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Chronic Fatigue Syndrome

(Systemic Exertion Intolerance Disease; SEID)

By Stephen Gluckman, MD, Professor of Medicine; Medical Director, Perelman School of Medicine at The University of Pennsylvania; Penn Global Medicine

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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 in both sexes.

CFS is not malingering (intentional feigning of symptoms). CFS does share many features with 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-gamma 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. In February 2015, the Institute of Medicine (now the Health and Medicine Division of The National Academies of Science, Engineering, and Medicine) published an extensive review of this disease called Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. In this review they proposed a new name, systemic exertion intolerance disease (SEID), and new diagnostic criteria that simplified the diagnosis and emphasized the most consistent features (see Table: Diagnostic Criteria for Chronic Fatigue Syndrome*). In addition, the review clearly emphasized the validity of this debilitating disease.

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*

Diagnosis requires that the patient have the following 3 symptoms:

  • A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 mo and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest

  • Post-exertional malaise†

  • Unrefreshing sleep†

At least one of the following manifestations is also required:

  • Cognitive impairment†

  • Orthostatic intolerance

*Diagnostic criteria proposed by the Institute of Medicine (now the Health and Medicine Division of The National Academies of Science, Engineering, and Medicine) in February 2015.

†Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.


  • Clinical criteria

  • Laboratory evaluation to exclude non-CFS disorders

The diagnosis is made by the characteristic history combined with a normal physical examination and normal laboratory test results. The 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, sleep studies, and testing for adrenal insufficiency in selected patients. 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 though not necessarily back to their pre-illness state. However, that time is typically years and improvement is often only partial. Some evidence indicates that earlier diagnosis and intervention improve the prognosis.


  • Acknowledgment of patient's symptoms

  • 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; Institute of Medicine (now the Health and Medicine Division of The National Academies of Science, Engineering, and Medicine) 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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