The Biology of Chronic Fatigue Syndrome
Anthony L. Komaroff, M.D.
The Epidemiologic Context. The presenting complaint of chronic fatigue is a very common cause of visits to a doctor. Very often, an underlying depression (often with accompanying anxiety) is the cause of chronic fatigue. In our experience, overwork is another very common cause. Well-defined organic conditions such as anemia, hypothyroidism and occult malignancy are the underlying cause chronic fatigue in a small fraction (2-5%) of cases. Chronic fatigue syndrome (CFS) is found in another small fraction of cases (2%).
Symptoms. CFS is an illness with a formal case definition that has been developed with the leadership of the Centers for Disease Control and Prevention. The illness is characterized by at least six months of exceptional fatigue, with several associated chronic symptoms: Impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep, post-exertional malaise.
Patients may be of any age, either sex and from all walks of life: the typical patient is a 35-year old white woman. Often, the onset is sudden, often following an acute "viral" syndrome. Some patients appear to be completely disabled by the symptoms. The impairment in functional status of patients with CFS, as measured by the SF-36 instrument, is comparable to that of patients with congestive heart failure.
Past medical history is notable primarily for a high frequency of atopic or allergic illness (in approximately 50%-80%).
Physical examination is notable for posterior cervical adenopathy in about 35%; and abnormal tests of balance (Romberg and tandem gait) in about 25%.
Laboratory Tests. No single laboratory test has been identified that has both high sensitivity and specificity for CFS; hence, there is no diagnostic test for CFS. However, a growing literature reports a number of objective laboratory findings that clearly distinguish patients with CFS from healthy control subjects (and, in some cases, from comparison group patients with various fatiguing psychiatric and organic diseases). In our experience, several findings are seen more often in patients with CFS: circulating immune complexes (low levels), elevated total complement (CH50), elevated IgG, atypical lymphocytosis, and ANA (low levels).
Neuroendocrine Findings. Many studies have found that patients with CFS, in comparison with healthy control subjects, have a variety of abnormalities of the hypothalamic-pituitary axes. For example, there is reduced hypothalamic production of corticotropin releasing hormone, leading to diminished pituitary release of ACTH, leading to basal hypocortisolism. This axis abnormality is the opposite of what is seen in patients hospitalized for major, melancholic depression. A recent study, using CT, found that the adrenal glands of patients with CFS were half the size of adrenals from healthy control subjects. Neuroimaging. Several different groups have reported that magnetic resonance imaging (MRI) reveals punctate areas of high signal in the white matter, particularly in the subcortical areas, more frequently than in age and gender-matched healthy control subjects. Nevertheless, these findings are neither very sensitive nor specific. MRI is not recommended for the diagnosis of CFS, although it can be useful in pursuing the diagnosis of multiple sclerosis. MS is sometimes in the differential diagnosis, since patients with MS often present with prominent fatigue, paresthesias, visual blurring, and other symptoms suggestive of CFS, and since some patients (about 10%, in our experience) with CFS have had a transient focal neurologic deficit.
Single-photon emission tomography (SPECT) also reveals defects of perfusion and/or metabolism much more often in patients with CFS than in healthy control subjects. Depression also produces SPECT scan abnormalities; however, most studies indicate that SPECT abnormalities occur more often in CFS than in depression. SPECT is not recommended for the diagnosis of CFS. Autonomic Nervous System Testing. Studies from Johns Hopkins, Harvard and other institutions find evidence of both sympathetic and parasympathetic neuropathy in patients with CFS. Clinically, many patients meet criteria for neurally-mediated hypotension and postural tachycardia syndromes.
Studies of Infectious Agents. No infectious agent has been convincingly shown to be a cause of CFS, and most investigators think it is unlikely that a single novel agent is the cause. Nevertheless, there is evidence from several controlled studies of the reactivation of several chronic viral infections in CFS. In our opinion, the evidence is strongest for human herpesvirus-6, a neurotropic and immunotropic virus. CFS has been documented following a variety of acute infections with viruses (such as following acute infectious mononucleosis), bacteria (such as following properly-treated Lyme disease), and other microbial infections (such as following Q fever).
Immunological Studies. A variety of other immunologic abnormalities have been reported, especially impaired function of natural killer cells and increased numbers of activated CD8+ T cells. Neither of these two abnormalities, however, is adequately sensitive or specific to constitute a diagnostic test. They are consistent with the hypothesis that the immune system is chronically activated in patients with CFS.
Recently, two groups have reported what appears to be a more specific immune system abnormality in CFS: increased activity of the 2-5A pathway enzymatic pathway in lymphocytes. Patients with CFS were very different from patients with major depression, fibromyalgia or healthy control subjects. Further studies are needed to determine if this test is adequately sensitive and specific to constitute a diagnostic test. At this time, it is still experimental.
Psychiatric Issues. Probably only a small fraction of patients who seek medical care for fatigue have CFS; most fatigued patients probably suffer from depression or overwork. Of the few patients with chronic fatigue who meet criteria for CFS, most become depressed and anxious after the onset of the illness, and this depression and anxiety need to be recognized and treated, when present. Most patients with CFS have no prior history of significant psychiatric disease prior to the onset of CFS, according to several careful studies. However, at least 50% of patients develop depression, anxiety or other psychoneurotic disorders in the years after the onset of CFS. One randomized, placebo-controlled, double-blind trial of fluoxetine therapy in patients with CFS found no evidence of benefit: neither the fatigue nor the coexisting depression in some patients got better with fluoxetine.
Treatment. Treatment with low-dose tricyclics (e.g. amitriptyline, 10-20mg q.h.s.) has been proven efficacious in a randomized trial of a clinically similar condition (fibromyalgia), and is widely used in CFS. This treatment improves an objectively documented sleep disorder (alpha intrusion into delta wave sleep) seen in these conditions; results are apparent within days (not weeks) of initiating therapy. Such low doses of tricyclics do not appear to improve any coexisting depression. Recently, some improvement has been reported with the use of cognitive behavioral therapy, in skilled hands, and with slowly graded aerobic exercise programs.
What is CFS? In our view, the evidence above indicates that CFS has an organic basis: in many (but not all) patients, there are abnormalities of the limbic system of the brain and abnormal regulation of the immune system (possibly as a result of limbic system abnormalities). A single cause seems unlikely; multiple different triggering agents (infectious agents, toxins, stress) could be involved in different cases.