Bruce R. Gordon M. D., F. A. C. S., F. A. A. O. A.

ABSTRACT

INTRODUCTION

There have been over 30 apparent CFS epidemics reported since 1934 [4], and although CFS is not known to be contagious, there have been cases of family members becoming simultaneously ill [8]. In 1990 the Centers for Disease Control (CDC) received about one to two thousand calls per month from CFS sufferers [9], and CFS accounted for almost 2% of all physician visits in the US [10]. Prevalence estimates for the United Sates range from about 75 to 267 CFS patients per 100,000 persons [11]. Although fatigue is one of the most common medical complaints, these data indicate that true CFS patients will be rarely seen. Both adults and children are affected [1], with younger age favoring more rapid recovery [6, 12]. CFS can cause prolonged disability, and in 1989 accounted for about one in 200 Canadian disability claims [13]. Affected women usually outnumber men 3 to 5 fold [12]. There also is a strong association between atopy and CFS [3, 14, 15]. This has implications for allergists, who will see CFS patients in their practices [16].

DEFINITION OF CHRONIC FATIGUE SYNDROME

PSYCHIATRIC AND RHEUMATIC CONNECTIONS

CFS symptoms overlap substantially with symptoms of fibromyalgia and of depression. About 70% of CFS patients meet fibromyalgia criteria, and over 50% of fibromyalgia patients meet CFS criteria [4, 19, 20]. The key fibromyalgia symptom which may be overlooked is the presence of painful tender points at the junction of muscles with their tendons [20, 21]. In addition, major depression occurs in at least 50% of CFS patients, and symptoms of depression may precede the onset of CFS [22]. Depression is much more common in CFS than in other serious illnesses such as cancer or myocardial infarction [22]. The cognitive defects experienced by CFS patients have been confirmed by neuropsychologic testing [11], and by evoked cognitive EEG potentials [2], but are not observed in simple depression. The relationships between CFS, fibromyalgia, and depression could indicate that these illnesses share some common physiologic derangements [23]. The clinical importance to CFS patients is that symptoms of both fibromyalgia and depression are treatable, and successful treatment may improve the way CFS patients feel.

TRIGGERS OF CHRONIC FATIGUE SYNDROME

Many causes of CFS have been proposed, ranging from stress, to chemical exposures and metabolic derangements, to post-infectious complications. Since the body has only a limited repertoire of metabolic and inflammatory responses, it is not unreasonable to expect that the symptom complex of CFS may result from a common biochemical response to a variety of incitants [3,4,14, 20, 24]. Many CFS victims date the onset very precisely in time to an infection, usually an acute respiratory, gastrointestinal, or mononucleosis-like illness [1,3]. In some cases, a simultaneous infection with two viruses [25], or a retrovirus [9], appears responsible. Bacterial infections, particularly Brucellosis and Lyme disease, also sometimes precede CFS [1], as can gastrointestinal Candida hypersensitivity syndrome [26], and probably, protozoan infections. Post-infectious, abrupt onset, cases of CFS may not be exactly the same illness as CFS triggered by other causes, since careful immunologic studies have shown that circulating cytokines and leucocyte cell surface markers in these cases of CFS suggest an infectious cause, while, in contrast, CFS cases with gradual onset have reduced numbers of NK cells [27].

Other CFS patients have no infection history, but have had one of a variety of medical, surgical, obstetrical, or psychiatric stresses prior to the onset [2]. Some patients may develop CFS as a consequence of depression alone, which is not surprising since disturbed sleep patterns are characteristic of depression, and at least some of the symptoms of CFS can be triggered by interrupting sleep [4].

FUNCTIONAL ABNORMALITIES IN CHRONIC FATIGUE SYNDROME

CFS patients, when carefully tested, may show a variety of subtle performance deficits, however, there is no abnormality that is consistently found. Sleep electroencephalogram (EEG) tracings show abnormal alpha waves correlating with arousal disturbances and deprivation of stage IV sleep [4], and this may produce both musculoskeletal pain and cognitive fatigue. These findings resemble those in sleep apnea [28]. Abnormal evoked cognitive EEG potentials indicate decreased alertness and reaction time, and decreased speed of information processing [29]. Some muscle biopsies show persistent viral replication [30], necrosis and inflammation around muscle fibers [31], and abnormal single fiber EMG tracings, as long as several years into the illness [31]. Resting cardiac examinations are usually normal, but graded exercise testing may show markedly reduced exercise tolerance compatible with viral cardiomyopathy [32]. In a single case report, abnormal forced expiratory flow and diffusion capacity, similar to acute viral effects, but persisting over six months into the illness, was found [33].

LABORATORY EVALUATION OF CHRONIC FATIGUE SYNDROME

General laboratory tests in CFS are usually normal [10]. Despite the low yield, it is still necessary to do basic tests to supplement the physical exam. The list of conditions which must be excluded is long [10, 34] (Table 2).

Some CFS patients have identifiable diseases. For example, asthma, temporal lobe epilepsy, polymyalgia rheumatica, sleep apnea, and major depression were discovered during one study of 100 fatigued adults [10]. However, the cause of fatigue was discovered in only 7 patients, even with careful physical exams and very extensive laboratory testing. In another study, 44% of male fibromyalgia patients had positive sleep studies indicating co-existing sleep apnea [35]. Structural or functional brain abnormalities may also occur in CFS, and may help distinguish depression, Lyme disease, and multiple sclerosis from CFS [7, 36]. Lyme disease may masquerade as, or, may trigger CFS [37, 38]. Hepatitis C, anemia, hypothyroidism, or hemochromatosis may also cause severe fatigue. Based on high test expense to low yield, initial tests in CFS are often limited to those shown in Table 3 [10, 18], but more extensive testing may be required. Examples of potentially useful additional tests are shown in Table 4 [3,17, 26].

IMMUNOLOGIC ABNORMALITIES IN CHRONIC FATIGUE SYNDROME

Derangements in immune functions have been suspected to occur in CFS, since several of the known triggering viruses [25], as well as psychological stress [3, 39], and sleep disturbances [4], have been shown to affect the immune system. This subject has been reviewed [15, 40, 41]. Many abnormalities have been identified in groups of CFS patients, but those which are frequently found include deficient delayed hypersensitivity and decreased serum levels of immunoglobulins IgG1 and IgG3 [40, 42] or IgA [15]. In contrast, most CFS patients show intact delayed hypersensitivity to childhood vaccines [43]. Despite these defects, specific antibodies to common viruses, including Epstein-Barr virus, are often elevated [44, 45], and, therefore, are not helpful in diagnosis. Defective natural killer (NK) cell activity [15, 40], and abnormalities of immune cell adhesion [1] and histocompatibility expression [46] also occur. Numbers of NK cells are normal, but NK cell activity is decreased in about 25% of CFS patients [47]. Although deficient cellular immunity also occurs in depression, it has previously only been identified in patients with depression severe enough to require hospitalization [42]. However, a recent comparison study of immune function in depression, with and without CFS, concluded that there is no evidence of immune activation in either group, rather, depressed patients and CFS patients both have lymphopenia of B and T cells [48]. Immune changes different from controls have not yet been observed following exercise in CFS patients [49], but overall, the observed immune changes in CFS are similar to those which are known to arise during periods of mental stress [39].

RELATIONSHIP OF ALLERGY TO CHRONIC FATIGUE SYNDROME

Most physicians who treat CFS have noticed the unusually high percent of CFS patients who have allergy symptoms. Incidences of allergy in CFS patients are usually given as between 55 and 80%, compared with about 20% in the general population, but these percentages are dependent on the sensitivity of the method used to assess atopy. About 20 to 47% of CFS patients exhibit chemical intolerance [50], and from 14 to 56% have nickel allergy [51]. Evaluation of the pre-morbid health of CFS patients also identified a significant excess of allergic rhinitis and asthma [52]. Seventy six percent of CFS patients in one study had rhinitis symptoms, but allergy prick testing showed no excess of allergy compared with controls [53], and analysis of nasal mucus showed no differences [54]. On the other hand, Conti and coworkers measured eosinophil cationic protein (ECP) and allergen-specific IgE in CFS patients, and showed elevations of ECP in almost all CFS patients, compared with controls. Also, 77% of CFS patients had a positive in vitro test to at least one inhalant allergen [55]. Subsequently, Borish and coworkers, in pivotal work, measured cytokines and their m-RNA transcripts directly in the peripheral mononuclear cells of CFS patients, allergic patients, depressed patients, and normal controls. They felt that many previous reports of CFS cytokine levels were inaccurate due to failure to recognize that most cytokines are cell-associated, and are not reliably detected in serum. They demonstrated that CFS patients and allergic patients were alike in having elevated cellular levels of tumor necrosis factor alpha and alpha interferon, and decreased levels of interleukin-10. Furthermore, CFS patients developed increased levels of alpha interferon during both seasonal allergen exposures and during symptomatic exacerbations of their CFS. It was therefore proposed that allergic inflammation, occurring in physiologically susceptible individuals, could produce CFS symptoms [56]. Together, the studies of Conti and Borish are strongly suggestive of allergy being a significant predisposing factor in the development of CFS.

NEUROENDOCRINE ABNORMALITIES IN CHRONIC FATIGUE SYNDROME

Interactions between the central nervous system, endocrine system, and immune system are well documented, but still imperfectly understood [39]. The process of neurogenic switching, whereby inflammation at one site can be neurally communicated to a distant site, resulting in either more inflammation, or in neuroendocrine stimulation, has been proposed as a mechanism for the widespread symptoms in many inflammatory disorders, including allergy and fibromyalgia [57]. Recently, research into neuroendocrine functions in CFS has identified hypothalamic-pituitary-adrenal (HPA) dysfunction [23]. Corticotropin-releasing hormone (CRH) in the cerebrospinal fluid is reduced, with reduced cortisone and dihydroepiandosterone (DHEA) secretion [58], and decreased adrenal capacity to respond to stress. The down regulation of the HPA axis is postulated to be caused by neural effects of CFS triggers, and is not observed in major depression [7]. In this viewpoint, CFS symptoms of fatigue, stress exacerbations, arthralgias and myalgias, fever and adenopathy, exacerbation of allergies, immune dysregulation, and mood, memory, and sleep disorders, are all secondary to adrenal deficiency [59]. Supporting physical findings are the presence of orthostatic hypotension in adolescent CFS patients [60], and the discovery, by computed tomography, of abnormally small adrenal glands in CFS patients who had a subnormal adrenocorticotrophin stimulation test [61]. However, HPA dysfunction is also seen in normal people exposed to work schedule shift changes between day and night, so the neuroendocrine changes in CFS might be a secondary phenomenon. Neuroendocrime changes in CFS might also arise from NK cells, since they are known to pass the blood-brain barrier and to interact with neurons [47].

FINAL COMMON PATHWAY: PRODUCTION OF SYMPTOMS IN CFS

The immunologic findings, combined with observations of persisting viral presence in some CFS patients, suggest that the CFS syndrome is caused by failure of the immune system to eliminate a pathogen, or perhaps, by molecular mimicry, when pathogen epitopes cross react with body components. The neuroendocrine findings suggest that the CFS syndrome also is caused by failure of the nervous system to resolve a psychologic or stress trigger. Chronic activation of immune mechanisms then occurs, either directly, or via neuroendocrine mechanisms. The resultant production of immune products, such as cytokines, then directly produces symptoms [42]. This mechanism is possible, since therapeutic administration of cytokines such as interferons [4, 42] or interleukin-2 [4] results in symptoms quite similar to those in CFS, including sleep disorders, depression, myalgias, fever, and fatigue. Furthermore, some CFS patients do show evidence of chronic immune activation, with elevated circulating immune complexes and complement depletion [15, 31], as well as elevated levels of alpha interferon [41], interleukin-2 [62], neopterin, transforming growth factor beta [11] and interleukin-6 [63]. Lymphocytes of CFS patients also show expression of activation markers, and abnormal NK cell function [11]. Another significant contributing factor may be hypoadrenalism, whose effects will exacerbate any immune-triggered symptoms [23].

MEDICAL TREATMENT OF CHRONIC FATIGUE SYNDROME

Anti-depressants and anti-inflammatory drugs. Most treatments for CFS have never been subjected to rigorous trials [3], and, treatment evaluations are complicated by the waxing and waning course of CFS patients [62]. However, anti-depressants are useful, both to treat depression, and also because they block pain perception [3]. Low doses of amitriptyline (10 to 50 mg) were more effective than placebo in decreasing fatigue and myalgia, and improving sleep. Bupropion was reported to be effective in two cases of CFS [64], and clinical reports suggest other selective serotonin elevating antidepressants are also effective, but results of controlled studies are contradictory [5]. Nefazodone improved some patients [65]. Serotonin has anti-depressant, sleep-promoting, and pain-blocking effects, and has been shown to be effective for fibromyalgia treatment [66]. Since serotonin levels are depressed in some patients with CFS, trial of these anti-depressants in CFS is reasonable. Anti-inflammatory drugs, including aspirin, acetaminophen, and nonsteroidal anti-inflammatory agents (NSAIDs), have mild benefits in CFS, especially for headache relief [7], and are synergistic with amitriptyline [3].

Hormone treatments. Adrenal steroids are current research topics. Glucocorticoids, in usual doses, either had no effect, or worsened symptoms [3]. However, Cleare and coworkers [67] reported a positive pilot study of low dose hydrocortisone treatment. Mineralocorticoids were ineffective in another study [68], but have not been tried in combination with glucocorticoids. DHEA replacement therapy may be of value, particularly for alleviating fatigue [69].

Antibiotics and immune system modifiers. When not used for a definite bacterial infection, anti-bacterial drugs may be ineffective or cause symptom worsening, according to an uncontrolled trial by Jessop, reported at the First Chronic Fatigue Syndrome Conference in San Francisco, CA, April 15,1989. Jessop also stated that oral anti-fungal drugs were often helpful, and should be considered for use when there is evidence of Candida hypersensitivity syndrome. Jessop's conference preprint was not published, but his subsequent CSF research has been [26]. Anti-viral drugs are under study. Acyclovir has shown no activity [34], but Ampligen (Hemispherx Biopharma, Philadelphia, PA), an RNA analog, is currently in phase III clinical trials, and appears promising [70]. Pooled intravenous gamma globulin, in a small trial, was effective, but in less than half of CFS patients [1,3, 71]. Transfer factor may reverse some CFS immunologic abnormalities, but is less effective with increasing age [72]. Trials of interleukin-2 and alpha interferon [25] are ongoing or proposed.

Vitamin and mineral supplements. Nutritional supplements have given conflicting results in uncontrolled trials [3,26], but vitamin, mineral, essential fatty acid, and amino acid supplements should, in theory, be helpful to replace nutrients depleted by prolonged immune system activation. Reduced nicotinamide adenine dinucleotide (NADH) did cause subjective improvement in a small pilot study [73], and L-cystine may be effective in restoring NK cell function in some CFS patients [47]. Magnesium has long been used for CFS, with reports of improvement in muscle aches. This has been controversial, since serum magnesium measurements are often normal. However, measurements of cellular magnesium levels have shown low levels in some CFS patients, and placebo-controlled magnesium treatment did cause subjective improvement in a small number of patients [74]. Malic acid and coenzyme Q10 (ubiquinone) have both been proposed to improve energy metabolism in CFS. Since these are natural food components, they might be considered for use in individual patients. Finally, abnormalities in essential fatty acid (EFA) metabolism may underlie susceptibility to CFS. Treatment with omega 3-desaturated EFAs has been reported to improve both the biochemical abnormalities and symptoms of CFS [14]. However, others were unable to replicate this work [75].

PHYSICAL AND BEHAVIORAL TREATMENT OF CHRONIC FATIGUE SYNDROME

Of all forms of therapy, probably the single most useful is to validate the patient's own perception that they are suffering from a disease [7, 12], and to give them hope. Counseling patients about moderating their activity, and conserving strength for the most essential activities, is also critical. Newly ill CFS patients often try to exercise their way to health, but this is counter-productive [12]. Instead, they should engage in regular, low-level, intermittent (short duration) physical activity such as walking, bicycling or swimming [20, 76], and ensure adequate time for rest and sleep. Patients should be encouraged to keep a daily record of their symptoms and activities [2], which allows progress to be monitored, and also provides a way for patients to learn to moderate their activities [12]. A psychiatric evaluation is useful, to determine if significant depression is present. Use of cognitive behavior therapy with goal setting may help prevent chronic disability from developing [77], and stress management and coping skills training may be helpful adjuncts [78]. Education is important, since patients must be able to understand what is known about CFS, in order to be able to explain their condition and limitations to their family and friends. A complete allergy evaluation (inhalant, food, and chemical) also is suggested, since treatment of allergies may help reduce some symptoms, and decrease the load of illness. Finally, the available treatments should be outlined to the patient, and a plan of therapy agreed upon. If conventional remedies are not helpful, then giving the patient emotional support, while they shop for alternative therapies, is the compassionate response.

CONCLUSION

Chronic Fatigue Syndrome remains a difficult medical and social problem. There is now enough hard evidence to conclude that this symptom complex results from derangements of the functioning of the immune, neurologic, and endocrine systems, and it is not simply a matter of depression or malingering. There appear to be subcategories of CFS, with different biochemical patterns that may be related to the various physical and emotional triggers that precipitate CFS. And, fibromyalgia, depression, and allergic diseases are much more frequent co-morbid conditions with CFS than would be expected by their incidences in the general population. We do not yet know if the relationship between these four illnesses is genetic, biochemical, or by environmental exposure, but when the details are known, it will likely lead to significant advances in our understanding of CFS. Finally, small trials have suggested several potentially useful therapies, but we do not yet have any rational means to select appropriate therapies for particular patients. The best current strategy for CFS treatment is a combination of ongoing evaluation, psychiatric support, trial of all available nontoxic therapies, and encouraging patient enrollment in research studies.

ACKNOWLEDGEMENTS

The author thanks June L. Bianchi, Sally C. Schumann, and Jeanie A. Vander Pyl, Cape Cod Hospital Medical Library, for their expertise in medical literature research.

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Table 1.

Centers for Disease Control 1987 Criteria for Diagnosis of Chronic Fatigue Syndrome

 MAJOR CRITERIA:

-persistent or relapsing fatigue, not resolved with bed rest, reducing daily activity at least 50%, for at least 6 months
and -exclusion of other chronic medical and psychiatric illnesses

CFS cases should have at least two physical signs and (1) meet both major criteria, or, (2) meet 6 minor criteria.

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• complete blood count and differential

• sedimentation rate

• blood urea nitrogen, creatnine, electrolytes

• fasting glucose

• total protein, albumin, globulin

• alanine aminotransferase, alkaline phosphatase

• calcium, phosphorus

• thyroid stimulating hormone

• urinalysis

• any other test suggested by history or physical exam

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