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Chronic Fatigue Syndrome

by Stephen Gluckman, MD

Chronic fatigue syndrome (CFS) is a syndrome of life-altering fatigue lasting > 6 mo that is unexplained and is accompanied by a number of associated symptoms. Management includes validating the patient's disability, treating specific symptoms, cognitive behavioral therapy, and a graded exercise program.

Although as many as 25% of people report being chronically fatigued (see Fatigue), only about 0.5% of people meet criteria for having CFS. Although the term CFS was first used in 1988, the disorder has been well described since at least the mid 1700s but has had different names (eg, febricula, neurasthenia, chronic brucellosis, effort syndrome). CFS is most common among young and middle-aged women but has been described in all ages, including children, and both sexes.

CFS is not malingering (intentional feigning of symptoms). CFS does share many features with fibromyalgia (see Fibromyalgia), such as sleep disorders, mental cloudiness, fatigue, pain, and exacerbation of symptoms with activity.


Etiology is unknown. No infectious, hormonal, immunologic, or psychiatric cause has been established. Among the many proposed infectious causes, Epstein-Barr virus, Lyme disease, candidiasis, and cytomegalovirus have been proven not to cause CFS. Similarly there are no allergic markers and no immunosuppression. Various minor immunologic abnormalities have been reported. These abnormalities include low levels of IgG, abnormal IgG, decreased lymphocytic proliferation, low interferon-γ levels in response to mitogens, poor cytotoxicity of natural killer cells, circulating autoantibodies and immune complexes, and many other immunologic findings. However, there is no consistent or reliably reproducible pattern of immunologic abnormalities, and none provide adequate sensitivity and specificity for defining CFS.

Relatives of patients with CFS have an increased risk of developing the syndrome, suggesting a genetic component or common environmental exposure. Recent studies have identified some genetic markers that might predispose to CFS. Some researchers believe the etiology will eventually be shown to be multifactorial, including a genetic predisposition, and exposure to microbes, toxins, and other physical and/or emotional trauma.

Symptoms and Signs

Before onset of CFS, most patients are highly functioning and successful.

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 initial syndrome resolves but seems to trigger protracted severe fatigue, which interferes with daily activities, and many of the other features of the syndrome (see Table: Diagnostic Criteria for Chronic Fatigue Syndrome). Patients are also unusually sensitive to the strains of physical activity and to drugs. Depression is common and is often associated with worsened symptoms.

The physical examination is normal, with no objective signs of muscle weakness, arthritis, neuropathy, or organomegaly. However, some patients have low-grade fever, nonexudative pharyngitis, and/or palpable or tender (but not enlarged) lymph nodes. Any abnormal physical findings must be evaluated and alternative diagnoses that cause chronic fatigue excluded before the diagnosis of CFS can be made.

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.


  • Clinical criteria

The diagnosis is made by the characteristic history combined with a normal physical examination and normal laboratory test results. The CDC case definition is sometimes useful but is mainly an epidemiologic and research tool and should not be strictly applied to individual patients.

Testing is directed at any non-CFS causes suspected based on objective clinical findings. If no cause is evident or suspected, a reasonable laboratory assessment includes CBC and measurement of electrolytes, BUN, creatinine, ESR, and TSH. If indicated by clinical findings, further testing may include chest x-ray and testing for adrenal insufficiency. Serologic testing for infections, antinuclear antibodies, and neuroimaging are not indicated without objective evidence of disease on examination (ie, not just subjective complaints) or on basic testing; in such cases, pretest probability is low and so the risk of false-positive results (and thus unnecessary treatment and/or confirmatory testing) is high.


Most patients improve over time, but that time is typically years and improvement is often only partial. Some evidence indicates that earlier diagnosis and intervention improve the prognosis.


  • Cognitive-behavioral therapy

  • Graded exercise

  • Drugs for depression, sleep, or pain if indicated

To provide effective care, physicians must acknowledge and accept the validity of patients' symptoms. Whatever the underlying cause, these patients are suffering and strongly desire a return to their previous state of health. However, patients need to reframe expectations. They need to accept and accommodate their disability, focusing on what they can still do instead of lamenting what they cannot do.

Cognitive-behavioral therapy and a graded exercise program are the only interventions proven helpful. Depression should be treated with antidepressants and/or psychiatric referral. Sleep disturbances should be aggressively managed with relaxation techniques and improved sleep hygiene (see Table: Sleep Hygiene). If these measures are ineffective, hypnotic drugs and/or referral to a sleep specialist may be necessary. Patients with pain (usually due to a component of fibromyalgia) can be treated using a number of drugs such as pregabalin, duloxetine, amitriptyline, or gabapentin. Physical therapy is also often helpful. Unproven or disproven treatments, such as antivirals, immunosuppressants, elimination diets, and amalgam extractions, should be avoided.

Key Points

  • Chronic fatigue syndrome (CFS) is life-altering fatigue lasting > 6 mo that typically affects previously healthy and active people; it is not malingering.

  • Etiology is unclear but probably involves multiple factors, including genetic susceptibility, microbial exposure, and environmental and psychologic factors.

  • Diagnose CFS based on characteristic symptoms in patients with a normal examination and normal basic laboratory test results; CDC criteria may be helpful but are not strictly applied to individual patients.

  • Validate patients' symptoms, encourage them to accept and accommodate to their disabilities, and treat using cognitive-behavioral therapy and graded exercise.

  • Use drugs as needed to treat specific symptoms (eg, pain, depression, insomnia).

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