Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Chronic Fatigue Syndrome Won Kyoo Cho & Gene H. Stollerman To cite this article: Won Kyoo Cho & Gene H. Stollerman (1992) Chronic Fatigue Syndrome, Hospital Practice, 27:9, 221-245, DOI: 10.1080/21548331.1992.11705493 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705493
Published online: 17 May 2016.
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Chronic Fatigue Syndrome WON KYOO CHO and GENE H. STOLLERMAN Downloaded by [University of Toronto Libraries] at 12:20 27 June 2016
Yale University and Boston University
E
very physician is familiar with the brain's hypersensitive perception of what the French express somewhat delicately as malaise-and Americans, less delicately but no less descriptively, as "the crud." What is its pathophysiology? In particular, what is the pathophysiology of its most extreme form: a total mental, emotional, and physical exhaustion? Are there one or more viral infections, some as yet unidentified, that plague and confuse their victims by activating a common pathway or specific nervous system center, exhausting not only the host but also caregivers and the society's health care resources? The need to identify the pathophysiology of chronic fatigue syndrome (as it has come to be called in the past few years) is made all the greater by the syndrome's unfortunate similarity to psychiatric disease. which, being "all in your head," has led to the stigmatization of chronic fatigue as something of a foible. Pathetic, and almost comical, is the relief expressed by patients who finally learn that their symptoms of chronic fatigue are indeed of exogenous origin. The chronic fatigue syndrome should be diagnosed as quickly and efficiently as posDr. Cho is a Fellow in Gastroenterology, Yale University School of Medicine, New Haven. Dr. Stollerman is Professor of Medicine and Public Health, Boston University School of Medicine, and Director, Health Services Research and Development Field Program, Edith Nourse Rogers Veterans Hospital, Bedford, Mass. Hospital Practice September 15, 1992
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sible (Figure 1). with the perception that sympathetic and supportive care, rather than simply an exhaustive pursuit of an almost endless differential diagnosis, is a major facet of clinical management. Such care requires a constant and faithful physician who forms a prospective partnership with the patient early in the relationship. The following case is illustrative of these issues. In one way, however, it is atypical: The patient was an unusually articulate and dynamic woman who eventually became an effective activist in the cause of all patients with chronic fatigue syndrome. She first came to our attention when she presented her own case at a medical conference!
Case Presentation 45-year-old single mother of four grown-up children presented in 1987 with a five-year history of persistent debilitating fatigue. She had been working part-time on an Associate degree in domestic engineering while engaged as an activist for numerous community antipoverty agencies. emergency food pantries, and organizations for the homeless. She had served, for example, as a speaker presenting the problems of the disadvantaged at various local, state, and federal levels. In the winter of 1982, however, she had experienced some flulike symptoms, including myalgias, generalized fatigue, headache, and dizziness. accompanied by a low-grade fever. The illness was persistent, and as time went on she began to experience confusion, problems with memory and comprehension, incoordination, insomnia, and depression. She went to several different physicians, but her complaints were dismissed as "all in your head," since the findings on repeated physical examinations and extensive laboratory tests were unremarkable. Her general condition continued to deteriorate. with some waxing and waning.
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In May 1987, prompted by a television program, she found an article on chronic Epstein-Barr viral infection in JAMA. She presented to another local physician and was discovered to have an Epstein-Barr viral capsid antigen titer of 1:2,560. A diagnosis of chronic fatigue syndrome was then made by a specialist at a Boston medical institution, where she has been followed ever since. The patient is currently on Social Security disability and is usually homebound, since profound fatigue after even minor exertion prevents her from performing any productive tasks. She takes amitriptyline (50 mg) at bedtime and eats a balanced diet with a vitamin supplement. Unfortunately, there have been no signs of improvement. 222
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Epidemiology According to recent epidemiologic studies, about one in five patients seen in general medical practice reports symptoms of chronic fatigue. Yet despite this high prevalence, chronic fatigue is one of the least understood of all medical complaints. Among the subsets of chronic fatigue, chronic fatigue syndrome is characterized by a persistent or recurring fatigue or easy fatigability severe enough to be disabling for average daily activity for at least six months. The disorder is frequently associated with other chronic and recurrent signs and symptoms, such as low-grade fever, myalgia, or pharyngitis, as well as disturbances in sleep, cognition, or temperament (Figure 2). It has a rather sudden onset, often preceded by an acute infectious illness, such as respiratory infection, gastroenteritis, or hepatitis. Chronic fatigue syndrome is often reported in well-educated high-achievers 20 to 50 years old, with some female and white predominance-patterns contributing to the popular 1980s stereotype of the disease as "yuppie flu." In fact, the syndrome is not limited to any particular social group. It has affected persons of all ages, races, and socioeconomic classes all over the world, with an overall prevalence thought to be one in several thousand.
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Nor did the syndrome arise in the 1980s. Although scientific interest in the disorder became intense at that time, the illness itself appears to be an old one with many names. In 1750, a thesis onjebricula by Sir Richard Manningham described "a lowgrade fever" with "great lassitude and weariness all over the body" and stated that similar descriptions were to be found in the writings of Hippocrates and his pupils. Manningham also reported that the disease was most prevalent among those who were sedentary and studious and among affluent women, and that it was often precipitated by grief. intense thoughts, and colds. In the 1800s, Austin Flint described chronic fatigue as "nervous exhaustion." However, it was George Beard who, in 1869, coined the term "neurasthenia." Beard believed that lack of strength of the nerves was the underlying cause of fatigue, but he also recognized that there were other possible causes, such as anemia. Thus, he stated, "the diagnosis is obtained partly by positive symptoms and partly by exclusion," and he reported that prognosis was quite as variable as were the inciting insults to the nervous system. Since Beard's time, chronic fatigue syndrome has been described in many different countries by many different names, including Iceland disease, Akureyri disease, Royal Free disease, epidemic vegetative neuritis, acute infective encephalomyelitis, and chronic Epstein-Barr virus syndrome. One of the most important landmarks in the characterization of the syndrome (continues)
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was the formulation of a working definition in 1988 by a group chaired by G. P. Holmes for the Centers for Disease Control (see Figure 1 ). Although the criteria may be overly restrictive, the definition is a noble effort to help clinicians as well as researchers.
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Pathogenesis espite numerous attempts to elucidate the pathologic processes responsible for chronic fatigue syndrome, the precise mechanisms remain unknown, and finding them appears to be a more formidable task than was anticipated. In the first place, there are no definitive diagnostic tests or findings to identify chronic fatigue syndrome, and many debilitating diseases, such as fibromyalgia, depression, and disseminated tuberculosis, overlap substantially with the disorder in their clinical presentation. Then too, the term "syndrome" signifies only a group of coincident symptoms or signs without necessarily implying a single etiology. The numerous attempts to elucidate the pathogenesis of chronic fatigue syndrome are evoked by the names Da Costa syndrome (effort syndrome or neurocirculatory asthenia), chronic brucellosis, chronic candidiasis, chronic Epstein-Barr virus infection, and total allergy syndrome (twentieth-century disease). Hypoglycemia, vitamin B 12 deficiency, myopathy, physical deconditioning, and the mercury toxicity from dental fillings have also been investigated.
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Infectious entities. In view of the fact that many patients with chronic fatigue syndrome give a history of a preceding infection, often a flu-like illness. it is understandable that infectious etiologies have received the most attention in seeking the cause of the syndrome. Numerous pathogens have been implicated, including bacteria (such as Brucella, Mycobacterium tuberculosis, and Borrelia burgdorjeri), viruses (such as Epstein-Barr virus, enteroviruses, and retroviruses), and mycotic agents (such as Candida). So far, none has been demonstrated consistently or convincingly to be a direct causative agent. On the other hand, it is known that the fatigue experienced in chronic fatigue syndrome is similar to the fatigue associated with therapeutic doses of a-interferon, and there is indirect evidence suggesting the possibility of an underlying viral infection producing elevated levels of the interferon-induced enzyme leukocyte 2',5'-oligoadenylate synthetase. Among the implicated viral pathogens, Epstein-Barr virus, a ubiquitous herpesvirus, has been one of the most prominent for many years. Persistent fatigue following infectious mononucleoHospital Practice September 15, 1992
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Figure 2. Symptoms and Signs of Chronic Fatigue Syndrome
Adapt Pel !rom Komaroll AL, But /1\\'aid D, 1991
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sis was first described in 1948, but the EBV agent was not implicated until 1968. In the early 1980s, several studies revealed that chronic fatigue can begin during an acute EBV infection (evidenced, for instance, by high titers of antibody to Epstein-Barr viral capsid antigen). Further studies showed, however, that the relation between chronic fatigue syndrome and active EBV infection was not clearcut. since there is considerable overlap between anti-EBV titers in patients and those in controls and there is no close correlation between titers and the severity of symptoms. About 95% of patients with chronic fatigue syndrome are EBV seropositivebut this is the same proportion as in the general population. Furthermore, acyclovir. which inhibits EBV and other herpesviruses, does not improve the syndrome. Although host susceptibilities and autoimmunity may prove to account for differential predilections to chronic fatigue following EBV infection. all that seems sure is that EBV is only one of many agents causing manifestations of "postviral asthenia." In the United Kingdom, enteroviruses, a picornavirus subset with 70 different serotypes. have been a popular etiologic candidate for chronic fatigue syndrome (under the name of myalgic encephalomyelitis). Enteroviral RNA has been detected in 20 of 96 selected patients (21 %) with chronic fatigue syndrome in a study that applied the in situ hybridization technique to muscle biopsy specimens. Another study, using the polymerase chain reaction (PCR) method, detected enteroviral sequences in muscle biopsies from 32 of 60 patients (53%). compared with 6 out of 41 controls ( 15%). Further studies have put the significance of these findings into question. since no clear morphologic or functional disturbance in the musculoskeletal system of patients with chronic fatigue syndrome has been demonstrated. Still, the findings suggest the possibility of viral persistence in target tissuesperhaps including the brain. Recently. human T-cellleukemia virus has been proposed as a possible pathogen in chronic fatigue syndrome. The virus has been detected by Western blot in 6 of 12 adults (50%) and 11 of 18 children (61%) with chronic fatigue syndrome. compared with 6 of 20 exposure controls (30%) and none of 20 nonexposure controls. Moreover. the gag sequence in the genome of HTLV-11 has been detected by PCR followed by Southern blot hybridization in 10 of 12 adults (83%) and 13 of 18 children (72%) with chronic fatigue syndrome, compared with 7 of 20 exposure controls (35%) and none of 20 nonexposure controls. None of the patients or the controls had HTLV-I or HTLV-11 tax sequences. These intriguing findings need to be validated-and to be put into clinical and epidemiologic contexts. Immunologic hypotheses. A variety of immunologic abnormalities have been described in patients with chronic fatigue syndrome (Table 1 ). It is known. for example, that such patients are remarkably likely to have a history of atopy predating the onset Hospital Practice September 15. 1992
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Table 1. Immunologic Abnormalities Reported in Chronic Fatigue Syndrome Elevated titers of antibodies to viral proteins Hypo- or hypergammaglobulinemia Increased or decreased levels of circulating immune complexes Decreased immunoglobulin production in vitro Increased leukocyte 2',5'-oligoadenylate synthetase Decreased interleukin-2 production in vitro Increased serum interleukin-2 levels
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Decreased y-interferon synthesis in vitro Increased helper/suppressor T-cell ratio Increased T-cell suppression of immunoglobulin synthesis in vitro Decreased or increased natural killer cell activity Decreased antithyroid antibody levels Variable antinuclear antibody levels
of chronic fatigue syndrome (50% to 83%, compared with a 20% to 30% probability of atopy in the general population). Still, the significance of the immunologic abnormalities is uncertain. The findings are not consistent from one patient to another, or even from one point in time to another. The abnormalities are often relatively small in magnitude, with consequent sources of error due to imprecisions in the assays. There is no clear correlation between the degree of abnormality and the severity of symptoms. One conceivable theory linking immunologic abnormalities to the development of chronic fatigue syndrome is that patients may have an immune system that responds overemphatically to environmental or internal stimuli. Alternatively, they may have inherent immunoregulatory defects such that aspects of the immune reaction may not be stoppable even after an insult is over. The situation may be analogous to that in postinfectious viral syndromes such as coxsackie B chronic myocarditis. Recent advances in research concerning the involvement of various cytokines in immune function may provide important clues to the pathogenesis of chronic fatigue syndrome. It is known that interleukin-1 can produce fever, fatigue, myalgias, and malaise. Moreover, the high doses of interleukin-2 administered to cancer patients produce severe lethargy, myalgias, and memory problems-symptoms that resemble those of chronic fatigue syndrome and resolve when the treatment has been completed. IL-2 is elaborated by activated lymphocytes, and receptors for IL-2 (continues)
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are widely distributed. The receptors are likely to vary in their amino acid sequence from one host to another. These various pieces of circumstantial evidence suggest some possible roles of cytokines in causing chronic fatigue-roles that may foretell the development of symptomatic therapy. Psychological explanations. Chronic fatigue syndrome is one among many disorders exemplifying the recurrent tendency to dismiss an unexplained illness that lacks a quantifiable basis as merely a psychological phenomenon. Yet, such prejudice (based on a mind-versus-body dualism that patients often translate as imagined-versus-real) may be "more virulent than any virus" (as Simon Wessely of the National Hospital for Nervous Diseases, London, has written). It is true that the role of psychological disorders, especially depression, in chronic fatigue syndrome is difficult to evaluate, because of considerable overlap between psychological disorders and the reactive depression of chronic fatigue syndrome. Indeed. clinicians must often attempt to determine whether psychiatric disease is a cause or an effect of debilitating chronic fatigue. It is known that patients with chronic fatigue syndrome have an incidence and lifetime prevalence of depression significantly greater than those in patients with other chronic diseases, and many studies have shown that 40% to 50% of fatigued patients had at least one major depressive episode antedating the onset of their fatigue syndrome. Several studies conducted in the 1950s also revealed that the prevalence of psychoneurotic traits was greater in those who took longer to recover from infections such as brucellosis or influenza. A variety of neurohormonal and immunologic abnormalities have been demonstrated in depressed patients, which gives the impression that similar abnormalities occurring in patients with chronic fatigue syndrome may be attributable to concomitant depression. These findings, however, do not imply, or even suggest, a clear cause-and-effect relationship, and even the prior presence of psychiatric symptoms does not preclude a diagnosis of chronic fatigue syndrome, according to most of the experts who formulated the Holmes diagnostic criteria. In any event. several circumstances-the sudden onset of chronic fatigue syndrome in previously healthy patients, occasional epidemics of chronic fatigue syndrome (as in Nevada in 1985), and the frequent presence of objective physical signs (such as low-grade fever, pharyngitis, or adenopathy) antecedent to chronic fatigue syndrome or early in the syndrome-argue against a purely psychological etiology (whatever that is!). It remains, of course. entirely possible that some persons may have a genetic predisposition to chronic fatigue syndrome, analogous to the predisposition to certain rheumatologic diseases associated with particular HLA genotypes. In this regard. it is Hospital Practice September 15, 1992
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intriguing that the genes encoding brain receptors for neurotransmitters are being found to have multiple alleles-five (so far) for the dopamine receptor, each characterized by varying degrees of response to the transmitter. Other possibilities. It has been reported that 85% of patients with chronic fatigue syndrome show reduced monocyte function. The function improves when the cells are incubated with the opioid antagonist naloxone-a hint suggesting a possible involvement of endogenous opioids in the syndrome. More information will be needed before the clinical significance of these findings can be judged. Other investigations are directed toward the possibility of dysfunction in the hypothalamus-pituitary-adrenal axis, such as is seen in glucocorticoid deficiency. Again, the findings are preliminary. Moreover, empiric corticosteroid therapy has not produced significant improvement in patients with chronic fatigue syndrome. Upregulation of hypothalamic serotonin receptors in patients with postviral fatigue syndrome has very recently been reported. It has also been found that some patients with chronic fatigue syndrome have areas of high-intensity signal in the subcortical white matter on MRI scans and certain regional hypoperfusion on SPECT and PET scans. Although the significance of these reports from various modalities of brain imaging is unknown. the research may eventually yield clues to the pathophysiology and diagnosis of chronic fatigue syndrome. In conclusion, there may be more than one pathogen-or even noninfectious factors-that place patients on a final common pathway to chronic fatigue syndrome. Alternatively, there may be a predominant pathogen, or even a single pathogen uniquely causative of the syndrome, perhaps in certain groups of persons with predispositions yet to be defined. The situation is analogous to the current state of knowledge regarding the etiology of. say, systemic lupus erythematosus.
Workup Strategy n ~he evaluatio~ of chronic fatigue, there are numerous etiologies to be considered (Table 2). On the other hand, extensive, undirected workups can be costly with low yield. For the physician confronted with this dilemma. some general rules may be helpful. First: The longer the duration of chronic fatigue-and the greater the number of symptoms-the less the need for extensive workup supporting a diagnosis of chronic fatigue syndrome. Second: Look with particular thoroughness for alternative diagnoses if the clinical picture is dominated by a single symptom
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Table 2. Differential Diagnosis of Chronic Fatigue Syndrome
Endocrinologic
Infectious
Hypothyroidism
Chronic Epstein-Barr virus infection
Hyperthyroidism Influenza infection Addison's disease HIV infection
Adrenal insufficiency
Other viral disease Cushing's disease Chronic brucellosis Diabetes Tuberculosis Rheumatologic
Lyme disease
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Fibromyalgia
Fungal disease
Sjogren syndrome
Hematologic/Oncologic
Polymyalgia rheumatica; giant cell arteritis Polymyositis; dermatomyositis
Anemia Lymphoma Occult malignancy
Neuropsychological
Other
Obstructive sleep syndromes Multiple sclerosis
Chronic illness (renal, hepatic, cardiac, pulmonary) Drug side effects (e.g., f3-blockers)
Parkinsonism Affective disorders; depression
Alcohol or other substance abuse Hypochondriasis; somatization disorder
CHRONIC
FATIGUE
SYNDROME
Heavy-metal toxicity
(continued)
other than fatigue, or if the patient has had a significant weight loss or has a high fever (exceeding 38.6°). Third: The patient's history is one of the most important clues to the diagnosis of chronic fatigue syndrome, and physical examination and laboratory tests may provide little additional information. Particular combinations of laboratory tests to rule out common etiologies of chronic fatigue are frequently recommended (Table 3). However, the workup needs to be customized, in response to the history and physical findings. For example, the possibility of a mimicking condition such as HIV or Lyme infection, tuberculosis, heavy-metal poisoning, or sleep apnea can be pursued if epidemiologic clues, the presence of risk factors, or clinical suspicion suggests this course. Detailed psychological evaluation or psychiatric consultation should be an important part of the workup, not only for the exclu(continues)
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Table 3. Recommended Data to Support Exclusion of Other Possibilities in Diagnosis of Chronic Fatigue Syndrome Serial weights (change > 10% suggests other diagnoses) Serial
A.M.
and
P.M.
temperatures
Complete blood count with differential Blood chemistries (electrolytes, glucose, BUN, creatinine, liver enzymes, creatine kinase) Erythrocyte sedimentation rate
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Serologies (Epstein-Barr virus, human immunodeficiency virus, cytomegalovirus, lyme disease, toxoplasmosis, RPR test, hepatitis screen, antinuclear antibodies) PPD skin test Chest x-rays (PA and lateral) Personal and family psychiatric history
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sian of psychiatric disorders but in preparation for long-term supportive care. Many patients with chronic fatigue syndrome may initially resist such evaluation unless they are clearly counseled regarding its helpfulness and are assured of the primary medical physician's continued involvement. Among the greatest difficulties in the diagnosis of chronic
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fatigue syndrome is the differentiation of the syndrome from other disease entities with significant overlap in their clinical manifestations. One such disease is fibromyalgia, characterized by the presence of generalized aches or stiffness at multiple anatomic sites (with reproducible tenderness at typical trigger points) but associated with many symptoms similar to those of chronic fatigue syndrome. In some patients, it is essentially impossible to choose between the diagnosis of chronic fatigue syndrome and that of fibromyalgia. Nevertheless, there are some features helpful in discriminating between the two (Table 4). The other major differentiation is between chronic fatigue syndrome and depression. Neither of them is a well-defined entity for which diagnostic laboratory tests are available, but again there are some helpful distinguishing features (Table 5). Somatic complaints in depressed patients are often diffuse (e.g., a combination of headache, musculoskeletal pain, and gastrointestinal distress). Such symptoms as anhedonia, sleep or sex or appetite disturbances, guilt, self-criticism, and pessimism are common. Conversely, low-grade fevers, lymphadenopathy, pharyngitis, and night sweats are more likely in chronic fatigue syndrome. {continues)
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Management
FATIGUE
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(continued)
s yet, there is no cure, nor even an optimal therapy, for chronic fatigue syndrome, even though myriads of drugs have been tried in various clinical trials. Indeed, the trials have been impeded by the discovery of potential factors confounding the interpretation of the results. For example, trials of high-dose acyclovir and an intramuscular liver extract-folic acid-cyanocobalamin combination have produced definite responses, but the responses were not superior to the effects of placebo-a finding indicative of a strong placebo effect in chronic fatigue syndrome (as in many other neurologic diseases). Some studies involving immunoglobulin therapy have yielded ambiguous results. Low-dose therapy ( 1 gm/kg) did not cause any significant improvement, whereas high-dose treatment (2 gm/kg) produced improvement in 38% to 43% of patients versus 12% of a placebo group, as assessed by blinded clinicians and psychiatrists. However, there was no benefit of treatment at either dose, as judged by patient-perceived measures. High doses of essential fatty acids have resulted in significant patient-reported improvements in fatigue, myalgias, dizziness, concentration impairment, and depression, assessed at one month and at three months. Intramuscular injection of magnesium sulfate has also shown a significant benefit (at seven weeks). These studies, however, are limited by the short duration of follow-up. Since chronic fatigue syndrome is known to have a highly variable clinical course, often marked by unpredictable exacerbations and remissions, the findings are difficult to assess (just as similar fmdings would be hard to judge in multiple sclerosis). 5-Hydroxytryptophan has shown a significant effect with good tolerability in primary fibromyalgia and the serotonin precursor may prove to be useful in patients with chronic fatigue syndrome. Ampligen (poly[I]:poly[C 12U]) also appears to be a promising drug. It has supposedly yielded "global improvements" with minimal side effects. In the absence of therapy proven to be effective in chronic fatigue syndrome, patient education and supportive symptomatic treatment remain the mainstays of management. Patient eduction is crucial. Although a few prospective studies have suggested that many patients with chronic fatigue syndrome recover or at least improve over time, most patients suffer from substantial occupational and psychosocial impairments and loss-including the social pressure and isolation arising from being characterized as "crazy or lazy." Accordingly, it is vital to assure patients that their fatigue is a physical symptom, produced by various physical and emotional factors. Patients should also be counseled that the fatigue is not progressive or lethal but will wax and wane, and that there is some definite possibility of recovery.
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Good dietary and sleep habits are an important aspect of general treatment. A continued exercise program, stepped up over time, should also be implemented. (It has been shown that frequent low-intensity exercise can have a beneficial effect on the immune response.) Drug therapy is indicated only for certain patients. As in fibromyalgia, low-dose antidepressants at bedtime can help to ameliorate sleep disturbances and myalgias. The addition of an NSAID (such as naproxen) to the antidepressant appears to be helpful. Cognitive behavior therapy may also be valuable (to promote a positive outlook as well as improving overall disability, fatigue, and psychosomatic symptoms). For a primary care physician, patients with chronic fatigue syndrome require considerable effort, patience, and commitment. Many support groups and associations are also available to patients.
Conclusion hronic fatigue syndrome appears to be a heterogeneous disease with many different etiologies. The external causes, however, may somehow be influenced by underlying psychoimmunologic risk factors. with convergence on a final common pathway of chronic fatigue. Refinement of the definition of chronic fatigue syndrome will be an important next step in understanding the pathogenesis and the risk factors. Meanwhile, the primary physician's task for patients affected by the syndromeor any other currently incurable disease-is to comfort, educate, and protect. D
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Selected Reading Calabress Let al: Chronic fatigue syndrome. Am Fam Physician 45: 1205. 1992 Kyle DV. deShazo RD: Chronic fatigue syndrome: A conundrum. Am J Med Sci 303: 28. 1992 Matthews DA. Manu P, Lane T J: Evaluation and management of patients With chronic fatigue. Am J Med Sci 302: 269. 1991 Shafran SO: The chronic fatigue syndrome. Am J Med 90: 730. 1991 Komar offAL. Buchwald D: Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis 13(suppl I}: 8S. 1991 Holmes GP: Defining the chronic fatigue syndrome. Ibid: 53S Evans AS: Chronic fatigue syndrome: Thoughts on pathogenesis. Ibid: 56S Abbey SE. Garfinkel PE: Chronic fatigue syndrome and depression: Cause. effect. or covariate. Ibid: 73S Kroenke K: Chronic fatigue syndrome: Is it real? Postgrad Med 89:44. 1991 Gantz NM: Treatment of patients with chronic fatigue syndrome. Drugs 38:855.1989
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ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Chronic Fatigue Syndrome Won Kyoo Cho & Gene H. Stollerman To cite this article: Won Kyoo Cho & Gene H. Stollerman (1992) Chronic Fatigue Syndrome, Hospital Practice, 27:9, 221-245, DOI: 10.1080/21548331.1992.11705493 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705493
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [University of Toronto Libraries]
Date: 27 June 2016, At: 12:20
Chronic Fatigue Syndrome WON KYOO CHO and GENE H. STOLLERMAN Downloaded by [University of Toronto Libraries] at 12:20 27 June 2016
Yale University and Boston University
E
very physician is familiar with the brain's hypersensitive perception of what the French express somewhat delicately as malaise-and Americans, less delicately but no less descriptively, as "the crud." What is its pathophysiology? In particular, what is the pathophysiology of its most extreme form: a total mental, emotional, and physical exhaustion? Are there one or more viral infections, some as yet unidentified, that plague and confuse their victims by activating a common pathway or specific nervous system center, exhausting not only the host but also caregivers and the society's health care resources? The need to identify the pathophysiology of chronic fatigue syndrome (as it has come to be called in the past few years) is made all the greater by the syndrome's unfortunate similarity to psychiatric disease. which, being "all in your head," has led to the stigmatization of chronic fatigue as something of a foible. Pathetic, and almost comical, is the relief expressed by patients who finally learn that their symptoms of chronic fatigue are indeed of exogenous origin. The chronic fatigue syndrome should be diagnosed as quickly and efficiently as posDr. Cho is a Fellow in Gastroenterology, Yale University School of Medicine, New Haven. Dr. Stollerman is Professor of Medicine and Public Health, Boston University School of Medicine, and Director, Health Services Research and Development Field Program, Edith Nourse Rogers Veterans Hospital, Bedford, Mass. Hospital Practice September 15, 1992
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sible (Figure 1). with the perception that sympathetic and supportive care, rather than simply an exhaustive pursuit of an almost endless differential diagnosis, is a major facet of clinical management. Such care requires a constant and faithful physician who forms a prospective partnership with the patient early in the relationship. The following case is illustrative of these issues. In one way, however, it is atypical: The patient was an unusually articulate and dynamic woman who eventually became an effective activist in the cause of all patients with chronic fatigue syndrome. She first came to our attention when she presented her own case at a medical conference!
Case Presentation 45-year-old single mother of four grown-up children presented in 1987 with a five-year history of persistent debilitating fatigue. She had been working part-time on an Associate degree in domestic engineering while engaged as an activist for numerous community antipoverty agencies. emergency food pantries, and organizations for the homeless. She had served, for example, as a speaker presenting the problems of the disadvantaged at various local, state, and federal levels. In the winter of 1982, however, she had experienced some flulike symptoms, including myalgias, generalized fatigue, headache, and dizziness. accompanied by a low-grade fever. The illness was persistent, and as time went on she began to experience confusion, problems with memory and comprehension, incoordination, insomnia, and depression. She went to several different physicians, but her complaints were dismissed as "all in your head," since the findings on repeated physical examinations and extensive laboratory tests were unremarkable. Her general condition continued to deteriorate. with some waxing and waning.
A
In May 1987, prompted by a television program, she found an article on chronic Epstein-Barr viral infection in JAMA. She presented to another local physician and was discovered to have an Epstein-Barr viral capsid antigen titer of 1:2,560. A diagnosis of chronic fatigue syndrome was then made by a specialist at a Boston medical institution, where she has been followed ever since. The patient is currently on Social Security disability and is usually homebound, since profound fatigue after even minor exertion prevents her from performing any productive tasks. She takes amitriptyline (50 mg) at bedtime and eats a balanced diet with a vitamin supplement. Unfortunately, there have been no signs of improvement. 222
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Epidemiology According to recent epidemiologic studies, about one in five patients seen in general medical practice reports symptoms of chronic fatigue. Yet despite this high prevalence, chronic fatigue is one of the least understood of all medical complaints. Among the subsets of chronic fatigue, chronic fatigue syndrome is characterized by a persistent or recurring fatigue or easy fatigability severe enough to be disabling for average daily activity for at least six months. The disorder is frequently associated with other chronic and recurrent signs and symptoms, such as low-grade fever, myalgia, or pharyngitis, as well as disturbances in sleep, cognition, or temperament (Figure 2). It has a rather sudden onset, often preceded by an acute infectious illness, such as respiratory infection, gastroenteritis, or hepatitis. Chronic fatigue syndrome is often reported in well-educated high-achievers 20 to 50 years old, with some female and white predominance-patterns contributing to the popular 1980s stereotype of the disease as "yuppie flu." In fact, the syndrome is not limited to any particular social group. It has affected persons of all ages, races, and socioeconomic classes all over the world, with an overall prevalence thought to be one in several thousand.
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Nor did the syndrome arise in the 1980s. Although scientific interest in the disorder became intense at that time, the illness itself appears to be an old one with many names. In 1750, a thesis onjebricula by Sir Richard Manningham described "a lowgrade fever" with "great lassitude and weariness all over the body" and stated that similar descriptions were to be found in the writings of Hippocrates and his pupils. Manningham also reported that the disease was most prevalent among those who were sedentary and studious and among affluent women, and that it was often precipitated by grief. intense thoughts, and colds. In the 1800s, Austin Flint described chronic fatigue as "nervous exhaustion." However, it was George Beard who, in 1869, coined the term "neurasthenia." Beard believed that lack of strength of the nerves was the underlying cause of fatigue, but he also recognized that there were other possible causes, such as anemia. Thus, he stated, "the diagnosis is obtained partly by positive symptoms and partly by exclusion," and he reported that prognosis was quite as variable as were the inciting insults to the nervous system. Since Beard's time, chronic fatigue syndrome has been described in many different countries by many different names, including Iceland disease, Akureyri disease, Royal Free disease, epidemic vegetative neuritis, acute infective encephalomyelitis, and chronic Epstein-Barr virus syndrome. One of the most important landmarks in the characterization of the syndrome (continues)
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was the formulation of a working definition in 1988 by a group chaired by G. P. Holmes for the Centers for Disease Control (see Figure 1 ). Although the criteria may be overly restrictive, the definition is a noble effort to help clinicians as well as researchers.
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Pathogenesis espite numerous attempts to elucidate the pathologic processes responsible for chronic fatigue syndrome, the precise mechanisms remain unknown, and finding them appears to be a more formidable task than was anticipated. In the first place, there are no definitive diagnostic tests or findings to identify chronic fatigue syndrome, and many debilitating diseases, such as fibromyalgia, depression, and disseminated tuberculosis, overlap substantially with the disorder in their clinical presentation. Then too, the term "syndrome" signifies only a group of coincident symptoms or signs without necessarily implying a single etiology. The numerous attempts to elucidate the pathogenesis of chronic fatigue syndrome are evoked by the names Da Costa syndrome (effort syndrome or neurocirculatory asthenia), chronic brucellosis, chronic candidiasis, chronic Epstein-Barr virus infection, and total allergy syndrome (twentieth-century disease). Hypoglycemia, vitamin B 12 deficiency, myopathy, physical deconditioning, and the mercury toxicity from dental fillings have also been investigated.
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Infectious entities. In view of the fact that many patients with chronic fatigue syndrome give a history of a preceding infection, often a flu-like illness. it is understandable that infectious etiologies have received the most attention in seeking the cause of the syndrome. Numerous pathogens have been implicated, including bacteria (such as Brucella, Mycobacterium tuberculosis, and Borrelia burgdorjeri), viruses (such as Epstein-Barr virus, enteroviruses, and retroviruses), and mycotic agents (such as Candida). So far, none has been demonstrated consistently or convincingly to be a direct causative agent. On the other hand, it is known that the fatigue experienced in chronic fatigue syndrome is similar to the fatigue associated with therapeutic doses of a-interferon, and there is indirect evidence suggesting the possibility of an underlying viral infection producing elevated levels of the interferon-induced enzyme leukocyte 2',5'-oligoadenylate synthetase. Among the implicated viral pathogens, Epstein-Barr virus, a ubiquitous herpesvirus, has been one of the most prominent for many years. Persistent fatigue following infectious mononucleoHospital Practice September 15, 1992
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Figure 2. Symptoms and Signs of Chronic Fatigue Syndrome
Adapt Pel !rom Komaroll AL, But /1\\'aid D, 1991
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sis was first described in 1948, but the EBV agent was not implicated until 1968. In the early 1980s, several studies revealed that chronic fatigue can begin during an acute EBV infection (evidenced, for instance, by high titers of antibody to Epstein-Barr viral capsid antigen). Further studies showed, however, that the relation between chronic fatigue syndrome and active EBV infection was not clearcut. since there is considerable overlap between anti-EBV titers in patients and those in controls and there is no close correlation between titers and the severity of symptoms. About 95% of patients with chronic fatigue syndrome are EBV seropositivebut this is the same proportion as in the general population. Furthermore, acyclovir. which inhibits EBV and other herpesviruses, does not improve the syndrome. Although host susceptibilities and autoimmunity may prove to account for differential predilections to chronic fatigue following EBV infection. all that seems sure is that EBV is only one of many agents causing manifestations of "postviral asthenia." In the United Kingdom, enteroviruses, a picornavirus subset with 70 different serotypes. have been a popular etiologic candidate for chronic fatigue syndrome (under the name of myalgic encephalomyelitis). Enteroviral RNA has been detected in 20 of 96 selected patients (21 %) with chronic fatigue syndrome in a study that applied the in situ hybridization technique to muscle biopsy specimens. Another study, using the polymerase chain reaction (PCR) method, detected enteroviral sequences in muscle biopsies from 32 of 60 patients (53%). compared with 6 out of 41 controls ( 15%). Further studies have put the significance of these findings into question. since no clear morphologic or functional disturbance in the musculoskeletal system of patients with chronic fatigue syndrome has been demonstrated. Still, the findings suggest the possibility of viral persistence in target tissuesperhaps including the brain. Recently. human T-cellleukemia virus has been proposed as a possible pathogen in chronic fatigue syndrome. The virus has been detected by Western blot in 6 of 12 adults (50%) and 11 of 18 children (61%) with chronic fatigue syndrome. compared with 6 of 20 exposure controls (30%) and none of 20 nonexposure controls. Moreover. the gag sequence in the genome of HTLV-11 has been detected by PCR followed by Southern blot hybridization in 10 of 12 adults (83%) and 13 of 18 children (72%) with chronic fatigue syndrome, compared with 7 of 20 exposure controls (35%) and none of 20 nonexposure controls. None of the patients or the controls had HTLV-I or HTLV-11 tax sequences. These intriguing findings need to be validated-and to be put into clinical and epidemiologic contexts. Immunologic hypotheses. A variety of immunologic abnormalities have been described in patients with chronic fatigue syndrome (Table 1 ). It is known. for example, that such patients are remarkably likely to have a history of atopy predating the onset Hospital Practice September 15. 1992
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Table 1. Immunologic Abnormalities Reported in Chronic Fatigue Syndrome Elevated titers of antibodies to viral proteins Hypo- or hypergammaglobulinemia Increased or decreased levels of circulating immune complexes Decreased immunoglobulin production in vitro Increased leukocyte 2',5'-oligoadenylate synthetase Decreased interleukin-2 production in vitro Increased serum interleukin-2 levels
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Decreased y-interferon synthesis in vitro Increased helper/suppressor T-cell ratio Increased T-cell suppression of immunoglobulin synthesis in vitro Decreased or increased natural killer cell activity Decreased antithyroid antibody levels Variable antinuclear antibody levels
of chronic fatigue syndrome (50% to 83%, compared with a 20% to 30% probability of atopy in the general population). Still, the significance of the immunologic abnormalities is uncertain. The findings are not consistent from one patient to another, or even from one point in time to another. The abnormalities are often relatively small in magnitude, with consequent sources of error due to imprecisions in the assays. There is no clear correlation between the degree of abnormality and the severity of symptoms. One conceivable theory linking immunologic abnormalities to the development of chronic fatigue syndrome is that patients may have an immune system that responds overemphatically to environmental or internal stimuli. Alternatively, they may have inherent immunoregulatory defects such that aspects of the immune reaction may not be stoppable even after an insult is over. The situation may be analogous to that in postinfectious viral syndromes such as coxsackie B chronic myocarditis. Recent advances in research concerning the involvement of various cytokines in immune function may provide important clues to the pathogenesis of chronic fatigue syndrome. It is known that interleukin-1 can produce fever, fatigue, myalgias, and malaise. Moreover, the high doses of interleukin-2 administered to cancer patients produce severe lethargy, myalgias, and memory problems-symptoms that resemble those of chronic fatigue syndrome and resolve when the treatment has been completed. IL-2 is elaborated by activated lymphocytes, and receptors for IL-2 (continues)
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are widely distributed. The receptors are likely to vary in their amino acid sequence from one host to another. These various pieces of circumstantial evidence suggest some possible roles of cytokines in causing chronic fatigue-roles that may foretell the development of symptomatic therapy. Psychological explanations. Chronic fatigue syndrome is one among many disorders exemplifying the recurrent tendency to dismiss an unexplained illness that lacks a quantifiable basis as merely a psychological phenomenon. Yet, such prejudice (based on a mind-versus-body dualism that patients often translate as imagined-versus-real) may be "more virulent than any virus" (as Simon Wessely of the National Hospital for Nervous Diseases, London, has written). It is true that the role of psychological disorders, especially depression, in chronic fatigue syndrome is difficult to evaluate, because of considerable overlap between psychological disorders and the reactive depression of chronic fatigue syndrome. Indeed. clinicians must often attempt to determine whether psychiatric disease is a cause or an effect of debilitating chronic fatigue. It is known that patients with chronic fatigue syndrome have an incidence and lifetime prevalence of depression significantly greater than those in patients with other chronic diseases, and many studies have shown that 40% to 50% of fatigued patients had at least one major depressive episode antedating the onset of their fatigue syndrome. Several studies conducted in the 1950s also revealed that the prevalence of psychoneurotic traits was greater in those who took longer to recover from infections such as brucellosis or influenza. A variety of neurohormonal and immunologic abnormalities have been demonstrated in depressed patients, which gives the impression that similar abnormalities occurring in patients with chronic fatigue syndrome may be attributable to concomitant depression. These findings, however, do not imply, or even suggest, a clear cause-and-effect relationship, and even the prior presence of psychiatric symptoms does not preclude a diagnosis of chronic fatigue syndrome, according to most of the experts who formulated the Holmes diagnostic criteria. In any event. several circumstances-the sudden onset of chronic fatigue syndrome in previously healthy patients, occasional epidemics of chronic fatigue syndrome (as in Nevada in 1985), and the frequent presence of objective physical signs (such as low-grade fever, pharyngitis, or adenopathy) antecedent to chronic fatigue syndrome or early in the syndrome-argue against a purely psychological etiology (whatever that is!). It remains, of course. entirely possible that some persons may have a genetic predisposition to chronic fatigue syndrome, analogous to the predisposition to certain rheumatologic diseases associated with particular HLA genotypes. In this regard. it is Hospital Practice September 15, 1992
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intriguing that the genes encoding brain receptors for neurotransmitters are being found to have multiple alleles-five (so far) for the dopamine receptor, each characterized by varying degrees of response to the transmitter. Other possibilities. It has been reported that 85% of patients with chronic fatigue syndrome show reduced monocyte function. The function improves when the cells are incubated with the opioid antagonist naloxone-a hint suggesting a possible involvement of endogenous opioids in the syndrome. More information will be needed before the clinical significance of these findings can be judged. Other investigations are directed toward the possibility of dysfunction in the hypothalamus-pituitary-adrenal axis, such as is seen in glucocorticoid deficiency. Again, the findings are preliminary. Moreover, empiric corticosteroid therapy has not produced significant improvement in patients with chronic fatigue syndrome. Upregulation of hypothalamic serotonin receptors in patients with postviral fatigue syndrome has very recently been reported. It has also been found that some patients with chronic fatigue syndrome have areas of high-intensity signal in the subcortical white matter on MRI scans and certain regional hypoperfusion on SPECT and PET scans. Although the significance of these reports from various modalities of brain imaging is unknown. the research may eventually yield clues to the pathophysiology and diagnosis of chronic fatigue syndrome. In conclusion, there may be more than one pathogen-or even noninfectious factors-that place patients on a final common pathway to chronic fatigue syndrome. Alternatively, there may be a predominant pathogen, or even a single pathogen uniquely causative of the syndrome, perhaps in certain groups of persons with predispositions yet to be defined. The situation is analogous to the current state of knowledge regarding the etiology of. say, systemic lupus erythematosus.
Workup Strategy n ~he evaluatio~ of chronic fatigue, there are numerous etiologies to be considered (Table 2). On the other hand, extensive, undirected workups can be costly with low yield. For the physician confronted with this dilemma. some general rules may be helpful. First: The longer the duration of chronic fatigue-and the greater the number of symptoms-the less the need for extensive workup supporting a diagnosis of chronic fatigue syndrome. Second: Look with particular thoroughness for alternative diagnoses if the clinical picture is dominated by a single symptom
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Table 2. Differential Diagnosis of Chronic Fatigue Syndrome
Endocrinologic
Infectious
Hypothyroidism
Chronic Epstein-Barr virus infection
Hyperthyroidism Influenza infection Addison's disease HIV infection
Adrenal insufficiency
Other viral disease Cushing's disease Chronic brucellosis Diabetes Tuberculosis Rheumatologic
Lyme disease
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Fibromyalgia
Fungal disease
Sjogren syndrome
Hematologic/Oncologic
Polymyalgia rheumatica; giant cell arteritis Polymyositis; dermatomyositis
Anemia Lymphoma Occult malignancy
Neuropsychological
Other
Obstructive sleep syndromes Multiple sclerosis
Chronic illness (renal, hepatic, cardiac, pulmonary) Drug side effects (e.g., f3-blockers)
Parkinsonism Affective disorders; depression
Alcohol or other substance abuse Hypochondriasis; somatization disorder
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Heavy-metal toxicity
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other than fatigue, or if the patient has had a significant weight loss or has a high fever (exceeding 38.6°). Third: The patient's history is one of the most important clues to the diagnosis of chronic fatigue syndrome, and physical examination and laboratory tests may provide little additional information. Particular combinations of laboratory tests to rule out common etiologies of chronic fatigue are frequently recommended (Table 3). However, the workup needs to be customized, in response to the history and physical findings. For example, the possibility of a mimicking condition such as HIV or Lyme infection, tuberculosis, heavy-metal poisoning, or sleep apnea can be pursued if epidemiologic clues, the presence of risk factors, or clinical suspicion suggests this course. Detailed psychological evaluation or psychiatric consultation should be an important part of the workup, not only for the exclu(continues)
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Table 3. Recommended Data to Support Exclusion of Other Possibilities in Diagnosis of Chronic Fatigue Syndrome Serial weights (change > 10% suggests other diagnoses) Serial
A.M.
and
P.M.
temperatures
Complete blood count with differential Blood chemistries (electrolytes, glucose, BUN, creatinine, liver enzymes, creatine kinase) Erythrocyte sedimentation rate
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Serologies (Epstein-Barr virus, human immunodeficiency virus, cytomegalovirus, lyme disease, toxoplasmosis, RPR test, hepatitis screen, antinuclear antibodies) PPD skin test Chest x-rays (PA and lateral) Personal and family psychiatric history
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sian of psychiatric disorders but in preparation for long-term supportive care. Many patients with chronic fatigue syndrome may initially resist such evaluation unless they are clearly counseled regarding its helpfulness and are assured of the primary medical physician's continued involvement. Among the greatest difficulties in the diagnosis of chronic
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fatigue syndrome is the differentiation of the syndrome from other disease entities with significant overlap in their clinical manifestations. One such disease is fibromyalgia, characterized by the presence of generalized aches or stiffness at multiple anatomic sites (with reproducible tenderness at typical trigger points) but associated with many symptoms similar to those of chronic fatigue syndrome. In some patients, it is essentially impossible to choose between the diagnosis of chronic fatigue syndrome and that of fibromyalgia. Nevertheless, there are some features helpful in discriminating between the two (Table 4). The other major differentiation is between chronic fatigue syndrome and depression. Neither of them is a well-defined entity for which diagnostic laboratory tests are available, but again there are some helpful distinguishing features (Table 5). Somatic complaints in depressed patients are often diffuse (e.g., a combination of headache, musculoskeletal pain, and gastrointestinal distress). Such symptoms as anhedonia, sleep or sex or appetite disturbances, guilt, self-criticism, and pessimism are common. Conversely, low-grade fevers, lymphadenopathy, pharyngitis, and night sweats are more likely in chronic fatigue syndrome. {continues)
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s yet, there is no cure, nor even an optimal therapy, for chronic fatigue syndrome, even though myriads of drugs have been tried in various clinical trials. Indeed, the trials have been impeded by the discovery of potential factors confounding the interpretation of the results. For example, trials of high-dose acyclovir and an intramuscular liver extract-folic acid-cyanocobalamin combination have produced definite responses, but the responses were not superior to the effects of placebo-a finding indicative of a strong placebo effect in chronic fatigue syndrome (as in many other neurologic diseases). Some studies involving immunoglobulin therapy have yielded ambiguous results. Low-dose therapy ( 1 gm/kg) did not cause any significant improvement, whereas high-dose treatment (2 gm/kg) produced improvement in 38% to 43% of patients versus 12% of a placebo group, as assessed by blinded clinicians and psychiatrists. However, there was no benefit of treatment at either dose, as judged by patient-perceived measures. High doses of essential fatty acids have resulted in significant patient-reported improvements in fatigue, myalgias, dizziness, concentration impairment, and depression, assessed at one month and at three months. Intramuscular injection of magnesium sulfate has also shown a significant benefit (at seven weeks). These studies, however, are limited by the short duration of follow-up. Since chronic fatigue syndrome is known to have a highly variable clinical course, often marked by unpredictable exacerbations and remissions, the findings are difficult to assess (just as similar fmdings would be hard to judge in multiple sclerosis). 5-Hydroxytryptophan has shown a significant effect with good tolerability in primary fibromyalgia and the serotonin precursor may prove to be useful in patients with chronic fatigue syndrome. Ampligen (poly[I]:poly[C 12U]) also appears to be a promising drug. It has supposedly yielded "global improvements" with minimal side effects. In the absence of therapy proven to be effective in chronic fatigue syndrome, patient education and supportive symptomatic treatment remain the mainstays of management. Patient eduction is crucial. Although a few prospective studies have suggested that many patients with chronic fatigue syndrome recover or at least improve over time, most patients suffer from substantial occupational and psychosocial impairments and loss-including the social pressure and isolation arising from being characterized as "crazy or lazy." Accordingly, it is vital to assure patients that their fatigue is a physical symptom, produced by various physical and emotional factors. Patients should also be counseled that the fatigue is not progressive or lethal but will wax and wane, and that there is some definite possibility of recovery.
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Good dietary and sleep habits are an important aspect of general treatment. A continued exercise program, stepped up over time, should also be implemented. (It has been shown that frequent low-intensity exercise can have a beneficial effect on the immune response.) Drug therapy is indicated only for certain patients. As in fibromyalgia, low-dose antidepressants at bedtime can help to ameliorate sleep disturbances and myalgias. The addition of an NSAID (such as naproxen) to the antidepressant appears to be helpful. Cognitive behavior therapy may also be valuable (to promote a positive outlook as well as improving overall disability, fatigue, and psychosomatic symptoms). For a primary care physician, patients with chronic fatigue syndrome require considerable effort, patience, and commitment. Many support groups and associations are also available to patients.
Conclusion hronic fatigue syndrome appears to be a heterogeneous disease with many different etiologies. The external causes, however, may somehow be influenced by underlying psychoimmunologic risk factors. with convergence on a final common pathway of chronic fatigue. Refinement of the definition of chronic fatigue syndrome will be an important next step in understanding the pathogenesis and the risk factors. Meanwhile, the primary physician's task for patients affected by the syndromeor any other currently incurable disease-is to comfort, educate, and protect. D
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Selected Reading Calabress Let al: Chronic fatigue syndrome. Am Fam Physician 45: 1205. 1992 Kyle DV. deShazo RD: Chronic fatigue syndrome: A conundrum. Am J Med Sci 303: 28. 1992 Matthews DA. Manu P, Lane T J: Evaluation and management of patients With chronic fatigue. Am J Med Sci 302: 269. 1991 Shafran SO: The chronic fatigue syndrome. Am J Med 90: 730. 1991 Komar offAL. Buchwald D: Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis 13(suppl I}: 8S. 1991 Holmes GP: Defining the chronic fatigue syndrome. Ibid: 53S Evans AS: Chronic fatigue syndrome: Thoughts on pathogenesis. Ibid: 56S Abbey SE. Garfinkel PE: Chronic fatigue syndrome and depression: Cause. effect. or covariate. Ibid: 73S Kroenke K: Chronic fatigue syndrome: Is it real? Postgrad Med 89:44. 1991 Gantz NM: Treatment of patients with chronic fatigue syndrome. Drugs 38:855.1989
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