Chronic fatigue syndrome (CFS) is defined as long-standing, severe, disabling fatigue without demonstrable muscle weakness. Underlying disorders that could explain the fatigue are absent. Depression, anxiety, and other psychologic diagnoses are typically absent. Treatment is psychologic support, often including antidepressants, and limited rest.

This definition of chronic fatigue syndrome (CFS) has several variants, and heterogeneity among patients who meet the criteria of this definition is considerable. Prevalence is impossible to state precisely; it is usually estimated to be between 7 and 38/100,000 people. However, a recent telephone survey found the prevalence to be many times higher. Prevalence estimates may vary because of differences in diagnostic evaluation, physician-patient attitudes, social acceptability, risk of exposure to an infectious or toxic agent, or definition and case finding. CFS occurs slightly more often in women. In office-based studies, prevalence is highest among whites. However, community surveys indicate a higher prevalence among blacks, Hispanics, and American Indians than among whites.

Etiology

Etiology is controversial, and the precise cause remains unknown. Psychologic factors may be the cause in an unknown percentage of cases; however, CFS seems to be distinct from typical depression, anxiety, or other psychologic disorders. A chronic viral infection has been proposed as a cause because many patients relate onset of CFS to an acute bout of Lyme disease, mononucleosis, influenza, Q fever, Ross River virus, parvovirus, and other infectious diseases. Epstein-Barr virus has also been proposed as a cause, but immunologic markers of exposure do not appear to be sensitive or specific. Other possible but unproven viral causes include rubella, HIV, enteroviruses, human herpesvirus 6, and human T-cell lymphotropic virus. Allergic reactions have also been proposed; about 65% of patients report previous allergies, and the rate of cutaneous reactivity to inhalants or foods is 25 to 50% higher in this group than in the general population.

Various immunologic abnormalities have been reported. They include low levels of IgG, decreased lymphocytic proliferation, low interferon-γ levels in response to mitogens, and poor cytotoxicity of natural killer cells. Some patients have abnormal IgG, with circulating autoantibodies and immune complexes. Many other immunologic abnormalities have been studied; none provides adequate sensitivity and specificity for defining CFS. Additionally, no consistent or readily reproducible pattern of immunologic abnormalities has been identified.

Other proposed mechanisms include neuroendocrine abnormalities, abnormal levels of neurotransmitters, inadequate cerebral circulation, prolonged bed rest, undernutrition, and elevated levels of ACE.

Data indicate that relatives of patients with CFS have an increased risk of developing the syndrome, suggesting a familial or genetic component.

Some researchers believe the syndrome ultimately will prove to have multiple causes, including genetic predisposition and exposure to microbial agents, toxins, and other physical and emotional traumas.

Symptoms and Signs

Onset is usually abrupt, and many patients report an initial viral-like illness with swollen lymph nodes, extreme fatigue, fever, and upper respiratory symptoms. The main symptom is severe fatigue (usually for ≥ 6 mo) that interferes with daily activities (Table 1: Syndromes of Uncertain Origin: Diagnostic Criteria for Chronic Fatigue Syndrome for usual symptoms and signs).

Usually, no signs of muscle weakness, arthritis, neuropathy, or organomegaly are present. However, some definitions require the presence of low-grade fever, nonexudative pharyngitis, or palpable or tender lymph nodes.

Table 1
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Diagnostic Criteria for Chronic Fatigue Syndrome Unexplained, persistent, or relapsing chronic fatigue with all of the following characteristics: Lasts for ≥ 6 mo Is new or has a definite onset Is not due to ongoing exertion Is not substantially alleviated by rest Substantially reduces occupational, educational, social, or personal activities At least 4 of the following for ≥ 6 mo*: Impaired short-term memory (self-reported) severe enough to substantially reduce occupational, educational, social, or personal activities Sore throat Low-grade fever Tender, enlarged, painful cervical or axillary lymph nodes Muscle pain Abdominal pain Multijoint pain without joint swelling or tenderness (arthralgia) Headaches that are new in type, pattern, or severity Unrefreshing sleep Postexertional malaise lasting > 24 h Cognitive difficulties (especially with concentrating and sleeping) *Must not predate the fatigue. Data from the Centers for Disease Control and Prevention, the National Institutes of Health, and the International Chronic Fatigue Study Group.

Diagnosis

• Clinical criteria

Because there is no definitive diagnostic test, diagnosis is by clinical criteria (see Table 1: Syndromes of Uncertain Origin: Diagnostic Criteria for Chronic Fatigue Syndrome). However, because multiple definitions exist, the criteria are not agreed on universally and should not always be strictly applied to individual patients. The criteria are more useful for epidemiologic and clinical studies than for excluding the diagnosis in individual patients. Further evaluation aims to exclude treatable disorders. A reasonable assessment includes CBC and measurement of electrolytes, ESR, and thyroid-stimulating hormone. In some cases, chest x-ray and tests for antinuclear antibody, rheumatoid factor, hepatitis, and HIV should be added. Other viral antibody and other expensive tests are unlikely to shed light on the diagnosis or cause. Obvious depression or severe anxiety excludes the diagnosis of CFS.

Treatment

• Sometimes nonsedating antidepressants
• Sometimes psychologic intervention, physical rehabilitation, and/or regular exercise
• Avoidance of prolonged rest

Nonsedating antidepressants are commonly prescribed, although their value is undetermined. Antiviral treatments with acyclovirSome Trade Names
ZOVIRAX
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and amantadineSome Trade Names
SYMMETREL
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do not seem effective. ValganciclovirSome Trade Names
VALCYTE
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is under study. Studies of immunologic treatments, including high-dose immune globulins, dialyzable WBC extract, amphigen, interferons, isoprinosine, and corticosteroids, have been inconclusive and mostly disappointing. Dietary supplements and high-dose vitamins are commonly used, but their usefulness has not been substantiated.

Psychologic intervention (eg, individual or group therapy) may help some patients as may formal, structured physical rehabilitation programs. Regular aerobic exercise (eg, walking, swimming, cycling, jogging) under close medical supervision may reduce fatigue and improve physical function.

Persistent or prolonged rest should be firmly discouraged because it can worsen deconditioning and promote progressive frailty.

Symptoms tend to lessen over time.

Last full review/revision December 2008 by Margaret-Mary G. Wilson, MD

Content last modified February 2012