Version May 2024
INTRODUCTION — Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is an illness of uncertain cause. While underlying objective findings involving the central and autonomic nervous systems, the immune system, and energy metabolism have been described, these objective abnormalities have not yet led to a clear understanding of pathophysiology or to a diagnostic test of adequate sensitivity and specificity [1].
The condition has long been recognized, and many different terms have been used to describe it (eg, DaCosta's syndrome, effort syndrome, soldier's heart, neurasthenia, myalgic encephalitis/encephalomyelitis, Iceland disease, Akureyri disease, Royal Free disease, and chronic fatigue and immune dysfunction syndrome) [2,3].
The clinical manifestations and diagnosis of CFS are reviewed here. The general approach to a patient with fatigue and the treatment of CFS are discussed separately. (See "Approach to the adult patient with fatigue" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)
DEFINITION — There are multiple case definitions for CFS, and these have changed over time [4-9]. The Institute of Medicine (IOM; now known as the National Academy of Science) diagnostic criteria focus on the most specific features of the disease. As with previous definitions, symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least one-half of the time. In addition to fatigue, other criteria include: post-exertional malaise, unrefreshing sleep, cognitive impairment, and orthostatic-related symptoms.
These clinical case definitions are standard epidemiologic tools employed when there is no diagnostic test for a specific disorder. They are "intentionally restrictive, to maximize the chances that research studies will detect significant associations if such associations truly exist" [7]. Although a clinical case definition is a well-established instrument, its strict application may not always be appropriate in the evaluation of a specific patient.
EPIDEMIOLOGY — While fatigue is a very common presenting complaint in primary care practice, patients meeting formal case definitions of CFS are unusual. The prevalence of CFS is uncertain, in part due to difficulties in establishing the diagnosis; however, using the clinical case definition allows for some estimates. In one study of 1000 consecutive patients in a primary care clinic, for example, 8.5 percent had debilitating fatigue of at least six months' duration without apparent cause; however, only 15 percent of these patients satisfied the clinical definition for CFS [10].
In resource-rich settings, studies have reported that approximately 10 to 25 percent of patients seen in primary care practices complain of chronic fatigue [11,12]. A similar population-based survey in India found that 12 percent of patients complained of fatigue for at least six months [13]. (See "Approach to the adult patient with fatigue".)
CFS represents a very small subset of those who complain of chronic fatigue [10,14]. A random digit-dialing survey in Wichita, Kansas estimated the point prevalence of CFS to be 235 per 100,000; a one-year telephone survey follow-up among those not fatigued or fatigued for <6 months found the incidence of CFS to be 180 per 100,000 [15]. Similar findings were noted in a prospective cohort study of over 4000 patients in a health maintenance organization; the estimated crude point prevalence of CFS ranged from 75 to 267 cases per 100,000 persons; the point prevalence of chronic fatigue not meeting the syndromic definition was strikingly higher, ranging from 1775 to 6321 cases per 100,000 persons [14]. Thus, even among patients with fatigue of at least six months' duration, the prevalence of CFS is well under 10 percent [10,14].
CFS is primarily a disorder of young to middle-aged adults, but cases in children have been recognized. It may also occur in older adults, although coexisting medical conditions usually preclude its consideration in this population. Most series report that CFS is about twice as common in women as in men [16-18]. While relatively fewer people from lower socioeconomic groups or minority populations seek care for this illness, a community-based study of nearly 17,000 people conducted by the United States Centers for Disease Control and Prevention (CDC) found that the prevalence of the illness was actually higher in such people [19]. Thus, the incidence in these groups may be underestimated due to their lack of equivalent access to health care institutions in which CFS is studied.
Cases of CFS usually arise in a sporadic manner, although closely related (if not identical) illnesses have occurred in outbreaks [20-25]. Other names for these types of outbreaks include epidemic neuromyasthenia and myalgic encephalomyelitis [22,23]. However, careful investigations of a putative "cluster" of CFS cases failed to reveal that there was a true epidemic [24].
Synthesizing all of the epidemiologic studies of CFS, the Institute of Medicine of the US National Academy of Sciences has estimated that there are between 836,000 and 2.5 million people in the United States with CFS, and that the direct and indirect economic costs of the illness range from USD $17 to 24 billion, annually [9].
PROPOSED ETIOLOGIES — Considerable effort has gone into investigating possible causes of CFS. Among the many possible precipitants, the ones that have been most thoroughly studied are viruses, immune dysfunction, endocrine-metabolic dysfunction, and neuropsychiatric factors.
Infection — There has been intense interest in whether certain viruses could be responsible for causing CFS, including Epstein-Barr virus (EBV), retroviruses, and others. No infectious agent has been proven to cause CFS. Nonetheless, many patients attribute their symptoms to a viral infection.
Viral infections
●Epstein-Barr virus – EBV received a great deal of attention in the mid-1980s as a possible etiologic agent for CFS. This hypothesis was based upon three observations. First, EBV persists for life and reactivates frequently, thereby affording the virus the biologic potential for chronic illness. Second, patients with CFS were often found to possess higher than expected titers of antibodies to EBV capsid and early antigens, or to lack antibodies to EBV nuclear antigens (EBNA), each suggestive of recent or active infection. Third, some patients clearly attributed the onset of their illness to a mononucleosis-like infection. Several studies have documented that CFS can develop following a well-documented case of mononucleosis or primary EBV infection not producing full-blown mononucleosis [26,27]. Thus, primary infection with the virus appears capable of triggering the illness. However, there is no evidence that chronic EBV infection is responsible for ongoing, chronic symptoms.
Most studies have found higher levels of certain antibodies to EBV antigens in patients with CFS compared with matched healthy control subjects. However, that does not prove a causal relationship. Indeed, one possible explanation is that the higher level of antibodies against EBV is an epiphenomenon reflecting subtle immune dysfunction.
●SARS-CoV-2 – Some patients can develop post-coronavirus disease 2019 (COVID-19) conditions following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of illness severity. This has been referred to as "long-COVID," "post-COVID," "long-haul Covid," and other terms.
Such patients present with a broad range of symptoms (physical and mental) that develop during or after COVID-19, continue for ≥3 months following the onset of illness, and are not explained by an alternative diagnosis [28]. There are probably a number of different mechanisms involved in the genesis of these clinical manifestations, including tissue damage from the infection as well as treatment, post-traumatic stress disorder (PTSD), and post-intensive care unit (ICU) syndrome. In addition, many patients with post-COVID-19 conditions fit the criteria for CFS with SARS-CoV-2 being the viral trigger.
Post-COVID-19 symptoms are discussed in detail in a separate topic review. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)
●Retroviruses – Several studies reported finding evidence of novel exogenous retroviruses in patients with CFS [29-31]. However, subsequent studies have failed to confirm those reports [32-34], and several of the original reports have been retracted [35,36]. Another report failed to find that a human endogenous retrovirus (HERV) transcript, one that has been incriminated in other illnesses, was playing a role in CFS [37]. HERVs are ancient retroviruses that infected human germ line cells and became permanently integrated into the genome [37]. HERV genes are usually silenced but can become activated in response to viral infections.
●Other viruses – In addition to EBV, a number of other viruses have been proposed as a cause of CFS, although the published evidence is inconsistent. These include human herpesvirus type 6 (HHV-6), enteroviruses, Ross river virus, and Borna disease virus [26,38].
Bacterial infections — A syndrome similar to CFS has been reported following classical Lyme disease that has been promptly treated [26,39]. (See "Clinical manifestations of Lyme disease in adults".)
A syndrome similar to CFS also has been reported following Q fever [26,40]. Further information regarding Q fever can be found on the United States Centers for Disease Control and Prevention website [41,42].
Immune system differences — True immune deficiency is not a feature of this syndrome. Persons with CFS are not at increased risk for opportunistic infections. Some immunologic differences between persons with CFS and healthy controls have been reported, although their clinical significance is not yet clear.
The most frequently reported include depressed natural killer (NK) cell function [43], low levels of autoantibodies (often directed at targets in the nervous system) [44], increased numbers of activated CD8+ T cells [45], and increased levels of cytokines that correlate with CFS symptom severity [46,47]. A widely held hypothesis is that activation of the immune system in the brain leads to production of cytokines, and that the cytokines produce the symptoms of the illness [48,49].
Endocrine-metabolic dysfunction — A number of metabolic abnormalities have been described in CFS, but their causal role is unclear. Metabolic abnormalities that have been associated with CFS include:
●A hypometabolic state (akin to hibernation) [50]
●Abnormalities in the pathways converting sugars, lipids, and amino acids to energy [51-53]
●Decreased serum cortisol and undersecretion of corticotropic-releasing hormone [54]
●Increased levels of insulin-like growth factor [55]
●Abnormalities in central nervous system serotoninergic activity [56]
However, some of these changes are not specific for CFS since similar neuroendocrine abnormalities are seen in patients with fibromyalgia [57], in other syndromes with atypical depressive features [58], and after an alteration in sleep pattern in otherwise healthy subjects [59]. Furthermore, some studies have not confirmed a defect in the pituitary-adrenal axis in patients with CFS [60].
Neurally mediated hypotension — One study suggested that neurally mediated hypotension might play an important role in CFS symptoms. In this report, 23 subjects with CFS underwent tilt-table testing: 22 were found to have an abnormal test (compared with 4 of 14 unmatched controls) [61]. Those patients with a positive test were treated with escalating doses of fludrocortisone, atenolol, and disopyramide; almost all reported complete or partial resolution of symptoms. In a subsequent study of 600 patients with CFS from the same investigators, 77 percent of patients were found to have an abnormal tilt-table test [62]; however, no control group was mentioned.
A group from Israel developed a hemodynamic instability score in association with tilt testing and found that patients with CFS had positive scores or were unable to complete the test due to changes in blood pressure or heart rate, while patients with other conditions, such as chronic fatigue that did not meet CFS definitions, fibromyalgia, neurally mediated syncope, and familial hypertension, and otherwise healthy subjects, had negative scores [63]. The study was not blinded and control patients were not matched with CFS subjects.
Although these results appear intriguing, these early studies were not placebo-controlled, blinded, or randomized. A study in 21 pairs of monozygotic twins, in which one of the set had CFS and one did not, found abnormal tilt-table tests in 19 percent of those with CFS and 19 percent of those without [64]. In addition, a preliminary blinded study of 20 individuals with CFS who had not undergone tilt-table testing found that low-dose fludrocortisone (0.1 to 0.2 mg) did not provide any benefit compared with placebo after six weeks of therapy [65]. Thus, the role of neurally mediated hypotension in CFS is unclear.
Depression — The role of depression in CFS is controversial. Depression and anxiety are generally felt to occur as a consequence of CFS, although some studies have asserted that the fatigue results from depression [26,66].
Three observational studies verified that two-thirds or more of patients with CFS met existing psychiatric criteria for anxiety disorders, dysthymia, or depression after becoming ill [67-69]; however, they did not determine what fraction of the patients had suffered from depression before becoming ill with CFS. Even if depression is not the underlying cause but rather a consequence of CFS, it should be aggressively treated so that the patient can better manage CFS.
Sleep disruption — Sleep disruption has been proposed as a possible cause of CFS. A small study showed that CFS patients had significant differences in polysomnographic findings and felt sleepier than controls after a night's sleep [70]. CFS patients had less total sleep time, lower sleep efficiency, and less rapid eye movement (REM) sleep than controls. The findings in the CFS group could neither be attributed to diagnosable sleep disorders nor to fibromyalgia.
Genetic studies — Data generated from 227 patients with CFS who underwent detailed clinical evaluations, measurements of sleep physiology, cognitive function, autonomic nervous system function, and blood analyses of the sequence and expression of 20,000 genes have linked CFS to certain genes involved in immune and stress responses [71,72]. The following findings were noted in CFS patients compared with controls:
●Different levels of expression of genes with roles in the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system; functionally, these led to differences in how the body responds to hormones and other chemical messengers that are released in response to challenges and stressors, such as trauma, injury, and other adverse events [71].
●DNA sequence changes in three genes associated with brain function, stress reactions, and emotional responses [72].
Additional studies have identified further potential genetic differences in persons with CFS when compared with asymptomatic controls [73-75]. These findings suggest the possibility that there is not a single cause of CFS, but that there may be a number of different stressors, physical and emotional, that could trigger the illness in those with a genetic predisposition. These studies are the strongest evidence for a biologic basis for CFS and may help to more effectively diagnose and develop effective treatments for this disease.
CLINICAL PRESENTATION
Common symptoms — CFS is not a homogeneous disorder. Certain features are common to nearly all affected patients, while other subjective symptoms fluctuate with time but do not appear to progress (table 1) [16-18].
Key clinical features include:
●Onset that may be sudden, often associated with a typical infection such as an upper respiratory infection or mononucleosis, or gradual over several months.
●Overwhelming fatigue associated with additional symptoms (eg, altered sleep and cognition).
●Symptoms characteristically exacerbated by excessive physical activity.
●A pre-CFS medical history that is not one of multiple somatic problems (eg, chronic backache or chronic headache). Affected patients are typically highly functioning individuals who are "struck down" with this disease.
Examination findings — Once the inciting illness (if any) is resolved, the physical examination typically is normal.
●Although patients commonly feel febrile, few ever demonstrate elevated temperatures).
●Joints ache (arthralgia), but there are no objective signs of arthritis (ie, no erythema, effusion, or limitation of motion).
●Although the muscles are easily fatigued, strength is normal, as are biopsies and electromyograms.
●Mild cervical and/or axillary lymphadenitis is occasionally noted, and painful lymph nodes (lymphadenia) are a frequent complaint, but not true lymphadenopathy. Biopsied lymph nodes show only reactive hyperplasia. The cervical lymph nodes are involved most commonly, but the axillary lymph nodes may also be affected.
If the examination reveals objective abnormalities, such as inflamed joints, enlarged lymph nodes, or fever, these findings should be thoroughly evaluated to determine the cause. These findings are not consistent with CFS.
There is considerable overlap between CFS and fibromyalgia, and approximately 70 percent of patients with fibromyalgia also meet the criteria for CFS (table 2) [76,77]. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
Many patients with CFS are partially or totally disabled by its manifestations. Some of these patients appear outwardly healthy, which may cause relatives and colleagues to accuse them of malingering. This can cause a vicious cycle of frustration, anger, and depression, compounded by the fact that their disabling symptoms are not visible to others.
CFS in pregnancy — There is little published information about CFS in pregnancy. In a survey of 86 women who had 252 pregnancies before and after a diagnosis of CFS, approximately one-third of patients reported no change, one-third reported improvement, and one-third reported worsening of their symptoms both during and after pregnancy [78]. Pregnancy outcomes were similar before and after the onset of CFS when compared with a large Danish population-based survey. These data are limited by the nature of the survey, which relied on self-reporting, the lack of a healthy comparison group, and the somewhat low survey response rate (63 percent).
DIAGNOSIS AND EVALUATION — We use the 2015 Institute of Medicine (IOM) criteria to diagnose CFS (table 3) [9]. Symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least one-half of the time.
We obtain the following initial laboratory studies in patients with chronic fatigue:
●Complete blood count with differential count
●Chemistries (including glucose, electrolytes, calcium, renal and hepatic function tests)
●Thyroid-stimulating hormone
●Creatine kinase (if muscle pain or weakness is present)
If the history or examination suggest sleep apnea, then we perform a sleep study. If the history or exam suggest adrenal insufficiency, then we evaluate for adrenal insufficiency. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Determining the etiology of adrenal insufficiency in adults".)
We do not perform routine neuroimaging. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) scan abnormalities seem to occur more frequently in patients with CFS than controls; however, these findings are of unknown significance and do not affect diagnosis or management [79,80].
The evaluation of the more general and common problem of chronic fatigue is discussed in detail elsewhere. (See "Approach to the adult patient with fatigue", section on 'Evaluation of chronic fatigue'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Myalgic encephalomyelitis/chronic fatigue syndrome (The Basics)")
●Beyond the Basics topic (see "Patient education: Myalgic encephalomyelitis/chronic fatigue syndrome (Beyond the Basics)")
Additional information for patients with CFS and those caring for them can be obtained from the United States Centers for Disease Control and Prevention:
Centers for Disease Control and Prevention (CDC)
US Department of Health and Human Services
1600 Clifton Rd
Atlanta, GA 30329-4027
Telephone: 800-232-4636
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Myalgic encephalomyelitis/chronic fatigue syndrome".)
SUMMARY
●Overview – Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is an extremely debilitating illness of uncertain cause. While objective findings involving the central and autonomic nervous systems, the immune system, and energy metabolism have been described, these abnormalities have not yet led to a clear understanding of the pathophysiology of this condition or to a diagnostic test of adequate sensitivity and specificity. (See 'Introduction' above.)
●Definition – There are multiple case definitions for CFS, and these have changed over time. Using the Institute of Medicine (now the National Academy of Science) definition, symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least one-half of the time. In addition to fatigue, other criteria include post-exertional malaise, unrefreshing sleep, cognitive impairment, and orthostatic-related symptoms. However, the strict application of this definition may not always be appropriate in the evaluation of a specific patient. (See 'Definition' above.)
●Epidemiology – The US National Academy of Sciences has estimated that there are between 836,000 and 2.5 million people in the United States with CFS. CFS is primarily a disorder of young to middle-aged adults. It is about twice as common in women than in men. Of patients seeking medical care for this condition, relatively few are from minority or lower socioeconomic groups. However, the incidence in these groups may be underestimated due to more limited access to health care institutions in which CFS is studied. (See 'Epidemiology' above.)
●Proposed etiologies – Proposed etiologies for CFS include the following (see 'Proposed etiologies' above):
•Infection – There has been intense interest in whether certain viruses could be responsible for causing CFS, including Epstein-Barr virus (EBV). None have been proven to cause CFS. (See 'Infection' above.)
•Immune dysfunction – CFS may be associated with mild immune dysregulation of uncertain pathogenetic importance. True immune deficiency is not a feature of this syndrome. (See 'Immune system differences' above.)
•Endocrine-metabolic dysfunction – Several metabolic abnormalities have been described in CFS, but their role in causing the symptoms of the illness is unclear. (See 'Endocrine-metabolic dysfunction' above.)
•Depression – Whether depression contributes to the development of CFS is controversial. Nonetheless, depression should be aggressively treated so that the patient can better manage CFS. (See 'Depression' above.)
●Clinical features – CFS is a severely debilitating illness of at least six months' duration that often starts suddenly (typically with an infectious-like illness) but can start more gradually as well. (See 'Common symptoms' above.)
CFS is typically characterized by fatigue and:
•Post-exertional malaise – A prolonged exacerbation of symptoms after physical, cognitive, or orthostatic exertion or stress
•Unrefreshing sleep after sleeping many hours
•Cognitive impairment, exacerbated by exertion or stress
•Orthostatic intolerance – A worsening of symptoms after assuming or maintaining an upright posture, improved by recumbency
•Other symptoms, as summarized in the table (table 1)
The pre-CFS medical history of the patient is not one of multiple somatic problems such as chronic backache or chronic headache. Affected patients are typically highly functioning individuals who are "struck down" with this disease. (See 'Common symptoms' above.)
●Evaluation and diagnosis – There is no diagnostic test for CFS. The diagnosis is based upon history and physical examination findings that meet the 2015 Institute of Medicine (IOM) criteria (table 3) and limited laboratory testing to exclude other causes of fatigue (see 'Examination findings' above and 'Diagnosis and evaluation' above):
•Complete blood count with differential count
•Chemistry screen
•Thyroid-stimulating hormone level
•Creatine kinase (if muscle pain or weakness is present)
•Other tests when clinically indicated (see 'Diagnosis and evaluation' above)
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