CHRONIC FATIGUE SYNDROME: An Update

A. L. Komaroff, MD
Division of General Medicine and Primary Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
D. S. Buchwald, MD
Department of Medicine, Harborview Medical Center, University of Washington School of Medicine, Seattle, Washington 98104

KEY WORDS: lymphocyte function, lymphocyte phenotyping, neuroendocrine system, major depression, virology

	ABSTRACT
	Introduction
	Prevalence of CFS
	Clinical Presentation
	Differential Diagnosis of Chronic Fatigue
	Differences Between CFS and Major Depression
	Evidence of Central Nervous System Abnormalities
	Evidence of Chronic Immune Activation
	The Possible Role of Infectious Agents
	Diagnostic Evaluation of Patients with Chronic Fatigue
	Treatment of CFS
	Summary
	LITERATURE CITED

	ABSTRACT

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Among the many patients who seek medical care for the complaint of fatigue, a small number suffer from chronic fatigue syndrome (CFS). CFS is a poorly understood condition characterized by debilitating fatigue and associated symptoms lasting at least six months. Studies indicate that the illness is not simply a manifestation of an underlying psychiatric disorder, but rather is an illness characterized by activation of the immune system, various abnormalities of several hypothalamic-pituitary axes, and reactivation of certain infectious agents.

	Introduction

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For more than a century, syndromes characterized by debilitating fatigue and other associated symptoms have engaged the attention of physicians. The syndromes have gone by a wide variety of names, including neurasthenia, Icelandic Disease, and myalgic encephalomyelitis. In the mid-1980s, interest in such syndromes was rekindled by several reports describing a chronic debilitating illness in association with various virologic and immunologic abnormalities (1, 2, 3). The US Centers for Disease Control and Prevention (CDC) named the illness chronic fatigue syndrome (CFS) and developed a case definition (4), which was subsequently revised (Table 1) (5). The CDC and National Institutes of Health (NIH) also launched studies of the illness, galvanizing further research in laboratories around the world. Much has been learned about CFS in the past decade as a result of these efforts, although the causes and treatment of the illness remain elusive. Nevertheless, CFS has been a controversial illness. Some observers have doubted that there is any biological basis for CFS and postulated that it represents some form of depression, anxiety, or somatization. Many patients have been told "it's all in your head" or "you're just depressed." For reasons discussed below, we believe that view is no longer tenable.

	Prevalence of CFS

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CFS occurs in men and women of all age groups, including children as young as 5 years of age and older adults. It also occurs in all ethnic, racial, and socioeconomic groups. Among patients seen in clinical settings, the typical patient is a middle-class white woman in her thirties. The prevalence of CFS has been studied in various populations. In the community at large, independent of whether subjects have sought medical attention for the illness, approximately 1 in 1000 US adults meet the CDC criteria for the syndrome (6). Prevalence of the illness in children has not been established. Among patients seeking primary medical care for any reason, CFS occurs in approximately 1 in 100 adults (7).

	Clinical Presentation

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The symptoms that constitute the case definition of CFS (Table 1) are reported much more frequently by patients with CFS than by healthy subjects or by patients with other diseases that produce chronic fatigue, such as multiple sclerosis and major depression (8). In addition to symptoms included in the case definition, many patients with CFS also frequently report anorexia, nausea, drenching night sweats, intolerance of alcohol and pharmaceuticals that affect the central nervous system, and dizziness (8). An important feature of CFS is that—in contrast to most patients with the presenting complaint of persistent fatigue—the onset of CFS typically is sudden, often with a flu-like illness. Patients often say that their chronic illness "all started with that virus that never went away."

	Differential Diagnosis of Chronic Fatigue

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Among the large number of patients who seek primary medical care for the symptom of chronic fatigue, only a small fraction (2–5%) meet the criteria for CFS. Another equally small fraction turn out to have a well-recognized organic disorder, such as anemia, hypothyroidism, or an occult malignancy. Thus, while the presenting complaint of chronic fatigue is very common, CFS and established organic disorders rarely are present in these patients. Instead, depression and anxiety appear to be the most common underlying causes of the presenting complaint of chronic fatigue (9, 10). In many cases, there is no apparent explanation for chronic fatigue. Since the length and intensity of the work week for US citizens has increased progressively over the past 30 years (11), we believe that overwork explains many cases.

Some depressed patients find the diagnosis of depression to be stigmatizing and self-diagnose themselves as having CFS to avoid the stigma. On rare occasions, some patients fabricate the syndrome of CFS in order to achieve some secondary gain. Recognizing the patient with CFS from among the much larger group of patients with chronic fatigue is difficult. Unfortunately, the current case definition of CFS may not identify a truly discrete group of individuals suffering from the same pathophysiology (12).

	Differences Between CFS and Major Depression

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Although many patients with chronic fatigue suffer from major depression, a growing body of evidence indicates that the symptoms of CFS are not simply an atypical manifestation of major depression. First, while some of the symptoms of CFS could reflect a primary psychiatric disorder, many other symptoms are not characteristic of psychiatric illnesses: sore throat, adenopathy, arthralgias, post-exertional malaise. In fact, there is a striking difference in symptoms between patients with major depression and CFS—the latter having a virtual absence of classic depressive symptoms such as anhedonia, guilt, and lack of motivation (13).

Second, patients with major depression often have a central up-regulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in mild hypercortisolism; patients with CFS often have a central down-regulation of the HPA axis, resulting in mild hypocortisolism (14). Third, controlled trials have failed to demonstrate an improvement from treatment with fluoxetine (Prozac) in patients with CFS, even those with a concomitant major depression (15).

Finally, studies employing structured psychiatric interviews have demonstrated that many patients (25–60%) have no evidence of major depression at any time in their lives, either before or after the onset of the CFS. Even among those with a history of depression, the majority of patients do not have a current, active psychiatric illness that might be held responsible for their symptoms. At the same time, these studies generally have found somewhat higher lifetime levels of non-psychotic psychiatric illness, particularly major depression, in patients with CFS, as contrasted to healthy subjects or those with other chronic illnesses (16, 17, 18, 19, 20, 21). In summary, while coexisting psychiatric disorders, and depression in particular, must be sought and treated in any patient with CFS, many CFS patients do not suffer from mood, anxiety, or somatization disorders.

	Evidence of Central Nervous System Abnormalities

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Patients with CFS often complain of symptoms that suggest central nervous system (CNS) involvement: difficulty with concentration, attention, and memory; photophobia; paresthesias. In our experience, 5–15% of patients have also experienced an episode (always transient, often in the first six months off illness) indicating focal CNS involvement: paresis, visual loss, ataxia, or frank confusion that is witnessed by reliable observers. These events were not recurrent and have not heralded the onset of a neurological or other medical condition.

A number of diagnostic studies of the CNS have found abnormalities in patients with CFS. Magnetic resonance imaging (MRI) has demonstrated punctate areas of high signal in white matter more often in patients with CFS than in healthy control subjects (22, 23, 24). Most often the white matter abnormalities are in subcortical areas; sometimes, deeper structures are involved. Usually, the MRI findings in CFS are distinct from those in multiple sclerosis, where larger plaques located in the periventricular white matter are typical. Since tissue has not been obtained in CFS patients from the areas of signal abnormality, the pathophysiologic basis of the MRI abnormalities is unknown. One hypothesis is that these lesions represent areas of inflammation and/or demyelination.

Single-photon emission computed tomography (SPECT) abnormalities also have been reported to occur more often in CFS than in healthy control subjects or patients with depression (25, 26). Indeed, the signal abnormalities in CFS patients most closely resemble those seen in acquired immunodeficiency syndrome (AIDS) encephalopathy (26). Again, without tissue to examine directly, the pathophysiology cannot be determined. A reasonable hypothesis is that these findings represent reduced small vessel blood flow and/or dysfunction of neuronal or glial cells.

Abnormalities of the autonomic nervous system involving both the sympathetic and parasympathetic systems have also been reported in CFS patients. Such abnormalities have most commonly been demonstrated with tilt table testing (27, 28, 29, 30). With vertical tilt, patients with CFS more often have hypotension and tachycardia; these findings are consistent with neurally mediated hypotension. In one study, neither physical deconditioning nor concomitant depression explained the abnormalities (30). Whether treatments commonly used for neurally mediated hypotension—such as increasing salt and water intake, fludrocortisone, or beta-blockers—provide any benefit to patients with CFS remains to be shown. In our anecdotal experience, some patients with postural hypotensive symptoms or fatigue after long periods of standing improve with added salt or fludrocortisone, but none have completely recovered.

Several studies have identified abnormalities of hypothalamic function in CFS. As mentioned above, there appears to be hypofunction of corticotrophin-releasing hormone (CRH) neurons in the hypothalamus (14). In addition, disruption of both serotonergic and noradrenergic pathways has been demonstrated in patients with CFS (31, 32, 33, 34, 35, 36). For example, perturbations have been demonstrated in the metabolism of 5-hydroxy-indoleacetic acid, arginine-vasopressin, 5-hydroxytryptamine and prolactin; typically, the abnormalities in patients with CFS are in patterns opposite to that seen in depression. Such disruption could directly affect hypothalamic function and also produce many of the symptoms of CFS (37).

Testing of both central and peripheral balance centers has also revealed abnormalities in patients with CFS (38, 39). The treatment implications of this observation are untested and unclear.

Self-perceived impairment of cognition is one of the most common and disabling symptoms. Formal neuropsychological testing of cognition has not yielded consistent results. Although in most studies, cognitive function is in the normal range, CFS patients often have abnormalities of memory and/or attention during timed tasks. (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50). One study found that the immunologic and cognitive abnormalities were associated (51). While mood disorders alone can cause cognitive impairment, the studies that have most carefully addressed this possibility of association have not found that the cognitive impairment is explained by a coexisting depression (50).

	Evidence of Chronic Immune Activation

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Currently, there are many studies of the immune system in patients with CFS. Various abnormalities have been put forward, but only a few have been consistently reported by different laboratories studying different groups of patients with CFS. The most robust findings are increased numbers of CD8+ cytotoxic T cells that bear antigenic markers of activation on their cell surface (52), and depressed function of natural killer lymphocytes (53, 54, 55, 56, 57, 58). Other reported findings of immune activation (59, 60, 61) are elevated levels of circulating immune complexes and immunoglobulin G, and higher frequencies of various autoantibodies. Whether these abnormalities have any relationship to the symptoms reported by patients with CFS remains unclear. In the only study to examine this question, clinical improvement in CFS was not associated with changes in lymphocyte subsets or activation (62). It has been postulated that a state of immune activation could lead to the production of cytokines that disrupt neurotransmitter function and result in the symptoms of CFS, but that hypothesis remains unproven.

	The Possible Role of Infectious Agents

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Many patients state that their CFS began with a flu-like illness, and some of the chronic symptoms of CFS suggest a chronic infection. The state of immune activation in CFS also suggests the possibility of a chronic infectious process. Nevertheless, except in a few cases, there is no convincing evidence that CFS results from an infection. While many physician-scientists studying CFS believe that infectious agents may trigger and even perpetuate the symptoms of CFS, few believe that the illness will prove to be caused by a single, novel infectious agent—such as the central role of HIV in AIDS.

There is evidence that chronic active infection with various viruses may be present in some cases of CFS. Studies of the human herpesvirus called Epstein-Barr virus (EBV) triggered a resurgence of interest in CFS in the mid-1980s. While EBV may be reactivated in CFS (2, 3), few researchers today believe that EBV plays a central role in CFS. Infrequently, CFS has followed a case of classic acute infectious mononucleosis; this suggests that EBV may somehow have triggered the illness in these unusual patients. Several studies have found that human herpesvirus-6 (HHV-6) is activated more often in patients with CFS (22, 63, 64, 65, 66, 67), but a causal role for HHV-6 has not yet been established. Some studies have found that enterovirus infection may be involved in CFS (68, 69, 70, 71, 72), but others have reported negative (73, 74, 75) or equivocal (76) results. Although one report claimed the discovery of a novel retrovirus in CFS (77), subsequent work has strongly challenged that claim (78, 79, 80). Recently, some provocative evidence has been reported that a virus that can produce CNS disease in animals—Borna disease virus—may be present in patients with CFS (81, 82) and in certain psychiatric disorders (83, 84).

More circumstantial evidence of a chronic viral infection in many CFS patients comes from reports of an abnormality in an antiviral lymphocyte enzyme system called the 2-5A pathway. This antiviral pathway appears to be chronically activated in patients with CFS (85, 86).

Finally, in some patients, CFS follows in the wake of a well-documented acute infection—as contrasted to the nonspecific "infectious-like" symptoms that many patients report at the onset of the illness. CFS can follow not only acute infectious mononucleosis (as discussed above), but also properly diagnosed and treated Lyme disease (87, 88). These reports provide strong evidence that CFS can be triggered by an acute infection with an agent (viral or bacterial) that has the capacity to produce a chronic and (in the case of the herpesviruses) ineradicable infection.

	Diagnostic Evaluation of Patients with Chronic Fatigue

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An NIH panel has recommended a group of diagnostic tests (Table 2) for patients who have had debilitating fatigue for at least six months (89). These tests are largely to diagnose various organic illnesses causing fatigue. Careful assessment of an underlying depression is important in any patient. Although, as summarized above, a wide variety of abnormalities have been found in patients with CFS following various diagnostic studies, these tests must still be regarded as experimental. Of importance is the fact that no test is sufficiently sensitive or specific to constitute a diagnostic test for CFS. Patients should be reassessed at regular intervals for organic and psychiatric disorders; however, extensive laboratory testing without additional indications is unnecessary.

	Treatment of CFS

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Many clinicians have found that very low doses of tricyclic drugs—such as amitriptyline, 10–20 mg at bedtime—improve the quality of sleep and reduce the symptoms of CFS. Beneficial effects are reported within 48 h of initiating treatment. The low doses (relative to doses used in the treatment of depresssion) and rapid onset of beneficial effects are not consistent with treatment-mediated reversal of an underlying depression. In the first 1–2 weeks of therapy, many patients experience temporary grogginess on awakening, even at these low doses; usually this ceases, and patients should be encouraged to try the therapy for at least one month. Several randomized, controlled trials of low-dose tricyclics have demonstrated benefit in the syndrome called fibromyalgia (90, 91), although a recent study has challenged their long-term efficacy (92). There are many similarities between fibromyalgia and CFS (93, 94), and some observers believe they may be the same illness, with different labels. Nonsteroidal antiinflammatory drugs appear to be useful in treating the myalgias, arthralgias, and headaches that often occur in CFS patients. Recently, cognitive behavior therapy has been shown in randomized, controlled trials to be an acceptable, effective treatment for CFS (95, 96); of importance is the fact that improvements are sustained and continue over 6–12 months of follow-up.

Finally, CFS is a "delegitimizing" illness: In addition to suffering from the symptoms of the illness, patients often experience rejection by family, friends, and physicians. It is always anti-therapeutic to dismiss a patient's suffering (97).

	Summary

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Among the many patients seeking medical care for the presenting complaint of chronic fatigue, very few meet the criteria for CFS: Instead, they are often suffering from depression, anxiety, or overwork. Indeed, patients who do meet the criteria for CFS probably constitute a heterogeneous group with different underlying etiologies. No diagnostic test for CFS yet exists, and only one treatment has been proven to be beneficial. While the pathophysiology is still obscure, there is growing evidence that abnormal, objective biologic processes are present in many patients with CFS—in particular, subtle abnormalities of the CNS, chronic activation of the immune system, and reactivation of several latent viruses.

Annu. Rev. Med. 1998. 49:1-13
Copyright \copyright\ 1998 by Annual Reviews Inc. All rights reserved
0066-4219/98/0201-0001

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