Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

INTRODUCTION — 

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), previously known as chronic fatigue syndrome (CFS), is a chronic, often debilitating illness, characterized by severe fatigue and other symptoms. The name ME/CFS has been adopted by the United States Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the National Academy of Medicine (NAM; previously the Institute of Medicine [IOM]), and the World Health Organization (WHO).

The name "myalgic encephalomyelitis" was given to the illness in the 1950s in response to several outbreaks worldwide. Though inflammation of the central nervous system and spinal cord was thought to be the underlying cause, medical advances to confirm such neuroinflammation were not available at the time. The CDC gave the illness the name chronic fatigue syndrome in its first case definition.

In persons with ME/CFS, multiple underlying abnormalities involving the central and autonomic nervous systems, the immune system, energy metabolism, the cardiovascular system, and the gut microbiome have been described. However, there is only a limited understanding of what triggers the abnormalities and how the abnormalities cause symptoms. In addition, there are no diagnostic tests of adequate sensitivity and specificity to confirm the diagnosis and no proven effective treatments.

The epidemiology, pathophysiology, clinical manifestations, and diagnosis of ME/CFS are reviewed here. The general approach to patients with fatigue and the management of patients with ME/CFS are discussed separately. (See "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome" and "Approach to the adult patient with fatigue".)

DEFINITION — 

There are multiple case definitions for ME/CFS [1-6]. We agree with the widely used case definition put forth by the National Academy of Medicine (NAM; previously the Institute of Medicine [IOM]) that focuses on the most specific features of the disease [6] (table 1).

This case definition requires that the symptoms be present for at least six months and have moderate, substantial, or severe intensity at least half of the time. In addition to fatigue, other essential criteria include profound post-exertional malaise, unrefreshing sleep, cognitive impairment, and orthostatic-related symptoms. (See 'Clinical manifestations' below.)

Clinical case definitions are standard epidemiologic tools employed primarily to assure that patients included in different studies of an illness are clinically similar. However, the strict application of a case definition to make a clinical diagnosis may not always be appropriate in a specific patient, especially if clinical observations suggest alternative diagnoses. (See 'Differential diagnosis' below and 'Evaluation and diagnosis' below.)

EPIDEMIOLOGY — 

Fatigue is a universal human experience. A state of chronic fatigue, severe enough to interfere with a person's ability to function optimally, is reported by 2000 to 6500 per 100,000 adults in the community [7] and is one of the most common presenting complaints in primary care practice [8]. (See "Approach to the adult patient with fatigue".)

In contrast, the fraction of fatigued patients who meet criteria for ME/CFS is well under 10 percent [7,9], even in patients with fatigue of at least six months' duration. (See 'Clinical manifestations' below and 'Evaluation and diagnosis' below.)

Sporadic (endemic) ME/CFS — Most cases of ME/CFS arise in a sporadic manner. The reported prevalence of sporadic ME/CFS ranges widely because of differences in the case definitions used and in the populations being surveyed. The National Academy of Medicine (NAM; previously the Institute of Medicine [IOM]) has estimated that there are between 836,000 and 2.5 million people in the United States with ME/CFS [6].

●Prevalence in specific populations – The point prevalence of ME/CFS in community-based samples, including people who have never sought medical care for fatigue, ranges between 400 and 800 per 100,000 [10-12].

In primary care practice-based samples between 1990 and 2005 (when the illness was not widely known) the point prevalence in adults seeking care for all presenting complaints ranged from 100 to 300 per 100,000 [9,13]. However, in a more recent study, the prevalence in medical practices was estimated to be as high as 1000 per 100,000 [14].

The point prevalence in children is approximately half that in adults and is greater in teenagers than in younger children [15].

●Risk factors – ME/CFS is 1.5 to 3 times more prevalent in females than in males [7,10,11,16-20]. In studies evaluating patients seeking medical care, those with ME/CFS tend to have more education and a higher socioeconomic level; by contrast, community-based studies find that the prevalence is higher in less affluent, African American, and Latinx populations [11,15,21,22]. The incidence in these groups may be underestimated in some samples due to their lack of equivalent access to health care.

Epidemic ME/CFS — Outbreaks of illnesses similar to ME/CFS have been reported all over the world [23-28]. However, it is not possible to know if these conditions share the same pathology with ME/CFS since some of these epidemics occurred decades ago, and patients were not tested for the same underlying abnormalities that have been found in ME/CFS. Names that have been given for the illnesses in these apparent epidemics include epidemic neuromyasthenia, Da Costa syndrome, effort syndrome, soldier's heart, neurasthenia, Iceland disease, Akureyri disease, and Royal Free disease [25,26]. Although enteroviruses have been postulated as a cause of epidemic ME/CFS-like illness, since they are known to spread rapidly in human populations and are neurotropic, the known enteroviruses have not been convincingly linked to such epidemics. (See 'Triggers of disease' below.)

MECHANISMS OF DISEASE — 

Although unique pathologic features have been demonstrated in people with ME/CFS, a complete understanding of the pathophysiology is only just emerging. Current theories hypothesize a role for genetic predisposition, ongoing immune response due to a failure to eradicate a triggering infectious agent, and dysregulation of proinflammatory cytokines [29-31].

Potential contributing factors — Abnormalities involving multiple organ systems have been reported [32,33].

●Central and autonomic nervous system – ME/CFS has been classified as a neurologic disease by the World Health Organization (WHO). Physiologic findings suggesting central and autonomic nervous system involvement include the following [32,34]:

•Cognitive deficits, particularly in attention and reaction time.

•Brain imaging demonstrating reduced cerebral blood flow, increased white matter signal, increased glial cell activation, neuroinflammation, and/or hypometabolic state.

•Down-regulation of the hypothalamic-pituitary-adrenal axis.

•Autonomic dysfunction, often manifested clinically as postural orthostatic tachycardia syndrome (POTS) and orthostatic intolerance.

•Sleep disturbances, including longer sleep latency and reduced sleep efficiency.

•Elevated protein in the cerebrospinal fluid suggesting inflammation.

•Autoantibodies directed at neural targets that correlate with symptom severity.

Though depression and other psychiatric symptoms are common in patients with ME/CFS, the underlying pathophysiology may be distinct from major depression. Studies show patients with ME/CFS have unique electroencephalographic abnormalities that are not present in healthy control subjects or patients with major depression [35,36]. Furthermore, whereas upregulation of the hypothalamic-pituitary-adrenal axis is an established biomarker for major depression, this axis is more commonly downregulated in patients with ME/CFS [37-39].

●Immune system – Persons with ME/CFS may have alternations in their immune system; however, patients with ME/CFS are not considered immunocompromised and are not at increased risk for opportunistic infections.

The most frequently reported immunologic abnormalities include depressed natural killer (NK) cell function [40], low levels of autoantibodies (often directed at targets in the nervous system) [41], B cell activation and expansion [32], increased numbers of activated CD8+ T cells [42], chronic antigenic stimulation and consequent T cell exhaustion in people with long-term illness [34,43-46], and increased levels of cytokines that correlate with ME/CFS symptom severity [43,47].

●Endocrine/metabolic dysfunction – A number of metabolic abnormalities have been described in ME/CFS, although their clinical significance is unclear. These include a hypometabolic state (akin to hibernation) [48]; abnormalities in the pathways converting sugars, lipids, and amino acids to energy [49-51]; undersecretion of corticotropin-releasing hormone with resulting reductions in levels of adrenocorticotropic hormone and serum cortisol [37]; increased levels of insulin-like growth factor [52]; abnormalities in central nervous system serotoninergic activity [53]; and redox imbalance (increased oxidative and nitrosative stress) [29].

The hypometabolic state and broad impairment in generating adenosine triphosphate (ATP) from its sources are unusual in illnesses other than ME/CFS. However, abnormalities in hypothalamic-pituitary-adrenal axis activity are also seen in patients with fibromyalgia [54], and abnormalities in corticotropin-releasing hormone activity have been reported in syndromes with atypical depressive features [55] and after alterations in sleep patterns in otherwise healthy subjects [56].

●Cardiovascular abnormalities – Several cardiovascular abnormalities are found in people with ME/CFS [32]. These include reduced peak VO₂ (diminished exercise capacity) on cardiopulmonary exercise testing (CPET); reduced venous return to the heart on CPET; reduced blood volume; and endothelial dysfunction, both macrovascular and microvascular. Patients with ME/CFS have also been found to have deterioration in performance on the second day of a two-day CPET test compared with healthy controls whose performance improves on the second day [57].

●Dysbiosis of gut microbiome – Several case-control studies have documented a proinflammatory gut microbiome with increased proinflammatory species and decreased anti-inflammatory species. This dysbiosis of the gut microbiota is theorized to weaken the gut-blood barrier, allowing bacterial products (eg, lipopolysaccharide) to enter the circulation and generate systemic inflammation [58-62].

Triggers of disease

●Role of acute infection or injury – ME/CFS may be triggered by an acute infectious illness [63,64]. A persisting illness similar to ME/CFS has been reported following a number of different well-documented viral, bacterial, and protozoal infections [63-65].

In addition, a similar illness has been described following recovery from major noninfectious trauma, often called the post-intensive care syndrome (PICS) [66] (see "Post-intensive care syndrome (PICS) in adults: Clinical features and diagnostic evaluation"). In some patients, other severe stresses can also trigger the onset of ME/CFS [67].

One plausible theory holds that post-acute infection/post-injury syndromes result from the activation of a protective biologic response designed to prioritize available energy (ATP) for the eradication of infection and the healing of injury. This is achieved, in part, by generating symptoms that discourage energy-consuming behavior. As a result, more ATP is available for the immune response. This biological response has been evolutionarily preserved throughout the animal kingdom [32,33].

●Potential genetic predisposition – Studies of both gene structure (polymorphisms) and gene expression comparing people with ME/CFS with healthy control subjects have linked ME/CFS to certain genes involved in immune and stress responses, neurochemistry, energy metabolism, redox balance, and endothelial function [32,33,68-72]. As examples:

•Different levels of expression have been noted in genes with roles in the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system; functionally, these gene expression differences have 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 [68].

•Deoxyribonucleic acid (DNA) sequence changes in three genes associated with brain function, stress reactions, and emotional responses [69].

These findings are more consistent with the theory that ME/CFS involves a dysfunctional response to infection or to other stressors (physical, emotional) and is less supportive of the theory that the illness is caused by a single infectious agent.

A novel technique assessing combinations of multiple polymorphisms has found statistically robust associations and striking similarities between people with ME/CFS and people with long COVID; however, this has not yet been replicated by other laboratories [73,74]. (See "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")".)

●Role of specific pathogens – Many people with ME/CFS say that their chronic illness began with an acute, infectious-like illness characterized primarily by respiratory symptoms, in addition to myalgias, fatigue, fever, adenopathy, and/or other symptoms associated with common viral infections [67].

This history of an "infectious-like" illness at the onset of ME/CFS has led to searches for a single novel infectious agent that might be the cause of all cases. As with many nonspecific respiratory infections, no single, specific inciting agent has been identified. Rather, several infectious agents have been linked to ME/CFS to varying degrees:

•Coronaviruses – Up to 25 percent of people with long COVID also meet the criteria for ME/CFS [75-77]. Such patients have physical and mental symptoms that continue for ≥3 months following the onset of illness and are not explained by an alternative diagnosis [78].

Similar ME/CFS-like illnesses have also been reported following two prior coronavirus outbreaks, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [32]. Additional studies are ongoing to further define similarities and underlying biologic abnormalities between ME/CFS and long COVID [32]. Post-COVID-19 symptoms are discussed in detail in a separate topic review.

•Herpesviruses – Three herpesviruses (Epstein-Barr virus [EBV] and human herpesviruses 6A and 6B [HHV-6A/B]) have been studied in people with ME/CFS. These neurotropic viruses infect most humans early in life and produce lifelong latent infections. Reactivation of long-standing latent infection with these viruses, including reactivation in the brain, has been postulated as a cause of ME/CFS in some patients. Early studies based on antibody testing suggested that these viruses are reactivated more often in people with ME/CFS than in healthy control subjects [16,17,79-82]. More recently, studies have suggested that reactivation of EBV appears to be common in people who developed long COVID versus those who have returned to normal health [83-85].

Although reactivated herpesviruses have been suggested as a cause of ME/CFS, reactivation does not occur in many people with ME/CFS and, if present, does not distinguish if this is causal or a consequence of ME/CFS. Furthermore, antiviral treatment in such patients has not been shown to benefit either disease. (See "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)

With the exception of cases of ME/CFS that follow the onset of acute infectious mononucleosis caused by EBV, new primary infection with these viruses is not likely to trigger ME/CFS. Herpesviruses are also particularly unlikely to cause apparent epidemics of an ME/CFS-like illness since herpesviruses do not spread rapidly through populations.

•Enteroviruses – Enteroviruses have been linked to some cases of ME/CFS. Some [86-88], but not all [89], studies have found enteroviral nucleic acids and proteins in blood, stool, gut, muscle, and cerebrospinal fluid in a subset of people with ME/CFS. One study reported the detection of enteroviral antigen in the stomach mucosa of 135 of 165 (82 percent) people with ME/CFS versus 7 of 34 (20 percent) healthy controls and people with other gastric diseases [87]; however, these results have not been replicated in other published studies. Given conflicting study results, the theory that enteroviruses may cause some cases of ME/CFS remains unproven [90].

•Retroviruses – Several novel retroviruses have been postulated to cause ME/CFS [91-93]. However, subsequent studies have not confirmed those reports [94-96], and two of the original reports have been retracted [97,98].

•Other infectious agents – In addition to the organisms above, a chronic illness similar to ME/CFS has been reported over the past century following a number of different, acute infections with specific viruses (eg, dengue, Ebola, West Nile virus, Ross River virus), bacteria (Borrelia, Coxiella burnetii), and protozoa (Giardia lamblia) [63-65].

CLINICAL MANIFESTATIONS — 

ME/CFS is characterized by fatigue and associated symptoms lasting at least six months and causing a substantial reduction in the person's ability to engage in pre-illness levels of activity, both at home and outside the home (eg, work or school) (table 1).

Variable symptom onset — ME/CFS most often presents in young to middle-aged adults. It may also start in childhood or at an older age, although coexisting medical conditions may make it difficult to confidently diagnose in an older population.

There is no specific pattern regarding the onset of symptoms. In some cases, the onset may be sudden and associated with an "infectious-like" illness with respiratory symptoms, fatigue, myalgias, and sometimes gastrointestinal symptoms, low-grade fevers, and swollen and/or painful lymph nodes. Alternatively, the onset can be gradual, without a clear precipitating event. In either case, people with the illness typically have been functioning at a normal or high level prior to the onset of the illness.

Fatigue is a primary feature — Patients with ME/CFS have new and profound fatigue that is not directly due to exertion nor relieved by rest.

Additional features of fatigue include the following:

●Post-exertional malaise (PEM) – PEM is a hallmark symptom of ME/CFS. It typically starts 12 to 48 hours after physical or cognitive exertion [99,100]. PEM can be profound and can markedly limit a person's ability to function normally. Some patients may not recognize this as a symptom unless asked by their provider.

●Reduced functional status – Most people with ME/CFS report their ability to function is greatly reduced in comparison with what they were able to do before the onset of the illness. Instruments measuring functional status have found that people with ME/CFS are as functionally impaired as people with congestive heart failure, acute myocardial infarction, type 2 diabetes mellitus, multiple sclerosis, and other illnesses [101-103].

Some people can continue to work or go to school and fulfill their primary responsibilities at home. Cycles of waxing and waning symptoms have been reported. Others have been able to continue their pre-ME/CFS activities but on a modified schedule. However, in 25 percent of people, the symptoms are so severe that they are bed-ridden or house-bound most or all of the time and require specialized care [104-107]. More detailed information on assessing disability and providing the necessary supports for persons with ME/CFS are presented separately. (See "Disability assessment and determination in the United States" and "Treatment of myalgic encephalomyelitis/chronic fatigue syndrome".)

Additional symptoms — Certain features are common to nearly all affected patients, although the presence and severity of symptoms may vary:

●Neurocognitive impairment – Patients often report cognitive deficits (often using the term "brain fog"). Formal cognitive testing confirms deficits in attention and reaction time. These may be exacerbated by exertion.

●Orthostatic intolerance – Orthostatic intolerance can manifest not only as lightheadedness, palpitations, or syncope but also as nausea, increased fatigue, or confusion. Assuming or maintaining an upright posture often worsens these symptoms, whereas reclining or foot elevation may provide relief. Symptoms may occur with blood pressure changes below the usual thresholds for orthostatic hypotension.

●Sleep disturbance – Sleep is unrefreshing, often with frequent unexplained interruptions of sleep at night.

●Psychiatric symptoms – Depression and anxiety disorders are present in two-thirds or more of patients with ME/CFS after they become ill [104,108,109]. Pre-existing depression is unlikely to be a risk factor; studies have found that in the years before becoming ill, the prevalence of depression in people with ME/CFS was similar to that of the community at large [105]. A recent Mendelian randomization study of over 800,000 people reported that gene polymorphisms strongly linked to major depressive disorder (MDD) were not found more frequently in people with ME/CFS than in people without the illness: there was no causal relationship between MDD and ME/CFS [110].

Other symptoms that have been reported in people with ME/CFS include headache, sore throat, myalgias, arthralgias (without arthritis), new or worse allergies, abdominal cramps, and unpleasant reactions to alcoholic beverages or psychoactive medications, even in small amounts or low doses [106].

Association with comorbid conditions — Some comorbid conditions occur more often in people with ME/CFS than in the population at large. The more common comorbid conditions include postural orthostatic tachycardia syndrome (POTS), fibromyalgia, Ehlers-Danlos syndrome, temporomandibular joint dysfunction, sicca syndrome, sensory hypersensitivities (light, sound, smell), migraine headaches, small fiber neuropathy, new or worsened allergies, mast cell activation syndrome, food allergies, gut motility dysfunction, irritable bowel syndrome, small intestinal bacterial overgrowth, overactive bladder, endometriosis, and premenstrual syndrome [111].

Examination and laboratory findings — The physical examination in patients with ME/CFS is typically normal.

However, certain abnormalities may be present. These include:

●Orthostatic intolerance may be apparent with blood pressure measurement or when the patient changes position during the visit (eg, from chair to examination table).

●Small, soft, and often nontender nodes in the posterior cervical, posterior auricular, axillary, or inguinal areas.

●Easy fatigability or post-exertional malaise after strength testing, with normal objective strength examination.

Objective abnormalities such as fever, inflamed joints (eg, synovitis), or markedly enlarged or hard lymph nodes are not consistent with ME/CFS. Routine laboratories including complete blood count, comprehensive metabolic panel, and urinalysis are also normal in ME/CFS. If abnormalities are detected, evaluation for alternate etiology should be pursued.

The diagnostic evaluation for a patient with suspected ME/CFS is discussed in further detail below. (See 'History and physical examination' below and 'Laboratory testing' below.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of ME/CFS is broad. Other important causes of fatigue and functional impairment include anemia, thyroid, adrenal and other endocrine disorders, autoimmune conditions, sleep disorders, postural orthostatic tachycardia syndrome (POST), fibromyalgia, and depression or other primary psychiatric conditions. Additional causes of subacute and chronic fatigue are reviewed in the table (table 2).

While some of these alternative diagnoses are excluded during the course of evaluation in patients with suspected ME/CFS, other diagnoses require additional diagnostic testing and need only be performed in selected patients with suggestive features. The evaluation of these associated conditions is discussed in associated topic reviews separately.

●(See "Diagnostic approach to anemia in adults".)

●(See "Clinical manifestations of hypothyroidism" and "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

●(See "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults".)

●(See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis".)

●(See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●(See "Postural tachycardia syndrome".)

●(See "Fibromyalgia: Clinical manifestations and diagnosis in adults".)

●(See "Approach to the adult patient with suspected depression".)

EVALUATION AND DIAGNOSIS

Overview of diagnostic approach — ME/CFS should be suspected in patients with fatigue and reduced ability to engage in pre-illness levels of activities for at least six months, with associated post-exertional malaise (PEM), neurocognitive impairment, and/or orthostatic intolerance. Symptoms should have moderate, substantial, or severe intensity at least half of the time. A clinical diagnosis of ME/CFS requires the fulfillment of these symptom-based diagnostic criteria and a limited evaluation to exclude underlying organic disease.

ME/CFS is a relatively rare cause of the more general and common complaint of chronic fatigue. The evaluation of chronic fatigue in the absence of PEM, neurocognitive impairment, orthostatic intolerance, or other features suggestive of ME/CFS is discussed in detail separately. (See "Approach to the adult patient with fatigue", section on 'Evaluation of chronic fatigue'.)

Diagnostic criteria — We use the 2015 National Academy of Medicine (NAM; previously the Institute of Medicine [IOM]) criteria to diagnose ME/CFS (table 1) [6]. These facilitate the standardization of the diagnosis of ME/CFS in the absence of a diagnostic test.

History and physical examination — The medical history serves to identify clinical manifestations of ME/CFS and other possible causes of similar symptoms.

●History – We perform a thorough history with particular attention to the timeline and onset of symptoms. The history should include a medication review to identify medications that may contribute to orthostatic symptoms or neurocognitive symptoms (table 3 and table 4).

A detailed review of systems with specific attention to fatigue, memory and neurocognitive symptoms, life stressors, and psychiatric symptoms should be performed to distinguish primary memory or psychiatric conditions from ME/CFS (table 2 and table 5). Standardized tools for assessing fatigue and depression may be helpful (table 6 and table 7).

We also perform a detailed sleep history, including attention to features suggestive of obstructive sleep apnea (table 8).

●Physical examination – The physical examination is usually normal in patients with ME/CFS. When patients have symptoms of orthostatic intolerance, we document orthostatic vital signs, paying careful attention to associated symptoms [112,113].

The NASA Lean Test assists with diagnosing orthostatic intolerance in the clinical setting [114]:

•The patient should rest quietly in the supine position for 5 to 10 minutes without shoes or socks.

•Measure blood pressure and heart rate in the supine position.

•The patient is then instructed to stand, position their heels six inches from the wall, and lean backward, resting the shoulder blades against the wall.

•Measure blood pressure and heart rate every minute for 10 minutes and assess for symptoms of orthostatic intolerance.

The test is most accurate if measures that reduce orthostatic intolerance are discontinued before testing, including removing compression socks, limiting extra fluid and sodium intake for one to two days, and discontinuing medications that might affect blood pressure and heart rate (unless contraindicated); however, strict adherence to these measures is often not feasible in the clinic setting.

Orthostatic vital signs, dizziness, palpitations, lightheadedness, cognitive impairment, or color or temperature changes in the extremities indicate a positive test for orthostatic intolerance. Compared to healthy control subjects, people with ME/CFS have significantly higher heart rate and abnormally narrowed pulse pressure and more frequent symptoms of orthostatic intolerance [113,114].

We also perform an evaluation for tender areas, though specific "trigger points" are not helpful (figure 1), as there is considerable overlap between ME/CFS and fibromyalgia, and approximately 70 percent of patients with fibromyalgia also meet the criteria for ME/CFS (table 9) [115,116]. (See "Fibromyalgia: Clinical manifestations and diagnosis in adults".)

Laboratory testing — There is no definitive diagnostic laboratory test for ME/CFS. The purpose of laboratory testing is primarily to exclude an alternative diagnosis. In all patients with suspected ME/CFS, we obtain the following:

●Complete blood count with differential

●Chemistries (including glucose, electrolytes, calcium, renal and hepatic function tests)

●Thyroid-stimulating hormone

●Creatine kinase if muscle pain or weakness is present

Other tests — We perform a limited number of additional studies guided by the clinical presentation. As examples:

●Tests for adrenal insufficiency in patients with weakness, fatigue, anorexia, weight loss, or other signs and symptoms of adrenal insufficiency (table 10). A morning cortisol is a good screen. When the results are equivocal, then a cortrosyn stimulation test should be done.

●Vitamin B12 and folate if the patient has macrocytic anemia, pancytopenia, or other signs and symptoms of deficiency.

●Sleep studies for patients with a history and examination suggestive of sleep apnea.

We do not perform routine laboratory testing for autoimmune disease, including serum inflammatory markers or ANA testing, unless features of the history and physical examination are suggestive (eg, swollen joints, photosensitive skin lesions, etc). The presentation and evaluation of lupus and other autoimmune diseases are presented separately. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'When to suspect SLE'.)

Similarly, we do not perform routine neuroimaging. Magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Scan abnormalities occur more frequently in patients with ME/CFS than controls; however, these findings are of unknown significance and do not affect diagnosis or management [117,118]. Neuroimaging should be pursued only if primary neurologic disease (eg, multiple sclerosis or dementia) is suspected based on objective findings.

CFS IN PREGNANCY — 

There is little published information about ME/CFS in pregnancy. In a survey of 86 women with ME/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 [119]. Pregnancy outcomes were generally similar in pregnancies that occurred after the onset of ME/CFS to those that occurred before, although there was a higher rate of spontaneous abortion in pregnancies that occurred after the onset of ME/CFS. 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).

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 5^th to 6^th 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 10^th to 12^th 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 ME/CFS and those caring for them can be obtained from the United States Centers for Disease Control and Prevention: www.cdc.gov/cfs.

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

●Definition – Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), previously known as chronic fatigue syndrome (CFS), is a chronic, often debilitating illness, characterized by severe fatigue and associated symptoms.

There are multiple case definitions for ME/CFS. We use the National Academy of Medicine (NAM; previously the Institute of Medicine [IOM]) definition, which states symptoms should be present for at least six months and have moderate, substantial, or severe intensity at least half of the time (table 1). In addition to fatigue, other criteria include post-exertional malaise (PEM), unrefreshing sleep, cognitive impairment, and orthostatic-related symptoms. (See 'Definition' above.)

●Epidemiology – By some estimates, between 836,000 and 2.5 million people in the United States have ME/CFS. ME/CFS most often begins in young to middle-aged adults and is approximately twice as common in females compared with males. Affected patients are typically highly functioning individuals prior to the onset of symptoms. (See 'Epidemiology' above.)

●Mechanisms of disease – Multiple underlying abnormalities involving the central and autonomic nervous systems, the immune system, the cardiovascular system, the gut microbiome, and energy metabolism have been described in patients with ME/CFS. However, the pathophysiology remains unclear. (See 'Mechanisms of disease' above.)

●Clinical features – For many patients, the symptoms associated with ME/CFS start suddenly (typically with an infectious-like illness), although others may experience a more gradual onset of symptoms. (See 'Clinical manifestations' above.)

CFS is typically characterized by fatigue causing a substantial reduction in the person's ability to engage in pre-illness levels of activity and the following additional symptoms:

•Post-exertional malaise – A prolonged exacerbation of symptoms after physical, cognitive, or orthostatic exertion or stress.

•Unrefreshing sleep despite 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 include headache, sore throat, myalgias, arthralgias (without arthritis), new or worse allergies, abdominal cramps, and unpleasant reactions to drinking even small amounts of alcoholic beverages or to taking even low doses of most medications that act directly on the brain.

●Evaluation and diagnosis – There is no diagnostic test for ME/CFS. The diagnosis is based upon history and physical examination findings that meet the 2015 NAM criteria (table 1) as well as limited laboratory testing to exclude other causes of fatigue (eg, complete blood cell count, thyroid stimulating hormone, comprehensive metabolic panel). (See 'Evaluation and diagnosis' above.)

We do not perform laboratory testing for autoimmune disease or routine neuroimaging as part of the diagnostic evaluation for ME/CFS unless there are objective features suggestive of primary autoimmune or neurologic disease. (See 'Other tests' above.)