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Chronic Fatigue Syndrome

(Systemic Exertion Intolerance Disease; SEID; Myalgic Encephalomyelitis; ME/CFS)


Stephen Gluckman

, MD, Perelman School of Medicine at The University of Pennsylvania

Last full review/revision Mar 2020| Content last modified Mar 2020

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

Although as many as 25% of people in the United States report being chronically fatigued, 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 described among young and middle-aged women but has been noted 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 of Chronic Fatigue Syndrome

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, none provide adequate sensitivity and specificity for defining CFS. They do, however, underscore the physiologic legitimacy of 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 of Chronic Fatigue Syndrome

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

Onset is usually abrupt, often following a psychologically or medically stressful event. 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 typically worsens with exertion but is alleviated poorly or not at all by rest. Patients often also have disturbances of sleep and cognition, such as memory problems, "foggy thinking," hypersomnolence, and a feeling of having had unrefreshing sleep. Important general characteristics are diffuse pains and sleep problems.

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.

Because patients typically appear healthy, friends, family, and even health care practitioners sometimes express skepticism about their condition, which can worsen the frustration and/or depression patients often feel about their poorly understood disorder.

Diagnosis of Chronic Fatigue Syndrome

  • 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. Any abnormal physical findings or laboratory tests must be evaluated and alternative diagnoses that cause those findings and/or the patient's symptoms excluded before the diagnosis of CFS can be made. The case definition is often useful but should be considered an epidemiologic and research tool and in some circumstances 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 complete blood count and measurement of electrolytes, blood urea nitrogen, creatinine, erythrocyte sedimentation rate, and thyroid-stimulating hormone. If indicated by clinical findings, further testing in selected patients may include chest x-ray, sleep studies, 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 situations, pretest probability is low and so the risk of false-positive results is high. This can result in incorrect diagnoses, additional unnecessary testing, and inappropriate treatments.

In February 2015, the Institute of Medicine (now the Health and Medicine Division of The National Academies of Science, Engineering, and Medicine ["the National Academies"]) 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. In addition, the review clearly emphasized the validity of this debilitating disease.

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 months 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.

Prognosis for Chronic Fatigue Syndrome

Most patients improve over time though often not back to their pre-illness state. That time is typically years and improvement is often only partial. Some evidence indicates that earlier diagnosis and intervention improve the prognosis.

Treatment of Chronic Fatigue Syndrome

  • Acknowledgment of patient's symptoms
  • Sometimes cognitive-behavioral therapy
  • Sometimes graded exercise, limited to avoid a setback
  • 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 not malingerers but are suffering and strongly desire a return to their previous state of health. For successful management patients 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 have been helpful in some studies but not in others (1, 2). They should be considered for patients who are willing to try them and have access to the appropriate services. Depression is common and expected in any patient with a disability. This should be treated with antidepressants and/or psychiatric referral. Sleep disturbances should be aggressively managed with relaxation techniques and improved sleep hygiene (see table Approach to Patient, 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. Treatment for orthostatic hypotension may also be helpful.

Unproven or disproven treatments, such as antivirals, immunosuppressants, elimination diets, and amalgam extractions, should be avoided.

Treatment references

  • 1. Vink M, Vink-Niese A: Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychol Open 5(2):2055102918805187, 2018. doi:10.1177/2055102918805187.
  • 2. Larun  L, Brurberg  KG, et al: Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews Issue 10. Art. No.: CD003200, 2019. doi: 10.1002/14651858.CD003200.pub8.

Key Points

  • Chronic fatigue syndrome (CFS) is life-altering fatigue lasting > 6 months 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 perhaps try cognitive-behavioral therapy and/or graded exercise.
  • Use drugs as needed to treat specific symptoms (eg, pain, depression, insomnia).

More Information

  • Centers for Disease Control and Prevention: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Drugs Mentioned In This Article

Drug Name Select Trade
amitriptyline No US brand name
pregabalin LYRICA
gabapentin NEURONTIN
duloxetine CYMBALTA

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