1547–58.
2004). Clearly these observations of presympto-
Huntington G. On chorea. Med Surg Rep 1872; 26: 317–21.
matic carriers have implications for preventative
Huntington’s Disease Collaborative Research Group. A
therapeutic strategies and monitoring of efficacy novel gene containing a trinucleotide repeat that is
of therapeutic measures. Nonetheless, despite expanded and unstable on Huntington’s disease
these findings, it remains the case that in clinical chromosomes. Cell 1993; 72: 971–83.
practice HD almost invariably presents as a Huntington’s Study Group. Unified Huntington’s Disease
consequence of movement disorder rather than Rating Scale: reliability and consistency. Mov Disord
because of cognitive decline (Larner, 2008). 1996; 11: 136–42.
Kirkwood SC, Siemers E, Hodes ME, et al. Subtle changes disease on semantic memory. Neuropsychology 1999;
among presymptomatic carriers of the Huntington’s 13: 381–8.
disease gene. J Neurol Neurosurg Psychiatry 2000; 69: Rosenblatt A, Ranen NG, Rubinsztein DG, et al. Patients
773–9. with features similar to Huntington’s disease, without
Kosinski CM, Landwehrmeyer B. Huntington’s disease. CAG expansion in huntingtin. Neurology 1998; 51:
In: Beal MF, Lang AE, Ludolph A (eds.), Neurodegen- 215–20.
erative Diseases: Neurobiology, Pathogenesis and Rosser AE, Hodges JR. The Dementia Rating Scale in
Therapeutics. Cambridge: Cambridge University Press, Alzheimer’s disease, Huntington’s disease and progres-
2005: 847–60. sive supranuclear palsy. J Neurol 1994a; 241: 531–6.
Larner AJ. Monogenic Mendelian disorders in general Rosser AE, Hodges JR. Initial letter and semantic category
neurological practice. Int J Clin Pract 2008; 62: in press. fluency in Alzheimer’s disease, Huntington’s disease
Lawrence AD, Hodges JR, Rosser AE, et al. Evidence for and progressive supranuclear palsy. J Neurol Neurosurg
specific cognitive deficits in preclinical Huntington’s Psychiatry 1994b; 57: 1389–94.
disease. Brain 1998; 121: 1329–41. Shelton PA, Knopman DS. Ideomotor apraxia in
Lawrence AD, Sahakian BJ, Hodges JR, et al. Executive and Huntington’s disease. Arch Neurol 1991; 48: 35–41.
mnemonic functions in early Huntington’s disease. Snowden J, Craufurd D, Griffiths H, Thompson J, Neary D.
Brain 1996; 119: 1633–45. Longitudinal evaluation of cognitive disorder in
Lawrence AD, Watkins LH, Sahakian BJ, et al. Visual object Huntington’s disease. J Int Neuropsychol Soc 2001; 7:
and visuospatial cognition in Huntington’s disease: 33–44.
implications for information processing in corticostria- Speedie LJ, Brake N, Folstein SE, Bowers D, Heilman KM.
tal circuits. Brain 2000; 123: 1349–64. Comprehension of prosody in Huntington’s disease.
Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vanden- J Neurol Neurosurg Psychiatry 1990; 53: 607–10.
bussche E, Dom R. Cognitive changes in patients with Stevanin G, Fujigasaki H, Lebre AS, et al. Huntington’s
Huntington’s disease (HD) and asymptomatic carriers disease like phenotype due to trinucleotide repeat
of the HD mutation: a longitudinal follow-up study. expansions in the TBP and JPH3 genes. Brain 2003;
J Neurol 2004; 251: 935–42. 126: 1599–603.
McHugh PR, Folstein MF. Psychiatric symptoms of Vonsattel JPG, Lianski M. Huntington’s disease. In: Esiri
Huntington’s chorea: a clinical and phenomenological MM, Lee VMY, Trojanowski JQ (eds.), The Neuropath-
study. In: Benson DF, Blumer D (eds.), Psychiatric ology of Dementia (2nd edition). Cambridge: Cambridge
Aspects of Neurological Disease. New York: Raven Press, University Press, 2004: 376–401.
1975: 267–85. Zakzanis KK. The subcortical dementia of Huntington’s
Massman PJ, Delis DC, Butters N, Levin BE, Salmon DP. disease. J Clin Exp Neuropsychol 1998; 20: 565–78.
Are all subcortical dementias alike? Verbal learning and
memory in Parkinson’s and Huntington’s disease
5.1.2 Dentatorubropallidoluysian atrophy
patients. J Clin Exp Neuropsychol 1990; 12: 729–44.
(DRPLA)
Paulsen JS, Conybeare RA. Cognitive changes in Hunting-
ton’s disease. Adv Neurol 2005; 96: 209–25. This autosomal dominant trinucleotide repeat
Peinemann A, Schuller S, Pohl C, et al. Executive disorder due to a CAG (polyglutamine) expansion
dysfunction in early stages of Huntington’s disease is in the gene encoding atrophin-1 on chromosome
associated with striatal and insular atrophy: a neuro-
12p13.31 often has a clinical presentation identical
psychological and voxel-based morphometric study.
to Huntington’s disease, with movement disorders
J Neurol Sci 2005; 239: 11–19.
including chorea, dystonia, myoclonus, and par-
Randolph C, Braun AR, Goldberg TE, Chase T. Semantic
fluency in Alzheimer’s, Parkinson’s, Huntington’s kinsonism, as well as cerebellar ataxia, psychosis,
disease: dissociation of storage and retrieval failures. and epilepsy; the latter may be commoner than in
Neuropsychology 1993; 7: 82–8. HD. Likewise, cognitive dysfunction similar to that
Rohrer D, Salmon DP, Wixted JT, Paulsen JS. The disparate in HD is seen, including slowed thinking, difficulty
effects of Alzheimer’s disease and Huntington’s retrieving information and in sequencing tasks,
progressing to a more severe dementia (Ross et al., patients thought to be affected clinically (with
2005), in other words a subcortical pattern of def- limb/gait ataxia, mild spastic paraparesis).
icits. Chiefly described in reports from Japan, Impairment of delayed recognition and, particu-
DRPLA has also been seen in European and North larly, recall memory was found, with additional
American families, in which clinical features are impairments in delayed visual recall in some
noted to be diverse even within individual families patients. General intelligence, naming, frontal lobe
(Warner et al., 1995). functions, and perception were preserved. These
changes were associated with deep white matter
hyperintensities and lacunar infarcts on MR brain
REFERENCES imaging (Mead et al., 2000).
Ross CA, Ellerby LM, Wood JD, Nucifora FC Jr. Denta-

torubral-pallidoluysian atrophy (DRPLA): model for REFERENCES
Huntington’s disease and other polyglutamine dis-
eases. In: Beal MF, Lang AE, Ludolph A (eds.), Neuro-
Mead S, James-Galton M, Revesz T, et al. Familial British
degenerative Diseases: Neurobiology, Pathogenesis
dementia with amyloid angiopathy: early clinical,
and Therapeutics. Cambridge: Cambridge University
neuropsychological and imaging findings. Brain 2000;
Press, 2005: 861–70.
123: 975–91.
Warner TT, Williams LD, Walker RW, et al. A clinical and
Plant GT, Ghiso J, Holton JL, Frangione B, Revesz T.
molecular genetic study of dentatorubropallidoluysian
Familial and sporadic cerebral amyloid angiopathies
atrophy in four European families. Ann Neurol 1995; 37:
associated with dementia and the BRI dementias. In:
452–9.
Esiri MM, Lee VMY, Trojanowski JQ (eds.), The Neuro-
pathology of Dementia (2nd edition). Cambridge: Cam-
5.1.3 Familial British dementia (FBD) bridge University Press, 2004: 330–52.
Vidal R, Frangione B, Rostagno A, et al. A stop-codon
Familial British dementia, previously known as mutation in the BRI gene associated with familial
Worster-Drought syndrome, is an autosomal British dementia. Nature 1999; 399: 776–81.
dominant progressive dementia syndrome with Worster-Drought C, Hill TR, McMenemey WH. Familial
associated cerebellar ataxia and spastic paraparesis presenile dementia with spastic paralysis. J Neurol
with pathological evidence of deposition of cere- Psychopathol 1933; 14: 27–34.
brovascular amyloid distinct from that observed in
Alzheimer’s disease (Worster-Drought et al., 1933; 5.1.4 Familial Danish dementia (FDD)
Plant et al., 2004). It results from a mutation in the
BRI gene on the long arm of chromosome 13, in Originally known as heredopathia ophthalmo-
which substitution in a stop codon increases the oto-encephalica, this autosomal dominant disorder
open reading frame, resulting in the production of is characterized by cataracts and ocular haemor-
an amyloidogenic C-terminal peptide, A-Bri (Vidal rhages around the age of 30 years, impaired hear-
et al., 1999). This condition is sometimes classified ing and hearing loss in the 40s or 50s, cerebellar
with the cerebral amyloid angiopathies (see Section ataxia in the 40s, and paranoid psychosis and
3.6.3). dementia in the 50s. Once the neurological disease
Memory impairment early in the course of the is established, clinical manifestations are similar to
disease is marked, ultimately progressing to global those of familial British dementia (Plant et al.,
dementia. Personality change, either irritability or 2004). It results from mutation of the BRI gene with
depression, may also be an early manifestation a 10-nucleotide duplication resulting in an out-of-
(Plant et al., 2004). In a study of patients at risk, frame stop codon giving rise to an extended pre-
cognitive problems were identified in some cursor protein with an amyloidogenic C-peptide,
A-Dan (Vidal et al., 2000), which is found in the showed frontal or frontal-subcortical impairment
amyloid deposits in the brain (Holton et al., 2002). in mildly to moderately affected individuals, with
Like FBD, it may be classified with the cerebral impaired attention, concentration, and response
amyloid angiopathies (Section 3.6.3). Detailed regulation functions, whilst recall memory was
accounts of the neuropsychological profile in this not as affected as other cognitive domains. A more
condition have not been identified. global pattern of impairment was seen in more
severely affected individuals. This pattern was
corroborated by SPECT imaging studies which
REFERENCES showed exclusively frontal anomalies in the less
affected patients, with more global but patchy
Holton JL, Lashley T, Ghiso J, et al. Familial Danish hypoperfusion in those more severely affected
dementia: a novel form of cerebral amyloidosis associated (Bradshaw et al., 2001).
with deposition of both amyloid-Dan and amyloid-b.
J Neuropathol Exp Neurol 2002; 61: 254–67.
Plant GT, Ghiso J, Holton JL, Frangione B, Revesz T. REFERENCES
Familial and sporadic cerebral amyloid angiopathies
associated with dementia and the BRI dementias. In:
Bradshaw CB, Davis RL, Shrimpton AE, et al. Cognitive
Esiri MM, Lee VMY, Trojanowski JQ (eds.), The Neuro-
deficits associated with a recently reported familial
pathology of Dementia (2nd edition). Cambridge:
neurodegenerative disease: familial encephalopathy
Cambridge University Press, 2004: 330–52.
with neuroserpin inclusion bodies. Arch Neurol 2001;
Vidal R, Revesz T, Rostagno A, et al. A decamer
58: 1429–34.
duplication in the 30 region of the BRI gene originates
Davis RL, Shrimpton AE, Carrell RW, et al. Association
an amyloid peptide that is associated with dementia in
between conformational mutations in neuroserpin and
a Danish kindred. Proc Natl Acad Sci USA 2000; 97:
onset and severity of dementia. Lancet 2002; 359: 2242–7.
4920–5.
Davis RL, Shrimpton AE, Holohan PD, et al. Familial
dementia caused by polymerization of mutant neuro-
serpin. Nature 1999; 401: 376–9.
5.1.5 Familial encephalopathy with
neuroserpin inclusion bodies (FENIB) 5.1.6 Polycystic lipomembranous
This rare autosomal dominant disorder is one of osteodysplasia with sclerosing
the serpinopathies linked to a point mutation in leukoencephalopathy (PLOSL),
the gene on chromosome 3 encoding neuroserpin, Nasu–Hakola disease, presenile dementia
a serine proteinase inhibitor, the mutant protein with bone cysts
undergoing polymerization. FENIB is characterized This autosomal recessive disorder, described in both
pathologically by cytoplasmic neuroserpin inclu- Japan and Finland, is characterized by large-scale
sions (Collins bodies) within the deep cortical destruction of cancellous bone resulting in bone
layers, substantia nigra, and subcortical nuclei. cysts in the third decade of life, causing pain,
Clinical phenotype is determined by genotype: swelling, and sometimes fracture of the wrists and
neuroserpin mutations causing greater conforma- ankles; and presenile dementia in the fourth decade,
tional change (G392E) cause early-onset progres- sometimes with epileptic seizures. MR brain
sive myoclonus epilepsy, whereas lesser degrees of imaging reveals frontal myelin loss and massive
conformational change (S49P) cause dementia in gliosis (‘sclerosing leukoencephalopathy’) as well
the fifth decade (Davis et al., 1999, 2002). as basal ganglia calcification. The condition is gen-
Neuropsychological assessment of patients with etically heterogeneous, with mutations being
the S49P mutation in the neuroserpin gene identified in the DAP12 gene on chromosome 19q13.1
(deletions, point mutations, and single-base dele- dentate nucleus, and deeper cortical layers, which
tions) in some families (Paloneva et al., 2001; Kondo may be asymptomatic or associated with any
et al., 2002), and in the TREM2 gene (Klünemann et al., combination of dementia, seizures, movement
2005), both encoding different subunits of a multi- disorder (parkinsonism, dystonia, tremor, ataxia),
subunit receptor complex, resulting in an identical with or without endocrine parathyroid disorder of
phenotype (Bianchin et al., 2004). calcium metabolism. The familial idiopathic
The cognitive impairment may be of frontal lobe syndrome seems to be often associated with
type, sometimes without preceding osseous intellectual decline, with impairment of recent
symptoms (Paloneva et al., 2001). Healthy subjects memory and memory retention, as well as par-
heterozygous for a TREM2 mutation have been kinsonism and cerebellar ataxia (Kobari et al.,
reported with a deficit of visuospatial memory, 1997). Cases of Fahr’s syndrome presenting with
with basal ganglia hypoperfusion on functional subacute dementia and without a movement dis-
neuroimaging (SPECT), not seen in homozygotes order have been reported (Benke et al., 2004;
for the wild-type allele (Montalbetti et al., 2005). Modrego et al., 2005), characterized in one case by
executive deficits, anterograde amnesia, atten-
tional impairment, and neuropsychiatric features,
REFERENCES with the functional imaging correlate of reduced
glucose metabolism in the basal ganglia and
Bianchin MM, Capella HM, Chaves DL, et al. Nasu– frontal lobes (Benke et al., 2004). One wonders
Hakola disease (polycystic lipomembranous osteodys- if there might be overlap here with polycystic
plasia with sclerosing leukoencephalopathy – PLOSL): a lipomembranous osteodysplasia with sclerosing
dementia associated with bone cystic lesions. From leukoencephalopathy (Nasu–Hakola disease), a
clinical to genetic and molecular aspects. Cell Mol condition characterized by presenile dementia
Neurobiol 2004; 24: 1–24. with basal ganglia calcification.
Klünemann HH, Ridha BH, Magy L, et al. The genetic
causes of basal ganglia calcification, dementia, and
bone cysts: DAP12 and TREM2. Neurology 2005; 64:
1502–7. REFERENCES
Kondo T, Takahashi K, Kohara N, et al. Heterogeneity of
presenile dementia with bone cysts (Nasu–Hakola Benke T, Karner S, Seppi K, et al. Subacute dementia and
disease): three genetic forms. Neurology 2002; 59: imaging correlates in a case of Fahr’s disease. J Neurol
1105–7. Neurosurg Psychiatry 2004; 75: 1163–5.
Montalbetti L, Ratti MT, Greco B, et al. Neuropsychological Kobari M, Nogawa S, Sugimoto Y, Fukuuchi Y. Familial
tests and functional nuclear neuroimaging provide idiopathic brain calcification with autosomal dominant
evidence of subclinical impairment in Nasu–Hakola inheritance. Neurology 1997; 48: 645–9.
disease heterozygotes. Funct Neurol 2005; 20: 71–5. Modrego PJ, Mojonero J, Serrano M, Fayed N. Fahr’s
Paloneva J, Autti T, Raininko R, et al. CNS manifestations syndrome presenting with pure and progressive pre-
of Nasu–Hakola disease: a frontal dementia with bone senile dementia. Neurol Sci 2005; 26: 367–9.
cysts. Neurology 2001; 56: 1552–8.
5.1.8 Inclusion body myopathy associated

5.1.7 Fahr’s syndrome (striatopallidal with Paget’s disease of bone and
calcification) frontotemporal dementia (IBMPFD)
This rubric encompasses a heterogeneous group of This rare autosomal dominant disorder maps to
conditions, both familial and sporadic, variably chromosome 9p21.1–p12 and results from muta-
characterized by calcification of the basal ganglia, tions in the gene encoding valosin-containing
protein (VCP), a member of the AAA-ATPase REFERENCES

superfamily, which has many roles in cellular
metabolism including the ubiquitin–proteasome Al-Din NAS, Wriekat A, Mubaidin A, Dasouki M, Hiari M.
pathway (Watts et al., 2004; Haubenberger et al., Pallido-pyramidal degeneration, supranuclear upgaze
2005; Kimonis & Watts, 2005; Schröder et al., 2005). paresis and dementia: Kufor–Rakeb syndrome. Acta
The clinical findings are heterogeneous, with 90% Neurol Scand 1994; 89: 347–52.
of cases having myopathy, 40% Paget’s disease Davidson C. Pallido-pyramidal disease. J Neuropathol Exp
Neurol 1954; 13: 50–9.
of bone, and 30% dementia of frontotemporal
Ramirez A, Heimbach A, Gründemann J, et al. Hereditary
type. Intrafamilial heterogeneity has been noted.
parkinsonism with dementia is caused by mutations in
The neuropathology of the dementia is character-
ATP13A2, encoding a lysosomal type 5 P-type ATPase.
ized by the presence of neuronal inclusions con- Nat Genet 2006; 38: 1184–91.
taining both ubiquitin and VCP (Schröder et al.,
2005).
5.1.10 Urbach–Wiethe disease (lipoid
proteinosis)
REFERENCES
This rare autosomal recessive condition is charac-
Haubenberger D, Bittner RE, Rauch SS, et al. Inclusion terized by bilateral calcification of the anterior
body myopathy and Paget disease is linked to a novel medial temporal lobe, especially the amygdala, but
mutation in the VCP gene. Neurology 2005; 65: 1304–5. with sparing of the hippocampus. It has permitted
Kimonis VE, Watts GDJ. Autosomal dominant inclusion an analysis of the contribution of the amygdala to
body myopathy, Paget disease of bone, and frontotem-
cognitive function. Clinical studies suggest
poral dementia. Alzheimer Dis Assoc Disord 2005; 19
impaired learning and recall of odour–figure asso-
(suppl 1): S44–7.
ciations but no amnesia as such (Markowitsch
Schröder R, Watts GDJ, Mehta SG, et al. Mutant valosin-
containing protein causes a novel type of frontotem-
et al., 1994), and also impairments in emotional
poral dementia. Ann Neurol 2005; 57: 457–61. judgment and memory (Siebert et al., 2003).
Watts GDJ, Wymer J, Kovach MJ, et al. Inclusion body Amygdala damage may also contribute to the
myopathy associated with Paget disease of bone and cognitive sequelae of herpes simplex encephalitis
frontotemporal dementia is caused by mutant valosin- (Caparros-Lefebvre et al., 1996).
containing protein. Nat Genet 2004; 36: 377–81.
5.1.9 Kufor–Rakeb syndrome (PARK9) REFERENCES

Unlike the clinically similar pallido-pyramidal
syndrome (Davidson, 1954), dementia may be a Caparros-Lefebvre D, Girard-Buttoz I, Reboul S, et al.
feature of this very rare autosomal recessive Cognitive and psychiatric impairment in herpes
nigrostriatal-pallido-pyramidal degeneration syn- simplex virus encephalitis suggest involvement of the
amygdalo-frontal pathways. J Neurol 1996; 243:
drome linked to chromosome 1p36 (Al-Din et al.,
248–56.
1994). Detailed description of the dementia was not
Markowitsch HJ, Calabrese P, Würker M, et al. The
given, but considering the topography of disease a
amygdala’s contribution to memory: a study on two
frontal-subcortical pattern might be anticipated. patients with Urbach–Wiethe disease. Neuroreport
The condition has been described as PARK9, 1994; 5: 1349–52.
resulting from mutations in a neuronal P-type Siebert M, Markowitsch HJ, Bartel P. Amygdala, affect and
ATPase gene, ATP13A2, whose product may be cognition: evidence from 10 patients with Urbach–
located in lysosomes (Ramirez et al., 2006). Wiethe disease. Brain 2003; 126: 2627–37.
5.1.11 Fragile X syndrome (FRAX), fragile X REFERENCES

tremor/ataxia syndrome (FXTAS)
Bennetto L, Pennington BF, Porter D, Taylor AK,
Fragile X syndrome (FRAX) is the commonest gen-
Hagerman RJ. Profile of cognitive functioning in
etically determined cause of intellectual disability in
women with the fragile X mutation. Neuropsychology
males (Davies, 1989), resulting from a trinucleotide 2001; 15: 290–9.
(CGG) repeat expansion in the 50 promoter region of Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X
the Fragile Site Mental Retardation 1 (FMR1) gene premutation carriers: characteristic MR imaging find-
located on the X chromosome (Verkerk et al., 1991). ings of adult male patients with progressive cerebellar
The mechanism by which the mutation causes and cognitive dysfunction. AJNR Am J Neuroradiol 2002;
mental retardation, and the normal function of 23: 1757–66.
FMR1, remain unknown. Healthy male patients with Davies KE (ed.). The Fragile X Syndrome. Oxford: Oxford
FRAX showed poorer attention and short-term University Press, 1989.
Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile X-associated
memory function than a comparison group of
tremor/ataxia syndrome (FXTAS) in females with the
Down’s syndrome patients (Schapiro et al., 1995).
FMR1 premutation. Am J Hum Genet 2004; 74: 1051–6.
Women with FRAX are worse than controls on tests
Hall DA, Berry KE, Jacquemont S, et al. Initial diagnoses
of executive function (Bennetto et al., 2001). given to persons with the fragile X associated tremor/
Smaller numbers of repeats, 50–200, are termed ataxia syndrome (FXTAS). Neurology 2005; 65: 299–301.
premutations, and are associated with the fragile X Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X
tremor/ataxia syndrome (FXTAS). Clinically this is premutation tremor/ataxia syndrome: molecular, clin-
characterized by progressive cerebellar ataxia and ical and neuroimaging correlates. Am J Hum Genet
tremor (this may be postural, action, or resting), 2003; 72: 869–78.
with or without parkinsonism, peripheral neur- Schapiro MB, Murphy DG, Hagerman RJ, et al. Adult
opathy, and autonomic features, features which do fragile X syndrome: neuropsychology, brain anatomy,
and metabolism. Am J Med Genet 1995; 60: 480–93.
not occur in FRAX and which have caused frequent
Steyaert J, Legius E, Borghgraef M, Fryns JP. A distinct
misdiagnosis of the condition, for example as other
neurocognitive phenotype in female fragile-X premuta-
tremor or ataxia syndromes (Hall et al., 2005). MR
tion carriers assessed with visual attention tasks. Am J
brain imaging typically shows high-signal-intensity Med Genet A 2003; 116: 44–51.
lesions on T2-weighted images in the cerebellar Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a
peduncles and in white matter inferior and lateral gene (FMR1) containing a CGG repeat coincident with a
to the deep cerebellar nuclei, with additional breakpoint cluster region exhibiting length variation in
cerebellar and cortical atrophy (Brunberg et al., fragile X syndrome. Cell 1991; 65: 905–14.
2002; Jacquemont et al., 2003).
Cognitive impairment and dementia may also be a
feature of FXTAS, specifically in the domains of 5.2 Hereditary ataxias
short-term memory and executive function, impair-
ments which are included in suggested diagnostic Classically the cerebellum has been viewed as a
criteria (Jacquemont et al., 2003). FXTAS has on component of the motor system, with damage
occasion been misdiagnosed as a dementia syn- resulting in motor signs, first clearly defined by
drome of Alzheimer’s or vascular type (Hall et al., Gordon Holmes (1922), of localizing value (ataxia,
2005). FXTAS has also been described in women: dysdiadochokinesia, nystagmus). More recently, a
they are not demented (Hagerman et al., 2004), but it role for the cerebellum in cognition has been
has been suggested that some perform poorly on increasingly acknowledged, with the description of
certain tests of visual selective attention (Steyaert a ‘cerebellar cognitive affective syndrome’, par-
et al., 2003). ticularly in association with posterior lobe and
vermis lesions, characterized by executive dysfunc- mutations responsible for some of these syn-
tion (set-shifting, planning, verbal fluency, abstract dromes (Paulson, 2005). At time of writing at least
reasoning, working memory), and difficulties with 28 loci have been defined. SCAs are characterized
spatial cognition, memory, and language, as well as by ataxia of gait and limb, ataxic dysarthria, spas-
personality change (Schmahmann & Sherman, ticity, and decreased vibration perception, with
1998). additional parkinsonism, tremor, neuropathy,
In this section, hereditary ataxias are considered ophthalmoparesis, and seizures, with cognitive
according to their pattern of inheritance, although impairment in some cases. Marked cerebellar
a pathogenetic classification of the hereditary atrophy, sometimes with cerebral cortical atrophy,
ataxias has been proposed (De Michele et al., is seen on structural brain imaging. Variability of
2004). So-called idiopathic late-onset cerebellar phenotype despite identical genetic mutation may
ataxias, possibly with added cognitive problems, occur. Several SCAs may fall within the old clinical
may in fact be caused by multiple system atrophy classification of ADCA type I (i.e. with cognitive
(MSA-C: see Section 2.4.4), fragile X tremor/ataxia impairment) including SCAs 1–4, 12, and 17. Clues
syndrome (FXTAS: Section 5.1.11), or gluten ataxia to the particular SCA may be obtained from the
with or without coeliac disease (Bürk et al., 2001; clinical examination: the presence of early and/or
Section 8.2.2). prominent dementia suggests that SCA2 or SCA17
may be the cause. A frontal lobe-like syndrome
may occur in SCA1; dementia may be present in
REFERENCES elderly patients with SCA12; and cognitive diffi-
culties have been described in SCAs 6, 8, and 19.
Bürk K, Bösch S, Müller CA, et al. Sporadic cerebellar Classification of the dominant hereditary ataxias
ataxia associated with gluten sensitivity. Brain 2001; also includes the episodic ataxias, channelopathies,
124: 1013–19.
and the prion disease Gerstmann–Straussler–
De Michele G, Coppola G, Cocozza S, Filla A. A
Scheinker disease (GSS: see Section 2.5.3).
pathogenetic classification of hereditary ataxias: is the
time ripe? J Neurol 2004; 251: 913–22.
Holmes G. The Croonian lectures on the clinical symp- SCA1
toms of cerebellar disease and their interpretation.
Lancet 1922: i: 1177–82; 1231–7; ii: 59–65; 111–15. Generally intellect remains intact until the late stages
Schmahmann JD, Sherman JC. The cerebellar cognitive of disease in SCA1, associated with a CAG/polyQ
affective syndrome. Brain 1998; 121: 561–79. mutation in the ataxin-1 gene at 6p22.3, when
behavioural changes and a frontal lobe-like syn-
drome may occur. One study found impairments of
5.2.1 Autosomal dominant hereditary
verbal memory and executive dysfunction with rela-
ataxias, spinocerebellar ataxias (SCA)
tive preservation of visuospatial memory and atten-
The phenotypic classification of autosomal dom- tion, a pattern labelled typical of frontal-subcortical
inant cerebellar ataxias (ADCA) proposed by dementia (Bürk et al., 2001). As for other SCAs, cog-
Harding acknowledged the concurrence of nitive impairments were not related to age of onset,
dementia in some patients with these conditions, disease duration, or trinucleotide repeat length.
specifically in type I, whereas type II was charac-
terized by having pigmentary maculopathy and
SCA2
type III a pure ataxia (Harding, 1984). This nos-
ology has been superseded by a genotypic classi- Cognitive changes are prominent in SCA2, associ-
fication of the spinocerebellar ataxias (SCA) based ated with a CAG/polyQ mutation in the ataxin-2
on the discovery of gene loci and specific genetic gene at 12q24.12. In one series, 25% of patients
were demented, and the cognitive defects were also migraine and episodic ataxia type 2. This common
apparent in non-demented individuals (Bürk et al., SCA is generally a ‘pure’ cerebellar ataxia (hence
1999). Impairments have been noted in frontal originally classified as ADCA type III), but a case
executive function, as measured by the Stroop Test, has been reported with slowly progressive mental
verbal fluency, and the Wisconsin Card Sorting disorders labelled as schizophrenia and dementia
Test, with visuospatial memory and attention (Tashiro et al., 1999).
spared; these changes may be found despite a
normal MMSE (Bürk et al., 1999; Storey et al., 1999;
SCA7
Boesch et al., 2000). Verbal memory function has
been reported to be impaired in some cases but not SCA7 results from CAG/polyQ mutation in the
in others. Cognitive impairments are not related to ataxin-7 gene at chromosome 3p14.1. The clinical
motor disability (Bürk et al., 1999) or trinucleotide phenotype is marked by progressive visual loss due
repeat size (Storey et al., 1999). A correlation of to retinal dystrophy, and hence the condition was
deficits with disease duration has been reported in originally classified as ADCA type II. Dementia has
one series (Boesch et al., 2000) but not in another been mentioned as a symptom in some cases
(Storey et al., 1999). (Walker & Farrell, 2006).
SCA3, Machado–Joseph disease (MJD) SCA8
This is probably the commonest dominantly Executive, visuospatial, and affective problems,
inherited ataxia in the world, due to a CAG/polyQ with normal MMSE, have been described in add-
mutation in the ataxin-3 gene at 14q32.12. In ition to ataxia in a mother and son with SCA8 due
addition to ataxia, there is levodopa-responsive to a combined CTA/CTG expansion on chromo-
parkinsonism, and variable peripheral involve- some 13q2; the neuropsychological features, rather
ment, ophthalmoparesis, lingual and facial fasci- than ataxia, were the major clinical symptom
culations. Cognitive impairments have also been (Stone et al., 2001). Two of seven patients with
described on occasion. Deficits in visual attentional SCA8 reported from Portugal were said to have
function with slowed processing of visual infor- mild to moderate memory impairment (Silveira
mation were reported using a computerized test et al., 2000).
battery, along with inability to shift attention to
previously irrelevant stimuli; learning and visual
SCA12
memory were normal. A frontal-subcortical pattern
of impairments was claimed, apparently inde- Dementia has been reported in some patients in
pendent of motor dysfunction (Maruff et al., 1996). the later stages of SCA12, due to a CAG mutation in
Abnormal behaviour, uncooperativeness, crying, the PPP2R2B gene at 5q32. Disorientation, memory
slow thought processes, hallucinations, and delu- loss, inability to calculate, and perseveration were
sions were reported in four Japanese patients the clinical features (O’Hearn et al., 2001).
(Ishikawa et al., 2002).
SCA17
SCA6
Cognitive decline and dementia, as well as extra-
SCA6 results from CAG/polyQ mutation in the pyramidal features, are common in SCA17 (Rolfs
alpha1A voltage-dependent calcium channel et al., 2003), due to a CAG/polyQ mutation in the
(CACNL1A4) gene at chromosome 19p13.2, and is TATA binding protein gene (TBP or TFIID) at
allelic with some cases of familial hemiplegic chromosome 6q27, and behavioural disorder and
dementia may dominate the early stages of the Stone J, Smith L, Watt K, Barron L, Zeman A. Incoordi-
disease. A frontal picture, with distractibility, poor nated thought and emotion in spinocerebellar ataxia
judgment, and impaired verbal fluency, has been type 8. J Neurol 2001; 248: 229–32.
reported (Bruni et al., 2004). Storey E, Forrest SM, Shaw JH, Mitchell P, McKinley
Gardner RJ. Spinocerebellar ataxia type 2: clinical
features of a pedigree displaying prominent frontal-
executive dysfunction. Arch Neurol 1999; 56: 43–50.
SCA19
Tashiro H, Suzuki SO, Hitotsumatsu T, Iwaki T. An
Cognitive difficulties are an occasional feature of this autopsy case of spinocerebellar ataxia type 6 with
disorder, linked to 1p21–q21 (Verbeek et al., 2002). mental symptoms of schizophrenia and dementia.
Clin Neuropathol 1999; 18: 198–204.
Verbeek DS, Schelhaas JH, Ippel EF, et al. Identification
of a novel locus (SCA19) in a Dutch autosomal
REFERENCES dominant cerebellar ataxia family on chromosome
region 1p21–q21. Hum Genet 2002; 111: 388–93.
Boesch SM, Globas C, Bürk K, Poewe W, Dichgans J. Walker M, Farrell D. Spinocerebellar ataxia type 7 (SCA7).
Cognitive deficits in spinocerebellar ataxia type 2 (SCA2): Pract Neurol 2006; 6: 44–7.
a comparative study in two founder populations. Mov
Disord 2000; 15 (suppl 3): 235 (abstract P1092).
Bruni AC, Takahashi-Fujigasaki J, Maltecca F, et al.
5.2.2 Autosomal recessive hereditary
Behavioral disorder, dementia, ataxia, and rigidity in a ataxias
large family with TATA Box-binding protein mutation. Friedreich’s ataxia (FA)
Arch Neurol 2004; 61: 1314–20.
Bürk K, Bosch S, Globas C, et al. Executive dysfunction in The most common autosomal recessive cause of
spinocerebellar ataxia type 1. Eur Neurol 2001; 46: 43–8. ataxia, Friedreich’s ataxia (FA) is characterized by
Bürk K, Globas C, Bösch S, et al. Cognitive deficits in ataxia, dysarthria, axonal polyneuropathy and
spinocerebellar ataxia 2. Brain 1999; 122: 769–77. pyramidal weakness of the legs (absent ankle jerks
Harding AE. The Hereditary Ataxias and Related Disorders. and upgoing plantars), optic atrophy, scoliosis, and
Edinburgh: Churchill Livingstone, 1984.
cardiac conduction abnormalities, usually with
Ishikawa A, Yamada M, Makino K, et al. Dementia and
onset before the age of 20 years. Intronic trinu-
delirium in 4 patients with Machado-Joseph disease.
cleotide repeat expansions in the frataxin gene on
Arch Neurol 2002; 59: 1804–8.
Maruff P, Tyler P, Burt T, et al. Cognitive deficits in chromosome 9q13 resulting in disordered mito-
Machado–Joseph disease. Ann Neurol 1996; 40: 421–7. chondrial function are the cause of FA. The clinical
O’Hearn E, Holmes SE, Calvert PC, Ross CA, Margolis RL. phenotype has broadened as a result of the dis-
SCA-12: tremor with cerebellar and cortical atrophy is covery of the causative genetic mutations (Dürr,
associated with a CAG repeat expansion. Neurology 2002; Puccio & Koenig, 2005).
2001; 56: 299–303. Any assessment of neuropsychological function
Paulson HL. Autosomal dominant cerebellar ataxia. In: in FA must take account of possible confounders
Beal MF, Lang AE, Ludolph A (eds.), Neurodegenerative such as dysarthria and fatigue, and any educational
Diseases: Neurobiology, Pathogenesis and Therapeutics.
shortcomings engendered by physical disability.
Cambridge: Cambridge University Press, 2005: 709–18.
Nonetheless, studies suggest that FA is attended by
Rolfs A, Koeppen AH, Bauer I, et al. Clinical features and
cognitive impairments, such as lengthened mental
neuropathology of autosomal dominant spinocerebellar
ataxia (SCA17). Ann Neurol 2003; 54: 367–75. reaction times and colour–word interference in the
Silveira I, Alonso I, Guimaraes L, et al. High germinal Stroop task. One group found no impairment in
instability of the (CTG)n at the SCA8 locus of both tests sensitive to neocortical (particularly pre-
expanded and normal alleles. Am J Hum Genet 2000; 66: frontal cortex) function, including verbal fluency,
830–40. Wisconsin Card Sorting, Tower of Hanoi, and
picture arrangement (White et al., 2000), whereas ‘complicated’ hereditary spastic paraparesis, or as
another group found deficits in letter fluency, as an early-onset autosomal recessive cerebellar
well as impaired acquisition and consolidation of ataxia with retained reflexes. Pedigrees from Que-
verbal information and alterations in visuopercep- bec and Tunisia showed linkage to chromosome
tual and visuoconstructive abilities (Wollmann 13q11–12 (Mrissa et al., 2000), whence positional
et al., 2002). All agree that cerebellar degeneration cloning techniques permitted characterization of
and interruption of cerebellar afferent and efferent the sacsin gene (Engert et al., 2000). Many sacsin
connections is probably responsible for these gene mutations have now been reported from
findings. pedigrees throughout the world, expanding the
spectrum of sacsinopathies (Gomez, 2004). Two
siblings reported from Japan had a unique
Ataxia telangiectasia (AT)
phenotype of dementia, ophthalmoplegia, and
This childhood-onset autosomal recessive absence of prominent retinal myelinated fibres
syndrome is characterized by progressive ataxia, (Hara et al., 2005).
oculomotor apraxia requiring head thrusts to
achieve ocular fixation, dysarthria, telangiectasia,
and a tendency to develop recurrent infections Ataxia with vitamin E deficiency (AVED)
(especially sinopulmonary) and malignancies. The This autosomal recessive disorder manifests as
molecular defect is in the ATM gene on chromo- spinocerebellar ataxia and polyneuropathy without
some 11, which encodes a protein required for evidence of cognitive impairment, suggesting that
DNA repair (Spacey et al., 2000; Gatti et al., 2005). vitamin E is not crucial to cognitive function.
Cognitive status is said to be normal in most cases,
some patients completing university-level educa-
tion, and significant neuropsychological impair-
REFERENCES
ments have been said to be uncommon. However,
Colvin and Lennox (1997) reported frontal lobe
Colvin IB, Lennox GG. Cognitive function in ataxia
dysfunction in a series of 18 AT patients as assessed
telangiectasia. J Neurol Neurosurg Psychiatry 1997; 62:
with Wisconsin Card Sorting Test, Tower of London
210 (abstract).
Test, verbal fluency, and similarities. Impairments Dürr A. Friedreich’s ataxia: treatment within reach. Lancet
of visual memory assessed with the Warrington Neurol 2002; 1: 370–4.
Recognition Memory Test, and failure on some Engert JC, Berube P, Mercier J, et al. ARSACS, a spastic
elements of the VOSP, were attributed to impaired ataxia common in northeastern Quebec, is caused by
oculomotor function. mutations in a new gene encoding an 11.5-kb ORF. Nat
Genet 2000; 24: 120–5.
Gatti RA, Crawford TO, Mandir AS, Perlman S, Mount HTJ.
Autosomal recessive spastic ataxia of Ataxia telangiectasia. In: Beal MF, Lang AE, Ludolph A
Charlevoix–Saguenay (ARSACS) (eds.), Neurodegenerative Diseases: Neurobiology,
Pathogenesis and Therapeutics. Cambridge: Cambridge
This autosomal recessive disorder of childhood,
initially reported from northeastern Quebec,
Gomez CM. ARSACS goes global. Neurology 2004; 62:
Canada, is characterized by childhood onset of a 10–11.
slowly progressive pyramidal syndrome, dysarthria, Hara K, Onodera O, Endo M, et al. Sacsin-related
ataxia, abnormal eye movements (nystagmus), autosomal recessive ataxia without prominent retinal
retinal striation (¼ hypermyelinated retinal fibres), myelinated fibers in Japan. Mov Disord 2005; 20: 380–2.
sphincter involvement, mitral incompetence, Mrissa N, Belal S, Ben Hamida M, et al. Linkage to
and motor neuropathy. It may be classified as a chromosome 13q11-12 of an autosomal recessive
cerebellar ataxia in a Tunisian family. Neurology 2000; autosomal dominant Alzheimer’s disease (see
54: 1408–14. Section 2.1) associated with certain of the pre-
Puccio H, Koenig M. Friedreich’s ataxia and other auto- senilin-1 mutations (Larner & Doran, 2006), some
somal recessive ataxias. In: Beal MF, Lang AE, Ludolph of the hereditary cerebral amyloid angiopathies
A (eds.). Neurodegenerative Diseases: Neurobiology,
(Section 3.6.3), and autosomal recessive spastic
Pathogenesis and Therapeutics. Cambridge: Cambridge
ataxia of Charlevoix–Saguenay (ARSACS: Section
5.2.2). Spastic paraparesis has also been reported in
Spacey SD, Gatti RA, Bebb G. The molecular basis and
clinical management of ataxia telangiectasia. Can J
Krabbe disease (Section 5.5.2).
Neurol Sci 2000; 27: 184–91.
White M, Lalonde R, Botez-Marquard T. Neuropsycholo-
gic and neuropsychiatric characteristics of patients with REFERENCES
Friedreich’s ataxia. Acta Neurol Scand 2000; 102: 222–6.
Wollmann T, Barroso J, Monton F, Nieto A. Neuropsycho- Ferrer I, Olivé M, Rivera R, et al. Hereditary spastic
logical test performance of patients with Friedreich’s paraparesis with dementia, amyotrophy and peripheral
ataxia. J Clin Exp Neuropsychol 2002; 24: 677–86. neuropathy: a neuropathological study. Neuropathol
Appl Neurobiol 1995; 21: 255–61.
Fink JK. The hereditary spastic paraplegias: nine genes
5.3 Hereditary spastic paraplegia and counting. Arch Neurol 2003; 60: 1045–9.
Larner AJ, Doran M. Clinical phenotypic heterogeneity of
Alzheimer’s disease associated with mutations of the
The hereditary spastic paraplegias (HSP) are a
presenilin-1 gene. J Neurol 2006; 253: 139–58.
heterogeneous group of inherited motor system
McDermott CJ, Shaw PJ. Hereditary spastic paraplegia. Int
disorders, typically presenting with lower limb Rev Neurobiol 2002; 53: 191–204.
spasticity and, to a lesser extent, weakness. Clin- Webb S, Hutchinson M. Cognitive impairment in families
ically, HSP may be divided into pure (uncompli- with pure autosomal dominant hereditary spastic
cated) and complicated types, the latter paraparesis. Brain 1998; 121: 923–9.
manifesting other neurological features in addition
to spasticity, such as seizures, amyotrophy, extra-
5.3.1 SPG4
pyramidal signs, peripheral neuropathy, and cog-
nitive impairment, sometimes amounting to The commonest form of autosomal dominant HSP
dementia. Subtle cognitive deficits have also been is that linked to the SPG4 locus on chromosome 2p
detected in so-called ‘pure’ HSP types. To date where the gene that encodes spastin is found.
around 20 genetic loci linked to HSP have been Although classified as a pure form of HSP, cognitive
described, with dominant, recessive, and X-linked deficits have been noted in patients, sometimes
inheritance, and deterministic mutations have amounting to a global dementia with a profile
been described in at least 10 genes, encoding the similar to that in subcortical dementias (Webb
proteins L1-CAM, proteolipid protein (PLP), atlas- et al., 1998). Mild cognitive problems may be the
tin, spastin, paraplegin, spartin, maspardin, hsp60, first clinical manifestation in carriers of spastin
KIF5A, and NIPA1 (McDermott & Shaw, 2002; Fink, gene mutations. Studies in Irish families reported
2003). Cognitive impairment has been noted in cognitive decline affecting orientation, memory,
both autosomal dominant (Webb & Hutchinson, and language that was age-dependent (Byrne et al.,
1998) and autosomal recessive HSP (Ferrer et al., 2000) and progressive over time (McMonagle et al.,
1995). 2004), whereas French studies found that cognitive
Spastic paraparesis may be a feature of other decline was correlated with disease progression
monogenic Mendelian disorders which may also be and not with age (Tallaksen et al., 2003). These
associated with cognitive impairment, such as researchers found only mild, asymptomatic,
cognitive loss, particularly affecting executive REFERENCES

functions, more frequently observed in patients
with missense rather than truncating spastin Cross HE, McKusick VA. The mast syndrome: a recessively
mutations. A report of a large series of patients with inherited form of presenile dementia with motor
spastin mutations made no mention of any cog- disturbances. Arch Neurol 1967; 16: 1–13.
nitive impairments (McDermott et al., 2006). D’Hooge M. Probable cases of mast syndrome in a non-
Amish family. J Neurol Neurosurg Psychiatry 1992; 55: 1210.
Simpson MA, Cross H, Proukakis C, et al. Maspardin is
mutated in mast syndrome, a complicated form of
REFERENCES hereditary spastic paraplegia associated with dementia.
Am J Hum Genet 2003; 73: 1147–56.
Byrne P, McMonagle P, Webb S, et al. Age-related
cognitive decline in hereditary spastic paraparesis
linked to chromosome 2p. Neurology 2000; 54: 1510–17.
5.4 Hereditary movement disorders
McDermott CJ, Burness CE, Kirby J, et al. Clinical features
of hereditary spastic paraplegia due to spastin muta-
tion. Neurology 2006; 67: 45–51. 5.4.1 Wilson’s disease (hepatolenticular
McMonagle P, Byrne P, Hutchinson M. Further evidence degeneration)
of dementia in SPG4-linked autosomal dominant
Wilson’s disease is an autosomal recessive disorder
hereditary spastic paraplegia. Neurology 2004; 62:
of copper metabolism resulting from mutations in
407–10.
the gene ATP7B, encoding a copper-binding
Tallaksen CME, Guichart-Gomez E, Verpillat P, et al.
Subtle cognitive impairment but no dementia in membrane-bound ATPase, resulting in elevated
patients with spastin mutations. Arch Neurol 2003; 60: blood and urine copper and reduced blood caer-
1113–18. uloplasmin levels. The condition usually presents
Webb S, Coleman D, Byrne P, et al. Autosomal dominant in young adults with hepatic and/or neurological
hereditary spastic paraparesis with cognitive loss linked disease due to accumulation of copper in affected
to chromosome 2p. Brain 1998; 121: 601–9. tissues. In the brain, although copper deposition
occurs throughout, it is the basal ganglia which are
particularly vulnerable, resulting in movement
5.3.2 SPG21, mast syndrome
disorders (parkinsonism, dystonia, grimacing,
Mast syndrome is an autosomal recessive, com- excessive salivation); likewise the cerebellum
plicated, form of HSP with a clinical phenotype of (ataxia, wing-beating tremor, dysarthria). Copper
onset in the second decade with paraplegia, dys- deposition in Descemet’s membrane may be
arthria, athetosis, and dementia. It was originally observed as Kayser–Fleischer rings, a reliable sign
described in the Old Order Amish community of brain copper deposition (LeWitt & Brewer, 2005).
(Cross & McKusick, 1967), but possible non-Amish Neuropsychiatric features are also common, such
cases have been reported with bradyphrenia and as personality change, depression, and occasionally
comprehension difficulties in their 40s, progress- psychosis (Brewer, 2005). Motor and neu-
ing to rare, inappropriate, single-syllable answers ropsychiatric features might possibly confound
in the 50s (D’Hooge, 1992). It is slowly progressive, neuropsychological testing in Wilson’s disease.
with cerebellar and extrapyramidal features In his seminal paper on the disorder that now
emerging in advanced disease. It maps to bears his name, Kinnier Wilson (1912) noted a
chromosome 15q22.31 and frameshift mutations distinct pattern of neurobehavioural disturbances
have been identified in a gene that encodes a without agnosia, apraxia, or severe memory loss in
protein product named maspardin (Simpson association with disease of the basal ganglia.
et al., 2003). The cognitive impairments in patients with
neurological and/or hepatic symptoms may be Polson RJ, Rolles K, Calne RY, Williams R, Marsden D.
mild (Rathbun, 1996), or involvement may be Reversal of severe neurological manifestations of
widespread, including impaired memory, visuo- Wilson’s disease following orthotopic liver transplant-
spatial processing, and frontal-executive function ation. Q J Med 1987; 64: 685–91.
Rathbun JK. Neuropsychological aspects of Wilson’s
(Medalia et al., 1988; Seniów et al., 2002). Rate of
disease. Int J Neurosci 1996; 85: 221–9.
information processing may be spared, although
Rosselli M, Lorenzana P, Rosselli A, Vergara I. Wilson’s
response latencies are prolonged, probably as a
disease, a reversible dementia: case report. J Clin Exp
consequence of the motor disorder (Littman et al., Neuropsychol 1987; 9: 399–406.
1995). Neuropsychological deficits may be present Seniów J, Bak T, Gajda J, Poniatowska R, Czlonkowska A.
early in the course of the disease (Goldstein et al., Cognitive functioning in neurologically symptomatic
1968), but patients with exclusive hepatic involve- and asymptomatic forms of Wilson’s disease. Mov
ment do not differ from controls and adequate Disord 2002; 17: 1077–83.
early treatment may prevent cognitive decline Wilson SAK. Progressive lenticular degeneration: a familial
(Lang et al., 1990). If untreated, dementia develops nervous disease associated with cirrhosis of the liver.
with disease progression, hence the need to screen Brain 1912; 34: 295–509.
all younger patients with movement disorders for

abnormalities of copper metabolism. Once estab- 5.4.2 Neurodegeneration with brain
lished, the dementia is generally held to be irre- accumulation of iron-1 (NBAI-1),
versible, although anecdotal reports of cognitive (as Hallervorden–Spatz disease
well as motor) improvement after chelation ther-
apy (Rosselli et al., 1987) and liver transplantation Hallervorden and Spatz were the first to describe a
(Polson et al., 1987, case 2) have appeared. familial syndrome, now known to be of autosomal
recessive inheritance, of dysarthria and progressive
dementia with brown discoloration of the globus
pallidus and substantia nigra at postmortem. The
REFERENCES
name Hallervorden–Spatz disease was used for this
condition (Halliday, 1995) but has fallen from
Brewer GJ. Behavioral abnormalities in Wilson’s disease.
favour because of Hallervorden’s association with
Adv Neurol 2005; 96: 262–74.
unethical practices during the Nazi era, the term
Goldstein NP, Ewert JC, Randall RV, Gross JB. Psychiatric
aspects of Wilson’s disease (hepatolenticular degener- neurodegeneration with brain accumulation of
ation): results of psychometric tests during long-term iron-1 (NBAI-1) now being used (Pearce, 2006).
therapy. Am J Psychiatry 1968; 124: 1555–61. A distinction was drawn between Hallervorden–
Lang C, Müller D, Claus D, Druschky KF. Neuropsycho- Spatz disease and Hallervorden–Spatz syndrome
logical findings in treated Wilson’s disease. Acta Neurol (Halliday, 1995), the former being childhood cases of
Scand 1990; 81: 75–81. either familial or sporadic origin with a fairly
LeWitt PA, Brewer GJ. Neurological aspects of Wilson’s homogeneous phenotype of dystonia, dysarthria,
disease. In: Beal MF, Lang AE, Ludolph A (eds.), rigidity, choreoathetosis, pigmentary retinopathy,
Neurodegenerative Diseases: Neurobiology, Pathogenesis
and, in about a quarter of cases, cognitive decline.
and Therapeutics. Cambridge: Cambridge University
Hallervorden–Spatz syndrome was used for ‘atypical’
Press, 2005: 890–908.
cases, usually of later onset (second to third decade),
Littman E, Medalia A, Senior G, Scheinberg IH. Rate of
information processing in patients with Wilson’s dis- with speech difficulty, with or without extra-
ease. J Neuropsychiatry Clin Neurosci 1995; 7: 68–71. pyramidal and pyramidal signs, and in some cases
Medalia A, Isaacs Glaberman K, Scheinberg IH. Neuro- with cognitive decline said to be reminiscent of
psychological impairment in Wilson’s disease. Arch frontotemporal dementia, with personality change,
Neurol 1988; 45: 502–4. impulsivity, violent outbursts, and emotional lability
(Halliday, 1995). Typical pathological findings are multisystem neurodegenerative disorder inherited
pallidal iron deposition, axonal spheroids, and glio- as an autosomal recessive condition linked to
sis. T2-weighted MR brain scans show decreased chromosome 9q21 and associated with mutations
signal intensity in the pallidal nuclei with central in the VPS13A gene, encoding the protein chorein.
hyperintensity, the ‘eye-of-the-tiger’ sign, which is The clinical phenotype includes movement dis-
highly suggestive although not specific. Such orders (orofaciolingual dystonia, chorea, parkin-
imaging findings have permitted diagnosis of more sonism), axonal polyneuropathy, epileptic seizures,
cases and broadened the phenotype (Hickman and neuropsychiatric abnormalities, as well as
et al., 2001). Mutations in the gene encoding pan- cognitive impairments. Salient investigation find-
tothenate kinase (PANK2) on chromosome 20p13 ings are acanthocytes on fresh blood films (more
have been identified in NBAI-1 (Zhou et al., 2001), in than one film may need to be examined) and raised
both classic cases and in around one-third of atyp- creatine phosphokinase, but there is no abnor-
ical late-onset cases (Hayflick et al., 2003). mality of lipid metabolism (Hardie et al., 1991;
The neuropsychological profile is, as might be Danek et al., 2005; Storch et al., 2005).
expected, of frontal-subcortical type, with brady- Personality change, such as impulsive and dis-
phrenia, reduced verbal fluency, judgment diffi- tractible behaviour or apathy and loss of insight, may
culties, and attentional impairment, but with be observed. We have encountered a patient who was
relative preservation of memory. Phenotype may served with an Anti-Social Behaviour Order because
be variable, even in siblings sharing the same of personality problems due to undiagnosed neu-
mutation (Marelli et al., 2005). roacanthocytosis (Doran et al., 2006). Consistent
with this suggestion of frontal lobe dysfunction, tests
of executive function may be impaired sufficient to
REFERENCES amount to a subcortical dementia (Kartsounis &
Hardie, 1996). Hence in both its clinical and neuro-
Halliday W. The nosology of Hallervorden–Spatz disease. J
psychological features, neuroacanthocytosis may
Neurol Sci 1995; 134 (suppl): 84–91.
resemble Huntington’s disease.
Hayflick SJ, Westaway SK, Levinson B, et al. Genetic,
clinical, and radiographic delineation of Hallervorden–
Spatz syndrome. N Engl J Med 2003; 348: 33–40.
Hickman SJ, Ward NS, Surtees RA, Stevens JM, Farmer SF.
REFERENCES
How broad is the phenotype of Hallervorden–Spatz
disease? Acta Neurol Scand 2001; 103: 201–3.
Danek A (ed.). Neuroacanthocytosis Syndromes. Dordrecht:
Marelli C, Piacentini S, Garavaglia B, Girotti F, Albanese A.
Springer, 2004.
Clinical and neuropsychological correlates in two
Danek A, Jung HH, Melone MAB, et al. Neuroacanthocy-
brothers with pantothenate kinase-associated neurode-
tosis: new developments in a neglected group of
generation. Mov Disord 2005; 20: 208–12.
dementing disorders. J Neurol Sci 2005; 229–30:
Pearce JMS. Neurodegeneration with brain iron accumu-
171–86.
lation: a cautionary tale. Eur Neurol 2006; 56: 66–8.
Doran M, Harvie AK, Larner AJ. Antisocial behaviour
Zhou B, Westaway SK, Levinson B, et al. A novel
orders: the need to consider underlying neuropsychia-
pantothenate kinase gene is defective in Hallervorden–
tric disease. Int J Clin Pract 2006; 60: 861–2.
Spatz syndrome. Nature Genet 2001; 28: 345–9.
Hardie RJ, Pullon HW, Harding AE, et al. Neuroacantho-
cytosis: a clinical, haematological and pathological
5.4.3 Neuroacanthocytosis study of 19 cases. Brain 1991; 114: 13–49.
Kartsounis LD, Hardie RJ. The pattern of cognitive
There are various neuroacanthocytosis syndromes impairments in neuroacanthocytosis. Arch Neurol
(Danek, 2004), of which chorea-acanthocytosis is a 1996; 53: 77–80.
Storch A, Kornhass M, Schwarz J. Testing for acanthocy- Curtis AR, Fey C, Morris CM, et al. Mutation in the gene
tosis: a prospective reader-blinded study in movement encoding ferritin light polypeptide causes dominant
disorder patients. J Neurol 2005; 252: 84–90. adult-onset basal ganglia disease. Nat Genet 2001; 28:
350–4.
Maciel P, Cruz VT, Constante M, et al. Neuroferritino-
5.4.4 Neuroferritinopathy pathy: missense mutation in FTL causing early-onset
Mutations in the gene encoding ferritin light bilateral pallidal involvement. Neurology 2005; 65:
polypeptide (FLP) or ferritin light chain (FTL) have 603–5.
Vidal R, Ghetti B, Takao M, et al. Intracellular ferritin
been associated with a variety of autosomal dom-
accumulation in neural and extraneural tissue char-
inant movement disorders, including dystonia,
acterizes a neurodegenerative disease associated with a
chorea, and akinetic-rigid syndrome. The extra-
mutation in the Ferritin Light Polypeptide gene.
pyramidal features may resemble Huntington’s J Neuropath Exp Neurol 2004; 63: 363–80.
disease or parkinsonism. There is a low serum Wills AJ, Sawle GV, Guilbert PR, Curtis ARJ. Palatal tremor
ferritin with brain aggregates of ferritin and iron and cognitive decline in neuroferritinopathy. J Neurol
(Curtis et al., 2001; Vidal et al., 2004). Neurosurg Psychiatry 2002; 73: 91–2.
Although few pedigrees have been reported thus
far, cognitive decline does seem to be associated
5.4.5 Acaeruloplasminaemia
with neuroferritinopathy, at least in some cases. In
one case, frontal lobe function was particularly This autosomal recessive condition results from the
affected (perseveration, poor cognitive estimates, absence of caeruloplasmin ferroxidase activity due
impaired non-verbal abstract reasoning, and some to mutations in the caeruloplasmin gene, with
word-retrieval difficulties), although the patient had subsequent effects on iron metabolism. There is
been treated with high-dose anticholinergic agents low serum iron, raised ferritin, absent caer-
for the movement disorder before cognitive decline uloplasmin, and increased liver iron on biopsy, and
occurred (Wills et al., 2002). In a French family, two although serum copper is low this is in proportion
of the seven members had a frontal syndrome and to reduced caeruloplasmin, as normal urine and
another was demented (Chinnery et al., 2003), and in liver copper indicate that there is no copper over-
another family the index case had a frontal syn- load. Unlike the situation with haemochromatosis,
drome and dementia (Vidal et al., 2004). The index neurological presentations are common in acaer-
case in a Portuguese family had non-progressive uloplasminaemia, usually with a movement dis-
mental retardation with IQ of 60 (Maciel et al., 2005). order (dystonia, chorea, ataxia), with imaging
Overall, cognitive impairment seems to be absent or evidence of iron deposition in the brain, particu-
subtle in the early stages, unlike the situation in larly the basal ganglia. A role for caeruloplasmin in
Huntington’s disease, with subcortical-frontal dys- brain iron metabolism is therefore likely (Harris
function developing later (Chinnery et al., 2007). et al., 1996).
Occasional cases of dementia have been reported
in association with acaeruloplasminaemia (Morita
REFERENCES et al., 1992; Logan et al., 1994; Harris et al., 1996).
The limited information available on the pattern of
Chinnery PF, Crompton DE, Birchall D, et al. Clinical
cognitive impairment indicates defects in imme-
features and natural history of neuroferritinopathy
diate and delayed recall of verbal material, inability
caused by the FTL1 460InsA mutation. Brain 2007;
to learn new verbal material, with preservation of
130: 110–19.
Chinnery P, Curtis A, Fey C, et al. Neuroferritinopathy in a
long-term memory, at least initially. The findings
French family with late onset dominant dystonia. J Med were said to be ‘similar to subcortical dementia’
Genet 2003; 40: e69. (Logan et al., 1994; Harris et al., 1996).
REFERENCES noted in another study, akin to those seen in idio-

pathic Parkinson’s disease (PD), prompting the
Harris ZL, Migas MC, Hughes AE, Logan JI, Gitlin JD. suggestion that this frontal lobe dysfunction may
Familial dementia due to a frameshift mutation in the reflect dysregulation of frontal-subcortical dopa-
caeruloplasmin gene. Q J Med 1996; 89: 355–9. mine pathways (Gasparini et al., 2001). Although ET
Logan JI, Harveyson KB, Wisdom GB, Hughes AE, and PD are clinically and genetically unrelated
Archbold GPR. Hereditary caeruloplasmin deficiency, (Plumb & Bain, 2007), the occasional concurrence of
dementia and diabetes mellitus. Q J Med 1994; 87:
familial ET and restless legs syndrome (Larner &
663–70.
Allen, 1997) may support the idea of dopaminergic
Morita H, Inoue A, Yanagisawa N. A case of caeruloplas-
dysfunction. Lacritz et al. (2002) found mild cogni-
min deficiency which showed dementia, ataxia and iron
deposition in the brain [in Japanese]. Rinsho Shinkei- tive impairment in about half of a small cohort of ET
gaku 1992; 32: 483–7. patients being evaluated for tremor surgery (hence a
highly selected group), with deficits identified in
cognitive flexibility, figural fluency, and selective
5.4.6 Essential tremor (ET)
attention. Attentional problems were also identified
Classic hereditary essential tremor (ET), in which in another study (Duane & Vermilion, 2002).
similarly affected family members are found in at Although these studies have some shortcomings in
least three generations, is typified by early onset, terms of selection bias and, in some, lack of appro-
complete penetrance by age 65 years, invariable priate control data, nonetheless they do suggest
onset of tremor in the hands, and absence of cognitive impairments in ET, albeit mild, affecting
rigidity, rest tremor, persistent unilateral tremor, frontal-subcortical or cerebellar-frontal circuitry.
and isolated head, tongue, voice, jaw, or leg tremor
(Bain et al., 1994). The role of genetic factors has
been confirmed by the demonstration of linkage of
REFERENCES
ET to loci on chromosomes 3q and 2p. However,
many cases clinically labelled as ET either lack a
Bain PG, Findley LJ, Thompson PD, et al. A study of
family history (non-familial or sporadic ET), sug-
hereditary essential tremor. Brain 1994; 117: 805–24.
gesting that environmental factors may contribute
Duane DD, Vermilion KJ. Cognitive deficits in patients
to aetiology, or vary from the classical clinical with essential tremor. Neurology 2002; 58: 1706.
phenotype (Louis, 2005). Such cases are sometimes Gasparini M, Bonifati V, Fabrizio E, et al. Frontal lobe
labelled as ‘possible ET’ although other diagnoses dysfunction in essential tremor: a preliminary study.
need to be borne in mind, such as enhanced J Neurol 2001; 248: 399–402.
physiological tremor, early Parkinson’s disease, or Lacritz LH, Dewey R Jr, Giller C, Cullum CM. Cognitive
dystonic tremor (Schrag et al., 2000). functioning in individuals with benign essential tremor.
Although ET is generally considered a mono- J Int Neuropsychol Soc 2002; 8: 125–9.
symptomatic tremor disorder, administration of Larner AJ, Allen CMC. Hereditary essential tremor and
restless legs syndrome. Postgrad Med J 1997; 73: 254.
neuropsychological tests has revealed subclinical
Lombardi WJ, Woolston DJ, Roberts JW, Gross RE.
impairments in tests sensitive to frontal lobe
Cognitive deficits in patients with essential tremor.
function. One study noted impaired verbal fluency,
Neurology 2001; 57: 785–90.
naming, mental set-shifting, verbal memory, and Louis ED. Essential tremor. Lancet Neurol 2005; 4: 100–10.
working memory. Deficits did not correlate with Plumb M, Bain P. Essential Tremor: the Facts. Oxford:
tremor severity. Prefrontal cortical involvement, Oxford University Press, 2007.
perhaps encompassing frontocerebellar circuits, Schrag A, Münchau A, Bhatia KP, Quinn NP, Marsden CD.
was surmised (Lombardi et al., 2001). Impairments Essential tremor: an overdiagnosed condition? J Neurol
in attentional and conceptual thinking tasks were 2000; 247: 955–9.
5.4.7 Restless legs syndrome (RLS) and recognition memory, speed of motor initiation
and execution during problem solving, but with
The negative impact of restless legs syndrome
preserved verbal memory and language tasks. The
(RLS) on sleep may also affect cognitive functions,
deficits may perhaps be related to difficulties in
particularly those thought to be mediated by pre-
inhibitory functions (Chamberlain et al., 2005), or
frontal cortex (Pearson et al., 2006), producing
in sustaining attention and forming internal
deficits similar to those seen with sleep deprivation
representations of stimuli, reflecting abnormal
(Durmer & Dinges, 2005). Possible associations of
frontal-basal ganglia connections (Maruff et al.,
RLS with Parkinson’s disease, essential tremor
2002).
(Larner & Allen, 1997), and migraine (Larner, 2007)
might also contribute to observed cognitive deficits
(see Sections 2.4, 5.4.6, and 3.7.2, respectively).
REFERENCES
REFERENCES Bornstein RA. Neuropsychological correlates of obsessive

characteristics in Tourette syndrome. J Neuropsychiatry
Clin Neurosci 1991; 3: 157–62.
Durmer JS, Dinges DF. Neurocognitive consequences of
Chamberlain SR, Blackwell AD, Fineberg NA, Robbins TW,
sleep deprivation. Semin Neurol 2005; 25: 117–29.
Sahakian BJ. The neuropsychology of obsessive com-
Larner AJ. Migraine with aura and restless legs syndrome.
pulsive disorder: the importance of failures in cognitive
J Headache Pain 2007; 8: 141–2.
and behavioural inhibition as candidate endophenoty-
Larner AJ, Allen CMC. Hereditary essential tremor and
pic markers. Neurosci Biobehav Rev 2005; 29: 399–419.
restless legs syndrome. Postgrad Med J 1997; 73: 254.
Jankovic J. Tourette’s syndrome. N Engl J Med 2001; 345:
Pearson VE, Allen RP, Dean T, et al. Cognitive deficits
1184–92.
associated with restless legs syndrome (RLS). Sleep Med
Maruff P, Purcell R, Pantelis C. Obsessive-compulsive
2006; 7: 25–30.
disorder. In: Harrison JE, Owen AM (eds.), Cognitive
Deficits in Brain Disorders. London: Martin Dunitz,
2002: 249–72.
5.4.8 Tourette syndrome (TS), obsessive-
Robertson MM. Tourette syndrome, associated conditions
compulsive disorder (OCD)
and the complexities of treatment. Brain 2000; 123:
There is a high concordance of Tourette syndrome 425–62.
(TS) and the related obsessive-compulsive disorder Stewart JT, Williams LS. Tourette’s-like syndrome and
(OCD) in monozygotic twins, although the genetic dementia. Am J Psychiatry 2003; 160: 1356–7.
basis remains to be determined. The psychopath-

ology of Tourette syndrome includes both anxiety
and depression (Robertson, 2000; Jankovic, 2001). A 5.5 Hereditary metabolic disorders
correlation between obsessive-compulsive symp-
toms and performance on the Wisconsin Card This section encompasses those disorders once
Sorting Test has been noted in children with TS styled as ‘inborn errors of metabolism’.
(Bornstein, 1991). A Tourette-like syndrome of
vocal motor tics has been reported in fronto-
5.5.1 Mitochondrial disorders
temporal dementia (see Section 2.2), responding to
clonidine (Stewart & Williams, 2003). Mitochondrial disorders are a heterogeneous
Neuropsychological testing has been undertaken group, with respect to both phenotype and geno-
in patients with OCD. When corrected for comor- type. Both peripheral and central nervous systems
bidity with anxiety and depression, these suggest may be affected, the former including myopathy
selective impairments on tests of spatial working and peripheral neuropathy, the CNS features
including epilepsy, migraine, stroke-like episodes, A subcortical dementia resembling Binswanger’s

ophthalmoplegia, ataxia, and spasticity, as well as disease (see Section 3.2), but without lipohyali-
cognitive impairment. There may also be involve- nosis, in association with mitochondrial DNA
ment of other systems, such as cardiomyopathy, variants has been described under the rubric of
diabetes mellitus, pigmentary retinal degeneration, disseminated neocortical and subcortical enceph-
and sensorineural hearing loss. Various more or alopathy (DNSE: Haferkamp et al., 1998).
less characteristic phenotypes may be identified,
including Kearns–Sayre syndrome, chronic pro-
gressive external ophthalmoplegia (CPEO), the REFERENCES
syndrome of mitochondrial encephalomyopathy,
lactic acidosis, and stroke-like episodes (MELAS), Finsterer J. Central nervous system manifestations of
and the syndrome of myoclonic epilepsy and mitochondrial disorders. Acta Neurol Scand 2006; 114:
ragged red fibres (MERRF). At the level of genotype, 217–38.
mitochondrial disorders may result from mutations Haferkamp O, Rosenau W, Scheuerle A, et al. Dissemin-
ated neocortical and subcortical encephalopathy
(deletions, point mutations) within the small
(DNSE) with widespread activation of macrophages: a
mitochondrial genome or within nuclear genes
new dementia disorder? Autopsy report of two post-
(autosomal, X-linked) which encode mitochondrial
menopausal women from families with mitochondrial
respiratory chain proteins (Schapira & DiMauro, DNA mutations. Clin Neuropathol 1998; 17: 85–94.
2002; Finsterer, 2006). Kartsounis LD, Truong DD, Morgan Hughes JA, Harding
The possibility that neuropsychological deficits AE. The neuropsychological features of mitochondrial
might be common in mitochondrial disorders was myopathies and encephalomyopathies. Arch Neurol
suggested by Kartsounis et al. (1992), who noted in 1992; 49: 158–60.
a series of 36 patients with myopathies and ence- Kornblum C, Bosbach S, Wagner M, et al. Neuropsycho-
phalomyopathies that 14 patients were thought to logical testing of patients with PEO and Kearns–Sayre
be cognitively impaired on clinical grounds, but 21 syndrome reveals distinct frontal and parieto-occipital
deficits. J Neurol 2000; 247 (suppl 3): III/73 (abstract
were found to have general intellectual decline on
P266).
testing and a further 5 of the remaining 15 had
Montagna P, Gallassi R, Medori R, et al. MELAS syndrome:
focal cognitive deficits, in the domains of language,
characteristic migrainous and epileptic features and
memory, or perception (frontal lobe tests were not maternal transmission. Neurology 1988; 38: 751–4.
administered in this series). Turconi et al. (1999) Schapira AHV, DiMauro S (eds.). Mitochondrial Disorders
found no global cognitive decline in 16 patients in Neurology (2nd edition). Boston: Butterworth-
with mitochondrial encephalomyopathies but Heinemann, 2002.
selective impairments of visuospatial skills and Turconi AC, Benti R, Castelli E, et al. Focal cognitive
short-term memory, unrelated to clinical pheno- impairment in mitochondrial encephalomyopathies: a
type and genetic mutations. Kornblum et al. (2000) neuropsychological and neuroimaging study. J Neurol
studied 18 patients with progressive external oph- Sci 1999; 170: 57–63.
thalmoplegia and Kearns–Sayre syndrome. None
had general intellectual deterioration, but disturb- 5.5.2 Leukodystrophies
ances were identified in visual construction, vigi-
lance and concentration, abstraction/flexibility, Leukodystrophies are genetic metabolic diseases
and verbal/visual memory, suggesting the presence which generally present in early childhood, often at
of frontal and parieto-occipital deficits. the time of myelination. Occasionally, however,
In MELAS, repeated cerebral infarctions may these disorders may present in adulthood (Baumann
ultimately lead to dementia (Montagna et al., & Turpin, 2000), and dementia may be one feature
1988). of the clinical phenotype. These conditions may be
recessive (e.g. metachromatic leukodystrophy) or suggestive of frontal lobe dysfunction have been
sex-linked (e.g. X-linked adrenoleukodystrophy). prominent in many of these cases (Powers et al.,
This is a heterogeneous group, including lysosomal 1980; Esiri et al., 1984; Sereni et al., 1987; Panegyres
and peroxisomal disorders. et al., 1989; Larner, 2003). Patients presenting with
marked personality change and labelled as having
manic-depressive psychosis (Angus et al., 1994) or
Metachromatic leukodystrophy (MLD)
mania with disinhibition, impulsivity, hypersexu-
Reduced enzymatic activity of arylsulphatase A ality, and perseveration (Garside et al., 1999) may
(ARSA) due to mutations in the ARSA gene result in possibly represent the same phenotype. Presenta-
accumulation of sulphatide in Schwann cells and tion with Balint syndrome and dementia has also
oligodendroglia with peripheral and central been described (Uyama et al., 1993). The patho-
demyelination, causing peripheral neuropathy and genesis of these features is presumably the func-
leukodystrophy. Depending on the degree of tional disconnection of cortical regions by an
residual enzyme activity, disease may range from advancing wave of inflammatory demyelination,
severe, late infantile, to mild, adult-onset. Cases of either anterior or posterior, which is the typical
MLD with adult-onset dementia have been pathological substrate of X-ALD. A correlation
reported. These may vary in the pattern of cognitive between frontal type dementia and an anterior
impairment: cases with amnesia, visuospatial dys- pattern of white matter change on MR imaging has
function, and attentional difficulties, with medial been noted in one case (Larner, 2003).
temporal and frontal cortical hypometabolism on With developments in diagnostic techniques,
functional imaging, are reported (Johannsen et al., particularly neuroimaging and neurogenetic test-
2001), as are cases with more typical frontal features ing, X-ALD may now be diagnosed in asymptom-
of behavioural change, apathy, and psychosis akin atic but at-risk individuals. Study of neurologically
to schizophrenia, with frontal hypoperfusion on and radiologically asymptomatic boys has shown
functional imaging (Fukutani et al., 1999; Salmon overall normal cognitive function, with the emer-
et al., 1999). Concurrent peripheral neuropathy may gence of subtle visual perceptual and visuomotor
be a clue to diagnosis, although cases with adult- deficits with age in a few (Cox et al., 2005). Early
onset dementia without neuropathy have been therapeutic intervention might be predicted to
reported (Marcão et al., 2005). preserve cognitive function, and there is some
evidence to support the view that bone marrow
transplantation may preserve neuropsychological
X-linked adrenoleukodystrophy (X-ALD)
outcome (Shapiro et al., 1995).
X-linked adrenoleukodystrophy (X-ALD) is a per-
oxisomal disorder associated with mutations in the
Alexander’s disease and Rosenthal fibre
ATP-binding cassette (ABCD1) gene, which encodes
encephalopathy (RFE)
a peroxisomal membrane protein. The clinical
phenotype varies, dependent on the age of presen- Alexander’s disease is typically a disease of child-
tation: children most often have rapidly progressive hood characterized by megalencephaly and relentless
cerebral disease, whereas adults most often present neurological deterioration, with a leukodystrophy
with adrenomyeloneuropathy (AMN), these two and the neuropathological finding of Rosenthal
phenotypes accounting for more than 75% of all fibres, eosinophilic cytoplasmic inclusions within
cases. Adult cerebral disease is the least frequently astrocyte processes adjacent to areas of demyelina-
observed phenotype (Moser et al., 2005). tion. These are immunopositive for glial fibrillary
X-ALD cases presenting with adult-onset acidic protein (GFAP), ubiquitin, and heat shock
dementia have only rarely been reported. Features proteins such as hsp27 and ab-crystallin. Mutations
in the gene encoding GFAP on chromosome 17 have Krabbe disease (globoid cell leukodystrophy)
been associated with the condition (Brenner et al.,
This autosomal recessive leukodystrophy results from
2001), including occasional adult-onset cases
deficiency of the lysosomal enzyme galactocerebro-
(Namekawa et al., 2002).
side b-galactosidase (GALC) due to mutations in the
Rosenthal fibre encephalopathy (RFE) is the name
encoding gene located on chromosome 14q24.3–
used for a condition in which the pathological
q32.1. In addition to the infantile and late-infantile/
finding of Rosenthal fibres occurs without clinical
juvenile forms that account for most cases, an adult
features of demyelinating lesions typical of Alexan-
form is also described, manifesting with spastic
der’s disease. Rosenthal fibres are typically found in
paraparesis. Dementia, optic atrophy, and peripheral
subependymal, subpial, and perivascular regions,
neuropathy also develop, although a protracted
often confined to the brainstem, and often in the
course with apparently preserved intellect has been
context of systemic illness (Wilson et al., 1996).
reported (Jardim et al., 1999). Bone marrow trans-
Occasional adult-onset cases of Alexander’s dis-
plantation may be effective in preventing dementia if
ease and RFE have been described (Jacob et al.,
performed early enough (Shapiro et al., 1995).
2003), some with dementia, for example in a patient
with learning disability who developed further
cognitive decline, ataxia, and dysarthria (Walls et al., 18q deletion (18q–) syndrome
1984). A review of adult-onset cases (Jacob et al., Deletion of the long arm of chromosome 18, also
2003) suggested that dementia was more common known as de Grouchy syndrome (OMIM #601808),
in RFE (4/11) than in Alexander’s disease (2/15). produces a variable phenotype encompassing
learning disability, short stature, variable dys-
Pelizaeus–Merzbacher disease (PMD) morphism, and neurological symptoms and signs
(de Grouchy et al., 1964). Magnetic resonance brain
Pelizaeus–Merzbacher disease (PMD) is an X- imaging shows white matter abnormalities with
linked recessive disorder of myelin due to defi- incomplete myelination and poor differentiation of
ciency of proteolipid protein (PLP) which usually grey and white matter, features ascribed to loss of
presents in the first months of life with a combin- the myelin basic protein gene (MBP) which lies on
ation of a movement disorder (head tremor, chromosome 18q. Rare deletions in which the MBP
laryngeal stridor, choreoathetosis, spastic para- gene is retained have normal-appearing white
paresis) and intellectual decline. Various forms matter. For this reason, the condition has been
have been described, including a late-onset form classified with the leukodystrophies. Occasional
known as Löwenberg–Hill syndrome (Bruyn et al., cases presenting in adult life have been reported,
1985). Point mutations, duplications, and deletions but these are due to seizure disorder rather than
of the PLP gene have been identified, as have cases cognitive decline (Adab & Larner, 2006). Lower
with the clinical phenotype of PMD but normal cognitive ability predicts larger 18q deletion size
PLP gene, suggesting that other regulatory genes (Semrud Clikeman et al., 2005)
may also be involved in disease pathogenesis
(Garbern et al., 1999).
Adult cases with dementia and movement dis- REFERENCES
order are unusual. Cases with or without PLP gene
mutation have been described, as has a case of Adab N, Larner AJ. Adult-onset seizure disorder in 18q
dementia, gait disorder, and MR evidence of deletion syndrome. J Neurol 2006; 253: 527–8.
leukodystrophy in the mother of a man with PMD, Angus B, de Silva R, Davidson R, Bone I. A family with
presumably a manifesting carrier (Saito et al., 1993; adult-onset cerebral adrenoleucodystrophy. J Neurol
Nance et al., 1996; Sasaki et al., 2000). 1994; 241: 497–9.
Baumann N, Turpin JC. Adult-onset leukodystrophies. Moser HW, Raymond GV, Dubey P. Adrenoleukodystro-
J Neurol 2000; 247: 751–9. phy: new approaches to a neurodegenerative disease.
Brenner M, Johnson AB, Boespflug-Tanguy O, et al. JAMA 2005; 294: 3131–4.
Mutations in GFAP, encoding glial fibrillary acidic Namekawa M, Takiyama Y, Aoki Y, et al. Identification of
protein, are associated with Alexander disease. Nat GFAP gene mutation in hereditary adult-onset Alexan-
Genet 2001; 27: 117–20. der’s disease. Ann Neurol 2002; 52: 779–85.
Bruyn GW, Weenink HR, Bots GT, Teepen JL, van Wolferen Nance MA, Boyadjiev S, Pratt VM, et al. Adult-onset
WJ. Pelizaeus–Merzbacher disease: the Löwenberg–Hill neurodegenerative disorder due to proteolipid protein
type. Acta Neuropathol (Berl ) 1985; 67: 177–89. gene mutation in the mother of a man with Pelizaeus–
Cox CS, Dubey P, Raymond GV, et al. Cognitive evaluation Merzbacher disease. Neurology 1996; 47: 1333–5.
of neurologically asymptomatic boys with X-linked Panegyres PK, Goldswain P, Kakulas BA. Adult-onset
adrenoleukodystrophy. Arch Neurol 2005; 63: 69–73. adrenoleukodystrophy manifesting as dementia. Am J
de Grouchy J, Royer P, Salmon C, Lamy M. Délétion Med 1989; 87: 481–3.
partielle des bras longs du chromosome 18. Pathol Biol Powers JM, Schaumburg HH, Gaffney CL. Kluver–Bucy
1964; 12: 579–82. syndrome caused by adreno-leukodystrophy. Neurology
Esiri MM, Hyman NM, Horton WL, Lindenbaum RH. 1980; 30: 1231–2.
Adrenoleukodystrophy: clinical, pathological and bio- Saito Y, Ando T, Doyu M, Takahashi A, Hashizume Y. An
chemical findings in two brothers with the onset of adult case of classical Pelizaeus–Merzbacher disease:
cerebral disease in adult life. Neuropath Appl Neurobiol magnetic resonance images and neuropathological find-
1984; 10: 429–45. ings [in Japanese]. Rinsho Shinkeigaku 1993; 33: 187–93.
Fukutani Y, Noriki Y, Sasaki K, et al. Adult-type metachro- Salmon E, van der Linden M, Maerfens-Noordhout A,
matic leukodystrophy with a compound heterozygote et al. Early thalamic and cortical hypometabolism in
mutation showing character change and dementia. adult-onset dementia due to metachromatic leukody-
Psychiatry Clin Neurosci 1999; 53: 425–8. strophy. Acta Neurol Belg 1999; 99: 185–8.
Garbern J, Cambi F, Shy M, Kamholz J. The molecular Sasaki A, Miyanaga K, Ototsuji M, et al. Two autopsy cases
pathogenesis of Pelizaeus–Merzbacher disease. Arch with Pelizaeus–Merzbacher disease phenotype of adult
Neurol 1999; 56: 1210–14. onset, without mutation of proteolipid protein gene.
Garside S, Rosebush PI, Levinson AJ, Mazurek MF. Late-onset Acta Neuropathol (Berl ) 2000; 99: 7–13.
adrenoleukodystrophy associated with long-standing psy- Semrud Clikeman M, Thompson NM, Schaub BL, et al.
chiatric symptoms. J Clin Psychiatry 1999; 60: 460–8. Cognitive ability predicts degree of genetic abnormality
Jacob J, Robertson NJ, Hilton DA. The clinicopathological in participants with 18q deletions. J Int Neuropsychol
spectrum of Rosenthal fibre encephalopathy and Alex- Soc 2005; 11: 584–90.
ander’s disease: a case report and review of the literature. Sereni C, Ruel M, Iba-Zizen T, et al. Adult adrenoleuko-
J Neurol Neurosurg Psychiatry 2003; 74: 807–10. dystrophy: a sporadic case? J Neurol Sci 1987; 80: 121–8.
Jardim LB, Giugliani R, Pires RF, et al. Protracted course of Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuro-
Krabbe disease in an adult patient bearing a novel psychological outcomes of several storage diseases with
mutation. Arch Neurol 1999; 56: 1014–17. and without bone marrow transplantation. J Inherit
Johannsen P, Ehlers L, Hansen HJ. Dementia with Metab Dis 1995; 18: 413–29.
impaired temporal glucose metabolism in late-onset Uyama E, Iwagoe H, Maeda J, et al. Presenile onset
metachromatic leukodystrophy. Dement Geriatr Cogn cerebral adrenoleukodystrophy presenting as Balint’s
Disord 2001; 12: 85–8. syndrome and dementia. Neurology 1993; 43: 1249–51.
Larner AJ. Adult-onset dementia with prominent frontal lobe Walls TJ, Jones RA, Cartlidge NEF, Saunders M. Alexan-
dysfunction in X-linked adrenoleukodystrophy with R152C der’s disease with Rosenthal fibre formation in an adult.
mutation in ABCD1 gene. J Neurol 2003; 250: 1253–4. J Neurol Neurosurg Psychiatry 1984; 47: 399–403.
Marcão AM, Wiest R, Schindler K, et al. Adult onset Wilson SP, Al-Sarraj S, Bridges LR. Rosenthal fiber
metachromatic leukodystrophy without electroclinical encephalopathy presenting with demyelination and
peripheral nervous system involvement: a new muta- Rosenthal fibers in a solvent abuser: adult Alexander’s
tion in the ARSA gene. Arch Neurol 2005; 62: 309–13. disease? Clin Neuropathol 1996; 15: 13–16.
5.5.3 Lysosomal storage disorders system), dermatological, renal, ocular, gastro-

enterological, cardiac, and respiratory features
Around 40 lysosomal storage disorders affecting
(Mehta, 2002), with variable age at diagnosis.
the brain are described (Platt & Walkley, 2004).
A slowly progressive vascular dementia has been
Learning disability/mental retardation is a feature
described (Mendez et al., 1997) with multiple cog-
in many of these disorders, but some may present
nitive deficits including memory impairment,
in adulthood with cognitive impairment as a fea-
anomia, perseveration, and visuospatial difficulties,
ture (Coker, 1991). Some of these are mentioned
with additional behavioural changes. This is due to
elsewhere: e.g. metachromatic leukodystrophy
multiple subcortical strokes and diffuse ischaemic
Krabbe disease (see Section 5.5.2).
white matter disease due to pathological involve-
ment of small penetrating arteries, hypertension
Acid maltase deficiency (glycogenosis type IIb) (secondary to renal disease), and cardiogenic
emboli. Although this is an extremely rare presen-
This autosomal recessive lysosomal disorder of tation of Anderson–Fabry disease, a case-registry
glycogen storage results from deficiency of the series reported dementia in 18% of patients, in all
lysosomal enzyme acid a-glucosidase, or acid mal- cases associated with recurrent strokes or transient
tase, due to mutation of the gene located on ischaemic attacks (MacDermott et al., 2001). Pre-
chromosome 17 which encodes this protein. The vention may be feasible with enzyme replacement
clinical phenotype is variable, with age of onset therapy.
ranging from infancy to adulthood, with myopathy,
cardiomyopathy, and organomegaly. Adult-onset
disease (Engel’s disease) may present with respira- Gangliosidosis
tory failure due to diaphragmatic involvement Late-onset GM2 gangliosidosis, also known as late-
(Trend et al., 1985). One case of adult-onset acid onset Tay–Sachs disease, resulting from autosomal
maltase deficiency (AMD) associated with low IQ recessive hexosaminidase A deficiency, may result
and impairments of frontal lobe function has been in cognitive dysfunction in about half of patients,
reported; other family members with AMD did not with impaired executive and memory function.
have dementia. As the authors point out, this may Studies disagree as to whether dementia occurs at
be a fortuitous association, but equally acid maltase all (Zaroff et al., 2004), or is common (Frey et al.,
is expressed in brain as well as in muscle, and brain 2005).
levels may be low (Prevett et al., 1992).
Gaucher’s disease
Anderson–Fabry disease (Fabry’s disease,
A rare adult neuronopathic form of this autosomal
angiokeratoma corporis diffusum, hereditary
recessive disease, due to deficiency of b-glucocer-
dystonic lipidosis)
ebrosidase, is recognized (Guimarães et al., 2003),
This autosomal recessive lysosomal storage dis- causing akinetic-rigid syndrome, supranuclear
order is due to mutations in the gene encoding gaze palsy, myoclonus, seizures, and cognitive
a-galactosidase A, with resultant enzyme deficiency decline. There is elevated serum acid phosphatase
leading to accumulation of glycosphingolipids such and bone marrow infiltration with lipid-laden
as ceramide trihexoside in the vascular endothe- fibroblasts known as Gaucher’s cells. A possible
lium and smooth muscle cells of visceral tissues link between Gaucher’s disease and the synuclei-
including brain, and in body fluids. The resultant nopathies (see Section 2.4) has been postulated,
multisystem disease has a broad phenotype, with based on the finding of synuclein-positive Lewy
neurological (peripheral and central nervous bodies in Gaucher’s patients with parkinsonism
and an increased incidence of Lewy body disorders decade (Uc et al., 2000; Battisti et al., 2003).
in the relatives of Gaucher’s probands. Carriers of Mutations in the gene encoding the cholesterol
glucocerebrosidase mutations have a wide spec- binding protein HE1 (NPC2) have been reported to
trum of parkinsonian disorders including dementia cause dementia in the 30s with focal frontal
with Lewy bodies (Hruska et al., 2006). involvement. Tau-positive neurofibrillary tangles
as well as lysosomal inclusions were seen at post-
mortem (Klünemann et al., 2002).
Neuronal ceroid lipofuscinosis (NCL), Kuf’s
disease
The neuronal ceroid lipofuscinoses (NCL) are a large Sanfilippo syndrome
group of neurodegenerative disorders with onset (mucopolysaccharidosis III)
between infancy and adulthood, characterized by This autosomal recessive disorder, associated with
accumulation of autofluorescent inclusion bodies excessive urinary excretion of heparan sulphate,
in neurones and other tissues (Wisniewski et al., comes in four biochemical and genetic variants, all
2001a,b). Kuf’s disease is the name often applied to due to deficiencies of different enzymes, usually
adult-onset variants, which may be sporadic or causing childhood-onset dementia and neurobe-
inherited, and manifest with a progressive myoclo- havioural problems. The clinical phenotype is
nus epilepsy and cognitive decline and dementia or variable, and type B cases with dementia onset in
with movement disorders such as facial dyskinesia the third or fourth decade have been reported (van
(Berkovic et al., 1988). Families with disease onset in Schrojenstein-de Valk & van de Kamp, 1987). Bone
the fourth decade, heralded by seizures and with marrow transplantation provides no benefit and is
subsequent dementia, have been reported (Joseph- therefore not recommended (Shapiro et al., 1995).
son et al., 2001). In addition to the various patho-
logical inclusions (fingerprint, curvilinear,
rectilinear, granular osmiophilic), neuritic plaques
REFERENCES
and possibly neurofibrillary tangles may also be
seen in Kuf’s disease (Wisniewski et al., 1979),
Battisti C, Tarugi P, Dotti MT, et al. Adult onset Niemann–
leading to the suggestion of an overlapping patho- Pick type C disease: a clinical, neuroimaging and
genesis with Alzheimer’s disease (Larner, 1996). molecular genetic study. Mov Disord 2003; 18: 1405–9.
Various genetic loci have been identified in the Berkovic SF, Carpenter S, Andermann F, et al. Kufs’
neuronal ceroid lipofuscinoses, with both auto- disease: a critical reappraisal. Brain 1988; 111: 27–62.
somal recessive and dominant patterns of inherit- Coker SB. The diagnosis of childhood neurodegenerative
ance (Wisniewski et al., 2001a; Mole et al., 2005). disorders presenting as dementia in adults. Neurology
1991; 41: 794–8.
Frey LC, Ringel SP, Filley CM. The natural history of
Niemann-Pick disease type C cognitive dysfunction in late-onset GM2 gangliosidosis.
Arch Neurol 2005; 62: 989–94.
This autosomal recessive disorder is a lipidosis,
Guimarães J, Amaral O, Sá Miranda MC. Adult-onset
resulting from a defect in cellular trafficking of
neuronopathic form of Gaucher’s disease: a case report.
cholesterol, leading to the accumulation of chol- Parkinsonism Relat Disord 2003; 9: 261–4.
esterol and sphingolipids in late endosomes/lyso- Hruska KS, Goker-Alpan O, Sidransky E. Gaucher disease
somes. It results from mutations in the genes NPC1 and the synucleinopathies. J Biomed Biotechnol 2006;
and NPC2. The clinical phenotype of the former is 2006: 78549 [sic].
broad, including dystonia, supranuclear gaze palsy, Josephson SA, Schmidt RE, Millsap P, McManus DQ,
ataxia, dysarthria, seizures, and progressive cogni- Morris JC. Autosomal dominant Kufs’ disease: a cause
tive decline with onset from the first to the fifth of early onset dementia. J Neurol Sci 2001; 188: 51–60.
Klünemann HH, Elleder M, Kaminski WE, et al. Frontal Zaroff CM, Neudorfer O, Morrison C, et al. Neuropsycho-
lobe atrophy due to a mutation in the cholesterol logical assessment of patients with late onset GM2
binding protein HE1/NPC2. Ann Neurol 2002; 52: 743–9. gangliosidosis. Neurology 2004; 62: 2283–6.
Larner AJ. Alzheimer’s disease, Kuf’s disease, tellurium,
and selenium. Med Hypotheses 1996; 47: 73–5.
MacDermott KD, Holmes A, Miners AH. Anderson–Fabry 5.5.4 Cerebrotendinous xanthomatosis (CTX)
disease: clinical manifestations and impact of disease in This autosomal recessive lipid storage disorder
a cohort of 98 hemizygous males. J Med Genet 2001; 38:
results from mutations in the mitochondrial
750–60.
enzyme 27-sterol hydroxylase on chromosome 2p,
Mehta A. New developments in the management of
causing impaired bile acid synthesis. Brain imaging
Anderson–Fabry disease. Q J Med 2002; 95: 647–53.
Mendez MF, Stanley TM, Medel NM, Li Z, Tedesco DT. shows global atrophy and demyelination, such that
The vascular dementia of Fabry’s disease. Dement some authorities classify CTX with the leukodys-
Geriatr Cogn Disord 1997; 8: 252–7. trophies. Spasticity, ataxia, and peripheral neur-
Mole SE, Williams RE, Goebel HH. Correlations between opathy are included amongst the neurological
genotype, ultrastructural morphology and clinical features as well as dementia, with onset in the third
phenotype in the neuronal ceroid lipofuscinoses. decade. A survey of 32 patients found low IQ in
Neurogenetics 2005; 6: 107–26. 66%, and in 81% of 181 patients reported in the
Platt FM, Walkley SU (eds.). Lysosomal Disorders of the literature (Verrips et al., 2000a,b). No detailed
Brain: Recent Advances in Molecular and Cellular
neuropsychological profile has been identified,
Pathogenesis and Treatment. Oxford: Oxford University
although a subcortical pattern might be expected.
Press, 2004.
Prevett M, Enevoldson TP, Duncan JS. Adult onset acid
maltase deficiency associated with epilepsy and demen-
tia: a case report. J Neurol Neurosurg Psychiatry 1992; REFERENCES
55: 509.
Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuro- Verrips A, Hoefsloot LH, Steenbergen GCH, et al. Clinical
psychological outcomes of several storage diseases with and molecular genetic characteristics of patients with
and without bone marrow transplantation. J Inherit cerebrotendinous xanthomatosis. Brain 2000a; 123:
Metab Dis 1995; 18: 413–29. 908–19.
Trend PStJ, Wiles CM, Spencer GT, et al. Acid maltase Verrips A, van Engelen BGM, Wevers RA, et al. Presence of
deficiency in adults. Brain 1985; 108: 845–60. diarrhea and absence of tendon xanthomas in patients
Uc EY, Wenger DA, Jankovic J. Niemann–Pick disease with cerebrotendinous xanthomatosis. Arch Neurol
type C: two cases and an update. Mov Disord 2000; 15: 2000b; 57: 520–4.
1199–203.
van Schrojenstein-de Valk HMJ, van de Kamp JJP. Follow-
5.5.5 Haemochromatosis
up on seven adult patients with mild Sanfilippo B
disease. Am J Med Genet 1987; 28: 125–30. Genetic, primary, or hereditary haemochromatosis
Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM. is an autosomal recessive disorder characterized by
Alzheimer neurofibrillary tangles in diseases other iron overload with pathological deposition in liver
than senile and presenile dementia. Ann Neurol 1979;
and pancreas, with resulting liver impairment and
5: 288–94.
diabetes mellitus respectively. Iron does not nor-
Wisniewski KE, Kida E, Golabek AA, et al. Neuronal ceroid
mally cross the blood–brain barrier, and elevated
lipofuscinoses: classification and diagnosis. Adv Genet
2001a; 45: 1–34. brain iron content is rarely if ever a feature of
Wisniewski KE, Zhong N, Philippart M. Pheno/genotypic haemochromatosis, the clinical correlate being that
correlations in neuronal ceroid lipofuscinoses. Neurol- neurological symptoms are also rare, despite sys-
ogy 2001b; 57: 576–81. temic iron overload equivalent to that seen in
acaeruloplasminaemia (see Section 5.4.5). Cognitive 5.5.6 Lafora body disease

features may be seen in hereditary movement dis-
This autosomal recessive progressive myoclonic
orders associated with abnormal iron metabolism
epilepsy syndrome typically presents in the 10- to
(e.g. neuroferritinopathy, acaeruloplasminaemia),
18-year-old age group, with epileptic seizures,
and iron content is reported to be increased in the
myoclonus, and neurological deterioration with
striatum in Huntington’s disease and in the
cognitive impairment and eventually dementia,
posterior putamen in parkinsonian-type multiple
with typical Lafora body inclusions in brain, liver,
system atrophy.
skin, and muscle. Deterministic mutations have
Cases of haemochromatosis presenting with
been demonstrated in two genes, EPM2A and
dementia and ataxia have been reported in the
EPM2B, encoding the proteins laforin and malin
context of advanced liver disease, progressing to
respectively (Minassian et al., 1998; Chan et al.,
death within 2 years of the onset of neurological
2003), which colocalize to the endoplasmic reticu-
features (Jones & Hedley-Whyte, 1983). Two cases
lum. Delayed onset up to about the age of 25 years
with mild systemic features and concurrent
has been infrequently reported (Messouak et al.,
dementia of frontotemporal type (one semantic
2002; Baykan et al., 2005). Mutations in certain
dementia, one frontal variant) have been reported,
exons of the laforin gene may be associated with an
with the suggestion that this may reflect linkage of
earlier onset (Ganesh et al., 2002).
genetic diseases, rather than a toxic consequence of
abnormal iron metabolism, although in the absence
of brain pathology the matter remains unresolved
REFERENCES
(Harvey et al., 1997). One patient had sensorineural
hearing loss, which may be significant (see superfi-
Baykan B, Striano P, Gianotti S, et al. Late-onset and slow-
cial siderosis of the nervous system, Section 3.4.3). progressing Lafora disease in four siblings with EPM2B
The association of these cases might reflect mutation. Epilepsia 2005; 46: 1695–7.
chance concurrence. It has been argued that Chan EM, Young EJ, Ianzano L, et al. Mutations in
movement disorders occurring in the context of NHLRC1 cause progressive myoclonus epilepsy. Nat
hereditary haemochromatosis should prompt a Genet 2003; 35: 125–7.
search for another cause (Russo et al., 2004), and Ganesh S, Delgado-Escueta AV, Suzuki T, et al. Genotype–
the same is probably true of cognitive impairment, phenotype correlations for EPM2A mutations in
although this might be anticipated as a conse- Lafora’s progressive myoclonus epilepsy: exon 1 muta-
tions associate with an early-onset cognitive deficit
quence of complications such as hepatic failure
subphenotype. Hum Mol Genet 2002; 11: 1263–71.
and/or diabetes mellitus.
Messouak O, Yahyaoui M, Benabdeljalil M, et al. La
maladie de Lafora à révélation tardive. Rev Neurol Paris
REFERENCES 2002; 158: 74–6.
Minassian BA, Lee JR, Herbrick JA, et al. Mutations in a
gene encoding a novel protein tyrosine phosphatase
Harvey RJ, Summerfield JA, Fox NC, Warrington EK,
cause progressive myoclonus epilepsy. Nat Genet 1998;
Rossor MN. Dementia associated with haemochroma-
20: 171–4.
tosis: a report of two cases. Eur J Neurol 1997; 4: 318–22.
Jones HR, Hedley-Whyte ET. Idiopathic hemochromatosis
(IHC): dementia and ataxia as presenting signs. Neurol- 5.5.7 Polyglucosan body disease
ogy 1983; 33: 1479–83.
Russo N, Edwards M, Andrews T, O’Brien M, Bhatia KP. Glycogen storage disease type IV, also known as
Hereditary haemochromatosis is unlikely to cause amylopectinosis or Andersen’s disease, is an auto-
movement disorders. A critical review. J Neurol 2004; somal recessive disorder associated with deficiency
251: 849–52. of the glycogen branching enzyme (GBE) encoded
5.6 Hereditary neurocutaneous syndromes 155
on chromosome 3p14. The clinical phenotype is 5.5.8 Porphyria

extremely heterogeneous (Moses & Parvari, 2002),
Although a recognized cause of various neurological
ranging from progressive liver cirrhosis and death in
and neuropsychiatric syndromes, including delir-
childhood, through cardiomyopathic and benign
ium in response to precipitating factors such as
myopathic variants, to an adult-onset neurodegen-
infection or drugs (Crimlisk, 1997; Peters & Sarkany,
erative disorder, polyglucosan body disease (PGBD).
2005), it is not clear that any one of the porphyrias
This latter is a rare disorder, often characterized by a
causes or leads to dementia, although there may be
combination of upper and lower motor neurone
complaints of poor memory. This is mentioned
signs, the latter due to an axonal sensorimotor
because of the popular association of porphyria with
peripheral neuropathy, along with urinary incon-
the madness of King George III, but the evidence for
tinence and other motor disorders. Nerve biopsy
him having had this condition is not compelling.
may be diagnostic, showing the typical poly-
glucosan bodies, which may also be seen in dermal
sweat glands or brain tissue. Dementia has been REFERENCES
reported on occasion in PGBD (Robertson et al.,
1998), apparently of frontal type (Boulan Predseil Crimlisk HL. The little imitator – porphyria: a neuropsy-
et al., 1995), sometimes associated with white chiatric disorder. J Neurol Neurosurg Psychiatry 1997;
matter changes on MR imaging (Berkhoff et al., 62: 319–28.
2001). Familial cases are reported (Bigio et al., Peters TJ, Sarkany R. Porphyria for the general physician.
1997). Mild cognitive impairment has been docu- Clin Med 2005; 5: 275–81.
mented in an individual heterozygous for a point
mutation in the GBE gene and with other clinical 5.5.9 Unverricht–Lundborg disease (Baltic
features suggesting manifesting heterozygote sta- myoclonus)
tus (Ubogu et al., 2005).
This condition, due to mutations in the cystatin B
gene, enters the differential diagnosis of progres-
REFERENCES sive myoclonic epilepsy along with Lafora body
disease, neuronal ceroid lipofuscinosis, and mito-
Berkhoff M, Weis J, Schroth G, Sturzenegger M. Extensive chondrial disorders, amongst others. In addition to
white-matter changes in case of adult polyglucosan the polymyoclonus and cerebellar ataxia, the
body disease. Neuroradiology 2001; 43: 234–6. phenotype may include a mild and slowly pro-
Bigio EH, Weiner MF, Bonte FJ, White CL. Familial gressive dementia (Mazarib et al., 2001).
dementia due to adult polyglucosan body disease. Clin
Neuropathol 1997; 16: 227–34.
Boulan Predseil P, Vital A, Brochet B, et al. Dementia of REFERENCES
frontal lobe type due to adult polyglucosan body
disease. J Neurol 1995; 242: 512–16. Mazarib A, Xiong L, Neufeld MY, et al. Unverricht–Lundborg
Moses SW, Parvari R. The variable presentations of glycogen disease in a five-generation Arab family: instability of
storage disease type IV: a review of clinical, enzymatic dodecamer repeats. Neurology 2001; 57: 1050–4.
and molecular studies. Curr Mol Med 2002; 2: 177–88.
Robertson NP, Wharton S, Anderson J, Scolding NJ. Adult
polyglucosan body disease associated with extrapyramidal 5.6 Hereditary neurocutaneous
syndrome. J Neurol Neurosurg Psychiatry 1998; 65: 788–90. syndromes (phakomatoses)
Ubogu EE, Hong STK, Akman HO, et al. Adult polygluco-
san body disease: a case report of a manifesting This category of hereditary disorders is character-
heterozygote. Muscle Nerve 2005; 32: 675–81.
ized by involvement of ectodermal structures
(nervous system, skin, eyes) with slow evolution Huson SM, Hughes RAC (eds.). The Neurofibromatoses: a
during childhood and adolescence with a tendency Pathogenetic and Clinical Overview. London: Chapman &
to formation of benign tumours or hamartomas. Hall, 1994.
The terminology may also sometimes be taken to Korf BR, Rubenstein AE. Neurofibromatosis: a Handbook
for Patients, Families, and Health Care Professionals
include conditions with cutaneous angiomatosis
(2nd edition). New York: Thieme, 2005.
and CNS abnormalities, such as ataxia telangiectasia
Larner AJ. Monogenic Mendelian disorders in general
(see Section 5.2.2) and Anderson–Fabry disease
neurological practice. Int J Clin Pract 2008; 62: in press.
(Section 5.5.3).
5.6.2 Tuberous sclerosis

5.6.1 Neurofibromatosis
Tuberous sclerosis was initially identified as a
Neurofibromatosis type 1 (NF1) is one of the com-
syndrome of mental retardation, epilepsy, and
monest monogenic Mendelian disorders seen in
facial angiofibroma, with the neuropathological
general neurology outpatient practice, but reasons
finding of tubers. The phenotype has extended to
for consultation may often be incidental to the
less severe cases with the identification of linkage
diagnosis of NF1 (Larner, 2008). However, many
to genes (TSC1, TSC2) which may act as tumour
possible neurological problems may be encountered
suppressors, and the appreciation that sub-
in both NF1 and NF2 (Huson & Hughes, 1994; Korf &
ependymal nodules reflecting abnormal neuronal
Rubenstein, 2005). In a series of 103 NF1 patients
migration occur in the majority of cases. The dif-
aged between 6 and 75 years, IQ was lower than in
ferent localization of these lesions might be pre-
control patients, although the impairment was gen-
dicted to cause differing deficits in individual
erally mild. NF1 patients had poorer reading and
patients. Neuropsychological studies in this het-
impaired short-term memory, and on computerized
erogeneous disorder have confirmed this, with a
tests had slower reaction times, higher error rates,
possible emphasis on executive tasks related to
and impaired attention. However, no particular
prefrontal pathology (Harrison & Bolton, 2002).
profile emerged (Ferner et al., 1996). Intellectual
Many patients have normal cognition. Refractory
problems in NF1 are not thought to be progressive.
seizures and presence of the TSC2 mutation have
Severe impairments are unusual and should man-
been associated with adverse cognitive outcome
date a search for another cause, either related to NF1
(Winterkorn et al., 2007).
(such as tumour or hydrocephalus) or unrelated.
Deficits of spatial memory and navigation asso-
ciated with bilateral hippocampal atrophy have
REFERENCES
been reported in bilateral vestibulopathy associated
with neurofibromatosis type 2 (see Section 6.15).
Harrison JE, Bolton PF. Cognitive dysfunction in tuber-
ous sclerosis and other neuronal migration disorders.
In: Harrison JE, Owen AM (eds.), Cognitive Deficits
REFERENCES in Brain Disorders. London: Martin Dunitz, 2002:
325–39.
Ferner RE, Hughes RAC, Weinman J. Intellectual impair- Winterkorn EB, Pulsifer MB, Thiele EA. Cognitive progno-
ment in neurofibromatosis 1. J Neurol Sci 1996; 138: sis of patients with tuberous sclerosis complex. Neurol-
125–33. ogy 2007; 68: 62–4.
6
Inflammatory, immune-mediated, and

systemic disorders
6.1 Multiple sclerosis (MS) 157

6.2 Acute disseminated encephalomyelitis (ADEM) 165
6.3 Sarcoidosis 165
6.4 Systemic lupus erythematosus (SLE) 166
6.5 Sjögren’s syndrome 168
6.7 Rheumatoid arthritis (RhA) 170
6.8 Scleroderma, systemic sclerosis 170
6.9 Relapsing polychondritis 171
6.10.1 Primary angiitis of the CNS (PACNS) 171
6.10.2 Systemic vasculitides 172
6.11 Sydenham’s chorea, paediatric autoimmune neuropsychiatric disorders
associated with streptococcal infections (PANDAS) 173
6.12.1 Paraneoplastic limbic encephalitis (PNLE) 174
6.12.2 Non-paraneoplastic limbic encephalitis (NPLE) 175
6.13 Hashimoto’s encephalopathy (HE) 176
6.14 Erdheim–Chester disease 176
6.1 Multiple sclerosis (MS) course, permitting classification into a number of

groups, which are helpful in defining cohorts for
Multiple sclerosis (MS) is a common inflammatory study: relapsing–remitting disease (RRMS), when
demyelinating disorder of CNS white matter, acute exacerbations resolve over time with no per-
the most common cause of neurological disability manent disability, is common at disease onset, but
in young adults. Ultimately, it results from this may evolve into secondary progressive disease
immune-mediated attack on the myelin–oligo- (SPMS) when disability accrues between or in
dendrocyte complex, although many features of the absence of acute exacerbations; rarely, disease
pathogenesis remain unclear (Compston & Coles, is relentlessly progressive from the onset, the pri-
2002; Compston et al., 2006). Viral infections may mary progressive pattern (PPMS). Benign variants
be a sufficient but not necessary triggering or are also recognized. Diagnostic criteria for MS
exacerbating factor (Larner, 1986; Kennedy & Stei- encompass the clinical, neuroradiological, and
ner, 1994; Dalgleish, 1997). Natural history studies laboratory findings (McDonald et al., 2001; Polman
indicate that the disease may follow a variable et al., 2005).
157
158 Inflammatory, immune-mediated, and systemic disorders
Although MS is most commonly recognized as a commonly used bedside neuropsychological tests

cause of physical disability, cognitive impairment such as the MMSE may be insensitive, particularly
is also common. This was described by Charcot, to early changes (Swirsky-Sacchetti et al., 1992).
and a large literature has subsequently developed, Recommended screening instruments include the
most particularly in the last two decades (Rao, Brief Repeatable Battery of Neuropsychological
1986; Langdon, 1997; Thornton & Raz, 1997; Tests (BRB-N: Rao, 1990; Rao et al., 1991) and the
Wishart & Sharpe, 1997; Feinstein, 1999; Foong & MS Inventory of Cognition (MUSIC: Calabrese,
Ron, 2000; Kesselring & Klement, 2001; Bobholz & 2006). The Paced Auditory Serial Addition Test
Gleason, 2006; Calabrese, 2006; Fischer & Rao, (PASAT) and its visual equivalent (PVSAT), Digit
2007). Cross-sectional community-based studies Symbol substitution, backward Digit Span, and
have shown that around 40–60% of patients with the learning stage of the California Verbal Learn-
MS have cognitive deficits, even in the early stages ing Test (CVLT) are suggested as elements to be
of disease (McIntosh-Michaelis et al., 1991; Rao included in meaningful batteries for neuro-
et al., 1991). Literature reviews suggest an even psychological screening (Lensch et al., 2006; Sartori
higher percentage (Peyser et al., 1990). Clearly all & Edan, 2006). PASAT is also included in the
series are subject to some degree of selection bias, Multiple Sclerosis Functional Composite (MSFC)
and obviously may mask individual variability, but scale. Impairments in these screening tests may be
nonetheless cognitive dysfunction appears to be followed up with more comprehensive batteries
common in MS. such as the Minimal Assessment of Cognitive
Concomitant neurological and psychiatric fea- Function in MS (MACFIMS: Benedict et al., 2002)
tures might contribute to this morbidity, including and WMS-R.
depression, fatigue, primary sensory abnormalities The relationship of cognitive impairment to the
of vision or hearing, dominant hand dysfunction, natural history, neurological signs, and neuroima-
or concurrent medications, factors which need to ging correlates of MS has been extensively investi-
be considered when assessing subjective memory gated. As regards natural history, cognitive
complaints in MS patients (Maor et al., 2001). impairment may be an early feature of disease. IQ
Nonetheless, in many instances impairments decline and auditory attention deficits were found in
occur independent of these factors, i.e. the disease one study of patients with clinically isolated syn-
per se is responsible. The neuropsychological dromes of the kind which often evolve to MS (optic
domains most commonly affected are verbal and neuritis, brainstem and partial spinal cord syn-
non-verbal memory, with impaired attention, dromes), with a mean duration of symptoms of over
reduced speed of information processing, and 2 years (Callanan et al., 1989). Even in patients with
abstract reasoning and verbal fluency deficits, symptoms of only a few days’ duration, impaired
with or without mild visuospatial impairments. auditory (PASAT) and visual (PVSAT) attention has
Since deficits typical of cortical dementia, such as been recorded, particularly in patients with radio-
aphasia, agnosia, and apraxia, seldom occur, the logical evidence of brain lesions (Feinstein et al.,
cognitive impairment in MS has been classified as 1992b). Attention and non-verbal memory may be
a subcortical dementia. impaired in early disease (Schulz et al., 2006).
Such is the frequency of cognitive deficits in Cognitive impairments in newly diagnosed
MS, with their effects on quality of life and patients were also observed by Jønsson et al. (2006)
vocational status, that a systematic search has in a group consisting mostly of patients with
been recommended, using instruments sensitive relapsing–remitting disease (RRMS), in which
to the most commonly affected domains. Since, situation Zivadinov et al. (2001) showed a correl-
typically for a white matter dementia, these def- ation of cognitive deterioration with brain paren-
icits may be regarded as subcortical (Rao, 1996), chymal volume atrophy, suggesting that axonal loss
6.1 Multiple sclerosis 159
was the key substrate for early development and With respect to neurological dysfunction, the
progression. In acute relapses or disease exacer- correlations with cognitive impairments are gen-
bations, attention and memory test performance erally poor. For example, cognitive dysfunction far
may be compromised, but may improve with greater than neurological disability has been
remission, with a decrease in gadolinium-enhanced described in association with frontal release signs
MR lesion load (Foong et al., 1998). Hence cognitive (Franklin et al., 1989), or even in the absence of
decline may be reversible in the early stages of physical disability (Tinnefeld et al., 2005). A rare
disease. ‘cortical variant’ of MS has also been reported,
A study of patients with primary progressive dis- presenting with a progressive dementia with
ease (PPMS) showed no change in mean cognitive prominent amnesia, with or without aphasia,
scores over a 2-year follow-up period. One-third alexia, and agraphia, often with prominent mood
showed absolute cognitive decline on individual test disturbance (Zarei et al., 2003). Presumably this
scores, but only a weak relation between cognitive syndrome correlates with small cortical lesions in
and MR imaging measures was found (Camp et al., MS, under-represented by MR imaging (Kidd et al.,
2005). Comparing different MS types, cognitive def- 1999; Kutzelnigg & Lassmann, 2006).
icits are reported to be more marked in secondary With respect to neuroimaging correlates, total
progressive as compared to RRMS (Heaton et al., lesion score in terms of area or volume on MR
1985). Comparing primary and secondary progres- imaging shows significant correlation with cogni-
sive disease (PPMS versus SPMS), Wacowius et al. tive dysfunction (Rao et al., 1989a; Feinstein et al.,
(2005) reported PPMS patients to be more frequently 1992b) and it is this overall burden rather than
and more severely affected than SPMS patients, with regional brain disease which is most important in
poorer performance in verbal learning and verbal determining cognitive deficits (Rovaris et al., 1998).
fluency. However, a review of cross-sectional and Longitudinal studies indicate that progression of
longitudinal studies came to the conclusion that brain pathology correlates with cognitive decline
cognitive dysfunction was more frequent in SPMS (Feinstein et al., 1992a; Hohol et al., 1997). Stable
than in PPMS or RRMS (Amato et al., 2006). MR lesion scores seem to be associated with no
Longitudinal studies suggest that cognitive cognitive decline. Brain atrophy may also be rele-
deterioration occurs in a minority of MS patients, vant: Rao et al. (1989a) showed an association
with considerable individual variation over time. between corpus callosum atrophy and reduced
Following up a cohort of patients with clinically speed of information processing, and Zivadinov
isolated syndromes (Callanan et al., 1989), Feinstein et al. (2001) showed a correlation between cogni-
et al. (1992a) found that at the group level only tive deterioration and brain parenchymal volume
visual memory had deteriorated significantly, whilst atrophy in RRMS. In a 5-year prospective cohort
patients who had developed a chronic progressive study of RRMS, T1 lesion volumes were predictive
course were more impaired on tests of verbal of future cognitive impairment, and IQ decline and
memory and auditory attention. Follow-up studies memory impairment were more severe in those
of patients with established MS have shown with higher atrophy scores (Summers et al., 2006).
considerable individual variation, many patients Hence both inflammatory and degenerative pro-
not progressing, although some new deficits may cesses may contribute to cognitive dysfunction.
become apparent in others (Jennekens-Schinkel
et al., 1990; Amato et al., 1995; Hohol et al., 1997).
Those with cognitive impairment at baseline seem
more likely to develop progressive cognitive decline, The cognitive profile in MS is heterogeneous, as for
whereas those who are cognitively normal may the neurological findings, so only a general picture
remain so (Kujala et al., 1997). can be given (Table 6.1).
Table 6.1. Neuropsychological deficits in multiple sclerosis (MS).
Attention Impaired processing speed, working memory (backward Digit Span, PASAT)
General intelligence, IQ # FSIQ vs. premorbid IQ; PIQ typically more impaired than VIQ
Memory Impaired verbal and spatial learning, acquisition þ/ encoding; semantic and implicit
memory relatively preserved
Language Aphasia rare
Perception Visuospatial and visuoperceptual deficits may occur
Praxis Praxis difficult to assess with concurrent motor deficits
Executive function Dysexecutive syndrome common: impaired abstract reasoning, concept formation, and
problem solving
Attention these findings it has been suggested that impaired

Although simple tests of attention such as Digit speed of information processing may be a key
Span may be normal in MS, analysis of the more deficit in MS, with implications for rehabilitation
demanding backwards component of this task strategies (Demaree et al., 1999). Attentional def-
demonstrates more impairment in MS patients icits may be present even in the early stages of
than in controls (Rao et al., 1991; Feinstein et al., disease (Callanan et al., 1989; Schulz et al., 2006).
1997). The capacity to store and access information
held in working memory seems intact, although it General intelligence, IQ
may become impaired in disease exacerbations Measures of general intelligence in MS, virtually all
(Grant et al., 1984) or if disease course becomes using the NART to predict premorbid IQ, have
progressive (Beatty et al., 1988). More stringent tests consistently found a fall in IQ, but this is mainly
of attention may be abnormal even in early disease; related to measures on the performance scales,
for example, the PASAT is generally performed worse impairments in which may be related to sensori-
by MS patients than by controls (Feinstein et al., motor dysfunction. Verbal IQ scores generally
1992b; D’Esposito et al., 1996), and likewise the vis- remain stable.
ual version, PVSAT (Feinstein et al., 1992b). Sub-
clinical working memory dysfunction may be Memory
evident on neurophysiological studies measuring Although impairments in ‘short-term memory’ are
event-related potentials (Pelosi et al., 1997). present (considered under attention, above), deficits
These results may reflect an inability to devote specifically of long-term (secondary) memory are
sufficient attentional resources to process simul- probably the commonest memory impairment in
taneously the multiple components of these tasks. MS (Rao et al., 1989b; Feinstein, 1999; Calabrese,
These are also tests of speed of information pro- 2006). This refers to both verbal and non-verbal
cessing (as well as of arithmetical ability and short- memory (Grant et al., 1984; Rao et al., 1991). Since
term memory), such that fatigue is a potential deficits are more apparent on tests of recall than
confounder. In support of a defect in cognitive recognition, a defect of retrieval rather than
speed, slowed scanning of working memory (Reed– encoding has been postulated, although there is also
Sternberg paradigm) has been demonstrated (Rao evidence of impaired acquisition or encoding of
et al., 1989c), as has slowed information processing new information (DeLuca et al., 1994; Thornton &
in both auditory and visual tasks when controlling Raz, 1997). As regards remote (retrograde) memory
for accuracy of task performance. On the basis of deficits, deficits in famous faces recognition tests
have been reported by some authors (Beatty et al., Impairments in tests reliant on complex spatial
1988) but not others (Rao et al., 1991), although the stimuli, such as Raven’s Progressive Matrices, have
patients in these two studies were not comparable. been detected by some authors (Rao et al., 1991)
Impairments in verbal fluency also suggest a retro- but not others (Jennekens-Schinkel et al., 1990).
grade memory loss (Rao et al., 1991). Implicit (pro- Visual form agnosia has been reported on occasion
cedural) memory seems relatively intact in MS (Okuda et al., 1996).
(Beatty et al., 1990; Grafman et al., 1991).
Praxis
Language Motor deficits (weakness, spasticity) may confound
Although disorders of speech, dysarthria, are assessment of praxis in MS. Apraxia has occasion-
common in MS, disorders of language, aphasia, ally been mentioned as a symptom (Herscovitch
have been considered rare (Murdoch & Theodoros, et al., 1984; Okuda et al., 1996). Callosal discon-
2000). However, careful assessment of language nection syndromes seem to be rare in MS (Schnider
function may reveal abnormalities in patients with et al., 1993), notwithstanding the predilection for
onset of cognitive decline (Kujala et al., 1996). corpus callosum involvement so evident on MR
Aphasia, alexia, and agraphia may be present in the brain imaging.
‘cortical variant’ of MS, which presents with pro-
gressive dementia with prominent amnesia (Zarei Executive function
et al., 2003). A study of 2700 patients from three Tests of planning, problem solving, concept for-
centres in France found 22 cases (0.81%) of acute mation, utilization of feedback, and abstract rea-
aphasia in MS (Lacour et al., 2004). This may rarely soning, all of which may be subsumed under the
occur as a monosymptomatic presentation of MS heading of ‘executive function’ or cognitive flexi-
(Erdem et al., 2001; Di Majo et al., 2002; Lacour bility (even though different skills and neuroana-
et al., 2004), or as a feature of acute exacerbation in tomical substrates may be implicated), have been
association with new left hemisphere white matter found to be impaired in some MS patients. On the
lesions on MR imaging in established MS (Achiron Wisconsin Card Sorting Test, MS patients may
et al., 1992; Devere et al., 2000). However, aetiolo- show poor performance (Heaton et al., 1985; Rao
gies other than acute inflammation need to be et al., 1987, 1991), sufficient to differentiate them
considered in MS patients with acute aphasia, from healthy controls, perhaps more so in chronic
including non-convulsive ‘aphasic’ status epilepti- progressive disease. Problem solving with Raven’s
cus (Primavera et al., 1996; Trinka et al., 2001), Progressive Matrices is also impaired (Rao et al.,
which has also been reported as the initial pre- 1991), although this also tests visuospatial skills.
senting symptom of MS (Trinka et al., 2002) and of Tests of verbal fluency, such as the COWAT, are
MS relapse (Spatt et al., 1994). Second pathologies, affected (Rao et al., 1991).
as well as alternative aetiologies, may need to be Whether it may be inferred that these deficits
ruled out (Larner & Lecky, 2007). It has also been reflect ‘frontal lobe’ dysfunction in MS has been
suggested that aphasic presentations of MS may in harder to answer. Poor performance on executive
fact be cases of acute disseminated encephalo- tasks could not be attributed solely to frontal lobe
myelitis (ADEM: Section 6.2; Brinar et al., 2004). MR changes in one study, suggesting that there is a
general effect of cerebral dysfunction on tasks such
Perception as WCST (Foong et al., 1997). Moreover, because of
Assessment of visuospatial and visuoconstructive the links of frontal cortex to subcortical structures
functions is problematic in MS because of con- (thalamus, basal ganglia), remote lesions might
current peripheral visual impairments; motor produce these symptoms, e.g. white matter lesions
deficits may also contribute to testing difficulties. undercutting frontal-subcortical circuits.
Treatment of neuropsychological deficits Amato MP, Zipoli V. Clinical management of cognitive

impairment in multiple sclerosis: a review of current
Little is currently known about the optimal treatment evidence. Int MS J 2003; 10 (3): 72–83.
of cognitive disorders in MS. Options include dis- Amato MP, Zipoli V, Portaccio E. Multiple sclerosis-
ease-modifying agents, symptomatic treatments, and related cognitive changes: a review of cross-sectional
cognitive rehabilitation techniques including cogni- and longitudinal studies. J Neurol Sci 2006; 245: 41–6.
tive behavioural therapy (Amato & Zipoli, 2003). Barak Y, Achiron A. Effect of interferon-beta-1b on
Increasingly cognitive measures are being included cognitive functions in multiple sclerosis. Eur Neurol
as endpoints in therapeutic trials. Occasionally, acute 2002; 47: 11–14.
focal deficits may resolve following administration of Beatty WW, Goodkin DE, Monson N, Beatty PA. Implicit
learning in patients with chronic-progressive multiple
steroids (Rozewicz et al., 1996; Devere et al., 2000),
sclerosis. Int J Clin Neuropsychol 1990; 12: 153–62.
but generally deficits are more likely to accrue. Trials
Beatty WW, Goodkin DE, Monson N, Beatty PA, Herts-
of ‘disease-modifying drugs’ have sometimes sug-
gaard D. Anterograde and retrograde amnesia in
gested benefits in particular cognitive domains, for patients with chronic progressive multiple sclerosis.
example with the interferons (e.g. Pliskin et al., 1996; Arch Neurol 1988; 42: 611–19.
Fischer et al., 2000; Barak & Achiron, 2002), or sta- Benedict RHB, Fischer JS, Archibald CJ, et al. Minimal
bility of cognitive function over time, for example neuropsychological assessment of MS patients: a
with glatiramer (Weinstein et al., 1999). consensus approach. Clin Neuropsychol 2002; 16:
Cholinesterase inhibitors (ChEIs), established 381–97.
agents in the treatment of Alzheimer’s disease, have Bobholz JA, Gleason A. Cognitive dysfunction in multiple
been suggested for use in MS (Porcel & Montalban, sclerosis. In: Gauthier S, Scheltens P, Cummings JL
(eds.), Alzheimer’s Disease and Related Disorders Annual
2006). Small trials suggest that ChEIs may be helpful
5. London: Taylor & Francis, 2006: 165–80.
in MS patients with mild cognitive impairments
Brinar VV, Poser CM, Basic S, Petelin Z. Sudden onset
(Krupp et al., 2004). Functional imaging studies
aphasic hemiplegia: an unusual manifestation of dis-
suggesting that ChEIs may modulate functional seminated encephalomyelitis. Clin Neurol Neurosurg
adaptive neuroplasticity in the MS brain (Parry 2004; 106: 187–96.
et al., 2003) may lend some support to the rationale Calabrese P. Neuropsychology of multiple sclerosis: an
for ChEI use in MS. However, changes in brain overview. J Neurol 2006; 253 (Suppl 1): I/10–15.
activation patterns observed on fMRI during cogni- Callanan M, Logsdail SJ, Ron MA, Warrington EK.
tive testing in MS patients compared with controls Cognitive impairment in patients with clinically isolated
may be interpreted as compensatory, adaptive lesions of the type seen in multiple sclerosis: a
responses, reflecting inherent brain neuroplasticity psychometric and MRI study. Brain 1989; 112: 361–74.
Camp SJ, Stevenson VL, Thompson AJ, et al. A longitu-
(Staffen et al., 2002). Such changes may need to be
dinal study of cognition in primary progressive multiple
taken into account when assessing whether MS
sclerosis. Brain 2005; 128: 2891–8.
disease-modifying drugs or ChEIs have any effect on
Compston A, Coles A. Multiple sclerosis. Lancet 2002; 359:
cognitive function. 1221–31.
Compston A, Confavreux C, Lassmann H, et al. McAlpine’s
Multiple Sclerosis (4th edition). London: Churchill
REFERENCES Livingstone, 2006.
Dalgleish AG. Viruses and multiple sclerosis. Acta Neurol
Achiron A, Ziv I, Djaldetti R, et. al. Aphasia in multiple Scand 1997; 169 (suppl): 8–15.
sclerosis: clinical and radiologic correlations. Neurology DeLuca J, Barbieri-Berger S, Johnson SK. The nature of
1992; 42: 2195–7. memory impairments in multiple sclerosis: acquisition
Amato MP, Ponziani G, Pracucci G, et al. Cognitive versus retrieval. J Clin Exp Neuropsychol 1994; 16: 183–9.
impairment in early-onset multiple sclerosis. Arch Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed
Neurol 1995; 52: 168–72 of information processing as a key deficit in multiple
sclerosis: implications for rehabilitation. J Neurol Grafman J, Rao S, Bernardin L, Leo GJ. Automatic memory
Neurosurg Psychiatry 1999; 67: 661–3. processes in patients with multiple sclerosis. Arch
D’Esposito M, Onishi K, Thompson H, et al. Working Neurol 1991; 48: 1072–5.
memory impairments in multiple sclerosis: evidence Grant I, McDonald WI, Trimble MR, Smith E, Reed R.
from a dual-task paradigm. Neuropsychology 1996; 10: Deficient learning and memory in early and middle
51–6. phases of multiple sclerosis. J Neurol Neurosurg
Devere TR, Trotter JL, Cross AH. Acute aphasia in multiple Psychiatry 1984; 47: 250–5.
sclerosis. Arch Neurol 2000; 57: 1207–9. Heaton RK, Nelson LM, Thompson DS, Burks JS, Franklin
Di Majo L, Bisceglia M, Lanzillo R, et al. Aphasia as a rare GM. Neuropsychological findings in relapsing–remitting
presentation of monosymptomatic demyelinating dis- and chronic–progressive multiple sclerosis. J Consult
ease: case report and review of the literature. Neurol Sci Clin Psychol 1985; 53: 103–10.
2002; 23: 79–82. Herscovitch P, Trotter JL, Lemann W, Raichle ME.
Erdem H, Stålberg E, Caglar I. Aphasia in multiple Positron emission tomography (PET) in active MS:
sclerosis. Ups J Med Sci 2001; 106: 205–10. demonstration of demyelination and diaschisis. Neurol-
Feinstein A. The Clinical Neuropsychiatry of Multiple ogy 1984; 34 (suppl 1): 78.
Sclerosis. Cambridge: Cambridge University Press, 1999: Hohol MJ, Guttmann CRG, Orav J, et al. Serial neuro-
96–196. psychological assessment and magnetic resonance
Feinstein A, Feinstein KJ, Gray T, O’Connor P. Neuro- imaging analysis in multiple sclerosis. Arch Neurol
behavioral correlates of pathological crying and 1997; 54: 1018–25.
laughing in multiple sclerosis. Arch Neurol 1997; 54: Jennekens-Schinkel A, Laboyrie PM, Lanser JB, van der
1116–21. Velde EA. Cognition in patients with multiple sclerosis:
Feinstein A, Kartsounis L, Miller D, Youl B, Ron M. after four years. J Neurol Sci 1990; 99: 229–47.
Clinically isolated lesions of the type seen in multiple Jønsson A, Andresen J, Storr L, et al. Cognitive impairment
sclerosis: a cognitive, psychiatric and MRI follow-up in newly diagnosed multiple sclerosis patients: a 4-year
study. J Neurol Neurosurg Psychiatry 1992a; 55: 869–76. follow-up study. J Neurol Sci 2006; 245: 77–85.
Feinstein A, Youl B, Ron M. Acute optic neuritis: a Kennedy PGE, Steiner I. On the possible viral aetiology of
cognitive and magnetic resonance imaging study. multiple sclerosis. Q J Med 1994; 87: 523–8.
Brain 1992b; 115: 1403–15. Kesselring J, Klement U. Cognitive and affective disturb-
Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological ances in multiple sclerosis. J Neurol 2001; 248: 180–3.
effects of interferon beta-1a in relapsing multiple Kidd D, Barkhof F, McConnell R, et al. Cortical lesions in
sclerosis. Multiple Sclerosis Collaborative Research multiple sclerosis. Brain 1999; 122: 17–26.
Group. Ann Neurol 2000; 48: 885–92. Krupp LB, Christodoulou C, Melville P, et al. Donepezil
Fischer JS, Rao SM. Assessment of neuropsychological improved memory in multiple sclerosis in a randomized
function in multiple sclerosis. In: Cohen JA, Rudick RA clinical trial. Neurology 2004; 63: 1579–85.
(eds.), Multiple Sclerosis Therapeutics (3rd edition). Kujala P, Portin R, Ruutiainen J. Language functions in
Abingdon: Informa Healthcare, 2007: 79–99. incipient cognitive decline in multiple sclerosis.
Foong J, Ron M. Cognitive impairment and neuropsycho- J Neurol Sci 1996; 141: 79–86.
logical assessment in multiple sclerosis. Int MS J 2000; Kujala P, Portin R, Ruutiainen J. The progress of cognitive
7 (1): 31–4. decline in multiple sclerosis: a controlled 3-year follow-
Foong J, Rozewicz L, Quaghebeur G, et al. Executive up. Brain 1997; 120: 289–97.
function in multiple sclerosis. The role of frontal lobe Kutzelnigg A, Lassmann H. Cortical demyelination in
pathology. Brain 1997; 120: 15–26. multiple sclerosis: a substrate for cognitive deficits?
Foong J, Rozewicz L, Quaghebeur G, et al. Neuropsycho- J Neurol Sci 2006; 245: 123–6.
logical deficits in multiple sclerosis after acute Lacour A, De Seze J, Revenco E, et al. Acute aphasia in
relapse. J Neurol Neurosurg Psychiatry 1998; 64: multiple sclerosis: a multicenter study of 22 patients.
529–32. Neurology 2004; 62: 974–7.
Franklin GM, Nelson LM, Filley CM, Heaton RK. Cognitive Langdon DW. Cognitive dysfunction in multiple sclerosis:
loss in multiple sclerosis: case reports and review of the what are we measuring and why does it matter? In:
literature. Arch Neurol 1989; 46: 162–7. Thompson AJ, Polman C, Hohlfeld R (eds.), Multiple
Sclerosis: Clinical Challenges and Controversies. London: Primavera A, Gianelli MV, Bandini F. Aphasic status
Martin Dunitz, 1997: 253–63. epilepticus in multiple sclerosis. Eur Neurol 1996; 36:
Larner AJ. Aetiological role of viruses in multiple sclerosis: 374–7.
a review. J R Soc Med 1986; 79: 412–17. Rao SM. Neuropsychology of multiple sclerosis: a critical
Larner AJ, Lecky BRF. Acute aphasia in MS revisited. Int review. J Clin Exp Neuropsychol 1986; 8: 503–42.
MS J 2007; 14: 76–7. Rao SM. A Manual for the Brief Repeatable Battery of
Lensch E, Matzke M, Peteriet HF, et al. Identification and Neuropsychological Tests in Multiple Sclerosis. New
management of cognitive disorders in multiple scler- York: National Multiple Sclerosis Society, 1990.
osis: a consensus approach. J Neurol 2006; 253 (suppl 1): Rao SM. White matter disease and dementia. Brain Cogn
I/29–31. 1996; 31: 250–68.
McDonald WI, Compston A, Edan G, et al. Recommended Rao SM, Hammeke TA, Speech TJ. Wisconsin Card Sorting
diagnostic criteria for multiple sclerosis: guidelines Test performance in relapsing–remitting and chronic–
from the International Panel on the Diagnosis of progressive multiple sclerosis. J Consult Clin Psychol
Multiple Sclerosis. Ann Neurol 2001; 50: 121–7. 1987; 55: 263–5.
McIntosh-Michaelis SA, Wilkinson SM, Diamond ID, et al. Rao SM, Leo GJ, Bernadin L, Unversagt F. Cognitive
The prevalence of cognitive impairment in a commu- dysfunction in multiple sclerosis. I. Frequency, patterns
nity survey of multiple sclerosis. Br J Clin Psychol 1991; and predictions. Neurology 1991; 41: 685–91.
30: 333–48. Rao SM, Leo GJ, Haughton VM, St Aubin-Faubert P,
Maor Y, Olmer L, Mozes B. The relation between objective Bernadin L. Correlation of magnetic resonance imaging
and subjective impairment in cognitive function among with neuropsychological testing in multiple sclerosis.
MS patients: the role of depression. Multiple Sclerosis Neurology 1989a; 39: 161–6.
2001; 7: 131–5. Rao SM, Leo GJ, St Aubin-Faubert P. On the nature of
Murdoch B, Theodoros D (eds.). Speech and Language memory disturbance in multiple sclerosis. J Clin Exp
Disorders in Multiple Sclerosis. London: Whurr, 2000. Neuropsychol 1989b; 11: 699–712.
Okuda B, Tanaka H, Tachibana H, et al. Visual form agnosia Rao SM, St Aubin-Faubert P, Leo GJ. Information
in multiple sclerosis. Acta Neurol Scand 1996; 94: 38–44. processing speed in patients with multiple sclerosis.
Parry AMM, Scott RB, Palace J, Smith S, Matthews PM. J Clin Exp Neuropsychol 1989c; 11: 471–7.
Potentially adaptive functional changes in cognitive Rovaris M, Filippi M, Falautano M, et al. Relation between
processing for patients with multiple sclerosis and their MR abnormalities and patterns of cognitive impairment
acute modulation by rivastigmine. Brain 2003; 126: in multiple sclerosis. Neurology 1998; 50: 1601–8.
2750–60. Rozewicz L, Langdon DW, Davie CA, Thompson AJ, Ron
Pelosi L, Geesken JM, Holly M, Hayward M, Blumhardt MA. Resolution of left hemisphere cognitive dysfunction
LD. Working memory impairment in early multiple in multiple sclerosis with magnetic resonance correl-
sclerosis: evidence from an event-related potential ates: a case report. Cognit Neuropsychiatry 1996; 1:
study of patients with clinically isolated myelopathy. 17–25.
Brain 1997; 120: 2039–58. Sartori E, Edan G. Assessment of cognitive dysfunction in
Peyser JM, Rao SM, LaRocca NG, Kaplan E. Guidelines for multiple sclerosis. J Neurol Sci 2006; 245: 169–75.
neuropsychological research in multiple sclerosis. Arch Schnider A, Benson F, Rosner LJ. Callosal disconnection in
Neurol 1990; 47: 94–7. multiple sclerosis. Neurology 1993; 43: 1243–5.
Pliskin NH, Hamer DP, Goldstein DS, et al. Improved Schulz D, Kopp B, Kunkel A, Faiss JH. Cognition in the
delayed visual reproduction test performance in mul- early stage of multiple sclerosis. J Neurol 2006; 253:
tiple sclerosis patients receiving interferon beta-1b. 1002–10.
Neurology 1996; 47: 1463–8. Spatt J, Goldenberg G, Mamoli B. Simple dysphasic
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria seizures as the sole manifestation of relapse in multiple
for multiple sclerosis: 2005 revisions to the McDonald sclerosis. Epilepsia 1994; 35: 1342–5.
criteria. Ann Neurol 2005; 58: 840–6. Staffen W, Mair A, Zauner H, et al. Cognitive function and
Porcel J, Montalban X. Anticholinesterasics [sic] in the fMRI in patients with multiple sclerosis: evidence for
treatment of cognitive impairment in multiple sclerosis. compensatory cortical activation during an attention
J Neurol Sci 2006; 245: 177–81. task. Brain 2002; 125: 1275–82.
6.3 Sarcoidosis 165
Summers M, Anderson VM, Fisniku L, et al. Predicting Höllinger et al., 2002). Although usually a mono-
cognitive impairment in relapsing–remitting multiple phasic illness, multiphasic and recurrent variants
sclerosis. J Neurol 2006; 253 (suppl 2): II/7 (abstract have occasionally been described, making it diffi-
O35). cult to differentiate ADEM from a first episode of
Swirsky-Sacchetti T, Field HL, Mitchell DR, et al. The
multiple sclerosis (MS). Suggested operational cri-
sensitivity of the Mini-Mental State Examination in the
teria (Schwarz et al., 2001) may be confounded in
white matter dementia of multiple sclerosis. J Clin
clinical practice (John et al., 2003). The clinical
Psychol 1992; 48: 779–86.
Thornton AE, Raz N. Memory impairment in multiple
picture is heterogeneous, with encephalopathy,
sclerosis: a quantitative review. Neuropsychology 1997; focal neurological signs, and even psychosis being
11: 357–66. the presenting features. Aphasia has been reported
Tinnefeld M, Treitz FH, Haase CG, et al. Attention and as a presenting feature with hemiplegia, hemi-
memory dysfunctions in mild multiple sclerosis. Eur sensory deficit, and facial palsy (Brinar et al., 2004),
Arch Psychiatry Clin Neurosci 2005; 255: 319–26. prompting the suggestion that acute aphasic pre-
Trinka E, Unterberger I, Luef G, et al. Acute aphasia in sentations of MS may in fact be cases of ADEM.
multiple sclerosis. Arch Neurol 2001; 58: 133–4.
Trinka E, Unterberger I, Spiegel M, et al. De novo aphasic
status epilepticus as presenting symptom of multiple
sclerosis. J Neurol 2002; 249: 782–3.
REFERENCES
Wacowius U, Talley M, Silver N, Heinze HJ, Sailer M.
Cognitive impairment in primary and secondary pro- Brinar VV, Poser CM, Basic S, Petelin Z. Sudden onset
gressive multiple sclerosis. J Clin Exp Neuropsychol aphasic hemiplegia: an unusual manifestation of dis-
2005; 27: 65–77. seminated encephalomyelitis. Clin Neurol Neurosurg
Weinstein A, Schwid SI, Schiffer RB, et al. Neuropsycho- 2004; 106: 187–96.
logic status in multiple sclerosis after treatment with Höllinger P, Sturzenegger M, Mathis J, Schroth G, Hess
glatiramer. Arch Neurol 1999; 56: 319–24. CW. Acute disseminated encephalomyelitis in adults: a
Wishart H, Sharpe D. Neuropsychological aspects of reappraisal of clinical, CSF, EEG, and MRI findings.
multiple sclerosis: a quantitative review. J Clin Exp J Neurol 2002; 249: 320–9.
Neuropsychol 1997; 19: 810–24. John L, Khaleeli AA, Larner AJ. Acute disseminated
Zarei M, Chandran S, Compston A, Hodges J. Cognitive encephalomyelitis: a riddle wrapped in a mystery inside
presentation of multiple sclerosis: evidence for a an enigma. Int J Clin Pract 2003; 57: 235–7.
cortical variant. J Neurol Neurosurg Psychiatry 2003; Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-
74: 872–7. Hagenlocher B. Acute disseminated encephalomyelitis:
Zivadinov R, Sepcic J, Nasuelli D, et al. A longitudinal a follow-up study of 40 adult patients. Neurology 2001;
study of brain atrophy and cognitive disturbances in the 56: 1313–18.
early phase of relapsing–remitting multiple sclerosis. Wang PN, Fuh JL, Liu HC, Wang SJ. Acute disseminated
J Neurol Neurosurg Psychiatry 2001; 70: 773–80. encephalomyelitis in middle-aged or elderly patients.
Eur Neurol 1996; 36: 219–23.
6.2 Acute disseminated encephalomyelitis

(ADEM) 6.3 Sarcoidosis
Acute disseminated encephalomyelitis (ADEM) Sarcoidosis is a systemic immunologically medi-

is an inflammatory CNS disorder of presumed ated disorder of uncertain aetiology characterized
autoimmune aetiology. Although affecting mainly pathologically by non-caseating epithelioid cell
children, sometimes following infection or granulomata. The organs most commonly affected
immunization, ADEM is also well recognized in are the lymph nodes, lungs, liver, spleen, skin, and
adults (Wang et al., 1996; Schwarz et al., 2001; eyes. Neurosarcoidosis as one feature of systemic
sarcoidosis is relatively rare (5–15% of cases), isol- ances of a skin lesion. Focal cognitive deficits
ated intracranial disease even more so, the com- related to the rare presentation of sarcoidosis as a
monest neurological features being hypothalamic cerebral mass lesion (‘sarcoid tumour’: Larner
involvement and cranial nerve palsy (Nowak & et al., 1999) or as cerebral haemorrhage related to
Widenka, 2001). thrombocytopenia (Larner, 1990) might also be
Dementia as a presenting manifestation of sar- anticipated.
coidosis has been reported to be rare. Schielke et al.
(2001) identified only 10 cases in addition to their
own report, in which frontal-subcortical deficits REFERENCES
were evident: apathy, bradyphrenia, verbal per-
severation, impaired speech fluency, as well as Flowers JM, Omer SM, Wren DW, Al-Memar AY. Neuro-
memory difficulties, with associated paratonia, sarcoidosis presenting with cognitive impairment: a
series of five cases. J Neurol Neurosurg Psychiatry 2006;
grasp reflex, and motor perseveration. All had
77: 128 (abstract 010).
abnormal CSF indices (raised protein, white cell
Larner AJ. Life-threatening thrombocytopenia in sarcoid-
count) where these were tested. The importance of
osis. BMJ 1990; 300: 317–19.
obtaining tissue confirmation of diagnosis prior to Larner AJ, Ball JA, Howard RS. Sarcoid tumour: continuing
commencement of steroid therapy and exclusion diagnostic problems in the MRI era. J Neurol Neurosurg
of CNS tuberculosis was emphasized. These Psychiatry 1999; 66: 510–12.
patients were noted to be older at age of onset Nowak DA, Widenka DC. Neurosarcoidosis: a review of its
(> 50 years) than expected for sarcoidosis (median intracranial manifestation. J Neurol 2001; 248: 363–72.
35 years). In this context, it should be remembered Schielke E, Nolte C, Muller W, Bruck W. Sarcoidosis
that chance concurrence of dementia and sarcoid- presenting as a rapidly progressive dementia: clinical
osis may occur: a patient with relatively indolent and neuropathological evaluation. J Neurol 2001; 248:
522–4.
pulmonary sarcoidosis who developed Alzheimer’s
Willigers P, Kohler P. Amnesic syndrome caused by
disease has been seen in the author’s clinic.
neurosarcoidosis. Clin Neurol Neurosurg 1993; 95:
Against this apparent rarity, in a series of 68
131–5.
patients with or without systemic sarcoidosis, cog- Zajicek JP, Scolding NJ, Foster O, et al. Central nervous
nitive decline was reported to be the clinical pre- system sarcoidosis: diagnosis and management. Q J
sentation of neurosarcoidosis in seven (10%) Med 1999; 92: 103–17.
patients (Zajicek et al., 1999). The alleged rarity of
dementia as the presentation of neurosarcoidosis
has also been questioned by Flowers et al. (2006), 6.4 Systemic lupus erythematosus (SLE)
who reported five biopsy-confirmed patients. The
index case presented at age 29 years with short-term Systemic lupus erythematosus (SLE) is a multi-
and spatial memory difficulties. Neuropsychological system autoimmune disorder of the collagen vas-
assessment showed impaired mental tracking, con- cular disease group, seldom associated with true
centration, cognitive speed, and memory retrieval, vasculitis, with systemic, dermatological, rheum-
as well as subtle expressive language difficulties. atological, renal, pulmonary, cardiac, and haem-
Improvement was reported with immunosuppres- atological, as well as neurological, complications
sion, the authors suggesting that sarcoidosis is a (Scolding & Joseph, 2002). Diagnostic criteria for
treatable cause of cognitive impairment. SLE have been formulated (Tan et al., 1982) and
Neurosarcoidosis causing an isolated amnesic revised (Hochberg, 1997).
syndrome has been reported (Willigers & Kohler, Neurological features may affect both the CNS
1993), but without neuropsychological assessment (delirium, psychosis, headache, cerebrovascular
and with diagnosis based on histological appear- disease, myelopathy, movement disorder,
6.4 Systemic lupus erythematosus 167
demyelination, seizures, aseptic meningitis) and agraphia, acalculia) with an appropriately placed
the PNS (cranial neuropathy, polyneuropathy, white matter lesion (left parieto-occipital, under-
plexopathy, mononeuropathy/multiplex, Guillain– lying the angular gyrus) due to SLE has been
Barré syndrome, autonomic neuropathy, myas- reported (Jung et al., 2001). An amnesic syndrome
thenia gravis) (ACR Ad Hoc Committee on mimicking limbic encephalitis has also been
Neuropsychiatric Lupus Nomenclature, 1999; West, reported (Stubgen, 1998). Relatively isolated auto-
2002). Because of the frequency of neuropsychia- biographical amnesia in a patient with SLE and
tric complications, nervous system involvement is temporal lobe epilepsy is reported (Kapur, 2001),
sometimes referred to as ‘NP-SLE’. What contri- but the cognitive syndrome may have been inci-
bution antiphospholipid antibodies, which are dental to the SLE, since the limited clinical details
found in 30% of SLE cases, make to these clinical were not suggestive of NP-SLE.
features is uncertain (see Hughes’ syndrome The possible role of inflammatory and hormonal
(primary antiphospholipid antibody syndrome), factors in the cognitive impairments of SLE has
Section 3.6.8). been suggested by a study of patients without
Cognitive dysfunction is said to be common in neuropsychiatric symptoms (‘non-CNS SLE’) who
SLE: up to 66% of adult SLE patients without a nonetheless had lower learning and attention
history of NP-SLE have ‘mild cognitive impair- scores, which were related to these biochemical
ment’, usually subclinical and conforming to no measures (Kozora et al., 2001). If inflammatory
specific pattern, and many patients with a previous factors are involved in the pathogenesis of cogni-
history of NP-SLE have significant cognitive dys- tive impairment, this may have implications for
function which may progress to dementia, possibly reversibility (Hanly et al., 1997), other than in
due to active CNS disease, ‘burned-out’ NP-SLE, multi-infarct disease (Briley et al., 1989).
and/or multiple infarcts (Carbotte et al., 1986;
Kozora et al., 1996; Denburg et al., 1997). One
longitudinal study found cognitive impairment in
REFERENCES
around one-third of SLE patients in ‘stable neuro-
logical condition’ with or without neuropsychiatric
ACR Ad Hoc Committee on Neuropsychiatric Lupus
symptoms, deficits which persisted at retest (mean Nomenclature. The American College of Rheumatology
interval between assessments 21.5 months), sug- nomenclature and case definitions for neuropsychiatric
gesting that cognitive impairment is a consistent lupus syndromes. Arthritis Rheum 1999; 42: 599–608.
finding of CNS involvement in SLE. No relationship Briley DP, Coull BM, Goodnight SHJ. Neurological disease
with neuropsychiatric disorder, neuroradiological associated with antiphospholipid antibodies. Ann
findings, disease activity, or use of immunosup- Neurol 1989; 25: 221–7.
pressive therapy was found. The most sensitive Carbotte RM, Denburg SD, Denburg JA. Prevalence of
tests were those examining visuospatial reasoning cognitive impairment in systemic lupus erythematosus.
J Nerv Ment Dis 1986; 174: 357–64.
and visuoconstructive function (Carlomagno et al.,
Carlomagno S, Migliaresi S, Ambrosone L, et al. Cognitive
2000). Another study found that cognitive impair-
impairment in systemic lupus erythematosus: a follow-
ments in SLE patients included attentional skills,
up study. J Neurol 2000; 247: 273–9.
psychomotor speed, and abstract problem solving, Denburg SD, Carbotte RM, Denburg JA. Psychological
in other words executive function. This was felt to aspects of systemic lupus erythematosus: cognitive
be largely due to cerebral infarction, and hence function, mood, and self-report. J Rheumatol 1997; 24:
potentially amenable to prevention with anti- 998–1003.
coagulation (Waterloo et al., 2001). Focal, cortical- Hanly JG, Cassell K, Fisk JD. Cognitive function in
type, deficits may also occur: a case of Gerstmann systemic lupus erythematosus: results of a 5-year
syndrome (finger agnosia, right–left confusion, prospective study. Arthritis Rheum 1997; 40: 1542–3.
Hochberg MC. Updating the American College of manifestations may occur in skin, lung, heart, kid-
Rheumatology revised criteria for the classification of neys, and nervous system, both central and per-
systemic lupus erythematosus. Arthritis Rheum 1997; ipheral (Fox, 2005). Diagnostic criteria (Vitali, 2003)
40: 1725. include ocular and oral symptoms, objective evi-
Jung RE, Yeo RA, Sibbitt WL Jr, et al. Gerstmann syndrome
dence of dry eyes and salivary gland involvement,
in systemic lupus erythematosus: neuropsychological,
and laboratory abnormalities (at least one of anti
neuroimaging and spectroscopic findings. Neurocase
SS-A (anti-Ro) or SS-B (anti-La), ANA, IgM RhF).
2001; 7: 515–21.
Kapur N. Autobiographical amnesia and temporal lobe
Neurological manifestations occur in about 20%
pathology. In: Parkin AJ (ed.), Case Studies in the of patients and include CNS involvement, cranial
Neuropsychology of Memory. Hove: Psychology Press, nerve palsies, myelopathy, peripheral neuropathy
1997: 37–62 [at 43–7]. (especially sensory, including a ganglionopathy),
Kozora E, Laudenslager M, Lemieux A, West SG. Inflam- and a multiple-sclerosis-like syndrome (Delalande
matory and hormonal measures predict neuropsycho- et al., 2004). Abnormalities may be found on
logical functioning in systemic lupus erythematosus neuropsychological tests, particularly of frontal
and rheumatoid arthritis patients. J Int Neuropsychol lobe function and memory, which correlate with
Soc 2001; 7: 745–54.
defects on functional imaging with SPECT when
Kozora E, Thompson L, West S, et al. Analysis of cognitive
MR imaging is normal; hence it has been argued
and psychological deficits in systemic lupus erythema-
that neuropsychological testing is the most sensi-
tosus patients without overt central nervous system
disease. Arthritis Rheum 1996; 39: 2035–45.
tive test for CNS involvement in Sjögren’s (Belin
Scolding NJ, Joseph FG. The neuropathology and patho- et al., 1999). However, similar deficits on functional
genesis of systemic lupus erythematosus. Neuropathol imaging have been reported in patients with or
Appl Neurobiol 2002; 28: 173–89. without ‘psychoneurological’ symptoms (Lass
Stubgen JP. Nervous system lupus mimics limbic enceph- et al., 2000).
alitis. Lupus 1998; 7: 557–60. Isolated cognitive impairment has been
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria described in Sjögren’s syndrome. The pattern of
for the classification of systemic lupus erythematosus. neuropsychological impairment in one series of
Arthritis Rheum 1982; 25: 1271–7.
patients was fairly homogeneous, with either sub-
Waterloo K, Omdal R, Sjoholm H, et al. Neuropsycho-
corticofrontal or corticosubcortical dysfunction. In
logical dysfunction in systemic lupus erythematosus is
the former group there was normal intellectual
not associated with changes in cerebral blood flow.
J Neurol 2001; 248: 595–602.
quotient, normal memory and visuoconstructional
West SG. Systemic lupus erythematosus and the nervous skills but impaired attention control, abstraction,
system. In: Wallace DJ, Hahn BH (eds.), Dubois’ Lupus response inhibition, and set-shifting abilities (i.e.
Erythematosus (6th edition). Philadelphia: Lippincott dysexecutive frontal-type pattern); in the latter
Williams & Wilkins, 2002: 693–738 [esp. 702–3]. there was additional intellectual decline and poor
visuoconstructional abilities, associated with overt
signs of CNS involvement (spastic tetraparesis,
6.5 Sjögren’s syndrome pseudobulbar syndrome, cerebellar syndrome). MR
brain imaging was normal or showed only non-
Sjögren’s syndrome is a chronic autoimmune dis- specific punctate periventricular white matter high
order of the exocrine glands associated with signal intensities on T2-weighted scans, with nor-
lymphocytic infiltrates, occurring either alone mal findings in CSF or only mild protein elevation
(primary Sjögren’s syndrome) or in the presence of (Lafitte et al., 2001). Cases mimicking Alzheimer’s
another autoimmune disorder such as rheumatoid disease have also been reported, but retrospectively
arthritis, SLE, or progressive systemic sclerosis certain features were identified that argued against
(secondary Sjögren’s syndrome). Extraglandular AD, including no disproportionate loss of memory
or anomia, and presence of cognitive fluctuation, paresis, and pyramidal signs, with accompanying or
psychotic features, and somatic symptoms and preceding cognitive and neuropsychiatric changes.
signs such as tremor, hyperreflexia, and gait ataxia Non-parenchymal involvement usually takes the
(Caselli et al., 1993). form of intracranial hypertension due to dural sinus
thrombosis, wherein cognitive evaluation is usually
normal (Akman-Demir & Serdaroglu, 2002; Kidd
REFERENCES et al., 1999).
If sought, cognitive impairments may be com-
Belin C, Moroni C, Caillat-Vigneron N, et al. Central mon in neuro-Behçet’s disease. For example, of 74
nervous system involvement in Sjögren’s syndrome: patients tested in a cohort of 200, 65 were abnor-
evidence from neuropsychological testing and HMPAO- mal, the most common impairments being in
SPECT. Ann Med Interne Paris 1999; 150: 598–604. memory (verbal and visual), attention, and frontal
Caselli RJ, Scheithauer BW, O’Duffy JD, et al. Chronic lobe functions, with relative sparing of orientation,
inflammatory meningoencephalitis should not be mis- language, arithmetic, and visuospatial function
taken for Alzheimer’s disease. Mayo Clin Proc 1993; 68: (Akman-Demir et al., 1999). In a more detailed
846–53.
analysis of 12 patients with neuro-Behçet’s disease,
Delalande S, de Seze J, Fauchais AL, et al. Neurologic
memory deficit was the commonest finding, par-
manifestations in primary Sjögren’s syndrome: a study
ticularly delayed recall of both verbal and visual
of 82 patients. Medicine (Baltimore) 2004; 83: 280–91.
Fox RI. Sjögren’s syndrome. Lancet 2005; 366: 321–31. material, suggesting a retrieval deficit, although
Lafitte C, Amoura Z, Cacoub P, et al. Neurological acquisition and storage were also affected. Attention
complications of primary Sjögren’s syndrome. J Neurol and executive function deficits also occurred, whilst
2001; 248: 577–84. language and visuospatial function were largely
Lass P, Krajka-Lauer J, Homziak M, et al. Cerebral blood spared. Neuropsychological deficits were evident
flow in Sjögren’s syndrome using 99Tcm-HMPAO brain before detectable changes on structural brain
SPET. Nucl Med Commun 2000; 21: 31–5. imaging, and insidious deterioration was observed
Vitali C. Classification criteria for Sjögren’s syndrome. independent of neurological relapses (Oktem-Tanör
Ann Rheum Dis 2003; 62: 94–5.
et al., 1999). Another series noted cognitive and/or
behavioural features in 16% of patients, a frequency
less common than headache, upper motor neurone
6.6 Behçet’s disease type weakness, and brainstem and cerebellar signs
(Siva et al., 2001). A case of Behçet’s disease resem-
Behçet’s disease is a recurrent systemic inflamma- bling herpes simplex encephalitis has been reported
tory disorder of unknown aetiology, diagnostic cri- (Hasegawa et al., 2005).
teria for which include recurrent aphthous ulceration Cognitive deficits may also be common in Beh-
plus any two of genital ulceration, skin lesions (such çet’s patients without overt neurological involve-
as erythema nodosum), eye involvement (anterior or ment: Monastero et al. (2004) found deficits in
posterior uveitis or retinal vasculitis), and positive almost half of a cohort of 26 patients, memory being
pathergy test (skin hypersensitivity to pin prick) the domain most affected, although visuospatial
(International Study Group for Behçet’s Disease, skills were also impaired relative to controls. High
1990). Neuro-Behçet’s disease, confined almost disease activity and high prednisolone dosage were
entirely to the central rather than the peripheral independently associated with cognitive impair-
nervous system, occurs in about 5% of cases. ment after adjustment for demographic variables.
Involvement may be defined as either parenchymal Reports of dementia in neuro-Behçet’s disease
or non-parenchymal, the former affecting particu- are rare (Wakayama, 2004), possibly because of
larly the brainstem with ataxia, dysarthria, hemi- the predilection for brainstem disease (although
lesions isolated to the brainstem have been asso- meningeal or parenchymal nodules, vasculitis.
ciated with cognitive impairment in cerebrovas- Rheumatoid arthritis with cerebral vasculitis causing
cular disease and central pontine myelinolysis). Gerstmann syndrome and dementia has been
However, severe neurological prognosis, including reported (Ramos & Mandybur, 1975). An inverse
dementia, has been reported to be the norm by relation between RhA and Alzheimer’s disease has
some authors (Wechsler et al., 1999). been suggested, admittedly in a highly selected
inpatient geriatric population (Jenkinson et al., 1989).
Because of the rarity of CNS involvement, RhA
REFERENCES patients are sometimes used in studies of cognitive
deficits in other disorders in order to control for
Akman-Demir G, Serdaroglu P. Neuro-Behçet’s disease: a chronic, inflammatory, but non-CNS disease (e.g.
practical approach to diagnosis and treatment. Pract Kozora et al., 2001). However, in a study of the
Neurol 2002; 2: 340–7.
prevalence of cognitive impairment in multiple
Akman-Demir G, Serdaroglu P, Tasçi B, and the Neuro-
sclerosis, in a control group of RhA patients
Behçet Study Group. Clinical patterns of neurological
included to control for any possible effects of
involvement in Behçet’s disease: evaluation of 200
patients. Brain 1999; 122: 2171–81.
depression related to chronic illness, 12% of the
Hasegawa T, Kanno S, Kato M, et al. Neuro-Behçet’s RhA group were found to be impaired (McIntosh-
disease presenting initially as mesiotemporal lesions Michaelis et al., 1991). Whether inflammatory
mimicking herpes simplex encephalitis. Eur J Neurol mediators may contribute to these deficits remains
2005; 12: 661–2. uncertain (Kozora et al., 2001).
International Study Group for Behçet’s Disease. Criteria
for the diagnosis of Behçet’s disease. Lancet 1990; 335:
1078–80. REFERENCES
Kidd D, Steuer A, Denman AM, Rudge P. Neurological
complications in Behçet’s syndrome. Brain 1999; 122:
Jenkinson ML, Bliss MR, Brain AT, Scott DL. Rheumatoid
2183–94.
arthritis and senile dementia of the Alzheimer’s type. Br
Monastero R, Camarda C, Pipia C, et al. Cognitive
J Rheumatol 1989; 28: 86–8.
impairment in Behçet’s disease patients without overt
Kozora E, Laudenslager M, Lemieux A, West SG. Inflam-
neurological involvement. J Neurol Sci 2004; 220: 99–104.
matory and hormonal measures predict neuropsycho-
Oktem-Tanör O, Baykan-Kurt B, Gurvit IH, Akman-Demir
logical functioning in systemic lupus erythematosus
G, Serdaroglu P. Neuropsychological follow-up of 12
and rheumatoid arthritis patients. J Int Neuropsychol
patients with neuro-Behçet disease. J Neurol 1999; 246:
Soc 2001; 7: 745–54.
113–19.
McIntosh-Michaelis SA, Wilkinson SM, Diamond ID, et al.
Siva A, Kantarci OH, Saip S, et al. Behçet’s disease:
The prevalence of cognitive impairment in a commu-
diagnostic and prognostic aspects of neurological
nity survey of multiple sclerosis. Br J Clin Psychol 1991;
involvement. J Neurol 2001; 248: 95–103.
30: 333–48.
Wakayama Y. Dementia due to Behçet’s disease [in
Ramos M, Mandybur TI. Cerebral vasculitis and rheuma-
Japanese]. Nippon Rinsho 2004; 62 (suppl): 445–8.
toid arthritis. Arch Neurol 1975; 32: 271–5.
Wechsler B, Gerber S, Vidailhet M, Dormont D. Neurolo-
gic manifestations of Behçet’s disease [in French]. Ann
Med Interne Paris 1999; 150: 555–61.
6.8 Scleroderma, systemic sclerosis
6.7 Rheumatoid arthritis (RhA) CNS involvement is rare in this disorder, which is
characterized by excess collagen deposition in
CNS involvement is rare in rheumatoid arthritis blood vessels. Occasional cases associated with
(RhA), but not unheard of, as exemplified by dementia and cerebrovascular calcification have
been reported (Héron et al., 1998). A vasospastic 6.10 Cerebral vasculitides

mechanism was suggested in a patient with
scleroderma and Raynaud’s phenomenon who The vasculitides are inflammatory disorders of blood
suffered two episodes of transient global amnesia vessels, probably of autoimmune origin. Vasculitis
(Nishida et al., 1990). may be exclusive to the CNS, as in primary or isolated
angiitis of the CNS (PACNS), also known as intra-
cranial vasculitis or, in older texts, granulomatous
REFERENCES angiitis (Schmidley, 2000), but more commonly CNS
involvement is part of a systemic disorder (Younger,
Héron E, Fornes P, Rance A, et al. Brain involvement in 2004). Primary vasculitides include polyarteritis
scleroderma: two autopsy cases. Stroke 1998; 29: 719–21. nodosa, Churg–Strauss syndrome, Wegener’s granu-
Nishida A, Kaiya H, Uematsu M, et al. Transient global lomatosis, giant cell (temporal) arteritis, and Takaya-
amnesia and Raynaud’s phenomenon in scleroderma. su’s arteritis. Connective tissue disorders may also
Acta Neurol Scand 1990; 81: 550–2. be complicated by vasculitis, such as rheumatoid
arthritis, systemic lupus erythematosus, Sjögren’s
syndrome, progressive systemic sclerosis, and der-
6.9 Relapsing polychondritis matomyositis/polymyositis. Vasculitis is also recog-
nized secondary to certain infections, neoplasias, and
This rare disorder, characterized by recurrent epi- toxins/drugs (Moore & Richardson, 1998).
sodes of inflammation of the cartilage of ear, nose,
trachea, and larynx, as enshrined in proposed
clinical diagnostic criteria (McAdam et al., 1976),
REFERENCES
may be complicated by systemic and cerebral
vasculitis, with clinical presentations including
Moore PM, Richardson B. Neurology of the vasculitides
aseptic meningitis, encephalopathy, seizures,
and connective tissue diseases. J Neurol Neurosurg
stroke, and transient ischaemic attacks. Cases with Psychiatry 1998; 65: 10–22.
cognitive impairment due to a non-paraneoplastic Schmidley JW. Central Nervous System Angiitis. Boston:
limbic encephalitis have been reported (Fujiki Butterworth-Heinemann, 2000.
et al., 2004; Ohta et al., 2004; Irani et al., 2006). Younger DS. Vasculitis of the nervous system. Curr Opin
Neurol 2004; 17: 317–36.
REFERENCES
6.10.1 Primary angiitis of the CNS (PACNS)
Fujiki F, Tsuboi Y, Hashimoto K, et al. Non-herpetic Dementia may be a feature of pathologically con-
limbic encephalitis associated with relapsing polychon- firmed PACNS (Koo & Massey, 1988; Chu et al.,
dritis. J Neurol Neurosurg Psychiatry 2004; 75: 1646–7. 1998), and this disorder is occasionally the neuro-
Irani SR, Soni A, Beynon H, Athwal BS. Relapsing pathological substrate for dementia of unknown
‘encephalo’ polychondritis. Pract Neurol 2006; 6: cause submitted to brain biopsy (Warren et al.,
372–5.
2005). ‘Rapidly progressive dementia’ as the pre-
McAdam LP, O’Hanlan MA, Bluestone R, Pearson CM.
sentation of primary (isolated) angiitis of the CNS
Relapsing polychondritis: prospective study of 23
has been reported (Castelnovo et al., 2001),
patients and a review of the literature. Medicine
(Baltimore) 1976; 55: 193–215. although one wonders whether this was a disease-
Ohta Y, Nagano I, Niiya D, et al. Nonparaneoplastic limbic related encephalopathy, since intermittent confu-
encephalitis with relapsing polychondritis. J Neurol Sci sion, and behavioural and psychiatric symptoms
2004; 220: 85–8. are not uncommon in PACNS. Dementia evolving
in a patient with biopsy-proven but quiescent medium arteries: Kawasaki disease; classical
angiitis may reflect a second pathology such as polyarteritis nodosa
Alzheimer’s disease (Brotman et al., 2000). small vessels and medium arteries: Wegener’s
Cognitive problems are reported to be prominent granulomatosis; Churg–Strauss syndrome;
in the rare syndrome of Ab-related angiitis (ABRA), microscopic polyangiitis
a granulomatous angiitis resembling PACNS with small vessels: Henoch–Schonlein purpura; essen-
additional sporadic amyloid-b-peptide-related tial cryoglobulinaemia; cutaneous leukocytoclas-
cerebral amyloid angiopathy. Alterations in mental tic vasculitis
status were common in ABRA and, although not Some of these systemic vasculitides may be
systematically examined, were said to include accompanied by autoantibodies directed against
confusion, and poor memory and concentration, constituents of the neutrophil azurophil granules
sometimes progressing to frank dementia that was (ANCA): cytoplasmic ANCA (c-ANCA) is associated
sometimes diagnosed premortem as Alzheimer’s with Wegener’s granulomatosis with approximately
disease (Scolding et al., 2005). 95% specificity; perinuclear ANCA (p-ANCA) dir-
ected at myeloperoxidase is found in microscopic
polyangiitis and Churg–Strauss syndrome with
REFERENCES
lesser specificity. A distinction may be drawn
between primary disorders and vasculitides occur-
Brotman DJ, Eberhart CG, Burger PC, McArthur JC,
Hellmann DB. Primary angiitis of the central nervous
ring secondary to infection (e.g. hepatitis B, syphilis,
system and Alzheimer’s disease: clinically and patho- HIV), drugs (e.g. sulphonamides, cocaine), or other
logically evident in a single patient. J Rheumatol 2000; connective tissue disorder (e.g. rheumatoid arthritis,
27: 2935–7. SLE, Sjögren’s syndrome). ANCA assays are some-
Castelnovo G, Bouldy S, Vladut M, Marty-Double C, times positive in SLE (Joseph & Scolding, 2002).
Labauge P. Rapidly progressive dementia disclosing Neurological presentations of systemic vasculitis
primary angiitis of the central nervous system [in are very diverse, but those affecting the CNS gen-
French]. Ann Med Interne Paris 2001; 152: 273–5. erally manifest as an acute or subacute encephal-
Chu CT, Gray L, Goldstein LB, Hulette CM. Diagnosis of
opathy, or as an ‘MS-like’ relapsing–remitting
intracranial vasculitis: a multi-disciplinary approach. J
disorder with features atypical for multiple scler-
Neuropathol Exp Neurol 1998; 57: 30–8.
osis such as seizures and headache, or as a rapidly
Koo EH, Massey EW. Granulomatous angiitis of the central
nervous system: protean manifestations and response to
progressive space-occupying lesion (Scolding et al.,
treatment. J Neurol Neurosurg Psychiatry 1988; 51: 1126–33. 1997). Cognitive disorders are unusual, but occa-
Scolding NJ, Joseph F, Kirby PA, et al. Ab-related angiitis: sionally described.
primary angiitis of the central nervous system associ- Occasional reports of dementia as a symptom,
ated with cerebral amyloid angiopathy. Brain 2005; 128: sometimes the presentation, of giant cell arteritis
500–15. (GCA) have appeared, the dementia presumed
Warren JD, Schott JM, Fox NC, et al. Brain biopsy in to reflect multiple infarctions, sometimes in asso-
dementia. Brain 2005; 128: 2016–25. ciation with bilateral carotid artery occlusion,
but without brain pathology to confirm the sup-
position (Howard et al., 1984; Gamboa et al., 1991;
6.10.2 Systemic vasculitides
Mouritsen & Junker, 1991; Pascual et al., 1992;
The systemic vasculitides may be classified Morris & Lockie, 2005). If this occurs it must be
according to the size of the affected blood vessels rare: GCA typically affects the extracranial carotid
(Scolding, 1999; Siva, 2001): artery, and stroke is an uncommon vasculitic
large arteries: giant cell arteritis; Takayasu’s complication which usually involves the posterior
arteritis intracranial circulation. Moreover, most patients
6.11 Sydenham’s chorea 173
with GCA are over 50 years of age so there may be vasculitis: a connectionist account. Neurocase 1996; 2:
other, confounding, factors which might contribute 1–12.
to cognitive decline. CNS involvement in Takaya- Gamboa F., Iriarte LM, Garcia-Bragado F, et al. Multi-
su’s arteritis is due to carotid stenosis, cerebral infarct dementia in giant cell arteritis (temporal
arteritis) [in Spanish]. Med Clin Barc 1991; 97: 617–19.
hypoperfusion, and subclavian steal syndrome.
Harlé JR, Disdier P, Ali Cherif A, et al. Curable dementia
Diffuse encephalopathy with cognitive decline
and panarteritis nodosa [in French]. Rev Neurol Paris
and seizures or stroke-like episodes may occur in
1991; 147: 148–50
polyarteritis nodosa. Dementia in the context of Howard GF, Ho SU, Kim KS, Wallach J. Bilateral carotid
lymphocytic meningitis and encephalitis has been artery occlusion resulting from giant cell arteritis. Ann
reported in polyarteritis nodosa, reversing after Neurol 1984; 15: 204–7.
immunosuppressive treatment (Harlé et al., 1991). Joseph FG, Scolding NJ. Cerebral vasculitis: a practical
Encephalopathy and stroke-like episodes may occur approach. Pract Neurol 2002; 2: 80–93.
in Churg–Strauss syndrome, although peripheral Mattioli F, Capra R, Rovaris M, et al. Frequency and
nervous system involvement is more common. patterns of subclinical cognitive impairment in patients
Rapid-onset dementia with microscopic poly- with ANCA-associated small vessel vasculitides. J
Neurol Sci 2002; 195: 161–6.
angiitis, ascribed to CNS small vessel disease but
Morris OC, Lockie P. Giant cell arteritis: presenting as
without pathological proof, and also causing per-
stroke, transient ischaemic attack and dementia. Aust
ipheral neuropathy, has been described, with some
Fam Physician 2005; 34: 653–5.
patients improving cognitively following institution Mouritsen M, Junker P. Reversible dementia caused by giant
of immunosuppressive therapy (Capra et al., 1998). cell arteritis [in Danish]. Ugeskr Laeg 1991; 153: 2572.
Cerebral vasculitis as a cause of Gerstmann Pascual JM, Cantero J, Boils P, Solanas JV, Redón J.
syndrome and dementia in a patient with Dementia as a presentation symptom of giant cell
rheumatoid arthritis has been reported (Ramos & arteritis [in Spanish]. An Med Interna 1992; 9: 39–40.
Mandybur, 1975). Cerebral vasculitis causing Ramos M, Mandybur TI. Cerebral vasculitis and rheuma-
severe autobiographical amnesia but with pre- toid arthritis. Arch Neurol 1975; 32: 271–5.
served semantic memory has also been docu- Scolding N. Cerebral vasculitis. In: Scolding N (ed.),
Immunological and Inflammatory Disorders of the
mented (Evans et al., 1996).
Central Nervous System. Oxford: Butterworth-Heine-
In a group of non-demented patients with ANCA-
mann, 1999: 210–57.
associated small vessel vasculitides (Wegener’s
Scolding NJ, Jayne DRW, Zajicek JP, et al. Cerebral
granulomatosis, Churg–Strauss syndrome, micro- vasculitis: recognition, diagnosis and management. Q J
scopic polyangiitis), neuropsychological testing Med 1997; 90: 61–73.
revealed subclinical deficits in abstract reasoning, Siva A. Vasculitis of the nervous system. J Neurol 2001;
speed of information processing, and visual mem- 248: 451–68.
ory in just under a third of patients, the suggestion
being that small vessel vasculitis may mediate sub-
cortical brain damage (Mattioli et al., 2002). 6.11 Sydenham’s chorea, paediatric
autoimmune neuropsychiatric disorders
associated with streptococcal infections
REFERENCES (PANDAS)
Capra R, Gregorini G, Mattioli F, Santostefano M, Galluzzi

Postinfectious (post-streptococcal) movement and
S. Rapid onset dementia in patients with microscopic neuropsychiatric disorders of autoimmune origin
polyangiitis. J Neurol 1998; 245: 397 (abstract P64). have been increasingly recognized in recent times.
Evans JJ, Breen EK, Antoun N, Hodges JR. Focal retrograde The neuropsychiatric features usually reported have
amnesia for autobiographical events following cerebral been those of obsessive-compulsive disorder, but
the spectrum of psychiatric symptoms is widening 6.12.1 Paraneoplastic limbic encephalitis

(Martino & Giovannoni, 2005). Basal ganglia (stria- (PNLE)
tal) involvement may be observed on structural and
Paraneoplastic limbic encephalitis (PNLE) was first
functional imaging (hyperperfusion and hyperme-
described as such in the 1960s (Corsellis et al., 1968).
tabolism). Neuropsychological deficits do not seem
The syndrome is most often associated with lung
to be a clinical feature of these conditions, although
tumours but also with breast and testicular neo-
dementia associated with striatal hypermetabolism
plasms, and a variety of onconeural antibodies may
and the detection of antistriatal antibodies which
be found, including anti-Hu, anti-Ma2, and ANNA-3,
reversed with steroids has been reported (Léger
although their absence does not exclude the diagno-
et al., 2004). Cases clinically resembling Sydenham’s
sis (Gultekin et al., 2000; Lawn et al., 2003). Whole-
chorea, with additional dementia associated with
body PET scanning may identify an occult tumour
antiphospholipid antibodies, have also been
when other imaging modalities have been negative
described (Van Horn et al., 1996).
(Rees et al., 2001). Detailed reports of neuropsycho-
logical assessment in PNLE are relatively few, perhaps
REFERENCES because of concurrent confusion, altered conscious-
ness, and psychiatric features precluding assessment.
Léger GC, Johnson N, Horowitz SW, et al. Dementia-like Martin et al. (1996) found severe anterograde
presentation of striatal hypermetabolic state with anti- amnesia for both verbal and visual information but
striatal antibodies responsive to steroids. Arch Neurol preserved visual perception and construction, lan-
2004; 61: 754–7. guage, speed of information processing, and verbal
Martino D, Giovannoni G. Autoaggressive immune-medi- abstract reasoning, all consistent with pathology
ated movement disorders. Adv Neurol 2005; 96: 320–35. confined to the mesial temporal lobes. A case with
Van Horn G, Arnett FC, Dimachkie MM. Reversible topographical disorientation as well as amnesia in
dementia and chorea in a young woman with the
association with anti-Hu antibodies has been
lupus anticoagulant. Neurology 1996; 46: 1599–603.
reported, with MR signal change not only in the
anteromedial temporal lobes bilaterally but also in
6.12 Limbic encephalitis the right retrosplenial region and inferior precuneus
(Hirayama et al., 2003). More widespread deficits and
Limbic encephalitis is a syndrome of subacute imaging changes may have prognostic implications:
onset characterized by cognitive decline, particu- Bak et al. (2001) reported two patients with PNLE, one
larly memory impairment, due to limbic system with pure anterograde amnesia and normal MRI who
involvement, with or without additional epileptic recovered completely with tumour remission, the
seizures of temporal lobe origin and MR imaging other with dense anterograde and extensive retro-
evidence of signal change in the limbic system, grade amnesia with anomia and executive impair-
particularly the hippocampus. Initially described as ments, with atrophy of hippocampus and amygdala
a remote effect of occult neoplasia (paraneoplasia), on MR imaging and frontotemporal hypoperfusion
a similar picture may also result from infective and on SPECT, who showed no cognitive recovery fol-
autoimmune pathologies (Schott, 2006). lowing tumour regression.
REFERENCES REFERENCES
Schott JM. Limbic encephalitis: a clinician’s guide. Pract Bak TH, Antoun N, Balan KK, Hodges JR. Memory lost,
Neurol 2006; 6: 143–53. memory regained: neuropsychological findings and
neuroimaging in two cases of paraneoplastic limbic (plasma exchange, IVIg, high-dose steroids),
encephalitis with radically different outcomes. J Neurol memory problems may persist, associated with
Neurosurg Psychiatry 2001; 71: 40–7. medial temporal lobe atrophy, even if the other
Corsellis JA, Goldberg GJ, Norton AR. ‘Limbic encephal- clinical features remit, and early treatment is
itis’ and its association with carcinoma. Brain 1968; 91:
therefore recommended. There may be other
481–96.
antibody-mediated limbic encephalitides with tar-
Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic
get antigens yet to be defined (Castillo et al., 2006).
limbic encephalitis: neurological symptoms, immuno-
logical findings and tumour association in 50 patients.
Cases resembling limbic encephalitis have
Brain 2000; 123: 1481–94. occasionally been reported in association with
Hirayama K, Taguchi Y, Sato M, Tsukamoto T. Limbic connective tissue disorders such as SLE (Stubgen,
encephalitis presenting with topographical disorien- 1998), Behçet’s disease (Hasegawa et al., 2005), and
tation and amnesia. J Neurol Neurosurg Psychiatry 2003; relapsing polychondritis (Fujiki et al., 2004; Ohta
74: 110–12. et al., 2004). Of the infective causes of limbic
Lawn ND, Westmoreland BF, Kiely MJ, et al. Clinical, encephalitis, herpes simplex encephalitis is the
magnetic resonance imaging, and electroencephalo- commonest (see Section 9.1.1), but other patho-
graphic findings in paraneoplastic limbic encephalitis.
gens include herpes simplex type 2 and human
Mayo Clin Proc 2003; 78: 1363–8.
herpes viruses 6 and 7 (Section 9.1.5), particularly
Martin RC, Haut MW, Goeta Kreisler K, Blumenthal D.
in immunocompromised patients, and neurosy-
Neuropsychological functioning in a patient with para-
neoplastic limbic encephalitis. J Int Neuropsychol Soc
philis (Section 9.4.1; Schied et al., 2005).
1996; 2: 460–6.
Rees JH, Hain SF, Johnson MR, et al. The role of [18F]
fluoro-2-deoxyglucose-PET scanning in the diagnosis of
paraneoplastic neurological disorders. Brain 2001; 124: REFERENCES
2223–31.
Buckley C, Oger J, Clover L, et al. Potassium channel
antibodies in two patients with reversible limbic
6.12.2 Non-paraneoplastic limbic encephalitis. Ann Neurol 2001; 50: 73–8.
encephalitis (NPLE) Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive
encephalopathy associated with autoimmune thyroid-
Of the non-paraneoplastic causes, a syndrome of
itis. Arch Neurol 2006; 63: 197–202.
limbic encephalitis associated with voltage-gated
Fujiki F, Tsuboi Y, Hashimoto K, et al. Non-herpetic
potassium channel (VGKC) antibodies in serum limbic encephalitis associated with relapsing poly-
(and sometimes CSF) has been reported in recent chondritis. J Neurol Neurosurg Psychiatry 2004; 75:
times (Buckley et al., 2001; Pozo-Rosich et al., 2003; 1646–7.
Schott et al., 2003; Vincent et al., 2004). The anti- Hasegawa T, Kanno S, Kato M, et al. Neuro-Behçet’s
bodies are likely to be pathogenic, since target disease presenting initially as mesiotemporal lesions
antigens are found within the molecular layer of mimicking herpes simplex encephalitis. Eur J Neurol
the hippocampus. Clinically this is a subacute 2005; 12: 661–2.
amnesic syndrome with associated behavioural Ohta Y, Nagano I, Niiya D, et al. Nonparaneoplastic limbic
encephalitis with relapsing polychondritis. J Neurol Sci
features, epileptic seizures, and sometimes hypo-
2004; 220: 85–8.
natraemia due to the syndrome of inappropriate
Pozo-Rosich P, Clover L, Saiz A, et al. Voltage-gated
ADH secretion. The neuropsychological profile,
potassium channel antibodies in limbic encephalitis.
when it can be tested, shows prominent episodic Ann Neurol 2003; 54: 530–3.
memory impairment with frontotemporal dys- Schied R, Voltz R, Vetter T, et al. Neurosyphilis and
function but sparing of parietal lobe function. paraneoplastic limbic encephalitis: important differen-
Despite treatment with immunosuppressive agents tial diagnoses. J Neurol 2005; 252: 1129–32.
Schott JM, Harkness K, Barnes J, et al. Amnesia, cerebral 2005), the clinical phenotype often closely
atrophy, and autoimmunity. Lancet 2003; 361: 1266. resembling sporadic Creutzfeldt–Jakob disease.
Stubgen JP. Nervous system lupus mimics limbic enceph- Cases of pathologically confirmed CJD resembling
alitis. Lupus 1998; 7: 557–60. Hashimoto’s encephalopathy have also been
Vincent A, Buckley C, Schott JM, et al. Potassium channel
reported (Schott et al., 2003). Hence, though rare,
antibody-associated encephalopathy: a potentially
this is an important diagnosis to consider since the
immunotherapy-responsive form of limbic encephalitis.
dementia may be reversible with steroids.
Brain 2004; 127: 701–12.
REFERENCES
6.13 Hashimoto’s encephalopathy (HE)
Brain L, Jellinek EH, Ball K. Hashimoto’s disease and
This entity, first reported in the 1960s (Brain et al.,
encephalopathy. Lancet 1966; 2: 512–14.
1966), consists of a clinical syndrome of enceph- Chaudhuri A, Behan PO. The clinical spectrum, diagnosis,
alopathy associated with stroke-like episodes, pathogenesis and treatment of Hashimoto’s encephal-
seizures, and psychosis in association with high opathy (recurrent acute disseminated encephalomy-
serum titres of antithyroid autoantibodies (micro- elitis). Curr Med Chem 2003; 10: 1645–53.
somal, thyroglobulin). Thyroid function may vary Chong JY, Rowland LP, Utiger RD. Hashimoto encephal-
from overt hypothyroidism to overt hyperthyroid- opathy. Syndrome or myth? Arch Neurol 2003; 60:
ism, but most commonly there is subclinical 164–71.
hypothyroidism. Females are more commonly Creutzfeldt CJ, Haberl RL. Hashimoto encephalopathy: a
do-not-miss in the differential diagnosis of dementia.
affected (4 : 1). The course may be relapsing–
J Neurol 2005; 252: 1285–7.
remitting in half of patients, for which reason some
Forchetti CM, Katsamakis G, Garron DC. Autoimmune
authors envisage Hashimoto’s encephalopathy as a
thyroiditis and a rapidly progressive dementia: global
form of recurrent acute disseminated encephalo- hypoperfusion on SPECT scanning suggests a possible
myelitis (ADEM: Chaudhuri & Behan, 2003). CSF mechanism. Neurology 1997; 49: 623–6.
protein is often elevated, and EEG abnormalities Schott JM, Warren JD, Rossor MN. The uncertain nosology
(diffuse slowing) are almost ubiquitous. The con- of Hashimoto encephalopathy. Arch Neurol 2003; 60:
dition is usually (96%) responsive to steroids 1812.
(Chong et al., 2003). The antithyroid auto- Seipelt M, Zerr I, Nau R, et al. Hashimoto’s encephalitis as
antibodies are probably epiphenomenal, unrelated a differential diagnosis of Creutzfeldt–Jakob disease.
to disease pathogenesis; a-enolase antibodies may J Neurol Neurosurg Psychiatry 1999; 66: 172–6.
Spiegel J, Hellwig D, Becker G, Müller M. Progressive
be a better marker. It has been suggested by some
dementia caused by Hashimoto’s encephalopathy:
authors that the name Hashimoto’s encephal-
report of two cases. Eur J Neurol 2004; 11: 711–13.
opathy be abandoned because of uncertainty about
Wilhelm-Gössling C, Weckbecker C, Brabant EG, Dengler
nosology, ‘steroid-responsive encephalopathy’ R. Autoimmune encephalopathy in Hashimoto’s thy-
being one proposed name. Differential diagnosis roiditis. A differential diagnosis in progressive dementia
encompasses mitochondrial disease, vasculitides, syndrome [in German]. Dtsch Med Wochenschr 1998;
non-paraneoplastic limbic encephalitis due to 123: 279–84.
voltage-gated potassium channel antibodies, and
even Creutzfeldt–Jakob disease (Schott et al., 2003).
Cases presenting with a progressive dementia 6.14 Erdheim–Chester disease
have been reported on occasion (Forchetti et al.,
1997; Wilhelm-Gössling et al., 1998; Seipelt et al., Erdheim–Chester disease is a rare, sporadic, non-
1999; Spiegel et al., 2004; Creutzfeldt & Haberl, Langerhans cell histiocytosis which may affect
multiple organs, including the CNS (Wright et al., Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al.
1999). Proposed diagnostic criteria require typical Erdheim–Chester disease: clinical and radiologic char-
histological findings of foamy histiocytes nested acteristics of 59 cases. Medicine 1996; 75: 757–69.
among polymorphic granuloma and fibrosis or Wright RA, Hermann RC, Parisi JE. Neurological mani-
festations of Erdheim–Chester disease. J Neurol Neuro-
xanthogranulomatosis with CD68-positive and
surg Psychiatry 1999; 66: 72–5.
CD1a-negative immunohistochemical staining,
with typical skeletal findings of bilateral symmet-
rical cortical osteosclerosis and/or increased
labelling of the distal ends of the lower limb long 6.15 Bilateral vestibulopathy
bones on 99Tc bone scintigraphy (Veyssier-Belot
et al., 1996). Besides skeletal involvement, common The syndrome of bilateral peripheral loss of ves-
findings are diabetes insipidus, and retro- tibular function is characterized by oscillopsia dur-
peritoneal, orbital, cutaneous, and cardiac ing walking and head movements, and unsteadiness
involvement. In a review of over 200 cases, Lache- of gait in the dark and on uneven ground. Although
nal et al. (2006) found neurological features in often idiopathic, some cases are associated with
about one-third, most often cerebellar and/or autoantibodies to inner ear structures. Deficits of
pyramidal signs, but in six there was dementia, spatial memory and navigation associated with
cognitive impairment, or amnesia. bilateral hippocampal atrophy have been reported
in bilateral vestibulopathy associated with neurofi-
bromatosis type 2 (Brandt et al., 2005).
REFERENCES
Lachenal F, Cotton F, Desmurs-Clavel H, et al. Neuro- REFERENCES

logical manifestations and neuroradiological presenta-
tion of Erdheim–Chester disease: report of 6 cases and Brandt T, Schautzer F, Hamilton D, et al. Vestibular loss
systematic review of the literature. J Neurol 2006; 253: causes hippocampal atrophy and impaired spatial
1267–77. memory in humans. Brain 2005; 128: 1579–89.
7
Structural brain lesions

7.1.1 Meningiomas 179
7.1.2 Gliomas 179
7.1.3 Pituitary tumours 179
7.1.4 Craniopharyngiomas 180
7.1.5 Primary CNS lymphoma 180
7.1.6 Splenial tumours 180
7.1.7 Gliomatosis cerebri 180
7.1.8 Radiotherapy and chemotherapy 181
7.2.1 Normal pressure hydrocephalus (NPH) 182
7.2.2 Aqueduct stenosis 184
7.2.3 Colloid cyst, fornix lesions 184
7.2.4 Paget’s disease of bone (osteitis deformans) 185
7.3.1 Subdural haematoma (SDH) 186
7.3.2 Arachnoid cyst 187
7.1 Brain tumours and their treatment (hippocampus, frontal lobes, fornix) may produce
specific deficits. Longitudinal neuropsychological
Cognitive decline in patients with brain tumours decline may be an early marker of tumour recur-
may have many causes, including the tumour rence (Armstrong et al., 2003).
itself, concurrent tumour-related seizures, mood
disorder, steroid therapy, and as a sequel of sur-
gery, radiotherapy, and chemotherapy for the REFERENCES
tumour, or any combination thereof (Taphoorn &
Klein, 2004). Cognitive decline related to the Armstrong CL, Goldstein B, Shera D, Ledakis GE, Tallent
tumour per se may be more common with certain EM. The predictive value of longitudinal neuropsycho-
logical assessment in the early detection of brain tumor
tumour types (CNS lymphoma, gliomatosis cere-
recurrence. Cancer 2003; 97: 649–56.
bri) and with slowly, as opposed to rapidly,
Taphoorn MJB, Klein M. Cognitive deficits in adult
growing tumours (Tucha et al., 2000). Dominant
patients with brain tumours. Lancet Neurol 2004; 3:
as opposed to non-dominant hemisphere lesions 159–68.
may be associated with greater cognitive deficit, Tucha O, Smely C, Preier M, Lange KW. Cognitive deficits
but the profile is more global than localized. before treatment among patients with brain tumors.
Lesions located in specific eloquent structures Neurosurgery 2000; 47: 324–33.
178
7.1.1 Meningiomas REFERENCES

Meningiomas have a predilection for certain
Archibald YM, Lunn D, Ruttan LA, et al. Cognitive
intracranial sites, including the olfactory groove,
functioning in long-term survivors of high-grade
falx, parasagittal region, and sphenoid bone, in
glioma. J Neurosurg 1994; 80: 247–53.
some of which there may be prominent cognitive Klein M, Heimans JJ, Aaronson MK, et al. Effect of
as well as focal neurological signs. Meningioma is radiotherapy and other treatment-related factors on
recognized to be a potentially treatable cause of mid-term to long-term cognitive sequelae in low-grade
dementia (Erkinjuntti et al., 1987; Sahadevan et al., gliomas: a comparative study. Lancet 2002; 360: 1361–8.
1997). Interhemispheric parafalcine (subfrontal) Torres IJ, Mundt AJ, Sweeney PJ, et al. A longitudinal
meningiomas may grow to a huge size without neuropsychological study of partial brain radiation in
producing neurological signs, but impaired execu- adults with brain tumors. Neurology 2003; 60: 1113–18.
tive function may be found on neuropsychological
testing (Hanna et al., 1996). Rare intraventricular 7.1.3 Pituitary tumours
meningiomas may also be associated with cogni-
Tumours of the pituitary gland usually manifest with
tive change (Bertalanffy et al., 2006).
local effects of space occupation and compression of
adjacent structures (e.g. the optic chiasm) or with
endocrine effects. Memory disturbance has been
REFERENCES
reported with massive pituitary tumours (Williams &
Pennybacker, 1954). A potentially reversible demen-
Bertalanffy A, Roessler K, Koperek O, et al. Intraventricular
tia has also been mentioned on occasion. For
meningiomas: a report of 16 cases. Neurosurg Rev 2006;
instance, Brisman et al. (1993) saw a patient with
29: 30–5.
Erkinjuntti T, Sulkava R, Kovanen J, Palo J. Suspected
personality change, labelled as depression but unre-
dementia: evaluation of 323 consecutive referrals. Acta sponsive to antidepressant medication, inappropri-
Neurol Scand 1987; 76: 359–64. ate and uninhibited behaviour which evolved to
Hanna MG, Papanastassiou V, Greenhall RCD. [Minerva]. apathy, and with memory loss (5-minute recall 0/3),
BMJ 1996; 313: 502. who on imaging had a large pituitary tumour with
Sahadevan S, Pang WS, Tan NJ, Choo GK, Tan CY. suprasellar extension that proved to be a macro-
Neuroimaging guidelines in cognitive impairment: prolactinoma. Within a month of starting treatment
lessons from 3 cases of meningiomas presenting with a dopamine agonist (bromocriptine) the patient
as isolated dementia. Singapore Med J 1997; 38:
was subjectively normal. No detailed neuropsycho-
339–43.
logical assessment was performed. Decrements
in both memory and attention in comparison to
7.1.2 Gliomas normative data were observed in patients with
both treated pituitary Cushing’s disease and non-
Cognitive deficits are common in survivors of low- functioning pituitary adenomas (Heald et al., 2006),
grade glioma, whether or not they have received perhaps reflecting an effect of pituitary tumours
radiotherapy, suggesting that the tumour per se, per se.
and/or other factors (e.g. antiepileptic drug ther-
apy), may contribute to impairment (Klein et al.,
2002; Torres et al., 2003). In high-grade gliomas, REFERENCES
survivors may have moderate to severe cognitive
deficits. Although these may be treatment-related, Brisman MH, Fetell MR, Post KD. Reversible dementia
nonetheless there is evidence that the tumour itself due to macroprolactinoma: case report. J Neurosurg
may contribute (Archibald et al., 1994). 1993; 79: 135–7.
180 Structural brain lesions
Heald A, Parr C, Gibson C, O’Driscoll K, Fowler H. A 7.1.5 Primary CNS lymphoma

cross-sectional study to investigate long-term cogni-
tive function in people with treated pituitary
The risk of developing dementia in survivors of
Cushing’s disease. Exp Clin Endocrinol Diabetes 2006; primary CNS lymphoma has been high, possibly
114: 490–7. related to patient age, and treatment modalities
Williams M, Pennybacker J. Memory disturbance in third (whole-brain irradiation, systemic chemotherapy).
ventricle tumours. J Neurol Neurosurg Psychiatry 1954; Whether tumour-related factors render these
17: 115–23. patients more susceptible to cognitive impairment,
such as the tendency to seed by CSF pathways
(Larner et al., 1999), or to side effects of treatment,
7.1.4 Craniopharyngiomas
is unknown.
Memory disturbances have been reported in asso-
ciation with craniopharyngiomas (Williams &
Pennybacker, 1954). Cases of severe anterograde REFERENCES
amnesia associated with third ventricle cranio-
pharyngioma causing relatively selective damage to Larner AJ, D’Arrigo C, Scaravilli F, Howard RS. Bilateral
the mammillary bodies has been reported (e.g. symmetrical enhancing brainstem lesions: an unusual
Tanaka et al., 1997; Kupers et al., 2004). In one case, presentation of primary CNS lymphoma. Eur J Neurol
amnesia improved following tumour removal, 1999; 6: 721–3.
although memory was still impaired, and MR brain
imaging showed small atrophic mammillary bodies 7.1.6 Splenial tumours
(Tanaka et al., 1997). In another case, in which the
right hippocampus was involved as well as the Tumours involving the splenium of the corpus
mammillary bodies, albeit to a lesser extent, callosum are reported to produce amnesia, thought
tumour removal was associated with complete to be related to damage to the fornix due to its
recovery of memory function. Functional imaging anatomical propinquity to the splenium, and visual
(PET) showed no preoperative activity in memory- perceptual impairment due to hemispheric dis-
related structures, but improved perfusion of connection, whilst intellect is relatively preserved
anterior thalamic nuclei postoperatively (Kupers (Rudge & Warrington, 1991).
et al., 2004). Relatively selective mammillary body
damage may thus result in a severe anterograde
amnesia, which may be partially or completely REFERENCES
reversible.
Rudge P, Warrington EK. Selective impairment of memory
and visual perception in splenial tumours. Brain 1991;
114: 349–60.
REFERENCES
Kupers RC, Fortin A, Astrup J, Gjedde A, Ptito M. Recovery 7.1.7 Gliomatosis cerebri
of anterograde amnesia in a case of craniopharyngioma.
Arch Neurol 2004; 61: 1948–52. Gliomatosis cerebri is a neoplastic disorder in which
Tanaka Y, Miyazawa Y, Akaoka F, Yamada T. Amnesia malignant cells widely infiltrate the brain without
following damage to the mammillary bodies. Neurology forming mass lesions. Clinically, the condition pre-
1997; 48: 160–5. sents with progressive headache, gait disorder, and
Williams M, Pennybacker J. Memory disturbance in third seizures (partial, with or without secondary gener-
ventricle tumours. J Neurol Neurosurg Psychiatry 1954; alization), with signs of raised intracranial pressure
17: 115–23. (papilloedema, ophthalmoparesis), hemiparesis,
and neurobehavioural changes (Chamberlain, cognition are severe in only a minority of patients
2004). Neuropsychological deficits reflecting (Armstrong et al., 2004).
affected brain region may occur: for example, Late delayed post-radiation cognitive decline,
executive dysfunction and verbal memory impair- occurring more than 3 years post-treatment, is a
ment were reported in a patient with bifrontal and rare but feared complication of treatment, and of
left temporal white matter involvement on neuro- increasing importance as an outcome measure,
imaging (Filley et al., 2003). A case with progressive given improved survival from the underlying
cognitive decline and parkinsonism clinically malignancy. It is associated with diffuse white
resembling sporadic Creutzfeldt–Jakob disease has matter change (leukoencephalopathy) and cortical/
also been reported (Slee et al., 2006). Progression to subcortical atrophy on brain imaging, a subcortical
a dementia of white matter type occurs with bihe- pattern of cognitive deficits, with psychomotor
mispheric white matter infiltration (Filley et al., slowing, executive and memory dysfunction,
2003). sometimes sufficiently severe to constitute demen-
tia, and pathological changes of gliosis, demyelina-
tion, and thickening of small vessels (Crossen et al.,
REFERENCES 1994; Armstrong et al., 2004; Omuro et al., 2005). In
a series of patients with primary CNS lymphoma, 5-
Chamberlain MC. Gliomatosis cerebri: better definition, year cumulative incidence of delayed neurotoxicity
better treatment. Neurology 2004; 63: 204–5. was nearly 25% (Omuro et al., 2005). An annual
Filley CM, Kleinschmidt-DeMasters BK, Lillehei KO,
incidence of 11% was noted in an older, retro-
Damek DM, Harris JG. Gliomatosis cerebri: neurobeha-
spective, series in which relatively high doses of
vioral and neuropathological observations. Cogn Behav
radiation were used (DeAngelis et al., 1989).
Neurol 2003; 16: 149–59.
Slee M, Pretorius P, Ansorge O, Stacey R, Butterworth R.
Neurotoxicity from chemotherapeutic agents is
Parkinsonism and dementia due to gliomatosis cerebri more likely if they are given concomitantly with
mimicking sporadic Creutzfeldt–Jakob disease (CJD). radiotherapy, or via intrathecal or intra-arterial
J Neurol Neurosurg Psychiatry 2006; 77: 283–4. routes as compared to systemically, all these fac-
tors increasing drug concentration in normal brain
tissue by compromising or bypassing the blood–
7.1.8 Radiotherapy and chemotherapy
brain barrier.
The risk of cognitive deficits related to radiother-
apy is a vexed question. The risk is known to
increase with high radiation dose, large fraction REFERENCES
and field size (whole brain versus focal), but is also
related to patient age and concurrent chemo- Armstrong CL, Gyato K, Awadalla AW, Lustig R, Tochner
therapy. Moreover, there are potential con- ZA. A critical review of the clinical effects of therapeutic
founders, including the malignancy per se (e.g. irradiation damage to the brain: the roots of the
disease progression), comorbid medical, neuro- controversy. Neuropsychol Rev 2004; 14: 65–86.
logical (e.g. epilepsy), or psychiatric conditions Crossen JR, Garwood D, Glatstein E, Neuwelt EA.
Neurobehavioral sequelae of cranial irradiation in
(e.g. depression), and surgical treatment
adults: a review of radiation-induced encephalopathy.
(Armstrong et al., 2004; Laack & Brown, 2004;
J Clin Oncol 1994; 12: 627–42.
Taphoorn & Klein, 2004; Sarkissian, 2005). Recent
DeAngelis LM, Delattre JY, Posner JB. Radiation-induced
reviews of the literature have concluded that focal dementia in patients cured of brain metastases. Neurology
radiotherapy in patients with glioma is not the 1989; 39: 789–96.
main reason for cognitive deficits (Taphoorn & Laack NN, Brown PD. Cognitive sequelae of brain
Klein, 2004) and that radiation effects on radiation in adults. Semin Oncol 2004; 31: 702–13.
Omuro AMP, Ben Porat LS, Panageas KS, et al. Delayed REFERENCES
neurotoxicity in primary central nervous system lymph-
oma. Arch Neurol 2005; 62: 1595–600. Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult
Sarkissian V. The sequelae of cranial irradiation on human hydrocephalus with ‘normal’ cerebrospinal fluid pres-
cognition. Neurosci Lett 2005; 382: 118–23. sure. N Engl J Med 1965; 273: 117–26.
Taphoorn MJB, Klein M. Cognitive deficits in adult Benson DF. Hydrocephalic dementias. In: Frederiks
patients with brain tumours. Lancet Neurol 2004; 3: JAM (ed.), Handbook of Clinical Neurology. Vol. 2 (46):
159–68. Neurobehavioural Disorders. Amsterdam: Elsevier, 1990:
323–33.
Bret P, Guyotat J, Chazal J. Is normal pressure hydrocepha-
lus a valid concept in 2002? A reappraisal in five questions
7.2 Hydrocephalic dementias and proposal for a new designation of the syndrome as
‘chronic hydrocephalus’. J Neurol Neurosurg Psychiatry
The association of dementia with hydrocephalus 2002; 73: 9–12.
may arise in a number of situations (Benson, 1990; Esiri MM, Rosenberg GA. Hydrocephalus and dementia.
Esiri & Rosenberg, 2004). Hydrocephalus may be In: Esiri MM, Lee VMY, Trojanowski JQ (eds.), The
classified according to whether there is obstruction Neuropathology of Dementia (2nd edition). Cambridge:
to the flow of CSF, and whether the ventricles Cambridge University Press, 2004: 442–56.
are communicating or not. Obstructive non-
communicating hydrocephalus in the context of
7.2.1 Normal pressure hydrocephalus (NPH)
neoplasms, inflammation (ependymitis, arachnoid-
itis, pachymeningitis), and acquired aqueduct That normal pressure hydrocephalus (NPH) com-
stenosis may present as a subacute dementia. Non- prises the clinical triad of gait difficulties of par-
obstructive communicating hydrocephalus may kinsonian type, urinary problems, and cognitive
result from ex vacuo brain atrophy, perhaps in the decline is a fact known to virtually every medical
context of parenchymal brain disease or previous student, and a huge literature on the subject has
brain trauma, or, extremely rarely, from CSF developed since the condition was first described
hypersecretion, as for example from a choroid (Adams et al., 1965; Hakim & Adams, 1965), much of
plexus tumour. Perhaps the most challenging it related to predicting which patients will respond
clinical situation, in terms of both diagnosis and to surgical shunting procedures (Vanneste, 2000;
management, relates to cases of communicating Bret et al., 2002; Malm & Eklund, 2006). The advent
hydrocephalus. These may be obstructive, sec- of widespread structural neuroimaging with CT has
ondary to subarachnoid haemorrhage, trauma, increased the frequency with which this disorder is
meningitis or diffusely infiltrating tumour, or some considered: relative preservation of cortical gyri
other process (for example Paget’s disease of despite ventricular expansion is suggested to point
the skull: Section 7.2.4); or primary or idiopathic, to this diagnosis, and various radiological param-
the condition which has come to be known as eters (e.g. Evans ratio) have been suggested to be
idiopathic normal pressure hydrocephalus (iNPH). helpful in predicting shunt-responsiveness. Yet,
Whether these latter cases represent some form of despite this ‘evidence base’, the condition remains
occult obstruction remains unclear. Because of the in many ways obscure and perplexing, perhaps
uncertainties about aetiopathogenesis, retention of particularly for neurologists with an interest in
the term ‘occult hydrocephalus’ as originally sug- cognitive disorders. Is it certain, for example, that at
gested by Adams et al. (1965), or use of the term least some of these patients do not in fact have an ex
‘chronic hydrocephalus’ (Bret et al., 2002), may be vacuo non-obstructive communicating hydro-
preferable. cephalus due to occult primary intraparenchymal
pathology causing subcortical atrophy, a well- cognitive impairment was seen in those cases with
recognized correlate of Alzheimer’s disease (AD)? greater degrees of AD pathology. Low verbal
Very few NPH patients come to pathological memory baseline scores were found to be pre-
analysis, either biopsy or autopsy, and when they do dictors of poor response in a cohort of iNPH
alternative pathologies may be found, such as AD patients undergoing shunting, the more so if there
(Golomb et al., 2000; Silverberg et al., 2002; Bech- was concurrent visuoconstructional deficit or
Azeddine et al., 2007), Parkinson’s disease (Krauss et executive dysfunction (Thomas et al., 2005): one
al., 1997), cerebrovascular disease (Bech-Azeddine wonders whether these more impaired patients
et al., 2007), or progressive supranuclear palsy may have been harbouring primary neurodegen-
(Schott et al., 2007), even when patients have proven erative disease. Cognitive impairment in iNPH was
to be temporarily ‘shunt-responsive’. Other sec- reported to be more severe than in Binswanger’s
ondary causes of NPH have been reported, such as disease (Gallassi et al., 1991). A case of NPH with
neuroborreliosis (see Section 9.4.3). The CSF tap transient prosopagnosia, topographical disorien-
test, the withdrawal of 25–30 ml of CSF with pretation and visual object agnosia which improved
and post-test assessment of gait and cognitive after shunting has also been reported (Otani et al.,
function, has been advocated as a predictor of shunt 2004), but without prolonged follow-up or patho-
responsiveness, but both false negatives and false logical examination. Again one may wonder
positives may occur, the latter possibly due to the whether this is an example of a shunt-responsive
presence of alternative, primary neurodegenerative, primary neurodegenerative disorder.
pathology (Larner & Larner, 2006). Hence, there are significant methodological dif-
With these diagnostic uncertainties, it is apparent ficulties in defining the cognitive profile of iNPH.
that delineating the neuropsychological profile of Nonetheless, disruption of frontal-subcortical
idiopathic NPH will be difficult, yet there have been pathways would seem the most likely pathological
attempts (Merten, 1999; Devito et al., 2005). In a substrate (for example, to account for the parkin-
very selected cohort (n ¼ 11), Iddon et al. (1999) sonian gait), with a corresponding subcortical type
identified two groups: those with MMSE < 24 pre- of neuropsychological profile.
operatively, performing in the demented range, who
showed significant postoperative recovery; and
those showing no signs of dementia either pre- or REFERENCES
post-shunt but who did show a specific pattern of
neuropsychological impairments in comparison Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult
with healthy volunteers on tests sensitive to fron- hydrocephalus with ‘normal’ cerebrospinal fluid pres-
tostriatal dysfunction, changes distinct from AD. sure. N Engl J Med 1965; 273: 117–26.
Ogino et al. (2006) found disproportionate Bech-Azeddine R, Høgh P, Juhler M, Gjerris F, Waldemar G.
impairment of frontal lobe functions (attention/ Idiopathic normal-pressure hydrocephalus: clinical
comorbidity correlated with cerebral biopsy findings
concentration subtest of WMS-R; digit span,
and outcome of cerebrospinal fluid shunting. J Neurol
arithmetic, block design, and digit symbol substi-
tution subtests of WAIS-R) in iNPH patients com-
Bret P, Guyotat J, Chazal J. Is normal pressure hydro-
pared to AD, but disproportionately mild memory cephalus a valid concept in 2002? A reappraisal in five
impairment (general memory and delayed recall in questions and proposal for a new designation of the
WAIS-R). Impaired frontal lobe function as syndrome as ‘chronic hydrocephalus’. J Neurol Neuro-
assessed by the Frontal Assessment Battery and surg Psychiatry 2002; 73: 9–12.
verbal fluency tests was also reported by the same Devito EE, Pickard JD, Salmond CH, et al. The neuro-
group (Miyoshi et al., 2005). Perhaps unsurpris- psychology of normal pressure hydrocephalus. Br J
ingly, in the cohort of Golomb et al. (2000) more Neurosurg 2005; 19: 217–24.
Gallassi R, Morreale A, Montagna P, et al. Binswanger’s 7.2.2 Aqueduct stenosis

disease and normal pressure hydrocephalus: clinical
and neuropsychological comparison. Arch Neurol 1991;
Cases have been reported in which aqueduct
48: 1156–9. stenosis is associated with schizophrenic psychosis
Golomb J, Wisoff J, Miller DC, et al. Alzheimer’s disease (Roberts et al., 1983; O’Flaithbheartaigh et al., 1994)
comorbidity in normal pressure hydrocephalus: preva- and delusional depression with possible dience-
lence and shunt response. J Neurol Neurosurg Psychiatry phalic dysfunction (Motohashi et al., 1990), but
2000; 68: 778–81. whether these are chance concurrences or causal
Hakim S, Adams RD. The special clinical problem of associations remains unclear. No convincing report
symptomatic hydrocephalus with normal cerebrospinal of dementia associated with congenital aqueduct
fluid pressure: observations on cerebrospinal fluid
stenosis has been identified.
hydrodynamics. J Neurol Sci 1965; 2: 307–27.
Iddon JL, Pickard JD, Cross JJ, et al. Specific patterns of
cognitive impairment in patients with idiopathic normal
pressure hydrocephalus and Alzheimer’s disease: a REFERENCES
pilot study. J Neurol Neurosurg Psychiatry 1999; 67:
723–32. Motohashi N, Ishizuka Y, Asada T, et al. A case of
Krauss JK, Regel JP, Droste DW, et al. Movement disorders aqueduct stenosis in adults with various neurological
in adult hydrocephalus. Mov Disord 1997; 12: 53–60. and psychiatric symptoms. Eur Arch Psychiatry Clin
Larner MJ, Larner AJ. Normal pressure hydrocephalus: Neurosci 1990; 240: 13–15.
false positives. Pract Neurol 2006; 6: 264. O’Flaithbheartaigh S, Williams PA, Jones GH. Schizo-
Malm J, Eklund A. Idiopathic normal pressure hydro- phrenic psychosis and associated aqueduct stenosis. Br
cephalus. Pract Neurol 2006; 6: 14–27. J Psychiatry 1994; 164: 684–6.
Merten T. Neuropsychology of normal pressure hydro- Roberts JK, Trimble MR, Robertson M. Schizophrenic
cephalus [in German]. Nervenarzt 1999; 70: 496–503. psychosis associated with aqueduct stenosis in adults.
Miyoshi N, Kazui H, Ogino A, et al. Association between J Neurol Neurosurg Psychiatry 1983; 46: 892–8.
cognitive impairment and gait disturbance in patients
with idiopathic normal pressure hydrocephalus.
Dement Geriatr Cogn Disord 2005; 20: 71–6. 7.2.3 Colloid cyst, fornix lesions
Ogino A, Kazui H, Miyoshi N, et al. Cognitive impairment
Colloid cysts are thought to arise from ependymal
in patients with idiopathic normal pressure hydro-
cells in the vestigial paraphysis in the anterior
cephalus. Dement Geriatr Cogn Disord 2006; 21: 113–19.
Otani N, Nawashiro H, Ishihara S, et al. Normal pressure portion of the third ventricle, where they may block
hydrocephalus manifesting as topographical disorien- the third ventricle and cause obstructive hydro-
tation and visual objective [sic] agnosia. J Clin Neurosci cephalus. Clinical presentation is either with
2004; 11: 313–17. intermittent obstruction causing severe bifrontal-
Schott JM, Williams DR, Butterworth R, et al. Shunt bioccipital headache, unsteady gait, incontinence,
responsive progressive supranuclear palsy ? Mov Disord visual impairment, and drop attacks without loss
2007; 22: 902–3. of consciousness, or with a picture resembling
Silverberg GD, Levinthal E, Sullivan EV, et al. Assessment of ‘normal pressure hydrocephalus’. Some cases are
low-flow CSF drainage as a treatment for AD: results of a
now found incidentally when patients undergo
randomized pilot study. Neurology 2002; 59: 1139–45.
brain imaging for other reasons. Surgical resection
Thomas G, McGirt MJ, Woodworth G, et al. Baseline
of the cyst may be undertaken, although symptoms
neuropsychological profile and cognitive response to
cerebrospinal fluid shunting for idiopathic normal may sometimes be more easily controlled with
pressure hydrocephalus. Dement Geriatr Cogn Disord shunting or stereotactic decompression.
2005; 20: 163–8. Damage to the fornix as a consequence of sur-
Vanneste JA. Diagnosis and management of normal gery for colloid cyst may result in a persistent
pressure hydrocephalus. J Neurol 2000; 247: 5–14. anterograde amnesia (Hodges & Carpenter, 1991;
Gaffan et al., 1991; McMackin et al., 1995; Aggleton McMackin D, Cockburn J, Anslow P, Gaffan D. Correlation
et al., 2000; Spiers et al., 2001; Poreh et al., 2006). of fornix damage with memory impairment in six cases
Bilateral fornix interruption was a predictor of poor of colloid cyst removal. Acta Neurochir Wien 1995; 135:
memory performance in one study (Aggleton et al., 12–18.
Moudgil SS, Azzouz M, Al-Azzaz A, Haut M, Gutmann L.
2000); severity of damage to the left fornix was
Amnesia due to fornix infarction. Stroke 2000; 31: 1418–19.
suggested to be the most important determinant of
Poreh A, Winocour G, Moscovitch M, et al. Anterograde
severity of impairment in verbal memory in
and retrograde amnesia in a person with bilateral fornix
another (McMackin et al., 1995). Recall may be less lesions following removal of a colloid cyst. Neuropsy-
impaired than recognition (Aggleton et al., 2000). chologia 2006; 44: 2241–8.
Relative absence of retrograde amnesia was noted Spiers HJ, Maguire EA, Burgess N. Hippocampal amnesia.
in some reports (Hodges & Carpenter, 1991; Spiers Neurocase 2001; 7: 357–82.
et al., 2001), but in others retrograde amnesia for Yasuno F, Hirata M, Takimoto H, et al. Retrograde
autobiographical episodes and for semantic mem- temporal order amnesia resulting from damage to the
ory was noted (Poreh et al., 2006). fornix. J Neurol Neurosurg Psychiatry 1999; 67: 102–5.
Fornix damage with subsequent neuropsycho-
logical deficits may also be a consequence of sur- 7.2.4 Paget’s disease of bone (osteitis
gery for other tumours (Calabrese et al., 1995; deformans)
Yasuno et al., 1999; Ibrahim et al., 2007), focal
This disorder of increased bone turnover with
stroke (Moudgil et al., 2000; see Section 3.3.2), or
excessive osteoclastic resorption and disorganized
carbon monoxide poisoning (Kesler et al., 2001;
new bone formation has a predilection for involve-
Section 8.2.3).
ment of the skull and vertebral column. Neurological
complications are well recognized, particularly cra-
nial nerve palsies due to foraminal entrapment and
REFERENCES
extradural myelopathy due to disease in vertebral
bodies. Dementia as a consequence of basilar inva-
Aggleton JP, McMackin D, Carpenter K, et al. Differential
gination is reported, producing a syndrome some-
cognitive effects of colloid cysts in the third ventricle
that spare or compromise the fornix. Brain 2000; 123: times likened to normal pressure hydrocephalus,
800–15. although there may be debate as to whether the
Calabrese P, Markowitsch HJ, Harders AG, Scholz M, hydrocephalus is in some sense obstructive or non-
Gehlen W. Fornix damage and memory: a case report. communicating, and which may be treated with
Cortex 1995; 31: 555–64. ventricular shunting (Gottschalk, 1973; Culebras
Gaffan EA, Gaffan D, Hodges JR. Amnesia following et al., 1974; Dohrmann & Elrick, 1982; Chan et al.,
damage to the left fornix and to other sites: a compara- 2000; Fereydoon et al., 2005).
tive study. Brain 1991; 114: 1297–313. Paget’s disease may rarely occur in association
Hodges JR, Carpenter K. Anterograde amnesia with
with an autosomal dominant frontotemporal
fornix damage following removal of a third ventricle
dementia with or without inclusion body myopathy
colloid cyst. J Neurol Neurosurg Psychiatry 1991; 54:
(IBMPFD) caused by mutations in the valosin-
633–8.
Ibrahim I, Young CA, Larner AJ. Cognitive impairments containing protein gene on chromosome 9 (Watts
associated with fornix damage caused by subependy- et al., 2004; see Section 5.1.8).
mal giant-cell astrocytoma (SEGA). Eur J Neurol 2007;
14 (Suppl 1): 104 (abstract P1285).
REFERENCES
Kesler SR, Hopkins RO, Blatter DD, Edge Booth H, Bigler ED.
Verbal memory deficits associated with fornix atrophy in
carbon monoxide poisoning. J Int Neuropsychol Soc 2001; Chan YP, Shui KK, Lewis RR, Kinirons MT. Reversible
7: 640–6. dementia in Paget’s disease. J R Soc Med 2000; 93: 595–6.
Culebras A, Feldman RG, Fager CA. Hydrocephalus and syndrome, features which may be fixed or transi-
dementia in Paget’s disease of the skull. J Neurol Sci ent. Gerstmann syndrome has been reported
1974; 23: 307–21. (Maeshima et al., 1998). Recognized risk factors for
Dohrmann PJ, Elrick WL. Dementia and hydrocephalus in the accumulation of blood and its liquefaction in
Paget’s disease: a case report. J Neurol Neurosurg
the subdural space include increasing age, history
Psychiatry 1982; 45: 835–7.
of direct head trauma (although not invariably
Fereydoon R, Mann D, Kula RW. Surgical management of
present), use of antiplatelet or anticoagulant drugs,
hydrocephalic dementia in Paget’s disease of bone: the
6-year outcome of ventriculo-peritoneal shunting. Clin
and alcohol misuse. A history of falls may be a
Neurol Neurosurg 2005; 107: 325–8. particular ‘red flag’ (Adhiyaman et al., 2002). The
Gottschalk PG. Normal pressure hydrocephalus with diagnosis may be overlooked, symptoms being
basilar impression due to Paget’s disease of the skull. attributed to other causes, such as a dementia
Wisconsin Med J 1973; 72: 192. syndrome, and brain imaging with CT may not be
Watts GDJ, Wymer J, Kovach MJ, et al. Inclusion body diagnostic if the collection is isodense, rather than
myopathy associated with Paget disease of bone and hyperdense (acute) or hypodense (> 4 weeks), or if
frontotemporal dementia is caused by mutant valosin- bilateral collections cause no mass effect or mid-
containing protein. Nat Genet 2004; 36: 377–81.
line shift (Davenport et al., 1994). Surgical evacu-
ation is often the treatment of choice.
Variable mental changes have been reported in
7.3 Other structural lesions chronic SDH: lethargy and poor concentration;
withdrawal; confusion with aggressive outbursts;
Subdural haematoma and arachnoid cyst are
and failing memory and intelligence reminiscent
considered here. Other potentially relevant struc-
of a dementia syndrome (Luxon & Harrison, 1979).
tural brain lesions, such as arteriovenous malfor-
Slowed mental abilities, but with normal abbre-
mations and fistulas, are considered elsewhere
viated mental test score, have been reported with
(see Section 3.5).
akinetic-rigid syndrome (Abdulla & Pearce, 1999).
However, there have been no prospective sys-
7.3.1 Subdural haematoma (SDH) tematic studies. Chronic subdural haematoma is
often listed in textbooks as a cause of reversible
Cognitive sequelae associated with acute subdural dementia, but the published evidence base for this
haematoma (SDH) may be related to traumatic is slim. Ishikawa et al. (2002) reported that nearly
brain injury in the context of head injury, the most 70% of a series of 26 patients operated on for
common cause of acute SDH; alcohol misuse may chronic SDH (i.e. a highly selected cohort) were
be a precipitating factor. Chronic SDH without a demented preoperatively on the basis of their
history of head trauma most commonly occurs in performance on MMSE, with 50% (i.e. nine
the elderly, where concurrent neurodegenerative patients) making a good recovery. Younger
disease (AD, dementia with Lewy bodies), with patients with a higher preoperative MMSE showed
associated risk of repeated falls, may be present. better recovery, as did patients diagnosed and
Despite these possible confounding factors, SDH evacuated early.
per se may be associated with cognitive deficits
(Machulda & Haut, 2000).
Chronic SDH may present with altered mental REFERENCES
state with features of delirium or dementia, and
with or without focal neurological deficits such as Abdulla AJJ, Pearce VR. Reversible akinetic-rigid syn-
hemiparesis, aphasia (Moster et al., 1983), hemi- drome due to bilateral subdural haematomas. Age
sensory loss, seizures, headache, and akinetic-rigid Ageing 1999; 28: 582–3.
Adhiyaman V, Asghar M, Ganeshram KN, Bhowmick BK. perceptual task (dichotic listening technique),
Chronic subdural haematoma in the elderly. Postgrad which disappeared within hours of decompressive
Med J 2002; 78: 71–5. cyst surgery performed for symptoms such as
Davenport RJ, Statham PFX, Warlow CP. Detection of headache, epilepsy, or hemiparesis. This was a
bilateral isodense subdural haematomas. BMJ 1994;
highly selected (convenience?) sample (n ¼ 13),
309: 792–4.
since one of the inclusion criteria was symptomatic
Ishikawa E, Yanaka K, Sugimoto K, Ayuzawa S, Nose T.
improvement after surgery! The symptoms listed
Reversible dementia in patients with chronic subdural
haematomas. J Neurosurg 2002; 96: 680–3.
are probably rarely encountered with arachnoid
Luxon LM, Harrison MJG. Chronic subdural haematoma. cysts, most of which are asymptomatic, incidental,
Q J Med 1979; 48 (189): 43–53. findings. A case of presenile dementia associated
Machulda MM, Haut MW. Clinical features of chronic with a left temporofrontal cyst without mass effect
subdural hematoma: neuropsychiatric and neuropsy- was reported by Richards & Lusznat (2001), but this
chologic changes in patients with chronic subdural may be simply chance concurrence: the neuro-
hematoma. Neurosurg Clin North Am 2000; 11: 473–7. logical diagnosis was AD and the patient showed
Maeshima S, Okumura Y, Nakai K, Itakura T, Komai N. initial improvement with cholinesterase inhibitor
Gerstmann’s syndrome associated with chronic subdural
treatment.
haematoma: a case report. Brain Inj 1998; 12: 697–701.
Moster ML, Johnston DE, Reinmuth OM. Chronic sub-
dural hematoma with transient neurological deficits: a
REFERENCES
review of 15 cases. Ann Neurol 1983; 14: 539–42.
Gallassi R, Ciardulli C, Ferrara R, et al. Asymptomatic

7.3.2 Arachnoid cyst large arachnoid cyst of the middle cranial fossa: a
clinical and neuropsychological study. Eur Neurol
Arachnoid cysts are not infrequent incidental 1985; 24: 140–4.
findings on brain imaging, most commonly in the Lang W, Lang M, Kornhuber A, Gallwitz A, Kriebel J.
middle cranial fossa. Whether they sometimes have Neuropsychological and neuroendocrinological dis-
symptomatic effects related to space occupation turbance associated with extracerebral cysts of the
(pressure, brain displacement, both, or other anterior and middle cranial fossa. Eur Arch Psychiatr
mechanisms) is debated. Some studies have found Neurol Sci 1985; 235: 38–41.
impaired learning and memory specific to the Richards G, Lusznat RM. An arachnoid cyst in a patient
with pre-senile dementia. Prog Neurol Psychiatry 2001;
hemisphere affected (Lang et al., 1985), while
5(3): 21–2.
others have failed to show such impairments
Wester K, Hugdahl K. Arachnoid cysts of the left temporal
(Gallassi et al., 1985). Wester and Hugdahl (1995)
fossa: impaired preoperative cognition and postopera-
identified cognitive deficits affecting memory and tive improvement. J Neurol Neurosurg Psychiatry 1995;
the ability to direct attention in an auditory 59: 293–8.
8
Endocrine, metabolic, and toxin-related disorders
8.1 Endocrine disorders 188

8.1.1 Diabetes mellitus 188
8.1.2 Thyroid disorders 190
8.1.3 Parathyroid disorders 191
8.1.4 Cushing’s syndrome (hypercortisolism) 192
8.1.5 Conn’s syndrome (primary hyperaldosteronism) 193
8.2 Metabolic disorders 193
8.2.1 Central pontine (and extrapontine) myelinolysis, osmotic demyelination syndrome 193
8.2.2 Gastrointestinal disease 194
8.2.3 Respiratory disorders 197
8.3 Toxin-related disorders 200
8.3.1 Alcohol-related disorders 200
8.3.2 Solvent exposure 203
8.3.3 Domoic acid poisoning (amnesic shellfish poisoning) 203
8.1 Endocrine disorders

increase relative risk in certain subgroups (Akomo-
lafe et al., 2006).
8.1.1 Diabetes mellitus
Epidemiological studies provide some evidence
A link between diabetes mellitus per se and cognitive that cognition may be impaired in the early stages of
decline may be obscured by comorbid cerebrovas- type 2 diabetes. In the Whitehall II study, a pro-
cular disease (both microvascular and macro- spective study of the incidence of diabetes, an asso-
vascular), hypertension, or depression (Messier, ciation was noted between diabetes and poor
2005), since these conditions may confound any performance on a test of inductive reasoning (Alice
assessment of cognitive performance. Nonetheless, a Heim 4) in stroke-free patients, but verbal memory,
meta-analysis of studies of cognitive performance in verbal meaning, and verbal fluency tests were not
type 1 diabetes found evidence for slowing of mental affected. The study suggested that effects of diabetes
speed and diminished mental flexibility with sparing on cognitive performance may be evident within 5
of learning and memory (Brands et al., 2005). Sys- years of diagnosis (Kumari & Marmot, 2005). Hence,
tematic reviews have shown a greater risk and rate of cognitive dysfunction is one of the chronic compli-
cognitive functional decline (Cukierman et al., 2005) cations of diabetes, but the pathophysiology is
and of dementia (Biessels et al., 2006) in diabetes, uncertain. Possible mediating and modulating factors
with processing speed and verbal memory the may include the aforementioned comorbidities and
domains most affected (Messier, 2005). Diabetes effects of glycaemic control: hyperglycaemia, insulin
does not appear to be a risk factor for the develop- resistance (hyperinsulinaemia), and treatment-
ment of Alzheimer’s disease overall, but might induced hypoglycaemia.
188
It might be anticipated that, as for neuropathic tests than those who had never experienced severe
and nephropathic complications of diabetes, hypoglycaemia (Wredling et al., 1990; Sachon et al.,
stricter glycaemic control might reduce the risk of 1992). Cohort studies have also suggested a modest
cognitive impairment. Observational studies sug- association between reported frequency of severe
gest that acute hyperglycaemia is associated with a hypoglycaemia, lower IQ, and slowed and more
slowing of cognitive performance in some subjects variable reaction times (Langan et al., 1991; Lincoln
with either type 1 or type 2 diabetes, with a possible et al., 1996). In contrast, however, longitudinal
threshold around 15 mmol/l (Cox et al., 2005). studies have failed to find any deleterious cognitive
Whether this is a consequence of hyperglycaemia effects of repeated severe hypoglycaemia (Reichard
per se or of underlying insulin resistance is not & Pihl, 1994; Diabetes Control and Complications
certain: hyperinsulinaemia is reported in epidemi- Trial Research Group, 1996). This is a vexed ques-
ological studies to be a risk factor for the develop- tion, with currently no clear-cut answer (Deary &
ment of dementia and memory decline (Luchsinger Frier, 1996).
et al., 2004).
A management strategy of strict glycaemic control
may exacerbate the risk of episodes of treatment- REFERENCES
induced hypoglycaemia, which might also contrib-
ute to cognitive impairment. Hypoglycaemia is Akomolafe A, Beiser A, Meigs JB, et al. Diabetes mellitus
recognized to cause acute neuropsychiatric features and risk of developing Alzheimer disease: results from
as a consequence of neuroglycopaenia, with or the Framingham Study. Arch Neurol 2006; 63: 1551–5
without concurrent features of autonomic activation. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens
Severe hypoglycaemia is also a recognized cause of P. Risk of dementia in diabetes mellitus: a systematic
acute amnesia (Fisher, 2002). An amnesic syndrome review. Lancet Neurol 2006; 5: 64–74.
has on occasion been reported in patients with dia- Brands AMA, Biessels GJ, De Haan EHF, Kappelle LJ,
Kessels RPC. The effects of type 1 diabetes on cognitive
betes experiencing profound hypoglycaemia as a
performance. Diabetes Care 2005; 28: 726–35.
consequence of intensive insulin treatment, for
Cox DJ, Kovatchev B, Gonder-Frederick LA, et al. Rela-
example using a subcutaneous pump, in the
tionships between hyperglycemia and cognitive per-
absence of confounding epileptic seizures. Bilateral formance among adults with type 1 and type 2 diabetes.
high-signal-intensity hippocampal lesions on MR Diabetes Care 2005; 28: 71–7.
brain imaging have been noted in some patients Cukierman T, Gerstein HC, Williamson JD. Cognitive
(Holemans et al., 2001) but are not invariably found decline and dementia in diabetes: systematic overview
(Larner et al., 2003). Prognosis is variable: the of progressive observational studies. Diabetologia 2005;
amnesia may be completely reversible (Holemans 48: 2460–9.
et al., 2001) or partially reversible (Larner et al., 2003). Deary IJ, Frier BM. Severe hypoglycaemia and cognitive
Amnesia for hypoglycaemia is reported to be a impairment in diabetes. BMJ 1996; 313: 767–8.
Diabetes Control and Complications Trial Research Group.
common feature in patients with insulinomas (Dizon
Effects of intensive diabetes therapy on neuropsycho-
et al., 1999). Presumably this amnesia induced by
logical function in adults in the diabetes control and
profound hypoglycaemia reflects hippocampal vul-
complications trial. Ann Intern Med 1996; 124: 379–88.
nerability to the effects of neuroglycopaenia. Whether Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and
repeated episodes of hypoglycaemia cause persistent other symptoms in patients with insulinomas. Am J Med
cognitive deficits in diabetes remains an open ques- 1999; 106: 307–10.
tion. Small studies have suggested that adults with Fisher CM. Unexplained sudden amnesia. Arch Neurol
a history of severe hypoglycaemia (i.e. episodes 2002; 59: 1310–13.
requiring assistance from another person to be Holemans X, Dupuis M, Missan N, Vanderijst JF. Revers-
reversed) scored lower on some neuropsychological ible amnesia in a type 1 diabetic patient and bilateral
190 Endocrine, metabolic, and toxin-related disorders
hippocampal lesions on magnetic resonance imaging having their thyroid function tests checked. An
(MRI). Diabet Med 2001; 18: 761–3. examination of the evidence base, however, tells a
Kumari M, Marmot M. Diabetes and cognitive function in rather different story. In a literature search of studies
a middle-aged cohort: findings from the Whitehall II on the aetiology of dementia, Clarnette and Patterson
study. Neurology 2005; 65: 1597–603.
(1994) found only a single case due to hypothyroid-
Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative
ism in 2781 cases of reversible dementia. Non-
cognitive impairment following severe hypoglycaemia
reversible cases have also been reported (Menne-
in adult patients with insulin-treated diabetes mellitus.
Diabetologia 1991; 34: 337–44.
meier et al., 1993). Dugbartey (1998) noted that
Larner AJ, Moffat MA, Ghadiali E, et al. Amnesia following hypothyroidism has been associated with deficits in
profound hypoglycaemia in a type 1 diabetic patient. general intelligence, complex attention and concen-
Eur J Neurol 2003; 10 (Suppl 1): 92 (abstract P1170). tration, memory, perceptual and visuoperceptual
Lincoln NB, Faleiro RM, Kelly C, Kirk BA, Jeffcoate WJ. function, expressive and receptive language, and
Effect of long-term glycemic control on cognitive executive/frontal functions. A study of thyroid cancer
function. Diabetes Care 1996; 19: 656–8. patients on and off thyroxine suggested that the
Luchsinger JA, Tang-Ming X, Shea S, Mayeux R. Hyper- memory defect in delayed recall of verbal infor-
insulinemia and risk of Alzheimer disease. Neurology
mation could not be solely attributed to reduced
2004; 63: 1187–92.
attentional resources (Burmeister et al., 2001).
Messier C. Impact of impaired glucose tolerance and type
Subclinical hypothyroidism (SCH) is character-
2 diabetes on cognitive aging. Neurobiol Aging 2005; 26
(Suppl 1): 26–30.
ized by low levels of thyroid-stimulating hormone
Reichard P, Pihl M. Mortality and treatment side effects (TSH) but normal levels of T4, T3, free T4, and free
during long-term intensified conventional insulin treat- T3, and may reflect incipient hypothyroidism.
ment in Stockholm Diabetes Intervention Study. Diabetes Some studies have suggested cognitive impair-
1994; 43: 313–17. ments in SCH, including logical memory (Baldini
Sachon C, Grimaldi A, Digy JP, et al. Cognitive function, et al., 1997) and working memory (Zhu et al., 2006),
insulin-dependent diabetes and hypoglycaemia. whereas others have found cognitive performance
J Intern Med 1992; 231: 471–5. to be within the normal range (Bono et al., 2004).
Wredling R, Levander S, Adamson U, Lins P. Permanent
Verbal fluency (and mood) may improve after thy-
neuropsychological impairment after recurrent epi-
roxine treatment in asymptomatic individuals with
sodes of severe hypoglycaemia in man. Diabetologia
mild biochemical hypothyroidism (Bono et al.,
1990; 33: 152–7.
2004), as may memory and working memory per-
formance. A positive correlation between plasma
8.1.2 Thyroid disorders thyroid hormone (T4) level and cognitive function
as assessed with MMSE has been noted in euthyroid
Hypothyroidism
older women (Volpato et al., 2002).
Hypothyroidism is well recognized to have neu- Since the risk of hypothyroidism, like dementia,
ropsychiatric features, popularized by Richard increases with age, the possibility that cognitive
Asher in his 1949 paper as ‘myxoedematous mad- impairment is a comorbid rather than a causal factor
ness’; interestingly, a number of his cases were in some cases cannot be ruled out. Mood may also
stated to have dementia (cases 4, 6, 13), one was need to be taken into account (Mennemeier et al.,
initially referred with a suspected diagnosis of 1993; Bono et al., 2004). Currently there seems little
Alzheimer’s disease, and others were mentally slow, justification in submitting all cognitively impaired
becoming more alert with treatment (Asher, 1986). patients to thyroid function tests unless there are
Hypothyroidism now features ubiquitously in the other somatic and/or neurological symptoms and
textbook rubric of ‘reversible dementia’, and few signs pointing to the possibility of thyroid dysfunc-
patients complaining of memory problems escape tion, although TSH remains a mandatory test in the
revised guidelines for dementia investigation pro- Clarnette RM, Patterson CJ. Hypothyroidism: does treat-
mulgated by the European Federation of Neuro- ment cure dementia? J Geriatr Psychiatry Neurol 1994;
logical Societies (Waldemar et al., 2006). 7: 23–7.
Thyroid dysfunction may also be seen in associ- Dugbartey AT. Neurocognitive aspects of hypothyroidism.
Arch Intern Med 1998; 158: 1413–18.
ation with cognitive disorder in Hashimoto’s
Fukui T, Hasegawa Y, Takenaka H. Hyperthyroid demen-
encephalopathy (see Section 6.13).
tia: clinicoradiological findings and response to treat-
ment. J Neurol Sci 2001; 184: 81–8.
Hyperthyroidism Kalmijn S, Mehta KM, Pols HA, et al. Subclinical
hyperthyroidism and the risk of dementia: the Rotter-
Occasional reports of dementia associated with dam study. Clin Endocrinol (Oxf) 2000; 53: 733–7.
hyperthyroidism with reversal upon correction of Larner AJ. Caleb Hillier Parry (1755–1822): clinician,
thyroid status have appeared (Bulens, 1981). An scientist, friend of Edward Jenner (1749–1823). J Med
epidemiological study suggesting that subclinical Biogr 2005; 13: 189–94.
hyperthyroidism is a risk factor for dementia and Mennemeier M, Garner RD, Heilman KM. Memory, mood
Alzheimer’s disease has appeared (Kalmijn et al., and measurement in hypothyroidism. J Clin Exp
2000). A case–control study of patients with newly Neuropsychol 1993; 15: 822–31.
diagnosed thyrotoxicosis of Graves’ type (a condi- Vogel A, Elberling TV, Hørding M, et al. Affective
symptoms and cognitive functions in the acute phase
tion originally described by Parry: Larner, 2005)
of Graves’ thyrotoxicosis. Psychoneuroendocrinology
found subjective reports of cognitive deficits in the
2007; 32: 36–43.
toxic phase, but no impairment was found on
Volpato S, Guralnik JM, Fried LP, et al. Serum thyroxine
comprehensive neuropsychological testing (Vogel level and cognitive decline in euthyroid older women.
et al., 2007), contrasting with a case report of Neurology 2002; 58: 1055–61.
impairments of attention, memory, and constructive Waldemar G, Dubois B, Emre M, et al. Alzheimer’s disease
skills in a man with Graves’ disease, whose symp- and other disorders associated with dementia. In:
toms and temporoparietal hypoperfusion on SPECT Hughes R, Brainin M, Gilhus NE (eds.), European
scanning improved with a return to euthyroidism Handbook of Neurological Management. Oxford:
(Fukui et al., 2001). Blackwell, 2006: 266–98.
Zhu DF, Wang ZX, Zhang DR, et al. fMRI revealed neural
substrate for reversible working memory dysfunction in
subclinical hypothyroidism. Brain 2006; 129: 2923–30.
REFERENCES
Asher R. Myxoedematous madness. In: Avery Jones F (ed.), 8.1.3 Parathyroid disorders
Richard Asher Talking Sense. Edinburgh: Churchill Liv-
ingstone, 1986: 77–95. Idiopathic hypoparathyroidism, probably an
Baldini IM, Vita A, Mauri MC, et al. Psychopathological and immune diathesis of the parathyroid glands, may
cognitive features in subclinical hypothyroidism. Prog result in a variety of systemic and neurological dis-
Neuropsychopharmacol Biol Psychiatry 1997; 21: 925–35. orders, the latter including seizures, extrapyramidal
Bono G, Fancellu R, Blandini F, Santoro G, Mauri M. signs, altered mental state, and signs of raised
Cognitive and affective status in mild hypothyroidism intracranial pressure including papilloedema,
and interactions with L-thyroxine treatment. Acta
neuromuscular hyperactivity (carpopedal spasm,
Neurol Scand 2004; 110: 59–66.
muscle cramps, Chvostek’s and Trousseau’s signs),
Bulens C. Neurological complications of hyperthyroidism:
as well as dementia. Many of these features may be
remission of spastic paraplegia, dementia, and optic
neuropathy. Arch Neurol 1981; 38: 669–70. explained by the accompanying hypocalcaemia, and
Burmeister LA, Ganguli M, Dodge HH, et al. Hypothyroid- reverse with its correction. Dementia has on occa-
ism and cognition: preliminary evidence for a specific sion been reported as the presenting sign of hypo-
defect in memory. Thyroid 2001; 11: 1177–85. parathyroidism (Robinson et al., 1954; Eraut, 1974;
Slyter, 1979), which may respond to treatment with ropsychiatric features such as depression. Cognitive
1,25-dihydroxycholecalciferol (Mateo & Gimenez- dysfunction may also occur: experimental animal
Roldan, 1982). A case of dementia associated studies have shown the hippocampus to be vulner-
with hypoparathyroidism but normocalcaemia able to glucocorticoid excess.
which proved reversible with treatment with 1,25- The cognitive impairments identified in Cush-
dihydroxycholecalciferol has also been presented ing’s syndrome patients have varied between
(Stuerenburg et al., 1996). studies: selective memory impairments were
Occasional cases of cognitive impairment asso- documented in one case–control study (Mauri et al.,
ciated with hypercalcaemia due to primary hyper- 1993), whereas selective attention and visual spatial
parathyroidism have been reported, with reversal processing seemed most affected in another report
after parathyroidectomy (Logullo et al., 1998). (Forget et al., 2000). Hence, cognitive dysfunction
may be variable from case to case (Whelan et al.,
1980). Another study showed no differences in
REFERENCES cognitive function between patients with pituitary
Cushing’s disease and a control group composed of
Eraut D. Idiopathic hypoparathyroidism presenting as patients with non-functioning pituitary adenomas,
dementia. BMJ 1974; 1: 429–30. although the scores of both groups for memory and
Logullo F, Babbini MT, Di Bella P, Provinciali L. Reversible attention showed significant decrements compared
combined cognitive impairment and severe polyneuro- to normative data (Heald et al., 2006), perhaps
pathy resulting from primary hyperparathyroidism. Ital
reflecting an effect of pituitary tumours per se (see
J Neurol Sci 1998; 19: 86–9.
Section 7.1.3). Some studies report cognitive
Mateo D, Gimenez-Roldan S. Dementia in idiopathic
improvement after pituitary surgery (Mauri et al.,
hypoparathyroidism: rapid efficacy of alfacalcidol. Arch
Neurol 1982; 39: 424–5.
1993), while others document little or no change in
Robinson KC, Kallberg MH, Crowley MF. Idiopathic performance, suggesting long-lasting deleterious
hypoparathyroidism presenting as dementia. BMJ effects of hypercortisolism (Forget et al., 2002).
1954; 2: 1203–6. Reduced hippocampal volume on structural brain
Slyter H. Idiopathic hypoparathyroidism presenting as imaging has been reported in Cushing’s syndrome,
dementia. Neurology 1979; 29: 393–4. and this correlated with memory dysfunction as
Stuerenburg HJ, Hansen HC, Thie A, Kunze K. Reversible measured by verbal recall (Starkman et al., 1992).
dementia in idiopathic hypoparathyroidism associated Similar findings have also been reported in elderly
with normocalcemia. Neurology 1996; 47: 474–6.
individuals with elevated cortisol as compared to
those with normal cortisol (Lupien et al., 1998).
8.1.4 Cushing’s syndrome (hypercortisolism)
Most cases of Cushing’s syndrome, due to hyper- REFERENCES
cortisolaemia, result from pituitary adenomas
secreting adrenocorticotrophic hormone (ACTH), Forget H, Lacroix A, Cohen H. Persistent cognitive
others from ectopic ACTH-producing tumours impairment following surgical treatment of Cushing’s
(most often in the lung), and adrenal cortex tumours. syndrome. Psychoneuroendocrinology 2002; 27: 367–83.
Forget H, Lacroix A, Somma M, Cohen H. Cognitive
Exogenous steroid, most often given therapeutically
decline in patients with Cushing’s syndrome. J Int
for a wide variety of diseases, neurological and
Neuropsychol Soc 2000; 6: 20–9.
otherwise, can also result in cushingoid features.
Heald A, Parr C, Gibson C, O’Driscoll K, Fowler H. A cross-
Complications include hypertension, impaired glu- sectional study to investigate long-term cognitive
cose tolerance or diabetes, osteoporosis, cushingoid function in people with treated pituitary Cushing’s
habitus, cutaneous striae, myopathy, and neu- disease. Exp Clin Endocrinol Diabetes 2006; 114: 490–7.
Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels 8.2.1 Central pontine (and extrapontine)
during human aging predict hippocampal atrophy and myelinolysis, osmotic demyelination
memory deficits. Nat Neurosci 1998; 1: 69–73. syndrome
Mauri M, Sinforiani E, Bono G, et al. Memory impairment
in Cushing’s disease. Acta Neurol Scand 1993; 87: 52–5. Central pontine myelinolysis was first described as
Starkman MN, Gebarski SS, Berent S, Schteingart DE. such by Adams et al. (1959) as a relatively symmet-
Hippocampal formation volume, memory dysfunction, rical destruction of myelin sheaths in the basal pons,
and cortisol levels in patients with Cushing’s syndrome. sometimes extending beyond (hence ‘extrapontine
Biol Psychiatry 1992; 32: 756–65. myelinolysis’), often associated with hyponatraemia
Whelan TB, Schteingart DE, Starkman MN, Smith A. or its treatment, particularly but not exclusively seen
Neuropsychological deficits in Cushing’s syndrome.
in chronic alcoholics or other patients with chronic
J Nerv Ment Dis 1980; 168: 753–7.
undernourishment (Kleinschmidt-DeMasters et al.,
2006). Since change in serum osmolality is common
8.1.5 Conn’s syndrome (primary to many of the recognized precipitating factors,
hyperaldosteronism) the terms osmotic demyelination or osmotic myelin-
Gudin et al. (2000) reported a 64-year-old woman olysis are preferred by some authors (Sterns
with a confusional state, disorientation, and apathy, et al., 1986).
with investigation findings of hypokalaemia, meta- Although a range of neuropsychiatric disorders
bolic alkalosis, and raised aldosterone levels and complicating this syndrome are well recognized,
radiological evidence of a suprarenal adenoma. A neuropsychological studies have been rare
7-year history of decline in cognitive function had (Ruchinskas, 1998; Vermetten et al., 1999; Lee et al.,
been noted 2 years earlier, ascribed to vascular 2003). Findings include mildly reduced IQ and
dementia because of hypertension and CT evidence impaired attention, information processing speed,
of cerebrovascular change. The patient’s confusional memory (especially retrieval), and executive func-
state improved with ion replacement and spiro- tion, with relatively spared language, features more
nolactone, and following surgical removal of the suggestive of a ‘white matter’ than a cortical
adenoma the pre-existing cognitive decline also dementia. Deficits do not necessarily reverse with
improved. The authors suggested Conn’s syndrome clinical recovery. In one case such changes, accom-
is a treatable cause of dementia, albeit extremely rare. panied by pathological crying and laughter, occurred
with lesions confined to the pons (Lee et al., 2003), in
which context it may be noted that cognitive dys-
REFERENCES function with exclusively pontine pathology has also
been reported with cerebrovascular disease (van
Gudin M, Sanabria C, Legido B, et al. Cognitive dysfunc- Zandvoort et al., 2003; see Section 3.3.8).
tion related to hormonal and ionic levels in a patient ‘Callosal dementia’ (see Section 1.12), a discon-
diagnosed of [sic] Conn syndrome. J Neurol 2000; 247 nection syndrome, has been described in associ-
(Suppl 3): III/75 (abstract P275). ation with central and extrapontine myelinolysis
(Ghika Schmid et al., 1999).
8.2 Metabolic disorders

REFERENCES
Included here are cognitive disorders related to
vitamin deficiencies not covered elsewhere (for Adams RD, Victor M, Mancall EL. Central pontine
thiamine deficiency, see Wernicke–Korsakoff Syn- myelinolysis: a hitherto undescribed disease occurring
drome, Section 8.3.1), electrolyte-related problems, in alcoholic and malnourished patients. Arch Neurol
and impairment or failure of specific organs. Psychiatr Chicago 1959; 81: 154–72.
Ghika Schmid F, Ghika J, Assal G, Bogousslavsky J. A low vitamin B12 is not an uncommon finding in
Callosal dementia: behavioral disorders related to patients with dementia or cognitive decline. For
central and extrapontine myelinolysis [in French]. Rev example, in 170 consecutive patients diagnosed
Neurol Paris 1999; 155: 367–73. with dementia, Teunisse et al. (1996) found low
Kleinschmidt-DeMasters BK, Rojiani AM, Filley CM.
vitamin B12 in 26 (15%), all but one of whom ful-
Central and extrapontine myelinolysis: then . . . and
filled diagnostic criteria for Alzheimer’s disease
now. J Neuropathol Exp Neurol 2006; 65: 1–11.
(AD). At the group level, no patient improved with
Lee TMC, Cheung CCY, Lau EYY, Mak A, Li LSW. Cognitive
and emotional dysfunction after central pontine mye-
vitamin B12 repletion, nor was there any evidence
linolysis. Behav Neurol 2003; 14: 103–7. for slowing of AD progression. One patient with a
Ruchinskas R. Cognitive dysfunction after central pontine sudden onset of cognitive decline after a respiratory
myelinolysis. Neurocase 1998; 4: 173–9. tract infection did improve, but this may have been
Sterns RH, Riggs JE, Schochet SS. Osmotic demyelination coincidental with recovery from the infection.
syndrome following correction of hyponatremia. N Engl Likewise, Eastley et al. (2000) found low vitamin B12
J Med 1986; 314: 1535–42. in 125 of 1432 consecutive clinic attenders (8.7%).
van Zandvoort M, de Haan E, van Gijn J, Kappelle LJ. No demented patient improved with repletion.
Cognitive functioning in patients with a small infarct in
Hence, these studies would seem to suggest that in
the brainstem. J Int Neuropsychol Soc 2003; 9: 490–4.
most cases a low vitamin B12 in a demented patient
Vermetten E, Rutten SJ, Boon PJ, Hofman PA, Leentjens
is a coexistent, rather than a causal, abnormality,
AF. Neuropsychiatric and neuropsychological manifest-
ations of central pontine myelinolysis. Gen Hosp
perhaps related to prolonged dietary neglect. Other
Psychiatry 1999; 21: 296–302. studies have found low vitamin B12 and folate and
elevated levels of total homocysteine in AD
patients, independent of nutritional status (Clarke
8.2.2 Gastrointestinal disease et al., 1998; McCaddon et al., 1998), and epidemi-
ological studies suggest that low vitamin B12 may
Cobalamin (vitamin B12) deficiency
increase the risk of developing AD (Wang et al.,
Addison’s original description of pernicious 2001). The mechanism is not known, but an
anaemia in 1853 included the clinical observation hypothesis has been proposed suggesting that
that ‘the mind occasionally wanders’. Cobalamin functional vitamin B12 deficiency contributes to the
(vitamin B12) is a cofactor in several metabolic pathogenesis of AD (McCaddon et al., 2002). Cur-
pathways, and its deficiency may be associated with rent guidelines from the American Academy of
dementia; indeed this may be the sole manifest- Neurology advise that vitamin B12 levels should be
ation (no anaemia). The belief that vitamin B12 assessed in cases of dementia, since this is a com-
deficiency is a reversible cause of dementia became mon comorbidity and may influence cognitive
prevalent in the 1950s. Practically every textbook of function (Knopman et al., 2001), but revised
neurology lists vitamin B12 deficiency as a reversible guidelines from the European Federation of
cause of dementia or cognitive impairment. Rec- Neurological Societies state only that vitamin B12
ommendations that all patients attending memory level will often be required in individual cases
clinics should have their vitamin B12 level checked (Waldemar et al., 2006).
are not hard to find. Yet the evidence base for such Individual cases and case series of dementia and
definitive statements and recommendations is, at vitamin B12 deficiency are few. In a 17-year study
best, weak. Reversible dementias in general are of cobalamin deficiency, Healton et al. (1991)
increasingly rare (Clarfield, 2003), and convincing recorded 18 cases of mental impairment in
documentation of cognitive impairment associated 143 cases, 8 with global dementia and 9 with
with vitamin B12 deficiency with reversal on reple- recent memory loss; 11/18 recovered completely
tion is simply not to be found in the literature. with repletion. Another study suggested that
improvement may be related to symptom duration, functional deficiency of methylmalonyl CoA

as for other neurological consequences of vitamin mutase and methionine synthase with resulting
B12 deficiency (Martin et al., 1992). Chiu (1996) methylmalonic aciduria and homocystinuria. Most
found 25 cases of dementia attributed to B12 defi- cases present before 2 months of age, but cases in
ciency reported between 1958 and 1995, 10 with children and even young adults have been
marked improvement on repletion; all had some reported, presenting with a rapidly progressive
haematological abnormality (anaemia, raised MCV, dementia and myelopathy, of which the dementia
hypersegmented neutrophils) or neurological signs is on occasion responsive to hydroxycobalamin
in addition to cognitive impairment. injections (Shinnar & Singer, 1984; Al-Memar et al.,
Reports with careful and sequential neuro- 1998; Augoustides Savvopoulou et al., 1999).
psychological assessment are also lacking. The case
reported by Meadows et al. (1994) was confounded
Gluten sensitivity and coeliac disease
by a history of alcohol misuse. Another patient, a
health professional with marked clinical improve- The neurological associations of gluten sensitivity,
ment after repletion therapy, declined repeat with or without bowel disease (coeliac disease) are
neuropsychological assessment (Larner et al., 1999; protean, the most common being epilepsy, cere-
Larner & Rakshi, 2001). A report claiming a sub- bellar ataxia, axonal neuropathy, myelopathy,
cortical dementia pattern associated with vitamin myoclonus, intracerebral (especially occipital) cal-
B12 deficiency was based on clinical observations, cification, migraine, and cerebral vasculitis with
unsubstantiated by neuropsychological assessment encephalopathy (Pengiran Tengah et al., 2002), as
(Saracaceanu et al., 1997). well as neurological sequelae following dissemin-
Eastley et al. (2000) found that patients with ation of enteropathy-type T-cell lymphoma, which
cognitive decline but without dementia did, at the may complicate the disease (Doran et al., 2005).
group level, show improvement in verbal fluency Although a presenile dementia of uncertain aeti-
with vitamin B12 repletion, leading them to suggest ology has also been reported on occasion (Collin
that vitamin B12 may improve frontal lobe and et al., 1991), a review of the neurological compli-
language function in patients with cognitive cations of coeliac disease concluded that there was
impairment. Studies of vitamin B12 in mild cogni- no firm evidence of a link between dementia and
tive impairment might be of interest, but none has gluten sensitivity (Pengiran Tengah et al., 2002).
been identified, and it is not amongst recom- However, Hu et al. (2006) reported a series of 13
mended biomarkers for mild cognitive impairment patients seen over a 35-year period with cognitive
(see Section 2.6). impairment coincident with gastrointestinal symp-
Hence, in the view of this author, it would seem tom onset or exacerbation. A frontal subcortical
that if vitamin B12 deficiency does cause cognitive pattern of cognitive impairment was typical; many
decline, this is an extremely rare occurrence, with patients had concurrent ataxia or neuropathy. In
only a handful of reversible cases of sometimes three patients cognitive function was reported to
dubious authenticity recorded in the literature, improve or stabilize on gluten withdrawal.
much less common than non-pathogenic coexist-
ence of dementia with vitamin B12 deficiency. This
Pellagra
may simply reflect the low positive predictive value
of a low vitamin B12 measurement (Chiu, 1996; This condition, a deficiency of vitamins of the B
Connick et al., 2006). group, including but not necessarily confined to
Defective cobalamin transport and/or metabol- niacin (nicotinic acid, nicotinamide), is sometimes
ism secondary to impaired biosynthesis of methyl- remembered as the ‘3 Ds’: diarrhoea, dermatitis,
cobalamin and adenosylcobalamin produces a dementia; or sometimes the 4 Ds (+ death). As far as
can be ascertained, the nature of this dementia has review). Report of the Quality Standards Subcommittee
not been fully described. A pellagra encephalopathy of the American Academy of Neurology. Neurology
of alcoholic aetiology has been described (Serdaru 2001; 56: 1143–53.
et al., 1988), but of course alcohol per se may con- Larner AJ, Janssen JC, Cipolotti L, Rossor MN. Cognitive
profile in dementia associated with vitamin B12 defi-
tribute to any cognitive impairment irrespective of
ciency due to pernicious anaemia. J Neurol 1999; 246:
vitamin status.
317–9.
Larner AJ, Rakshi JS. Vitamin B12 deficiency and dementia.
Eur J Neurol 2001; 8: 730.
REFERENCES McCaddon A, Davies G, Hudson P, Tandy S, Cattell H.
Total serum homocysteine in senile dementia of
Al-Memar AY, Preece MA, Ross C, Green S, Pall HS. Alzheimer type. Int J Geriatr Psychiatry 1998; 13:
Combined methylmalonic aciduria and homocysti- 235–9.
nuria: a defect in cellular metabolism of cobalamin McCaddon A, Regland B, Hudson P, Davies G. Functional
and a treatable cause of dementia. J Neurol Neurosurg vitamin B12 deficiency and Alzheimer disease. Neurology
Psychiatry 1998; 65: 420 (abstract). 2002; 58: 1395–9.
Augoustides Savvopoulou P, Mylonas I, Sewell AC, Martin DC, Francis J, Protetch J, Huff FJ. Time depend-
Rosenblatt DS. Reversible dementia in an adolescent ency of cognitive recovery with cobalamin replacement:
with cblC disease: clinical heterogeneity within the report of a pilot study. J Am Geriatr Soc 1992; 40:
same family. J Inherit Metab Dis 1999; 22: 756–8. 168–72.
Chiu HFK. Vitamin B12 deficiency and dementia. Int J Meadows ME, Kaplan RF, Bromfield EB. Cognitive recov-
Geriatr Psychiatry 1996; 11: 851–8. ery with vitamin B12 therapy: a longitudinal neuropsy-
Clarfield AM. The decreasing prevalence of reversible chiatric assessment. Neurology 1994; 44: 1764–5.
dementia: an updated meta-analysis. Arch Intern Med Pengiran Tengah DSNA, Wills AJ, Holmes GKT. Neuro-
2003; 163: 2219–29. logical complications of coeliac disease. Postgrad Med J
Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, 2002; 78: 393–8.
and serum total homocysteine in confirmed Alzheimer Saracaceanu E, Tramoni AV, Henry JM. An association
disease. Arch Neurol 1998; 55: 1449–55. between subcortical dementia and pernicious anaemia:
Collin P, Pirttilä T, Nurmikko T, et al. Celiac disease, brain a psychiatric mask. Compr Psychiatry 1997; 38:
atrophy, and dementia. Neurology 1991; 41: 372–5. 349–51.
Connick P, Cooper S, Grosset D. Investigating B12 Serdaru M, Hausser-Hauw C, Laplane D, et al. The clinical
deficiency amongst neurological patients. J Neurol spectrum of alcoholic pellagra encephalopathy. Brain
Neurosurg Psychiatry 2006; 77: 126 (abstract 002). 1988; 111: 829–42.
Doran M, du Plessis DG, Larner AJ. Disseminated Shinnar S, Singer HS. Cobalamin C mutation (methylma-
enteropathy-type T-cell lymphoma: cauda equina syn- lonic aciduria and homocystinuria) in adolescence: a
drome complicating coeliac disease. Clin Neurol Neu- treatable cause of dementia and myelopathy. N Engl J
rosurg 2005; 107: 517–20. Med 1984; 311: 451–4.
Eastley R, Wilcock GK, Bucks RS. Vitamin B12 deficiency in Teunisse S, Bollen AE, van Gool WA, Walstra GJM.
dementia and cognitive impairment: the effects of Dementia and subnormal levels of vitamin B12: effects
treatment on neuropsychological function. Int J Geriatr of replacement therapy on dementia. J Neurol 1996;
Psychiatry 2000; 15: 226–33. 243: 522–9.
Healton EB, Savage DG, Brust JCM, et al. Neurologic Waldemar G, Dubois B, Emre M, et al. Alzheimer’s disease
aspects of cobalamin deficiency. Medicine (Baltimore) and other disorders associated with dementia. In:
1991; 70: 229–45. Hughes R, Brainin M, Gilhus NE (eds.), European
Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA. Handbook of Neurological Management. Oxford:
Cognitive impairment and celiac disease. Arch Neurol Blackwell, 2006: 266–98.
2006; 63: 1440–6. Wang HX, Wahlin A, Basun H, et al. Vitamin B12 and folate
Knopman DS, DeKosky ST, Cummings JL, et al. Practice in relation to the development of Alzheimer’s disease.
parameter: diagnosis of dementia (an evidence-based Neurology 2001; 56: 1188–94.
8.2.3 Respiratory disorders mild AD, the exception being a reduced letter flu-
ency. The fact that three-quarters of the patients
Chronic obstructive pulmonary disease
were receiving supplementary oxygen therapy may
(COPD)
account for the preservation of cognitive function in
A study by Grant et al. (1982) found that patients this study.
with chronic obstructive pulmonary disease In a community-based longitudinal study of
(COPD) were worse than control patients on all cognitive impairment and dementia, COPD was
neuropsychological tests prior to treatment, espe- noted to be more likely in patients with non-
cially ‘higher’ functions such as abstracting ability progressive cognitive decline, i.e. in those patients
and complex perceptual–motor integration. There in whom an original diagnosis of dementia was not
was some evidence that performance was worse the confirmed at follow-up (Schofield et al., 1995).
greater the degree of hypoxaemia, and this was
confirmed in a later study (Grant et al., 1987).
Obstructive sleep apnoea–hypopnoea
Chronic oxygen therapy was associated with a small
syndrome (OSAHS)
improvement in neuropsychological functioning,
with a suggestion that continuous therapy was Obstructive sleep apnoea–hypopnoea syndrome
better than solely nocturnal treatment (Heaton (OSAHS) is caused by critical narrowing of the upper
et al., 1983). airway during sleep when reduced muscle tone leads
A study of 36 patients with COPD reported that to increased resistance to the flow of air, and partial
just under half had a specific pattern of cognitive obstruction often results in loud snoring. Sleep is
deterioration characterized by impairments of ver- restless due to successive episodes of apnoea, often
bal and visual memory tasks despite preserved witnessed by the bed partner, which are relieved by
visual attention, and with diffuse worsening of brief arousal from sleep. A narrow anteroposterior
other functions. These changes were distinct from pharyngeal diameter, obesity, high alcohol intake,
those seen in AD patients, and were correlated with and male sex seem to be risk factors. As a conse-
age and duration of respiratory failure (Incalzi et al., quence of sleep fragmentation, the commonest
1993). In a further study from this group, decline of daytime symptom is excessive somnolence, manifest
verbal memory was found to parallel that of overall as a tendency to fall asleep in monotonous or
cognitive function, due to impairment of both inappropriate situations. OSAHS is diagnosed using
active recall and passive recognition of learned nocturnal polysomnography or, more practically in
material. Poor adherence to medication was asso- routine clinical work, pulse oximetry. The severity of
ciated with abnormal delayed recall scores (Incalzi OSAHS may be measured using the apnoea/hypop-
et al., 1997). In a follow-up study, onset of depres- noea index (AHI), or respiratory disturbance index
sion was a risk factor for cognitive decline (Incalzi (RDI), which is calculated from polysomnographic
et al., 1998). Roehrs et al. (1995) found deficits in recordings as the number of apnoeas/hypopnoeas
complex reasoning and memory in COPD patients per hour of sleep. AHI or RDI of 10–20 indicates mild,
as well as motor skills, the latter sensitive to hyp- 20–50 moderate, and > 50 severe disease. With pulse
oxaemia. Another group reported MMSE abnor- oximetry, a desaturation index (DI) may be calcu-
malities in 62% of COPD patients, affecting recent lated as the number of desaturations (decrease in
memory, construction, attention, language, and oxygen saturation by 4%) per hour of sleep or, if
orientation, the cognitive abnormalities correlating the recording is unattended, per time of recording.
with functional abnormalities (Özge et al., 2004). DI 5 may be used to define sleep-disordered
However, a study by Kozora et al. (1999) found that breathing (Redline et al., 2000).
most COPD patients studied were similar to con- OSAHS may present with various neurological
trols on most tests, and easily distinguishable from symptoms besides excessive daytime sleepiness,
including blackouts and headache, sometimes with An overview of case–control studies of neuro-
features suggestive of raised intracranial pressure, psychological function in patients with sleep-
and may be mistaken for narcolepsy, epilepsy, and disordered breathing found that impairment was
idiopathic intracranial hypertension, respectively. generally greater with increasing severity of disease
Apparent intellectual decline, which may be mis- (Engelman et al., 2000), recognizing that some tasks
taken for dementia, is also reported to be a recog- are more sensitive to hypoxaemia, and others more
nized feature of OSAHS, which may improve after sensitive to sleepiness. Comparing groups of
appropriate treatment of the underlying condition patients with OSAHS and COPD, Roehrs et al. (1995)
(Douglas, 2003; Larner, 2003). found that deficits in complex reasoning and
Findley et al. (1986) found impairments in meas- memory were not specific to diagnosis, whereas
ures of attention, concentration, complex problem sustained attention was worse in the OSAHS group,
solving, and short-term recall of verbal and spatial reflecting its sensitivity to sleepiness, and motor
information in OSAHS patients with hypoxaemia as skills were worse in the COPD group, reflecting their
compared with OSAHS patients without hypox- sensitivity to hypoxaemia. A study comparing
aemia; cognitive impairment did not correlate with OSAHS patients with AD, multi-infarct dementia,
measures of sleep fragmentation, suggesting that it and COPD found a distinctive cognitive profile
was hypoxia rather than sleep disturbance (a rec- suggestive of subcortical damage (Antonelli Incalzi
ognized cause of cognitive dysfunction: Durmer & et al., 2004).
Dinges, 2005) that accounted for the cognitive def- Central sleep apnoea is characterized by periodic
icits. A patient reported by Scheltens et al. (1991), in apnoea due to loss of ventilatory motor output, due
whom cognitive impairment was the presenting to an unstable ventilatory control system, resulting
feature of a sleep apnoea syndrome, had impaired in lack of inspiratory muscle effort (Abad &
learning and retention, impaired sustained atten- Guilleminault, 2004; Badr, 2005). There are diverse
tion, impaired visuospatial reasoning, vulnerability causes, including neurological diseases such as
to interference, impaired verbal fluency, but no multiple system atrophy, but some cases remain
aphasia, apraxia, or agnosia. Polysomnography idiopathic. We have encountered a patient with
showed a mixed picture of central and obstructive central sleep apnoea presenting with cognitive
apnoeas in this patient. The authors suggested that complaints, whose neuropsychological profile
both cerebral hypoxia and sleep fragmentation showed marked impairments in non-verbal rea-
contributed to cognitive impairment, which reversed soning and processing speed, indicative of a sub-
with appropriate treatment (nocturnal continuous cortical type dementia, but the interpretation was
positive airway pressure). Mild cognitive impairment confounded by prior radiotherapy for a malignant
with slight reductions in verbal reasoning and verbal brain tumour (Larner & Ghadiali, unpublished
comprehension performance, poor performance on observations).
tests of short-term memory and learning, reduced
verbal fluency, and mild attentional problems, but
Carbon monoxide poisoning
with intact non-verbal reasoning, language, visuo-
spatial, and constructional functions were noted in A delayed encephalopathy may develop a few days to
another patient (Larner & Ghadiali, unpublished weeks after carbon monoxide (CO) poisoning, with
observations), deficits more typical of subcortical or without a history of acute poisoning, sometimes
pathology due to interruption of frontal-subcortical with extrapyramidal or pyramidal signs and psych-
circuits. This neuropsychological profile may cor- osis (Ernst & Zibrak, 1998). MR imaging abnormal-
relate with white matter cerebral metabolic impair- ities occur in about 12% of patients, most typically
ments seen with magnetic resonance spectroscopy widespread periventricular white matter changes,
in OSAHS patients (Kamba et al., 2001). although basal ganglia involvement is also reported.
A prospective study of episodes of CO poisoning Goodale MA, Milner AD. Sight Unseen: an Exploration of
found cognitive deficits in 30% of patients Conscious and Unconscious Vision. Oxford: Oxford
(Parkinson et al., 2002). Occasionally these deficits University Press, 2004.
may be very focal, as for example in a renowned Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms
RM. Neuropsychologic findings in hypoxemic chronic
case of visual-form agnosia (Goodale & Milner,
obstructive pulmonary disease. Arch Intern Med 1982;
2004), and a case of apparent visual motion blind-
142: 1470–6.
ness (akinetopsia) has been reported (Larner, 2005).
Grant I, Prigatano GP, Heaton RK, et al. Progressive
Delayed onset of cognitive, including memory, neuropsychologic impairment and hypoxemia: relation-
problems by up to 30 days after acute poisoning ship in chronic obstructive pulmonary disease. Arch
may occur, associated with extensive diffuse white Gen Psychiatry 1987; 44: 999–1006.
matter change (Balla et al., 2005). Delayed atrophy Heaton RK, Grant I, McSweeny AJ, Adams KM, Petty TL.
of the fornix, correlating with decline on tests of Psychologic effects of continuous and nocturnal oxygen
verbal memory, has also been reported in patients therapy in hypoxemic chronic obstructive pulmonary
poisoned with CO (Kesler et al., 2001). disease. Arch Intern Med 1983; 143: 1941–7.
The complications of CO poisoning typically Incalzi RA, Chiappini F, Fuso L, et al. Predicting cognitive
decline in patients with hypoxaemic COPD. Respir Med
improve with time, but patients may sometimes be
1998; 92: 527–33.
left with permanent neurological and/or neuro-
Incalzi RA, Gemma A, Marra C, et al. Chronic obstructive
psychological sequelae (e.g. Goodale & Milner, 2004).
pulmonary disease: an original model of cognitive
decline. Am Rev Respir Dis 1993; 148: 418–24.
Incalzi RA, Gemma A, Marra C, et al. Verbal memory
REFERENCES impairment in COPD: its mechanisms and clinical
relevance. Chest 1997; 112: 1506–13.
Abad VC, Guilleminault C. Neurological perspective on Kamba M, Inoue Y, Higami S, et al. Cerebral metabolic
obstructive and nonobstructive sleep apnea. Semin impairments in patients with obstructive sleep apnoea:
Neurol 2004; 24: 261–9. an independent association of obstructive sleep apnoea
Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does with white matter change. J Neurol Neurosurg Psych-
cognitive dysfunction conform to a distinctive pattern iatry 2001; 71: 334–9.
in obstructive sleep apnea syndrome? J Sleep Res 2004; Kesler SR, Hopkins RO, Blatter DD, Edge Booth H, Bigler
13: 79–86. ED. Verbal memory deficits associated with fornix
Badr MS. Central sleep apnea. Prim Care 2005; 32: 361–74. atrophy in carbon monoxide poisoning. J Int Neuro-
Balla C, Kanta O, Paschalidou M, Artemis N, Milonas I. psychol Soc 2001; 7: 640–6.
Delayed encephalopathy of carbon monoxide (CO) Kozora E, Filley CM, Julian LJ, Cullum CM. Cognitive
poisoning. Eur J Neurol 2005; 12 (Suppl 2): 290 (abstract functioning in patients with chronic obstructive pul-
P2484). monary disease and mild hypoxemia compared with
Douglas NJ. The obstructive sleep apnoea/hypopnoea patients with mild Alzheimer disease and normal
syndrome. Pract Neurol 2003; 3: 22–8. controls. Neuropsychiatry Neuropsychol Behav Neurol
Durmer JS, Dinges DF. Neurocognitive consequences of 1999; 12: 178–83.
sleep deprivation. Semin Neurol 2005; 25: 117–29. Larner AJ. Obstructive sleep apnoea syndrome presenting
Engelman HM, Kingshott RN, Martin SE, Douglas NJ. in a neurology outpatient clinic. Int J Clin Pract 2003;
Cognitive function in the sleep apnea/hypopnea syn- 57: 150–2.
drome (SAHS). Sleep 2000; 23 (Suppl 4): S102–8. Larner AJ. Delayed motor and visual complications after
Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J attempted suicide. Lancet 2005; 366: 1826.
Med 1998; 339: 1603–8. Özge C, Ünal O, Özge A, Saraçoglu M. Cognitive and
Findley LJ, Barth JT, Powers DC, et al. Cognitive functional deterioration in patients with severe
impairment in patients with obstructive sleep apnea COPD. Eur J Neurol 2004; 11 (Suppl 2): 24–5 (abstract
and associated hypoxemia. Chest 1986; 90: 686–90. SC221).
Parkinson RB, Hopkins RO, Cleavinger HB, et al. White (WKS), due to thiamine (vitamin B1) deficiency,
matter hyperintensities and neuropsychological out- have been extensively studied (Victor et al., 1989).
come following carbon monoxide poisoning. Neurology Although most cases relate to alcohol misuse with
2002; 58: 1525–32. consequent undernutrition, WKS may also occur in
Redline S, Kapur VK, Sanders MH, et al. Effects of varying
the context of malnutrition from other causes,
approaches for identifying respiratory disturbances on
such as prolonged vomiting in pregnancy or par-
sleep apnea assessment. Am J Respir Crit Care Med
enteral nutrition with inadequate supplementation
2000; 161: 369–74.
Roehrs T, Merrion M, Pedrosi B, et al. Neuropsychological
(Monaghan et al., 2006), or with other diencephalic
function in obstructive sleep apnea syndrome (OSAS) lesions such as tumours or trauma.
compared to chronic obstructive pulmonary disease Initially WKS was characterized as a neurological
(COPD). Sleep 1995; 18: 382–8. disorder with nystagmus, ophthalmoplegia, and
Scheltens P, Visscher F, Van Keimpema ARJ, et al. Sleep ataxia, and a neuropsychological syndrome of
apnea syndrome presenting with cognitive impairment. selective anterograde amnesia with relative preser-
Neurology 1991; 41: 155–6. vation of intelligence, sometimes complicated by
Schofield PW, Tang M, Marder K, et al. Consistency of confabulations (Butters & Cermak, 1980). For this
clinical diagnosis in a community-based longitudinal
reason, Korsakoff patients have often been used in
study of dementia and Alzheimer’s disease. Neurology
group studies to compare their cognitive profile
1995; 45: 2159–64.
with that seen in other cognitive disorders such as
Alzheimer’s disease and Huntington’s disease
(Butters, 1984). However, with the development of
8.3 Toxin-related disorders
new diagnostic criteria (Caine et al., 1997) the
spectrum of WKS has broadened to include patients
8.3.1 Alcohol-related disorders
without the classical neurological signs. In this
Alcohol is probably the most widely available and broader group there is evidence for generalized
socially tolerated neuroactive substance. Although cognitive impairment or dementia (‘thiamine
epidemiological studies suggest it to be protective dementia’) rather than selective (‘diencephalic’)
against dementia in modest dosage (Ruitenberg amnesia (Bowden & Ritter, 2005). Because of the
et al., 2002), escalating dosage unequivocally potential reversibility of cognitive deficits with
increases the risk of late-life dementia (Saunders thiamine repletion, and the fact that many cases
et al., 1991). Wernicke–Korsakoff syndrome is the were previously overlooked on clinical grounds,
best known of the syndromes of cognitive impair- there is a strong case for making a presumptive
ment related to alcohol, although it can on occasion diagnosis of WKS in any patient with a history
occur in the absence of a history of alcohol overuse. suggestive of alcohol dependence.
Other syndromes of cognitive impairment which Neuropathologically there is shrinkage of the
might also be encompassed under the rubric of mammillary bodies, structures around the third and
‘alcohol-related’, since alcohol overuse is a risk fourth ventricles (i.e. the diencephalon), and the
factor for their development, include subdural medial thalamus. Which of these is the substrate of
haematoma (see Section 7.3.1), pellagra (Section the cognitive impairments has been argued, but
8.2.2), and obstructive sleep apnoea–hypopnoea generally the mammillary bodies are not thought to
syndrome (Section 8.2.3). be relevant (Victor, 1987), with better correlations
for the medial thalamus, although the exact nuclei
involved (mediodorsal, centromedial, anterior) may
Wernicke–Korsakoff syndrome (WKS)
vary (Mayes et al., 1988; Halliday et al., 1994;
The neurological and neuropsychological conse- Harding et al., 2000). There may be loss of hippo-
quences of the Wernicke–Korsakoff syndrome campal volume but without neuronal loss (Harper
& Scolyer, 2004), but this does not necessarily imply It is therefore not surprising that no specific
normal hippocampal function: functional imaging neuropsychological profile for alcohol-related
studies have suggested loss of hippocampal memory dementia has been defined. Working memory and
encoding in WKS patients, possibly as a consequence executive deficits may occur, perhaps reflecting
of hippocampal–thalamic involvement (Caulo et al., frontal neuropathological changes, as may declines
2005). Neuronal loss in the nucleus basalis of Mey- in memory and aspects of crystallized intelligence
nert might also be relevant (Butters, 1985). (Bates et al., 2002).
Alcohol-related dementia, primary alcoholic Marchiafava–Bignami disease

dementia
Marchiafava–Bignami disease is a rare alcohol-
Whether alcohol (i.e. ethanol) per se is neurotoxic, associated disorder characterized by demyelination
and may cause cognitive decline independent of and necrosis of the corpus callosum; lesions may
thiamine deficiency, remains a subject of debate also occur in the putamen. Clinically a distinction
(Moriyama et al., 2006). Although provisional diag- may be drawn between those cases in which
nostic criteria for alcohol-related dementia have impaired consciousness occurs, with a poorer
been proposed (Oslin et al., 1998), others suggest prognosis, and those in which consciousness is
that this syndrome may be better conceptualized as preserved. Cognitive impairment may occur in both
a multifactorial ‘alcohol-induced dementia’, related the prodrome and recovery phase of the former, as
to comorbidities such as nutritional deficiency may interhemispheric disconnection syndromes
(perhaps causing prior episodes of WKS); damage to (Kohler et al., 2000; Heinrich et al., 2004). The latter
other organs, particularly liver, with repeated epi- may include combinations of apraxia, agraphia, and
sodes of hepatic encephalopathy; head injury, sub- Balint syndrome, along with neurobehavioural
dural haematoma, epileptic seizures, hydrocephalus, features (Kalckreuth et al., 1994), the syndrome
Marchiafava–Bignami disease, obstructive sleep which has been labelled ‘callosal dementia’ (Ghika
apnoea; and pre-existing cognitive status. Concur- Schmid et al., 1999).
rent morbidity such as cerebrovascular disease and/
or Alzheimer’s disease may also contribute to cog-
Acquired non-Wilsonian hepatocerebral
nitive decline. Many patients conforming to the
degeneration
proposed criteria might also conform to the criteria
for WKS (Caine et al., 1997). An important differen- This condition has been characterized as a syn-
tial diagnosis is frontal variant frontotemporal drome of fixed or progressive neurological deficits,
dementia (see Section 2.2.1), in which hyperorality including dementia, dysarthria, gait ataxia, inten-
may include alcohol overconsumption. tion tremor, parkinsonism, spastic paraparesis, and
Neuropathological studies have shown cerebral choreoathetosis, as a consequence of cerebral
atrophy due to white matter loss, and neuronal and degeneration in the context of repeated episodes of
synaptic losses in some areas such as frontal asso- hepatic encephalopathy, the liver damage usually
ciation cortex (Harper, 1998); these frontal changes following alcohol misuse. It is argued that indi-
are likened by some authors to those seen in fron- vidually such episodes of hepatic encephalopathy
totemporal dementia (Brun & Andersson, 2001). may be reversible, but that cumulatively there is a
There is relative sparing of other areas including the degenerative effect on neural tissue, with micro-
hippocampus (Harper & Scolyer, 2004). However, a cavitary changes in layers V and VI of the cortex,
specific neuropathological substrate for alcohol- underlying white matter, basal ganglia, and
related dementia has not yet been defined (Bowden cerebellum (Victor et al., 1965). Others have
& Ritter, 2005). doubted whether this condition exists as a separate
entity. Cases with features overlapping those of Halliday G, Cullen K, Harding A. Neuropathological correl-
extrapontine myelinolysis (see Section 8.2.1) have ates of memory dysfunction in the Wernicke–Korsakoff
been reported (Kleinschmidt-DeMasters et al., syndrome. Alcohol Alcohol Suppl 1994; 2: 245–51.
2006). Functional imaging may show reduced par- Harding A, Halliday G, Caine D, Kril J. Degeneration of
anterior thalamic nuclei differentiates alcoholics with
ieto-occipital perfusion, and structural imaging
amnesia. Brain 2000; 123: 141–54.
typically shows abnormal signal in the pallidum
Harper C. The neuropathology of alcohol-specific brain
and midbrain, although cerebellar involvement has
damage, or does alcohol damage the brain? J Neuro-
also been reported (Park & Heo, 2004). Clinical and pathol Exp Neurol 1998; 57: 101–10.
radiological changes have been improved with Harper C, Scolyer RA. Alcoholism and dementia. In: Esiri
branched chain amino acids (Ueki et al., 2002), but MM, Lee VMY, Trojanowski JQ (eds.), The Neuropath-
there is no report of cognitive improvement. ology of Dementia (2nd edition). Cambridge: Cambridge
Heinrich A, Runge U, Khaw AV. Clinicoradiologic subtypes
of Marchiafava-Bignami disease. J Neurol 2004; 251:
REFERENCES
1050–9.
Kalckreuth W, Zimmermann P, Preilowski B, Wallesch
Bates ME, Bowden SC, Barry D. Neurocognitive impairment CW. Incomplete split-brain syndrome in a patient with
associated with alcohol use disorders: implications for chronic Marchiafava–Bignami disease. Behav Brain Res
treatment. Exp Clin Psychopharmacol 2002; 10: 193–212. 1994; 64: 219–28.
Bowden SC, Ritter AJ. Alcohol-related dementia and the Kleinschmidt-DeMasters BK, Filley CM, Rojiani AM. Over-
clinical spectrum of Wernicke–Korsakoff syndrome. In: lapping features of extrapontine myelinolysis and
Burns A, O’Brien J, Ames D (eds.), Dementia (3rd acquired chronic (non-Wilsonian) hepatocerebral degen-
edition). London: Hodder Arnold, 2005: 738–44. eration. Acta Neuropathol (Berl) 2006; 112: 605–16.
Brun A, Andersson J. Frontal dysfunction and frontal Kohler CG, Ances BM, Coleman AR, et al. Marchiafava–
cortical synapse loss in alcoholism: the main cause of Bignami disease: literature review and case report. Neu-
alcohol dementia? Dement Geriatr Cogn Disord 2001; ropsychiatry Neuropsychol Behav Neurol 2000; 13: 67–76.
12: 289–94. Mayes AR, Mendell PR, Mann D, Pickering A. Location of
Butters N. The clinical aspects of memory disorders: lesions in Korsakoff’s syndrome: neuropsychological
contributions from experimental studies of amnesia and neuropathological data on two patients. Cortex
and dementia. J Clin Neuropsychol 1984; 6: 17–36. 1988; 24: 367–88.
Butters N. Alcoholic Korsakoff’s syndrome: some unre- Monaghan TS, Murphy DT, Tubridy N, Hutchinson M.
solved issues concerning etiology, neuropathology, and The woman who mistook the past for the present. Adv
cognitive deficits. J Clin Exp Neuropsychol 1985; 7: Clin Neurosci Rehabil 2006; 6 (3); 27–8.
181–210. Moriyama Y, Mimura M, Kato M, Kashima H. Primary
Butters N, Cermak LS. Alcoholic Korsakoff’s Syndrome: an alcoholic dementia and alcohol-related dementia.
Information-Processing Approach to Amnesia. London: Psychogeriatrics 2006; 6: 114–8.
Academic Press, 1980. Oslin D, Atkinson RM, Smith DM, et al. Alcohol related
Caine D, Halliday GM, Kril JJ, Harper CG. Operational dementia: proposed clinical criteria. Int J Geriatr
criteria for the classification of chronic alcoholics: Psychiatry 1998; 13: 203–12.
identification of Wernicke’s encephalopathy. J Neurol Park SA, Heo K. Prominent cerebellar symptoms with
Neurosurg Psychiatry 1997; 62: 51–60. unusual magnetic resonance imaging findings in
Caulo M, Van Hecke J, Toma L, et al. Functional MRI acquired hepatocerebral degeneration. Arch Neurol
study of diencephalic amnesia in Wernicke–Korsakoff 2004; 61: 1458–60.
syndrome. Brain 2005; 128: 1584–94. Ruitenberg A, van Swieten JC, Witteman JCM, et al. Alcohol
Ghika Schmid F, Ghika J, Assal G, Bogousslavsky J. consumption and risk of dementia: the Rotterdam Study.
Callosal dementia: behavioral disorders related to Lancet 2002; 359: 281–6.
central and extrapontine myelinolysis [in French]. Rev Saunders PA, Copeland JR, Dewey ME, et al. Heavy
Neurol Paris 1999; 155: 367–73. drinking as a risk factor for depression and dementia
in elderly men. Findings from the Liverpool longitudinal factors, following cessation of exposure. Neurotoxicol-
community study. Br J Psych 1991; 159: 213–16. ogy 2000; 21: 659–66.
Ueki Y, Isozaki E, Miyazaki Y, et al. Clinical and Ogden JA. The psychological and neuropsychological
neuroradiological improvement in chronic acquired assessment of chronic occupational solvent neurotoxi-
hepatocerebral degeneration after branched-chain city: a case series. NZ J Psychol 1993; 23: 83–94.
amino acid therapy. Acta Neurol Scand 2002; 106: Ridgway P, Nixon TE, Leach JP. Occupational exposure to
113–16. organic solvents and long-term nervous system damage
Victor M. The irrelevance of the mammillary body lesions detectable by brain imaging, neurophysiology or histo-
in the causation of the Korsakoff amnesic state. Int J pathology. Food Chem Toxicol 2003; 41: 153–87.
Neurol 1987; 21–22: 51–7.
Victor M, Adams RD, Cole M. The acquired (non-
Wilsonian) type of chronic hepatocerebral degener- 8.3.3 Domoic acid poisoning (amnesic
ation. Medicine (Baltimore) 1965; 44: 345–95. shellfish poisoning)
Victor M, Adams RD, Collins GH. The Wernicke–Korsakoff
In Prince Edward Island, Canada, in 1987, an out-
Syndrome and Related Neurologic Disorders Due to
break of food poisoning following ingestion of
Alcoholism and Malnutrition (2nd edition). Phila-
mussels occurred (Perl et al., 1990. Patients pre-
delphia: Davis, 1989.
sented within hours of eating mussels with diar-
rhoea, vomiting, abdominal cramps, with or
8.3.2 Solvent exposure without headaches. Other features included delir-
Long and intense occupational exposure to certain ium, seizures, myoclonus, ataxia, alternating
organic solvents may cause chronic organic-solvent hemiparesis, and complete external ophthalmo-
neurotoxicity (e.g. painter’s encephalopathy), mani- plegia. In the acute stages EEG showed slowing and
fested as neuropsychiatric symptoms and cognitive PET scanning showed hypometabolism of the
decline, particularly slowed information processing amygdala and hippocampus. Gradual and spon-
and reaction time, easy fatigue, and impairments on taneous recovery occurred over 3 months, but some
tests of frontal lobe function and memory for new patients were left with residual anterograde
material (Arlien-Soberg et al., 1979; Ogden, 1993; amnesia, temporal lobe epilepsy, and motor neu-
Dryson & Ogden, 2000). Whether chronic low-level ronopathy or sensorimotor axonal neuropathy.
exposure can also cause cognitive decline is less Autopsy studies of non-survivors showed cell loss
certain (Ridgway et al., 2003). Recreational solvent and astrocytosis in the amygdala and hippocam-
inhalation (‘glue sniffing’) may produce impairments pus. The syndrome of amnesic shellfish poisoning
in memory, attention and concentration, and non- was shown to be due to production of domoic acid,
verbal intelligence in the long term (Allison & Jerrom, an excitotoxin which binds to kainate-type glu-
1984), as well as neuropsychiatric symptoms. tamate receptors, produced in mussels infested
with the phytoplankton Nitzschia pungens. The
diagnosis can be made using a mouse bioassay for
REFERENCES the toxin, although the condition is no longer seen
in Canada as shellfish are now screened for
Allison WM, Jerrom DW. Glue sniffing: a pilot study of the the toxin.
cognitive effects of long-term use. Int J Addict 1984; 19:
453–8.
Arlien-Soberg P, Bruhn P, Gyldensted C, Melgaard B. REFERENCES
Chronic painters’ syndrome: toxic encephalopathy in
house painters. Acta Neurol Scand 1979; 60: 149–56. Perl TM, Bédard L, Kosatsky T, et al. An outbreak of toxic
Dryson E, Ogden JA. Organic solvent induced chronic encephalopathy caused by eating mussels contamin-
toxic encephalopathy: extent of recovery and associated ated with domoic acid. N Engl J Med 1990; 322: 1775–80.
9
Infective disorders
9.1 Encephalitides and meningoencephalitides 205

9.1.1 Herpes simplex encephalitis (HSE) 205
9.1.2 Herpes zoster encephalitis 206
9.1.3 Adenovirus encephalitis 207
9.1.4 Coxsackie virus encephalitis 207
9.1.5 Human herpes virus 6 infection 207
9.1.6 Rotavirus encephalitis 207
9.1.7 Subacute sclerosing panencephalitis (SSPE) 207
9.1.8 Tick-borne encephalitis 208
9.1.9 Japanese encephalitis 208
9.1.10 Post-encephalitic parkinsonism, encephalitis lethargica, von Economo
disease 208
9.2 Meningitides 209
9.2.1 Bacterial meningitis 209
9.2.2 Viral meningitis 209
9.2.3 Fungal meningitis 209
9.3 Human immunodeficiency virus (HIV) and related conditions 210
9.3.1 HIV dementia, AIDS dementia 210
9.3.2 Progressive multifocal leukoencephalopathy (PML) 211
9.3.3 HTLV-1 211
9.4 Other disorders of infective aetiology 211
9.4.1 Neurosyphilis 211
9.4.2 Tuberculosis 212
9.4.3 Neuroborreliosis (Lyme disease) 212
9.4.4 Neurocysticercosis 213
9.4.5 Whipple’s disease 214
The spectrum of infectious diseases causing cog- deficiency virus and herpes viruses, and diseases
nitive impairment and dementia has changed over caused by prions (see Section 2.5), are perhaps the
the past century. Whereas neurosyphilis was once most notable infectious causes of cognitive decline
common, now infection with human immuno- and dementia (Almeida & Lautenschlager, 2005).
204
REFERENCES temporal lobes, sometimes involving insular and

cingulate cortices, with an overlying meningitis.
Almeida OP, Lautenschlager NT. Dementia associated Typically the presentation is with fever and head-
with infectious diseases. Int Psychogeriatr 2005; 17 ache, sometimes with behavioural changes which
(Suppl 1): S65–77. may progress to clouding of consciousness and
coma, sometimes complicated by focal or second-
ary generalized seizures (Kennedy & Chaudhuri,
9.1 Encephalitides and 2002). However, presentation with isolated memory
meningoencephalitides impairment has been described (Young et al., 1992).
MR brain imaging may show focal oedema in the
Infection of the brain parenchyma with or without medial temporal lobes, orbital surface of the frontal
involvement of the surrounding meninges may be lobes, insular and cingulate cortex, sometimes
caused by a wide variety of organisms, most usually asymmetrically, with gadolinium enhancement.
viral, but sometimes protozoan, rickettsial, or fun- CSF is typically under raised pressure with a
gal (Anderson, 2001). Despite intensive investi- lymphocytic pleocytosis (10–200 cells/mm3), with a
gation, a causative organism is not always found raised protein (0.6–6.0 g/l) but a normal glucose
and treatment may of necessity be empirical, level. CSF PCR for HSV is a highly sensitive and
covering the most likely candidate organisms. specific test for confirmation of the diagnosis,
Encephalitis is often a medical emergency, although false negatives may be encountered early
requiring intensive supportive care and control of (< 48 hours) or late (> 10 days) in the disease pro-
epileptic seizures. With the advent of antiviral cess. EEG is invariably abnormal, showing non–
agents such as aciclovir, mortality has declined specific disorganized and slow background rhythm
considerably, leaving increased numbers of sur- in the early stages, with epileptiform abnormalities
vivors who may have neuropsychological sequelae. such as high-voltage periodic lateralizing epilepti-
Encephalitides and meningoencephalitides form discharges (PLEDs) appearing later. Since
covered elsewhere include Rasmussen’s syndrome of early and appropriate treatment of HSE (e.g. aci-
chronic encephalitis and epilepsy (see Section 4.2.2), clovir) has been shown to reduce mortality and
in which an infective aetiology remains a possibility, morbidity significantly, brain biopsy may be con-
and chronic inflammatory meningoencephalitis, sidered to establish the diagnosis in atypical cases,
a term sometimes used for Sjögren’s syndrome or when a tumour in the temporal lobe is considered
(Section 6.5). part of the differential diagnosis.
Cognitive sequelae of HSE have been recognized
for some time (Gordon et al., 1990; Kapur et al.,1994;
REFERENCES Caparros-Lefebvre et al., 1996; Utley et al., 1997).
The typical pattern of impairment is of new learning
Anderson M. Encephalitis and other brain infections. In: in both verbal and visual domains. The severity of
Donaghy M (ed.), Brain’s Diseases of the Nervous System the amnesic syndrome is related to the severity of
(11th edition). Oxford: Oxford University Press, 2001: damage, judged neuroradiologically, to medial lim-
1117–80.
bic structures (hippocampus and amygdala).
Amnesia may occur despite appropriate treatment
9.1.1 Herpes simplex encephalitis (HSE) of HSE with aciclovir, but shorter delay between
symptom onset and treatment may be associated
Herpes simplex virus type 1 (HSV) is the commonest with better outcome. In addition to amnesia, deficits
recognized cause of encephalitis, producing an may less frequently be found in retrograde memory,
acute necrotizing encephalitis of orbitofrontal and executive functions, and language (with mild
206 Infective disorders
anomia). Impaired autobiographical memory may Kapur N, Barker S, Burrows EH, et al. Herpes simplex
occur in patients with bilateral damage (Eslinger, encephalitis: long term magnetic resonance imaging
1998). Intractable epilepsy and affective disorder and neuropsychological profile. J Neurol Neurosurg
may contribute to neuropsychological outcome. It Psychiatry 1994; 57: 1334–42.
Kennedy PGE, Chaudhuri A. Herpes simplex encephalitis.
should be pointed out that cognitive recovery occurs
in many patients (Hokkanen & Launes, 1997a).
Utley TFM, Ogden JA, Gibb A, McGrath N, Anderson NE.
Although persistent anterograde and retrograde
The long-term neuropsychological outcome of herpes
(global) amnesia after HSE is well described in simplex encephalitis in a series of unselected survivors.
patients selected for symptoms of memory Neuropsychiatry Neuropsychol Behav Neurol 1997; 10:
impairment, it seems to be an unusual compli- 180–9.
cation, although the risk is greater (by 2–4 times) Young CA, Humphrey PR, Ghadiali EJ, Klapper PE, Cleator
than in non-herpetic encephalitis. Greater deficits GM. Short-term memory impairment in an alert patient
in verbal memory, verbal semantic functions, and as a presentation of herpes simplex encephalitis.
visuoperceptual functions have been noted in Neurology 1992; 42: 260–1.
herpetic as compared to non-herpetic encephalitis
(Hokkanen et al., 1996a,b). Executive deficits may 9.1.2 Herpes zoster encephalitis
also been seen following recovery from HSE, pre-
sumably reflecting orbitofrontal injury (Utley et al., Varicella zoster virus (VZV), a herpes virus, may lie
1997). Duration of transient encephalitic amnesia dormant for many years after a primary infection,
correlates with neuropsychological outcome to be reactivated as herpes zoster or shingles, and
(Hokkanen & Launes, 1997b). this may sometimes be complicated by encephal-
itis (herpes zoster encephalitis, HZE).
Neuropsychological sequelae of HZE were
REFERENCES reported by Hokkanen et al. (1997) in nine
immunocompetent patients. These included for-
Caparros-Lefebvre D, Girard-Buttoz I, Reboul S, et al. getfulness, slowing of thought processes, emotional
Cognitive and psychiatric impairment in herpes simplex and personality changes, and impaired cognitive
virus encephalitis suggest involvement of the amygdalo- ability, suggesting a subcortical type of impair-
frontal pathways. J Neurol 1996; 243: 248–56.
ment. In contrast, a report of eight patients
Eslinger PJ. Autobiographical memory after temporal and
undergoing neuropsychological assessment 4–52
frontal lobe lesions. Neurocase 1998; 4: 481–95.
months after onset of HZE found no significant
Gordon B, Selnes OA, Hart J, Hanley DF, Whitley RJ. Long-
term cognitive sequelae of acyclovir-treated herpes differences between patients and controls (Wetzel
simplex encephalitis. Arch Neurol 1990; 47: 646–7. et al., 2002). The discrepancy in these studies may
Hokkanen L, Launes J. Cognitive recovery instead of relate to the timing of assessment, which was car-
decline after acute encephalitis: a prospective follow up ried out in most of the patients in the Hokkanen
study. J Neurol Neurosurg Psychiatry 1997a; 63: 222–7. et al. (1997) study directly after they were able to
Hokkanen L, Launes J. Duration of transient amnesia cooperate adequately after the acute stage of
correlates with cognitive outcome in acute encephalitis. infection.
Neuroreport 1997b; 8: 2721–5.
Hokkanen L, Poutiainen E, Valanne L, et al. Cognitive
impairment after acute encephalitis: comparison of
herpes simplex and other aetiologies. J Neurol Neuro- REFERENCES
surg Psychiatry 1996a; 61: 478–84.
Hokkanen L, Salonen O, Launes J. Amnesia in acute Hokkanen L, Launes J, Poutiainen E, et al. Subcortical type
herpetic and nonherpetic encephalitis. Arch Neurol cognitive impairment in herpes zoster encephalitis.
1996b; 53: 972–8. J Neurol 1997; 244: 239–45.
Wetzel K, Asholt I, Herrmann E, et al. Good cognitive 2001). High-intensity signal change has been seen on
outcome of patients with herpes zoster encephalitis: a MR brain imaging in the medial temporal lobe
follow-up study. J Neurol 2002; 249: 1612–14. including the hippocampus, and hence this may be
considered a form of non-paraneoplastic limbic
9.1.3 Adenovirus encephalitis encephalitis (see Section 6.12.2). Similar cases have
been seen rarely with human herpes virus 7 infection
Cases with severe amnesia, resembling herpes (Dewhurst, 2004).
simplex encephalitis, have been reported (Hokkanen
et al., 1996).
REFERENCES
REFERENCES
Bollen AE, Wartan AN, Krikke AP, Haaxma-Reiche H.
Amnestic syndrome after lung transplantation by human
Hokkanen L, Poutiainen E, Valanne L, et al. Cognitive herpes virus-6 encephalitis. J Neurol 2001; 248: 619–20.
impairment after acute encephalitis: comparison of Dewhurst S. Human herpesvirus type 6 and human
herpes simplex and other aetiologies. J Neurol Neurosurg herpesvirus type 7 infections of the central nervous
Psychiatry 1996; 61: 478–84. system. Herpes 2004; 11: 105A–11A.
Kapur N, Brooks DJ. Temporally-specific retrograde
amnesia in two cases of discrete bilateral hippocampal
9.1.4 Coxsackie virus encephalitis
pathology. Hippocampus 1999; 9: 247–54.
A possible case of subcortical type cognitive Wainwright MS, Martin PL, Morse RP, et al. Human
impairment has been described following enceph- herpesvirus 6 limbic encephalitis after stem cell
alitis due to this RNA virus (Peatfield, 1987). transplantation. Ann Neurol 2001; 50: 612–19.
9.1.6 Rotavirus encephalitis

REFERENCES
A case with cognitive impairment has been
Peatfield RC. Basal ganglia damage and subcortical reported (Hokkanen et al., 1996), although this is
dementia after possible insidious Coxsackie virus likely to be the exception rather than the rule.
encephalitis. Acta Neurol Scand 1987; 76: 340–5.
9.1.5 Human herpes virus 6 infection REFERENCES
Infection with human herpes virus 6 (HHV-6) causes Hokkanen L, Poutiainen E, Valanne L, et al. Cognitive
fever and a rash (exanthema subitum) in children, a impairment after acute encephalitis: comparison of
benign, self-limiting condition. Seropositivity occurs herpes simplex and other aetiologies. J Neurol Neurosurg
in most children by age 3 years, with decline after Psychiatry 1996; 61: 478–84.
the age of 40 years. Symptomatic infection in adults
is very rare, mostly occurring in the context of
9.1.7 Subacute sclerosing panencephalitis
immunosuppression. Cases of persistent amnesia
(SSPE)
(anterograde and retrograde) have been reported as
a consequence of HHV-6 infection (Kapur & Brooks, Subacute sclerosing panencephalitis (SSPE) is usu-
1999; Bollen et al., 2001; Wainwright et al., 2001), for ally a disorder of late childhood or early adolescence,
example in the context of immunosuppression due to reactivation of measles virus infection causing
associated with lung transplantation (Bollen et al., progressive inflammation and gliosis of the
2001) or stem cell transplantation (Wainwright et al., brain. The clinical phenotype is characterized by
behavioural change, myoclonic jerks, seizures, and relation to aseptic meningo-encephalitis of other
progressive dementia, followed by pyramidal signs, etiology: a prospective study of clinical course and
stupor, decorticate postures, and death. Character- outcome. J Neurol 1997; 244: 230–8.
istic investigation findings include antibodies against
measles virus and oligoclonal bands in CSF, a path- 9.1.9 Japanese encephalitis
ognomonic EEG signature with periodic bursts of
high-voltage waves at a rate of 2–3 per second, and According to one review, 20% of survivors of
periventricular and subcortical white matter change Japanese encephalitis have severe cognitive and
on MR imaging. Only occasional adult-onset cases language, as well as motor, impairment (Solomon
have been reported (Singer et al., 1997), usually with et al., 2000).
the characteristic clinical picture, but one atypical
case presenting with a ‘pure cortical dementia’
without movement disorder has been described REFERENCES
(Frings et al., 2002). The clinical description was of
initial apathy, disorientation in time, psychomotor Solomon T, Dung NM, Kneen R, et al. Japanese encephal-
slowing, and depression, followed 3 years later by itis. J Neurol Neurosurg Psychiatry 2000; 68: 405–15.
verbal perseverations, anomia, phonemic para-

phasia, dysgraphia, dyslexia, ideomotor and idea- 9.1.10 Post-encephalitic parkinsonism,
tional apraxia, with MMSE score of 9.5/30. No more encephalitis lethargica, von Economo
detailed neuropsychological assessment was pre- disease
sented. Serial MR brain imaging showed progressive
generalized cerebral atrophy. The exact relationship of this condition, which
occurred in epidemic proportions following the
First World War, to brain infection remains
REFERENCES uncertain: a suspected relationship to influenza
infection has not been corroborated by examin-
Frings M, Blaeser I, Kastrup O. Adult-onset subacute ation of archival tissues. Basal ganglia auto-
sclerosing panencephalitis presenting as a degenerative immunity may play a role in pathogenesis (as in
dementia syndrome. J Neurol 2002; 249: 942–3. Sydenham’s chorea: Section 6.11). Occasional
Singer C, Lang AE, Suchowersky O. Adult-onset subacute cases of encephalitis lethargica still occur, generally
sclerosing panencephalitis: case reports and review of dominated clinically by movement disorders (par-
the literature. Mov Disord 1997; 12: 342–53. kinsonism, dystonia, oculogyric crises, myoclonus)
and neuropsychiatric features. Neuropsychological
features have been little studied, but in one case a
9.1.8 Tick-borne encephalitis
general cognitive decline was seen initially, par-
Cognitive impairment has been described as a long- ticularly affecting memory and executive functions,
term complication of tick-borne encephalitis, spe- which improved over time concurrent with cogni-
cifically deficits in memory, concentration, verbal tive rehabilitation strategies (Dewar & Wilson,
fluency, and verbal learning (Günther et al., 1997). 2005).
REFERENCES REFERENCES
Günther G, Haglund M, Lindquist L, Forsgren M, Dewar BK, Wilson BA. Cognitive recovery from encephal-
Skoldenberg B. Tick-borne encephalitis in Sweden in itis lethargica. Brain Inj 2005; 19: 1285–91.
9.2 Meningitides 209
9.2.2 Viral meningitis

9.2 Meningitides
Viral meningitis is generally considered a benign,
9.2.1 Bacterial meningitis self-limiting condition without cognitive sequelae. A
postal questionnaire controlled study reported that
Although neurological recovery is now the norm
survivors of viral meningitis showed a slight, non-
when bacterial meningitis is promptly diagnosed
significant, increase in prevalence of chronic fatigue
and appropriately treated in adults, nonetheless
syndrome compared to controls who had had non-
functional impairments precluding return to
enteroviral, non-CNS viral infections, but this dis-
employment may persist, particularly in the cog-
appeared on correction for age, sex, and duration of
nitive domain. Cohort studies have indicated
follow-up (Hotopf et al., 1996). Mild cognitive
impairments in psychomotor performance, con-
impairment has been reported following viral
centration, visuoconstructive capacity, and mem-
meningitis due to enterovirus, myxovirus, and her-
ory functions compared to healthy controls, a
pes virus infection (Sittinger et al., 2002). Follow-up
pattern resembling the subcortical type of cogni-
studies to see whether such deficits progress,
tive impairment (Merkelbach et al., 2000). Deficits
reverse, or remain static are awaited. Schmidt et al.
were found in 73% of patients in this study,
(2006) found impairments in cognitive performance
whereas only 27% were impaired in another study
in viral meningitis patients in similar domains to
(van de Beek et al., 2002), although both suggested
bacterial meningitis patients, but these were less
that pneumococcal meningitis had a worse cog-
severe and without the neuroradiological correlates
nitive outcome than meningococcal meningitis.
found in bacterial meningitis.
This differential outcome according to infecting
organism was not found in the study of Schmidt
et al. (2006), in which a history of alcoholism, a REFERENCES
recognized predisposing cause for pneumococcal
meningitis, was an exclusion criterion. This study Hotopf M, Noah N, Wessely S. Chronic fatigue and minor
found impairments in short-term and working psychiatric morbidity after viral meningitis: a controlled
memory and in executive tasks, with additional study. J Neurol Neurosurg Psychiatry 1996; 60: 504–9.
difficulties in language and visuoconstructive Schmidt H, Heimann B, Djukic M, et al. Neuropsycho-
function. Reduced brain volume and increased logical sequelae of bacterial and viral meningitis. Brain
2006; 129: 333–45.
ventricular volume was noted in neuroradiological
Sittinger H, Müller M, Schweizer I, Merkelbach S. Mild
studies, and white matter lesions correlated
cognitive impairment after viral meningitis in adults.
negatively with short-term and working memory
J Neurol 2002; 249: 554–60.
performance.
9.2.3 Fungal meningitis

REFERENCES Meningitis due to the fungus Cryptococcus
neoformans, in which the clinical picture was
Merkelbach S, Sittinger H, Schweizer I, Müller M. thought to mimic vascular dementia, has been
Cognitive outcome after bacterial meningitis. Acta reported (Aharon-Peretz et al., 2004).
Neurol Scand 2000; 102: 118–23.
Schmidt H, Heimann B, Djukic M, et al. Neuropsycho-
logical sequelae of bacterial and viral meningitis. Brain REFERENCES
2006; 129: 333–45.
van de Beek D, Schmand B, de Gans J, et al. Cognitive Aharon-Peretz J, Kilot D, Finkelstein R, et al. Cryptococcal
impairment in adults with good recovery after bacterial meningitis mimicking vascular dementia. Neurology
meningitis. J Infect Dis 2002; 186: 1047–52. 2004; 62: 2135.
9.3 Human immunodeficiency virus (HIV) diagnosis of HIV dementia and of lesser degrees of
and related conditions HIV-associated cognitive impairment have been
proposed (American Academy of Neurology AIDS
Human immunodeficiency virus (HIV, originally Task Force, 1991; Grant & Atkinson, 1995). The fre-
named human T-lymphotropic virus type III, quency of neurocognitive impairments in seroposi-
HTLV-III) is the best known of the retroviruses, tive asymptomatic individuals remains uncertain
responsible for the AIDS pandemic. In the body, (Grant et al., 2005). Other factors which might
the virus is spread haematogenously and is thought contribute to neuropsychological impairment in
to enter the brain within blood-derived macro- HIV positive individuals include drug and alcohol
phages. Neurological complications are prominent misuse, educational attainment, and head injury.
in HIV infection (Harrison & McArthur, 1995; The neuropsychological profile of HIV dementia
Gendelman et al., 2005), and their pathogenesis is is characterized by psychomotor slowing, memory
thought to be multifactorial, related to primary HIV impairment (typically impaired free recall with
infection, opportunistic CNS infection (toxoplas- relatively preserved recognition recall), and
mosis, cryptococcal meningitis, CMV encephalitis, executive dysfunction, all suggestive of a subcort-
tuberculous meningitis, neurosyphilis, progressive ical pattern of dementia. There may be concurrent
multifocal leukoencephalopathy related to JC virus motor problems with gait and postural reflexes,
activation), or tumour formation (CNS lymphoma), and impaired reaction times. Neuropsychological
sometimes resulting in dementia. Concurrent deficits correlate with neuroradiological and neu-
substance misuse and mood disorder may con- ropathological studies indicating frontostriatal
tribute to cognitive impairment in some cases. involvement, although cortical areas may also be
affected with disease evolution (Oechsner et al.,
1993; Power & Johnson, 1995).
REFERENCES Treatment with antiretrovirals, and particularly
combination highly active antiretroviral treatment
Gendelman HE, Grant I, Everall IP, Lipton SA, Swindells S (HAART), has resulted in a dramatic decline in the
(eds.). The Neurology of AIDS (2nd edition). Oxford: incidence of HIV dementia (Catalan & Thornton,
Oxford University Press, 2005. 1993; Sacktor et al., 2002). However, with increased
Harrison MJG, McArthur JC. AIDS and Neurology. survival, aging may emerge as a risk factor for HIV-
Edinburgh: Churchill Livingstone, 1995. associated cognitive disorder. HAART has been
reported to reverse partially clinical and spectroscopic
features in AIDS patients with subcorticofrontal cog-
9.3.1 HIV dementia, AIDS dementia
nitive impairment (Stankoff et al., 2001).
Cognitive impairment associated with HIV infec-
tion in the absence of mood disorder or oppor-
tunistic infection was recognized soon after the
REFERENCES
epidemic was first defined, ranging from psycho-
motor slowing and mental dullness through to
American Academy of Neurology AIDS Task Force.
frank dementia (Grant et al., 2005). Dementia may
Nomenclature and research case definitions for neuro-
sometimes be the initial manifestation of HIV logic manifestations of human immunodeficiency
infection (Navia et al., 1986), but seems to progress virus-type 1 (HIV-1) infection: report of a Working
more rapidly when there is concurrent advanced Group of the American Academy of Neurology AIDS
immunosuppression (CD4 count < 200) and hence Task Force. Neurology 1991; 41: 778–85.
in parallel with progressive systemic disease (Price Catalan J, Thornton S. Whatever happened to HIV
et al., 1988; McArthur et al., 1993). Criteria for the dementia? Int J STD AIDS 1993; 4: 1–4.
Grant I, Atkinson J. Psychiatric aspects of acquired REFERENCES

immune deficiency syndrome. In: Sadock B (ed.),
Comprehensive Textbook of Psychiatry. Baltimore: Berger JR, Pall L, Lanska D, Whiteman M. Progressive
Williams & Wilkins, 1995: 1644–69. multifocal leukoencephalopathy in patients with HIV
Grant I, Sacktor N, McArthur J. HIV and neurocognitive infection. J Neurovirol 1998; 4: 59–68.
disorders. In: Gendelman HE, Grant I, Everall IP,
Lipton SA, Swindells S (eds.), The Neurology of AIDS
(2nd edition). Oxford: Oxford University Press, 2005: 9.3.3 HTLV-1
357–73.
The retrovirus HTLV-1 classically causes a myelo-
McArthur JC, Hoover DR, Bacellar H, et al. Dementia in
pathy (HTLV-1-associated myelopathy, HAM, or
AIDS patients: incidence and risk factors. Neurology
1993; 43: 2245–52.
tropical spastic paraparesis, TSP), but other
Navia BA, Jordan BD, Price RW. The AIDS dementia features have been described including cognitive
complex: I. Clinical features. Ann Neurol 1986; 19: decline and even subcortical dementia. Silva et al.
517–24. (2003) reported psychomotor slowing, verbal and
Oechsner M, Möller AA, Zaudig M. Cognitive impairment, visual memory deficits, impaired attention, and
dementia and psychological functioning in human visuomotor problems in both asymptomatic HTLV-
immunodeficiency virus infection: a prospective study 1 carriers and patients with HAM/TSP, but there
based on DSM-III-R and ICD-10. Acta Psychiatr Scand was no association with degree of motor disability.
1993; 87: 13–17.
Power C, Johnson RT. HIV-1 associated dementia: clinical
features and pathogenesis. Can J Neurol Sci 1995; 22:
REFERENCES
92–100.
Price RW, Brew B, Sidtis J, et al. The brain in AIDS: central
Silva MTT, Mattos P, Alfano A, Araújo AQC. Neuropsycho-
nervous system HIV-1 infection and AIDS dementia
logical assessment in HTLV-1 infection: a comparative
complex. Science 1988; 239: 586–92.
study among TSP/HAM, asymptomatic carriers and
Sacktor N, McDermott MP, Marder K, et al. HIV-
healthy controls. J Neurol Neurosurg Psychiatry 2003;
associated cognitive impairment before and after the
74: 1085–9.
advent of combination therapy. J Neurovirol 2002; 8:
136–42.
Stankoff B, Tourbah A, Suarez S, et al. Clinical and
spectroscopic improvement in HIV-associated cognitive 9.4 Other disorders of infective aetiology
impairment. Neurology 2001; 56: 112–15.
9.4.1 Neurosyphilis
Neurosyphilis of the parenchymatous, rather than
9.3.2 Progressive multifocal
meningovascular, type has long been recognized to
leukoencephalopathy (PML)
cause dementia: as ‘general paresis [or paralysis] of
Progressive multifocal leukoencephalopathy the insane’ (GPI), it was once a common cause of
(PML) is a white matter disorder related to JC virus cognitive and behavioural decline (Dewhurst, 1969;
activation, rarely seen outside the context of HIV- Nieman, 1991). The advent of the antibiotic era saw
induced immunosuppression. Hemiparesis, a dramatic decline in cases, but now the disease is
hemianopia, and dementia are common clinical once again being seen more frequently, in part
features. One series examining the initial symp- associated with HIV infection and AIDS (Carr, 2003).
toms of PML in AIDS patients found cognitive In a recent series of cases of neurosyphilis, defined
disorders in 36% and speech disturbance in 40% by a positive CSF fluorescent treponemal antibody
(Berger et al., 1998). absorption test, very few with concurrent HIV
positivity, the most common presentation (50%) cause cognitive features (Akritidis et al., 2005), and a
was with ‘neuropsychiatric’ disease (= psychosis, pure amnesic syndrome has been reported following
delirium, dementia). Stroke, spinal cord disease recovery from probable tuberculous meningitis with
(myelopathy), and seizures were the other typical evidence of medial temporal lobe and mammillary
presentations. No neuropsychological data were body involvement (Ceccaldi et al., 1995).
presented and hence the pattern, if any, of cognitive
deficits was not disclosed. Residual cognitive loss
was reported in nearly 50% of patients for whom
REFERENCES
outcome was known. The authors suggested that
the term ‘syphilitic encephalitis’ was preferable to
Akritidis N, Galiatsou E, Kakadellis J, Dimas K, Paparounas
GPI (Timmermans & Carr, 2004). Syphilis has always K. Brain tuberculomas due to miliary tuberculosis.
been described as the great mimic of other South Med J 2005; 98: 111–13.
conditions, and one important differential diagnosis Ceccaldi M, Belleville S, Royere ML, Poncet M. A pure
is with limbic encephalitis (Schied et al., 2005). reversible amnesic syndrome following tuberculous
Dementia related to meningovascular neurosyphilis meningoencephalitis. Eur Neurol 1995; 35: 363–7.
in the context of HIV infection (see Section 9.3) has Jha S, Patel R. Some observations on the spectrum of
been reported (Fox et al., 2000). dementia. Neurol India 2004; 52: 213–14.
Meador KJ, Loring DW, Sethi KD, et al. Dementia
associated with dorsal midbrain lesion. J Int Neuropsy-
chol Soc 1996; 2: 359–67.
REFERENCES
Carr J. Neurosyphilis. Pract Neurol 2003; 3: 328–41.

9.4.3 Neuroborreliosis (Lyme disease)
Dewhurst K. The neurosyphilis psychoses today: a survey
of 91 cases. Br J Psychiatry 1969; 115: 31–8. Infection with the spirochaete Borrelia burgdorferi,
Fox PA, Hawkins DA, Dawson S. Dementia following an transmitted by the bite of infected Ixodes ticks, causes
acute presentation of meningovascular neurosyphilis in the zoonosis borreliosis, which may produce multi-
an HIV-1 positive patient. AIDS 2000; 14: 2062–3. system disease with dermatological, cardiological,
Nieman EA. Neurosyphilis yesterday and today. J R Coll
and neurological sequelae. Neuroborreliosis may
Physicians Lond 1991; 25: 321–4.
include aseptic meningitis, with or without multiple
Schied R, Voltz R, Vetter T, et al. Neurosyphilis and
radicular or peripheral nerve lesions; myelitis; cranial
paraneoplastic limbic encephalitis: important differen-
tial diagnoses. J Neurol 2005; 252: 1129–32. neuropathy, especially involving the facial nerve; and
Timmermans M, Carr J. Neurosyphilis in the modern era. meningoradiculitis of the cauda equina (Steere, 1989;
J Neurol Neurosurg Psychiatry 2004; 75: 1727–30. Halperin et al., 1991). Cognitive complications may
also occur, in late (stage III) Lyme disease. Guidelines
for the diagnosis of neuroborreliosis have been pub-
9.4.2 Tuberculosis
lished (American Academy of Neurology Quality
Recent years have seen a resurgence in cases of Standards Subcommittee, 1996).
tuberculosis as an opportunistic infection in the Lyme encephalopathy occurring years after the
context of HIV infection, and this association needs acute illness was reported in one series to produce
to be considered when assessing cognitive sequelae defects in verbal memory, mental flexibility, verbal
of tuberculosis. Studies from the Indian subcontin- associative functions, and articulation, but with
ent list tuberculosis as a cause of dementia (Jha & preserved intellectual and problem-solving skills,
Patel, 2004). Dementia has also been associated with sustained attention, visuoconstructive abilities, and
a dorsal midbrain tuberculous granuloma (Meador mental speed (Benke et al., 1995). Mental activation
et al., 1996). Disseminated brain tuberculomas may speed, as measured by response times, was found
to be slower in Lyme patients, but perceptual and cephalus: a cause of reversible dementia. J Am Geriatr
motor speed was preserved (Pollina et al., 1999). Soc 2003; 51: 579–80.
Involvement primarily of frontal systems was the Halperin JJ, Volkman DJ, Wu P. Central nervous system
conclusion of one review of neuropsychological abnormalities in Lyme neuroborreliosis. Neurology
1991; 41: 1571–82.
function in Lyme disease (Westervelt & McCaffrey,
Kaplan RF, Jones Woodward L, Workman K, et al.
2002), and a case of rapidly progressive frontal-type
Neuropsychological deficits in Lyme disease patients
dementia has been reported (Waniek et al., 1995).
with and without other evidence of central nervous
Although depression may complicate the presen- system pathology. Appl Neuropsychol 1999; 6: 3–11.
tation, memory impairment does seem to be Kobayashi K, Mizukoshi C, Aoki T, et al. Borrelia
associated with evidence of CNS involvement (CSF burgdorferi-seropositive chronic encephalomyelopathy:
intrathecal antibodies to B. burgdorferi, elevated Lyme neuroborreliosis? An autopsied report. Dement
protein, or positive PCR for B. burgdorferi Geriatr Cogn Disord 1997; 8: 384–90.
DNA: Kaplan et al., 1999). Children when appro- Pollina DA, Sliwinski M, Squires NK, Krupp LB. Cognitive
priately treated seem to have an excellent cognitive processing speed in Lyme disease. Neuropsychiatry
prognosis (Adams et al., 1999). Few cases have Neuropsychol Behav Neurol 1999; 12: 72–8.
Steere AC. Lyme disease. N Engl J Med 1989; 321: 586–96.
come to autopsy: one showed evidence of spongi-
Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. Rapidly
form change, neuronal loss, and microglial acti-
progressive frontal-type dementia associated with Lyme
vation, along with silver-impregnated organisms
disease. J Neuropsychiatry Clin Neurosci 1995; 7: 345–7.
strongly suggesting B. burgdorferi in both cortex Westervelt HJ, McCaffrey RJ. Neuropsychological func-
and thalamus to account for the cognitive changes tioning in chronic Lyme disease. Neuropsychol Rev
(Kobayashi et al., 1997). 2002; 12: 153–77.
Occasional cases of borreliosis have been
reported presenting as ‘normal pressure hydro-
cephalus’ (see Section 7.2.1), cognitive impairments
9.4.4 Neurocysticercosis
reversing after appropriate antibiotic treatment Infection with the larval stage (cysticercus) of the
(Danek et al., 1996; Etienne et al., 2003). helminth cestode Taenia solium, the pork tape-
worm, usually results from eating undercooked
pork. Various neurological syndromes may occur
REFERENCES when cysticerci reach the CNS: intraparenchymal
disease typically induces focal or generalized epi-
Adams WV, Rose CD, Eppes SC, Klein JD. Long-term lepsy, extraparenchymal disease causes mass effect
cognitive effects of Lyme disease in children. Appl and intracranial hypertension (Garcia & Del Brutto,
Neuropsychol 1999; 6: 39–45. 2005; Garcia et al., 2006).
American Academy of Neurology Quality Standards Sub- Cognitive decline is occasionally reported,
committee. Practice parameter: diagnosis of patients sometimes sufficient to cause dementia. A study
with nervous system Lyme borreliosis (Lyme disease).
from Mexico City found 15% of patients with
Summary statement. Neurology 1996; 46: 881–2.
untreated neurocysticercosis fulfilled DSM-IV cri-
Benke T, Gasse T, Hittmair Delazer M, Schmutzhard E.
teria for dementia, more than three-quarters of
Lyme encephalopathy: long-term neuropsychological
deficits years after acute neuroborreliosis. Acta Neurol whom no longer fulfilled criteria after treatment
Scand 1995; 91: 353–7. with albendazole and steroids, suggesting that this
Danek A, Uttner I, Yousry T, Pfister HW. Lyme neuro- is a reversible cause of dementia. Dementia was
borreliosis disguised as normal pressure hydrocephalus. associated with the number of parasitic lesions
Neurology 1996; 46: 1743–5. seen in frontal, temporal, and parietal lobes
Etienne M, Carvalho P, Fauchais AL, et al. Lyme (Ramirez Bermudez et al., 2005). In a study from
neuroborreliosis revealed as a normal pressure hydro- Brazil, patients with mesial temporal lobe epilepsy
due to hippocampal sclerosis with incidental cal- been published and it has been estimated that
cified neurocysticercosis had no greater cognitive 11% of CNS Whipple’s disease cases present
deficits than those without, suggesting that these with cognitive decline in the absence of other
chronic lesions do not contribute to cognitive neurological symptoms and signs (Louis et al.,
performance (Terra Bustamente et al., 2005). 1996). Cognitive features may be prominent in
primary Whipple’s disease of the brain along with
other symptoms such as seizures and ataxia
REFERENCES (Panegyres et al., 2006).
Detailed reports of the cognitive impairments in
Garcia HH, Del Brutto OH. Neurocysticercosis: updated Whipple’s disease are few. Manzel et al. (2000)
concepts about an old disease. Lancet Neurol 2005; 4: reported a biopsy-confirmed case with impair-
653–61. ments in sustained attention, memory, executive
Garcia HH, Gonzalez AE, Tsang VCW, Gilman RH, for function, and constructional praxis, with behav-
the Cysticercosis Working Group in Peru. Neurocys-
ioural disinhibition and confabulation, features
ticercosis: some of the essentials. Pract Neurol 2006;
which correlated with MR imaging changes in the
6: 288–97.
mesial temporal lobe and basal forebrain. The
Ramirez Bermudez J, Higuera J, Sosa AL, et al. Is dementia
reversible in patients with neurocysticercosis? J Neurol
cognitive picture was thought to resemble that
Neurosurg Psychiatry 2005; 76: 1164–6. seen after herpes simplex encephalitis or sub-
Terra Bustamente VC, Coimbra ER, Rezek KO, et al. arachnoid haemorrhage from a ruptured anterior
Cognitive performance of patients with mesial temporal communicating artery aneurysm.
lobe epilepsy and incidental calcified neurocysticerco-
sis. J Neurol Neurosurg Psychiatry 2005; 76: 1080–3.
REFERENCES
9.4.5 Whipple’s disease
Although extremely rare, Whipple’s disease is a Anderson M. Neurology of Whipple’s disease. J Neurol
diagnosis which is often considered by neurolo- Neurosurg Psychiatry 2000; 68: 2–5.
gists, because of the possibility of reversing the Louis ED, Lynch T, Kaufmann P, Fahn S, Odel J. Diagnostic
movement and cognitive disorder which results guidelines in central nervous system Whipple’s disease.
Ann Neurol 1996; 40: 561–8.
from infection with the causative organism,
Manzel K, Tranel D, Cooper G. Cognitive and behavioral
Tropheryma whippelii. It is a multisystem granu-
abnormalities in a case of central nervous system
lomatous disorder, the clinical phenotype of which
Whipple disease. Arch Neurol 2000; 57: 399–403.
is pleomorphic, but neurological signs may occur Panegyres PK, Edis R, Beaman M, Fallon M. Primary
in isolation from the more familiar gastrointestinal Whipple’s disease of the brain: characterization of the
and systemic symptoms (Anderson, 2000). Diag- syndrome and molecular diagnosis. Q J Med 2006; 99:
nostic guidelines for neurological Whipple’s have 609–23.
10
Neuromuscular disorders
10.1 Myotonic dystrophy (Steinert disease) 216

10.2 Myasthenia gravis (MG) 217
It may seem odd that disease of muscle or disease, associated with expansions of the CTG
neuromuscular junction, these most distal out- trinucleotide in the myotonic dystrophy protein
posts of the neurological system, might be asso- kinase gene (DMPK) on chromosome 19, is now
ciated with dysfunction of higher cortical function. known as myotonic dystrophy type 1 (DM1); the
However, diseases manifesting with neuropathy or entity previously known as proximal myotonic myo-
myopathy may in fact be multisystem disorders pathy (PROMM, Ricker’s disease), now known to be
with a broad phenotype that also encompasses associated with expansions of the CCTG tetra-
cognitive processes, sometimes related to expres- nucleotide in the ZIP9 gene on chromosome 3q, is
sion of abnormal or dysfunctional proteins now known as myotonic dystrophy type 2 (DM2)
(D’Angelo & Bresolin, 2006). Myotonic dystrophy is (International Myotonic Dystrophy Consortium,
the classic example, but other neuropathic and 2000; Udd et al., 2003). Adult-onset DM1 is a pleio-
myopathic disorders with concurrent cognitive fea- tropic disorder, one feature of which may be cognitive
tures covered elsewhere include mitochondrial dis- impairment. Features such as cognitive dysfunction,
orders (see Section 5.5.1), acid maltase deficiency visuospatial deficits, behavioural abnormalities, and
and Anderson–Fabry disease (Section 5.5.3), neuro- hypersomnia, are reported to be more prominent in
fibromatosis (Section 5.6.1), and adult polyglucosan DM1 than DM2 (Harper et al., 2004).
body disease (Section 5.5.7). The most commonly observed cognitive impair-
ments in DM1 relate to executive (frontal lobe)
dysfunction, with lack of initiative and apathy
REFERENCES despite preserved general intelligence. Features
may be static, or progressive, with temporal lobe
D’Angelo MG, Bresolin N. Cognitive impairment in (memory) impairments. Some studies have found
neuromuscular disorders. Muscle Nerve 2006; 34: 16–33. no correlation between cognitive impairment and
CTG repeat number or severity of muscle involve-
ment (Rubinsztein et al., 1997; Modoni et al., 2004),
10.1 Myotonic dystrophy (Steinert whilst others have found a correlation with CTG
disease) expansion size (Perini et al., 1999). Atypical pre-
sentation of DM1 as apparent primary dementia
Advances in the understanding of the genetic basis may occur. There is noted to be a high risk of
of myotonic dystrophy have led to a new classifi- cognitive impairments in childhood-onset disease,
cation. Classical dystrophia myotonica, Steinert’s particularly associated with maternal inheritance,
215
216 Neuromuscular disorders
whereas adult-onset disease is at lower risk. Wilson Kiuchi A, Otsuka N, Namba Y, Nakano I, Tomonaga M.
et al. (1999) reported an adult patient with paternal Presenile appearance of abundant Alzheimer’s neurofi-
inheritance and an 11-year decline in cognitive brillary tangles without senile plaques in the brain in
function, for which no cause other than DM1 was myotonic dystrophy. Acta Neuropathol (Berl) 1991; 82: 1–5.
Meola G, Sansone V, Perani D, et al. Reduced cerebral
identified.
blood flow and impaired visual–spatial function in
DM1 may be accompanied by white matter
proximal myotonic myopathy. Neurology 1999; 53:
changes on MR brain imaging (Di Costanzo et al.,
1042–50.
2002), which may (Censori et al., 1994) or may not Modoni A, Silvestri G, Pomponi MG, et al. Characteriza-
(Sinforiani et al., 1991) correlate with neuro- tion of the pattern of cognitive impairment in myotonic
psychological impairment. Sophisticated neuro- dystrophy type 1. Arch Neurol 2004; 61: 1943–7.
imaging techniques indicate neocortical damage in Perini GI, Menegazzo E, Ermani M, et al. Cognitive
DM1 brains even in the absence of white matter impairment and (CTG)n expansion in myotonic dys-
change (Giorgio et al., 2006), which might con- trophy patients. Biol Psychiatry 1999; 46: 425–31.
ceivably be related to cognitive deficits. Concurrent Rubinsztein JS, Rubinsztein DC, McKenna PJ, Goodburn
hypersomnia might also be relevant. Neurofibrillary S, Holland AJ. Mild myotonic dystrophy is associated
with memory impairment in the context of normal
tangles comparable to those seen in Alzheimer’s
general intelligence. J Med Genet 1997; 34: 229–33.
disease have been observed in DM1 brain (Kiuchi
Sergeant N, Sablonniere B, Schraen-Maschke S, et al.
et al., 1991), perhaps related to the altered splicing
Dysregulation of human brain microtubule-associated
patterns of the gene encoding tau in DM1 brain tau mRNA maturation in myotonic dystrophy type 1.
(Sergeant et al., 2001). Hum Mol Genet 2001; 10: 2143–55.
In DM2 impaired visuospatial recall and con- Sinforiani E, Sandrini G, Martelli A, et al. Cognitive and
struction has been noted, more prevalent than in neuroradiological findings in myotonic dystrophy.
DM1 (Meola et al., 1999). Funct Neurol 1991; 6: 377–84.
Udd B, Meola G, Krahe R, et al. Report of the 115th ENMC
workshop: DM2/PROMM and other myotonic dystro-
phies. 3rd workshop, 14–16 February 2003, Naarden,
REFERENCES The Netherlands. Neuromuscul Disord 2003; 13: 589–96.
Wilson BA, Balleny H, Patterson K, Hodges JR. Myotonic
Censori B, Provinciali L, Danni M, et al. Brain involvement dystrophy and progressive cognitive decline: a common
in myotonic dystrophy: MRI features and their relation- condition or two separate problems? Cortex 1999; 35:
ship to clinical and cognitive conditions. Acta Neurol 113–21.
Scand 1994; 90: 211–17.
Di Costanzo A, Di Salle F, Santoro L, et al. Pattern and
significance of white matter abnormalities in myotonic
dystrophy type 1: an MRI study. J Neurol 2002; 249: 10.2 Myasthenia gravis (MG)
1175–82.
Giorgio A, Dotti MT, Battaglini M, et al. Cortical damage in A central cholinergic deficit resulting in impaired
brains of patients with adult-form of myotonic dys- memory has been suggested in myasthenia gravis
trophy type 1 and no or minimal MRI abnormalities.
(Tucker et al., 1988; Davidov-Lusting et al., 1992),
J Neurol 2006; 253: 1471–7.
mirroring the peripheral (neuromuscular junction)
Harper PS, van Engelen B, Eymard B, Wilcox DE (eds.).
cholinergic transmission deficit responsible for the
Myotonic Dystrophy: Present Management, Future
Therapy. Oxford: Oxford University Press, 2004.
characteristic fatiguable weakness, particularly of
International Myotonic Dystrophy Consortium (IDMC). extraocular, bulbar, and proximal limb muscles.
New nomenclature and DNA testing guidelines for Central cholinergic dysfunction is, after all, thought
myotonic dystrophy type 1 (DM1). Neurology 2000; 54: to be central to the pathophysiology of cognitive
1218–21. deficits in Alzheimer’s disease and, possibly,
10.2 Myasthenia gravis 217
dementia with Lewy bodies (see Sections 2.1 and REFERENCES

2.4). Tucker et al. (1988) found MG subjects to be
impaired relative to both healthy controls and Davidov-Lusting M, Klinghoffer V, Kaplan DA, Steiner I.
subjects with chronic non-neurological disease on Memory abnormalities in myasthenia gravis: possible
the Boston Naming Test, WMS Logical Memory, fatigue of central nervous system cholinergic circuits.
and WMS Design Reproduction. Moreover, one Autoimmunity 1992; 14: 85–6.
patient with MG showed improvement in memory Glennerster A, Palace J, Warburton D, Oxbury S, Newsom-
Davis J. Memory in myasthenia gravis: neuropsycho-
after treatment with plasmapheresis. However,
logical tests of cerebral cholinergic function before and
others have found no evidence for memory
after effective immunologic treatment. Neurology 1996;
impairments in MG patients in comparison with
46: 1138–42.
normal controls, and hence no support for the Tucker DM, Roeltgen DP, Wann PD, Wertheimer RI.
idea of impaired central cholinergic mechanisms Memory dysfunction in myasthenia gravis: evidence for
(Glennerster et al., 1996). central cholinergic effects. Neurology 1988; 38: 1173–7.
Index
6 item Cognitive Impairment Test (6CIT) 23 cholinesterase inhibitors 45

18q deletion (18q–) syndrome 149 clinical diagnostic criteria 40
clinical diagnostic features 40--1
Abbreviated Mental Test Score (AMTS) 23 differentiation from VaD 91
acaeruloplasminaemia 144--5 DSM-IV diagnostic criteria 40
acid maltase deficiency 151 EEG changes 40
acquired non-Wilsonian hepatocerebral degeneration epidemiology 40
201--2 executive function 44
activities of daily living (ADL) scales 24 familial AD 40
acute disseminated encephalomyelitis (ADEM) 165 general intelligence, IQ 42
Addenbrooke’s Cognitive Examination (ACE) 13, 18, 28--9, 76 genetic mutations involved 40
executive function tests 21 language 43
verbal fluency tests 20 memantine 45
Addenbrooke’s Cognitive Examination-revised (ACE-R) memory impairment 12--13, 42--3
13, 18, 29, 68 neurofibrillary tangles 40
adenovirus encephalitis 207 neurological features which are less common 41
aging neuropathological criteria 40
effects on crystallised intelligence 32--3 neuropsychological features 40--1
effects on fluid intelligence 32--3 neuropsychological profile 41--4
normal changes in neurological function 32--3 neuropsychological testing 12--13
agnosia 16 see also perception perception 43--4
agraphia 15--16 posterior cortical atrophy (PCA) 41
AIDS see human immunodeficiency virus (HIV) and praxis 44
related conditions presymptomatic AD 44--5
akinetopsia (cerebral visual motion blindness) 17, 199 ‘senile dementia’ 40
alcohol-related dementia 201 senile plaques 40
alcohol-related disorders 200--2 sporadic AD 40
Alexander’s disease 148--9 structural brain imaging 40
alexia 15--16, 17 treatment of neuropsychological deficits 45
Alzheimer’s disease (AD) 40--5 treatments 40
age of onset 40 variants of AD 41
amyloid plaques 40 verbal fluency tests 20
apraxia 44 visual agnosic problems 17
as a disconnection syndrome 38 visual perceptual deficits 43--4
attention 41--2 volumetric magnetic resonance imaging 40
autosomal dominant AD 40 see also dementia
218
Index 219
Alzheimer’s Disease Assessment Scale–Cognitive Section neuroanatomical basis 9

(ADAS–COG) 31 selective 8--9
amnesia sustained 8--9
causes 12--13 tests of 9--10
forms of 12 types of attentional mechanism 8--9
amnesic shellfish poisoning 203 visual neglect 9, 10
amylopectinosis 154--5 attentional deficits, and impaired cognitive function 8
amyotrophic lateral sclerosis (ALS) see motor neurone disease ‘atypical’ parkinsonian syndromes 76
amyotrophic lateral sclerosis/parkinsonism–dementia amyotrophic lateral sclerosis/parkinsonism–dementia
complex (ALS/PDC) of Guam 81--2 complex (ALS/PDC) of Guam 81--2
Andersen’s disease 154--5 corticobasal degeneration (CBD) 76, 78--9
Anderson–Fabry disease 151 dementia pugilistica 81
aneurysmal SAH 102 lytico-bodig 81--2
angioendotheliomatosis 106 Marianas dementia 82
angiokeratoma corporis diffusum 151 multiple system atrophy (MSA) 76, 80
angular gyrus, strategic strokes 97 progressive supranuclear palsy (PSP) 76--7
anterograde memory 12 auditory agnosia 16--17
Anton’s syndrome 44 auditory comprehension testing 15
aphasias 15 Autobiographical Memory Interview 13
apperceptive agnosia 16 autosomal dominant nocturnal FLE (ADNFLE) 118
apraxia autosomal recessive spastic ataxia of Charlevoix–
definition 19 Saguenay (ARSACS) 139
forms of 19
testing for praxic difficulties 19 bacterial meningitis 209
aqueduct stenosis 184 Balint’s syndrome 17, 37, 44, 79, 148, 201
arachnoid cyst 187 Baltic myoclonus 155
argyrophilic grain disease (AGD) 61 basal forebrain, strategic strokes 100
arteriovenous fistulas (AVFs) 104, 105 basophilic inclusion body disease (BIBD) 62--3
arteriovenous malformations (AVMs) 104--5 ‘bedside’ neuropsychological test instruments 7, 22--32
associative agnosia 16 activities of daily living (ADL) scales 24
ataxia telangiectasia (AT) 139 Addenbrooke’s Cognitive Examination (ACE) 28--9, 76
ataxia with vitamin E deficiency (AVED) 139 Addenbrooke’s Cognitive Examination–revised (ACE-R) 29
ataxias Alzheimer’s Disease Assessment Scale–Cognitive
autosomal dominant hereditary 136--8 Section (ADAS-COG) 31
autosomal recessive hereditary 138--9 attention 9--10
attention 8--10 behavioural measurement 24
and working memory 9 CERAD battery 31
‘bedside’ tests 9--10 Clinical Dementia Rating (CDR) 31, 87
‘cocktail party phenomenon’ 8--9 Clock Drawing 28
definition 8 cognitive tests for clinical use 23--4
disturbance of consciousness 8 computerized test batteries 24
divided 8--9 dementia detection and diagnosis 23--4
extinction (suppression) 9 Dementia Rating Scale (DRS) 30, 76
Glasgow Coma Scale (GCS) 9 DemTect 30
intensity of consciousness 8 executive function (frontal function) 20, 21
level of consciousness 8 Global Deterioration Scale (GDS) 31--2, 87
monitoring level of consciousness 9 global function measurement 24
nature of consciousness 8 IADL scale 32
neglect (inattention) 9, 10 informant questionnaires 24
220 Index
‘bedside’ neuropsychological test instruments (Cont.) CERAD battery 31

language disorders 15--16 verbal fluency tests 20
memory 13 cerebellum
Mini-Mental State Examination (MMSE) 26--7 role in cognition 135--6 see also
perception 18 spinocerebellar ataxias (SCA)
primary care screening and diagnosis 23--4 strategic strokes 100--1
Queen Square Screening Test for Cognitive Deficits cerebral amyloid angiopathies (CAAs) 107--8
(QSSTCD) 28 cerebral autosomal dominant arteriopathy with
standards of reliability and validity 23 subcortical infarcts and leukoencephalopathy
Behavioural Assessment of the Dysexecutive Syndrome (CADASIL) 106--7
(BADS) 21 cerebral vasculitides 171--3
behavioural measurement 24 characteristics 171
Behçet’s disease 169--70 primary angiitis of the CNS (PACNS) 171--2
bilateral vestibulopathy 177 systemic vasculitides 172--3
Binswanger’s disease 95 cerebrotendinous xanthomatosis (CTX) 153
Blessed Information Memory Concentration Test cerebrovascular disease see vascular cognitive impairment
(BIMC) 23 (VCI); vascular dementia (VaD)
blindsight 17 cerebrovascular disorders
Boston Diagnostic Aphasia Examination (BDAE) 15 cortical venous sinus thrombosis (CVST) 112
Boston Naming Test 15 migraine 112--13
bovine spongiform encephalopathy (BSE) 82 transient global amnesia (TGA) 114
Braille alexia 17 Chamorro people of Guam 81--2
brain tumours and their treatment 178--81 cholinesterase inhibitors 40, 45, 72, 88, 96, 107, 124, 162, 187
causes of cognitive decline 178 chorea-acanthocytosis 143
chemotherapy 181 chronic obstructive pulmonary disease (COPD) 197
craniopharyngioma 180 chronic progressive external ophthalmoplegia (CPEO)
glioma 179 146--7
gliomatosis cerebri 180--1 Churg-Strauss syndrome 172--3
meningiomas 179 Clinical Dementia Rating (CDR) 31, 87
pituitary tumours 179 clinical neurologist, usefulness of neuropsychological
primary CNS lymphoma 180 examination 1--2
radiotherapy 181 Clinicians Interview-Based Impression of Change
splenial tumours 180 (CIBIC) 24
brainstem, strategic strokes 100--1 Clock Drawing test 18, 21, 23, 28
Broca’s aphasia 15 cobalamin (vitamin B12) deficiency 194--5
ideomotor apraxia 37--8 coeliac disease 195
Buschke Selective Reminding Test 13 cognitive decline and change in IQ 11
cognitive domains 6--7
California Verbal Learning Test 13 attention 8--10
Cambridge Gamble Test 21 executive function (frontal function) 20--1
Cambridge Neuropsychological Test Automated Battery, general intelligence (IQ) testing 10--11
Paired Associates Learning test (CANTAB-PAL) 24 language 15--16
Camden Recognition Memory Test 13 memory 11--13
Capgras’ syndrome 38 perception 16--18
carbon monoxide poisoning 198--9 praxis 19
caudate nucleus, strategic strokes 99 Cognitive Estimates Test 21
cavernous haemangiomas 105 cognitive function evaluation
central pontine (and extrapontine) myelinolysis 193 analysis from neuropsychological examination 1--2
central sleep apnoea 198 ‘bedside’ neuropsychological testing 7, 22--32
Index 221
cognitive decline and change in IQ 11 differential diagnosis 34

collateral history and observations 7 Delis–Kaplan Executive Function System (D-KEFS) 21
defining normal aging effects 32--3 dementia, cortical/subcortical debate 35--6
dementia diagnosis 33--4 dementia detection, ‘bedside’ neuropsychological test
‘formal’ testing 7 instruments 23--4
neuropsychological testing 7 dementia diagnosis 33--4
cognitive impairment ‘bedside’ neuropsychological test instruments 23--4
and attentional deficits 8 differential diagnosis 34
and delirium 34 distinction from delirium 34
and depression 34 distinction from depression 34
and schizophrenia 34 DSM-IV criteria 33
occurrence in neurological disorders 1 emphasis on memory impairment 33--4
collateral history and observations 7 ICD-10 criteria 33
colloid cyst 184--5 dementia of frontal type (DFT) 51--3
Comprehensive Aphasia Test 15 attention 51--2
computerized test batteries 24 characteristics 51
concentration see attention executive function 53
conduction aphasia (impaired repetition) 15 general intelligence, IQ 52
disconnection syndrome 37--8 language 52
Conn’s syndrome 193 memory 52
consciousness neuropsychological profile 51--3
disturbance of 8 perception 52--3
Glasgow Coma Scale 9 praxis 53
intensity of 8 treatment of neuropsychological deficits 53
level of 8 dementia pugilistica 81
monitoring level of 9 Dementia Rating Scale (DRS) 30, 76
nature of 8 verbal fluency tests 20
Continuous Performance Test 9--10 dementia syndrome of depression 34
controlled oral word association tests (COWAT) 20 dementia with Lewy bodies (DLB) 69--73
corpus callosum, strategic strokes 97 attention 70--1
cortical dementias 35--6 cholinesterase inhibitors 72
cortical vascular dementia 93--4 cognitive impairment in PD 69
cortical venous sinus thrombosis (CVST) 112 diagnostic criteria 70
corticobasal degeneration (CBD) 76, 78--9 differential diagnosis 70
Cotard’s syndrome 38 executive function 72
Coxsackie virus encephalitis 207 general intelligence, IQ 71
craniopharyngioma 180 genetic factors 70
Creutzfeldt–Jakob disease language 71--2
familial CJD 82, 86 Lewy body pathology 69
sporadic CJD (sCJD) 82, 83--4 memory 71
variant CJD (vCJD) 82, 84--5 neuropsychological profile 70--2
crystallized intelligence, effects of aging 32--3 perception 72
Cushing’s syndrome 192 praxis 72
cutaneous leukocytoclastic vasculitis 172--3 treatment of neuropsychological deficits 72--3
DemTect 13, 18, 30
declarative (explicit, conscious) memory 11--12 dentatorubropallidoluysian atrophy (DRPLA) 130--1
delirium depression
and cognitive impairment 34 and cognitive impairment 34
diagnosis 8 differential diagnosis 34
222 Index
depression-related cognitive dysfunction 34 frontal lobe epilepsy (FLE) 118

diabetes mellitus 188--9 historical associations 115
diffuse neurofibrillary tangles with calcification (DNTC, ictal speech arrest 121
Kosaka–Shibayama disease) 61--2 idiopathic generalized epilepsies (IGE) 120
disconnection syndromes 37--8 juvenile myoclonic epilepsy (JME) 120
Alzheimer’s disease 38 Landau–Kleffner syndrome 121
causes 37 localization-related (partial) epilepsies 117--18
conduction aphasia 37--8 Rasmussen’s syndrome (chronic encephalitis and
definition 37 epilepsy) 119
effects of 37 reasons for association 115--16
ideomotor apraxia 37--8 seizures causing acquired cognitive impairment
pure word deafness 37--8 120--1
domoic acid poisoning 203 shared underlying aetiology 116--17
DSM-IV criteria temporal lobe epilepsy (TLE) 117--18
delirium diagnosis 8 transient epileptic amnesia (TEA) 121
dementia diagnosis 33 treatment of cognitive problems in epilepsy 123--4
dysexecutive syndrome 20 epileptic aphasia 121
episodic (autobiographical) memory 11--12
encephalitides and meningoencephalitides 205--8 Erdheim–Chester disease 177
adenovirus encephalitis 207 essential cryoglobulinaemia 172--3
Coxsackie virus encephalitis 207 essential tremor (ET) 145
encephalitis lethargica 208 executive function (frontal function) 20--1
herpes simplex encephalitis (HSE) 205--6 ‘bedside’ tests 20, 21
herpes zoster encephalitis (HZE) 206 definition and components 20
human herpes virus-6 (HHV-6) infection 207 dysexecutive syndrome 20
Japanese encephalitis 208 frontal lobe damage clinical phenotypes 20
post-encephalitic parkinsonism 208 Go-No Go tests 20
rotavirus encephalitis 207 range of tests 20--1
subacute sclerosing panencephalitis (SSPE) 207--8 verbal fluency tests 20
tick-borne encephalitis 208 explicit (declarative, conscious) memory 11--12
von Economo disease 208 extinction (suppression) 9
encephalitis lethargica 208 extrasylvian aphasia 15
endocrine disorders 188--93
Conn’s syndrome 193 Fabry’s disease 151
Cushing’s syndrome 192 Fahr’s syndrome 61--2, 133
diabetes mellitus 188--9 familial British dementia (FBD) 131
hypercortisolism 192 familial Creutzfeldt–Jakob disease (CJD) 82, 86
hyperthyroidism 191 familial Danish dementia (FDD) 131--2
hypothyroidism 190--1 familial encephalopathy with neuroserpin inclusion
idiopathic hypoparathyroidism 191--2 bodies (FENIB) 132
parathyroid disorders 191--2 familial occipital calcifications, haemorrhagic strokes,
primary hyperaldosteronism 193 leukoencephalopathy, dementia and external carotid
primary hyperparathyroidism 192 dysplasia (FOCHS-LADD) 109
thyroid disorders 190--1 familial young-adult onset arteriosclerotic
epilepsy and cognitive impairment leukoencephalopathy with alopecia and lumbago
anti-epileptic drug therapy causing cognitive without arterial hypertension 109
impairment 122--3 Famous Faces Test 13
autosomal dominant nocturnal FLE (ADNFLE) 118 FAS test 20
epileptic aphasia 121 fatal familial insomnia (FFI) 36, 82, 86
Index 223
finger agnosia 17 diffuse neurofibrillary tangles with calcification (DNTC)

Florida Apraxia Screening Test–Revised (FAST--R) 19 61--2
fluid intelligence, effects of aging 32--3 EEG results 49--50
‘formal’ neuropsychological tests 7 frontal variant of frontotemporal dementia (fvFTD)
fornix 51--3
damage to 184--5 frontotemporal dementia (FTD) 51--3
strategic strokes 97 frontotemporal dementia with parkinsonism linked to
fragile X syndrome (FRAX) 135 chromosome 17 (FTDP-17) 50, 58--9
fragile X tremor/ataxia syndrome (FXTAS) 135 FTLD with tau immunopositive inclusions 50
Friedreich’s ataxia (FA) 138--9 FTLD with ubiquitin immunopositive inclusions
Frontal Assessment Battery 21,183 (FTLD-U) 50
Frontal Behavioural Inventory 21 functional neuroimaging 49--50
frontal function see executive function genetic mutations 50
frontal lobe damage clinical phenotypes 20 Kosaka–Shibayama disease 61--2
frontal lobe epilepsy (FLE) 118 neurofibrillary tangle dementia (NTD) 61
Frontal Lobe Personality Change Questionnaire neuronal intermediate filament inclusion disease
(FLOPS) 21 (NIFID) 62
frontal variant of frontotemporal dementia (fvFTD) 51--3 neuropsychiatric features 49
attention 51--2 neuropsychological features 49
characteristics 51 Pick’s disease 49, 50
executive function 53 prevalence rates 49
general intelligence, IQ 52 primary progressive aphasia (PPA) 56--7
language 52 progressive fluent aphasia 54--5
memory 52 progressive nonfluent aphasia (PNFA) 56--7
neuropsychological profile 51--3 progressive subcortical gliosis (of Neumann) 60
perception 52--3 range of names used 49
praxis 53 semantic dementia (SD) 54--5
treatment of neuropsychological deficits 53 structural brain imaging 49--50
frontotemporal dementia (FTD) 51--3 temporal variant of frontotemporal dementia (tvFTD)
attention 51--2 54--5
characteristics 51 Functional Assessment Staging (FAST) 24
executive function 53 fungal meningitis 209
general intelligence, IQ 52
language 52 gangliosidosis 151
memory 52 gastrointestinal disease 194--6
neuropsychological profile 51--3 Gaucher’s disease 151--2
perception 52--3 general intelligence factor (g) 10
praxis 53 general intelligence (IQ) testing 10--11
treatment of neuropsychological deficits 53 administration of tests 10--11
frontotemporal dementia with parkinsonism linked to cognitive decline and change in IQ 11
chromosome 17 (FTDP-17) 50, 58--9 full scale IQ (FSIQ) 10--11
frontotemporal lobal degenerations (FTLD) 49--63 general intelligence factor (g) 10
argyrophilic grain disease (AGD) 61 measurement of change in IQ 11
basophilic inclusion body disease (BIBD) 62--3 nonverbal tests 11
chromosomes associated with mutations 50 performance IQ (PIQ) 10--11
classification of FTLDs 50 role in neuropsychological assessment 10
dementia of frontal type (DFT) 51--3 standardized scoring 10--11
diagnostic criteria 49--50 types of tests 10
differentiation from AD 49--50 verbal IQ (VIQ) 10--11
224 Index
genu of the internal capsule, strategic strokes 99 fragile X tremor/ataxia syndrome (FXTAS) 135
Gerstmann–Straussler–Scheinker syndrome (GSS) 82, 86 Huntington’s disease 126--9
Gerstmann syndrome 17, 44, 97, 167, 170, 173, 186 inclusion body myopathy associated with Paget’s
giant cell arteritis 172--3 disease of bone and frontotemporal dementia
Glasgow Coma Scale (GCS) 9 (IBMPFD) 133--4
glioma 179 Kufor–Rakeb syndrome 134
gliomatosis cerebri 180--1 lipoid proteinosis 134
Global Deterioration Scale (GDS) 31--2, 87 Nasu–Hakola disease 132--3
global function measurement 24 polycystic lipomembranous osteodysplasia with
globoid cell leukodystrophy 149 sclerosing leukoencephalopathy (PLOSL) 132--3
globus pallidus, strategic strokes 99 presenile dementia with bone cysts 132--3
gluten sensitivity and coeliac disease 195 striatopallidal calcification 133
glycogen storage disease type IV 154--5 Urbach–Wiethe disease 134
glycogenosis type IIb 151 hereditary dystonic lipidosis 151
Go-No Go tests 20 hereditary endotheliopathy with retinopathy,
GPCOG 23 nephropathy and stroke (HERNS) 109
Graded Naming Test 15 hereditary metabolic disorders 146--55
amylopectinosis 154--5
Hachinski Ischaemic Score (HIS) 91 Andersen’s disease 154--5
haemochromatosis 153--4 Baltic myoclonus 155
Hallervorden–Spatz disease 142--3 cerebrotendinous xanthomatosis (CTX) 153
Halstead–Reitan Category Test 21 chronic progressive external ophthalmoplegia (CPEO)
Hashimoto’s encephalopathy (HE) 176 146--7
Hayling and Brixton Tests 21 glycogen storage disease type IV 154--5
head injury-related neuropsychological deficits 81 haemochromatosis 153--4
Henoch–Schonlein purpura 172--3 Kearns–Sayre syndrome 146--7
hepatolenticular degeneration 141--2 Lafora body disease 154
hereditary ataxias 135--9 leukodystrophies 147--9
ataxia telangiectasia (AT) 139 lysosomal storage disorders 151--2
ataxia with vitamin E deficiency (AVED) 139 mitochondrial disorders 146--7
autosomal dominant hereditary ataxias 136--8 mitochondrial encephalomyopathy, lactic acidosis and
autosomal recessive hereditary ataxias 138--9 stroke-like episodes (MELAS) 146--7
autosomal recessive spastic ataxia of Charlevoix– myoclonic epilepsy and ragged red fibres (MERRF)
Saguenay (ARSACS) 139 146--7
Friedreich’s ataxia (FA) 138--9 polyglucosan body disease 154--5
role of the cerebellum in cognition 135--6 porphyria 155
spinocerebellar ataxias (SCA) 136--8 Unverrlicht-Lundborg disease 155
hereditary cerebral haemorrhage with amyloidosis Dutch hereditary movement disorders 141--6
type (HCHWA-D) 108 acaeruloplasminaemia 144
hereditary cerebral haemorrhage with amyloidosis chorea-acanthocytosis 143
Icelandic type (HCHWA-I) 108 essential tremor (ET) 145
hereditary dementias 126--35 Hallervorden–Spatz disease 142--3
dentatorubropallidoluysian atrophy (DRPLA) 130--1 hepatolenticular degeneration 141--2
Fahr’s syndrome 133 neuroacanthocytosis 143
familial British dementia (FBD) 131 neurodegeneration with brain accumulation of iron-1
familial Danish dementia (FDD) 131--2 (NBAI-1) 142--3
familial encephalopathy with neuroserpin inclusion neuroferritinopathy 144
bodies (FENIB) 132 obsessive-compulsive disorder 146
fragile X syndrome (FRAX) 135 restless legs syndrome (RLS) 146
Index 225
Tourette syndrome 146 osteitis deformans 185

Wilson’s disease 141--2 Paget’s disease of bone 185
hereditary multi-infarct dementia of Swedish hypercortisolism 192
type 109--10 hyperthyroidism 191
hereditary neurocutaneous syndromes (phakomatoses) hypothyroidism 190--1
155--6
neurofibromatosis 156 IADL scale 32
tuberous sclerosis 156 ICD-10 criteria
hereditary spastic paraplegias (HSP) 140--1 delirium diagnosis 8
SPG4 140--1 dementia diagnosis 33
SPG21 (Mast Syndrome) 141 ictal speech arrest 121
heredopathia ophthalmo-oto-encephalica see familial ideomotor apraxia, disconnection syndrome 37--8
Danish dementia (FDD) idiopathic generalized epilepsies (IGE) 120
herpes simplex encephalitis (HSE) 205--6 idiopathic hypoparathyroidism 191--2
herpes zoster encephalitis (HZE) 206 idiopathic normal pressure hydrocephalus (iNPH) 182--3
hippocampal sclerosis 68, 117 immune-mediated, inflammatory and systemic disorders
hippocampus, strategic strokes 100 157--77
HIV see human immunodeficiency virus (HIV) and related implicit (non-declarative, procedural, unconscious)
conditions memory 11--12
Hopkins Verbal Learning Test 13 inclusion body myopathy associated with Paget’s disease
HTLV-1 infection 211 of bone and frontotemporal dementia (IBMPFD)
Hughes’ syndrome 110 133--4
human herpes virus-6 (HHV-6) infection 207 infective disorders 204--14
human immunodeficiency virus (HIV) and related encephalitides and meningoencephalitides 205--8
conditions 210--11 human immunodeficiency virus (HIV) and related
AIDS dementia 210 conditions 210--11
HIV dementia 210 Lyme disease 212--13
HTLV-1 infection 211 meningitides 209
progressive multifocal leukoencephalopathy (PML) 211 neuroborreliosis 212--13
Huntington’s disease 36, 126--9 neurocysticercosis 213--14
attention 127 neurosyphilis 211--12
characteristics 126 tuberculosis 212
executive function 128--9 Whipple’s disease 214
genetic factors 126--7 inflammatory, immune-mediated and systemic disorders
language 128 157--77
memory 127--8 informant questionnaires 24
neuropsychological profile 127--9 intracranial vascular malformations 104--5
perception 128 intravascular lymphomatosis 106
praxis 128 Iowa Gambling Test 21
presymptomatic gene mutation carriers 129 IQ see general intelligence (IQ) testing
studies of cognitive function 127
hydrocephalic dementias 182--5 Japanese encephalitis 208
aqueduct stenosis 184 Judgement of Line Orientation test 17--18
causes 182 juvenile myoclonic epilepsy (JME) 120
colloid cyst 184--5
fornix damage 184--5 Kawasaki disease 172--3
idiopathic normal pressure hydrocephalus (iNPH) Kearns–Sayre syndrome 146--7
182--3 Kingshill Test 23
normal pressure hydrocephalus (NPH) 182--3 Kosaka–Shibayama disease 61--2
226 Index
Krabbe disease 149 mucopolysaccharidosis III 152

Kuf’s disease 152 neuronal ceroid lipofuscinosis (NCL) 152
Kufor–Rakeb syndrome 134 Niemann–Pick disease type C 152
kuru 82, 85 Sanfilippo syndrome 152
lytico-bodig 81--2
lacunar state 95
Lafora body disease 154 Machado–Joseph disease (MJD, SCA3) 137
Landau–Kleffner syndrome 121 Marchiafava–Bignami disease 201
language disorders 15--16 Marianas dementia 82
agraphia 15--16 Mast Syndrome 141
alexia 15--16 memantine 40, 45, 96
aphasias 15 memory 11--13
auditory comprehension testing 15 amnesia 12
‘bedside’ testing 15--16 anterograde memory 12
Broca’s aphasia 15 ‘bedside’ test instruments 13
conduction aphasia (impaired repetition) 15 causes of amnesia 12--13
extrasylvian aphasia 15 declarative (explicit, conscious) memory 11--12
neural substrates of language function 15 episodic (autobiographical) memory 11--12
perisylvian aphasia 15 explicit (declarative, conscious) memory 11--12
reading and writing functions 15--16 implicit (non-declarative, procedural, unconscious)
tests of language 15--16 memory 11--12
transcortical aphasia (preserved repetition) 15 long-term memory 12
Wernicke’s aphasia 15 neuroanatomical substrates 12
leukodystrophies 147--9 non-declarative (implicit, procedural, unconscious)
18q deletion (18q–) syndrome 149 memory 11--12
Alexander’s disease 148--9 retrograde memory 12
definition 147--8 semantic memory 11--12
globoid cell leukodystrophy 149 short-term memory 12
Krabbe disease 149 taxonomies 11--12
metachromatic leukodystrophy (MLD) 148 tests available 13
Pelizaeus–Merzbacher disease (PMD) 149 Memory Alteration Test 23
Rosenthal fibre encephalopathy (RFE) 148--9 memory impairment
X-linked adrenoleukodystrophy (X-ALD) 148 Alzheimer’s disease 12--13
Lewy body pathology 69 causes 12--13
limbic dementia 35 diagnostic challenge 38
limbic encephalitis 174--5 emphasis in dementia diagnosis 33--4
lipoid proteinosis 134 meningiomas 179
long-term memory 12 meningitides 209
Lyme disease 212--13 bacterial meningitis 209
lysosomal storage disorders fungal meningitis 209
acid maltase deficiency 151 viral meningitis 209
Anderson–Fabry disease 151 meningoencephalitides see encephalitides and
angiokeratoma corporis diffusum 151 meningoencephalitides
Fabry’s disease 151 metabolic disorders 193--9
gangliosidosis 151 carbon monoxide poisoning 198--9
Gaucher’s disease 151--2 central pontine (and extrapontine) myelinolysis 193
glycogenosis type IIb 151 chronic obstructive pulmonary disease (COPD) 197
hereditary dystonic lipidosis 151 cobalamin (vitamin B12) deficiency 194--5
Kuf’s disease 152 coeliac disease 195
Index 227
gastrointestinal disease 194--6 progressive symmetric spinobulbar spasticity 67

gluten sensitivity and coeliac disease 195 pure hippocampal sclerosis 68
obstructive sleep apnoea–hypopnoea syndrome movement disorders see hereditary movement disorders
(OSAHS) 197--8 mucopolysaccharidosis III 152
osmotic demyelination syndrome 193 multi-infarct dementia 93--4
pellagra 195--6 multiple sclerosis (MS) 36, 157--62
respiratory disorders 197--9 attention 160
metachromatic leukodystrophy (MLD) 148 characteristics 157
microscopic polyangiitis 172--3 diagnostic criteria 157
Middelheim Frontality Score 21 executive function 161
migraine 112--13 frequency of cognitive impairment 158
mild cognitive impairment (MCI) 87--8 general intelligence, IQ 160
Mills’ syndrome 67 language 161
Mini-Mental State Examination (MMSE) 18, 26--7 memory 160--1
lack of executive function assessment 21 natural history and cognitive impairment 158--9
memory function testing 13 neuroimaging correlation with cognitive deficits 159
tests of attention or concentration 9--10 neurological dysfunction and cognitive impairment 159
use in primary care 23 neuropsychological profile 159--61
versions available 26 neuropsychological test instruments 158
mitochondrial disorders (hereditary) 146--7 perception 161
chronic progressive external ophthalmoplegia (CPEO) praxis 161
146--7 treatment of neuropsychological deficits 162
Kearns–Sayre syndrome 146--7 variable disease course 157
mitochondrial encephalomyopathy, lactic acidosis and multiple system atrophy (MSA) 76, 80
stroke-like episodes (MELAS) 146--7 myasthenia gravis (MG) 216--17
myoclonic epilepsy and ragged red fibres (MERRF) myoclonic epilepsy and ragged red fibres (MERRF)
146--7 146--7
mitochondrial encephalomyopathy, lactic acidosis and myotonic dystrophy 215--16
stroke-like episodes (MELAS) 146--7
Modified Wisconsin Card Sorting Test (MWCST) 20--1 Nasu–Hakola disease 132--3
motor neurone disease (MND) (amyotrophic lateral National Adult Reading Test (NART) 11
sclerosis) 36, 63--8 neglect (inattention) 9, 10
attention 64 neural substrates of language function 15
characteristics 63 neuroacanthocytosis 143
clinical diagnostic criteria 63--4 neuroborreliosis 212--13
clinical heterogeneity 63--4 neurocysticercosis 213--14
executive function 64--5 neurodegeneration with brain accumulation of iron-1
general intelligence, IQ 64 (NBAI-1) 142--3
genetic factors 64 neuroferritinopathy 144
hippocampal sclerosis 68 neurofibrillary tangle dementia (NTD) 61
language 64 neurofibromatosis 156
memory 64 neurogenetic disorders
Mills’ syndrome 67 hereditary ataxias 135--9
neuropsychological profile 64--5 hereditary dementias 126--35
overlap with FTD 63 hereditary metabolic disorders 146--55
perception 64 hereditary movement disorders 141--6
praxis 64 hereditary neurocutaneous syndromes (phakomatoses)
primary lateral sclerosis (PLS) 67 155--6
progressive muscular atrophy 68 hereditary spastic paraplegias (HSP) 140--1
228 Index
neurological disorders diagnostic criteria 70

diagnostic challenge of memory impairment 38 differential diagnosis 70
occurrence of cognitive dysfunction 1 executive function 72
neurological function, defining normal aging effects 32--3 general intelligence, IQ 71
neuromuscular disorders 215--17 genetic factors 70
myasthenia gravis (MG) 216--17 language 71--2
myotonic dystrophy 215--16 Lewy body pathology 69
proximal myotonic myopathy (PROMM) 215, 216 memory 71
Ricker’s disease 215, 216 neuropsychological profile 70--2
Steinert disease 215--16 perception 72
neuronal ceroid lipofuscinosis (NCL) 152 praxis 72
neuronal intermediate filament inclusion disease treatment of neuropsychological deficits 72--3
(NIFID) 62 parkinsonian syndromes see ‘atypical’ parkinsonian
Neuropsychiatric Inventory (NPI) 24 syndromes
neuropsychological assessment Pelizaeus–Merzbacher disease (PMD) 149
analysis of cognitive function 1--2 pellagra 195--6
role of general intelligence (IQ) testing 10 perception 16--18
usefulness to clinical neurologists 1--2 agnosia definition 16
neuropsychological tests of cognitive function see akinetopsia (cerebral visual motion blindness) 17, 199
cognitive function evaluation alexia 17
neurosarcoidosis 165--6 apperceptive agnosia 16
neurosyphilis 211--12 associative agnosia 16
Niemann–Pick disease type C 152 auditory agnosia 16--17
non-declarative (implicit, procedural, unconscious) ‘bedside’ test instruments 18
memory 11--12 blindsight 17
non-paraneoplastic limbic encephalitis (NPLE) 175 Braille alexia 17
normal pressure hydrocephalus (NPH) 182--3 finger agnosia 17
Gerstmann syndrome 17
obsessive-compulsive disorder 146 optic ataxia 17
obstructive sleep apnoea–hypopnoea syndrome (OSAHS) posterior cortical atrophy (PCA) 17, 43
197--8 progressive visual agnosia 17
olivopontocerebellar atrophy (OPCA) see multiple system prosopagnosia 16--17
atrophy (MSA) Riddoch’s syndrome 17
optic ataxia 17 tactile agnosia 16--17
osmotic demyelination syndrome 193 testing 17--18
osteitis deformans 185 visual agnosia 16--17
visual agnosia, progressive 17
Paced Auditory Serial Addition Test (PASAT) 9--10 visual form agnosia 17
paediatric autoimmune neuropsychiatric disorders visual processing pathways in the brain 17
associated with streptococcal infections (PANDAS) visual variant of Alzheimer’s disease 17
173--4 visuomotor control system 17
Paget’s disease of bone 185 visuospatial testing 17--18
paraneoplastic limbic encephalitis (PNLE) 174 performance IQ (PIQ) 10--11
parathyroid disorders 191--2 perimesencephalic (non-aneurysmal) SAH 103
Parkinson’s disease (PD) 36, 69 perisylvian aphasia 15
Parkinson’s disease dementia (PDD) 69--73 phakomatoses (hereditary neurocutaneous syndromes)
attention 70--1 155--6
cholinesterase inhibitors 72 Pick’s disease 49, 50
cognitive impairment in PD 69 pituitary tumours 179
Index 229
polyarteritis nodosa 172--3 sporadic forms 82, 83--4

polycystic lipomembranous osteodysplasia with variant Creutzfeldt–Jakob disease (vCJD) 82, 84--5
sclerosing leukoencephalopathy (PLOSL) 132--3 progressive fluent aphasia 54--5
polycythaemia rubra vera 111 attention 54
polyglucosan body disease 154--5 characteristics 54
Poppelreuter figures 17--18 executive function 55
porphyria 155 general intelligence, IQ 54
Porteus Mazes 21 language 54--5
post-encephalitic parkinsonism 208 memory 54
post-stroke dementia 93--4 neuropsychological profile 54--5
posterior cortical atrophy (PCA) 17, 43 perception 55
praxis 19 praxis 55
apraxia definition 19 Progressive Matrices 11
forms of apraxia 19 progressive multifocal leukoencephalopathy (PML) 211
testing for praxic difficulties 19 progressive muscular atrophy 68
presenile dementia with bone cysts 132--3 progressive non-fluent aphasia (PNFA) 56--7
primary alcoholic dementia 201 attention 56
primary antiphospholipid antibody syndrome 110 characteristics 56
primary care, dementia screening and diagnosis 23--4 executive function 57
primary CNS lymphoma 180 general intelligence, IQ 56
primary hyperaldosteronism 193 language 57
primary hyperparathyroidism 192 memory 56
primary lateral sclerosis (PLS) 67 neuropsychological profile 56--7
primary progressive aphasia (PPA) 56--7 perception 57
attention 56 praxis 57
characteristics 56 progressive subcortical gliosis (of Neumann) 60
executive function 57 progressive supranuclear palsy (PSP) 76--7
general intelligence, IQ 56 progressive symmetric spinobulbar spasticity 67
language 57 prosopagnosia 16--17
memory 56 proximal myotonic myopathy (PROMM) 215, 216
neuropsychological profile 56--7 pseudodementia 34
perception 57 Psycholinguistic Assessment of Language Processing in
praxis 57 Aphasia (PALPA) 15
prion diseases 36, 82--6 pure hippocampal sclerosis 68
abnormal prion proteins 82 pure word deafness, disconnection syndrome 37--8
aetiological agents 82 Pyramids and Palm Trees Test 13
bovine spongiform encephalopathy (BSE) 82
familial Creutzfeldt–Jakob disease (CJD) 82, 86 Queen Square Screening Test for Cognitive Deficits
fatal familial insomnia (FFI) 82, 86 (QSSTCD) 13, 18, 28
genetic forms 82, 86
Gerstmann–Straussler–Scheinker syndrome (GSS) Rasmussen’s syndrome (chronic encephalitis and
82, 86 epilepsy) 119
iatrogenic/acquired/transmissible forms 82, 84--5 Raven’s Progressive Matrices 21
inherited forms 82, 86 reading disorder (alexia) 15--16
kuru 82, 85 relapsing polychondritis 171
pathogenesis 82--3 respiratory disorders 197--9
rates of occurrence 83 restless legs syndrome (RLS) 146
spongiform encephalopathies 82--3 retrograde memory 12
sporadic Creutzfeldt–Jakob disease (sCJD) 82, 83--4 Rey Auditory Verbal Learning Test 13
230 Index
Rey–Osterrieth Complex Figure test 13, 17--18 angular gyrus 97

rheumatoid arthritis (RhA) 170 basal forebrain 100
Richardson’s syndrome 76--7 brainstem 100--1
Ricker’s disease 215, 216 caudate nucleus 99
Riddoch’s syndrome 17 cerebellum 100--1
Rosenthal fibre encephalopathy (RFE) 148--9 corpus callosum 97
rotavirus encephalitis 207 definition 97
fornix 97
Sanfilippo syndrome 152 genu of the internal capsule 99
sarcoidosis 165--6 globus pallidus 99
schizophrenia 34 hippocampus 100
scleroderma 170--1 thalamus 97--8
semantic dementia (SD) 54--5 striatonigral degeneration (SND) see multiple system
attention 54 atrophy (MSA)
characteristics 54 striatopallidal calcification 133
executive function 55 stroke, post-stroke dementia 93--4 see also strategic
general intelligence, IQ 54 strokes; subarachnoid haemorrhage (SAH)
language 54--5 Stroop Test 20--1
memory 54 structural brain lesions
neuropsychological profile 54--5 arachnoid cyst 187
perception 55 brain tumours and their treatment 178--81
praxis 55 hydrocephalic dementias 182--5
semantic memory 11--12 subdural haematoma (SDH) 186
short-term memory 12 subacute sclerosing panencephalitis (SSPE) 207--8
Shy–Drager syndrome see multiple system atrophy (MSA) subarachnoid haemorrhage (SAH) 101--4
sickle cell disease 111 aneurysmal SAH 102
Sjögren’s syndrome 168--9 characteristics 101
Sneddon’s syndrome 111 intracranial aneurysms 101
solvent exposure 203 perimesencephalic (non-aneurysmal) SAH 103
spastic paraplegias see hereditary spastic paraplegias superficial siderosis of the nervous system 103--4
(HSP) unruptured aneurysms 101, 102
Spatz–Lindenberg disease 112 subcortical dementias 35--6
spinocerebellar ataxias (SCA) 136--8 subcortical forms of VCI 95--6
SCA1 136 subcortical ischaemic vascular disease (SIVD) 96
SCA2 136--7 subcortical vascular dementia 95--6
SCA3 (Machado–Joseph disease, MJD) 137 subdural haematoma (SDH) 186
SCA6 137 superficial siderosis of the nervous system 103--4
SCA7 137 Susac syndrome 112
SCA8 137 Sydenham’s chorea 173--4
SCA12 137 Symbol Digit Modalities Test 9--10
SCA17 126, 137--8 systemic, immune-mediated and inflammatory disorders
SCA19 138 157--77
splenial tumours 180 systemic lupus erythematosus (SLE) 166--7
spongiform encephalopathies see prion diseases systemic sclerosis 170--1
sporadic Creutzfeldt–Jakob disease (sCJD) 82, 83--4 systemic vasculitides 172--3
Steele–Richardson–Olszewski (SRO) syndrome 76--7
Steinert disease 215--16 tactile agnosia 16--17
strategic infarct dementia 97 Takayasu’s arteritis 172--3
strategic strokes 97 Taylor Figure test 17--18
Index 231
temporal lobe epilepsy (TLE) 117--18 arteriovenous fistulas (AVFs) 104, 105
temporal variant of frontotemporal dementia (tvFTD) arteriovenous malformations (AVMs) 104--5
54--5 Binswanger’s disease 95
attention 54 cavernous haemangiomas 105
characteristics 54 cholinesterase inhibitors 96
executive function 55 classification 91
general intelligence, IQ 54 cortical vascular dementia 93--4
language 54--5 diagnostic criteria 91
memory 54 differentiation from AD 91
neuropsychological profile 54--5 hereditary causes 92
perception 55 intracranial vascular malformations 104--5
praxis 55 lacunar state 95
Test for Reception of Grammar 15 memantine treatment 96
thalamic dementia 36 multi-infarct dementia 93--4
thalamus, strategic strokes 97--8 neuropsychological profile 91--2
thyroid disorders 190--1 post-stroke dementia 93--4
tick-borne encephalitis 208 strategic infarct dementia 97
Token Test 15 strategic strokes 97
Topographical Recognition Memory Test 13 subarachnoid haemorrhage (SAH) 101--4
Tourette syndrome 146 subcortical ischaemic vascular disease
Tower tests (London, Hanoi) 21 (SIVD) 96
toxin-related disorders 200--3 subcortical vascular dementia 95--6
acquired non-Wilsonian hepatocerebral degeneration treatment of neuropsychological deficits 96
201--2 vasculopathies 106--12
alcohol-related dementia 201 verbal fluency tests 20
alcohol-related disorders 200--2 vasculitides see cerebral vasculitides
amnesic shellfish poisoning 203 vasculopathies 106--12
domoic acid poisoning 203 angioendotheliomatosis 106
Marchiafava–Bignami disease 201 CADASIL 106--7
primary alcoholic dementia 201 cerebral amyloid angiopathies (CAAs) 107--8
solvent exposure 203 definition 106
Wernicke–Korsakoff syndrome (WKS) 200--1 familial occipital calcifications, haemorrhagic strokes,
Trail-Making Tests 9--10, 21 leukoencephalopathy, dementia and external carotid
Trails A and B test 20 dysplasia (FOCHS-LADD) 109
transcortical aphasia (preserved repetition) 15 familial young-adult onset arteriosclerotic
transient epileptic amnesia (TEA) 121 leukoencephalopathy with alopecia and lumbago
transient global amnesia (TGA) 114 without arterial hypertension 109
tuberculosis 212 hereditary cerebral haemorrhage with amyloidosis
tuberous sclerosis 156 Dutch type (HCHWA-D) 108
hereditary cerebral haemorrhage with amyloidosis
Unverrlicht–Lundborg disease 155 Icelandic type (HCHWA-I) 108
Urbach–Wiethe disease 134 hereditary endotheliopathy with retinopathy,
nephropathy and stroke (HERNS) 109
variant Creutzfeldt–Jakob disease (vCJD) 82, 84--5 hereditary multi-infarct dementia of Swedish type
vascular cognitive impairment (VCI) 109--10
classification 91, 92 Hughes’ syndrome 110
definition 91 intravascular lymphomatosis 106
subcortical forms 95--6 polycythaemia rubra vera 111
vascular dementia (VaD) primary antiphospholipid antibody syndrome 110
232 Index
vasculopathies (Cont.) Wechsler Adult Intelligence Scale-III (WAIS-III) 10

sickle cell disease 111 Wechsler Adult Intelligence Scale–Revised (WAIS--R) 10
Sneddon’s syndrome 111 Block Design 17--18
Spatz–Lindenberg disease 112 Digit Span subtest 9--10
Susac syndrome 112 executive/frontal lobe function subtests 21
von Winiwarter–Buerger’s disease 112 Wechsler Intelligence Scale for Children
verbal fluency tests 20 (WISC) 10
verbal IQ (VIQ) 10--11 Wechsler Memory Scale, third edition (WMS-III) 13
Verbal Switching Test 21 Wegener’s granulomatosis 172--3
viral meningitis 209 Weigl Colour Form Sorting Test 21
visual agnosia 16--17 Wernicke–Korsakoff syndrome (WKS) 200--1
progressive 17 Wernicke’s aphasia 15
visual form agnosia 17, 199 Western Aphasia Battery (WAB) 15
visual neglect 9, 10 Whipple’s disease 214
Visual Object and Space Perception Battery Wilson’s disease 141--2
(VOSP) 17--18 working memory, and selective attention 9
visual processing pathways in the brain 17 Worster–Drought syndrome see familial British dementia
visuomotor control system 17 (FBD)
visuospatial testing 17--18 writing disorder (agraphia) 15--16
von Economo disease 208
von Winiwarter–Buerger’s disease 112 X-linked adrenoleukodystrophy (X-ALD) 36, 148

Neuropsychological Neurology The Neurocognitive Impairments of Neurological Disorders PDF

Uploaded by

Copyright:

Available Formats

Neuropsychological Neurology The Neurocognitive Impairments of Neurological Disorders PDF

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

Neuropsychological Neurology The Neurocognitive Impairments of Neurological Disorders PDF

Uploaded by

Copyright:

Available Formats

This page intentionally left blank

Cambridge University Press

This publication is in copyright. Subject to statutory exception and to the

ISBN-13 978-0-511-45520-9 eBook (EBL)

ISBN-13 978-0-521-71792-2 paperback

Cambridge University Press has no responsibility for the persistence or accuracy

Disorders of intellect . . . happen much more

2.5 Prion diseases 82 6.3 Sarcoidosis 165

First and foremost I thank my wife Philippa, and

Cognitive function, neuropsychological evaluation,

REFERENCES 1.2 General intelligence, IQ

1.8.2 Clock drawing Sociodemographic determinants in an elderly popula-

Warrington EK. The Queen Square Screening Test for

acknowledged shortcomings of the MMSE, sensitivity and specificity in a selected university

1.8.8 CERAD battery 1.8.10 Global Deterioration Scale (GDS)

Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global

Various changes in neurological function occur with

2.1 Alzheimer’s disease (AD) 40

Table 2.1. Neuropsychological deficits in Alzheimer’s disease (AD).

Attention # Selective, divided; sustained attention relatively preserved

and hypometabolism (Nestor et al., 2003). to show impairment; imitation of meaningless

Table 2.2. Neuropsychological deficits in frontal variant frontotemporal dementia (fvFTD).

Attention # Sustained attention; distractibility, apathy, economy of effort, poor self-monitoring,

General intelligence, IQ Language

performance with lack of attention to detail. Dot Treatment of neuropsychological deficits

Table 2.3. Neuropsychological deficits in semantic dementia (SD).

Attention Essentially intact

Chan D, Fox NC, Scahill RI, et al. Patterns of temporal lobe

Table 2.4. Neuropsychological deficits in progressive non-fluent aphasia (PNFA).

Attention Essentially intact

Mimura M, Oda T, Tsuchiya K, et al. Corticobasal www.molgen.ua.ac.be/Admutations). More recently,

2.2.7 Neurofibrillary tangle dementia (NTD),

frontal variant FTD (Godbolt et al., 2005), semantic Language

Table 2.5. Neuropsychological deficits in motor neurone disease (MND).

Attention # Sustained attention; economy of effort, impulsiveness, distractibility

Table 2.6. Neuropsychological deficits in dementia with Lewy bodies (DLB).

Attention Prominent deficits: ‘unstable platform of attention’; difficulty establishing attentional

Fluctuating consciousness, clinically distinguish- Memory

functions. There is no aphasia, and naming Executive function

2.4.1 Other (‘atypical’) parkinsonian

The neuropsychological impairments of PDC drome (Brownell–Oppenheimer (ataxic) variant),

2.5.1 Sporadic prion disease: sporadic

Cerebrovascular disease: vascular dementia and

3.1 Cortical vascular dementia, multi-infarct dementia (MID), post-stroke

3.7 Other cerebrovascular disorders 112

REFERENCES Moudgil SS, Azzouz M, Al-Azzaz A, Haut M, Gutmann L.

been noted. An apraxic, alien hand, syndrome has

REFERENCES with the vascular dementias (Reinglass et al., 1977;

3.6.4 Familial young-adult-onset

3.6.5 Familial occipital calcifications,

3.6.12 Spatz–Lindenberg disease 3.7 Other cerebrovascular disorders

4.1 Epilepsy and cognitive impairment 115

4.1 Epilepsy and cognitive impairment (generalized versus partial, or localization-related),

sharply after the age of 60 years. However, the REFERENCES

REFERENCES have long been a topic of research interest

factor, and one that may not be amenable to spe- REFERENCES

5.1 Hereditary dementias 126

5.5.8 Porphyria 155

Table 5.1. Neuropsychological deficits in Huntington’s disease (HD).