Chronic Fatigue Syndrome

State of the Science 

Conference 

Presented by

The U.S. Department of Health and Human Services

Chronic Fatigue Syndrome Coordinating Committee

October 23-24, 2000

Arlington, Virginia
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Overview

Chronic Fatigue Syndrome (CFS) is a debilitating and complex disorder characterized by 

profound fatigue that is not improved by bed rest and that may be worsened by physical or 

mental activity. Persons with CFS must often function at substantially lower levels of activity 

than they were capable of before the onset of illness. In addition to these key defining 

characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, 

impaired memory and/or mental concentration, insomnia, and post-exertional fatigue lasting 

more than 24 hours. In some cases, CFS can persist for years. The cause or causes of CFS have 

not been identified, and no specific diagnostic tests are available. Moreover, since many 

illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known 

and often treatable conditions before a diagnosis of CFS is made.

The state-of-the-science conference was organized by the U.S. Department of Health and Human 

Services (DHHS) Chronic Fatigue Syndrome Coordinating Committee (CFSCC), with the 

financial assistance of several DHHS agencies (listed in Appendix 1). The goals of the meeting 

were to focus on CFS research areas in which information is both mature and exciting; 

summarize current knowledge and identify important gaps in knowledge; garner the perspective 

of expert investigators not currently working on the problem of CFS; and identify expert 

investigators who might be attracted to study CFS as a clinical problem.

Seven topic areas of medical research were identified: neuroendocrinology; cognition; chronic 

pain; sleep; immunology; orthostatic intolerance/neurally mediated hypotension; and fatigue, 

functional status, and disability. For each topic, a clinical scientist studying CFS (CFS expert) 

was asked to present the most provocative aspects of current knowledge; then scientists working 

in that same research area, but not studying CFS (subject experts), were asked to provide 

additional information and insights from that discipline that could enhance understanding of 

CFS. Each session provided time for discussion among the presenters and comments/questions 

from the conference attendees. A lay audience session was also included as part of the agenda. 

The summary of the meeting is organized around the seven scientific topic areas. The sessions 

have been summarized without attributing comments to individual speakers; however, the 

speakers provided the main content of the sessions. (Speakers are listed in Appendix 2).

Introduction

Presentations about CFS from the perspective of the patient and the community physician laid 

the groundwork for the scientific presentations. A CFS patient described her 11 years of living 

with CFS, and how her previous highly active professional and personal life style had been 

restricted and diminished by the illness. She has had to change jobs to accommodate her body 

and her symptoms. Her relationships with her physicians have varied from supportive to 

suspicious to suggestions that other patients may be in more need of medical assistance. She 

would like to be able to have the quality of life of her earlier pre-CFS years and for her and her 

physician to have tools to manage the illness. She noted that CFS does not exist in a vacuum, 

and may be one of a group of chronic diseases with similar and overlapping symptoms. 

A community physician noted the problems of treating CFS in the current medical climate, 

which emphasizes a scientific/mechanistic basis for medical prevention, diagnosis, and 
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treatment. In the case of CFS, there is no known underlying disease mechanism around which to 

design treatment. Clearly, symptom relief is within the purview of all physicians, even without 

an etiology or cure for CFS. However, there is concern among some physicians that off-label 

use of medications or use of narcotics to treat CFS symptoms could cause problems with 

licensing bodies. There is also a concern by some members of the medical profession that 

making a CFS diagnosis or treating CFS may perpetuate illness. There is no medical specialty or 

sub-specialty that is identified with CFS, thus making patient referrals in the managed care 

environment difficult. Given that primary care physicians commonly provide much of the care 

for chronic illnesses with unknown etiologies, such as multiple sclerosis (MS) and rheumatoid 

arthritis (RA), it was suggested that these illnesses might be designated as the specialty of choice 

for CFS. While the research case definition of CFS is helpful for clinical studies, primary care 

physicians would benefit from a clinical case definition of CFS. 

Many primary care physicians can “recognize” the CFS symptom constellation when they see 

individual patients. Disability determination is also a problem for primary care physicians. 

Disability claims often focus on objective tests, which are not available for CFS. Children with 

CFS are often denied appropriate support (e.g., tutoring), as local schools do not recognize CFS 

as an entity and therefore abjure responsibility for needed services. 

A misperception that causes great problems is that CFS is considered by some to represent a 

character flaw in the patient. More education of primary care physicians about the nature of CFS 

and its legitimacy as an illness, the various kinds of coping styles and aggressive symptomatic 

treatment, and the need for patient respect and reassurance would greatly benefit the CFS patient 

community. More research needs to be done on CFS pathogenic mechanisms, so that physicians 

can prescribe treatments with confidence to patients and so that patients will be confident about 

the care they are receiving. 

Neuroendocrinology

The neuroendocrine system is involved in the body’s reaction to stress. It involves the central 

nervous system, endocrine glands, and a number of hormones and other mediators (including 

cytokines) that act in a variety of regulatory pathways and feedback loops. The stress system is 

designed for survival of the individual when faced with danger. It induces a state of arousal, 

alertness, vigilance, and cognition; and shuts down vegetative body functions, such as eating and 

sleeping, as well as the neuroendocrine programs involved in growth and reproduction. The 

regulatory pathways built into the neuroendocrine system are designed to stop the system when

the danger is no longer present. It is important to recognize that the stress, immune, and sleep 

systems are linked to one another by several common and multifunctional mediators.

Investigations of the stress system dysregulation/disorders that are associated with changes in 

arousal, mood, and energy levels were undertaken initially to understand the differences between 

two forms of depression—atypical depression and melancholic depression—with later studies 

including CFS and fibromyalgia (FMS). Atypical depression is characterized by increased sleep 

and appetite, weight gain, and profound lethargy and fatigue. Affected persons feel out of touch 

with themselves. By contrast, melancholic depression is characterized by a state of hyperarousal, 

with anxiety, decreased concentration, and a reduction in sleeping and eating. Persons with 

melancholic depression feel worthless and have a sense of hopelessness about the future. 
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To investigate the basis for the differences in symptoms, studies focused on a corticotropinreleasing hormone (CRH), which is a neurohormone produced in the hypothalamus region of the 

brain and is a component of that portion of the body’s stress system called the hypothalamic 

pituitary adrenal axis (HPA). Animal studies have shown CRH to recapitulate many of the 

physiological and behavioral aspects of the stress system. Studies of CRH levels have 

demonstrated that the hormone is down regulated in CFS, in atypical depression, and in seasonal 

affective disorder (SAD), but not in melancholic depression. When CFS patients are stimulated 

with a cortisol inducer, they have an exaggerated response to small doses and a reduced response 

to high doses. In both FMS and CFS, there are reduced levels of another stress mediator, 

norepinephrine. In addition, CRH response to exercise is blunted in CFS patients. Lower levels 

of CRH and HPA axis activity tend to result in hypoarousal, lethargy, decreased plasma volume, 

and inflammatory symptoms. 

Another aspect of the body’s response to stress is the shift in the type of the immune response, 

from cell-mediated immunity to humoral immunity. Studies in strains of rats that differ in their 

immune responses have shown the effect of this shift. Lewis rats, which have an enhanced 

immune response to multiple stimuli and thus are at risk of autoimmune diseases, have reduced 

levels of CRH after stress. By contrast, Fisher rats that have relatively low or suppressed 

immune responses responded adversely to stress, with some animals dying from a particular 

stressor. Thus, the immune system as a whole, as well as variations within individuals, can 

affect the stress response. Additional studies are needed to better understand the role of the HPA 

axis/stress response in CFS. Such studies would involve direct comparisons of basal levels and 

challenge responses of HPA axis in persons with CFS, SAD, and atypical depression. 

In addition to its role in stress, CRH is a modulator of wakefulness. In animal studies, if CRH is 

increased, then wakefulness increases; if CRH is reduced, wakefulness decreases. In addition, 

interleukin-1 (IL-1), a cytokine, enhances sleep in animal models and its concentration peaks in 

humans at sleep onset. Studies in animal models demonstrate a balance and regulation of CRH 

and IL-1 by one another. They also demonstrate genetic differences between rat strains in their 

CRH responsiveness to IL-1. Thus, the immune and stress systems are linked by mediators not 

only to one another but also to sleep regulation. 

Although cytokines were named for their immunomodulatory effects, they can penetrate the 

blood brain barrier, act as neuromodulators, and produce both acute and long-term effects in the 

brain, particularly in regions associated with cognition and endocrine activity. Two important 

aspects of this type of alteration are related to the action of cytokines in concert with other 

factors such as environmental stressors. Thus, IL-2 alone has only a modest effect in stimulating 

corticosterone in mice. However, in the presence of a relative ly mild stressor (i.e. novelty 

stress), IL-2 results in an increased magnitude and duration of the corticosterone response. 

Changes in neurochemical activity as measured by dopamine levels in the nucleus accumbens 

(an area of the brain important for motivation) are higher during a secondary immune response 

than during a primary response. In addition, animals initially receiving multiple injections of IL2 to replicate the effects of a chronic disorder showed an increased behavioral response to a 

highly selective dopamine uptake inhibitor 6 weeks after the initial multiple doses. There are 

studies in humans that also suggest that long-term alterations of the HPA axis can occur in a 

variety of trauma, stress, and abuse situations. 

Another important concept about cytokines is that they are potent modulators of 

neurotransmission, and that they may induce biphasic effects on neuronal excitability (e.g., IL-2 
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is a very potent modulator of the NMDA (glutamate) receptor in the ventral tegmental area, a 

brain region associated with aspects of reward, cognition, and motor activity. Low doses of IL-2 

result in inhibition of NMDA-activated current in this brain region, whereas high doses of IL-2 

have potentiating effects. Other cytokines may have opposite effects in that low doses 

potentiate NMDA-activated current whereas high doses have potentiating effects. Thus, the 

individual cytokine as well as its level needs to be taken into account in the design of studies.

In the brain, cytokines appear to act principally as neuromodulators rather than as 

immunomodulators. Studies of cytokines in humans are limited by the fact that peripheral 

(blood) cytokines are the only readily accessible ones; brain levels can be assessed but would 

require cerebrospinal fluid (CSF). Studies in rodents have demonstrated that while peripheral 

cytokine levels may influence the levels of cytokines in the brain, they may not reflect the brain 

levels, which appear to be very low and difficult to assay. New information indicates that 

adipose tissue, which is highly enervated, may be a significant source of peripheral cytokines 

that appear to be proinflammatory. The role of these adipose-tissue-associated cytokines will 

need to be considered in the design and analysis of future studies.

Cognition

Problems in cognition represent important impairments in persons with CFS. Studies of 

cognition in CFS must consider a number of factors, including the heterogeneity of the CFS 

population, the need to identify specific cognitive problems, the impact of psychiatric factors in 

cognition, and the relationship between cognition and cerebral dysfunction. 

Studies of carefully selected CFS subjects, which involved dividing CFS patients into those not 

having concurrent or previous psychiatric problems and those having them, have shown that 

intellectual functioning (e.g., global IQ) and simple concentration capacities are intact. Two 

reproducible abnormalities have been identified in CFS. They are difficulty with complex 

information processing tasks and reduced speed of processing (e.g., as measured in the PASAT, 

Paced Auditory Serial Addition Test). Studies of verbal learning and memory demonstrated that 

the problem in CFS appears to be in learning rather than recall. Once information is learned, it 

can be recalled. Thus, the problem appears to be in encoding information. Persons without 

psychiatric co-morbidity appeared to be more impaired in these studies. 

In studies of the prevalence of neuroimpairment, it appeared that about one-third of persons with 

CFS had objective cognitive problems. Depression and fatigue did not appear to be related to 

neuropsychological performance. The PASAT was the best predictor of neuropsychological 

problems. In studies trying to distinguish whether CFS represented a medical illness or an 

atypical presentation of primary depression, of anxiety, or of a somatization disorder, 

comparisons of persons with CFS, MS, or depression were made by using symptom measures of 

the Beck Depression scale, such as self-reproach, somatic features, and mood. The 

symptomatology of CFS and depression differed in these studies.

Magnetic Resonance Imaging (MRI) studies suggested that about one-third of persons with CFS 

and 10 percent of healthy controls had abnormal white matter, most often in the frontal lobes. If 

the CFS subjects were divided into those with and without psychiatric problems, 50 percent of 

CFS patients without psychiatric problems had abnormalities. SPECT studies were more 

problematic in outcome, but also showed abnormal areas in persons with CFS; these changes 

also appeared to be more severe in persons with CFS who did not have psychiatric problems. 
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Functional MRI studies suggested that when presented with a particular task, persons with CFS 

seemed to activate more areas of the brain, and those areas of the brain appeared to be working 

harder than similar areas in healthy subjects. This observation might explain the cognitive 

fatigue reported in CFS. It should be noted that there is no imaging pattern that is diagnostic of 

CFS. 

The cognitive dysfunction observed in CFS was relatively mild when compared to severe 

dysfunction, such as Alzheimer’s disease, but it was disabling to the person. The cognitive 

dysfunction found in CFS does not appear to be secondary to fatigue or to psychiatric factors, but 

these factors can exacerbate it. Future studies need to identify subsets and subtypes of CFS 

populations and need to relate cognition with neuroimaging, with medical factors (e.g., 

neuroendocrine or immunological findings), and with everyday activity levels.

The methods used to study cognitive problems in one disease have the potential to be translated 

into studying those in another illness; the approach used to study cognitive changes across the 

disease spectrum in HIV/AIDS patients was described to provide insights for CFS investigations. 

Cognitive changes can be measured as mean differences in scores or as a deficit score, that is, an 

aggregation of scores below a baseline cut-off level. Mean differences assume a common 

change across most persons with the illness, but these changes may or may not be clinically 

significant. Deficit scores can detect changes that are more sporadic and focus only on those 

persons who have changes.

Results from such neuropsychological studies can be used to characterize or diagnose a 

particular entity, to define subtle changes and determine their impact on function, to use patterns 

of cognitive changes as clues for defining underlying pathology, or to define predictors and 

correlates of cognitive change. Initial studies may use a large screening battery, and then as 

results become available, select tests for specific affected domains. Subsequent tests may use 

smaller screening batteries to identify persons with problems in specific domains for more 

extensive testing. However, with this approach, there is the potential to miss some persons with 

deficits that are not represented in the narrow screening battery.

Several investigational issues face researchers both in HIV/AIDS and CFS. The biological 

correlates of neuropsychological problems are poorly defined. Defining and clarifying cognitive 

complaints and translating these into specific domains have provided and should continue to 

provide additional insights into the underlying pathology. It is important to understand the 

impact of cognitive problems on patient function to devise coping strategies. The potential 

interaction of neuropsychological problems with affect or mood disorders needs to be 

considered.

Methods used in understanding and analyzing data from studies on brain function in depression 

could provide useful approaches in studying a multicomponent illness such as CFS, as in both 

cases there is a need to understand the interrelationship between the clinical syndrome, 

physiological changes, and cognitive deficits. Rather than looking at the results of tests for each 

component separately, it is possible to use mathematical and visual approaches to depict the data. 

In studies of patients with depression, data from cognitive scores, mood scores, and functional 

brain imaging were combined in a neuroplot. Scores from the various cognitive and mood 

instruments were color-coded and then plotted onto a map of the brain. Thus, changes in speed 

on the Stroop Test mapped to a different region of the brain than did the number of errors made 

on the Stroop Test. More important, neuroplots prepared after depressed patients were treated 
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with Prozac changed to a pattern similar to that in healthy controls. Thus, this approach can be 

used not only to visualize the interrelationship between functions but also to assess the effects of 

therapeutic interventions. A neural network approach was also used to map regions from PET 

scans and cognitive test results. Combining the results of the brain imaging and cognitive testing 

allowed the network model to identify depression more readily. Thus, these two meta-analytical 

approaches may allow for the better understanding of individual disorders and for comparisons 

with overlapping disorders. 

Chronic Pain

Pain is an area that has not been as actively investigated in the context of CFS. However, when 

one considers the minor criteria in the CFS Case Definition, the majority of them are related to 

pain, thus making pain a significant feature of CFS. There is also a group of disorders that can 

be characterized as “diffuse pain syndromes”, which includes CFS and also FMS, irritable bowel 

syndrome (IBS), post-infection pain, and post-operative pain. Moreover, there is also a high comorbidity between CFS, FMS, and IBS, as well as with multiple chemical sensitivity (MCS). 

The particular diagnosis made for this group of disorders may depend upon the clinical 

environment in which it is made or on the predominant symptom(s) at the time of diagnosis. The 

cluster of symptoms seen in these disorders could in fact be explained by mechanisms related to 

pain. The symptoms also seem to parallel the effects of cytokines; for example, patients who 

have been treated with interferons for malignancies have a variety of diffuse pain syndromes and 

many of the symptoms of CFS. 

Additionally, there are a number of apparently unrelated medical conditions that have fatigue, 

pain, and sleep problems as significant symptoms. For example, cancer patients who have been 

successfully treated with radiation therapy may still have a long term fatiguing state. Infection 

with Campylobacter jejuni may also be followed by months of lingering fatigue. The occurrence 

of this symptom constellation in diseases with specific known pathologies validates CFS as a 

clinical entity. 

Illness behavior is represented by a complex physiological array that includes fatigue, fever, 

pain, stress and neuroendocrine abnormalities, with influences by, cytokines, thus suggesting a 

sharing of common mechanisms across diseases. There is suggestive evidence that much of the 

symptomatology for diffuse pain symptoms of the type seen in CFS, FMS, and IBS may be 

mediated by the subdiaphragmatic portion of the vagus nerve. Part of the sex differences seen in 

pain syndromes may be explained by the structure of the adrenal medulla, which is part of the 

stress axis and one of the routes that is involved in vagus nerve feedback to the body. Adult 

female adrenal medulla retains sex hormone receptors, whereas adult male tissue does not.

The perception of pain is influenced by three factors. These are: (a) the intensity and character 

(e.g., heat, pressure) of the external or internal stimulus that activates nerve receptors; (b) the 

transmission of sensory information from these receptors to the spinal cord where it is further 

processed and then sent by ascending nerve tracts to specific sites in the brain; and (c) 

descending input from the brain to the spinal cord that may either inhibit or facilitate the 

ascending sensory transmission. An example of this involves studies of the nociceptors, or nerve 

fibers, that respond to stimuli that are tissue damaging or potentially tissue damaging. 

Nociceptors are innervated by two types of fibers, alpha-delta myelinated fibers, which transmit 

very rapidly, and unmyelinated C-fibers, which conduct more slowly and appear to be related to 

chronic pain. 
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Studies of pain perception using a combination of heat and capsaicin (the pungent substance of 

hot peppers) demonstrated how the presence of capsaicin altered the perception of pain. 

Capsaicin itself creates a warm sensation on the skin but does not cause damage. However, 

when capsaicin-sensitized skin is subjected to a heat stimulus (43oC) that alone is below the heat 

pain threshold (typically 45 oC) the person feels a subjective level of pain that is equal to a heat 

stimulus (47 oC) that is above the pain threshold on normal skin. Subtractive PET imaging 

studies of the two situations (43oC

 with capsaicin versus 47 oC on normal skin) indicated that in 

situations with abnormal sensitized nociceptive processing, the limbic areas of the cerebral 

cortex and thalamus appear to be involved. Other situations in which pain perception is modified 

include damage to nociceptors as a result of diabetes. Initially, the nerve injury in diabetes 

results in pain with normal processing of the information in the spinal cord. However, over time, 

the processing in the spinal cord appears to change and abnormal information is sent to the brain. 

Likewise, certain damage to the brain (e.g., the result of a stroke) can alter nociceptive 

processing, producing the sensation of pain without stimulation of nociceptors or damage to the 

nociceptors.

Some sex-related differences in pain perception may be explained by observations from PET 

scan studies that were combined with psychophysical studies. These studies showed that in 

response to noxious stimuli, the same brain areas were stimulated in men and women, but 

women have more brain activity than men do. In addition, women rated the stimulus as more 

intense. This difference was not seen with non-noxious stimuli. A critical area in pain research 

in general focuses on differentiating sex-related (i.e. biological) influences on pain from those 

from gender (i.e. sex-role) influences.

Neuroendocrine and imaging studies also 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 

diagnostic criteria for FMS. Accordingly, individuals with FMS exhibit lower pain threshold 

levels than persons with CFS who do not meet criteria for FMS; these FMS subjects are also 

better than CFS subjects and controls in discriminating between high and low intensity stimuli 

that are presented in random order. 

Neuroendocrine and imaging studies suggest a number of similarities and some differences 

between these syndromes. Thus, both CFS and FMS patients have low levels of cortisol and 

CRH. FMS patients have low levels of IGF-1 and growth hormone; there is inconsistent data for 

CFS for these markers. Persons with FMS have low serum levels of serotonin and low CSF 

levels of serotonin metabolites. Persons with CFS have high plasma levels of serotonin 

metabolites. FMS is also characterized by high cerebrospinal fluid levels of two factors 

promoting pain: nerve growth factor and substance P. MRI imaging studies of brain structure 

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 brain structure 

in patients with FMS. Resting state studies of regional cerebral blood flow, using SPECT or 

PET imaging, have produced different results for persons with CFS and those with FMS. The 

CFS patient studies generally have not produced consistent results, although two studies found 

evidence of brainstem hypoperfusion in patients with CFS. One recent British study found that 

CFS patients show higher levels of blood flow in the thalamus compared to healthy individuals. 

In contrast, two studies from the same laboratory in the U.S. reported that patients with FMS 
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show hypoperfusion of the thalamus and/or caudate nucleus during resting conditions. 

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. 

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 the anterior cingulate cortex. 

These findings suggest that both FMS and CFS are characterized by alterations in neural 

processing of sensory information. Future studies will examine changes in pain perception and 

regional cerebral blood flow in persons with CFS and FMS when they are stressed before 

exposure to painful stimulation.

Overall, the physiological approach to treatment of pain has been to eliminate the cause in acute 

illness, and to treat the signs and symptoms in chronic illness, while trying to understand 

physiology of the syndrome that could suggest unique therapies. Alterations in nociceptive 

information processing also need to be considered when assessing the origins and the 

mechanisms of pain. This type of approach could be carried into investigations and treatment of 

CFS.

Sleep

The body has a diurnal rhythm of sleep and wake cycles. A pattern of characteristic brain waves 

for sleep and waking activities can be obtained with electroencephalograms (EEG). Sleep itself 

can be divided into an orderly series of stages. Aspects of the sleep cycle are described by using 

the various brain wave patterns identifying rapid eye movement (REM) and non-REM stages. In

addition, mood, or how well one feels, also has a cyclic effect throughout a 24-hour period.

For healthy persons, the changes in mood throughout the day are relatively modest. However, 

for persons with CFS, the level of mood is significantly lower at baseline than for healthy 

persons and the best time of the day is from 10 a.m. to 2 p.m. or 3 p.m. and after that CFS 

patients feel significantly worse. Unrefreshing or non-restorative sleep is part of both CFS and 

FMS. Sleep studies have demonstrated objective evidence for disordered sleep in CFS with the 

presence of an alpha-delta EEG anomaly, which accounts for the lightness of sleep and the 

unrefreshing quality of sleep. Studies of cortisol levels in persons with CFS, FMS, and healthy 

controls demonstrated that cortisol levels fell earlier in the sleep-wake cycle in CFS and FMS 

subjects than those in healthy controls. Thus, cortisol levels in the sleep-wake cycle in CFS and 

FMS are lower and shifted in time. Interestingly, the percentage of natural killer (NK) cells also 

starts to decrease at about 3 p.m. in CFS patients. As part of a Centers for Disease Control and 

Prevention study, a 17-item sleep questionnaire was administered to persons with CFS and 

healthy controls; the results indicated that 10 percent of CFS subjects and two-thirds of healthy 

subjects had good sleep. The tests used in neurocognitive studies are sensitive to sleep 

deprivation. It was hypothesized that disordered sleep may lead to altered immune functions, 

which can lead to symptoms. Previous studies in healthy subjects have shown that disruption of 

deep sleep for as little as a few days leads to tenderness, aches and pains, and fatigue.

Persons with CFS may have disturbed sleep, and some may suffer from depression as well. 

Antidepressants have been given to CFS patients to relieve symptoms. Individual antidepressant 

drug classes have different degrees of impact on sleep that may also vary with the sex of the 

recipient. Information that has been gathered from the study of antidepressants in persons with 

depression is important to consider when these medications are prescribed in CFS.
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Major depression occurs in 10 to 17 percent of the U.S. population; thus, antidepressants are 

frequently administered drugs. During their reproductive years, women have a two-fold risk 

over men of having depression. Disturbed sleep increases the risk for depression and, in those 

who have suffered from depression, increases the risk of relapse and recurrence. Persistent 

insomnia also increases the risk of suicide. Sleep abnormalities are key symptoms of depression. 

Even after treatment for depression, about one-third of patients have sleep problems, thus 

making knowledge of the impact of the various drug classes on sleep important. 

Tricyclic antidepressants are inexpensive and widely used. They prolong REM latency, reduce 

REM sleep and increase total sleep time, but have little impact on depth or quality of sleep. (I.e. 

they do not enhance deep sleep). Although the side-effect profile does include some daytime 

sedation, tricyclics do not typically exacerbate sleep disturbances. Selective serotonin reuptake 

inhibitors (SSRIs), such as paroxitine (Paxil), sertraline (Zoloft), and fluoxetine (Prozac)) also 

act as REM sleep suppressors, although they are not as potent REM suppressors as tricyclics. 

More significantly, however, SSRIs increase arousal, intermittent wakefulness, and nonrestorative light sleep. Their adverse effects include insomnia, bruxism, and periodic limb 

movements. Typically, the adverse effects are more pronounced in women, particularly with 

fluoxetine. With regard to other types of antidepressants, trazodone (Deseryl), a 5HT2 

antagonist, decreases wakefulness and increases deep restorative slow-wave sleep. 

Unfortunately, it is associated with significant daytime sedation. A related compound, 

nefazodone (Serazone), a 5HT2 antagonist that also has some of the properties of SSRIs 

(serotonin reuptake inhibition), seems to improve sleep quality (decreased wakefulness and light 

non-restorative sleep) without causing extreme sedation or agitation.

When asked about their sleep, it is clear that patients are aware of the quality of their sleep, and 

their subjective reports correlate with laboratory polysomagraphic results. Thus, the sleep 

laboratory findings have strong relevance to clinical practice. There are a number of reasons for 

choosing an antidepressant that improves sleep. It not only decreases the need for concomitant 

medications, but if patients experience improved sleep, they may also be more compliant in

continuing medication usage until their depressive symptoms improve. 

Animal models of sleep may provide important insights for designing studies to elucidate sleep 

disorders and devise treatments for them. Studies in mice suggest that tumor necrosis factor 

(TNF) and IL-1, which are pro-inflammatory cytokines, have a central role in non-REM 

(NREM) sleep regulation and sleep pathology. The ability of IL-1 and TNF to increase growth 

hormone release (a sleep-related hormone) and sleep seems to be mediated via GHRH. For 

instance, antibodies to GHRH block IL-1 induced NREMS responses. A strain of mice 

(designated lit) lacking the growth hormone releasing hormone (GHRH) receptor was used to 

demonstrate that GHRH also plays a role in modulating NREM sleep In normal mice, acute 

influenza virus infection increases NREM sleep and decreases REM sleep. In contrast, the lit

mice have decreased NREMS after viral challenge, thereby implicating the GHRH-receptor in 

sleep responses induced by viruses. These mice also have a higher mortality after viral challenge 

and abnormal EEGs. It seems likely that in chronic viral infections, perhaps associated with 

chronic sleep disturbances, this mechanism may be important.
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Additional research is needed about sleep and sleep abnormalities in CFS. There are now 

technologies that allow sleep to be recorded in the home rather than in sleep laboratories. 

Treatment trials are also needed to test whether antidepressants do provide benefit in CFS over 

placebo. Studies of chronobiological treatments such as bright-light, phase-shifting and slowwave sleep enhancement might also be considered. A new drug that is a TNF-blocking agent has 

been used for RA and reduces fatigue in RA patients. This type of drug may have therapeutic 

implications for CFS. 

Immunology

A number of observations suggest a role for the immune system or immune modulators in CFS. 

Several HLA markers appear to be more commonly present in persons with CFS than in the 

population in general, and these markers are associated with autoimmune diseases. Studies in 

identical twins also suggest an increased risk of CFS in identical twins. Acute viral-like illnesses 

appear to precede the onset of CFS in 60 to 80 percent of CFS cases. Immune mediators could 

directly contribute to the symptoms of CFS (e.g., by allowing reactivation of infections), or they 

could indirectly contribute to CFS symptomatology by the interaction with the HPA axis, impact 

on sleep, or interactions with neurotransmitters. 

A broad range of lymphocyte markers has been studied in CFS patients and compared to those 

markers found in healthy subjects. Results from some studies are conflicting, and many studies 

were hampered by being cross sectional rather than longitudinal in design. There are some 

indications that markers of T-cell activation are increased during CFS patient flaring. CD3 

receptor expression may be reduced; this latter observation might help to explain the poor 

response to antigens as CD3 is involved in T-cell activation. Low levels of the IgG1 and/or IgG3 

subclasses in CFS patients were also seen in several studies. A number of studies also suggest 

low NK cell function. Some data suggest that the immune system might be constantly activated 

(“turned on”) and immune response blunted by the depletion of necessary cellular enzymes 

(“exhausted”). Cytokine studies suggest a shift to a TH2 pattern of response in CFS, with 

expression of the proinflammatory cytokines TNF-a and IL-1. This type of pattern is associated 

with the humoral side of the immune system, and in combination with proinflammatory 

cytokines, can be associated with a number of chronic conditions, including autoimmune disease 

and chronic infection. 

There are a number of examples in which the immune system does not properly regulate itself; 

these include chronic active hepatitis and insulin dependent diabetes. In most individuals a viral 

infection will be limited, with the body suffering some minimal damage. However, in some 

individuals, viral infection of islet cells is not limited; the immune system keeps on attacking the 

cells and the person develops insulin-dependent diabetes. The sickness pattern of loss of 

appetite, lethargy, etc., that is part of a virus infection is cytokine driven; some of the symptoms 

of CFS seem to resemble the perpetuation of the virus infection process that has not been shut 

off. 

There is a need for longitudinal studies and for studies that correlate patterns of cytokine 

expression with illness severity and with the progression of illness over time. Given the 

heterogeneity of the illness, it is important to study subsets of patients. Collection of specimens 

needs to be standardized and important confounders such as circadian cycles, menstrual cycle, 

and patient sex must be taken into consideration. Hypotheses related to the importance of 
11

immune alterations in CFS could be tested by giving immune-based therapies and measuring 

patient responses.

Psychoneuroimmunological models may also provide insight into the pathogenesis of CFS. 

During stress, there are changes in the immune system, in levels of hormones in the blood, and in 

activation of specific areas of the brain. However, in chronic stress models, the more the brain is 

activated, the more it becomes habituated, and the harder it becomes to activate. This 

phenomenon is demonstrated by following HPA pathway responses to stress. It is known that 

when humans are subjected to a stress, the level of cortisol is elevated the first day of the stress; 

for most people, cortisol is not elevated if the stress is repeated for the next four days, a 

habituated stress response. However, for some people, cortisol levels will elevate on each of the 

five days of the stress and these people have more illness and more anxiety. Rather than 

habituation, there appears to be a sensitization of the brain or a disruption of the regulatory 

mechanisms of the brain. Studies are needed of persons who habituate to cortisol versus persons 

who do not habituate to cortisol. In CFS, studies need to be done to determine whether CFS 

patients’ low cortisol levels represent a chronic habituation of the stress response, or if the HPA 

abnormalities represent a different form of stress response. The mechanistic significance of low 

cortisol in CFS needs further study. However, the observation of low cortisol in CFS is 

consistent with the observed chronic immune activation, as cortisol would serve to help down 

regulate immune activation.

There are a number of concepts from research on multiple sclerosis (MS) that may be relevant to 

CFS research. The MS disease process begins long before clinical attack. The disease pathology 

is an autoimmune process. However, the precipitator of attacks/relapse is less clear (e.g., acute 

viral but not bacterial infections often appear to precede attacks). Immune changes can be 

measured before an attack, such as increases in inflammatory cytokines, decreases in NK cell 

numbers, activation of T-cells, and evidence of blood vessel inflammation. After an attack, an 

anti-inflammatory immune profile is seen. In progressive disease, NK and suppressor cells are 

defective. In addition, at the time of relapse, immune changes can be detected in certain very 

specific precursor cells. However, the number of these cells was extremely small; without 

having the specific target on myelin basic protein, this level of change could not have been 

detected. There are many MRI changes seen in MS, nevertheless, during many of these times, 

patients may be asymptomatic. In addition, when looking at parts of the brain not thought to be 

involved in MS, metabolic abnormalities have been observed in “apparently normal” brain 

tissues, suggesting that smaller subtle changes could be important. 

Several strategies applicable to CFS can be drawn from research approaches used in MS. 

Diagnostic criteria should be constrained for research purposes. To ensure that patients within a 

study are uniform, markers should be added for specific studies and, if necessary, rejected if or 

when experimental findings no longer support their inclusion. Studies should concentrate on 

early diagnosis, as causal abnormalities are more likely to be detected at that time; long 

established patients may give false leads both in treatment and in pathogenesis. In terms of 

therapy, treatment failures in long-established patients may be discouraging, even for therapies 

that might work early in disease. Treatment studies should avoid “treatment contaminated” 

patients, that is, persons who have already received therapies, as alterations in markers may be 

the result of the therapy rather than the disease. Interdisciplinary collaborations should be 

fostered.
12

Orthostatic Intolerance/Neurally Mediated Hypotension

Although the description of CFS in the CFS Case Definition does not seem to indicate autonomic 

system involvement, evidence from the scientific literature provides several suggestions for its 

potential involvement. This includes (1) the description of myalgic encephalomyelitis cases that 

suggests autonomic system symptoms; (2) Streeten’s description of delayed orthostatic 

intolerance in 1992 and his proposal that CFS might result from a failure to maintain blood 

pressure in an upright position; and (3) the studies of Rowe and colleagues in 1995 of neurally

mediated hypotension in CFS cases.

Orthostatic tolerance is an autonomic nervous system response that allows people to move from 

the supine to the upright position without feeling lightheaded, weak, or fatigued. A rapid 

baroreceptor-mediated reflex is involved to counteract the pooling of blood that occurs in the 

lower part of the body. This involves vasoconstriction, increases in heart rate, and an 

approximately twofold increase in noradrenaline levels; blood pressure remains about the same. 

There are several types of orthostatic intolerant conditions in which this system does not properly 

operate when a person moves from the supine to the upright position. In orthostatic hypotension, 

blood pressure decreases, but the heart rate remains about the same; in neurally mediated 

syncopy or hypotension, the heart rate falls and the blood pressure drops; in orthostatic 

tachycardia, the heart rate increases, but blood pressure does not change; blood pressure may 

increase or decrease slightly. 

Studies of conditions involving orthostatic intolerance have shown a sharing of features with 

CFS such as fatigue, female predominance, and viral-like prodrome. Variations in definition of 

subjects and in test implementation may be contributing factors to differences in experimental 

findings about the type of orthostatic intolerance in persons with CFS. Nevertheless, orthostatic 

intolerance conditions may explain aspects of CFS symptomatology and may provide 

opportunities for therapeutic interventions.

To determine specific cardiovascular changes/deficits that may be associated with CFS, more 

studies are needed about blood pressure and heart rate during normal daily activities. 

Investigations are also needed on exercise and cardiovascular change in CFS, variation of blood 

pressure and heart rate during a 24-hour period, and autonomic outflow during normal daily 

activities and exercise. Venous end-organ abnormalities need further study, as do baroreceptor 

reflexes and autonomic control of cerebral blood flow. There are also a number of neurogenic 

aspects of CFS that need further investigation. These include determining the nature of reflex 

tachycardia, the basis of the hyperactivation of catecholamines, and whether there are 

appropriate or blunted vascular responses to them.

Animal models in which there is dysregulation of these systems may also provide additional 

insights. A transgenic rat model appears to have some aspects of orthostatic hypotension and 

defective baroreceptor reflexes.

Fatigue, Functional Status, and Disability

Most chronic illnesses have fatigue as a symptom, and studies of fatigue in a range of illnesses 

can provide approaches or insights for CFS research and therapies. However, fatigue is still a 

very problematic area in terms of measurement and clinical approach. The main difficulties in 

measuring fatigue are that it is multidimensional, and there is no “gold standard” against which 
13

to compare measures. In addition, there are differences between acute and chronic fatigue; 

fatigue may have multiple meanings (e.g., a sense of effort versus anticipatory fatigue), may be 

the result of both physical and mental tasks, is influenced by both physical and psychological 

factors, and needs to be distinguished from sleepiness or drowsiness. Aspects of fatigue that can 

be assessed include behavior (e.g., decline in performance); perception (e.g., proportionality of 

sense of fatigue to effort); mechanism (e.g., peripheral versus central nervous system); and 

context (e.g., influence of environmental factors). Domains of fatigue that can be measured 

include physical/level of activity, mental impairment, functional status/quality of life, and 

disability. For each of these, both self-report and objective measures are available. Thus, 

functional status can be assessed by self-report on the Standard Form-36 (SF-36) or measured in 

the laboratory by the ability of a person to perform specific physical activities (e.g., walking and 

squatting). 

Ideally, measurements of fatigue should be internally consistent and reproducible, should 

correlate with other measurements of fatigue, and should be sensitive to treatment effects. Selfreport measures have limitations in that there is rater bias, they require insight to complete, 

specific aspects of fatigue may be difficult to distinguish from one another, and fatigue may 

combine state with trait for those persons with long-standing fatigue. Performance-based 

measures are more objective and are defined as the inability to sustain the expected power 

output. In studies of MS, performance and self-report measures showed little correlation and 

neither alone provided sufficient information on the experience of fatigue. For example, one 

study used a neuropsychological test as a performance measure of cognitive fatigue in a situation 

in which there were multiple and repetitive tests. When healthy controls and persons with MS 

were compared, the healthy subjects had a positive practice learning effect, whereas MS patients 

did worse on repeated testing. However, both sets of participants felt exhausted, thus 

demonstrating the lack of concordance between self-report and performance-based measures. It 

is therefore important to include both types of measures in assessing fatigue.

Impairment of activity is a measure of fatigue. Inc reased activity is seen as a desired outcome 

for fatigued patients and as an outcome measure for intervention studies. Actigraphy is a general 

term for the quantification of activity. It is a behavioral, rather than performance-based, 

measurement of energy expensive movements, which allows the natural behavior of persons to 

be assessed in natural settings. A record of activities can be documented around the clock for 

weeks or months; thus, difficult-to-assess factors, such as restlessness at night, can be measured. 

Actigraphy allows an assessment of behavior before and after treatment, allows for comparison 

between subjects, and provides a visual representation to patients of impairments, such as sleep 

disruption, or of improvements, such as increased activities. Given the cyclic nature of CFS, 

measurements throughout the day and night and over extended periods of time would provide an 

important repeated-measures method to assess changes in activity that could be correlated with 

other biological markers as well as with subjective measures.

Functional status is a subject measure of health status. It may be generic or disease specific. 

Impairment is a physical or cognitive condition that alters lifestyle. Disability is a state in which 

impairment precludes a specific function. Thus, a person may be disabled in one area but not in 

another or may have an impairment that is not disabling. Quality-of-life measures put a value or 

utility on particular aspects of life. Thus, there is a need to assess fatigue, functional status, and 

impairment both uniformly and consistently. Part of the estimate of CFS disability is that in the 

United States about 50 percent of persons with CFS are unemployed. Studies in Seattle of 

persons with CFS and with FMS showed a degree of disability beyond that which is measured by 
14

the SF-36. Many persons have lost jobs, friends, and significant others and have suffered a 

decline of standard in their standard of living. Persons with CFS have about twice the average 

annual per capita medical expenses and have a mean number of 20 medical visits per year. 

Fatigue research in cancer may provide insights into research approaches for CFS. Fatigue is a 

frequent and significant side effect of cancer and cancer treatment, with about two-thirds of 

patients reporting fatigue. In some cases, fatigue may persist for months or years. It is equally 

common in men and women and has no age boundaries. The main focus of oncologists has been 

in relieving pain; however, in response to a survey, cancer patients indicated that fatigue was 

more important than pain in their daily life. Fatigue is often not reported because it is not asked 

about or because patients assume that it is part of the illness. Many factors contribute to fatigue 

in cancer patients, including the tumor itself, pre-existing medical conditions, treatment 

modalities, infection, depression, pain, sleep problems, and inactivity. Domains of psychosocial 

functioning are adversely affected by fatigue on a 0 to 10 scale at levels above 5.5. Beyond that 

level of intensity, virtually every domain of functioning is negatively affected from mood, to 

ambulation, work, enjoyment of life etc. Below the midpoint of the scale, fatigue has little effect. 

This circumstance is different than pain, where impairments pile up more gradually. Most 

patients are given advice on energy conservation such as prioritizing activities, delegating 

responsibilities, and getting rest and sleep. However, only two categories of intervention have 

been shown to reduce cancer-related fatigue: moderate exercise and epoetin-alpha therapy. 

Thus, a walking program was shown to reduce chemotherapy side effects and fatigue. Epoetinalpha increases hemoglobin levels; with each incremental increase in hemoglobin level, an 

increased quality-of-life was observed.

Rehabilitation medicine is an area that could provide much assistance and treatment to persons 

with CFS. It is an area that many physicians are not aware of as a treatment modality; moreover, 

many therapists are not knowledgeable in the unique needs of CFS patients. Among the 

rehabilitation medicine specialties, occupational therapy has a key role to play. There are several 

evaluation instruments, such as the Canadian Occupational Performance Measure, the Role 

Checklist, the NIH Activity Record, and the NIH Energy Conservation Workbook, that can allow 

the patient and therapist to identify roles that are important to the patient, and then to prioritize 

goals and devise strategies to allow patients to achieve the goals most important to them. Speech 

pathologists may be able to help persons with CFS deal with cognitive problems such as word 

finding and reading. Physical therapists can assess physical capacity and endurance and can 

provide interventions to increase these. Rehabilitation professionals can make recommendations 

for balance of the home and work tasks and for the use of adaptive equipment. There is a need 

for increased recognition of rehabilitation medicine and for training of professionals in the 

specific needs of persons with CFS. In addition, research studies are needed to document the 

effectiveness of rehabilitation medicine as a therapeutic approach. 
15

Issues for Future Research and Consideration in Study Design

There were a number of crosscutting themes throughout the meeting. 

CFS patients are heterogeneous. This is recognized by the current case definition, which also 

encourages the subgrouping and stratification of patients in studies. Patient populations need to 

be carefully selected and described and indications given in research papers about how the 1994 

Case Definition was applied to the study population. The panelists emphasized the need to 

design studies around specific subgroups of patients. 

Need for Longitudinal Studies. CFS symptoms are not static and can change during a day, as 

well as over days, months, and years. Longitudinal studies and studies considering multiple 

sampling points are therefore critical. Measurement or characterization of a patient at a single 

time point is inadequate. 

Sampling Methodologies. Sampling points and processing of samples need to be consistent 

within studies and carefully chosen based on the variables under study. Samples need to be 

carefully and consistently processed. It is important to consider that samples taken from 

peripheral blood may not reflect the levels of modulators at their active sites (e.g., in the brain or 

lymph nodes). 

Measurement Methodologies. Measurements of complex functions, such as cognition, need to 

consider the components of that function (e.g., learning versus recall) and the nature of the 

impairment (e.g., speed versus accuracy). New technologies, (such as actigraphy) and new 

analytical tools (such as neuroplots and neural networks) may provide important ways to gather 

and analyze the complex data that will be needed to study disease mechanisms and pathogenesis.

Potential Importance of Cytokines and Related Neurohormones. While medicine and 

research studies of necessity divide the body into individual physiological systems, there are in 

fact many common mediators and cross talk between and among the various bodily systems. For 

example, IL-1 is named after its immunomodulating functions; however, it plays a role in 

stimulation of sleep and is involved in stress pathways in that it affects and is affected by CRH. 

Many of the signs and symptoms of CFS could be attributable to the actions of cytokines; CFSlike symptoms are seen in persons with malignancies who are receiving immunotherapies with 

cytokines. Pain could explain a number of the symptoms seen in CFS. Studies of the physiology 

of pain irrespective of cause may provide important insights for understanding pain occurring in 

specific contexts. Many of the symptoms of CFS could also be caused by disrupted sleep. The 

role of cardiovascular system dysregulation/dysfunction in CFS symptomatology and pathology 

needs further investigation.

Dysregulation of control processes/systems was another common theme of the meeting. The 

consequences of long-term stimulation, aberrant processing of signals, and conditioning of 

responses were also noted as processes that could provide a mechanistic understanding of the 

diversity of patient symptomatology, as well as the lack of concordance between subjective 

symptom report and objective functional measurement. Thus, studies in which animals were 

subjected to both stress and cytokine administration resulted in changes in the magnitude and 

duration of the immediate corticosteroid response, as well as alterations to the same stimuli given 
16

at a subsequent time. Biphasic responses to modulators and mediators in which the response, 

inhibition, or stimulation was dependent on the dose administered were also noted.

Sex and Gender Differences. There are a number of mechanistic clues that might explain the 

sex and gender differences seen in pain syndromes. These include differences in HPA axis 

regulation, differences in neural processing, differences in sleep architecture, and differences in 

clinical responses to drugs.

Overlapping Syndromes. There are a number of syndromes that overlap with CFS, such as 

IBS, FMS, and MCS. Knowledge gained about one may provide insights for the others; in 

addition, further research may determine whether these syndromes represent a continuum of 

related human illnesses rather than being individual entities. Conversely, there are a finite 

number of symptoms that can occur in an affected organ or organ system; thus, sharing of 

symptoms may not imply sharing of mechanisms. Interdisciplinary/multidisciplinary studies are 

needed to address the complex mechanisms that cross physiological systems and research 

disciplines.

SUMMARY. CFS is a complex multisystemic, multifactorial illness. Its unique aspects and 

pathogenesis need further investigation and illumination; studies of overlapping symptoms and 

pathogenic mechanisms from other diseases/disorders may provide insights into the biological 

basis for this illness. 
17

 BIBLIOGRAPHY FOR TOPIC SESSIONS

DHHS CFSCC STATE OF THE SCIENCE CONFERENCE

October 23-24, 2000

Topic 1: Neuroendocrinology

Bou-Holaigah, I., Rowe, P.C., Kan, J., and Calkins, H. (1995) The relationship between neurally 

mediated hypotension and the chronic fatigue syndrome. JAMA, Vol. 274, No. 12, 961-967. 

(also, on Topic 6 list)

De Lorenzo, F., Hargreaves, J., and Kakkar, V.V. (1997) Pathogenesis and management of 

delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clinical Autonomic 

Research, Vol. 7, 185-190. 

Komaroff, A.L., Fagioli, L.R., Doolittle, T.H., Gandek, B., Gleit, M.A., Guerriero, R.T., 

Kornish, J., Ware, N.C., Ware, J.E., and Bates, D.W. (1996) Health status in patients with 

chronic fatigue syndrome and in general population and disease comparison groups. The 

American Journal of Medicine, Vol. 101, 281-290.

McKenzie, R., O’Fallon, A., Dale, J., Demitrack, M., Sharma, G., Deloria, M., GarciaBorreguero, D., Blackwelder, W., and Straus, S.E. (1998) Low-dose hydrocortisone for treatment 

of chronic fatigue syndrome. JAMA September 23/30, Vol. 280, No. 12, 1061-1066. 

Schondorf, R., Benoit, J., Wein, T., and Phaneuf, D. (1999) Orthostatic intolerance in the chronic 

fatigue syndrome. Journal of the Autonomic Nervous System, Vol. 75, 192-201.

Stewart, J., Weldon, A., Arlievsky, N., Li, K., and Munoz, J. (1998) Neurally mediated 

hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt 

testing in children with chronic fatigue syndrome. Clinical Autonomic Research, Vol. 8, No. 4, 

221-230. 

Streeten, D.H.P., Thomas, D., and Bell, D.S. (2000) The roles of orthostatic hypotension, 

orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic 

fatigue syndrome. The American Journal of the Medical Sciences, Vol. 320, No. 1, 1-8.

Topic 2: Cognition

Christodoulou, C., DeLuca, J., Lange, G., Johnson, S.K., Sisto, S.A., Korn, L., and Natelson, 

B.H. (1998) Relation between neuropsychological impairment and functional disability in 

patients with chronic fatigue syndrome. Journal of Neurosurgery and Psychiatry, Vol. 64, No. 4, 

431-434.

DeLuca, J., Johnson, S.K., Ellis, S.P., and Natelson, B.H. (1997) Cognitive functioning is 

impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of 

Neurology, Neurosurgery, and Psychiatry, Vol. 62, 151-155.

Greco, A., Tannock, C., Brostoff, J., and Costa, D.C. (1997) Brain MR in chronic fatigue 

syndrome. American Journal of Neuroradiology, Vol. 18, 1265-1269.
18

Johnson, S.K., DeLuca, J., and Natelson, B.H. (1996) Depression in fatiguing illness: comparing 

patients with chronic fatigue syndrome, multiple sclerosis and depression. Journal of Affective 

Disorders, Vol. 39, 21-30.

Joyce, E., Blumenthal, S., and Wessely, S. (1996) Memory, attention, and executive function in 

chronic fatigue syndrome. J. Neurology, Neurosurgery and Psychiatry, Vol. 60, 495-503.

Lange, G., DeLuca, J., Maldjian, J.A., Lee, H-J. Tiersky, L.A., and Natelson, B.H. (1999) Brain 

MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of the 

Neurological Sciences, Vol. 171, 3-7.

Marshall, P.S., Forstot, M., Gallies, A., Peterson, P.K., and Schenck, C.H. (1997) Cognitive 

slowing and working memory difficulties in chronic fatigue syndrome. Psychosomatic 

Medicine, Vol. 59, 58-66.

Suhr, J.A., and Boyer, D. (1999) Use of the Wisconsin card sorting test in the detection of 

malingering in student simulator and patient samples. Journal of Clinical and Experimental 

Neuropsychology, Vol. 21, No. 5, 701-705.

Tiersky, L., Johnson, S.K., Lange, G., Natelson, B.H., and DeLuca, J. (1997) Neuropsychology 

of chronic fatigue syndrome: a critical review. Journal of Clinical and Experimental 

Neuropsychology, Vol. 19, No. 4, 560-586.

Vollmer-Conna, U., Wakefield, D., Lloyd, A., Hickie, I., Lemon, J., Bird, K.D., and Westbrook, 

R.F. (1997) Cognitive deficits in patients suffering from chronic fatigue syndrome, acute 

infective illness or depression. Journal of Psychiatry, Vol. 171, 377-381.

Topic 3: Chronic Pain

Aaron, L.A., Burke, M.M., and Buchwald, D. (2000) Overlapping conditions among patients 

with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch. Intern. 

Med., Vol. 160, 221-227. (also on the Topic 7 list)

Dantzer, R., Bluthe, R.M., Laye, S., Bret-Dibat, J.L., Parnet, P., and Kelley, K.W. (1998) 

Cytokines and sickness behavior. Ann. N.Y. Acad. Sc., Vol. 840, 586-590.

Evengard, B., Schacterle, R.S., and Komaroff, A.L. (1999) Chronic fatigue syndrome: new 

insights and old ignorance. J. Intern. Med., Vol. 246, 455-469. 

Khasar, S.G., Miao, F. J.-P., Jänig, W., and Levine, J.D. (1998) Vagotomy-induced 

enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated. J. Neurosci., 

Vol. 18, 3043-3049.

Watkins, L.R., and Maier, S.F. (2000) The pain of being sick: implications of immune-to-brain 

communication for understanding pain. Annual Review of Psychology, Vol. 51, 29-57.
19

Topic 4: Sleep

Armitage, R. (1996) Effects of antidepressants on sleep EEG in depression. Journal of Clinical 

Neuropsychopharmacology, 10 (1, Supplement 5): 22-25.

Armitage, R., and Hoffmann, R. (1997) Sleep electrophysiology of major depressive disorders. 

Current Review of Mood and Anxiety Disorders, Vol. 1, 139-151.

Armitage, R., and Sussman, N. (1997) Effects of fluxetine on sleep architecture and quality of 

sleep in depressed patients. Primary Psychiatry, 49(0): 34-37.

Armitage, R. (1999) The effects of nefazodone on sleep in depressed patients and healthy 

controls. International Journal of Psychiatry and Clinical Practice, 3:73-79.

Armitage, R. (2000) The effects of antidepressants on sleep in depression. Canadian Journal of 

Psychiatry, in press.

Côté, K., and Moldofsky, H. (1997) Sleep, daytime symptoms and cognitive performance in

patients with fibromyalgia. J Rheumatol., Vol. 24, 2014-2023.

Dickstein, J.B., and Moldofsky, H. (1999) Sleep, cytokines and immune function. Sleep

Medicine Reviews, Vol. 3, 219-228.

Moldofsky, H. (1995) Sleep, neuroimmune and neuroendocrine functions in fibromyalgia

and chronic fatigue syndrome. Adv. Neuroimmunol, 5(1):39-56.

Moldofsky, H. (1997) Nonrestorative sleep, musculoskeletal pain, fatigue, and psychological 

distress in chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, temporalmandibular joint dysfunction disorders (CFIT). In Chronic Fatigue Syndrome. S. Yehuda and 

D.I. Mostofsky (eds). Plenum Press, New

York, pp. 95-117.

Moldofsky, H., and Dickstein, J.B. (1999) Sleep and cytokine-immune functions in medical,

psychiatric and primary sleep disorders. Sleep Medicine Reviews, Vol. 3, 325-337.

Roizenblatt, S., Moldofsky, H., Benedito, A.A., and Tufik, S. (2001) Alpha sleep characteristics

in fibromyalgia. Arthritis and Rheumatism (in press).

Topic 5: Immunology 

Patarca, R., Mark, T., Fletcher, M., and Klimas, N.G. (2000) Review: immunology of chronic 

fatigue syndrome, JCFS, Vol. 6(3/4), 69-107.
20

Topic 6: Orthostatic Intolerance/Neurally Mediated Hypotension 

Bou-Holaigah, I., Rowe, P.C., Kan, J., and Calkins, H. (1995) The relationship between neurally 

mediated hypotension and the chronic fatigue syndrome. JAMA Vol. 274, No.12, 961-967. (also 

on Topic 1 list)

Furlan, R., Jacob, G., Snell, M., Robertson, D., Porta, A., Harris, P., and Mosqueda-Garcia, R. 

(1998) Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular 

sympathetic control. Circulation, Vol. 98 (20), 2154-2159.

Rowe, P.C., Bou-Holaigah, I., Kan, J.S., and Calkins, H. (1995) Is neurally mediated 

hypotension an unrecognized cause of chronic fatigue? Lancet, Vol. 34, 623-624.

Schondorf, R., and Low, P.A. (1993) Idiopathic postural orthostatic tachycardia syndrome: an 

attenuated form of acute pandysautonomia? Neurology, Vol. 43, 132-137.

Streeten, D.H., and Anderson, G.H., Jr. (1992) Delayed orthostatic intolerance. Arch. Intern. 

Med., Vol. 152(5), 1066-1072.

Streeten, D.H., and Anderson, G.H., Jr. (1998) The role of delayed orthostatic hypotension in 

the pathogenesis of chronic fatigue. Clin. Auton. Res., Vol. 8(2), 119-124.

Topic 7: Fatigue, Functional Status, and Disability

Aaron, L.A., Burke, M.M., and Buchwald, D. (2000) Overlapping conditions among patients 

with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch. Intern. 

Med., Vol. 160, 221-227. (also on Topic 3 list)

Bombardier, C.H., and Buchwald, D. (1996) Chronic fatigue, chronic fatigue syndrome, and 

fibromyalgia disability and health-care use. Medical Care, Vol. 34., No. 9, 924-930.

Buchwald, D., Cheney, P.R., Peterson, D.L., Henry, B., Wormsley, S.B., Geiger, A., Ablashi, 

D.V., Salahuddin, S.Z., Saxinger, C., Biddle, R., Kikinis, R., Ferenc, A.J., Folks, T., 

Balachandran, N., Peter, J.B., Gallo, R.C., and Komaroff, A.L. (1992) A chronic illness 

characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus 

type 6 infection. Animals of Internal Medicine, Vol. 116, No 2, 103-113.

Buchwald, D., Pearlman, T., Umali, J., Schmaling, K., and Katon, W. (1996) Functional status 

in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. The 

American Journal of Medicine, Vol. 171, 364-370.

Buchwald, D., Umali, P., Umali, J., Kith, P., Pearlman, P., and Komaroff, A.L. (1995) Chronic 

fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. 

Annals of Internal Medicine, Vol. 123, 81-88.
21

Appendix 1 Financial sponsors of the conference

Centers for Disease Control and Prevention

National Institutes of Health:

Office of Research on Women’s Health

National Institute of Allergy and Infectious Diseases

National Institute of Neurological Disorders and Stroke

National Institute of Arthritis and Musculoskeletal and Skin Diseases

National Institute of Nursing Research

National Center for Complementary and Alternative Medicine

National Institute of Mental Health
22

Appendix 2 Conference Speakers

Overview of Conference and Conference Goals: Donna J. Dean, Ph.D., National Institutes of 

Health, and Anthony Komaroff, M.D., Harvard University, Conference Moderator

A Patient’s Perspective : Ms. Bernice Soohoo Lee, Oakland, California

A Community Physician’s Perspective: David Bell, M.D., FAAP, Lyndonville, New York

Topic Session 1: Neuroendocrinology: CFS Investigator, Philip W. Gold, M.D., National 

Institutes of Health—Subject Experts: Mark Opp, Ph.D., University of Texas at Galveston; Steve 

Zalcman, Ph.D., UMDNJ-New Jersey Medical School

Topic Session 2: Cognition: CFS Investigator, John De Luca, M.D., UMDNJ-New Jersey 

Medical School, Kessler Institute of Rehabilitation—Subject Experts: Yaakov Stern, Ph.D., 

Columbia University; Roderick Mahurin, Ph.D., University of Washington

Topic Session 3: Chronic Pain: CFS Investigator, Jon Levine, M.D., Ph.D.,University of 

California, San Francisco—Subject Experts: Kenneth Casey, M.D., University of Michigan; 

Laurence Bradley, Ph.D., University of Alabama

Topic Session 4: Sleep: CFS Investigator, Harvey Moldofsky, M.D., University of Toronto—

Subject Experts: Roseanne Armitage, Ph.D., University of Texas, Dallas; James Krueger, Ph.D., 

Washington State University

Topic Session 5: Immunology: CFS Investigator, Nancy Klimas, M.D., University of Miami—

Subject Experts: Bruce Rabin, M.D., Ph.D., University of Pittsburgh; Jerry Wolinsky, M.D., 

University of Texas, Houston

Topic Session 6: Orthostatic Intolerance/Neurally Mediated Hypotension: CFS Investigator, 

Roy Freeman, M.B., CH.B., Beth Israel-Deaconess Medical Center—Subject Expert: David 

Averill, Ph.D., Wake Forest University

Topic Session 7: Fatigue , Functional Status, and Disability: CFS Investigator, Dedra 

Buchwald, M.D., University of Washington,—Subject Experts: Lauren Krupp, M.D., SUNY, 

Stony Brook; Warren Tryon, Ph.D., Fordham University; Steven Passik, Ph.D., Community 

Cancer Care, Inc.; Gloria Furst, OTR/L, M.P.H., Clinical Center, NIH