Although as many as 25% of people in the United States report being chronically fatigued Fatigue Fatigue is difficulty initiating and sustaining activity due to a lack of energy and accompanied by a desire to rest. Fatigue is normal after physical exertion, prolonged stress, and sleep deprivation... read more (1 References Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) is a syndrome of life-altering fatigue lasting > 6 months that is unexplained and is accompanied... read more ), only about 0.5% of people meet criteria for having CFS (2 References Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) is a syndrome of life-altering fatigue lasting > 6 months that is unexplained and is accompanied... read more ). 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 Fibromyalgia Fibromyalgia is a common, incompletely understood nonarticular, noninflammatory disorder characterized by generalized aching (sometimes severe); widespread tenderness of muscles, areas around... read more , such as sleep disorders, mental cloudiness, fatigue, pain, and exacerbation of symptoms with activity.
1. Galland-Decker C, Marques-Vidal P, Vollenweider P: Prevalence and factors associated with fatigue in the Lausanne middle-aged population: a population-based, cross-sectional survey. BMJ Open 9(8):e027070, 2019. Published 2019 Aug 24. doi:10.1136/bmjopen-2018-027070
2. Valdez AR, Hancock EE, Adebayo S, et al: Estimating prevalence, demographics, and costs of ME/CFS using large scale medical claims data and machine learning. Front Pediatr 6:412, 2019. doi:10.3389/fped.2018.00412
Etiology of Chronic Fatigue Syndrome
Etiology of CFS is unknown. No infectious, hormonal, immunologic, or psychological 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. People with CFS are not at increased risk for opportunistic infections.
Some people who have recovered from COVID-19 infection COVID-19 COVID-19 is a respiratory illness caused by the novel coronavirus SARS-CoV-2. Infection may be asymptomatic or have symptoms ranging from mild upper respiratory symptoms to acute respiratory... read more have become "long-haulers" with persistent symptoms. Some of these symptoms result from organ damage from the infection and/or treatment, and others may be from posttraumatic stress disorder (PTSD) Posttraumatic Stress Disorder (PTSD) Posttraumatic stress disorder (PTSD) is a disabling disorder that develops after exposure to a traumatic event. It is characterized by intrusive thoughts, nightmares, and flashbacks; avoidance... read more . In addition, in some patients, COVID-19 seems to trigger typical CFS. This association is being actively studied.
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. Generalized pain is also a common complaint.
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 professionals 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
Laboratory evaluation to exclude non-CFS disorders
The diagnosis of CFS is made by the characteristic history combined with a normal physical examination and normal laboratory test results. Any abnormal physical findings or laboratory results 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 Testing Almost half of all people in the US report sleep-related problems. Disordered sleep can cause emotional disturbance, memory difficulty, poor motor skills, decreased work efficiency, and increased... read more , and testing for adrenal insufficiency Diagnosis Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more . 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 (see table ). In addition, the review clearly emphasized the validity of this debilitating disease. Referring the patient and family members to this document can help improve their understanding and emphasize the validity of their often disabling disease.
Diagnostic Criteria for Chronic Fatigue Syndrome*
Diagnosis requires that the patient have the following 3 symptoms:
At least one of the following manifestations is also required:
* 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 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Treatment of Chronic Fatigue Syndrome
Acknowledgment of patient's symptoms
Sometimes cognitive-behavioral therapy
Sometimes graded exercise, limited to avoid a setback
Medications for depression, sleep, or pain if indicated
To provide effective care to patients with CFS, 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 Treatment references Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) is a syndrome of life-altering fatigue lasting > 6 months that is unexplained and is accompanied... read more , 2 Treatment references Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) is a syndrome of life-altering fatigue lasting > 6 months that is unexplained and is accompanied... read more ). 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 ).
If these measures are ineffective, hypnotic medications and/or referral to a sleep specialist may be necessary. Patients with pain (usually due to a component of fibromyalgia Fibromyalgia Fibromyalgia is a common, incompletely understood nonarticular, noninflammatory disorder characterized by generalized aching (sometimes severe); widespread tenderness of muscles, areas around... read more ) can be treated using a number of medications such as pregabalin, duloxetine, amitriptyline, or gabapentin. Physical therapy is also often helpful. Treatment for orthostatic hypotension Treatment Orthostatic (postural) hypotension is an excessive fall in blood pressure (BP) when an upright position is assumed. The consensus definition is a drop of > 20 mm Hg systolic, > 10 mm Hg... read more may also be helpful.
Unproven or disproven treatments, such as antivirals, immunosuppressants, elimination diets, and amalgam extractions, should be avoided.
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
Prognosis for Chronic Fatigue Syndrome
Most patients with CFS 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.
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 psychological 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 medications as needed to treat specific symptoms (eg, pain, depression, insomnia).
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Centers for Disease Control and Prevention: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: General information about CFS symptoms and treatment and ongoing CFS research
Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Lyrica, Lyrica CR|
|Cymbalta, Drizalma, Irenka|
|Elavil, Tryptanol, Vanatrip|
|Active-PAC with Gabapentin, Gabarone , Gralise, Horizant, Neurontin|