Manual

COPYRIGHT INFORMATION
Copyright 2002 by The Academy of Medicine of New Jersey and the New Jersey Department of
Health and Senior Services. All rights reserved. No part of this publication may be reproduced, displayed on a computer system, transmitted, transcribed, stored in a retrieval system, or translated into
any language or computer language, in any form or by any means, electronic, mechanical, magnetic,
optical, chemical, manual or otherwise, without the prior written consent of The Academy of Medicine
of New Jersey and the New Jersey Department of Health and Senior Services.
Requests should be submitted to:
The Academy of Medicine of New Jersey
Director of Research and Education
Two Princess Road, Suite 101
Lawrenceville, NJ 08648
ACKNOWLEDGMENTS
The editors gratefully acknowledge New Jersey Senators Norman M. Robertson and Diane Allen,
and Assemblymen Gerald H. Zecker and Kenneth C. LeFevre, who sponsored legislation that enabled
the New Jersey Department of Health and Senior Services to provide the educational grant to the
Academy of Medicine of New Jersey to support the publication of this document.
The editors and authors of this CFS manual gratefully acknowledge the advocacy and support of
the New Jersey Chronic Fatigue Syndrome Association, Inc., and, in particular, the extraordinary determination and vision of Jonathan Sterling, Chairman of the Board of Directors of the CFIDS Association of America, Inc., and Mary Ellen McNamara, Vice President and Director of Research, New
Jersey CFS Association, Inc. Each of the authors has been inspired by the fortitude of our patients as
they confront the difficulty of living with a chronic illness whose cause and cure have yet to be defined.
The following individuals provided invaluable support in the coordination, editing, design, layout,
and publication of this document:
Sondra L. Moylan, RN, MS
Former Director of Research and Education
The Academy of Medicine of New Jersey
Edward J. Moylan, RPh

Consultant
Elizabeth B. Congdon, RN, MA

New Jersey Department of Health and
Senior Services
Lorraine T. Steefel, RN, MA, MSN

Consultant, Medical Writer
Finally, the editors, staff, and panel are indebted to Anthony Komaroff, MD, Professor of Medicine, Harvard Medical School, Brigham & Women's Hospital, and Editor-in-Chief, Harvard Health
Publications, Boston, for reviewing the final draft, making important observations to improve it, and
offering suggestions that will enhance future updates of this manual.
March, 2002
MEMBERS OF THE WRITING COMMITTEE AND CONSULTING ADVISORS
Richard L. Bruno, MD, PhD

Director, The Post Polio Institute and
Fatigue Management Program
Englewood Hospital and Medical Center
Englewood, New Jersey
Barbara B. Comerford, Esq.
Law Office of Barbara B. Comerford
Ridgewood, New Jersey
Terri Lynn Evans, RN
Consultant
Port Republic, New Jersey
Kenneth J. Friedman, PhD
Associate Professor of Pharmacology
and Physiology
UMDNJ-New Jersey Medical School
Newark, New Jersey
Paul J. Goodnick, MD
Professor of Psychiatry and Behavioral
Sciences
University of Miami
Miami, Florida
Carolyn Grace, PhD
Licensed Psychologist
Assistant Professor of Neurology
Department of Neurology
UMDNJ-Robert Wood Johnson Medical
School
New Brunswick, New Jersey
Joseph F. John, Jr., MD, Editor
Professor of Medicine, Molecular Genetics and Microbiology
Division of Allergy, Immunology & Infectious Disease
Department of Medicine
School
Kenneth R. Kaufman, MD, MRCPsyc

Associate Professor of Psychiatry and
Neurology
School
Richard N. Podell, MD
Clinical Professor of Family Medicine
Department of Family Medicine
School
Susan M. Levine, MD
Infectious Disease Specialist
New York, New York
Kenneth Rubin, MD
Chief of Gastroenterology
Jeffrey P. Levine, MD, MPH

Assistant Professor
Departments of Family Medicine, Obstetrics, Gynecology and Reproductive
Sciences
Director, Womens Health and Obstetrics Fellowship Programs
School
Alan Lichtbroun, MD
Clinical Assistant Professor
School
Mary Ellen McNamara, MBA, APC
Vice President and Director of Research
New Jersey CFS Association, Inc.
Chatham, New Jersey
James M. Oleske, MD, MPH, Associate Editor
Francis-Xavier Bagnoud Professor of
Pediatrics
Director, Division of Pulmonary, Allergy, Immunology & Infectious Diseases
Department of Pediatrics
UMDNJ-New Jersey Medical School
Newark, New Jersey
Donna L. Palumbo, LCSW
Consultant
Eatontown, New Jersey

Nurse Consultant
Medical Writer
Morganville, New Jersey
Jonathan Sterling, MA, ACAS
Chairman of the Board of Directors,
CFIDS Association of America, Inc.
Treasurer, NJCFS Association, Inc.
Member, US Department of Health &
Human Services, CFS Coordinating
Committee
Chatham, New Jersey
Julian M. Stewart, MD, PhD
Professor of Pediatrics
Research Professor of Physiology
Director, Center for Pediatric Hypertension
New York Medical College
New Rochelle, New York
Rosemary Underhill, MB, BS,
MRCOG (UK)
Consultant
Upper Saddle River, New Jersey
Jerald R. Zimmerman, MD
Chief, Department of Rehabilitation
Medicine
ii
A Consensus Manual for the Primary Care and

Management of Chronic Fatigue Syndrome
Foreword ............................................................................................................................. 1
1
Pathophysiology in CFS .............................................................................................. 3
Initiating Care of Patients with CFS ............................................................................ 9
Infections in CFS ........................................................................................................ 13
Depression in CFS...................................................................................................... 17
Cognitive Dysfunction in CFS ................................................................................... 23
Sleep Dysfunction in CFS .......................................................................................... 25
Dizziness in CFS......................................................................................................... 29
Pain in CFS.................................................................................................................. 35
Womens Health in CFS ............................................................................................. 43
10
Gastrointestinal Symptoms in CFS........................................................................ 49
11
CFS in Children and Adolescents .......................................................................... 51
12
Behavioral Rehabilitation for CFS.......................................................................... 57
13
Disability in CFS ...................................................................................................... 61
Glossary of Selected Acronyms...................................................................................... 65

References ........................................................................................................................ 67
iii
iv
Foreword
preciate the pathophysiology, differential diagnosis, and

therapeutic opportunities in patients with CFS. The extensive bibliography will allow the interested caregiver to
delve deeply into one of the most fascinating and complex maladies of modern medicine.
We want to thank first the State of New Jersey for
its decision to support the creation of this Consensus
Manual and to make it widely available. We thank the
New Jersey Chronic Fatigue Syndrome Association, Inc.
for its tireless support, in particular, Jon Sterling of that
group, who always gives us hope and makes us better
physicians. We thank the Academy of Medicine for its
management of the project, in particular Sondra and Edward Moylan for going beyond the call of duty to get the
project completed and, with great admiration, Lorraine
Steefel for her insightful transcription of the manual.
Most of all, we thank all our patients with CFS for
their faith and trust in us, that we can improve their lives
now and eventually conquer this dreadful disease. To
them we dedicate this manual.
he illness called Chronic Fatigue Syndrome (CFS)

plagues thousands, perhaps millions of people in the
US. It is hard to think of a worse malady, one that can
voraciously rob the patient of energy, cognition, sleep,
immune function, and a sense of well-being. That physicians are reluctant to assume care of such challenging,
distraught patients is understandable. Yet, we know that
competent management of these patients can be productive and rewarding for patient and physician alike.
The genesis of this manual begins with efforts by the
New Jersey Chronic Fatigue Association in conjunction
with the New Jersey Department of Health and Senior
Services to bring to the primary care physician a manual
that could facilitate and enhance the care of patients with
CFS. We have assembled a diverse group of experts in
the field of CFS and asked them to focus on the symptomatology of the disease (pain, dizziness, depression, brain
fog) and to deliver a product that would be helpful to the
primary care physician and specialist alike.
The stigma associated with having CFS and also
with caring for patients with CFS defies explanation. So,
we have attempted to destigmatize the primary care of
patients with CFS and to outline the range of therapies
across medical disciplines that can improve the lives of
these patients. These thirteen chapters are intended so that
the primary care physician, and specialist alike, can ap-
Joseph F. John, Jr., MD, Editor

James M. Oleske, MD, MPH, Associate Editor
Pathophysiology in CFS
Kenneth J. Friedman, PhD
successful description of the pathophysiology of

CFS must explain the mechanism(s) for all of its
symptoms. Based upon the current (U.S.) case definition
of CFS,1 the pathophysiology needs to account for impaired memory loss and the presence of a sore throat,
tender neck (cervical) or armpit (axillary) lymph nodes,
muscle pain (myalgia), headache, unrefreshing sleep,
post-exertional malaise lasting more than 24 hours, and
multi-joint pain (arthralgia) without swelling or redness.
While all these symptoms need not be present in any one
case of CFS, all are associated with the syndrome. At this
time, there is no one mechanism known which can produce all the symptoms or the variability of symptoms
found in patients with CFS.
This review will provide an assessment of what is
currently known about the pathophysiology of CFS. Not
all symptoms of CFS will be discussed, only those which
have been linked to its pathophysiology. Other symptoms
of CFS will be discussed in subsequent chapters.
Table 1-1
Conditions Associated with Profound or Chronic
Fatigue
AIDS
Anemia
Anxiety
Cancer
Chronic fatigue syndrome
Chronic obstructive pulmonary
disease
Diabetes mellitus
Syndrome X
Endocrinological imbalance
(e.g. adrenocortical insufficiency,
hypercortisolism, hypothyroidism)
Heart failure
Lyme disease
Malnutrition
Myasthenia gravis
Neuropathy
Renal failure
Sleep disorders
Multiple sclerosis
Systemic infection
(bacterial or viral)
Lupus erythematosis/
Collagen vascular syndromes
Mitrochondrial dysfunction
Valvular heart disease
Mechanism of Fatigue
The mechanism of physiological fatigue is not well understood. It is assumed to result from an imbalance at the
cellular or molecular level between the need for nutrients
and their actual supply and/or an imbalance between the
accumulation of waste product(s) and the need for waste
product removal. The lack of adequate nutrients or an
excess of waste products at the cellular level leads to
physiological fatigue.
Pathophysiologic Fatigue
To some extent, all of us have experienced fatigue: a
lessened capacity to perform work, accompanied by a
feeling of exhaustion and the desire to rest or sleep. It is
difficult, if not impossible, to quantify the amount of fatigue that a known amount of work or degree of stress
should produce in any given individual. One reason is the
dependence of fatigue upon personal factors. The welltrained athlete will experience less fatigue running a mile
than a sedentary individual. A second reason is the decline of physical prowess with age. These are but two
examples of personal factors that affect the magnitude of
fatigue experienced subsequent to a given activity.
A number of illnesses are known to produce disproportionately large amounts of persistent fatigue, which we
shall term pathophysiologic fatigue. Such illnesses include, but are not limited to, those listed in Table 1-1.
In addition, administration of certain drugs (particularly antihypertensives), cancer chemotherapy and
surgery produce chronic fatigue. Recently, it has been
proposed2 that CFS and Syndrome X have identical
clinical symptoms and may have a common pathology:
abnormal ion channel function.
Since the diagnosis of CFS is one of exclusion,
other known causes of pathologic fatigue should be excluded prior to the conclusion that the patient is suffering
from CFS. However, symptoms of CFS overlap with
other unexplained clinical conditions.3
The physiologists view of fatigue

Fatigue must arise in one or more of the bodys organ systems. The perception of fatigue is a function of the
central nervous system, which usually relies upon incoming information from the neuromuscular system.
Hence, a simplistic model would postulate that the perception of fatigue arises from consequences in either the
neuromuscular and/or the central nervous system. Perhaps
the perception of fatigue is similar to that of hunger:
physiological mechanisms in the gut (and elsewhere)
contribute to the perception of hunger, but over-riding
emotional stress can prevent an individual from perceiving hunger.
The Site of Fatigue in Chronic Fatigue
No muscle defect found to date
It is reasonable to postulate that the muscular fatigue
exhibited by patients with CFS arises from an abnormality
in affected muscle. The abnormality might be a biochemical or mechanical abnormality in the contractile apparatus, the muscles mitochondria (which supply energy for
muscle contraction), the failure of impulse transmission
from nerve to muscle, or hyperexcitability of sensory afferents from muscle to the central nervous system. There
have been several reports from one laboratory of altered

mitochondrial morphology in the skeletal muscle of patients with CFS4-6 and one report suggesting that CFS may
be related to a carnitine deficiency.7 (Carnitine plays a
role in mitochondrial energy production). Confirming
studies have been lacking.
and poliomyelitis are associated with chronic fatigue suggesting a link between reduced blood flow in the hindbrain and the perception of chronic fatigue. Preliminary
Positron Emission Spectroscopy (PET) studies suggest
hypometabolism in the brain stem, as well as the right
mediofrontal cortex.12
Chaudhuri2 has put forward the suggestion that abnormal ion channel activity in excitable membranes may
be responsible for CFS symptoms, since it is known that
channelopathies have been found to produce an array of
symptoms in several pathologic conditions. Fluctuating
symptoms, inducible by physical or mental stress, are
found in disorders associated with channelopathies (including hypokalemic periodic paralysis, episodic ataxia
type 2, neuromyotonia, myasthenic syndromes, multiple
sclerosis and inflammatory demyelinating polyneuropathies). SPECT scans of patients with CFS are similar to
those seen for Syndrome X patients a known channelopathy. Further, exposure to specific toxins known to
produce abnormal sodium channels may precipitate CFS.
Fatigue at the neuromuscular junction

There are few, if any, well-documented studies of
fatigue in humans or other intact animal models. However, fatigue has been studied in isolated neuromuscular
preparations designed to elucidate the mechanisms of
synaptic transmission and the consequences of delivering
rapid and repeated stimuli to a muscle fiber. Such studies
provide a basic understanding of neuromuscular fatigue,
but do not provide an understanding of the perception of
fatigue by an intact organism.8 Additional studies have
been done on vertebrate muscles and the nerves which
innervate them. Such studies reveal vertebrate muscles
are composed of many motor units, and when a task requires more muscle, additional motor units within that
muscle are recruited to contract and hence accomplish the
task. It is not difficult to imagine that the delivery of multiple nerve stimuli or the use of additional motor units to
accomplish a task would involve more metabolic energy
than usual and would be perceived as fatigue.
Pain - The Second Hallmark of CFS

Pain is another hallmark of CFS that may appear as
abdominal, joint, lymph node, muscle, and/or sore throat
pain, and/or headache. Many patients describe CFS as an
everything hurts syndrome, and to the frustration of both
patient and physician, the latter can find nothing wrong.13
From the physiological perspective, pain is caused
by the activation of nociceptors (pain receptors) in peripheral tissues by excessive mechanical or chemical
stimuli, or heat. Such stimuli depolarize the membranes
of nociceptors which in turn gives rise to action potentials. These action potentials are conducted to the central
nervous system along finely myelinated (A-delta) and
non-myelinated (C) afferent fibers. Nociceptors have
been found in cutaneous tissue, subcutaneous tissue and
visceral organs. These afferents excite neurons in the spinal cord which relay the impulses to the brain. Whereas
most receptors become less responsive when repeatedly
activated, it has been postulated that nociceptors become
sensitized by repeated noxious stimuli: subsequent innocuous stimuli may result in action potentials and pain.14
Animal studies and recent imaging studies of the awake
human brain indicate that the nociceptive afferent activity
can be modified by both endogenous and exogenous factors at the level of the spinal cord and the brain.15, 16
One possibility of the origin of CFS pain is that old
injuries may hurt anew, which suggests that the pain in
CFS is associated with a condition of primary hyperalgesia. But primary hyperalgesia is associated with tissue
damag, an injury, a disease, or inflammation that causes
the release of one or more algesic substances into the extracellular space. Known examples of algesic substances
include H+, K+, serotonin, histamine, one or more of the
prostaglandins, bradykinin, and substance P. These sub-
Altered electrical activity in neural networks

The synaptic fatigue documented to occur at the
neuromuscular junction is believed to occur at nervenerve synapses including those within the human brain.
Extending the synaptic fatigue model, activities that induce greater than normal electrical activity within the
brain could generate synaptic fatigue within its neural
networks and possibly be the source of the fatigue that
patients with CFS describe as brain fog and other cognitive difficulties associated with CFS. There is some
evidence to suggest that greater-than-normal electrical
activity (at particular sites) may be responsible for the
patients heightened perception of pain: quantitative
measurements demonstrate that stimuli that are not painful in healthy subjects are perceived as painful in patients
with CFS. It appears as if patients with CFS have an abnormal stimulus perception amplifier (within the CNS).
Brain scans reveal differences in metabolic activity
between patients with CFS and controls suggesting brain
involvement in the abnormal perceptions of patients with
CFS. Magnetic Resonance Imaging (MRI) has shown
differences in both the brain stem and subcortical areas of
patients with CFS when compared to control subjects.9
Single Photon Emission Computed Tomography
(SPECT) studies suggest reduced blood flow in patients
with CFS in the area of the hindbrain. Similar findings
have been reported for both multiple sclerosis and poliomyelitis patients.10, 11 Interestingly, both multiple sclerosis
hibitory fibers cannot only influence the perception of

received impulses, but can also modulate the ascending
input from dorsal horn cells. In recent years, four distinct
inhibitory descending systems have been identified,17 that
selectively inhibit nociceptor neurons via serotonergic
and monoaminergic (nor-epinephrine releasing) mechanisms. If the serotonin in neurons of the spinal cord or
medulla is depleted, the analgesic action of the central
nervous systems endogenous opioids (discussed below)
is blocked. Interestingly, abnormal serotonin metabolism
has been found in patients with FMS, a syndrome with
symptoms overlapping those of CFS.19-21 Norepinephrine-containing fibers also appear necessary for
opiate-induced analgesia22, 23 and mediate dorsal horn
inhibition. Both the serotonergic and monoaminergic neurons distribute widely, suggesting that these neurons have
multi-target effects, which might include modulation of
the response of spinal cord cells to incoming sensory information. Although unproven at this time, such pathways
and mechanisms could heighten the perception of pain to
incoming sensory information.
A final (fifth) possibility is the involvement of the
central nervous systems (the brains and spinal cords)
own intrinsic opioid system in the abnormal perception of
pain in CFS. Three classes of opioids are currently recognized (the enkephalins, the dynorphins, and endorphins) as being part of this system. Each class is a distinct
group of peptides, each having a distinct anatomic distribution. Enkephalins have a wide distribution throughout
the central nervous system, but are found in regions believed to contribute to pain control, including dorsal horn
cells of the spinal cord. Injection of dynorphin has been
found to produce analgesia and dynorphin-containing
cells have been found in the hypothalamus, reticular formation, and spinal and medullary dorsal horns.24 Neurons
containing the precursor of -endorphin are concentrated
in the hypothalamus and, if the hypothalamus is cut, certain forms of stress-induced analgesia are lost, which suggests that pituitary endorphins contribute to pain control.
Despite the anatomic appearance of the nervous
systems being a hard-wired system, physiological studies
suggest additional controls and complexities at every
level of the pain perception-pain reaction pathway. A
single neuron may be influenced by more than one neurotransmitter and the effect of different neurotransmitters
on that neuron can be different.
stances act on the membranes of pain-sensing neurons

(the nociceptors) producing primary hyperalgesia or alter
microcirculation. Often accompanying primary hyperalgesia is an increase in the area sensitive to pain, a phenomenon described as secondary hyperalgesia. The
mechanism of secondary hyperalgesia is believed to be
similar to that of primary hyperalgesia,17 involving the
release of endogenous agents. Alterations in some of the
concentrations of these substances have been found in
patients with CFS, but tissue damage has not been found.
Thus, while it may be attractive to postulate that the large,
painful areas found in patients with CFS are due to a
combination of primary and secondary hyperalgesia, it
must be remembered that the abnormal and/or excessive
production of algesics is a possible, but though yet unproven, mechanism of pain in CFS.
A second possibility as to the nature of CFS pain
comes from the description patients with CFS give for
their pain. Patients with CFS who have generalized pain
and hyperalgesia describe their pain as originating in their
musculature, being continuous even at rest, and being
generalized in all four body quadrants.18 The pain is
described as diminishing with moderate exercise, but becomes worse after exercise. The hyperalgesia found in
these patients is found at many locations and is chronic
(overlapping the type of pain syndrome found in Fibromyalgia Syndrome, (FMS). Tender points are found on
both the upper and lower body. Such symptoms suggest a
nociceptive disturbance in the central nervous system,
rather than in a particular muscle or particular group of
muscles. However, a particular muscle or a particular
group of muscles may play an essential role in generating
and maintaining the central nociceptive disturbance.
This description suggests an as yet unproven possible mechanism for the chronic pain of CFS: nociceptor
sensitization, or an increased sensitivity of nociceptors, to
stimulation. While most sensory organs become fatigued
with repeated stimulation, it has been shown that polymodal C fibers display enhanced sensitivity and lowered
thresholds to stimulation with repeated stimulation.17
A third possibility is that the abnormal pain experienced by patients with CFS might be generated at sites
other than the nociceptors. Other sites include the spinal
cord and the brain. Nociceptor activity results in a generalized activation of myelinated A-delta and nonmyelinated C fibers that project either to the dorsal horn
of the spinal cord or to the medulla. In these latter two
structures, other substances (such as substance P or calcitonin-gene-related peptide) and other neurotransmitters
(excitatory amino acids, for example) may modulate the
impulses conveying the perception of pain to the brain.
A fourth possibility is that once received in the
brain, impulses conveying the perception of pain may be
altered by emotions and motivation through corticofugal
and subcortical descending influences. Descending in-
Endocrine-HPA Involvement
The CFS symptoms of fatigue, myalgia, and sleep
disturbances are also found in patients having adrenal
insufficiency. Therefore, it is suspected that CFS has an
endocrine component. While there is no evidence documenting an endocrine origin of CFS, there is evidence
suggesting endocrine- or at least HPA-involvement in
CFS. The components of the hypothalamic-pituitary-
Thus, part of the challenge in determining the etiology of CFS is to distinguish between those physiological
changes that are a direct consequence of the syndromeprecipitating factor(s) and those changes that are the
bodys adaptation to the precipitating factor(s).
adrenal (HPA) axis, consisting of the hypothalamus, anterior pituitary, and the cortex of the adrenal gland are inter-related by a series of biochemical events known to
regulate the mammalian response to stress. In addition,
the HPA exhibits a circadian rhythm entrained to the
sleep/wake cycle.25 In healthy individuals, physical or
emotional stress activates the HPA, causing an increased release of cortisol and other hormones. Since
many patients with CFS report that physical and/or emotional stress precipitated their illness, it is tempting to
postulate that such patients become ill (at least in part)
because of an inability to activate an adequate HPA response to the stressor. A reduction in HPA activity has
been reported for patients with CFS.26, 27 Reduced levels
of basal evening glucocorticoids and decreased cortisol
excretion were found by Demitrack.26 These data have
been interpreted as suggesting a central nervous system
defect as a factor in CFS,25 and the thesis is supported by
a previous report of reduced cortisol levels (one of the
biochemical markers of HPA dysfunction) in chronic and
acute pain states.28 However, the question has been raised
as to whether this altered HPA activity is a consequence
of the syndrome itself or of the change in sleep patterns
associated with it.25, 29
Patients with CFS have been shown to have a reduced capacity for aerobic exercise,30, 31 but so do healthy
men after 3 weeks of bed rest.32 Indeed, some of the parameters found abnormal in patients with CFS are similar
to those found in deconditioned subjects who sleep less
well than fit subjects,33 and both patients with CFS and
deconditioned subjects respond favorably to physical
training.34
It is also known that cortisol and corticotrophinreleasing hormone (CRH) are produced during HPA activation. Both cortisol and CRH influence the immune and
other body system(s). Since cortisol suppresses inflammation and cellular immune activation, it is not difficult
to imagine the consequences of reduced cortisol levels.
Cortisol levels are low but still within the normal range in
patients with CFS. It is not known if elevation of cortisol
levels as a treatment for patients with CFS would be
therapeutic. Since cortisol levels are within the normal
range in patients with CFS, it cannot be used as a diagnostic marker for CFS.
An additional two arguments (articulated by25 supporting HPA involvement in CFS) are: (1) the observation of the resemblance of CFS symptoms to those of patients with glucocorticoid deficiency: debilitating fatigue,
and, in response to stress, the acute onset of arthralgias,
myalgias, fever, post-exertional fatigue, heightened allergic responses and disturbed mood and sleep, and (2) animal studies, which indicate that CRH induces signs of
physiological and behavioral arousal. Possibly, reduced
levels of CRH contribute to lethargy.
Involvement of Other Organ Systems

CFS affects a number of other organ systems: the
immune, cardiovascular, and gastrointestinal. In addition,
cognitive function is frequently impaired. Cognitive dysfunction suggests brain (CNS) involvement in CFS. Reviews of current knowledge of the pathophysiology of
these systems appear in other chapters of this manual.
The pathophysiology of immune system dysfunction

associated with CFS is discussed in Chapter 3.
The cardiovascular pathophysiology associated with
CFS is discussed in Chapter 7.
The pathophysiology of Irritable Bowel Syndrome,
the gastrointestinal disorder most often endured by
patients with CFS, is discussed in Chapter 10.
The documentation of the occurrence of cognitive
dysfunction in CFS, and a discussion as to whether it
is a primary symptom of CFS, or secondary to CFSinduced sleep deprivation, are presented in Chapter
5.
Epidemiology: Gender, Genetics, and the Environment

The epidemiology of CFS seems to be unclear, if
not unusual, in three areas: (1) it affects mostly women,
(2) the probability of exhibiting CFS may be genetically
transmitted from parent(s) to child, and (3) while outbreaks of CFS have been documented (in which CFS has
been found within communities), it infrequently seems to
be passed among family members. Any proposal of a
pathophysiological mechanism underlying CFS will need
to account for these unusual epidemiological observations.
The gender selectivity of known diseases and its implications for the pathophysiology of CFS are further
discussed in Chapter 9 of this manual.
The findings of inherited tendency for CFS and the
occurrence of outbreaks of CFS raise questions of
heredity vs. environment as factors in the transmission or precipitation of CFS. The implications of
these findings for the pathophysiology of CFS are
also presented in Chapter 3 of this manual.
Conclusion
A review of the current CFS literature indicates that
CFS is associated with alterations in the physiology of
many organ systems. CFS exhibits considerable overlap
might be involved. Unfortunately, there is no definitive

evidence for these mechanisms. Brain imaging techniques, however, reveal differences between normal subjects and CFS subjects. These differences might prove to
be indicative of abnormal pain-perception amplification
within the CNS.
Many of the symptoms endured by patients with
CFS, such as fatigue, myalgia, and sleep disturbances, are
found in patients having adrenal insufficiency. Therefore,
the possibility of CFS having an endocrine component
exists. There is no evidence documenting an endocrine
origin to CFS,q but there is evidence to suggest endocrine
involvement in CFS: A reduced level of hypothalamic/pituitary/adrenal (HPA) axis activity has been reported.
CFS affects a number of other organ systems and/or
functions. Patients with CFS often suffer with abnormal
cardiovascular reflexes, irritable bowel syndrome, and
cognitive dysfunction. The pathophysiologies of these
conditions, as they relate to CFS, are discussed in other
chapters of this manual.
Finally, an understanding of the epidemiology of
CFS should yield clues as to its pathophysiology. The
similarities between the symptoms of viral infection (particularly HHV-6, EBV, CMV, and poliomyelitis), viral
fatigue, and CFS cannot be ignored and are, therefore,
addressed in Chapter 12 of this manual. Additional clues
to the pathophysiology of CFS will come from better understanding of the preponderance of patients with CFS
being female and the resolution of the roles genetics vs.
environment have in predisposing patients to this syndrome.
.
with two other syndromes: FMS and Gulf War Illness.

The overlap of symptoms between CFS and these other
two syndromes, as well as findings of pathophysiological
changes associated with the latter two syndromes, mollifies assertions that CFS is a psychological disorder.
CFS presents a unique mosaic of symptoms that
cannot be explained by any single, known mechanism of
disease. If CFS is caused by a single mechanism, that
mechanism must be a broad-based mechanism - affecting
multiple organ systems. Perhaps a cellular membrane
defect, such as a channelopathy, will be found (as has
been proposed by Chaudhuri2 with the additional caveat
of targeting the specific tissues affected by CFS.
As the name implies, CFS is predominantly associated with overwhelming fatigue. That fatigue is perceived
as being muscular in origin. To date, no evidence of an
associated pathophysiology of muscle or of the nervemuscle junction has been found. The lack of evidence for
muscle pathophysiologys being responsible for the fatigue of CFS has led investigators to explore the possibility of the fatigues being a perception of fatigue within
the central nervous system (CNS).
The second hallmark of CFS is pain. The pathophysiology of pain generation in patients with CFS is not
understood. Hyperalgesia, the pain associated with tissue
damage, does not appear to be the likely mechanism of
pain in CFS, since tissue damage has not been found.
Increased sensitivity of pain receptors (nociceptors) has
been proposed,17 but not shown, in patients with CFS.
Such negative findings have led to the proposal of CNS
and brain involvement in the generation of pain in CFS.
Serotonin and monoamine pathways are suspected of being involved. In addition, the brains own opioid system
(consisting of enkephalins, dynorphins and endorphins)
Initiating Care of Patients with CFS

Susan M. Levine, MD
Joseph F. John, Jr., MD
The physician may act as a facilitator during the patients narrative account by incorporating a checklist such
as the one in Table 2-1.
his chapter introduces the primary care physician to

the unique, and challenging aspects of evaluating
patients who present with a large array of baffling
symptoms that are part of CFS, a condition whose cause
is unknown and whose treatment strategies are limited.
Patients greatly appreciate the provider who is knowledgeable about CFS; who takes an interest in listening
to their symptoms; who treats them with respect, even
without being able to offer a solution; and who can
guide them in supportive care for their chronic illness.
The first interaction between patient and provider
is often over the phone. The pleasant, informative receptionist who may provide a brief synopsis of the
doctors approach to treating CFS and related conditions may put the patient at ease and make him or her
actually look forward to the first encounter with the
physician. At this time, the receptionist should have the
patient forward pertinent medical records in advance of
the first visit; in addition, a standard health questionnaire, such as the SCL-90-R Symptom Checklist 90-R
or the SF-36 Health Status Survey, may be forwarded
to the patient to complete.
Table 2-1
Symptom Checklist for Initial CFS Interview*
History
On arriving at the office, the patient may desire
pamphlets, brochures, journals, and other reading materials relating to CFS. Announcements from support
groups that discuss important issues or feature patient
advocacy may also be available. While patients are
completing the usual intake form listing demographic
information, they may be asked to write at least three
important questions prior to seeing the doctor.
At the start of the interview process, it is helpful to
know something about the patients concerns. Often,
patients with CFS are seeking confirmation of their diagnosis. At other times, they may want to try certain
treatments, or they may need help filling out disability
forms. It is useful to focus patients on symptoms and
possible ways to cope with their disorder rather than
have patients spend their time completing paperwork.
After the introduction is complete, it may be easiest to begin the interview with an open-ended question
or observation: I see you have been diagnosed with
CFS... or Tell me what this illness has been like for
you.... Acting as non-judgmentally as possible from the
beginning sets the tone for the entire interview.
Sore throat
Painful cervical or axillary lymph nodes
Unexplained generalized muscle weakness
Prolonged (>24 hrs.) generalized fatigue
Generalized headaches
Migratory painful joints without swelling or redness
Areas of lost or depressed vision
Visual intolerance of light
Forgetfulness
Excessive irritability
Confusion
Difficulty thinking
Inability to concentrate
Depression
Non-refreshing sleep
*Patients can grade symptoms as mild, moderate, severe,

or absent.
The symptom checklist, the narrative, and the patient
history may include input from the patients companion or
family member participating in the interview. Due to the
extended list of symptoms in CFS, some of which are more
meaningful to the patient than others, the patient may focus
too long on one body system. It is important to move the
interview along without seeming uncaring, while reassuring
the patient that you will focus on more specific issues later
or during a follow-up encounter. It is important to question
the patient about the key points in the case definition for
CFS, in order to obtain some sense of the patients attitude
toward these symptoms. What may begin as an information
gathering session can also reveal something about the patients ability to cope with the myriad symptoms in CFS.
Also important to note is the degree of emotional support the patient receives from friends or relatives, as in the
process of the workup. As an invisible illness, CFS has its
share of liabilities, since the patient looks relatively well.
Therefore, the patients symptoms may inadvertently be
dismissed as trivial. From the first encounter with the pa-
perform vital signs and note them in the chart. Occasionally, if the patient reports tachycardia or a racing heart after
standing for a while, proceed to ask the patient to stand still
for 5 or 10 minutes while the pulse is measured. It is important to focus on the color of the pharynx, especially if
the patient reports a sore throat, and to determine whether
exudate is present for culture. A frequent sign in CFS is a
red crescent formed by inflamed anterior tonsillar pillars.
The physician should determine the presence of tender or
enlarged lymph nodes, as often present in the anterior cervical chain, noting their size, consistency, and location
(cervical, submental, and axillary).
At this junction, palpate the point of maximal impulse
to assess heart size; listen to the pulse for a full minute; and
try to discern a mid-systolic click characteristic of mitral
valve prolapse, common in patients with CFS. If the patient
has reported low grade fevers, ask that a temperature log be
kept. The scalp should be palpated and examined for areas
of alopecia, which can be seen in certain autoimmune disorders. The buccal mucosa should be examined for evidence of oral ulcers or canker sores, as well as the gums
and general condition of the teeth. The maxillary, ethmoid,
and sphenoid sinuses should be palpated to try to determine
the presence of acute versus chronic sinusitis, which can be
seen in patients with CFS. The thyroid gland should be
carefully palpated for its size and for the presence of nodules. Many patients present with serological evidence of
tient with CFS, it is important to convey a belief in the

credibility and severity of the patients clinical complaints.
At times, it is helpful to quantify the impact of
certain key symptoms, such as fatigue and muscle pain,
on routine aspects of daily life, such as cooking, cleaning, and shopping. A description of a typical day or a
month-long log of graded symptoms can be very illustrative for patients physicians. Patients can also be
asked to chart an overall sense of well-being on a 1-10
or 1-100 scale. (See Figure 2-1).
Near the end of the patients narrative, it may be
helpful to ask what therapeutic interventions, if any,
have been tried and to learn what their impact has been
on the underlying condition. This information helps to
discern whether a patient is averse to certain treatments
based on negative past experiences. The physician may
want to inquire as to where the patient acquired information about his condition, i.e., through the Internet, via
patient support groups, or by asking questions of other
medical professionals.
Physical Examination
At the onset of the physical examination, sometimes patients who are especially ill or who have traveled a long way will ask to lie down. The nurse may
Figure 2-1
D aily Patient L o g o f G rad ed Sym p to m s
T em perature
101.8
101.6
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100.8
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99.8
99.6
99.4
99.2
99.0
98.8
98.6
98.4
98.2
10
9
8
Headache
Nausea
Diarrhea
Stomach virus Fever blisters
6
5
4
3
2
Date
10
5/1
4
5/1
2
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0
5/8
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4/1
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4/1
0
Stamina
Temperature
S tam ina
autoimmune thyroiditis, but with perfectly normal thyroid function.

The chest and lung examination is conducted in
the usual manner. The patients skin should be examined for evidence of more commonplace skin conditions, such as eczema; telangiectasias and livedo reticularis, commonly found in chronic liver disease and
connective tissue disorders, respectively; a bulls eye
lesion characteristic of early Lyme disease pervasive in
the specific geographic locations; psoriasis, which is
rarely accompanied by an arthritis that affects the digits;
hypopigmentation, which suggests adrenal insufficiency; and, finally, the characteristic periorbital heliotropic discoloration that may be noted in dermatomyositis, another condition that presents with fatigue and
weakness. Raynauds phenomenon can be asked about,
while examining the patients hands. Nail beds should
be assessed for clubbing, which can be seen in chronic
smokers or patients with obstructive lung disease, another condition associated with chronic fatigue.
The abdominal examination is also rather routine,
but the physician should palpate the spleen, which can
be enlarged and tender, particularly during the acute
stages of mononucleosis. The liver span may be mildly
enlarged in chronic active hepatitis B or in the early
stages of hepatitis C infection.
The musculoskeletal examination should be conducted carefully and should focus on searching for areas
of joint swelling, which can be seen in either active lupus or other connective tissue diseases; gout; and infectious arthritis, such as gonococcal or those secondary to
Lyme disease, in which the skin overlying the joint may
also be warm and tender. Trigger points can be checked
in the typical locations, such as the occiput, the midtrapezius and lateral trochanters, but patients with CFS
often have multiple tender muscle groups as seen in
classic FMS. On the other hand, tenderness over proximal muscle groups in particular may be noted in polymyositis and in those patients on statins for control of
hyperlipidemia. The temporal artery should be palpated
gently to exclude the possibility of polymyalgia rheumatica, particularly in the elderly patient who complains
of unilateral visual deficits.
The neurologic examination is also of key importance and should be performed carefully on every patient. The physician should note the patients mental
status; assess his or her expression (flat or anxious affect); quality, quantity, and organization of speech; and
appropriate changes in facial expression. Cranial nerves
are tested (7th N. palsy noted in Lyme disease and herpes-related neuropathy). Then, a sensory examination
and motor examination should follow. Cerebellar function can be limited to rapid alternating hand movements, heel-to-shin, finger-to-nose, and gait. The bulk
and tone of the major muscle groups should be assessed
to determine the patients level, if any, of deconditioning.

Deep tendon reflexes are next and should be intact unless
there is cortical or spinal cord pathology. Mental status,
which is the area most often abnormal, should be evauated
last, with care including serial 7s, short-term memory, and
long-term memory
Occasionally, if it is apparent that the patient is clinically depressed by his affect or by remarks that are made
during the history, it is useful to perform a Beck Depression
Inventory, which may form a baseline prior to embarking
on treatment.
Laboratories
The following tests are important to perform at some
point in the workup: CBC with differential; chemistry profile; an early morning or spot serum cortisol level; hepatitis
B and C serology; TSH; ANA; RPR; and Lyme serology. If
tuberculosis is suspected, a PPD should be placed along
with an anergy panel. A blood test to determine the presence of an RNA low molecular weight protein, which has
been reported more commonly among patients with CFS,
may be ordered at the physicians discretion.
It may be helpful to question the patients about the
possibility of vasovagal syncope suggested by reports of
flushing, palpitations or an inability to stand for long periods of time, especially exacerbated by a warm environment.
Findings from tilt table testing can support the diagnosis of
CFS (See Chapter 7). Some patients may consider tilt table
testing too traumatic and precipitant of symptoms. Yet,
vasovagal syncope is potentially treatable and may afford
the patient some relief from his fatiguing symptoms.
Imaging
Most types of brain imaging procedures performed on
patients with CFS are elective and should not be ordered as
part of an automatic screen. Symptoms which suggest a
possible structural or functional abnormality of the brain,
such as cognitive dysfunction, abnormalities noted on the
neurologic examination or significant complaints of motor
or sensory weakness are appropriate reasons to order an
MRI of the brain to exclude infectious etiologies, such as
CNS involvement with Lyme disease; cerebral vasculitis,
which is rare; and demyelinating lesions associated with
MS. Unidentified bright spots reported by some researchers
on MRIs performed on patients with CFS are uncommon
and not helpful clinically in the patients management.35
Arnold-Chiari malformation, which was reported by one
group of researchers who examined a series of brain MRIs
in patients with CFS has been dismissed after a group of
radiologists failed to concur with these results in a blinded
study.36
Similarly, SPECT scans of the brain, which measure
perfusion of blood to different areas of the brain, and
BEAM scans, which evaluate glucose metabolism, are research tools that have shown some abnormalities, but have
11
a limited clinical role until more research data is accumulated.37-39

Working Diagnosis
At the close of the first visit, after review of the
data generated, in addition to whatever medical records
the patient may have brought, it is helpful to formulate a
working diagnosis. For patients who have already completed exclusionary laboratory work and possibly a psychiatric evaluation, a diagnosis may be evident. The
confirmation by the physician that the patient does indeed have a real illness usually provides an immeasurable amount of relief to the patient. If a diagnosis cannot be made, however, based on the paucity of data, this
fact should also be stated to the patient, with some expectation that physician and patient will work together
until his or her illness is identified.
Following the completion of the history-taking and
physical examination portions of the encounter, the
physician should sit down with the patient and his or her
family to review the findings and plans. Occasionally, at
this point, a working diagnosis is formulated, especially
if the patient has forwarded adequate records for review
and the diagnosis of CFS has already been made by
several specialists. Once the patient meets the CDC
criteria for the diagnosis of CFS and has laboratory results excluding other diagnoses, future management can
be discussed.
If the diagnosis of CFS remains in question, further evaluation will become necessary. More information is warranted at this time. Pamphlets or handouts
about the diagnosis of CFS and how it is substantiated,
in addition to a description of tests, will further educate
patients. Patients appreciate monographs, since it is
often difficult for them to absorb detailed information at
the first meeting.
Discussion of Therapy
The physician should review a variety of therapeutic approaches, mainly those that can help with
symptom relief, such as analgesics, sleep aids, and even
antidepressants. Low doses of certain drugs may help
considerably with sleep disturbances and have been
quite useful in helping relieve some daytime fatigue
(See Chapter 6).
Some patients are already quite familiar with various treatments, many of which have not been validated
in placebo-controlled studies.40 If the patient is already
taking herbal or homeopathic remedies, it is vital to
review each for efficacy or toxicity. Nicotinamide ade-
nine dinucleotide (ENADA) is an example of a relatively

safe over-the-counter medication being investigated in placebo-controlled trials. A six-week trial of this agent is not
unreasonable, but patients should be told that they may see
improvement in a narrow range of symptoms, e.g., cognition.
Ampligen is a double-stranded mismatched RNA immunemodulator with antiviral activity against a variety of
agents-much like interferon. This agent is studied in a placebo-controlled clinical trial at different sites across the
country. It might be well to encourage certain patients to
enroll in this type of study if their diagnosis of CFS is
rather certain at the conclusion of the initial interview.
Disability
If the patient is already out of work or if there are
constant, debilitating symptoms, it may be well to broach
the topic of disability at the first encounter. The patient
should gather the necessary paperwork from the employer.
Careful documentation will be necessary to file for Social
Security disability, due to the elusive nature of CFS (See
Chapter 13). Help from an attorney often benefits disabled
patients with the documentation.
Conclusion
The patient with CFS will appreciate the physician
who is not only knowledgeable about the pathophysiology
of this complex illness, but who also shows empathy and
understanding for the special needs of this population. Often, the first several patient encounters will cement the future relationship with the medical professional; therefore, it
is important to identify any areas of concern.
Arrangements for follow-up appointments or phone
contact should be made so that the patient and doctor can
discuss the results of tests ordered during the first meeting,
decide about disability plans and other lifestyle changes,
and, finally, suggest appropriate treatment modalities. Continuity of care is extremely important for this group of patients due to the chronicity of their disorder and the need to
establish a long-term working relationship with a medical
provider. Many patients want and do seek information on
the Internet. Though much of the public information about
CFS is misleading, there are several excellent websites that
patients will find useful and that they will want to discuss
with their physician. The website of the New Jersey
Chronic Fatigue Syndrome Association (NJCFS) can be
accessed at http://www.njcfsa.org. The website of the
CFIDS (Chronic Fatigue Immune Dysfunction Syndrome)
Association of America, Inc., can be accessed at
http://www.cfids.org.
12
Infections in CFS
Joseph F John, Jr., M.D.
Kenneth Friedman, Ph.D.
workers have reported that certain species of mycoplasma

are associated with precipitating or perpetuating the illness.41
Other evidence for an infectious basis for CFS
hinges on the recent observations that one of the major
antiviral pathways is dysfunctional. Over the last decade,
it has become clear that patients with CFS generate abnormal concentrations of an intracellular enzyme called
RNase L.41, 44, 45 Apparently, activated RNase L serves as
one final arm in a more general antiviral pathway, triggered initially by extracellular interferons. Interferons, in
response to foreign double-stranded DNA, stimulate the
activation of 2-5 adenylate that itself activates RNase L,
an enzyme capable of degrading single-stranded viral
RNA or perhaps other messenger RNA.44, 45 In a sense,
this system works as a nonspecific defense mechanism
before specific humoral (antibody) and other specific
cellular responses take over. It appears that patients with
CFS tend to fragment the functional large molecular
weight RNase L (80 Kda) and produce instead a dysfunctional, low molecular weight RNase L (37 Kda).
any patients with CFS complain of fever, sore

throat, and lymph node swelling and tenderness.
Since these symptoms are highly suggestive of microbial
disease, many physicians approach patients with CFS, at
least in the initial stages, as though infection is a central
mechanism or trigger. It is clear that at least 50% of
patients with CFS have an infectious episode as an initial
trigger for the syndrome.41 In some cases, the inciting
event is clearly a mononucleosis-like illness, occasionally
a standard EBV-associated mononucleosis. More often, it
is a non-specific upper respiratory infection, a sinusitis or
bronchitis, occasionally an influenza-like illness, the latter
characterized by severe myalgias, high fevers, and severe
malaise. Some patients may actually describe vividly an
event at a specific date and time of day when they became
ill, relating that after that event they never felt healthy
again. Paradoxically, over time for many patients with
CFS, the initial symptoms may blur and be difficult to
recapture in the medical history obtained years later.
Epidemiology/Pathophysiology
Many infectious agents seem capable of inciting
CFS, but few good studies provide an epidemiologic link
to specific agents. One early study depicted an outbreak
of disease probably associated with human herpes virus 6
(HHV-6) at Incline Village, Nevada. In this outbreak,
there was evidence of depletion of B-cell lymphocytes
and development of symptoms consistent with CFS.42, 43
Older observations from Europe suggested that an illness
called myalgic encephalomyelitis had occurred in clusters, which suggested an infectious/contagious basis for
the outbreak.43 Although it is tempting to attribute CFS to
an unresolved infection secondary to viral infection, such
as mononucleosis or influenza, it is difficult to attribute
the constellation of symptoms and signs that currently
define CFS as due to a single infectious agent.
There is some evidence, however, that CFS may be
associated with some unresolved or persistent infectious
agents. For example, most patients with CFS have persistently and, at times, markedly elevated antibodies to
portions of the EBV, particularly the viral capsid, early
antigen, and nuclear antigens. The same can be said, albeit less assuredly, for HHV-6. A certain percentage of
patients with highly reactive HHV-6 serology will also
have intermittent viremia with HHV-6, the significance of
which remains unclear, since there are no studies that
have been directed at eradicating HHV-6 from the vascular compartment. Recently, Belgian and French co-
Differential Diagnosis
Very few infectious diseases present with the panoply and diversity of symptoms seen in patients with CFS.
The disease that most resembles CFS is acute and subacute EBV infection, but patients with mononucleosis
tend to be younger and do not suffer with other cardinal
symptoms of CFS, such as cognitive dysfunction, sleeping
disorders, and allodynia. Nevertheless, the Epstein-Barr
virus (EBV) was initially thought to be the cause of CFS.
When serum was sampled for antibodies against two
EBV-replicating enzymes in patients with CFS, abnormal
titers of antibodies were found twice as often as in controls (34.1 % vs. 17.1 %). While this finding may indicate
a more frequent occurrence of EBV in patients with CFS,
or perhaps that EBV may precipitate CFS in a subset of
patients with CFS, EBV is not the universal cause or precipitant of CFS.46 Buchwald et al. (1996) tested 548
chronically fatigued patients, including patients with CFS,
for seroprevalence and/or geometric mean titer of antibodies to 13 viruses. No consistent differences were
found in patients with CFS for either of the two measured
parameters. An earlier study by Mawle, et al. (1995) at
the Center for Disease Control (CDC), could not find
elevated titers of antibody to any herpes virus, nor evidence of exposure to enterovirus in patients with CFS.47
Recently, workers at the CDC examined 26 patients and
13
ogy, coupled with newer techniques to amplify bartonella

DNA in blood, should help eliminate that diagnosis.
Some patients complain of recurrent oral or vaginal
candidiasis. Some patients may insist that they are chronically infected with yeast, a holdover from the pseudoepidemic promulgated by some health care providers claiming that many patients with undefined disease had deepseated, unresolved mycotic infection due to Candida albicans, thus the term the Yeast Connection.55 Nevertheless, in some patients C. albicans can be cultured at times
from the oral cavities and genital tracts of these patients,
and patients report improvement of fatigue when oral
azoles are used to treat the mucosal infections.
Patients with Lyme disease can have unusual presentations, but exhausting fatigue, deep bone and body
pain, and cognitive dysfunction are unusual. Nevertheless,
in areas of the country where Lyme disease caused by
Borrelia borgdorferi is endemic, patients with CFS and
physicians will fixate on Lyme Disease as a cause. To
confound the clinical picture, Lyme disease does have its
chronic form, and serology that was positive early in the
disease may persist for years. Ehrlichiosis caused by
agents related to the rickettsia is an emerging disease endemic in the same geographic regions as Lyme Disease.
The capacity for E. canis to produce a chronic disease
such as CFS has not been investigated.
Workers in Belgium have reported in abstract form
an association of circulating peripheral blood cellassociated Mycoplasma fermentans with CFS. This obligate intracellular wall-less bacterium, acting either as an
inciting or opportunistic pathogen, awaits more definitive
studies to define its role in CFS. Mycoplasmas can have
protean effects on cellular machinery, but can be interrupted by antimicrobial chemotherapy.
In this age of emerging infectious agents, including
those of bioterrorism, other new microbial agents will
surely arise as causes of chronic fatigue.
52 controls for the presence of HHV-6 and HHV-7 and

found no differences between patients and controls.48 The
recent report of an outbreak of CFS in Japan,49 which
may be affecting as much as 1/3 of the Japanese
workforce may rekindle efforts to identify an infectious
agent as the cause of CFS. A preliminary report suggests
that this is a post-hepatitis B vaccination outbreak and
may be due to a contaminating organism (De Merileir,
2000). The failure to find a single virus in all patients
with CFS has led to the assertion by some that CFS is not
caused by a viral agent. However, the failure to identify a
causative viral agent does not preclude the possibility that
CFS is caused by a yet-to-be-identified virus or coinfection with two or more viral agents or an unknown
infective agent. Physicians should keep in mind that disease due to CMV can mimic CFS for a short time but
usually resolves. Some patients complain of recurrent
herpes-like lesions of the oral cavity that suggests regular
recurrence of herpes simplex virus.
An intriguing, unifying hypothesis put forward by
Lerner et al. is that CFS symptoms are caused by viralinduced channelopathies.50 In other work, these investigators have described electrocardiographic changes explained by changes in ventricular cell membrane ion
channel function.51 These investigators believe that such
changes may be caused by the presence of a virus and
claim success with long-term therapy of antiviral medication. Other non-CFS literature documents the ability of
viral infection to alter excitable membrane activity. Human immunodeficiency virus type 1 (HIV-1) has been
shown to inhibit a large-conductance potassium channel
in human glial cells,52 while herpes simplex virus has
been shown to decrease membrane excitability of nerve
cells (a decrease in sodium channel activity in the plasma
membrane of dorsal root ganglion cells) of adult guinea
pigs.53 Virus-induced alteration of membrane excitability,
therefore, is a possible, but unproven, mechanism of CFS
pathophysiology.
There is other indirect immunologic evidence for
persistent viral infection. Patients with CFS often have
lymphocyte depletion, including mild to moderate reductions of CD4+, as well as CD8+ lymphocytes. This type
of depletion should not be confused with the CD4+ depletion seen with HIV infection. In HIV disease, the
CD4+ to CD8+ ratio is usually reversed. Still, HIV antibody testing should be done on any patient with CFS who
has any hint of risk factors for retroviral illness.
Bacteria, viruses, and parasites have been linked to
fatiguing syndromes, including brucella, bartonella, and
cyclospora.54 Not widely known, it is reported that the cat
scratch disease due to Bartonella henselae may present as
chronically fatiguing illness.51 In considering bartonella
infection, a good history of cat exposure including being
licked or sleeping with the cat, cat scratch disease serol-
Diagnostic Tests
Chapters 1 and 2 outline baseline diagnostic testing
for most patients with CFS. The primary care physician
can obtain serology for EBV, HHV-6, CMV, toxoplasmosis, and HIV. The next level of testing may include
other serologies, tests for HHV-6 viremia, RNase L determinations, and mycoplasma, rickettsial, or chlamydia
DNA amplification by PCR. Thise latter tests may be
difficult to obtain because of lack of third party coverage.
Patients often have to secure and pay for this testing
themselves by finding the most appropriate laboratory to
perform the testing and to arrange third party payment, a
very frustrating process for patients. Regional specialty
laboratories may be very helpful to patients arranging
specialized diagnostic testing. An infectious diseases physician specializing in CFS can assist the primary care
physician in choosing specialized tests that may support
14
such as isoprinosine, infliximab, or thalidomide, will

serve as another potentially exciting area for clinical trials.57-59
the diagnosis of CFS or consider other infectious diseases. Table 3-1 outlines the diagnostic tests involving
infectious agents that may be considered for patients with
CFS.
Conclusion
Many infectious agents can cause fatigue as part of a
constellation of symptoms, so they have to be considered
in the differential diagnosis. There are good data to suspect that CFS itself is triggered or perpetuated by microbial agents, but classic Kochs postulates have not been
demonstrated for any one agent. Newly described agents
such as HHV-6 seem to reactivate as opportunistic agents
and may play a role in causing persisting symptoms. Antibacterial or antiviral therapy remains empiric, but can be
useful in some patients. Future research using DNA microarrays and advanced immunological technology should
elucidate the role of the altered immune state in CFS and
the impact of opportunistic infections.
Therapy
There are no studies that support the routine use of
anti-infectives in the therapy of CFS.40 Nevertheless,
since CFS is devastating to the individual, and since there
is inferential evidence that CFS is associated with persistence of infectious agents, it is reasonable to use careful
empiric trials of antivirals, antibacterials and, in certain
instances, antifungal agents. Patients with early CFS and
high titers of antibody to DNA viruses may benefit from a
one-to-two month trial of antivirals, usually starting with
an agent such as valcyclovir at doses of 500 mg twice or
three times a day. If there is no response at two months,
the therapy should be stopped.
Ampligen is a 50-base-pair compound consisting of
double-stranded RNA (polyI-polyC12U) that several
studies have shown improve the Karnofsky score, a
measure of well-being.56 Preliminary evidence has also
been presented to show that Ampligen will decrease the
level of low molecular weight RNase L. A current clinical
trial underway with Ampligen compared to placebo will
determine if the product will be approved by the FDA.
Some patients will give a history of a profound response to an incidental antibacterial they had taken in the
past. While there are no studies to substantiate empiric
use of agents such as macrolides or quinolones, when
patients are debilitated, it seems reasonable to attempt
one or two month trials in selected patients who have had
such beneficial responses historically. New studies are
underway to determine the efficacy of antimicrobials in
those patients with evidence by serology or PCR of active
mycoplasma infection. Since cytokine regulation may
play a role in CFS, agents to modulate cytokine pathways,
Table 3-1
Useful Diagnostic Tests to Rule Out Infectious Causes
of Chronic Fatigue Syndrome
Diagnostic Test
Infectious Agent
CMV
EBV
HHV-6
Borrelia borgdorferi
Bartonella henslae
Brucella canis
Mycoplasma fermentans
Tropheryma whippelii
* Culture of urine most useful
15
Serology
Culture
DNA Amplification
16
Depression in CFS*
Kenneth R. Kaufman, MD, MRCPsych

Paul J. Goodnick, MD
myalgia, pharyngitis, painful lymph nodes, visual blurring, nausea, nocturia, night sweats, abnormal Romberg
balance test results, hepatomegaly, and abnormal ophthalmic findings.63, 64 Patients with CFS have been found
to frequently have small adrenal glands, as determined by
CT scan.65
Insomnia and hypersomnia are well-known symptoms of MDD,66 and 90% of patients with CFS report a
sleep abnormality64 (See Chapter 6). Fatigue in CFS is a
key criteria related to the complaint of being tired, with
an incidence of post-exertional malaise of 50% to 80%.64
Before CFS, these patients had been physically active. At
this time, although initially feeling well and energized
after exercise, within 6 to 24 hours most patients notice
the onset of extreme fatigue, loss of cognition, fever, and
sore throats requiring retirement to bed. Muscle fiber has
been found anatomically to be normal, but with reduced
exercise tolerance (8.1 vs. 11.3 minutes).67 CNS nerve
exhaustion has been defined from results that indicated
after exhaustion of peripheral nervous stimulation, there
remained added force in the muscles of patients with
CFS, as contrasted with controls (80% to 15%).68 Increased CNS fatigue led to a progressive failure to
fully activate the muscle during this strenuous exercise.
Other correlated findings include deficiencies in carnitine,
an essential regulator of mitochondrial metabolism.69 Another report found that in terms of aerobic power, CFS
patients had low fitness levels and a low range of maximal oxidative capacity.70
Further reports have confirmed the changes in muscle and muscle function in CFIDS that are not found in
MDD. There are three levels for evaluating muscle function: gross performance, oxygen delivery, and cortical
motor potentials. Recent reports have found significant
reductions in maximal voluntary strength (19%, p<.05)
and in submaximal aerobic performance scores (40%,
p<.05) in FM patients.71 However, fatigue loading has not
always found significant differences.72 Perhaps more important is focusing in on more specific chemical systems.
For example, time constant for oxygen delivery has been
found to be significantly reduced in CFS both after exercise (46.5s vs. 29s, p=.0019) and cuff ischemia (20s vs.
12s, p=.03).73 Motor-evoked potentials as investigated by
single and double magnetic stimulation revealed reduc-
he CDC criteria for CFS specifically recognizes that

patients can have both CFS and depression.1 The
clinicians challenge is to judge for each individual patient whether the complaint of fatigue is a primary depression, a physical illness, such as CFS, or a combination of
both.
Thus, depression can mimic CFS and other physical
illnesses, such as FMS. Patients with so-called atypical
depression are especially likely to present to their primary
care physicians complaining of feeling tired without being
aware their mood is depressed. Such patients often reject
the idea that their symptoms, which feel so real, might
not be physical. Of course, patients with CFS, or other
chronic physical illnesses can become depressed due to
that illness. The physical illness might cause depression
directly by physiologic effects on the brain. Additionally,
the frustration of being ill and the physical, social, and
financial loss of function can trigger depression.
Fibromyalgia (FM) overlaps with CFS in terms of
rates of fatigue, myalgia, sleep disturbance, and mood
problems, among other criteria.60 FM focuses more by
definition, on a three month history of generalized aches
and stiffness with a minimum of at least six typical and
reproducible tender points,61 there is no requirement for
fatigue. Other criteria for FM are headaches, neuropsychiatric symptoms, subjective joint swelling, irritable
bowel syndrome, and modulation of symptoms by activity, weather, and stress.
This chapter clearly differentiates CFS and FM, discussed as chronic fatigue syndrome and related immune
deficiency syndromes (CFIDS), from depression in
terms of physical signs and symptoms, sleep, fatigue,
memory, biological parameters, brain imaging, immunology, and treatment. The focus will be on practical applications of research findings, with a further focus on future
ability to show clear biologic separation and specific
treatment.
Physical Signs and Symptoms
Typically, patients with major depressive disorder
(MDD) have no specific signs or symptoms. Patients
with CFS typically do not have the following DSM-IV
criteria symptoms for major depression: anhedonia, guilt,
and lack of motivation.62 In contrast, patients with CFIDS
have been reported to have multiple findings including
*
Portions of this article were taken with permission from Jorge, C. & Goodnick, P. Chronic Fatigue Syndrome and Depression: Biological
Differentiation and Treatment, Psychiatric Annals 1997; 27(5):365-371.
17
of 10 CFS, 15 MDD, and 25 control subjects indicated

that prolactin responses to the 5HT-releasing agent fenfluramine were highest in CFS patients, followed by controls, and then by MDD patients (p=.01).27
Further serotonin research reveals that patients with
FM do not show the normal pain generally induced by IM
serotonin.88 Of interest is that patients with FM demonstrated an increase in T/C and C/C genotype of the T102C
polymorphism of the 5HT2a receptor gene; however,
these findings did not correlate to age of onset, duration
of disease, or Beck Depression Inventory score.89 In contrast to only 6% of blood donors, 74% of FM patients
have been reported to have anti-serotonin antibodies in
their sera.90 This finding was replicated with a 77% rate
of anti-5HT antibodies in FM, in contrast to only 19%
with acute eosinophilia-myalgia syndrome (EMS) and
18% in controls.91
Melatonin levels in CFIDS are controversial: one
study reported a significantly higher nocturnal melatonin
plasma level for FM compared to controls, but no significant difference between CFS patients and controls.92
However, another study reported lower levels of urine 6sulphatoxymelatonin levels in FM patients than in controls (9.2 vs. 16.8 ug/24h, p=.06).93 The lower urinary
levels were thought to explain sleep problems found in
CFIDS; consequently, the administration of 3mg melatonin nightly was found in the latter study to improve both
pain and visual analogue scale for sleep.93 Another recent
parameter found to be abnormal with possible etiologic
implications is nerve growth factor, which in FM has
been found to be markedly increased in cerebrospinal
fluid compared to controls (41.8 vs. 9.1 pg/ml).94 This
finding suggests that the painful symptoms of FM (and
possibly CFS) may come from elevated substance P concentrations that, in turn, are due to faulty regulation by
nerve growth factor.94
Among the most replicated findings in MDD are
those of abnormalities in the hypothalamic-pituitaryadrenal (HPA) axis. These include hypercortisolemia,
elevated urinary free cortisol, and exaggerated cortical
response to corticotropin.81 In contrast, CFS patients have
been found to have lower plasma cortisol (89 vs. 148
mmol/L, p<.01) and lower 24-hour urinary free cortisol
(2.9 vs. 8.9 mmol/L, p<.04) than controls and a reduction
in responsiveness to corticotropin.95 In the first direct
comparison study,27 levels of circulating cortisol were
highest in depressed patients, followed by normal controls, and, finally, in CFS patients (p=.01). Thus, it may
be possible in the future to easily differentiate CFS patients from MDD patients biologically, with a simple
combination of a plasma cortisol and serotonin test.
The importance in the differentiation between CFS
and depression in HPA axis response has led to further
studies and to a recent review that summarizes and contrasts these findings.96 Specifically, the previous findings
tions in function in both excitatory and inhibitory pathways in FM.74

Memory impairment has been commonly reported
both in MDD and CFS. Regarding short-term memory,
consensus of research focuses on the fact that deficits are
more a problem with attention than with memory storage.
Patients with CFS have had particular problems, in contrast to controls, with the Stroop Color/Word test, Digit
Symbol testing, and Trail Making B test.75 One study
contrasting CFS with MDD indicated paired associate
learning was much worse in CFS than in MDD; results
were interpreted to indicate that MDD deficits are because of reduced confidence and reaction time, whereas
CFS deficits were true deficits in memory consolidation.76
A further report showed CFS patients to have more trouble than controls sustaining attention to figural and verbal
stimuli.77 In contrast to depressed patients, who have
more trouble with figures than verbal stimuli, CFS patients are equally impaired in both areas. There have been
several recent studies looking at the impact of CFS and
FM on memory and concentration. One study contrasting
CFS and depressed patients with normal controls found
that CFS patients in general had similar patterns of impairment to those with affective disorders in some tests
(Stroop test for cognitive processing, and Buschke for
short-term memory), but lower in others in working
memory (Paced auditory serial addition task, Salthouse
reading span test)78 (See Chapter 5). The findings of
slowed reaction times and reduced pre-movement-related
motor potentials in CFS has been interpreted to suggest
that central motor mechanisms involved in motor response preparation are impaired in this disorder.79 Similarly, in FM, controlled studies have confirmed impairments in delayed and immediate recall, as well as sustained auditory focus; these results were correlated to
pain severity and trait anxiety.80
Biological Findings and Diagnosis
In terms of neurochemistry, although urinary methylhydroxyphenolglycol (MHPG) levels (mg/24 hours)
have been frequently found to be lower in MDD, plasma
studies of MHPG in melancholia have generally found
higher levels than in controls.81, 82 However, in CFS,
mean plasma MHPG has been reported as lower than in
controls (8.3 vs. 10.8, p<.002).83 With regard to serotonin, there appears to be a number of contrasts between
MDD and CFIDS. Patients with MDD have been reported
to have, in contrast to controls, lower plasma 5HIAA,84
lower cerebrospinal fluid 5HIAA,81 and lower platelet
imipramine binding (IB).85 In contrast, CFIDS patients
have been reported to have greater plasma 5HIAA than
controls (67.3 vs. 37.3, p=.002),84 higher cerebrospinal
fluid 5HIAA (111.1 vs. 95.1),84 and higher platelet IB in
some,86 but not all, studies.87 A study contrasting response
in age, weight, sex, and menstrual cycle-matched samples
18
of urinary free cortisol reductions in CFS but elevations

in depression when contrasted to controls was replicated.97 Dehydroepiandrosterone (DHEA) was found to
be significantly lower in CFS, but not in depression, when
compared to controls.98 Impairment in DHEA response to
IV adrenocorticotropin hormone (ACTH) was described
(4.9 vs. 8.4 ug/L, p=.0002).99 Impaired responses in CFS
to both corticotropin-releasing hormone (CRH) and
ACTH were reported.100, 101 In agreement with these results are the findings of reduced ACTH and epinephrine
to hypoglycemic challenge in FM.102 Consistent with previous proposals of abnormal hypothalamic functioning
with retained normal pituitary performance is a recent
report noting a marked decrease in mean growth hormone
(GH) secretion in FM when compared to controls (1.2 vs.
2.5 ug/L, p<.05) with retained normal GH responses to
growth hormone-releasing hormone (GHRH).103 In contrast, a test in CFS for GH parameters proved negative.104
A further area of interest has been the test of orthostatic intolerance in CFS. This test of cardiovascular response has been thought by many to be diagnostic for this
disorder. In three recent studies, two in adults and one in
adolescents, the rate of positive findings varied, with 28%
and 40% in adults and 96% in adolescents.105-107 Autonomic defects have been proposed, but not established,
since in one of the trials, rates for controls were similar to
that in CFS107 (See Chapter 7).
Brain imaging studies have proliferated in recent
years, including both positron emission tomography
(PET) and single-photon emission tomography (SPECT).
Frontal hypoperfusion has been reported in MDD and
CFS.35, 37 A recent study emphasized that perfusion patterns in CFS are similar, but not identical, to MDD with
increased perfusion noted in right thalamus, putamen, and
pallidum in both, increased perfusion noted in the left
thalamus in CFS, but decreased perfusion in the left prefrontal cortex in MDD.38 In addition to the previously
reported left anterior prefrontal cortex hypoperfusion in
MDD, temporal hypoperfusion has also been noted.35
CFS patients showed significantly lower brainstem perfusion than depressed patients.39 SPECT comparison studies have found, by degree, more severe findings in CFS
than in MDD.108 The midcerebral uptake index, an objective measurement reflecting radionuclide uptake in the
brain, was found to be reduced in CFS (0.667) and in
AIDS (0.650) in contrast to depression (0.731) and controls (0.716).108 White matter abnormalities on magnetic
resonance images have not been found with any regularity
in CFS patients.109 SPECT analysis of regional blood
flow in FMS revealed statistically significant reduction in
the right thalamus (p=.006) and in the inferior pontine
tegmentum.110 A recent PET study in FM patients reported a significant negative correlation between natural
killer cell activity and posterior cingulate cortex function.111 These imaging findings are gaining more favor as
a means to demonstrate abnormalities in the brains of

patients with CFS.
Although it might seem that CFS could be easily
separated from MDD on the basis of laboratory indices of
immune function, this is not the case. Differences are
those of degree, rather than absolute. Tests of mitogeninduced lymphocyte stimulation with phytohemagglutinin
(PHA) were reduced in six of 14 tests in MDD.112 A
comparison study reported PHA responsiveness to be
25% lower in CFS than in either MDD or control subjects.113 Natural killer cell function was reduced in five of
seven studies in severe MDD.112 CFS studies have found
70% reductions in lytic units of natural killer cells, i.e., 39
for CFS versus 120 for controls.114 The high vulnerability
to infection in CFIDS (CFS and/or FM) patients previously reported was replicated in a study showing a significantly increased rate of multiple mycoplasma blood
infections (52.8% or 48 of 91 patients, with double infections occurring in 30.8% and triple infections occurring in
22%).115 In contrast, one recent report found no increased
rate of HHV 6 or 7 or cytomegalovirus in civilian and
Persian Gulf War veterans meeting the CDC criteria for
CFS.116 Further, anti-Epstein-Barr virus and anti-HHV6
antibody titers showed no statistical difference between
CFS and control patients.116
Thus, diagnostic differentiation of CFS from MDD
should be focused on physical signs and symptoms. A
composite approach may include memory test differences
(See Chapter 5), sleep EEG (See Chapter 6), serotonin
function indices, and plasma cortisol testing.
Treatment
Non-psychotropic
In contrast to depressive disorders, the difference
between treatment of MDD and treatment of CFS is that
non-psychotropics have been used with some success in
CFS. These include antivirals, immune modifiers, and ion
flow treatments.117 Antiviral agents have included acyclovir, immunoglobulins, essential fatty acids, and adenosine. Acyclovir, based on the theory of causation of CFS,
failed clinically.118 Two of three studies using immune
globulin were successful;119-121 a minimum dose of 2
g/kg/mo appeared to be important. At that dose, improvements were noted in Quality of Life visual analogue
scale (41%), Hamilton Depression Rating Scale (42%),
and in CD4 count (37%). An initial study of essential
fatty acids (EFAs) at a dose of two capsules four times
daily for 3 months led to improvement in fatigue and myalgia, rather than in depression and concentration.122
Adenosine was beneficial in uncontrolled reports.123
The list of immune modifiers includes polyribonucleotide (Ampligen), LEFAC (liver extract, folic acid,
and B12), Kutapressin (liver derivative extract), interferon, interleukin-2, and transfer factor. Ampligen is
mismatched double-stranded RNA, which appears to
19
in CFS revealed no statistical difference in response (improvement on a global wellness scale) between fludrocortisone and placebo135(See Chapter 7).
regulate expression of interferon, interleukin, and tumor

necrosis factor (TNF), while activating intracellular
pathways that are antiviral and enhance immune resistance. Two studies that administered up to 400 mg twice
weekly for 24 weeks and a placebo-controlled study both
reported improvements in overall functioning, perceived
cognitive deficit, and exercise duration.56, 124 A brief LEFAC placebo-controlled, double-blind, crossover trial did
not show significant improvement; however, since CFS
features may require months to improve, it is likely that
this was too short a study.125 The follow-up open label
trial showed much more success. Kutapressin, a mixture
of polypeptides that may be a bradykinin potentiator, has
been reported to be successful in 75% of CFS patients
given a mean of 33 injections at an initial rate of once
weekly, followed by three times weekly.126 A single study
of oral alpha interferon at a dose greater than 1500
IU/day produced rapid relief in pain over 5 days with a
much slower change in muscle tone.127 Other case and
open label studies involving interleukin-2, transfer factor,
and magnesium showed initial success, but have failed in
attempts at replication.
More recent non-psychotropic treatment studies for
CFS and FM have addressed the potential efficacy of
amantidine, L-carnitine, hydrocortisone, gammahydroxybutyrate (GHB), nicotinamide adenine dinucleotide (NADH) and revisited the efficacy of essential fatty
acids. A well-controlled eight-week trial contrasting
amantidine and L-carnitine reported significant benefit
with L-carnitine, but not with amantidine.128 Consistent
with the HPA abnormalities noted with CFS (specifically,
CRH-ACTH-cortisol,100, 101) two separate placebocontrolled trials found modest therapeutic benefits from
oral low-dose hydrocortisone.129, 130 Open-label treatment
with GHB has been reported to improve fatigue and pain,
as well as to reduce the alpha sleep anomaly, found in
FM.131 A double-blind trial found that 10 mg of NADH
produced significant improvement over placebo in clinical outcome as determined using a rating scale based on
CDC criteria (p<.05).132 Unfortunately, in contrast, the
positive response to EFAs previously reported could not
be replicated in another three month study of high-dose
Efamol Marine, with no statistical difference found between the treatment and placebo groups.133
An unusual treatment for CFS was based on the hypothesis that this disorder might be related to neurally
mediated hypotension.134 Abnormal responses to upright
tilt testing were found in 22 of 23 patients and four of 14
control subjects (p<.001). Treatment was a general instruction to increase dietary salt intake by over 90% in
combination with 0.1mg fludrocortisone. Of 19 patients
treated for at least two weeks, nine reported subjective
improvement or remission. However, a recent randomized, double-blind, placebo-controlled monotherapy trial
of fludrocortisone to treat neurally mediated hypotension
Psychotropic
Antidepressants continue to be used in the treatment
of CFIDS. It is well known that tertiary tricyclic antidepressants, e.g., amitriptyline, produce relief of major depression generally at doses between 150 mg and 300
mg/day.81 As previously reviewed, patients with CFIDS
often improve at doses as low as 75 mg/day.136 In contrast
to MDD, there may be a differentiation in symptom response in CFS. Serotonin-based treatments may be more
effective for immune, pain, and global responses; norepinephrine-based treatments may be better for the depressive symptoms associated with CFIDS. In terms of tricyclic antidepressants, imipramine failed at a dose of 75
mg/day for 12 weeks.137 Amitriptyline has been reported
to be successful in most studies, even at 50 mg/day; but
the lowest study presented of 25 mg/day was not successful.138-141 Improvement was found in morning stiffness,
myalgia, fatigue, tender points, and pain tolerance. Nortriptyline, in a single A-B-A-B controlled case study, produced significant improvement in depression and overall
CFS ratings.142 Maproptyline was contrasted to clomipramine in a controlled study in FM; maproptyline was
better at improving depression, whereas clomipramine
was better at reducing pain.143 Despite two further reviews that found tricyclics to be effective in CFS and FM,
no further recent clinical trials have been done since
1997.144, 145
Monoamine oxidase inhibitors have also been reported to treat CFS.136 Phenelzine at 15 to 30 mg/day was
noted to produce good responses in 60% of patients, with
52% having prolonged improvement.146 There are two
recent clinical trials on the monoamine oxidase inhibitors
selegiline and phenelzine in CFS.147, 148 These short trials
of four weeks each managed to show benefit over placebo
in small sample studies by looking over a series of different ratings, with the plurality of patients showing improvement over worsening compared to placebo. However, the individual effects are not impressive clinically.
The lack of greater significance most likely can be explained by a combination of two factors: a) length of active drug administration was being only four weeks while
CFS patients often need as many as 12 weeks to show
improvement, and b) the dose used in each study was at
maximum at least 50% less than used in standard clinical
practice. The most recent study done with moclobemide,
a reversible inhibitor of monoamine oxidase-A, reported
improvement in key symptoms experienced by patients
with CFS.149
Bupropion, with specific effect to block reuptake of
norepinephrine and dopamine, has been found to be ex-
20
for 21 days and led to significant reductions in both trigger points and Hamilton Depression Rating Scale.169
5HTP, a precursor of serotonin, given in a double-blind,
placebo-controlled study and an open study for 3 months,
reduced numbers of tender points and improved measures
of fatigue, anxiety, pain intensity, and sleep.170, 171 Lithium augmentation of tricyclic antidepressants at serum
levels of 0.5 to 1.1 meq/L led to improvement in stiffness
and pain in three cases.172
Psychostimulants (methylphenidate, damphetamine, pemoline, and modafinil) are commonly used in the
treatment of medically impaired depressed patients and as
adjunctive agents in the treatment of MDD.173-176 To date,
these agents have not been evaluated in CFIDS beyond a
single negative case report of modafinil and FM (that may
have been negative due to the briefness of the trial).177
Thus, in terms of treatment of CFIDS, in contrast to
MDD, there is a spectrum of both non-psychotropic and
psychotropic treatments. IgG may be effective, particularly in patients with depressed serum levels; Ampligen
may be of universal benefit; Kutapressin may be of value.
Improvements are noted from L-carnitine, GHB, and
NADH. Regarding psychotropics, if the patients focus is
on chronic fatigue or depressive symptoms, bupropion
and/or low dose tricyclic antidepressants may be successful. In contrast, if the CFIDS symptom picture is more of
global dysfunction and immune difficulties, a serotonergic approach with sertraline may be particularly beneficial. An additional bonus to use of sertraline may be its
benefits on cognitive functioning.178 Venlafaxine and nefazodone also appear to have more global effects; however, further controlled trials for both of these promising
psychotropics in the treatment of CFIDS are indicated.
It is important to remember that beyond the presentation of depressive symptoms in CFIDS, there may be a
concomitant MDD that predated the CFIDS. Treatment
strategies should attempt to address both illnesses if feasible. Effective interventions for a concomitant MDD
does not preclude maximizing treatment specifically of
the MDD; but it is important to avoid approaches that
would negatively impact CFIDS secondary to psychotropic side effects.
cellent for improvement of depressive features of CFS,

but not for immune indices.150, 151
Regarding the selective serotonin reuptake inhibitors, results are available concerning fluoxetine, sertraline, and citalopram. After initially promising case reports at a dose of 20 to 40 mg/day, fluoxetine appears, in
controlled open studies for up to 12 weeks, to produce
benefit for both global functioning and natural killer cell
values.152-155 However, two double-blind studies, one in
FM156 of only six weeks and one in CFS157 of only eight
weeks, did not show the same success. There are three
reports available concerning sertraline; all are open studies that agree on significant improvement in fatigue, myalgia, sleep disturbances, depression, pain, and global
ratings.136, 158, 159 One of these studies clearly documented
that improvement in FM symptoms was independent of
the drugs efficacy as an antidepressant; thus, the biological activity of sertraline was directly responsible for its
efficacy in the immune disorder.158 Citalopram failed in
one double-blind, placebo-controlled study of FM.160 A
recent 4-month trial of citalopram in FM did not reveal
any statistically significant difference in the intention to
treat and completer analysis between citalopram and placebo in the global judgment of improvement, though a
tendency toward increased improvement in the completers was noted between the citalopram group (52.9%),
compared to the placebo group (22.2%); further, significant differences in pain ratings, as measured with the Fibrositis Impact Questionnaire, were noted, as well as depressive features, as measured by the Montgomery Asberg Depression Rating Scale (MADRAS).161
Venlafaxine, perhaps because of its balanced effect
to block reuptake of both norepinephrine and serotonin,
has been reported to improve depression and
pain/immune symptoms in case reports and open studies.162-164 An initial report on nefazodone (Serzone), a
serotonin receptor modulator, noted reduction in pain,
with improvement in sleep, memory, and exercise tolerance during a 12 week trial.165 In an open study of 10
patients with chronic fatigue, nefazodone treatment resulted in moderate/marked improvement in fatigue (40%),
sleep (70%), mood (80%), and overall functional status
(50%).166 Further, an open study of FM treatment with
tropisetron, a unique non-antidepressant 5HT3 serotonin
antagonist, reported 5 of 10 patients with statistical improvement in pain score, fatigue, sleep, and number of
tender points.167
Other reports have been presented on alprazolam
and basic molecules.136 Alprazolam at 3 mg/day maximum dose had no significant effect on any clinical measures.168
Basic
molecules
have
included
Sadenosylmethionine
(SAMe),
5-hydroxytryptophan
(5HTP), and lithium. SAMe, a methyl group donor that
has been used successfully in the treatment of depression,
was administered at a dose of 200 mg/day intramuscularly
Conclusion
When depressive symptoms exist with those of
chronic fatigue syndrome, an accurate differentiation can
usually be accomplished by focusing on diagnostic criteria. The presence of multiple symptoms and physical
signs of CFS may be of great value. In terms of laboratory
testing, a single helpful test may be measuring the plasma
cortisol, which is usually high in depression and low in
CFS. Future work should focus on the combination of
plasma cortisol with an index of serotonin function, which
is high in CFIDS and low in depression. Additional research should focus on neuroimaging and immune differ-
21
serotonin reuptake inhibitor, especially sertraline, to aid

improvement of global, pain, and immunologic parameters. Further research should focus on larger placebocontrolled, double-blind trials of these and other antidepressants, e.g., venlafaxine and nefazodone, as well as the
evaluation of psychostimulants.
entiation. The combination of multiple tests should result

in a significant and clinically useful separation between
CFIDS and MDD.
For treatment of the patient with significant depression or MDD with CFIDS, one should think of the
noradrenergic approach using bupropion or low-dose
tricyclic antidepressants in combination with a selective
22
Cognitive Dysfunction in CFS

Carolyn Grace, PhD
atients diagnosed with CFS who present for neuropsychological assessment are typically individuals
who have led previously active lifestyles with minimal to
no report of prior health or psychiatric disturbance. These
patients frequently report a significant level of stress secondary to experiencing functional declines in physical,
cognitive, social, academic and/or vocational areas. Many
patients are unable to work, thus they are either on disability or in the process of applying for disability.
Younger patients are often unable to attend school on a
full-time basis. In addition, patients typically report questioning psychological well-being and feelings of frustration at dealing with a syndrome that does not have a definitive test for diagnosis, nor a specifically defined
treatment regime. Vocational and/or educational difficulties present as attention/concentration difficulties, reduced information processing, short-term memory problems, depression, anxiety, fatigue, sleep disturbance,
mood disturbance, and difficulty with initiating and completing tasks. Patients often complain of cloudy sensorium, the brain fog of CFS.
Neuropsychological Diagnostic Work Up
Neuropsychological assessment is helpful to establish a baseline of neurocognitive functioning, to discern
the relative contribution of emotional factors in a patients clinical presentation, to confirm the presence of
cognitive symptoms consistent with CFS, and to make
treatment recommendations regarding potential cognitive
remediation and/or psychological interventions. A comprehensive neuropsychological evaluation includes review and assessment of the following areas: clinical interview with the patient, interview with a family member/close friend, neurocognitive assessment of general
intellectual functioning (See Table 5-1), and a review of
medical records, educational records, and/or vocational
records. A review of past educational records and/or resume documenting employment history provides critical
information for the clinician to both understand and best
objectify a patients report of symptoms.
Table 5-1
Neurocognitive Assessment of General Intellectual Functioning with Testing Instruments*
Instrument/Test
Wechsler Adult Intelligence Scale
III
Wechsler Memory Scale III
California Verbal Learning Test
Benton Visual Retention Test
Rey-Osterrieth Complex Figure
Tapping Test,
Grooved Peg Board
Grip Strength
Conners Continuous Performance
Test
PASAT
Controlled Oral Word Asso. Test
Animal Naming
Ruff Figural Fluency Test
Booklet Category Test
Wisconsin Card Sorting Test
Hooper Visual Organizational Test
Writing & Oral Story Generation
Aphasia Screening
Boston Naming Test
Stanford Diagnostic Reading Test
Wechsler Individual Achievement
Test
Measure of Test
General Intellectual Functioning
Verbal Learning & Memory
Verbal Learning & Memory
Visual Memory
Visual Construction & Memory
Motor Speed & Skill
Motor Speed & Skill
Motor Strength
Sustained Attention / Concentration
Auditory Processing Speed
Verbal Fluency
Verbal Fluency
Visual Fluency
Nonverbal Hypothesis Testing
Nonverbal Problem Solving
Visual Analysis & Synthesis
Language Functioning
Reading Abilities
Achievement Areas
*Adapted from Grafman, 1994179

sis.180, 181 Certainly psychiatric syndromes may confound
a patients neurocognitive presentation. The physician can
help to discern the relative contribution of psychological
symptoms to the report of neurocognitive difficulties.
Such decisions influence recommendations regarding the
possible utility of various treatment regimes (e.g., psychopharmacologics, various psychological therapies, or
cognitive remediation).
The major comorbid psychiatric diagnoses for patients with CFS include Major Depressive Episode, Panic
Disorder, Generalized Anxiety Disorder, and Somatization Disorder.182 It is possible impairment(s) that patients
with CFS demonstrate on cognitive testing may be a result of primary depression.181 In addition, ruling out malingering has benefits: validation of patient complaints,
clarification for the family and other health care professionals, and the establishment of eligibility for disability/Social Security Insurance. It has also been noted that
as a result of primary psychiatric illness, some patients
may experience greater fatigue, which may create an additional risk factor for prolonged disability due to CFS
symptoms. Conversely, the clinician must challenge psy-
Psychological Assessment of Mood

Psychological assessment is accomplished utilizing
clinical interviews, patient observation, self-report instruments (e.g., Beck Anxiety Scale, Beck Depression
Inventory II), objective testing instruments (e.g. MMPI,
MCMI), and instruments assessing for malingering (e.g.
Portland Digit Recognition Test, Rey 15-item test). Clinicians should be cognizant of issues of differential diagno-
23
emotional status, sleep patterns, stress level, self-esteem,

social relatedness, and illness-related schema. A typical
treatment format utilizes a protocol of 6-to-8 weekly
treatment sessions. Patients with CFS tolerate this model,
with the option to enroll in a maintenance CBT as needed.
The goal of CBT is to decrease symptoms by enabling
patients to develop coping skills, to recognize target areas
of change, to address adjustment issues, and to modify
cognitive schema and behavior patterns.
chiatric diagnoses when the symptoms fit chronic fatigue,

rather than a primary psychiatric disorder.182
Treatment
The treatment and management of the neurocognitive dysfunction in CFS includes a multidisciplinary approach to this often long-term debilitating syndrome. Aspects of treatment for consideration include psychoeducational resources, psychopharmacologic consultation,
behavioral medicine, and accommodation recommendations for the academic or vocational setting.
Patients with CFS welcome the opportunity to educate themselves and family members about the biological,
psychological, and environmental influences that contribute to their experience of physical, cognitive, and psychological complaints. Following neuropsychological
evaluation, the typical format would be to offer a psychoeducational meeting to provide neuropsychological
testing feedback, educational information related to biological and psychological factors contributing to symptoms (including discussion of basic principles of behavioral medicine, health psychology, and neuropsychology),
and treatment recommendations.
Accommodations in Academic or Vocational Settings

Many patients may benefit from accommodations
that modify physical or cognitive demands of an academic or work environment. Based on neuropsychological test data, a rationale may be established for various
accommodations, including, but not limited to, the following: abbreviated work or academic day, use of augmentative cognitive strategies in the classroom or work
environment, reduced academic course load, staggering
of examinations, etc.
Psychopharmacologic Interventions
Psychopharmacologic therapies can improve disturbances in attention/concentration, sleep-wake cycle, and
the management of mood disorders. Pharmacologic intervention involves discerning aspects of normal reactive
depression to a chronic illness versus endogenous/ neurobiologically based depression that may in fact benefit
from medication intervention. Chapters 4 and 6 discuss
some specific medications.
Cognitive Behavioral Treatment (CBT)

CBT strategies are aimed at addressing aspects of
cognitive schema, implementing behavior modification,
introducing basic cognitive strategies for patients with
cognitive complaints, and suggesting appropriate exercise
programs (e.g. yoga and meditation). The literature regarding the effectiveness of such CBT with CFS is sparse,
with some reports of significant improvement in symptoms and others stating no significant differences between
patients receiving CBT and those without CBT.183 Nevertheless, CBT is often a useful adjunctive treatment.
Sharpe184 has noted that cognitive-behavioral treatment is
a pragmatic approach for a syndrome without any specific
treatment regime. The literature regarding the effectiveness of such cognitive behavioral treatment in CFS includes reports of significant improvement in symptoms.183, 185 The focus of such treatment is to modify the
individuals perception of factors contributing to the experience of physical and psychological disability. Target
areas for interventions often include physical exercise,
Conclusion
Neuropsychological assessment is a critical dimension in the management of CFS and provides assistance in
the diagnosis of a complex, often debilitating syndrome.
A range of specific tests of cognitive dysfunction commonly present in patients with CFS are available. In addition, neuropsychological assessment provides a means to
portion out the relative contributions of potential emotional factors in the clinical presentation of CFS patients.
Overall, neuropsychological assessment is designed to
provide a cognitive baseline of patient abilities, assist
with diagnosis, and provide recommendations for specific
areas of therapeutic intervention.
24
Sleep Dysfunction in CFS

Richard N. Podell, MD, MPH
cause of fatigue. More often, CFS is the diagnosis, but

specific sleep disorders can complicate and exacerbate
the illness. Sleep disorders can be suspected by asking
patients about key symptoms, specifically about whether
they snore, struggle for breath at night, or have ever been
told that they stop breathing or have muscle twitching
often while asleep.
Teaching a family member or friend to observe the
sleeping patient for at least 30 minutes, one or several
nights, can be very useful. This is the minimum that
should be done for patients with chronic fatigue without a
clear-cut cause. The observer should look for severe
snoring, episodes of not breathing for 10 seconds or
more, snorting or struggling for breath. Frequent gross or
fine muscle or limb movements or twitches should be
noted.
One may observe Periodic Leg Movement Disorder
(PLMD) if there is a restless leg syndrome during the day
or evening.194, 195 However, lack of restless leg should not
deter evaluation for PLMD. Typically, patients are not
aware of nocturnal muscle twitches or limb jerks. (Having
one or two twitches while falling asleep or while waking
up can be normal, and does not suggest PLMD). Multiple,
30 minute observations by someone lying close to the
patient in bed may detect PLMD. This condition is often
missed unless a sleep study is done.
We cannot exclude a sleep disorder with a very high
any patients with CFS feel sleepy, as well as tired.

Whether or not they have difficulty falling asleep
(sleep onset insomnia) or difficulty staying asleep (sleep
maintenance insomnia), most CFS patients feel that their
sleep is not refreshing. They wake up in the morning
feeling as if they havent really rested.
Improving sleep is a realistic goal. As clinicians
know, this is often a complex and difficult task. Even
modest improvement in sleep can have important positive
effects on the patients sense of well-being.186-191
Pathophysiology
We only partly understand why people with CFS
lack restorative sleep. For many, especially those with
FMS, the EEG shows alpha wave activity inappropriately
intruding into the delta waves of deep sleep. A significant
minority have classic sleep disorders complicating their
CFS: periodic leg movement disorder or sleep apnea.
Others suffer from insomnia, hypersomnia or nonrestorative sleep. The mechanisms for these aspects of
CFS are not clear (See Table 6-1).
Diagnosis
When either insomnia or poor sleep is chronic, the
physician should consider whether a specific, treatable
sleep disorder is present. Occasionally, the diagnosis of
CFS is mistaken, and a primary sleep disorder is the main
Table 6-1
The Main Sleep Disorders That May Complicate CFS192, 193
Disorder
Obstructive Sleep Apnea
Central Sleep Apnea
Periodic Leg Movement Disorder (PLMD)
Delayed Phase Sleep Disorder
When to Suspect This Disorder

Heavy snoring or patient experiences sudden awakenings
with subjective apnea or struggling for breath.
The patient does not snore, snort, or struggle but has frequent periods of apnea lasting 10 seconds or more.
Repeated episodes of twitching muscles ranging from
microscopic to gross limb movements. Twitches might or
might not be noticeable to bed partner.
Typical night owl pattern. Patients usually feel much
better when they can keep to their preferred sleep cycle.192,
193
Alpha-Delta Sleep Disturbance
Narcolepsy
Anxiety, Depression, and/or

Chronic Pain
This disorder is common in patients with FMS or other

chronic pain syndromes. Alpha wave intrusion is associated with reduced time in deep stage 3 and 4 delta sleep.
This intrusion causes non-restful sleep.
Profound daytime sleepiness is the hallmark, often to the
point of falling asleep inadvertently.
Often complicate CFS. These tend to make the sleep disturbance worse.
25
Comments
Fairly common. Bed partner may be aware, especially if they are asked to observe for typical signs.
Less common, but less obvious to an observer.
Non-restful sleep might be the only symptom.
A common syndrome that may be more common
than average among patients with CFS.
Conscientious scheduling, bright light in the AM,
low dose Melatonin in the early evening, and
appropriate sleeping medication can help significantly.
Tricyclic antidepressants, cyclobenzaprine and
trazadone tend to restore more normal sleep architecture.190
Insufficient hours or poor quality sleep cause
daytime sleepiness that can mimic narcolepsy.
Recognizing narcolepsy requires the physician to
maintain a high index of suspicion.
Treat conditions as appropriate.
that that implies. Patients with CFS as a group tend to be

more sensitive than average to medication side-effects.
Even modest improvements in sleep quality can
make a meaningful difference in the quality of life of a
patient with CFS. However, better sleep is not, by itself, a
cure for CFS. Exercise intolerance and subjective fatigue
typically remain problems even after sleep improves.
Sleep specialists recommend an important role for
sleep hygiene and behavioral techniques. Ideally, a nurse
or patient educator would spend an hour with each patient
to review basic sleep hygiene and relaxation skills. Attention to these details can often make a major difference.
Table 6-2 lists basic principles of sleep hygiene that
should not be overlooked in patients with CFS.
Additional and more complex behavioral techniques
can often help sleep problems of any kind, especially
those where the overnight sleep test fails to disclose specifically treatable pathology192, 193, 196 (See Table 6-3).
degree of confidence without professional monitoring,

utilizing an overnight sleep study. We would recommend
that all patients with chronic insomnia or chronically nonrestorative sleep be evaluated in consultation with a sleep
specialist whenever cost or third-party payment is not an
issue. Therefore, clinicians should exercise judgment for
each patient regarding the indications for a formal sleep
evaluation. It is important to note that some patients with
CFS have relatively normal overnight sleep tests. These
patients also describe their sleep as not restful. The patients subjective report should be respected as valid and
be taken seriously.
Non-Pharmacologic Treatment of Sleep Problems in
CFS
Trial and error may be productive. Techniques that
work for one patient often fail for others. Often, longterm, rather than short-term, treatment may be needed,
with all the trade-offs of potential medication side effects
Table 6-2
Principles of Sleep Hygiene for Use in Patients with CFS
Discuss whether medications might be disrupting sleep, e.g. decongestants, diet pills, or stimulating antidepressants. Evening caffeine or
alcohol are often a problem.
Keep your sleep schedule regular. Shifting sleep time tends to disrupt sleep. Create a habit pattern of staging down your activities throughout
the evening. This process will help condition your body to expect to be able to sleep. Consider turning the TV off early. Try music or dull
reading.
Keep the bedroom dark and quiet and the mattress comfortable. Leave marital conflicts outside.
Bed should be used only for sleep and sex. Move to a chair or couch when not engaged in either.
Clear your mind of this days events and the next days worries. For example, write down your regrets and plans, then lock them in a drawer
so you can go back to them tomorrow.
Dont exercise just before bedtime. (Even relaxing meditation might make you too alert for sleep.)
Take a hot bath in the early evening. While it initially prompts alertness, drowsiness then follows as your body temperature drops.
Take a modest carbohydrate snack or warm milk before sleep which promotes drowsiness for some.
Use relaxation tapes, imagery, slow diaphragmatic breathing, or meditation.
Use ear plugs if it is too noisy. If it is too light, consider eye shades.
Use white noise (e.g. a fan) or calm music to soothe out and block out unwanted sounds.
Table 6-3
Behavioral Techniques for Sleep Onset Insomnia
Technique
Sleep Restriction/Consolidation Therapy
Paradoxical Intention
Relaxation Skills
Cognitive Therapy
Comment
Restriction of the total time in bed to 4 hours or less, whether patient actually sleeps or not.
As the proportion of time sleeping increases, the time allowed in bed is extended. This technique often increases the proportion of time that one is actually asleep.
Trying to stay up later may help put patient to sleep
Diaphragmatic breathing, visual imagery (e.g. counting sheep), muscle relaxation.
A form of brief psychotherapy that improves coping skills, e.g., not turning molehills into
mountains. Several studies show that cognitive therapy can improve quality of life in CFS.
Other forms, e.g., psychodynamic approaches might also be helpful, but have not been formally tested for CFS (See Chapter 5).
If chronic pain, sleep apnea, PLMD, anxiety or depression is a dominant problem, these symptoms should
Pharmacologic Treatments for Insomnia or NonRestorative Sleep
26
chronic pain. However, because of their long action, they

are often too sedating in the morning.192, 193 When used
for sleep, the tricyclics or trazadone (Desyrel) usually do
best at lower doses than are needed for treating depression. The most commonly used tricyclics, listed in order
of increasing sedation and increasing side effects: nortriptyline (Pamelor), doxepin (Sinequan) and imipramine
(Tofranil), as well as amitriptyline (Elavil).
For the tricyclics, low doses, e.g., 10 mg, can be
used at first. A few very sensitive patients might start with
1-2 mg of doxepin suspension), with stepwise increases in
dosage steps toward the 20-50 mg range. If also treating
depression, the increase can proceed to the usual full
therapeutic doses (75-150 mg). For trazadone (Desyrel), a
starting dose of 25-50 mg qhs is adequate. If necessary,
one can increase in steps toward the 150 mg range. When
using these antidepressant medicines, sleep benefits are
often seen the first night. This result contrasts with the
relatively high dose range and 3-4 weeks typically needed
to see effects for depression. Yet, maximum sleep benefit
probably takes several weeks.
Antidepressants can be useful sleep aids whether or
be addressed with their standard treatments. Whether or

not these disorders complicate sleep, pharmacologic
regimens specifically for sleep can be very useful (See
Table 6-4).
Sleep problems among many CFS patients are
chronic, not intermittent. While limiting sleep medicine to
intermittent use is a desirable goal, there may be good
medical and psychological reasons to encourage chronic
ongoing treatment. If sleep medicines are to be used
regularly, it is advantageous to use those medicines,
which are less likely to disrupt sleep architecture or to
induce tolerance or addiction. The physician should be
prepared to test a number of different sleep medicines.
Some patients do well with a combination of sleep medicines, each at a relatively low dose. A few may benefit by
rotating a different sleep medicine every night or every
few nights. Patients with CFS tend to be very sensitive to
medicine side effects, so it is often wise to start with new
medicines with a very low dose.
For better sleep, the first choice should often be either antidepressants, such as trazadone (Desyrel) or the
sedating tricyclic antidepressants, e.g., amitriptyline.
Table 6-4
Commonly Used Medicines for Sleep
Classification
Medication
Prominent Side Effects
Comments
Tricyclics
Amitriptyline (Elavil)
Doxepin (Sinequan)
Nortriptyline (Pamelor)
Antidepressant Misc.
type
Trazadone (Desyrel)
Muscle relaxer
Cyclobenzaprine (Flexeril)
Clonazepam (Klonopin)
Temazepam (Restoril)
Lorazepam (Ativan)
Estazolam (ProSom)
Guazepam (Doral)
Triazolam (short-acting)
Diphenhydramine (Benadryl)
Zolpidem(Ambien)
Zafeplon (Sonata)
Dry mouth; dizziness
Similar to the tricyclics
Useful for sleep onset and

maintenance, perhaps also
FMS
Often used for FMS
Tolerance; habituation;
antegrade amnesia; respiratory depression
Different drugs of this

class interact adversely
with specific SSRIs
Can help PLMD; duration

of sedation varies with
individual
Prolonged sedation; dry

mouth; urinary obstruction
Dizziness, amnesia, anxiety
Phenothiazines; MAO
inhibitors
Sertraline, rifampin, cimetidine
Aspirin
Ibuprofen
Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Gastritis, gastro-intestinal
bleeding, allergic reactions,
renal problems, fluid retention
Coumadin, cyclosporine,
(See package insert for
individual agents)
May be useful when other

medications not tolerated
May be habituating in
high doses or with prolonged use. Short-acting
May help sleep by reducing pain; A few individuals report sleep benefit
even if not in pain
Benzodiazepines
Sedating antihistamines
Non-benzodiazapine
hypnotic agent
NSAIDs
These medicines usually

nance insomnia, or sleep
sleep. They can be useful
sleep abnormality that is
Prolonged sedation; dry

mouth; tachycardia; urinary obstruction; weight
gain; heart arrhythmia;
conversion of depression to
manic phase
Priaprism (rare); dry
mouth; heart arrhythmia
Prominent Drug Interactions

Drugs metabolized by
P450 2D6, e.g. cimetidine;
quinidine; some SSRIs;
MAO inhibitors (contraindicated); anticholinergic
agents
Digoxin, phenytoin
do not disrupt sleep, maintearchitecture and may improve

for suppressing the alpha-delta
often seen with FMS or with
Especially useful in FMS,

caution if heart arrhythmia
not the patient is depressed. Also, some patients experience a paradoxical effect, becoming more agitated and
unable to sleep. For sleep onset insomnia, consider shortacting agents, such as zafeplon (Sonata) or triazolam
27
(Halcion). For sleep maintenance insomnia, consider zolpidem (Ambien) or one of these benzodiazepines: clonazepam (Klonopin), temazepam (Restoril), or lorazepam
(Ativan). Flurazepam (Dalmane), a long-acting benzodiazepine, usually leaves patients too sedated in the morning.
Benzodiazepines have a relatively high potential for
abuse, tolerance, habituation, and abuse. Ambien, a nonbenzodiazepine, has less potential for tolerance and perhaps also less for habituation. However, Ambien is not
entirely free from the risk of addiction. Transient amnesia
has been reported for benzodiazepines as a class, especially with triazolam.
In PLMD, employ a very brief diagnostic trial of
dopaminergic agonist, which is a moderately effective
treatment for PLMD, e.g., Sinemet 25/100. If subjective
sleep quality improves, consider PLMD as fairly likely.
Do not continue to treat empirically. Confirm the diagnosis with an overnight sleep study. Lack of improvement
with Sinemet does not rule out PLMD. Various antidepressants have been reported to exacerbate PLMD in
some patients.
Almost all sleeping medicines should be used with
caution for people who have to be alert when they first
wake or throughout the day. Most hypnotics will also
potentiate the sedating effects of alcohol and other sedating drugs. Use in pregnancy should be coordinated with
an obstetrician (See Chapter 9).
All of these natural products can potentially interact with

selected drugs or with specific nutrients or herbs. Books
on this topic and computer data bases in health food
stores and pharmacies are beginning to be available.203
Complementary Medicine Therapies for Sleep

There are several over-the-counter medications that
patients with CFS may use as sleep adjuncts. A few are
listed below:
might also help anxiety. Current evidence suggests

that Valerian does not usually impair mental or motor
performance, although some people find it too sedating to take during the day. It does not seem to be
addictive. There are no substantial long-term studies
of safety or benefit.199, 200
Lemon balm, hops, passion flower and skullcap are
other less well-studied herbs that might have value
for sleep and that are sometimes combined with Valerian.
5-Hydroxytryptophan (5 HTP) is available in health
food stores. Tryptophan is available by prescription
from compounding pharmacies. These are biochemical precursors to the neurotransmitter Serotonin (and
also melatonin). They might be effective for helping
sleep onset.201 Tryptophan or 5 OHT should not be
taken with SSRIs or other drugs such as MAOs that
affect serotonin, since hyperserotonin syndrome has
been reported. A tainted batch of tryptophan once
caused an epidemic of eosinophilic myalgia syndrome, including fatalities.
Lavender extract, used as aromatherapy, showed
benefit for sleep onset insomnia and accompanying
anti-anxiety effects in studies. No side effects are expected.202
Conclusion
Sleep disturbance is a major problem for patients
with CFS. Sleep studies will often disclose some abnormality. Pharmacologic and non-pharmacologic measures,
including cognitive therapies, can be of benefit .
Complementary medications available over-thecounter may be of help to some patients. When sleep dysfunction remains persistent and severe, a formal consultation with a sleep physiologist should be obtained.
Melatonin is probably effective for a small minority

of persons with insomnia, especially among the elderly. Little is known about potential long-term side
effects or drug interactions. It is probably useful for
delayed phase sleep disorder and for jet lag.93, 197, 198
Valerian Root is a mediocre short-term sedative.
However, at least 3 double-blind studies from Germany show benefit for sleep and for mood after 3-4
weeks of taking Valerian, 300 mg, bid. Valerian
28
Dizziness in CFS
Julian Stewart, MD, PhD
OI requires symptoms. For example, the incidence of

false positive faints during head-up tilt is high. If the
complaining symptoms are not reproduced, but the patient
has a simple faint, the test is judged as negative or, alternately, a false positive. It is not a sign of OI. Other patterns of hemodynamic disturbance seem invariably associated with symptoms and are more reliable indicators of
chronic impairment.
The normal response to HUT is a modest increase in
heart rate (See Figure 7-1), by 10-20 beats/min, without a
fall in systolic blood pressure. Abnormal tilt test responses can be used to categorize patterns and physiologic types of OI. The overall patient assessment of chronicity and severity of impairment should be combined
with these data to reach any conclusion concerning the
nature of OI in a particular patient. In addition to the
normal pattern, three typical patterns of OI are depicted in
the figures, which show the systolic blood pressure and
heart rate in patients during upright tilt.
atients with CFS classically complain of dizziness,

particularly with changes in posture. Orthostatic intolerance (OI) can be defined as the development of
symptoms during upright standing, relieved by recumbence. Acute orthostatic intolerance is usually manifested
as syncope (fainting). Many syncopal patients have no
intercurrent illness; between faints, they are well. Chronic
OI also occurs; the medical history is used to determine
chronicity. Defining symptoms of chronic OI include dizziness in all patients with a high incidence of altered vision (blurred, white outs, black-outs), fatigue, nausea,
and palpitations. A large fraction of patients also experience headache, tremulousness, difficulty breathing or
swallowing, sweating, pallor, and other vasomotor
symptoms.
Patterns of OI are determined by an orthostatic
stress test, i.e., a means by which upright gravitational
stress can be imposed in a controlled fashion and the
physiological response monitored in detail. While standing can be used, individual differences and patient motion
may make this difficult. Therefore, the standard of orthostatic assessment is the head-up tilt table test. Head-up tilt
(HUT) was used for research purposes for decades. It was
first used as a clinical orthostatic stress test in 1986.204
The device comprises a table driven by an electrical motor with a supportive footboard enabling positioning of a
patient at varying angles of upright tilt. Although it would
seem that an angle of 90o is most physiologic, this angle
usually induces too many false positives (patients with no
history of OI who have intolerance induced during testing). Therefore, lesser angles, such as 60o or 70o, are customarily used.205, 206 Following a resting period, the patients are placed upright. Their response over a period of
tilt is assessed, usually anywhere between 30-45 minutes.
At a minimum, blood pressure and continuous electrocardiography are assessed. Typically, a form of continuous
blood pressure assessment, such as finger plethysmography or arterial tonometry, is used. Respirations are also
assessed on a moment-to-moment basis. Other researchers
have used methods to assess peripheral, thoracic (chest),
and central nervous system blood flow. Many laboratories
use medications, often isoproterenol, to enhance the
fainting response which produces more true positive tests
(and more false positives), but lacks a physiological rationale. The central purpose of a tilt table test is to reproduce symptoms of OI in a setting in which hemodynamic
variables, such as blood pressure, heart rate, and blood
flow, can be assessed. Most often, there is correlation
with changing physiological signs, but the definition of
Classic Simple Faint (Vasovagal Syncope)

Simple faint is a form of syncope. Syncope is defined as a sudden transient loss of consciousness with loss
of postural tone and spontaneous recovery caused by impaired blood flow to the central nervous system. Impaired
flow is usually, but not always, caused by low blood pressure. Syncope may occur supine or upright and under a
wide variety of conditions. It may be due to medication;
cardiac disease, most commonly arrhythmic disease; or
severe impairment of cardiac blood flow caused by mechanical pump failure or obstruction. It may be due to
transient impairment of central nervous system function,
as in a transient ischemic attack (mild stroke), but this
cause is less common. However, although convulsive-like
movements may occur during syncope, it is distinct from
Figure 7-1
Normal Patterns of Blood Pressure Changes Seen
with HUT Testing
150
130
Normal
Blood pressure (mmHg)
Heart Rate (BPM)
126
102
Supine
78
54
114
98
82
66
Til
50
30
0
1000
Beat Number
29
2000
1000
Beat Number
2000
a seizure disorder and is distinct from coma, in which loss

of consciousness is not transient at all.207 Cardiac syncope
is often quite serious and should be regarded as lifethreatening. Although cardiac syncope is not often closely
associated with orthostasis, it may be. Causes of cardiac
syncope include the long QT syndrome, arrhythmogenic
right ventricular dysplasia, cardiomyopathies, left ventricular outflow obstruction, myocardial infarction, primary pulmonary hypertension, and most commonly ventricular tachycardia, bradyarrhythmias, and related arrhythmic events.208 The first job in evaluating syncope is
to evaluate the patient for possible cardiac syncope. Cardiac syncope may first manifest during exercise, which is
the best and most physiologic stressor of the myocardial
circulation and overall cardiac function.209 Nevertheless,
the large majority of exercise-related syncope is noncardiogenic in origin, at least for children and adolescents. Cardiogenic syncope is not common in patients
with CFS and will not be regarded further. There are numerous excellent texts on the subject.
A large fraction of syncope is either neurocardiogenic or unexplained. Often, the unexplained variety is
reclassified as neurocardiogenic once tilt table testing has
been performed.210 Neurocardiogenic is the current term
for fainting mediated through a combination of inappropriate vascular and heart rate control. It is rarely fatal
although it can be under certain unique circumstances
(e.g. driving a car) but it can be injurious. There is little
compelling evidence for a primary role for the heart in
neurocardiogenic syncope, once cardiogenic syncope has
been ruled out. The term is thus somewhat misleading.
Synonyms for neurocardiogenic include neurally mediated syncope and vasovagal syncope. Almost all of neurocardiogenic syncope in children can be deemed vasovagal, an appropriate descriptive designation coined by Sir
Thomas Lewis211 in which the vaso prefix denotes dilation of blood vessels, and the vagal suffix denotes
slowing of the heart rate through stimulation of the vagus
nerve. Vasovagal syncope almost always occurs in the
upright position, which may sometimes include sitting.
Therefore, it is regarded as a form of OI. Vasovagal faint
is depicted in Figure 7-2. Typically, patients easily tolerate the early parts of tilt with little change in blood pressure or sensorium. Following a variable period of time, on
the order of 3 to 20 minutes, patients develop orthostatic
symptoms of nausea, dizziness, heat, heavy breathing, and
sweatiness associated most commonly with a small, initial
slow fall in blood pressure, which can be seen if the figure is inspected closely, and then an abrupt drop in blood
pressure and heart rate. The early fall in blood pressure is
coincident with a decrease in normal vasoconstriction.
Blood pressure and heart rate may plummet precipitously,
and asystole may occur. When this drop happens, there is
a rapid loss of central nervous system activity and often a
dysinhibition of peripheral neurologic responses resulting
Figure 7-2
Vasovagal Patterns of Blood Pressure Changes Seen
with HUT Testing
150
130
Vasovagal
Heart Rate (BPM)
126
102
78
Til
54
114
98
82
66
Supine
30
50
0
400
800
1200
1600
Beat Number
2000
400
800
1200 1600 2000
Beat Number
in muscular movements mimicking a tonic-clonic seizure.

This is denoted convulsive syncope. The absence of true
seizure activity was confirmed as early as the 1950s by
Gastaut and associates212 and later reconfirmed using
HUT methods by Grubb and coworkers in the 1990s213
Such episodes, while relatively uncommon, are quite
dramatic.
Mechanisms for Vasovagal Faint
The most popular proposed mechanism holds that
fainting results from an errant stretch reflex from the left
ventricle. The reflex is activated by an underfilled due to
reduced venous return, overly contractile due to sympathetic activation, left ventricle. This results in a paradoxical reflex mediated by unmyelinated C-fiber nerves arising from the left ventricle to the nucleus tractus solitarius
in the CNS and causing vagally mediated bradycardia, as
well as vasodilation.212, 214 Treatment by increasing blood
volume should help relieve underfilling, while negative
inotropic contractile agents should help to reduce cardiac
contractility. Both hypercontractility and decreased ventricular stretch have been called into question by recent
research.212, 215 Also, patients receiving cardiac transplants retain the ability to faint, which implies that the
ventricular receptor theory cannot explain all simple
faints. Other theories of fainting include epinephrine or
renin surges, which would rationalize the common use of
isoproterenol as adjunctive provocation.212, 216 Such
surges do occur in those who faint and take some minutes
to develop. However, it remains unclear whether these are
the cause of the hemodynamic abnormalities or a response to decreased blood pressure during faint. A decrease in cerebral blood flow has also been shown to occur in syncopal patients and may precede a large fall in
blood pressure.212, 216 However, blood flow is similarly
impaired in chronic OI in which hypotension does not
usually occur.212, 217 Other proposed mechanisms include
changes in CNS neurotransmitters, such as serotonin,
norepinephrine, neuropeptide Y and substance P. Causation has not been established. In summary, it is fair to say
30
that we still have no precise understanding of the mechanics or the mechanism of simple faint.
Figure 7-3
Dysautonomic OI Patterns of Blood Pressure
Changes with HUT Testing
Dysautonomic OI
Included in this group are patients with true orthostatic
hypotension defined by the American Autonomic Society
to be a persistent fall in systolic blood pressure of >20
mm Hg within 3 minutes of assuming the upright position.205 This group includes patients with autonomic failure. Autonomic failure comprises primary forms, such as
primary autonomic failure and multiple system atrophy,
and more common secondary forms as occur with Parkinsons disease and diabetes. Dysautonomia may also be
drug-induced. Pediatric causes are rare and include familial dysautonomia as the only relatively common variant.218 Acute forms may occur during infectious and inflammatory diseases or be related to peripheral nerve
disease, e.g. Guillian-Barre syndrome. Using standard
tests of circulatory autonomic function, such as timed
breathing and the quantitative Valsalva maneuver, patients show signs of circulatory autonomic dysfunction.
Rarely do patients with CFS have circulatory abnormalities that fulfill generalized dysautonomic criteria. However, isolated autonomic changes may occur in some patients with CFS. Findings in dysautonomia may include
pupillary, gastrointestinal, and sweating abnormalities.
Neurologic damage, such as occurs in cerebral palsy and
trauma, may result in some autonomic dysfunction, in
addition to other neurologic disability. Responses to orthostasis in such patients differ from those in truly
dysautonomic patients in that compensatory mechanisms
may adapt the patient to orthostasis, e.g. increased blood
volume, which seldom occurs in the dysautonomic.
Dysautonomic OI is depicted in Figure 7-3. Blood
pressure falls while there is usually no important change
in heart rate throughout the course of the tilt. The appropriate heart rate response of the arterial baroreflex to hypotension is tachycardia, which fails to occur in these
illnesses. Dysautonomic patients may be so brittle that
they are hypertensive supine, hypotensive upright, and
may lose consciousness due to overzealous splanchnic
vasodilation, possibly due to vasoactive intestinal polypeptide, after a heavy meal.
150
130
Dysautonomic
Heart Rate (BPM)
126
102
78
Supine
114
98
82
66
54
30
Til
50
1000
2000
400
800
1200
1600
2000
Beat Number
Beat Number
thostatic disability and is present in virtually every patient

with sustained OI.226 Based on published Vanderbilt data,
some 30% of POTS patients fulfill criteria for CFS. However, these data originate from a select patient population.
Our understanding of the pathophysiology remains incomplete. The central physical finding in POTS is upright
tachycardia, although hypotension and resting tachycardia
may also be present. An operational definition of the syndrome includes symptoms of OI associated with an increase in heart rate from the supine to upright position of
more than 30 beats per minute or to a heart rate greater
than 120 beats per minute within 10 minutes of head-up
tilt (HUT). Such a response is depicted in Figure 7-4. In
the case shown, the patient became immediately symptomatic following the start of HUT and required the table to
be put down within a very few minutes. Although this
patient was not hypotensive, hypotension may follow or
occur with tachycardia. Often, it is delayed beyond the
onset of the symptoms and of the tachycardia, and only
shows up during the artificially sustained orthostasis enforced during HUT. Onset of symptoms often follows an
infectious disease and may be related to inflammatory
mediators.227 Data from the reports of the first pediatric
cases showed that POTS physiology underlies OI in the
large majority of adolescents with CFS.105, 228-230 POTS is
Figure 7-4
POTS (COI) Patterns of Blood Pressure Changes
with HUT Testing
Chronic OI and POTS

The postural tachycardia syndrome (POTS) is a disabling disease state described at least since 1940219 and is
the most common reason for referral for OI220-225 in
adults. It is an emerging form of OI in children. Patients
have day-to-day disability, a feature not shared with those
with simple faint. With some exception, traditional tests
of autonomic function are normal in these patients. Patients are often unable to hold jobs or attend schools.
Studies at the Vanderbilt autonomic laboratories have
stated that this is the most common form of chronic or-
150
114
Heart Rate (BPM)
126
102
Supine
78
Til
54
98
82
66
50
30
0
400
800
1200 1600
Beat Number
31
130
POTS (COI)
400
800
1200 1600 2000
Beat Number
tive mechanisms. Blood is redistributed peripherally and

redistribution is enhanced during orthostasis, producing
increased microvascular filtration and dependent edema.
Central hypovolemia causes reflex tachycardia, reduced
cerebral blood flow and hypotension. POTS results in a
circulation at high risk for simple fainting by virtue of a
depleted thoracic vascular bed. In many ways it resembles
hemorrhage or hypovolemia in that tachycardia and malperfusion are noted first, which may then proceed to hypotension or loss of consciousness or both.
common, affecting an undisclosed number of patients

mostly in the age range of 12 to 50 years, mostly female,
approximately 80%. There is an as yet undetermined, but
increasing, apparent prevalence in children and adolescents.229 The spectrum of illness closely parallels findings
in CFS.
Patients with the syndrome display an unusual
amount of pooling in the lower extremities often associated with acrocyanosis. The literature contains a number
of potential explanations for pooling and fluid collection
in POTS, including impaired innervation of the veins or
in their response to sympathetic stimulation.221 One such
explanation favors an autonomic neuropathy that predominantly affects the lower extremities.225, 231 1adrenergic denervation hypersensitivity results. A second
explanation invokes decreased 1- receptor sensitivity,226
a third, 1-receptor supersensitivity,224 a fourth, altered
venoconstriction,224 while a fifth232 suggests increased
capillary filtration as an explanation. However, 1adrenergic control of venous filling in response to baroreflex stimulation during orthostasis is important only in
skin and splanchnic circulations in humans,233-235 while
involvement of skeletal muscle 2-receptors remain controversial.233 -adrenergic effects may also alter venous
filling, but only indirectly through arterial vasoactivity,233,
236
and this mechanism may be most important during
exogenous -adrenergic agonist administration, isoproterenol, or during endogenous epinephrine release later
during HUT. It is uncertain how important active venoconstriction is to the orthostatic response.
Finally, venous capacitance properties in POTS
could be abnormal because of altered vascular structure,
altered muscle tone or both. A link with antecedent inflammatory disease is the chronic elaboration of cytokines, with potent vasoactive consequences, such as IL-1,
IL-6 and TNF. Such a link seems established in CFS in
which POTS and neurally mediated hypotension (actually
POTS) occur with high frequency.134, 237 Most recently,
Robertson and associates have isolated an aberrant gene
for the norepinephrine reuptake transporter protein, producing alternations between hypertension and hypotension in the same patient and her twin sister, dependent on
norepinephrine stores.237 This gene seems for now confined to a single family. Such results, however, highlight
the likelihood of different types of inherent vascular abnormalities, resulting in a common pathway of postural
tachycardia and symptoms of OI.
Preliminary data230 suggest the hypothesis that blood
pooling in patients with CFS with POTS results from a
defect in arterial vasoconstriction during orthostasis,
causing increased venous filling and enhanced microvascular filtration, leaking from the capillaries. This defect
may be due to central nervous system dysfunction, postganglionic dysfunction, or abnormal local vasoconstric-
OI in CFS
Much has been stated and written about OI as it applies to CFS, which has been confusing at best. Some of
the confusion originates from recent appreciation of the
clinical variants of OI, some from our emerging understanding that a variety of pathophysiologies underlie OI,
and some from nomenclature that seems to change nonstop.
The symptoms of CFS closely match those of
chronic OI, and research suggests that OI plays a role in
the symptomatology of CFS. Recent investigations support the hypothesis that findings in patients with CFS
result at least in part from impaired blood pressure and
heart rate regulation. OI has been implicated. In their initial observations, Rowe and coworkers134, 238 produced
neurally mediated hypotension in twenty-one of twentytwo adult patients with CFS using HUT. These observations have led investigators to propose that there are
autonomic defects in CFS.39, 237, 239-241 In earlier work,
Rowe, et. al., reported somewhat different findings in
adolescents with CFS who had tachycardia often associated with hypotension during orthostasis.238
The reported incidence of OI in CFS from other
laboratories is much more variable. A large factor has
been the criteria used to diagnose OI. Rowe, for example,
defined orthostatic hypotension in CFS by the presence of
hypotension, which is a somewhat restrictive definition
excluding many patients from consideration who otherwise would meet criteria for orthostatic hypotension.
Diagnosis of OI in CFS
The diagnosis of OI is often made on historical
grounds with typical symptoms guiding the evaluation
and treatment. These symptoms need to be chronic for the
diagnosis. Fainting may be present, but this is seldom the
case in CFS with POTS, unless patients are maintained
upright for an extended and abnormal time period. Acute
syndromes can represent other illnesses, which should be
ruled out. Physical examination is often unrewarding,
although resting tachycardia, pallor or acrocyanosis and
mottling of the extremities may be important clues.
Chronic sinus tachycardia may be suggestive, but other
causes, such as other arrhythmias, catecholaminessecreting tumors, and hyperthyroidism need to be elimi-
32
has been recently questioned. Its primary mechanism of

action is through sodium and water retention at the expense of some potassium wasting. In addition, Fludrocortisone may aid in sensitizing alpha-receptors and blocking
vasodilation. Fludrocortisone has modest, if any, corticosteroid side effects. A new, direct-acting alpha-1 agonist,
midodrine proamatine, given as 5-15 mg/dose (spaced 4
hours apart, three times a day) has been used to good effect in many patients with assorted forms of OI. This
medication treats a deficit in norepinephrine-related vasoconstriction. Other interventions have included alpha-2
adrenergic agents, both clonidine and yohimbine, which
have been used in select patients. Disopyramide has been
used occasionally, but controlled studies do not support
its efficacy.228
Recently, selective serotonin reuptake inhibitors
have been used to good effect in a variety of orthostatic
disabilities. These seem to interfere with hypotensive
responses at a central level. Grubb and associates have
demonstrated efficacy of sertraline and fluoxetine in a
series of controlled studies.242, 243 The studies were performed after careful psychiatric screening had ruled out
significant depression. Personal experience bears this
theory out and the SSRIs remain a useful form of therapy
for many forms of OI. It remains unclear whether any
treatment repairs any specific defect. Medical therapy
must therefore continue to be regarded as palliative.
Effective and specific treatment for chronic OI can
only be developed when a specific etiology or etiologies
are discovered. It seems likely that even when there is
clinically diagnosed POTS, CFS remains heterogeneous
with a variety of specific etiologies, giving rise to common clinical features.
nated. A standing test can be helpful. The blood pressure

and heart rate should be monitored every minute and the
patient needs to be immobile while standing. Also the test
should be performed in garb suitable for observing both
the upper and lower extremities. An excessive increase in
heart rate with symptoms defines POTS. Pulse pressure is
often decreased, despite maintained systolic BP in most
patients. Diastolic pressure is therefore high and reflects a
marked decrease in stroke volume.
Treatment of Vasovagal Faint and OI in CFS
Without a clear mechanism, there is no clear treatment. Moreover, many patients with infrequent simple
faints, who do not injure themselves and who do not have
convulsive syncope, may require no specific therapy, except for training in aversive maneuvers. However, there
are some general maneuvers and forms of treatment that
have been successfully used in syncopal patients, POTS
patients, dysautonomic patients, and patients with CFS
alike.
The simplest of these maneuvers is lying down.
Also, leg crossing, bending at the waist, squatting and
other physical maneuvers may be effective. Increased
fluid and salt intake is always helpful in ameliorating the
initial thoracic hypovolemia of orthostasis. Raising the
head of the bed while sleeping will retain fluid overnight
and decrease early morning lightheadedness. Lower body
exercise, particularly isometric exercise, can be a genuine
help by enhancing the muscle pump and by increasing
venous tone in the lower extremities. Elastic support hose
can be useful at times, but are often unacceptable to children and adults alike. Other investigators have advocated
a regimen of progressively longer quiet standing as a form
of orthostatic training.225
In terms of medication, beta-1 blockade works well
in some forms of syncope possibly by blunting the release
of epinephrine or renin, which are modulated by beta-1
receptors and by its central effects. Beta-1 blockade is
usually unsuccessful for treating POTS in which sympathetic compensatory mechanisms may already be maximally taxed. Fludrocortisone (Florinef) in doses ranging
from 0.1 to 0.4 mg/day has been a mainstay for palliative
therapy of all forms of OI, although its efficacy in CFS
Conclusion
The evidence is clear that OI plays a key role in the
pathophysiology and symptomatology of patients with
CFS. Recent scientific investigations have broadened the
scope of orthostatic abnormalities to include a wide range
of illness in which blood flow and blood pressure regulation are impaired. Several treatment modalities may improve the symptoms resulting from POTS associated with
CFS.
33
34
Pain in CFS
Alan Lichtbroun, MD
Although CFS and FMS share many similar symptoms, including myalgias, sleep disturbances, decreased
cognition, and neuroendocrine immune imaging study
abnormalities. There are few differences between these
syndromes, as well.
FS, FMS, and multiple chemical sensitivities syndrome (MCSS) are clinical syndromes that are
poorly understood in terms of cause, pathophysiology,
natural history and appropriate medical management.
Despite their different diagnostic labels, some data suggests that these illnesses may be similar conditions. In one
major study, 70% of patients with chronic fatigue syndrome when given the appropriate physical examination
met the criteria for FMS.244
CFS and FMS may represent a continuum of pain
and fatigue in the population at large, rather than discrete
diseases.245 However, the concept of FMS and CFS as
clinical syndromes has been useful both for epidemiologic and therapeutic studies.246 In the most recent American study, the prevalence of FMS in the general population was 2%.246 This prevalence increased with age,
reaching 7% in women from ages 60-80 years. Eighty to
90% of patients have been female.
This chapter will discuss the concept of pain found
in FMS and CFS, as well as discuss specifically where
pain in the two disorders may have different pathophysiologies. There have been tremendous advances in
the concepts of central pain mechanisms. We will discuss
what causes pain amplification in FMS and by extension
the cause in many cases of pain in CFS.
Pathophysiology
If pain is the sensation, nociception is the process.
The three components of nociception are: the site of the
body where the stimulus occurs; the spinal cord, where
the signal is chemically processed; and the brain, where
the pain message is interpreted for the signal location and
its magnitude. In FMS, nociception mechanisms are activated and pain is chemically amplified in the spinal cord
by a process known as central sensitization.
Normally, a stimulus from the peripheral tissue is
transmitted to the spinal cord by the unmyelinated A-delta
fibers and C fibers. During central sensitization, large
myelinated fibers can be recruited to participate in nociception transmission. These neurons have contact with the
spinal neurons and transmit signals much more rapidly
than A-delta and C fibers. Usually, these fibers carry messages of proprioception and soft touch. During central
sensitization, excitation of these fibers by relatively normal stimuli is interpreted by the cord and brain as if it
were a pain signal. We will discuss later the role of substance P, as well as nerve growth factors, in mediating
this switch.
Once an efferent neuroelectric signal reaches the
dorsal horn area, it becomes chemically mediated. There
are several chemical agents that facilitate the transmission
of this message. Among them are substance P, which is a
potent vasoactive peptide that also appears to be involved
in pain and temperature. The C terminal peptide of substance P and other excitatory amino acids, such as glutamate, aspartate prostaglandins, and nerve growth factors
stimulate the growth of neurons containing substance P.
Other neurochemicals that are involved have the affect of
inhibiting nociception. For example, serotonin from the
raphae nucleus of the brain stem, released in the region of
the dorsal horn of the spinal cord, inhibits the release of
substance P, thus down-regulating nociception.
After the magnitude of the afferent pain signal has
been determined, a spinal neuron is activated. The signal
then crosses the spinothalamic tract on the side contralateral to the original stimulus and travels up to the brainstem to the thalamus. From there, the signal projects to
the cingulate cortex or gyrus cinguli and the sensory motor cortex.
FMS Symptomatology
The current concept of FMS was ushered in by
studies from Smythe and Modofsky in the mid-1970s.247
They described that certain anatomical locations, termed
tender points, were more tender in patients than in controls. They also reported that patients with FMS had a
stage 4 sleep disturbance, and that experimental selective
stage 4 disturbance produced the symptoms of muscle
tenderness consistent with FMS. The diagnostic utility of
tender points was verified by a series of reports in the
1980s from different observers.
A North American multicenter criteria committee
determined the American College of Rheumatology 1990
criteria for the classification of FMS.248 Two hundred
ninety-three patients with FMS and 265 control patients
were interviewed and examined by trained, blinded assessors. Controls were matched for age and sex. All had a
rheumatic disorder that could be easily confused with
FMS. The combination of widespread pain defined as
bilateral, above and below the waist, and axial, and at
least 11 of 18 specified tender points, yielded a sensitivity
of 88.4% and a specificity of 81.1%.
35
patients by the availability of NGF peripherally at the

actual site of inflammation or tissue injury. Knowing that
injections of NGF in the spinal fluid of mice causes increased pain sensitivity, Larsen postulates that bathing the
central portion of sensory fibers (spinal cord) might also
sensitize them to pain and increase their pool of available
substance P.
Failure of regulation by anti-nociception neurochemicals, such as serotonin, could at least partially account for this high level of substance P in FMS patients.
Tryptophan, an essential amino acid, is irreversibly converted to hydroxytryptophan, which could then be converted to serotonin. The serotonin can be metabolized to
five hydroxy indolacetic acid (5 HIAA), which has also
been found to be low in cerebral spinal fluid of persons
with FMS.19, 251
Platelets are the primary storage source of serotonin
in the peripheral blood. A study comparing the concentration of serotonin and platelets in persons with FMS
with healthy controls showed serotonin to be significantly
lower in platelets of persons with FMS. Platelet serotonin
in persons with FMS correlated with the average pain
threshold. An assay of 24-hour urine samples demonstrated that persons with FMS also excreted less urinary 5
HIAA than did controls. (This is not the case in patients
who do have CFS, but who do not also have FMS.)
It is well-established that FMS is more prevalent in
woman than in men. It is interesting that normal woman
synthesize approximately seven times less serotonin in
their brains than normal men. This difference may be why
women are at greater risk for the development of chronic
pain syndromes. Under experimental conditions that reduce tryptophan levels in the blood of normal men and
woman, serotonin production in the men declined by a
factor of seven, while that for women declined by a factor
of 42.252
Like any other complex physiologic process, nociception can malfunction. Allodynia refers to one type of
nociception dysfunction in which pain results from a
stimulus that should not normally be painful. Patients
with FMS experience pain from less than 4 kg per cm2 of
pressure at anatomically defined tender point sites, while
healthy, normal persons would interpret that same amount
of pressure as painless. Intense or chronic amplification
of nociception can produce a semi-permanent change in
neuro-circuitry and conductivity at several levels, causing
the allodynia to spread. This semi-permanent process is
then known as neuroplasticity.
To date, four independent investigations conducted
in the United States and Scandinavia have shown that the
cerebral spinal fluid (CSF) of persons with FMS contains
markedly elevated levels of substance P, compared with
normal controls.244, 249 The average levels of substance P
in the CSF of patients with FMS are 2-3 times higher than
normal. This increase causes or facilitates a major increase in pain perception. If the physician were to use this
information to evaluate levels of substance P in CSF as a
test for FMS against normal controls, it would be 84%
sensitive and 100% specific.250
In addition to the rewiring of peripheral nerves,
where C fibers and A-beta nerve endings in the spinal
cord begin to sprout and grow just like tree roots, finding
each other and causing nociception, there are also pain
amplifying systems within the spinal cord and brain that
can influence the excitability threshold. The n-Methyl-Daspartate (NMDA) receptors in the spinal cord are known
to play a key role. Excitatory amino acids, such as aspartate and glycine (as mentioned above), activate the
NMDA system, along with elevated levels of dynorphin
A. A recent report from Norway indicates that dynorphin
is also elevated in FMS patients.94
Recent research has shown that increased levels of
nerve growth factor (CNGF) bathing these A-beta and C
fibers that terminate in the spinal cord have been shown
to lead to this sprouting and rewiring of the large myelinated fibers (A-beta fibers) into substance P, producing C
fibers.
Nerve growth factors also increase fourfold in the
CSF of patients with FMS, compared to healthy controls.94 What is surprising about the research is that this
fourfold increase is found only in patients who have primary FMS. If patients had a secondary condition (secondary to another inflammatory condition, such as rheumatoid arthritis or a pain condition, such as osteoarthritis
and low back pain), there was no significantly elevated
NGF in their spinal fluid. Thus, elevated concentration of
NGF in the spine appears unique to primary FMS.
Although substance P is markedly elevated in FMS
spinal fluid, all three groups, i.e., primary, secondary, as
well as regional, pain disorders, had elevated concentrations of substance P that did not differ significantly. The
concentration of substance P is likely increased in these
Psychological Distress in FMS

Several lines of evidence suggest that psychological
distress is central to the pain experienced and in overall
morbidity in FMS.253, 254 Although not all agree, increased
psychological distress is a common characteristic of FMS.
Psychological distress is strongly correlated with the
number of painful tender points, not only in FMS, but
also in rheumatoid arthritis. In fact, the number of painful
tender points is almost linearly related to the level of distress. As noted by Wolf, the tender point count functions
as a sedimentation rate for distress, irrespective of a diagnosis of FMS.250 High levels of anxiety and distress,
together with less certainty that pain is going to resolve
and a history of trauma, are predictors of who progresses
from acute pain to chronic pain.
Patients who have been diagnosed with FMS can be
separated by the level of psychological distress into distinct groups ranging in severity from adaptive copers,
who do well clinically, to highly dysfunctional patients,
36
who respond to treatment extremely poorly.255 Consistent

with the pain/psychological distress relationship developed above is the improvement that we see in measures of
self-efficacy, coping, depression, and pain that accompanied the application of stress management programs. Psychological distress can also be found in CFS especially in
that subgroup of patients who go on to developing FMS.
Although stress comes from many sources, in CFS, both
the fatigue and, possibly more importantly, the uncertain
prognosis that these patients anticipate, both contribute to
this distress.
correlated inversely with clinical observations of weakness or pain, as measured on a visual analog scale (VAS)
(40). Reduction of ATP in erythrocytes of patients with
FM has been observed, suggesting that this may be a
more general systemic phenomenon than previously
thought.
Diagnosis
Both CFS and FMS patients have low levels of cortisol and CRH.261 FMS patients have low levels of insulin-like growth factor 1 (IGF-1) and growth hormone.262,
263
There is inconsistent data for these markers for CFS.
Persons with FMS have low serum levels of serotonin264
and low cerebral spinal fluid levels of serotonin metabolites. Persons with CFS have high plasma levels of serotonin metabolites.251, 254 FMS is also characterized by
high cerebral spinal fluid levels of two factors that promote pain: nerve growth factor and substance P,249, 265
which has not been evaluated yet in CFS.
MRI imaging studies of brain structures suggest that
persons with CFS are characterized by a high number of
cortical white matter lesions, compared to healthy individuals. There are no published MRI studies of the brain
structure in FMS. Resting state regional cerebral blood
flow using SPECT or PET imaging has produced different results for persons with CFS and those with FMS. The
patients with CFS studies generally have not produced
consistent results, although two studies found evidence of
brain stem hypoperfusion in patients with CFS. One recent British study found that patients with CFS show
higher levels of blood flow in the thalamus, compared
with healthy controls.266 In contrast, two studies from the
same laboratory reported that patients with FMS show
hypoperfusion of the thalamus and/or caudate nucleus
during resting conditions.267
Preliminary evidence from the same laboratory indicates that during exposure to painful pressure stimulation
on the right side of the body, healthy individuals display
significant increases in blood flow in the contralateral
somatosensory cortex, thalamus, and anterior cingulate
cortex.39, 268 However, persons with FMS, as well as those
with CFS who do not meet criteria for FMS, show bilateral increases in blood flow in the somatosensory cortex
and cingulate cortex.264 These findings suggest that both
FMS and CFS are characterized by alterations in neural
processing of sensory information.
On the other hand, neuroendocrine studies suggest
that in FMS hyperexcitability of the spinal NMDA receptors increases ascending sensory transmission to the
brain that enhances pain perception. Persons with CFS
usually experience musculoskeletal pain, but they do not
show abnormal sensitivity to pressure stimulation at multiple anatomic sites, unless they also meet the criteria for
FMS. Individuals with FMS exhibit lower pain threshold
levels than persons with CFS.249, 269 They are also better
than subjects with CFS and controls in discriminating
Abnormalities of Muscle and Mechanical Factors

The trapezius muscles of patients with fibromylagia
have significantly lower ATP, ADP, phosphocreatine and
energy charge potential, and increased AMP and creatine
than in normals.256 However, when controls were matched
for levels of exercise and activity, there were no significant differences either of muscle structures or metabolism. We now believe that the muscle abnormalities that
are sometimes found are secondary to inactivity and pain,
although a recent article by Lane, et. al., examined muscle
fiber characteristics and lactate responses to exercise in
105 patients with CFS, as opposed to classic FMS.257
Using doppler laser flowmetry and skin temperature
measurements with infrared thermometers, a recent article
revealed vasoconstriction in the skin above tender points
in patients with FMS, supporting the hypothesis that FMS
is related to local hypoxia in the skin above tender points
and reduces ATP synthesis via oxidative phosphorylation
in mitochondria.258
A recent observation found growth hormone production is decreased by 30% in patients with FMS, especially in the early morning, possibly associated with stage
IV sleep anomaly. Corticol releasing hormone (CRH)
promotes the release of somatostatin, an antagonist of
growth hormones. Lower levels of growth hormones also
lead to decreases in DHEAs. Decreased levels also lead
to impaired muscle anabolism, which makes patients with
fibromylagia more susceptible to muscle trauma.
A recent report demonstrated the presence of significant metabolic abnormalities in the muscles of patients
with FM, as detected by P-31 Magnetic Resolution Spectroscopy (MRS).259 The spectroscopy camera used for
measuring ATP, PCr, and inorganic phosphate (Pi) was
placed directly over the quadriceps muscles.
Absolute levels of both ATP and PCr were significantly lower (15%) in muscles of the patients with FM
than in the normal control subjects at rest and during exercise at 25% MV. These findings are in rather close
agreement with biopsy determinations, which showed
reductions in ATP and PCr of 17% and 21% respectively,
in tender sites of the trapezius muscle in patients with
FM, as compared with non-tender sites in the anterior
tibialis or with the muscles of normal controls.260 The
reduced levels of ATP and PCr in the patients muscles
37
nodules; skin sensitivity, in the form of skin roll tenderness or dermatographism or purplish mottling of the skin,
especially of the legs following exposure to the cold. This
condition is sometimes thought to be livedo reticularis,
but more accurately represents cutis marmorata. These
clinical findings are usually absent in patients with CFS
who do not have FMS. As opposed to CFS, patients with
fibromylagia do not present with adenopathy or fevers
unless the FMS is a component of another disorder, such
as SLE. (Lupus and other autoimmune diseases can be
differentiated by their specific symptoms, including arthritis, i.e., warm, swollen joints, pleurisy, nephritis and
more specifically positive anti-DNA antibodies as well as
low complement, all of which would not be found in either CFS or FMS).
CFS also can present with arthralgias or joint pains,
but usually not warm, swollen joints. These pains are often intermittent with flares and remissions, although in
many cases the joint pains can be continuos.
between high and low intensity stimuli that are presented

in random order.
A recent abstract compares tilt table responses in
chronic fatigue from FMS showing significant differences, indicating that the homeostatic response in FMS
and CFS may be different.269, 270 Lastly, immune modulation appears to be important in both disorders. CFS appears to be promoted by a TH 2 response. Activated T
helper cells from patients with CFS, unlike those of FMS,
produce fewer TH 1 cytokines and produce more IL-5
and TH 2 type cytokines (to preferentially stimulate cells
to produce antibodies). When FMS pain arises, substance
P appears to stimulate other cytokines, such as IL-8 and
IL-6. Since IL-8 produces myopathic pain, IL-6 induces
hyperalgesia. It is hypothesized that they play a role in
modulating FMS pain syndrome in CFS patients.254
With the above background, we should realize that
although significant differences exist between the two
syndromes, many patients with CFS may have FMS. The
concept of allodynia pain processing is pivotal in understanding and treating the associated pain of both disorders.
Therapeutic Approaches
Nonmedicinal Treatments
Although widely used in the treatment of FMS,
nonmedicinal therapy rarely has been studied in a controlled fashion (See Table 8-1). Those few treatments
evaluated in controlled studies include cranial electrotherapy, cardiovascular fitness training (CFT),271 biofeedback,272 hypnotherapy,273 and cognitive behavioral therapy.274 Forty-two patients with fibromylagia were randomly assigned to a 20-week program of CFT or a flexibility exercise program. Eighty-three percent of those
patients assigned to the CFT program improved their
physical fitness by incremental stationary bicycle riding.
There was significant improvement in tender point pain
threshold and in patient and physician global assessment
in the CFT group, but no significant differences in pain
intensity or sleep disturbances in the two groups.
Clinical Examination
The diagnostic utility of a tender point evaluation
has been objectively documented with the use of dolorimeter or algometer, pressure-loaded gauges that accurately measure force per area, and by manual palpation.
Such instruments are useful in controlled studies, but in
the clinic, digital palpation is usually adequate. The nine
pairs of tender points are by no means inclusive, but they
are representative.
On examination, patients usually appear well, with
no obvious systemic illness or articular abnormalities, but
complain of a diffuse deep muscle ache. Other common
findings on examination include muscle spasm or taut
bands of muscle, sometimes referred to by patients as
38
quality in a randomized trial comparing a sham procedure

on 70 patients.276
Table 8-1
Nonmedicinal Therapeutic Treatments for Pain in
CFS
Medicinal Treatments
Despite the fact that there is no evidence of tissue
inflammation in FMS or CFS, anti-inflammatory medications are often utilized and have been studied in controlled trials.60 Therapeutic doses of naproxen (Naprosyn)
and ibuprofen (Motrin, Advil, Nuprin) and 20mg daily of
prednisone were not significantly better than placebo in
clinical trials. Nonsteroidal anti-inflammatory drugs
(NSAIDs) may have a synergistic effect when combined
with central nervous system (CNS) active medications,
but they may be no more effective than simple analgesics.140 Anti-inflammatory medications are better utilized
in chronic fatigue where there are arthralgias and myalgias rather than FMS complaints (See Table 8-2).
In contrast, certain CNS active medications, most
notably the tricyclics, amitriptyline, and cyclobenzaprine,
have been consistently found to be better than placebo in
controlled trials. The doses of amitriptyline studied have
been 25-50mg, usually given as a single dose at bedtime.139 In one report, amitriptyline was associated with
significant improvement, compared with placebo or naproxen in pain, sleep, fatigue, patient and physician
global assessment, and the manual tender point score.
Cyclobenzaprine, 10-40mg in divided doses, also improved pain, fatigue, sleep, and tender point count.277, 278
Clinically meaningful improvement with the tricyclic
medications has occurred in only 25-45% of patients, and
the efficacy of these medications may level off over time.
Other tricyclics and different classes of CNS active
medications, including venlafaxine (Effexor)163, alprazolam (Xanax),279 temazepam (Restoril),168 and fluoxetine
(Prozac),280 as well as 5-hydroxytryptophan281 and an
analgesic containing carisoprodol (Soma)282 and acetaminophen (paracetamol),169 have been found to be somewhat effective in preliminary studies.
Bennett assessed the efficacy of recombinant human
growth hormone in the treatment of 50 women with FMS
and low IGF-1.258 In a randomized double-blind, placebocontrolled study, women with FMS and low IGF-1 levels
experienced an improvement in their overall symptoms
and number of tender points after nine months of daily
growth hormone therapy. This author has used growth
hormone releasing factors (amino acids) ornithine, glutamine and arginine with some dramatic results in a few
patients (unpublished).
Efficacy Shown In Controlled Therapeutic Trials
Cardiovascular Fitness Training
Aqua Therapy
EMG-Biofeedback
Electroacupuncture
Cranial-electrotherapy Stimulation
Hypnotherapy
Cognitive Behavioral Therapy

Anecdotal Efficacy Show In Uncontrolled Trials
Transcutaneous Nerve Stimulation
Local Injection
Multidisciplinary Therapy
Resonance Biofeedback
Reiki
Feldenkrais
Neuromuscular Therapies (including)

Tai Chi
Yoga
Myofacial Release Technique
Cranial Sacral Therapy
Alexander Technique
Stain Counter Strain Therapy
Efficacy Lacking in Uncontrolled Trials
Ultrasound
The possible ameliorative effects of CFT on FMS

may involve mechanisms as diverse as improved muscle
blood flow or CNS-induced hypoalgesia, felt to be related
to activation of endogenous opioids. Vigorous exercise
also induces increases in adrenocorticotropic hormone
(ACTH) and cortisol, which may also promote analgesia.
The only controlled report of EMG biofeedback
training randomized 12 patients with fibromylagia to
EMG biofeedback or sham biofeedback.273 The EMG
biofeedback group had a significant improvement in pain,
morning stiffness and tender points. Hypnotherapy was
found to be better than physical therapy in 40 patients
with refractory FMS. The hypnotherapy group demonstrated better outcome in pain, fatigue, sleep and global
assessment, but not in tender points.274 Goldenberg has
found that a mindfulness meditation-based relaxation response program is helpful in FMS. Other less wellstudied non-medical treatments include transcutaneous
electrical nerve stimulation (TENS), acupuncture, laser
treatment, and tender point injections. A new modality
called cranial electrotherapy has recently been proposed
as a treatment for FMS.275 It has been found to improve
quality of life and sleep, as well as to decrease anxiety as
much as 100% in a double-blind controlled trial. Its benefit in alleviating pain, however, has been less dramatic,
but beneficial.
A recent article described the effectiveness of electroacupuncture in relieving symptoms of FMS, including
pain threshold, pain on visual analog scale, and sleep
39
Table 8-2
Pharmacologic Agents Used to treat CFS Patients with Musculoskeletal Pain
Classification
Anticonvulsant
Antidepressants
Centrally Acting Sympathetic

Agonist
Hormonal Agents
Mild CNS Stimulants

Monoamine Oxidase Inhibitors
Muscle Relaxants
Nonnarcotic Analgesic
Nonsteroidal Anti-inflammatory
Opioids
Opioids and Combination Opioids

Opioid Agonists/Antagonists
Opioid Extenders/Antiemetics
Over-the Counter
Detoxifier (alleged)
5 HT 3 Receptor Antagonists
Anesthetics
Substance P Antagonists
NMDA Receptor Antagonists
1
2
Medication
gabapentin (Neurontin)
clonazepam (Klonopin)
Tricyclics:
amitriptyline (Elavil)1
desipramine (Norpramin)
doxepin (Adapin, Sinequan)
nortriptyline (Pamelor)
SSRIs:
fluoxetine (Prozac)1
paroxetine (Paxil)1
nefazodone (Serzone)1
sertraline (Zoloft)1
Miscellaneous:
trazodone (Desyrel)
venlafaxine (Effexor)1
tizanidine HCL (Zanaflex)
Adverse Effects
Somnolence, Dizziness, Ataxia
Drowsiness, Dizziness, Dry mouth, Constipation
Nausea, Headache, Insomnia
Drowsiness, Dry Mouth, Dizziness, Lightheadedness

Nausea, Dizziness, Somnolence, Insomnia
Dry Mouth, Somnolence, Insomnia
somatatropin (Nutropin, Serostim)
Headache, Muscle Pain or Weakness, Mild Symptoms of Hyperglycemia

Possible Acceleration of Cancer Growth
Possible Acceleration of Cancer Growth
Lactation, Short-term Facial Flushing, Tingling
Acne, Menstrual Irregularities
Nervousness, Insomnia
Growth Hormone1
GH Releasers (amino acids)
oxytocin
DHEA
methylphenidate (Ritalin)
mogafinil (Provigil)
phenelzine (Nardil)
carisoprodol (Soma)1
cyclobenzaprine (Flexaril)1
metaxalone (Skelaxin)
methocarbamol (Robaxin)
orphenadrine (Norflex)
tramadol (Ultram)1
naproxen (Aleve, Naprosyn2 )
Cyclooxygenase-2 Inhibitors:
celecoxib (Celebrex)
rofecoxib (Vioxx)2
codeine
morphine (MS Contin)
oxycodone (Oxycontin)
oxycodone and acetaminophen (Percocet)
oxycodone and aspirin (Percodan)
acetamenophen (Tylenol #3 & #4)
nalbuphine (Nubain)
hydroxyzine (Vistaril)
acetaminophen
(Tylenol, Anacin-3, Panadol, Phenaphen, Valadol)
aspirin
ibuprofen (Advil, Motrin, Nuprin)
SAMe1
5 HTP
malic acid1
magnesium1
guaifenesin
tropisetron (Experimental use in US)
lidocaine
capsaisin1
Ketamine
dextromethorphan
Efficacy shown in placebo-controlled trials

Annecdotally successful
40
Dizziness, Headache, Drowsiness

Drowsiness, Dizziness, Vertigo
Drowsiness, Dry Mouth, Dizziness
Nausea, Vomiting, GI Upset
Lightheadedness, Dizziness, Drowsiness
Dry Mouth, Tachycardia, Palpitation
Dizziness, Drowsiness, Headache
Dizziness, Headache, Nausea, Flatulence, Diarrhea, Constipation,
GI Upset and Pain
Flatulence, Diarrhea, Dizziness, Headache, GI Upset, Pain
Dizziness, Mild Fatigue, Weakness, Diarrhea, GI Upset, Pain
Abuse Potential, Sedation, Confusion, Nausea, Vomiting, Decreased Appetite
Abuse Potential, Dizziness, Drowsiness, Nausea, Vomiting
Abuse Potential, Drowsiness, Sleepiness, Confusion

Dizziness, Drowsiness, Sleepiness, Confusion
Lightheadedness
Heartburn, Indigestion, Tinnitus
Dizziness, Headache, Nausea, Flatulence, Diarrhea
None
None
None
Diarrhea, Nausea
Increased Mucous, Increased Pain
Unknown
Cardiac Arrhythmia with Parenteral Infusion
Burning, Eye Burning on Contact
Abuse Potential
written, which the patient signs and agrees to close follow-up. The author uses longer acting narcotics, which
may have less risk of addiction. Physicians should also
understand terms such as drug dependence, tolerance, and
pseudo-addiction (a pattern of drug-seeking behavior in
patients who have adequate pain relief, but the patient is
drug-seeking to address this need for pain relief. This
behavior is often mistaken for addiction).
There have been few longitudinal studies of FMS.
These have demonstrated persistent pain and significant
impact on function. Thirty-nine patients were surveyed
for three consecutive years and, although more than 80%
of patients continued to take medications for FMS, 67%
reported feeling poor or fair and had moderate to severe
pain, with no significant change in symptoms over the
three years.287, 288 Factors associated with improved outcome were a younger age and lower global and pain
scores at the time of the initial survey. A recent follow-up
of the majority of those patients eight years later found
that although all still have FMS symptoms, 65% felt better than they were when initially diagnosed.
A benzodiazepine, such as clonazepam (Klonopin),

0.5 to 1 mg at bedtime, promotes improved sleep, relaxes
the muscles and helps restless leg syndrome. Psychometric tests showed significant improvements in depression
and anxiety state scores, while functional symptoms improved with extended tropisetron treatment. Patients with
elevated dopamine and/or reduced plasma 5-HT concentrations tended to show a higher response rate.283, 284
Adenosyl methionine, a methyl donor in many
methylation reactions in the brain, has an antidepressant
action. Placebo treatment did not cause any significant
improvement. Other studies using venlafaxine (Effexor)
in an open eight-week trial of 11 patients, 55% experienced 50% or more reduction of FMS symptoms. The
presence of lifetime psychiatric disorders, particularly
depression and anxiety disorders, predicted a positive
response to venlafaxine.163
As mentioned above, C fibers activated by noxious
stimuli promote the release of amino acids, such as aspartic acid, which activate NMDA receptors and produce
painful signals. The anesthetic ketamine, a noncompetitive antagonist to NMDA, decreases FMS pain
levels better than lidocaine or opiates.
Tramadol (Ultram) is a weak opioid that also inhibits norepinephrine and serotonin at the level of the spinal
cord, thereby augmenting the descending inhibitory pain
pathways. Results of a recent multicenter study showed
tramadol to have a very good safety and efficacy profile.285 In that study, approximately 90% of patients considered tramadol useful for managing FMS pain.
Finally, in rare instances, a small number of patients
will need stronger pain medications. There is a place for
narcotics in carefully selected patients with FMS.286 This
area, however, continues to be controversial. When they
are used, the author requires a narcotic contract to be
Conclusion
Pain symptoms are commonly found in CFS, be they
arthralgias, myalgias, or the lower pain threshold found in
FMS. There is often an overlap of pain syndromes in
chronic fatigue syndrome and FMS. The concepts of allodynia, central pain processing, and nocioceptive dysfunction in FMS may play a role in pain in CFS. A large
group of patients with CFS also have arthralgias and myalgias, which differ from the classic tender points and
decreased pain threshold found in FMS. Multiple nonpharmocologic and medicative approaches are palliative
for both disorders.
41
42
Womens Health in CFS
Rosemary Underhill, MB, BS, MRCOG(UK)

Jeffrey P. Levine, MD, MPH
where FSH levels are raised. The researchers suggested

that a chronic estrogen deficiency state is present in a
subgroup of women with CFS.292 There are a number of
central nervous system symptoms that are associated with
the low estrogen state: tiredness, headaches, dizziness,
lack of concentration, insomnia, depression, and anxiety.
These can overlap the symptoms of CFS.
At menopause, heavy irregular periods, scanty periods, or amenorrhea can occur. FSH levels are raised and
are associated with vasomotor instability, causing night
sweats, frequently feeling hot, and flushing of the face.
All of these symptoms may be due either to reproductive
hormone changes, to CFS, or a combination of both. One
point of difference is that vaginal dryness is usually present if estrogen levels are low and less likely to be present
if the symptoms are due to CFS. Many women with CFS
find that the symptoms of CFS worsen at menopause.
In a younger premenopausal woman, the presence of
a low estrogen state can be confirmed by measurement of
blood estradiol levels (low) and FSH levels (not raised).
In perimenopausal women between the ages of 40 and 50,
FSH levels may fluctuate, making serial measurements
helpful. In a woman over the age of 50, menopause is
more likely, and the blood FSH is characteristically
raised.
In premenopausal patients with CFS, treatment just
to regularize the periods is not necessary, but if estrogen
levels are low, the co-existing CNS symptoms may be
much improved by hormone replacement therapy, although it will not cure symptoms due to CFS. In one uncontrolled trial, it was found that symptoms improved in
80% of patients with CFS with low estrogen levels, following hormone treatment of estradiol patches and cyclical progesterone therapy.292 Hormone replacement therapy can also be helpful in menopausal patients. For example, insomnia associated with CFS is much improved if
a menopausal patient is no longer awakened several times
each night by hot sweats.
Women with CFS who may have had a low estrogen
state for some years are particularly at risk for osteoporosis. When osteoporosis is severe, it leads to loss of height
and bone fractures. A small study found that five of seven
hypoestrogenic, premenopausal women with CFS had a
low bone density.292 Other factors in patients with CFS
contributing to osteoporosis are exercise intolerance because exercise exacerbates CFS symptoms and lack of
vitamin D, due to inability to go outside in the sunlight, as
he incidence of CFS in women is twice that of

men.289 Patients with CFS can suffer from the entire
spectrum of gynecological illnesses, but diagnostic confusion can occur because some symptoms are common to
both CFS and some gynecological conditions, such as
premenstrual syndrome (PMS) or menopause. In many
women, these common gynecological conditions may also
cause an exacerbation of existing CFS symptoms. Although scientific studies are few, a number of gynecological conditions are found to occur more frequently in
women with CFS. These conditions are usually associated
with abnormal reproductive hormone levels, immune dysfunction, or pain. Some of these conditions may even
predate the onset of CFS.290, 291 It appears that endocrine
and/or immunological changes may be present in patients
with CFS before the full blown syndrome becomes manifest.
Gynecological Symptoms in CFS
Gynecological symptoms in women with CFS
should be properly evaluated and not assumed to be
merely part of the CFS symptomatology. In principle, a
full gynecological history should be taken. Examination
of the breasts, abdomen, and a pelvic examination should
be carried out; the latter with appropriate cultures and a
Pap smear, including specific laboratory tests. Any further investigation will depend on abnormalities found.
Referral to a gynecologist sensitive to patients with CFS
may be useful if further assessment is needed to make a
correct diagnosis. In this chapter, we will discuss or outline a number of specific symptoms and related problems
that are found more commonly in female patients with
CFS than in otherwise healthy women and suggest appropriate therapies.
Low Estrogen States, Menopause, and Osteoporosis

Many premenopausal patients with CFS have
scanty, irregular periods, intermenstrual bleeding, and
sometimes, periods of amenorrhea. These symptoms can
predate the onset of CFS, are typical of anovulatory or
oligo-ovulatory cycles and are associated with a low estrogen state. Hirsutism may be associated with oligomenorrhea. Researchers have found that ovarian hormone
(estradiol) levels were low in some 25% of a small group
of pre-menopausal women with CFS, who had normal
follicle stimulating hormone (FSH) levels.292 The normal
FSH levels distinguish this condition from menopause,
43
a result of weakness and photophobia. Vitamin D is

needed for calcium absorption. Calcium intake may also
be low, if the patient avoids milk due to lactose intolerance, which is common in CFS. The diagnosis of osteoporosis can be confirmed by bone density measurement.
Hormone replacement therapy; calcium, magnesium,
and vitamin D supplementation; and weight-bearing exercise, if tolerated, help to prevent and treat osteoporosis. If
the condition is severe, there are several pharmacologic
agents approved for the prevention and treatment of osteoporosis, which can reduce the incidence of fractures.
With the exception of hormone replacement therapy
(HRT), their potential effect on patients with CFS has not
been studied.
tion may be discovered only during surgery for another

condition, such as infertility. Dysmenorrhea is the most
frequent problem, and it can be out of all proportion to
the severity of the condition. Pain can also occur before
the onset of the menstrual period. Dyspareunia, intermittent pelvic pains, and pain related to the bladder or the
bowel can also occur. Endometriosis is often associated
with infertility.
In endometriosis, the endometrial cells that line the
uterus are found also in the pelvic cavity and to a lesser
extent in the abdominal cavity. Rarely are they present
elsewhere. This condition is thought to be due to retrograde transport of endometrial fragments along the fallopian tubes and occurs in many normal menstruating
women, most of whom have no sign of endometriosis.
These endometrial cells are most likely disposed of by the
scavenger cells of the immune system. In women with
immune abnormalities, such as CFS, the scavenging cells
may be overwhelmed. With each menstrual cycle, the
ectopic endometrial cells are shed. This process can result
in localized bleeding, which can be painful and may lead
to inflammation and scarring in the affected area.
A physical examination may show no abnormality,
but there may be thickening and lack of mobility of the
uterus due to scarring or cystic enlargement in the ovaries. An ultrasound scan may demonstrate enlarged cystic
ovaries. If symptoms are severe, the only certain way to
confirm the diagnosis, and exclude other conditions is by
laparoscopy and biopsy. Sometimes in spite of having all
the painful symptoms of endometriosis, no abnormality is
seen on laparoscopy. Then, the diagnosis should be reviewed because CFS is characterized by many different
painful syndromes.
The current treatment of endometriosis is by analgesics, such as nonsteroidal anti-inflammatories (NSAIDS),
oral contraceptive pills (OCPs), or progestational agents.
Also used are an anti-estrogen with some immune modulating effects, such as danocrine (Danazol), or the GnRH
agonist, leuprolide acetate (Lupron). Caution is advised in
the prescription of these treatments, as they all have side
effects that may not be tolerated in patients with CFS. For
the treatment of infertility, there is no proof that treatment
of mild endometriosis by hormones is any better than no
treatment. Women with endometriosis who become pregnant are often much improved following delivery of the
child. If severe pain caused by endometriosis does not
respond to hormone treatment, surgery may be required
as a last resort. It is very important to distinguish pain
from endometriosis from pain from other CFS problems
before embarking on any surgery. Otherwise, a traumatic
procedure will fail to relieve the pain.
Premenstrual Syndrome
Premenstrual Syndrome (PMS) occurs widely in the
general population, but seems to be more common in patients with CFS, occurring in over 50%.290 PMS can predate the onset of CFS; however, it seems to be less common before the onset of CFS than in normal control
women.290 The symptoms of PMS start in the luteal phase
of the menstrual cycle and rapidly improve within a day
or two of the period. The most common symptoms include mood swings, irritability, depression, headache,
insomnia, carbohydrate cravings, breast pain and tenderness, fluid retention and abdominal bloating. A patient
may incur a weight gain of two or more pounds at this
time. In addition, in women with CFS, the CFS symptoms
frequently worsen premenstrually.
There is some dispute about the cause of PMS. It is
thought to be hormonal in that it usually occurs in association with ovulatory cycles. In one study group of
women using gonadotropin-releasing hormone agonists,
when ovulation was abolished and estradiol levels fell,
PMS symptoms were relieved.293 Some recent research
has found that the condition is linked to a deficiency in
serotoninergic activity in the brain.294 In PMS, treatments
have been many and various, but until recently few have
been very satisfactory. In several placebo-controlled trials, serotoninergic antidepressants (SSRIs), such as
fluoxetine (Prozac), 20 mg either daily or on days 14 to
28 during the womans menstrual cycle, were found to be
successful, relieving PMS symptoms in up to 90% of patients.295 However, there are no specific studies in patients
with CFS. Side effects of treatment tended to improve
with time. Some different approaches used in the past
have been found to be no better than a placebo. These
include the use of progestogens, estrogens, vitamin B6,
and evening primrose oil.296
Endometriosis
Endometriosis is reported to occur in up to 20% of
women with CFS. It can predate the onset of the CFS.290
There may be no symptoms of the disease and the condi-
Dysuria
Twenty percent of patients with CFS have dysuria.290 Some patients with CFS have severe symptoms of
44
their relationship. They both need to understand the

causes of the problem and find ways to adjust to the
situation.
pain, frequency and urgency of urination occurring both

during the day and night. A urine culture may show a
bacterial infection, which can be treated with antibiotics.
Frequently, in spite of careful investigation, the urine is
sterile. The patient should be referred to a urologist or
urogynecologist for further investigation, as symptoms
may be due to interstitial cystitis, detruser instability,
urethral syndrome, or endometriosis. Interstitial cystitis is
thought to be associated with some immune system abnormalities. An informal survey of some patients with
interstitial cystitis found that 13.8% also suffered from
CFS.297
Galactorrhea
Leakage of milk from the breasts not associated with
pregnancy has been reported to occur more commonly in
patients with CFS than in control women. It can predate
the onset of CFS.290 Serum prolactin levels should be
checked. If elevated, and especially if the patient has associated headaches or visual complaints, an MRI of the
sella tursica should be undertaken. Although there is no
evidence of any increase in its incidence, breast cancer
must also be excluded by examination and mammography, especially if leakage is unilateral and no other cause
is found. The patient should be referred to a specialist.
Vaginal Problems
Twenty-nine percent of a series of CFS patients
complained of vaginal discharge.298 There are many
causes of vaginal discharge. A thick creamy vaginal discharge associated with vaginal irritation may denote a
vaginal infection with Candida albicans. The yeast organism is present vaginally in many symptomless women,
but overgrowth leading to symptoms is likely to occur in
patients with abnormal immune function or more likely in
patients who have had repeated courses of antibiotics, are
pregnant, or who have diabetes. Some doctors and their
patients believe that many women with CFS suffer from a
chronic multi-system yeast infection, which exacerbates
CFS symptoms, but this theory is unproven. Certainly,
positive cultures of oral swabs for yeast are unusual.
There is disagreement as to whether recurrent or persistent vaginal candidiasis is more common in women with
CFS. In all cases of vaginal discharge, a swab should be
obtained for diagnosis.
In culture-proven cases, there are a number of effective vaginal anti-fungal preparations that can be used.
A short course of treatment is often adequate, but treatment may need to be extended to two weeks if clearance
of yeast is slow. Vaginal yeast infection is normally a
very localized condition so that only local treatment is
indicated. If recurrence is persistent, reinfection from the
gastrointestinal tract should be considered.
Fibroids and Ovarian Cysts

A history of ovarian cysts, including polycystic ovaries, and uterine fibroids were found to be more common
in patients with CFS. These conditions have also been
found to predate the onset of CFS more often than is
found in control women.290 There is no reported evidence
of any increase in ovarian cancer in CFS. Referral to a
gynecologist may be indicated if either condition warrants
surgical intervention.
Pelvic Inflammatory Disease
A history of pelvic inflammatory disease, and of
sexually transmitted disease was reported in a retrospective survey to be more common in women prior to their
CFS.290 No studies have investigated the presence of any
specific infective agents. Pelvic inflammatory disease
may have stemmed from endometriosis, rather than from
a pelvic infection, or the symptoms and signs could have
been elicited from the presence of fibroids or ovarian
cysts in some CFS patients with pelvic pain.
Dysmenorrhea
About 15% of normal women suffer from dysmenorrhea, but at least 30% of patients with CFS are said to
suffer from it.299 Severe dysmenorrhea may occur on its
own or it can be a symptom of a number of gynecological
conditions, which are more common in patients with CFS
than in the general population. These are endometriosis,
fibroids, pelvic inflammatory disease, and ovarian cysts.
In all these conditions, menses may be heavy. If there is
any abnormality found on examination, such as a pelvic
mass, further gynecological investigation is indicated.
Mild dysmenorrhea usually responds to analgesics,
such as aspirin or acetaminophen (Tylenol), but NSAIDS,
such as ibuprofen may work better. Severe pain can be
treated by suppressing ovulation with cyclical hormone
treatment, such as OCPs.
Sexual Dysfunction
Sexual dysfunction is present in up to 20% of patients with CFS.13 Decreased libido is a common cause
and dyspareunia can also occur. Loss of libido can be
associated with low reproductive hormone levels, or be
due to the severe fatigue, malaise and pain that are so
prominent in CFS. Dyspareunia may be present due to
vaginal dryness from low estrogen levels or the presence
of a local pelvic cause, such as endometriosis or vulvodynia. For low estrogen syndromes, use of a vaginal estrogen cream locally or administration of hormone replacement therapy to the patient may be helpful. Sexual
problems can put a severe strain on both a patient and her
partner. They may need counseling to help them save
45
occur, although the incidence has not been established.

Genes certainly influence the occurrence of CFS because
twin studies have shown that monozygotic twins are almost three times as likely to both have CFS, compared
with dizygotic twins.302 An affected child usually initially
develops CFS later in childhood or adult life. The possibility of the babys developing CFS in infancy has not
been investigated.
Hysterectomy
Patients with CFS are significantly more likely than
controls to have had a hysterectomy.291 The reasons for
the excess of this surgery in patients with CFS is not
known, but may be associated with the increased numbers
of patients with endometriosis, fibroids, or ovarian cysts.
Gynecological Surgery in Patients with CFS
Surgery in women with CFS can be associated with
various problems that are rarely found in healthy women.
Many patients with CFS are found to require a much
smaller dose for their weight than normal women of anesthetic agents given either for an epidural or for a general anesthetic, or drugs used for pain relief.300 Some patients with CFS suffer from orthostatic intolerance. Because many anesthetic agents cause vasodilatation,301 efforts need to be made to ensure that blood volume and
blood pressure are maintained in these patients. A general
anesthetic can also aggravate CFS symptoms, and may be
associated with delayed recovery in patients with CFS.300
When a general anesthetic is necessary, potentially hepatotoxic gases should be avoided.300
Effects of Pregnancy on CFS

During pregnancy, many women with CFS feel better, especially after the first trimester. Others remain the
same, while some feel worse. Opinions vary as to how
many improve. Immediately after delivery, some mothers
remain better, while others relapse. Within weeks of delivery, most mothers symptoms return to their prepregnancy condition. Improvement during pregnancy is
thought to be due to the effect of hormones. Even if they
feel better, mothers with CFS will need much more rest
during pregnancy than healthy mothers.
Effects of CFS on Pregnancy
Many patients with CFS use a variety of both overthe-counter and prescribed medications to relieve symptoms. Some vitamins, such as folic acid, are known to be
beneficial both before and during pregnancy. Patients
should be advised to take a daily dose of folic acid before
becoming pregnant because it has been shown to reduce
the incidence of neural tube defects. However, some
medications can damage a growing fetus, especially in the
early stages of pregnancy. The effects of most herbal
preparations on the fetus is unknown. For this reason, the
patient should discuss with her healthcare provider which
potentially dangerous treatments should be stopped before pregnancy. The patient will then find out whether she
can cope if her CFS symptoms worsen as a result of stopping the medications.
Pregnancy is not recommended in the early stages of
CFS.303 This may be a time when a woman is very ill, the
diagnosis may be uncertain, and a possible infective agent
that might cause the disease may be actively multiplying.
Women known to have active viral replication with a virus such as HHV-6 need to discuss the risk of pregnancy
with an expert.
Infertility occurs in about 10% to 20% of normal
couples. It is possibly higher in patients with CFS because
many have problems that can cause infertility, such as
endometriosis or sexual problems, such as lack of libido.303
First trimester miscarriage occurs in 10% to 20% of
normal pregnancies. The miscarriage rate was reported to
be higher than normal (27%) in a group of women with
CFS.304 Patients with CFS may have to overcome the
frustration of becoming pregnant only to miscarry.
Pregnancy in Women with CFS

CFS commonly affects women in the peak childbearing years. Some may seek information about possible
risks of pregnancy from their healthcare provider, who
needs to be able to give them preconception counseling.
Because there is almost no peer-reviewed research, the
healthcare provider must base advice on these risks
mainly on anecdotal information.
Preconception Counseling
Because people with CFS vary greatly regarding severity of symptoms, they must make their own decisions
about whether to have children, depending upon their
own circumstances and on information about pregnancy
in other people with CFS. Both parents should be in
agreement because the babys father will almost certainly
have to do a great deal more for both mother and child
than in families where the mother is healthy. The following factors should be discussed with both potential parents:
Possible transmission of CFS to the child
Effects of pregnancy on CFS
Effects of CFS on pregnancy, labor, delivery,
and the puerperium
CFS and breastfeeding
Coping with childrearing
Possible Transmission of CFS to the Child
The majority of women with CFS have normal
healthy children. Most children with CFS have healthy
parents; however, CFS in both mother and child does
46
The most common symptom of early pregnancy is

morning sickness, which usually improves after the first
trimester. In women with CFS, this symptom may be
more severe, lasting throughout the day and even persisting into the later months of pregnancy.299 The extreme
form of sickness, hyperemesis gravidarum, is also more
common than in normal women. It is probably associated
with the impaired activity of the HPA axis seen in CFS26
because studies have shown that hyperemesis can be
completely alleviated by adequate doses of corticosteroids.305 For morning sickness, bed-rest and pharmacologic agents, such as promethazine hydrochloride (Phenergan) or ondansetron hydrochloride (Zofran), may be
used. Also, complementary therapies, such as fresh ginger
or Sea-bands worn around the wrists, may be helpful.
In mothers with CFS, there is some anecdotal evidence that slow growth of the baby before birth appears
to be much more common than in normal women.306 The
baby may well be diagnosed as being dysmature.
The incidence of premature birth is unknown, as
well as whether any other complications of pregnancy are
more or less common in mothers with CFS. There is no
evidence that the fetal abnormality rate is any different
from that which occurs in normal pregnancies.
Good prenatal care should start early in pregnancy.
An ultrasound scan should be done in the first trimester to
confirm the age of the fetus and the date of delivery, and
to reassure the parents of the presence of a fetal heart
beat. A dysmature baby also requires close monitoring in
pregnancy.
feeding or a standard oral contraceptive pill (OCP) used if

bottle feeding. The intra-uterine contraceptive device is
not advised because of a possible risk of infection303 that
may lead to pelvic inflammatory disease.
CFS and Breastfeeding
A mother with CFS should consider several factors
before deciding whether to breastfeed her infant. While
there is no evidence that an infectious agent that might be
the cause of CFS could be passed to the baby in breast
milk and could remain dormant in the child and active
later in life, such a scenario remains a theoretical possibility. Women should weigh the well-known benefits of
breastfeeding with theoretical, unproven risks of postnatal
exposure.
Many women feel less fatigue during pregnancy, but
frequently relapse after their baby is born. If so, previously successful CFS medications may be beneficial.
Bottle feeding is recommended if these medications pass
into the breast milk and could adversely affect the child.
Information on CFS medications and lactation should be
obtained.308
Many mothers with CFS successfully breastfeed
their babies, and some mothers feel better while they are
breastfeeding. However, if a new mother with CFS finds
nursing her baby overwhelming, the baby can easily be
bottle fed.
Coping with Childrearing
During childrearing, CFS really takes its toll. Both
parents will suffer frustration and difficulties that other
families do not have to face. In the majority of cases, the
happiness brought to the family by the child make the
effort more than worthwhile. New mothers who have severe CFS may have difficulty walking or lifting their
baby. They will need to remain within their own limits,
while spending their scarce resources of energy on their
child. Most mothers find that it is necessary to organize
help from their husbands, relatives, and friends. Advice
on how to cope can be obtained from other mothers in a
local support group.
Effect of CFS on Delivery of the Baby

A mother with CFS is likely to tire more quickly
than others in labor. In order to avoid this situation, adequate pain relief should be given. An epidural anesthetic
can be useful. Prolonged labor can be avoided and the
baby delivered before exhaustion occurs by using CSection in the first stage or forceps in the second stage of
labor. A C-Section before labor may be recommended. CSections require an epidural or a general anesthetic. Many
women with CFS require a much smaller dose than normal of both drugs given for pain relief in labor and drugs
used for epidural and general anesthetics.300
Medical Termination of Pregnancy

When an unwanted pregnancy occurs, patients with
CFS may seek advice on a medical termination of pregnancy. Dealing with the problem of an unwanted pregnancy and therapeutic abortion may well cause a relapse
of CFS symptoms.309 However, pregnancy complications
in CFS patients rarely constitute medical justification for
termination of pregnancy.
CFS and the Puerperium

Many women with CFS are exhausted by childbirth
and require a longer stay in the hospital afterward. The
fact that these are days of early discharge from the hospital after delivery should be taken into consideration and
arrangements made prior to delivery.
Postpartum depression is much more common in
women with CFS.292 The new mother may respond to
supplemental hormones,307 as well as to antidepressants.
After delivery, contraception should be discussed. One of
the progesterone-only pills can be used while breast
Conclusion
There are many gynecologic and obstetrical problems
experienced by women with CFS. The incidence of infertility, miscarriage, vomiting in pregnancy, exhaustion in
47
The conditions with abnormal reproductive hormone

levels include anovulatory and oligo-ovulatory cycles,
with low estrogen levels leading to a multitude of CNS
symptoms, loss of libido, and, in later years, osteoporosis.
Hirsutism may or may not also be present. Abnormal
prolactin levels may be associated with galactorrhea. Endometriosis and interstitial cystitis may be associated with
immune abnormalities. Painful conditions include endometriosis, pelvic inflammatory disease, dysmenorrhea,
dysuria, and dyspareunia. Ovarian cysts and fibroids are
also found more frequently in patients with CFS, as is a
history of having had a hysterectomy. Gynecological
symptoms should not be assumed to be merely part of the
CFS symptomatology. Their investigation and treatment
in patients with CFS should follow standard gynecological practice, and patients will benefit from relief of
symptoms.
labor, and puerperal depression is higher than in normal

women. Pregnancy, however, is usually uncomplicated
for the majority of these women. In fact, CFS symptoms
may improve in some patients after the first trimester. At
times, surgical delivery of the child may be necessary to
avoid exhaustion in labor. Before delivery, the advantages
and and disadvantages of breast feeding should be discussed.
Compared to the normal incidence, children of
women with CFS may have an increased likelihood of
developing CFS during their lifetime. Childrearing is often the biggest challenge for mothers with CFS.
Some common gynecological conditions, such as
menopause and PMS, make CFS symptoms worse and are
themselves made worse by CFS. Symptoms of other conditions that are more common in women with CFS may
predate the onset of CFS. These conditions are usually
associated with either abnormal reproductive hormone
levels, immune dysfunction, or pain.
48
10 Gastrointestinal Symptoms in CFS

Kenneth Rubin, MD
Kenneth Friedman, PhD
CFS and IBS have properties in common: IBS is

characterized as a functional gastrointestinal disease,
whose symptoms are controlled (at least in part) by serotonin (5-HT).315 Thus, alterations in 5-HT levels may play
a role in IBS, as has central nervous system 5-HT levels
been implicated as a mechanism for CFS. Both CFS and
IBS may have sensory dysfunction components,316 and
both are found to occur predominantly in women with
possible variations in severity associated with the menstrual cycle.317, 318
atients with chronic fatigue syndrome often suffer

from overlapping conditions, including FMS and
gastrointestinal (GI) disorders, particularly irritable bowel
syndrome (IBS). The diagnosis of IBS in this group of
patients may often be missed and go untreated, adding to
the already significant morbidity of CFS.
All clinicians involved with patients with CFS must
be aware that IBS often occurs as a coexistent condition.
IBS is defined as a functional disorder of the gastrointestinal tract characterized by abdominal pain and discomfort, accompanied by an alteration of bowel function.
Patients may experience diarrhea, constipation, or a combination of both, often with bloating and urgency. In our
experience, some patients with chronic fatigue syndrome
may have abdominal complaints that do not clearly fit the
criteria of IBS; this subgroup may be best defined as nonulcer dyspepsia. These patients experience bouts of postprandial upper abdominal pain, early satiety, nausea, abdominal distention, and bloating in the absence of organic
disease. Thus, the clinician caring for the patient with
CFS should have a clear understanding of the interaction
of IBS and CFS.
Diagnosis
The task of the physician caring for the patient with
CFS is not only to be aware of the common GI complaint
often associated with CFS, but also to be vigilant for GI
disorders that could masquerade as chronic fatigue syndrome. The diagnosis of CFS does not afford protection
from later development of an unrelated gastrointestinal
problem. It is imperative that the clinician recognize that
specific signs and symptoms, such as blood in the stool,
anemia, fever, weight loss, and nocturnal symptoms are
not usually attributable to chronic fatigue syndrome and
would require further radiologic or endoscopic evaluation
to rule out underlying malignancy or inflammatory bowel
disease. Infectious diseases, such as giardiasis and cyclosporidiosis may masquerade as an irritable bowel syndrome and should be excluded by careful analysis for
fecal ova and parasites. Finally, the diagnosis of ulcer
disease and erosive gastritis must be considered, particularly in patients with CFS and FMS who use aspirin or
nonsteroidal anti-inflammatory drugs. Gastric infection
with Helicobacter pylori usually can be eradicated with a
two- to three-week course of antimicrobials and may
protect the patient from eventual helicobacter-associated
cancer. Celiac sprue should be ruled out in those patients
with CFS and gluten sensitivity. Diagnosis can be suggested by the presence of anti-gluten antibodies.
Pathophysiology
Many patients who have CFS suffer episodes of
IBS. Although the pathophysiology of IBS is not fully
understood, the nature of the precipitating factors most
commonly include dietary factors and stress. Recently,
bacterial overgrowth has been implicated as a precipitating factor in some patients.310 In addition, disregulation of
the intestinal motor and sensory, as well as central nervous system, functions have been identified as key factors.311, 312 Serotonin receptors are believed to play an
important role in pain perception and gastrointestinal motility.
Even if the precipitating factors of IBS are uncertain, the symptoms of diarrhea and constipation involve
an alteration in the permeability of the intestinal cells or
the permeability between cells, as has been argued for
inflammatory bowel disease.313, 314 To the extent that cytokines are involved in regulating endothelial cell adhesion molecules and producing reactive oxygen metabolites,314episodes of IBS may reflect increasing levels of
specific cytokines associated with altered states of immune function. The finding of bacterial overgrowth of the
small intestines being associated with IBS symptoms
also implies an immune system dysfunction, which permits the overgrowth to occur.
Treatment
The management of IBS in patients with CFS revolves around the establishment of a firm diagnosis and
reassurance to the patient that he or she can be helped.
Treatment modalities are primarily empiric and include
dietary modification and pharmacologic therapies, as well
as patient education about IBS. Dietary management often involves eliminating offending items such as caffeine,
alcohol, fatty foods, and large meals. Increased fiber intake may be necessary, particularly in the setting of con-
49
Alosetron hydrochloride (Lotronex), which is a selective 5-HT3 receptor antagonist, has been shown to be
effective in alleviating pain and diarrhea in female patients with diarrhea-predominant IBS. Tegaserod maleate
(Zelnorrn), a serotonin receptor partial agonist, is being
investigated for treatment of IBS associated with constipation. Unfortunately, alosetron, which was removed
from the market due to adverse side effects, and tegaserod, are not currently clinically available. This class of
compounds will hopefully lead to improved therapies for
IBS.
stipation. If a patient depends on caffeine for treating

fatigue, a risk-to-benefit ratio needs to be done. Obesity
itself can be a long term problem for the CFS patient, due
to forced inactivity and altered eating habits and patterns.
At times, lactose and sorbitol may need to be eliminated. Patients with sprue or gluten sensitivity need not
eliminate all wheat-based products from the diet. After a
medical evaluation that which may include endoscopy,
ultrasound, and colonoscopy, patients with CFS may
benefit by a nutritional consult by a registered dietitian
(See Chapter 10).
GI medication can often help patients with CFS (See
Chapter 10). Dicyclomine, hyoscyamine sulfate, or clidinium bromide are some examples of medications that
may provide symptomatic relief from abdominal pain or
cramps. Pharmacologic measures may also include antidiarrheals, such as loperamide, or in more severe cases,
tricyclic type antidepressant therapy could be considered.
Recently, newer therapies have been based on the finding
that serotonin plays a key role in IBS, but currently there
are no selective 5-HT3 receptor antagonists on the market.
Conclusion
Intestinal symptoms in patients with CFS are very
common and resemble those of patients with IBS. Other
diagnoses to be considered in selected patients with CFS
who have GI symptoms include cancer and infectious
diseases. Therapy is empiric and symptomatic but can be
very helpful in reducing symptoms and improving quality
of life for patients who have a multitude of problems in
other organ systems.
50
11 CFS in Children and Adolescents

James M. Oleske, MD, MPH
Donna Palumbo, LCSW
Jonathan Sterling, MA
Terri Lynn Evans, RN
ike adults, children and adolescents can develop

CFS. Typical symptoms are of significant severity
and duration that they lead to age-specific dropout, school
failure, loss of friends, inability to participate in afterschool activities, and family disharmony.319-321 Children
and adolescents with CFS (CACFS) have more generalized complaints, such as vague abdominal pain, alternating constipation and diarrhea, rashes, fevers, and atopic
symptoms, including food intolerances.319, 322-324 The neurologic symptoms in children may be more difficult to
evaluate, due to language, cognitive ability and developmental stage. In addition, there is the recent appreciation
that there may be a continuum of developmental conditions, such as autism and CFS, that are linked by common
neuro-immuno- and endocrine abnormalities. As confusing as the individual symptoms are to the physician, so
are the usual lack of collaborating physical findings and
non-diagnostic laboratory studies. Until recently, the
evaluating physician had little available literature on
which to base a specific diagnosis.325, 326 Since 1988,
there has been an increasing number of studies examining
the epidemiology, natural history, and etiopathogenesis of
CFS, which have helped define the parameters of this
syndrome in adults.327-330
The literature for CACFS is more limited than that
on adults. The diagnosis of CFS in the pediatric population is complicated by the unique and changing developmental, physical, and emotional characteristics of children
compared to adults.331, 332 The long term impact of the
cognitive abnormalities with CFS is more pervasive in the
child, due to disease onset during a period of rapid intellectual development. Frustration and secondary depression are frequent components for the youth and families
trying to cope with a child having an undiagnosed illness,
who is always tired and unable to keep up with peers.
Many physician encounters with such patients are characterized by an all too brief history, curtailed physical
examination and limited laboratory evaluation. The diagnostic outcome is predictable: the patients illness is diagnosed as depression, a psychosomatic illness, and malingering or school phobia. The outcome for the individual and family members is also predictable: conflict, confusion, and the search for a diagnosis and cure from anyone, regardless of cost or competency.
Pathogenesis of CFS in Children and Adolescents

Pediatric patients with symptoms of CFS usually
present after the age of eight and frequently at the onset
of puberty. The adolescent patient is more likely to have
signs and symptoms similar to adults. As many as 15% of
CACFS have a history of another family member with
CFS, suggesting a genetic predisposition.333, 334 The pediatrician has to differentiate a number of illnesses and
syndromes, both congenital and acquired, that can have
fatigue as the major presenting complaint. Many of these
conditions that have fatigue as a major component will be
diagnosed by standard evaluations for known medical or
psychological disorders. Some of these disorders include
cystic fibrosis, inflammatory bowel disease, atopic conditions, complex seizure and other neurologic diseases, and
juvenile onset diabetes. While youths with unexplained
persistent fatigue of greater than six months meet the
same criteria that have been described in adults, pediatric
patients are more likely to have their illness associated
with viral infections, immune dysfunction, and persistent
inflammatory reactions that may cause the complex and
multiple symptoms of CFS.335-338
The human DNA Herpes viruses, with their ability
to maintain a latent life-long infection with periods of reactivation, are candidates for being one of the infectious
causes of CFS. The similarities between the prolonged
fatigue-like illness that can complicate acute infectious
mononucleosis (IM) due to Epstein-Barr Virus (EBV) in
the older child or adolescent and CFS described in adults,
led to the initial suspicion that EBV was a candidate as
the etiological agent of CFS. The findings in early studies
of patients with CFS demonstrating a distinctive EBV
serological response supported this assumption. Subsequent studies of larger numbers of adult patients with
CFS, however, did not consistently demonstrate this
unique serological response. Other viral illnesses associated with chronic fatigue include cytomegalovirus
(CMV), Human Herpes Virus-6 (HHV-6) infection, and
Parvovirus B-19. A subset of patients with CFS may represent the interaction of more than one latent viral infection and subsequent abnormal immune responses.339-345
Like adults, CACFS patients may have the etiology
of their illness based on other organ system abnormalities.
The possibility of orthostatic intolerance should be considered in the child with chronic fatigue who has a problem with dizziness or changes in position or in maintain-
51
it is recognized that there has been a slow, but gradual,

recovery over time from CFS for many patients. There
can be fluctuation in symptoms over the course of pediatric CFS, with episodes lasting from one to six weeks, interspersed with periods of improvement. Frequently,
some patients are made worse by intercurrent illnesses,
emotional or physical stress, and are unable to perform
daily activities of living. It has been recommended that a
more formal mental status examination by a neuropsychologist be included as part of the evaluation of CFS that
includes both subjective and performance aspects of fatigue level and overall functional performance. Some of
these instruments may not be appropriate for young adolescents and children, and physicians may need to collaborate with a clinical psychologist. Due to the chronicity of CFS, periodic measurement of quality of life should
also be part of the overall clinical evaluation, such as the
one proposed by Gortmacher.349-353
ing upright posture. Endocrine abnormalities including

hypothyroidism, diabetes, and sex hormone dysfunction
should be suspected in the child with obesity and maturation problems, which are complicated by onset of puberty.346-348
Evaluating CFS Patients
The physician presented with a child or adolescent
with complaints of chronic fatigue should consider the
following the medical evaluation: (1) Allow enough time
for an adequate history (at least hour) and, prior to the
initial patient visit, make every attempt to obtain previous
medical records. (2) Many patients with CFS have seen
multiple health care providers and specialists. (3) The
initial encounters with the physician for the patient with
CFS should be devoted to differential diagnosis to ensure
that the suspected CFS patients multiple complaints are
not due to other causes. This work-up of exclusion needs
to include selected laboratory studies guided by a thorough history and careful physical examination.
Laboratory Evaluations
As a baseline, children and adolescents with suspected CFS should have a CBC differential and platelet
count, sedimentation rate, multiple blood chemistry, thyroid functions, ANA, and a urine analysis. If there are
episodes of fever, patients should also have several blood
cultures taken. A more aggressive FUO evaluation will
need to be considered in patients with persistent episodes
of fever. Patients with predominant CNS symptomatology
suggesting a chronic encephalopathy (confusion, episodes
of lack of concentration, headache, depression, and insomnia) may benefit from a more detailed neurologic
evaluation by a consultant neurologist that may include
neuroimaging of the brain. Examination of spinal fluid is
usually reserved for patients with CFS suspected to have
multiple sclerosis or other significant CNS abnormalities.
A more intensive laboratory evaluation that would
be performed as part of a research protocol or by a specialist on selected patients may include: serological assays (IgM and IgG antibodies) or PCR assays for suspected infectious process (HHV-6, CMV, EBV, Paravirus
B-19, mycoplasma/chlamydia). Lymphocyte subsets can
reflect the degree of immunosuppression or immune
stimulation. Some patients with CFS have evidence of
Common Variable Immunodeficiency Syndrome (CVID)
that has an associated humoral immune dysfunction. Selected patients with unexplained fatigue associated with
fevers and a past history of recurrent infections should
have quantitative immunoglobulin (IgG,A,M,E) and IgG
subclass levels measured. If these humoral immune studies are abnormal, referral to an immunologist is appropriate for further immune system evaluation. If there is evidence of orthostatic intolerance, referral to a cardiac center with experience with diagnosis and management of
this condition is appropriate. Other subspecialist referrals
may be indicated.105, 228, 354
Clinical Evaluations
There are several similarities between adults meeting the diagnostic criteria of CFS and adolescents and
older children diagnosed with IM and other postinfectious fatigue illnesses. CFS and post-infectious fatigue cause significant fatigue, persisting for greater than
six months and can be associated with other symptoms.
Older children with acute IM present with one or more
signs and symptoms, including exudative tonsillitis, enlarged lymph glands, hepatosplenomegaly, encephalitis,
carditis, dermatitis, hemolytic anemia, thrombocytopenia,
jaundice, fever, and fatigue. This acute viral infection
with EBV is well characterized, but there remains, however, a general lack of appreciation as to how severe and
prolonged a bout of acute EBV mononucleosis can be for
the older child and youth. Adolescent patients may experience periodic flare-ups of sore throat, cervical adenopathy, and fatigue two years after the initial bout of
acute IM and have persistence of symptoms, especially
fatigue, for three to five years after a severe bout of acute
EBV infection. In general, however, older children and
adolescents with post-infectious related fatigue frequently
recover and do not progress into adulthood with CFS.
Only a longer period of observation of such patients will
answer the question of the relationship between the severity of acute IM, treatments given and the development
of CFS later in life..
In children with noninfectious background for their
CFS, there is no standard duration of their illness, but
most children outgrow it over four years. The course of
recovery varies greatly from patient to patient. There is
frequent exacerbation of symptoms, during which patients
feel they are again as sick as at disease onset. However,
when patients more objectively evaluate their symptoms,
52
antihistamines. Such antihistamines do not cross the

blood brain barrier and, therefore, do not exacerbate the
fatigue, as is the tendency of other classes of antihistamines. Additional allergic-based therapies and evaluations may be helpful, depending on the individuals specific symptoms.360
Many patients with CFS have insomnia or poor
sleep habits despite feeling exhausted. Such patients may
benefit from taking a low dose antidepressant before bedtime. When headache is a major manifestation of a CFS
patient, acetazolamide (Diamox Sequels, 500 mg), taken
prior to bedtime, acts as a mild diuretic and possibly lowers cerebral spinal fluid pressure. Some patients complain
of tingling in their hands with this drug and it should not
be used if there is a history of kidney stones. Patients
treated with acetazolamide may improve after two weeks
and can be maintained on a reduced dose schedule thereafter.186
The joint symptoms and generalized aches and pains
that many patients with CFS experience will frequently be
improved with a nonsteroidal anti-inflammatory agent.
Selected patients may require more intensive treatment
for chronic pain that may include opioids. The use of
steroids in CFS is controversial, and the serious side effects and toxicity of these hormones must always be considered. Only infrequently would the risks of using steroids be outweighed by possible benefits in a specific patient. There are indications for steroids in acute EBV IM
syndrome (impending upper airway obstruction, impending rupture of the spleen, cardiomyopathy, encephalitis,
and severe thrombocytopenia or hemolytic anemia). The
patient with acute IM treated with steroids often has dramatic improvement, including a feeling of well-being and
a lessening of fatigue. However, the long-term risk of
using steroids with a known latent viral agent (EBV)
having oncogenic potential is a major therapeutic decision
requiring careful evaluation of benefit and risk. In addition to prednisone, ACTH, and the cortisol metabolic
intermediate, dehydroepiandrosterone (DHEA) have been
suggested as possible therapies for adults with CFS, but
these medications in children and adolescents have not
been studied.
When a child or adolescent with CFS is identified to
have dysgammaglobulinemia, major or subclass deficiency, or poor function of subclass antibody, replacement therapy with intravenous gammaglobulin (IVIG)
may be helpful. This group of patients, when treated with
monthly IVIG (400 mg/kg/per dose), has symptomatic
improvement usually beginning after the third dose with
less fatigue, less cervical adenopathy, and fewer sore
throats. The cost of IVIG is significant, and this limits its
use to those patients with defined antibody deficiency
associated with their CFS.361-363
Patients with CFS may benefit by referral to recognized CFS experts, who may also have access to clinical
Treatment for CFS in Children and Adolescents

Just like adults, there is no specific therapy for
CACFS patients, but many agents may relieve symptoms.
It should be remembered that children with CFS may
have unusual sensitivity to medications and lower dosages
should be started with gradual increases in dosages. In the
few published natural history studies of pediatric CFS, 827% of children recovered, 28-46% improved, while 1230% did not improve during the study period. Antiviral
drug trials with acyclovir (directed against EBV, CMV,
HHV-6) have no demonstrated efficacy and may be toxic.
Long-term antibiotic therapy including many patients
diagnosed with chronic Lyme disease as the bases of their
CFS, is currently under further study and is not generally
recommended.
Children with CFS suffer many negative feelings
(See Table 11-1). Symptomatic care and emotional support are important in improving the quality of life and
general well-being of an individual with CFS. The best
individual to coordinate this program would be a nonjudgmental and committed pediatrician who has experience with children with a chronic illness. CACFS patients
usually do poorly when they receive fragmented care
from a number of specialists. Any patient with a chronic
illness needs emotional support to manage the stress of
the illness. Pediatric patients with CFS frequently have
multiple emotional/psychological symptoms during the
course of their illness that interfere with their ability to
fully participate in social and educational settings.355-359
Many CACFS patients benefit from the techniques available through an experienced mental health professional.
Table 11-1
Negative Feelings Many CACFS Experience
Fear
Anxiety
Stress
Depression
Loss
Sadness
Shame
Isolation
Resentment
Anger
Self-blame
Guilt
Decreased Self-Esteem
Confusion and Worry
Family Discord / Conflicts
Relationship Problems
Good nutrition is important in the management of

CFS, although it is not proven per se to be associated
with a specific vitamin/mineral deficiency. A daily vitamin/mineral supplement to include antioxidants is a reasonable recommendation, but high doses or intravenous
administered vitamins are not recommended. Patients
may benefit from limited exercise (therapeutic strengthening/breathing exercise, yoga) that gives a psychological
lift, but that is not so strenuous that it results in a relapse
of more severe fatigue. CACFS patients appear at greater
risk of having exacerbation or onset of typical allergic
diseases during the course of their CFS. Children experiencing asthma, rhinitis, sinusitis, conjunctivitis, and other
inhalant allergic symptoms should receive appropriate
allergic care, which may include the use of non-sedation
53
A range of mental health programs are available for

CACFS patients,367-369 as shown in the following table
(Table 11-2).
treatment trials that include study of physical therapy,

antidepressants, acetazolamide, IVIG, anti-inflammatory
agents, DHEA, treatment of orthostatic intolerance, and
other modalities, including complimentary therapies.
Children and adolescents with CFS should be incorporated into National Centers of Excellence for CFS.
Table 11-2
Mental Health Programs Available for CACFS
Program
Psychoeducational
Psychotherapy
Psychological Issues
CACFS patients may benefit from psychotherapy
(counseling from a trained professional, preferably one
who is knowledgeable about and sensitive to issues related to chronic illness) both for support and to achieve
the ability to better cope and manage the emotional/psychological and physical symptoms of CFS.
Counseling can also assist CACFS patients to work
through the stages of emotional conflict they experience,
which are similar to those experienced after the death of a
loved one: shock, denial, anger/depression, bargaining,
and acceptance. In CACSF patients, this process can be
described by four phases, as well: shock, defensive retreat,
acknowledgement,
and
adaptation.
The
stages/phases are not always clear-cut and vary considerably from one person to another. There exists a broad
range of how CFS affects each individual child. The more
severely afflicted, like other children with severe handicaps, will tend to become isolated, while the less severely
afflicted might be able to interact quite normally with
peers.321, 364-366 In general, CACFS patients may exhibit
the following behaviors:
DenialThey do not want to be considered sick. They
want to be like everyone else. They may especially
be in denial when they have good days and tend to
greatly overdo on those days.
IsolationThey often feel isolated from peers because
they cannot keep up socially. They may also feel
greatly misunderstood when friends or schoolmates
challenge their disability, especially when peers interpret a good day as a fair barometer of their
health status.
Depression/AnxietyThey may become depressed/
anxious in reaction to being sick, to not being what
they once were, to the realization that some of their
dreams or aspirations may have to be deferred or
even remain unfulfilled.
ResiliencyThey will often show great courage, resourcefulness, and determination in the face of physical disability, cognitive impairment, and social adversity.
One psychological reaction will usually be mixed
with another, and they do not usually occur in an orderly
sequence. As one CACFS patient explains, You deny it,
acknowledge it, resent it, and finally accept it as an obstacle, or stumbling block, not as something that has sealed
your fate.
Cognitive and
Behavioral
Psychotherapy
Individual
Psychotherapy
Family
Psychotherapy
Support
Groups
Group
Psychotherapy
Comments
Provides necessary information regarding chronic
illness, as well as a clear and critical understanding
of the emotional impact of the illness. It can also
aid in reducing self-blame and de-stigmatize the
CACFS patients experience.
In cases of any chronic illness, cognitivebehavioral interventions can assist individuals in
challenging and changing faulty perceptions and
beliefs regarding CFS that underlie the emotional
stress for CACFS patients. Therapists well-trained
in Cognitive and Behavioral Therapy may be
difficult to find.
May aid the student in enhancing self-esteem,
relieving depressive and anxious feelings, as well
as helping to develop more adequate coping
strategies.
May be recommended to assist CACFS patients
and their families in coping with the impact of
CFS. Families of CACFS patients are directly
affected by this illness, and relationships are often
under a great deal of stress. Family psychotherapy
can have a positive affect on interpersonal relationships and improve communication among all
involved family members.
May be therapeutic for CFS patients, as well as for
the families. They can promote relief in hearing
similar experiences that alleviate shame, as well
as provide validation in discovering they are not
the only ones.
Provides similar gains, as do support groups, with
the difference that psychotherapy groups are facilitated by a professional trained in guiding and
promoting specific and greater emotional healing,
as well as coping skills and strategies.
Pediatricians and other physicians providing primary care for CACFS patients should advise their patients
and their families to seek counseling services and make
necessary referrals.
The Role of Schools in Accommodating Students with
CFS
The majority of children with CFS cases (up to
94%) experience worsening of their school performance,
due to the physical and cognitive symptoms and 20 to
44% of CACFS may be home-schooled because they are
too ill to attend classes. CACFS who cannot attend school
miss out on important social development opportunities
and social functioning may be impaired in more than half
of all CACFS patients.370, 371
54
Given the physical limitations and cognitive deficits

often associated with CFS, children and adolescents with
this syndrome may qualify for Special Services under the
Individuals with Disabilities Education Act (IDEA). The
IDEA provides additional federal funding for educating
students with one or more of 13 listed conditions and students with CFS often qualify under other health impaired:
having limited strength, vitality, or alertness due to
chronic or acute health problems which adversely affect a childs educational performance. Eligible students
receive an Individualized Education Plan (IEP) written by
a multi-disciplined IEP team.
Superintendents, principals, supervisors of special
education, guidance counselors, school social workers,
and psychologists are very much involved in IDEA eligibility evaluations; yet, often the role of the school nurse
as a bridge between the medical and school communities
has been overlooked. Both in the eligibility evaluations
and in the IEP meetings, the school nurses medical
knowledge could be invaluable in successfully planning a
program that would meet the educational needs of children with CFS.
It is important that a multidisciplinary approach addresses the needs of the student and families and ensures
that the students teachers participate. The process should
also allow for parent/student involvement. Consultations
with the students physician(s) should be periodic, in light
of the relapsing/remitting nature of the syndrome.
As many as 40% of students with CFS are too ill to
attend school full-time and home tutorial services should
be provided. Where students can attend school for all or
part of the day, multiple accommodations (See Table
11-3) have proved successful in helping schools provide
appropriate educational settings for students with CFS.
Table 11-3
Accommodations Schools Can Provide for CACFS
Less rigid attendance and tardiness policies

Extra time for tests and assignments
Classroom committees and copies of lecture notes
Make-up work
Flexibility in scheduling with classes and assignment deadlines
Provision of a syllabus or schedule of upcoming assignments, so
the student can keep up with the class when unable to attend
school
Access to the school elevator
Tutor(s) for class work assistance and/or Home Instructor(s) for
classes taken at home
Extra sets of textbooks for home to eliminate the burden of carrying heavy textbooks to and from school
Transportation to and from school
Flexibility with course requirements, e.g. omitting physical education
Permission to graduate from high school in more than four years
and/or decreasing the required number of credits to graduate
individual patient, including neurology, psychology, cardiology, gastroenterology, rheumatology, rehabilitation,

allergy/immunology, and infectious diseases. In children
and adolescents, pediatric-trained specialists are preferable.
There are specific syndromes that are often confused
with CFS, in which referrals to specialists are especially
appropriate, such as Fibromyalgia rheumatica, which
should be diagnosed and managed in collaboration with a
rheumatologist. In selected areas of the United States,
Lyme disease is frequently misdiagnosed as CFS, especially when associated with arthralgia-like symptoms,
despite the lack of any confirmatory laboratory studies.
Without the help of an experienced infectious disease
specialist, patients misdiagnosed with Lyme disease are
frequently given prolonged courses of unnecessary antibiotics before an appropriate diagnosis of CFS is
made.372-374
The Role of Primary Care Providers in Care of Patients with CFS

While recognizing that the physician must evaluate
and suspect emotional/psychological illness and make
appropriate referrals, many patients with CFS are suffering from a poorly understood organic syndrome. Many of
these patients emotional distresses and depressions are
reactive and related to their chronic organic illnesses and
the frequent disbelief and frustration of physicians,
friends, and family. It is the role of a primary care provider to evaluate, to offer appropriate supportive care,
and to help their patient avoid victimization by health
providers offering often expensive, but unproven, therapies. Constant referrals to multiple specialists are usually
not helpful to the patient. There are, however, appropriate
subspecialties that may be helpful in evaluation of the
Conclusion
Children and adolescent patients presenting with
prolonged fatigue require a careful, thorough evaluation.
They deserve to have a physician who will provide compassionate care, appropriate advice and referral, while
maintaining patient contact and advocacy.319, 320, 375, 376
The pediatrician should help patients with CFS negotiate
the difficult problems they will encounter with entitlement
programs, schools, and managed care organizations.
Those patients who are disabled and unable to work or go
to school need to have their physician provide support
documentation to the Social Security Administration.
55
56
12 Behavioral Rehabilitation for CFS

Richard L. Bruno, MD, PhD
Jerald R. Zimmerman, MD
percent of patients with CFS have depressive disorders.

Unlike polio survivors, our research has found that 16%
of those with chronic fatigue have personality disorders or
factitious disorders. A higher percentage of patients with
these psychiatric diagnoses report moderate to severe
muscle weakness, difficulty with mind wandering and
muscle pain. Patients with factitious disorders had severe
deficits or inconsistent performance on neuropsychologic
testing, impairments that would have made impossible the
patients documented levels of daily functioning and academic achievement. They also had very low scores on the
Sensitivity to Criticism and Failure scale of the Reinforcement Motivation Survey, suggesting a diagnosis of
schizoid personality disorder.381 It was not surprising that
this small subgroup of patients neither fully participated
in treatment for their fatigue, nor did their symptoms or
level of functioning improve. Psychiatric disorders must
be ruled out before CFS is diagnosed or treated.
Patients with a co-morbid major depressive episode
are considered for an activating antidepressant medication. However, medication is only prescribed if symptoms
are severe or interfere with participating in treatment, or
if patients have had several weeks of psychotherapy as
part of the FMP and symptoms have not improved.
ver the past 19 years, we have studied the cause and

treatment of disabling fatigue in adults who had polio 40 years ago. Our clinical findings and laboratory
studies have shown that late-onset post-polio fatigue is
associated with impaired attention and information processing speed, blood glucose negatively correlated with
attention, a blunted ACTH response to fasting, plasma
prolactin correlated with fatigue, lesions on MRI in the
brains activating system and brain wave slowingfindings often identical to those in patients with CFS.340, 377
These findings led to the formulation of the Brain Fatigue
Generator (BFG) Model of post-viral fatigue syndromes
and our study and treatment of people with chronic fatigue from other causes.340, 378-382
Symptomatology
As in polio survivors, we have found that fatigue severity in patients with CFS is associated with difficulty
staying awake during the day, trouble concentrating, relatively mild deficits on neuropsychologic tests of attention,
and symptoms that are triggered by physical overexertion,
emotional stress, and cold exposure. Symptoms of sleepdisordered breathing and nocturnal myoclonus/periodic
movements in sleep are reported in half to nearly threequarters of patients with CFS, as frequently as they are
reported in polio survivors. The similarities between the
pathophysiology, signs and symptoms of post-polio fatigue and CFS prompted us to apply the multidisciplinary
evaluation and treatment program we developed to treat
post-polio fatigue to those with chronic fatigue.378, 379
Physical Medicine Evaluation

Medical records from and tests ordered by specialists in infectious diseases, neurology, cardiology, and
rheumatology are reviewed to insure that there are no
other medical causes for fatigue symptoms. Supine and
standing blood pressure is taken to document postural
tachycardia syndrome (POTS) or neurally mediated hypotension (NMH) which, if present, is treated by a consulting cardiologist. Patients medications are also reviewed. If patients or patients family members report
patient snoring, sleep apnea, or muscle twitching, patients
are referred for a sleep study.
When alternative causes for fatigue have been ruled
out, patients are diagnosed with idiopathic fatigue or
CFS, depending on whether they meet the 1994 CDC
criteria. All patients with fatigue are offered the opportunity to participate in the program, regardless of whether
or not they meet CFS diagnostic criteria or have been
fatigued for less than six months. Regardless of the diagnosis, it is vital to treat patients as soon as they realize
that they have unremitting fatigue that is impairing their
ability to function.
Diagnostic Approach
The Fatigue Management Program (FMP) evaluation consists of psychologic and physical medicine
evaluations to document the nature and severity of psychologic, cognitive and physical symptoms, functional
limitations and patients abilities to cope with their
symptoms and decreased ability to function.
Psychologic Evaluation
The psychological evaluation begins by asking patients to list their treatment goals and to complete a Fatigue Symptom Questionnaire that documents subjective
symptoms and functional limitations. Any psychiatric
diagnoses that could cause fatigue, cognitive impairment
and functional limitations, including major depressive
episode, somatoform, personality, and factitious disorders, are documented. Similar to polio survivors, 11%
57
team, which includes a physician, behavioral psychotherapist, nutritionist, occupational and physical therapists. Therapy begins by asking patients to keep a daily
log of steps (as measured by a pedometer), activities, perceived exertion, fatigue, muscle weakness, pain, diet,
emotional stress, thoughts, and emotions (Figure 12-1).
Such a log is used to relate physical and emotional
symptoms to activities, exertion, stressors, thoughts, and
feelings. Logs are reviewed with patients by each therapist and evaluation results are used by the treatment team
to formulate a behavioral plan to modify activities that
trigger and perpetuate symptoms to initiate self-care activities and symptom management strategies. Patients are
seen once a week by each therapist. The roles of each
type of therapist are:
Occupational therapists assess how patients use their
energy in doing daily activities, including self-care,
Therapeutic Approach
All physicians can adopt the FMP approach to some
degree within their own practice. The purpose of the FMP
is not curing CFS, but managing symptomspreventing
increases in symptoms; reducing symptoms, if possible;
and slowly, but consistently, increasing function without
increasing symptoms. The heart of the program is teaching patients to listen to their bodies by keeping daily
symptom and activity logs and to pace activities, to conserve energy, and to stop activities before symptoms occur or increase. This protocol ends the roller-coaster cycle
of activity-exhaustion-rest-activity that prevents symptoms from improving.
Treatment Protocol
The treatment of fatigue is approached from a behavioral perspective by all members of the treatment
Figure 12-1
DAILY LOG FORM
Name:
Day:
Time
Up
Activities & Steps
Food?
Date:
Perceived
Exertion
Rating
Specific
Overall
Pain
Muscle
Fatigue
Mood
Weakness
Rate as mild moderate severe
Activities that Produced

Symptoms & Modifications
Sleep Quality?
Activity:
Symptom:
Break
How did you do the activity
& how were you positioned?
How could you modify?
Noon
Food?
Activity:
Symptom:
Break
How did you do the activity
& how were you positioned?
How could you modify?
6 PM
Food?
Bed
Total Steps:
Perceived
Exertion
Rating
Scale:
Very, Very Light Very Light
10
11
Fairly Light
12
13
14
Somewhat Hard
58
15
Hard
16
17
Very Hard
18
19
20
Very Very Hard
have consistently applied the behavioral plan and incorporated symptoms management techniques, nonsteroidal
anti-inflammatory drugs may be prescribed for residual
muscle or joint pain. Patients are not prescribed stimulants, sleeping medications, narcotics, or muscle relaxants.
dressing, household, and work activities. British infectious disease specialist Melvin Ramsay, who first began
treating chronic fatigue in 1955, concluded, The fundamental tenet of the management of a case of CFS is REST
with graduated activity well within the limitations which
the disease imposes.383 A British survey of over 2,000
CFS patients and recent clinical studies have found that
pacing activities reduced symptoms in over 80%.384
Therefore, patients are helped to listen to their bodies and to use the daily logs to identify the causes of
symptoms and to learn to stop activities before symptoms
increase. The occupational therapist identifies ways to
simplify work, pace activities, and include mid-morning
and mid-afternoon rest breaks to conserve energy and
decrease fatigue. Also addressed are patients sleep/wake
cycles. Patients often shift their hour of sleep to early
morning and hour of waking to late morning. Some even
reverse the cycle, staying awake all night and sleeping all
day. Other patients nap frequently throughout the day.
Patients are helped to shift their hour of sleep, in halfhour increments, to between 11 PM and 12 PM. They are
also encouraged to limit the duration of a once-daily nap
to 90 minutes or less, to nap only in the afternoon, and
not to nap after 5 PM.
Nutritionists assess protein and calorie intake to help
maintain or decrease weight and to decrease fatigue. A
study of polio survivors has shown that eating a balanced
diet that includes about 16 grams of protein (0.5 grams of
protein/pound) at each mealespecially at breakfastand
small, 8 gram protein snacks during the twice-daily rest
breaks limits portion sizes, decreases daytime fatigue, and
promotes weight reduction.
Physical therapists assess muscle weakness and pain,
while evaluating posture and gait. Postural changes and
frequent stretching during the day is recommended to
decrease muscle pain. Only as fatigue comes under control through energy conservation is any non-fatiguing
exercise considered. The CFS patient survey and recent
clinical studies have found that exercise increased symptoms in 50% of CFS patients.384, 385
Behavioral psychotherapists monitor the behavioral
plan and patients ability to promote self-care by either
decreasing fatigue-producing activities or slowly increasing activity without increasing fatigue. Behavior
modification techniques are used to decrease and eliminate hyperactivity, which is often thought by patients to
be necessary to be accepted by family, friends and employers, or decrease and eliminate inactivity, which is
thought by patients to protect against increased fatigue
and pain.
As therapy progresses, patients are weaned from
medications that have been prescribed to treat specific
symptoms, e.g. stimulants for fatigue, sleeping medications for insomnia, and pain medications. When patients
Team and Family Meeting

In the fifth week of treatment, the FMP team meets
with patients and their family members to explain the
putative pathophysiology of CFS, why patients need to
modify behavior to manage fatigue, and how family
members, co-workers and friends can provide appropriate
assistance with housekeeping and work activities.
The treatment program lasts from eight to twelve
weeks. Patients graduate when their symptoms have been
reduced or do not increase from day to day and their
function has improved. They leave with a home program
of stretching, while they continue to keep daily logs until
their first follow-up visit with their treatment team at one
month post graduation. If symptoms are well-controlled at
that point, a non-fatiguing exercise program is prescribed.
Non-Compliance with Self-Care Issues
Non-compliance is the principle cause of patients
symptoms and functional ability not improving. Compliance problems arise with the daily logs and the behavioral
plan. Patients invariably have difficulty keeping logs because they interfere with the performance of their scheduled activities, require too much energy to complete, or
force patients to recognize the severity and pervasiveness
of their symptoms.
Invariably, patients have difficulty in complying
with the behavioral plan. They forget to alter their
schedules, to eat breakfast, and often refuse lifestyle
modifications. Many patients report a fear of increased
symptoms or fear of criticism and a sense of failure when
they merely contemplate lifestyle changes, even though
without necessary changes, symptoms persist. Studies of
patients with CFS, chronic pain, and PPS find that patents ability to change their behaviors and decrease
symptoms is directly related to their ability to challenge
long-held beliefs about what they believe they should
achieve and do for others in order to survive, to face fears
concerning their worthiness in spite of their decreased
activity or productivity, and to tolerate the emergence of
some increase in fatigue or pain, as their activity level
increases.340, 378-380
There are two types of non-compliers, hyperactive
and passive. Hyperactive non-compliers are those who
will not decrease activity in order to control fatigue and
pain, or who become excessively active again as soon as
their symptoms begin to decrease. Predictors of hyperactive non-compliance are: 1) a history of refusal to rest or
pace activities, 2) an elevated Type-A behavior score
59
factitious, and personality disorders that would be a primary cause for reports of fatigue and functional disability
and would make treatment in a behavioral program impossible.
above 50, or 3) an elevated Sensitivity to Criticism and

Failure score above 60.
The early identification of hyperactive noncompliers is important, since hyperactive behavior is often overlooked or even welcomed, since therapists are
pleased when a patient becomes active again and is apparently extremely well motivated for therapy. Hyperactive non-compliance should immediately be discussed
with the patient, and its persistence should be addressed
by requiring the patient to sign a behavioral contract
stating that the program will be followed and hyperactivity will be reduced.
Passive non-compliers are those who will not keep
treatment appointments, refuse to complete daily logs, to
slowly increase activity, or to include stretching in their
daily routines because of fear that their symptoms will
increase. Predictors of passive non-compliance are: 1) a
history of refusal to increase activity, 2) a low Type A
behavior score below 30, or 3) a low Sensitivity to Criticism and Failure score below 50. As with hyperactivity,
the occurrence of passive non-compliance should immediately be discussed with the patient and should be addressed with a behavioral contract. This contract should
make clear that continued treatment is contingent on
slowly, progressively and consistently increasing activity,
attending all therapy sessions, and fully complying with
prescribed therapies. Again, passive non-compliance
should trigger a referral to a behavioral psychotherapist.
Passive non-compliance is much more common in
patients with chronic fatigue and pain. In young people
with fatigue, an extremely low Type-A score (below 25)
was found to be associated with malingering, while a low
Sensitivity to Criticism and Failure score (below 40) was
associate with a schizoid personality disorder.340 These
patients appeared to be insensitive to suggestions from
the treatment team and the needs of and impact of their
disability on others and refused to continue treatment.
Patients who are passively non-compliant and have been
found to have marked cognitive deficits should be evaluated by a clinical psychologist to rule out malingering,
Follow Up
As fatigue and pain decrease, patients commonly increase activity and find that their symptoms also increase.
To help prevent this result, patients are asked to strictly
adhere to the modified daily schedule, as set forth in their
behavioral plan after they graduate from the program and
to keep daily logs until they are seen for the follow-up
meeting with the treatment team at one month postdischarge. To promote continued self-care, patients are
seen at three-, six- and twelve-months post-graduation
and are encouraged to call their therapists at any time
with questions or for support.
Conclusion
Chronic fatigue has been a recognized clinical entity
since the first documented outbreak in 1934, which sickened 150 doctors and nurses at the Los Angeles County
General Hospital who were caring for polio survivors.386
It is inexplicable that a condition whose epidemics have
been described in the medical literature for over 65 years
should have recently become one where patients are being
blamed for their symptoms, symptoms considered to be a
variant of depression, psychosomatic or the result of
deconditioning, in spite of research findings to the contrary.385
For nearly a decade, the behavioral rehabilitation
approach described above has helped patients in the US
and Britain to manage their symptoms, increase their
ability to function and take back their lives. We encourage clinicians to think about CFS from the brain up, instead of from the mind down, so that patients can receive
treatment for their symptoms, instead of being blamed for
them.
60
13 Disability in CFS
Barbara B. Comerford, Esq.
When such a patient requests assistance from her physician in the disability application process, the doctor may
be confused, irritated and without direction. Providing
medical information in the disability process, whether at
the behest of the Social Security Administration or the
disability insurance company requires time that is often in
short supply following the advent of managed care.
To assist a patient in the disability process, the physician must produce all records and complete reports requested by the government or the private disability insurance carrier. Unfortunately, many of the forms sent are
not adequate to depict the limitations or restrictions of the
CFS patient. Therefore, medical narratives are often required to explain special facts about the patients condition. A common problem in CFS cases is functional capacity evaluations in so far as patients experience good
days and bad days. A CFS patient who is well enough to
complete a functional capacity evaluation over one or two
days almost certainly rested for days in advance to do so.
The results of the evaluation will then reflect only the
level of function on good days. CFS patients experience
extremely low levels of function on bad days, and therefore, cannot be tested on those days. This condition must
be explained to the source requesting information so that
the actual extent of limitation is understood. The role of
the CFS-treating physician is to provide guidance and
understanding to the party requesting medical information.
While the Social Security Administration requires
proof that the patient is totally disabled, private long-term
disability insurance companies may only require proof
that the patient is incapable of performing the material
and substantial duties of her own occupation. However,
the same insurance policy might require proof of total
disability after 24 months. (See Table 13-1).
Toward that end, many insurance companies and the
Social Security Administration supply long forms that
require the physician to check boxes regarding the patients functional abilities. Typically, the categories include limitations listed in Table 13-2.
atients who seek treatment for CFS often suffer such

extreme functional limitations that they are unable to
work and must apply for disability benefits from the Social Security Administration and/or private long-term
disability insurance companies. Children may also present
with the same debilitating symptoms that affect their ability to perform activities of daily living, including limitations on school attendance. (See Chapter 11). Under certain circumstances, a child may be eligible to receive Social Security benefits.
All treating physicians are expected to provide
medical support for both private and government disability applications. In the context of a patient suffering from
CFS, medical support for functional limitations is critical.
This chapter provides an understanding of what medical
information is required from the treating physician to
support an application for disability benefits in the context of a patient with CFS.
Material Selection
The functional and medical requirements necessary
to establish disability discussed in this article are derived
both from state and federal laws. Those dealing with private long-term disability insurance policies arise as a result of federal legislation, known commonly as ERISA,
where the coverage is purchased by or through the employer,387 and under state law when the insurance policy
is obtained privately by an individual.
The Social Security Administration has promulgated
numerous regulations and rulings that govern accepted
medical evidence in the disability context, and specifically in Chronic Fatigue Syndrome cases.388-391
Medical/Legal Requirements To Establish Disability

In CFS Cases
A patient presenting with CFS frequently suffers
such debilitating physical and cognitive limitations that
activities of daily living are substantially restricted, frequently precluding the patient from performing activities
of daily living, such as household chores, work, school,
and in some cases, basic hygiene. Indeed, many patients
spend substantial periods of time virtually bedridden.
61
Therefore, if a patient were to respond sedentary, the

answer would not be accurate. So, if a patient has more
bad days than good, an accurate response might well be
less than sedentary. It is also important to note that
many individuals suffering from CFS are under the age of
50. As such, Social Security regulations identify them as
younger individuals. If a younger individual can perform sedentary work, the regulations require a finding of
not disabled. Therefore, a younger individual must be
classified as less than sedentary to be found disabled
under the Social Security Act.
Table 13-1
Items of Importance in Disability Determination
Area of specialty board certifications (if any) & degree

Patient history (onset of CFS symptoms)
The date treatment began
The frequency of treatment
The date the patient was last seen
The complaints, signs and symptoms presented by the patient
(e.g. with clinical documentation for six consecutive months
palpably swollen or tender lymph nodes; nonexudative pharyngitis; persistent reproducible muscle tenderness on repeat exams;
or other medically accepted CFS medical signs)
All laboratory findings, other diagnostic test results or objective
findings (e.g. an elevated antibody titer to Epstein Barr virus
capsid antigen equal to or greater than 1:5120, or early antigen
equal to or greater than 1:640; an abnormal MRI brain scan; neurally mediated hypotension by clinically accepted form of testing; or any other laboratory findings consistent with medically
accepted clinical practice)
A list of other disease processes excluded
All functional limitations (see Table 13-2)
Restrictions
Treatment rendered and patient response
Response and side effects of all medications
Prognosis for recovery
The opinion of the physician on the issue of total disability
Whether patient satisfies CDC requirements and why
Table 13-3
Activities Level Defined
Sedentary:
Light:
Medium:
Heavy:
The CDC definition should be used as a checklist

and whether or not it is satisfied should be indicated
within the body of the report; remember, the longitudinal
clinical requirements must also be met.
Therefore, if a disability form does not allow for accurate representation of the limitations, those details
should be included in a letter annexed to the form. This
addition is recommended in all CFS cases, due to the inherent problems presented.
All the information that both Social Security and
most long-term disability insurance companies require
from the treating physician is found in Table 13-1. The
Social Security Administration has incorporated the standards for determining eligibility for disability benefits in a
ruling, SSR 99 (2)(P). The ruling can be referenced at the
Social
Security
Administration
web
site
(http://www.ssa.gov).
Table 13-2
Functional Limitations Categories
Bending
Climbing Stairs
Cognitive Activity
Concentrating
Dexterity
Difficulty with
Verbal Retrieval
Fine Manipulation
Lifting
Pushing/Pulling
Power Grip (Bilateral)
Reaching
Remembering
10 lbs maximum lifting or carrying articles. Walking/standing on occasion. Sitting 6/8 hours.
20 lbs maximum lifting. Carrying 10 lb articles
frequently. Most jobs involving standing with a
degree of pushing and pulling.
50 lbs maximum lifting with frequent lifting/carrying of up to 25 lbs. Frequent standing and
walking.
100 lbs maximum lifting. Frequent lifting/carrying
of up to 50 lbs. Frequent standing/walking.
Simple Grasp
Sitting
Standing
Walking
Forms are often misleading, however, particularly in

the context of a chronic fatigue syndrome case, as was
noted above. The patient often presents with functional
limitations that ebb and flow, resulting in good days
and bad days. Frequently, patients report that on a
good day, they function somewhat normally, followed
by bad days of being bedridden and completely fatigued. Therefore, when an Attending Physician Form
requires the physician to provide a vocational classification from sedentary to heavy work, he is often confused
because of the good day/bad day manifestation of the
illness. On bad days, the patient is often incapable of
even sedentary work, in that she may be so fatigued she
spends most of the day resting, and most forms do not
provide a less than sedentary classification. Nevertheless, on good days, a patient may indeed have sedentary
abilities or more. Add to that the unpredictability of when
a patient experiences a good day, then the inadequacy of
the forms becomes even more apparent (See Table 13-3).
Documentation
Listing functional limitations presents the most difficulty for physicians, due to the ebb and flow of CFS
symptoms. Toward that end, the physician should request
from each patient a weekly diary during the period of
disability. That log can be incorporated into the patients
chart to chronicle the extent of limitation. It can be appended to the physician report, in response to the limitation inquiry by either the Social Security Administration
and/or the disability insurance company. The physician
must be sure to instruct the patient to provide accurate
information, including bad days, during which the diary
62
that the standard for disability is somewhat different from

adults. However, the pediatrician must also comply with
the above checklist (See Table 13-1), keeping in mind the
importance of clinical support with objective findings
concerning the extent of CFS impairment (See Chapter
1).
could not be done, due to fatigue and cognitive difficulties. This step is crucial because insurance claims representatives frequently remark that CFS claimants allege
cognitive impairments, but then write extensive cogent
letters that seemingly undermine that claim. The diary,
therefore, serves to memorialize the actual ebb and flow
of cognitive abilities on the part of the patient. Both the
Social Security Administration and the insurance industry
invest a substantial portion of revenue to investigate
fraud. Therefore, it is crucial that the information accurately reflect (without minimizing complaints, either) the
extent of daily limitations.
Both the Social Security Administration and the
long-term disability insurance companies require that the
treating physician support a finding of disability. Most
long-term disability insurance companies require not only
completion of attending physician reports, but also records of treating sources, including objective findings and
other information contained in the patient chart.
With respect to cases involving children who apply
for SSI Childhood benefits, it is important to note that
only indigent (welfare eligible) children are qualified, and
Conclusion
Disability evaluation in CFS can be made less arduous for the treating physician. The most important source
of medical information is the patients treating CFS physician. In Social Security cases, deference is given to the
treating physician by most fact finders where accurate
information is documented. On the other hand, disability
insurance companies are not required to give such deference. However, the more demonstrated knowledge in CFS
the physician has, the more persuasive the patient or her
attorney can be in advocating the claim. By providing the
information set forth here, the physician will assist the
patient in the disability process and will provide a strong
basis for appeal in the event of denial.
63
64
Glossary of Selected Acronyms

ACTH
CACSF
CFIDS
CFS
CMV
CRH
CVID
DHEA
EBV
FM
FMS
GH
HHV-6
HIAA
HIV
IGF-1
IL-1
IVIG
LE
MMPI
MS
NADH
NGF
NSAIDS
OI
PCR
PHA
POTS
Adrenocorticotropic Hormone
Children and Adolescents with Chronic
Fatigue Syndrome
Chronic Fatigue Immunodeficiency
Syndrome
Chronic Fatigue Syndrome
Cytomegalovirus
Corticotropin Releasing Hormone
Chronic Variable Immunodeficiency
Syndrome
Dihydroepieudorterone
Epstein Barr Virus
Fibromyalgia
Fibromyalgia Syndrome
Growth Hormone
Human Herpes Virus-6
Hydroxyindole Acetic Acid
Human Immunodeficiency Virus
Insulin-like Growth Factor
Interleukin-1
Intravenous Immunoglobin
Lupus Erythematosis
Minnesota Multiphasic Personality
Inventory
Multiple Sclerosis
Nicotinamide Adenine Dinucleotide
Nerve Growth Factor
Nonsteroidal Antiinflammatory Drug
Orthostatic Intolerance
Polymerase Chain Reaction
Phytohemagglutinim
Portural Orthostasis Syndrome
65
66
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Edward J. Moylan, RPh

Elizabeth B. Congdon, RN, MA

Lorraine T. Steefel, RN, MA, MSN

MEMBERS OF THE WRITING COMMITTEE AND CONSULTING ADVISORS

Richard L. Bruno, MD, PhD

Kenneth R. Kaufman, MD, MRCPsyc

Jeffrey P. Levine, MD, MPH

Lorraine T. Steefel, RN, MA, MSN

A Consensus Manual for the Primary Care and

Pathophysiology in CFS .............................................................................................. 3

Initiating Care of Patients with CFS ............................................................................ 9

Infections in CFS ........................................................................................................ 13

Cognitive Dysfunction in CFS ................................................................................... 23

Sleep Dysfunction in CFS .......................................................................................... 25

Womens Health in CFS ............................................................................................. 43

Gastrointestinal Symptoms in CFS........................................................................ 49

CFS in Children and Adolescents .......................................................................... 51

Behavioral Rehabilitation for CFS.......................................................................... 57

Disability in CFS ...................................................................................................... 61

Glossary of Selected Acronyms...................................................................................... 65

preciate the pathophysiology, differential diagnosis, and

he illness called Chronic Fatigue Syndrome (CFS)

Joseph F. John, Jr., MD, Editor

successful description of the pathophysiology of

The physiologists view of fatigue

have been several reports from one laboratory of altered

Fatigue at the neuromuscular junction

Pain - The Second Hallmark of CFS

Altered electrical activity in neural networks

hibitory fibers cannot only influence the perception of

stances act on the membranes of pain-sensing neurons

Involvement of Other Organ Systems

The pathophysiology of immune system dysfunction

Epidemiology: Gender, Genetics, and the Environment

might be involved. Unfortunately, there is no definitive

with two other syndromes: FMS and Gulf War Illness.

Initiating Care of Patients with CFS

his chapter introduces the primary care physician to

*Patients can grade symptoms as mild, moderate, severe,

tient with CFS, it is important to convey a belief in the

Stomach virus Fever blisters

autoimmune thyroiditis, but with perfectly normal thyroid function.

to determine the patients level, if any, of deconditioning.

a limited clinical role until more research data is accumulated.37-39

nine dinucleotide (ENADA) is an example of a relatively

workers have reported that certain species of mycoplasma

any patients with CFS complain of fever, sore

ogy, coupled with newer techniques to amplify bartonella

52 controls for the presence of HHV-6 and HHV-7 and

such as isoprinosine, infliximab, or thalidomide, will

Kenneth R. Kaufman, MD, MRCPsych

he CDC criteria for CFS specifically recognizes that

of 10 CFS, 15 MDD, and 25 control subjects indicated

tions in function in both excitatory and inhibitory pathways in FM.74

of urinary free cortisol reductions in CFS but elevations

a means to demonstrate abnormalities in the brains of

regulate expression of interferon, interleukin, and tumor