Fw: Chronic Fatigue Syndrome State of the Science Conference -Official Report

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From: ilena rose <ilena@...>

Sent: Wednesday, January 24, 2001 9:23 AM

Subject: Chronic Fatigue Syndrome State of the Science Conference -Official

Report

> http://www.immunesupport.com/library/showarticle.cfm?ID=2948

>

> Chronic Fatigue Syndrome State of the Science Conference - Official Report

>

>

> by The U.S. Department of Health and Human Services

> ImmuneSupport.com

> 01-07-2001 -

>

> 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.

>

> 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 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.

>

> To investigate the basis for the differences in symptoms, studies focused

> on a corticotropin-releasing 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. 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 IL-2 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 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.

>

> 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 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.

>

> Chonic 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 co-morbidity 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; ( 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 © 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.

>

> 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 (43 o C) that

> alone is below the heat pain threshold (typically 45 o C) the person feels

> a subjective level of pain that is equal to a heat stimulus (47 o C) that

> is above the pain threshold on normal skin. Subtractive PET imaging

studies

> of the two situations (43 o C with capsaicin versus 47 o C 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 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 symp toms. 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.

>

> 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 non-restorative 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 hormo ne) 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.

>

> 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 slow-wave 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 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.

>

> 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 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. Self-report 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. Increased

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 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. Epoetin-alpha 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.

>

> 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; CFS-like 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 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.

>

>

>