Myalgic encephalomyelitis/chronic fatigue syndrome: Difference between revisions

Myalgic encephalomyelitis/chronic fatigue syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome
Other names	Post-viral fatigue syndrome (PVFS), systemic exertion intolerance disease (SEID)
	The four primary symptoms of ME/CFS according to the National Institute for Health and Care Excellence
Specialty	Rheumatology, rehabilitation medicine, endocrinology, infectious disease, neurology, immunology, general practice, paediatrics, other specialists in ME/CFS
Symptoms	Worsening of symptoms with activity, long-term fatigue, sleep problems, others
Usual onset	Peaks at 10–19 and 30–39 years old
Duration	Long-term
Causes	Unknown
Risk factors	Being female, family history, viral infections
Diagnostic method	Based on symptoms
Treatment	Symptomatic
Prevalence	About 0.17% to 0.89% (pre-pandemic)

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term medical condition. People with ME/CFS experience delayed worsening of the illness after minor physical or mental activity, which is the hallmark symptom of the illness.^[10] Other core symptoms are a greatly reduced ability to do tasks that were previously routine, severe fatigue that does not improve much with rest, and sleep disturbances. Further common symptoms include dizziness or nausea when sitting or standing, along with memory and concentration issues and pain.^[3]

The root cause(s) of the disease are unknown.^[11] ME/CFS often starts after a flu-like infection, for instance, after mononucleosis.^[12] In some people, physical trauma or psychological stress may also act as a trigger.^[10]^: 10 ME/CFS can run in families, though the genes that contribute to ME/CFS risk are not known.^[13] ME/CFS is associated with changes in the nervous and immune systems, energy metabolism, and hormone production.^[14] Diagnosis is based on symptoms because no diagnostic test is available.^[7]

The severity of the illness can fluctuate over time, but full recovery is uncommon.^[12] Treatment is aimed at relieving symptoms, as no therapies or medications are approved to treat the condition.^[2]^: 29 Pacing one's activities to avoid flare-ups may help manage symptoms, and counselling may aid in coping with the illness.^[8] Before the COVID-19 pandemic, ME/CFS affected roughly one in every 150 people, although estimates varied widely.^[9] However, many people with long COVID fit ME/CFS diagnostic criteria.^[15] ME/CFS occurs more often in women as in men. It most commonly affects adults between ages 40 and 60 but can occur at other ages, including childhood.^[16]

ME/CFS has a large social and economic impact. About a quarter of individuals are severely affected and unable to leave their bed or home.^[10]^: 3 The disease can also be socially isolating.^[17] People with ME/CFS often face stigma in healthcare settings and care is complicated by controversies around the cause and potential treaments of the illness.^[18] Clinicians may be unfamiliar with ME/CFS, as it is often not covered in medical school.^[15] Historical research funding for ME/CFS has been far below that of diseases with comparable impact.^[19]

Classification[edit]

ME/CFS has been classified as a neurological disease by the World Health Organization (WHO) since 1969, initially under the name benign myalgic encephalomyelitis.^[20] In the ICD-10, the code for ME/CFS listed only (benign) ME, and there was no mention of CFS; clinicians often used diagnostic codes for fatigue and malaise, or fatigue syndrome, for people with CFS.^[21] In the WHO's most recent classification, the ICD-11, both chronic fatigue syndrome and myalgic encephalomyelitis are named in the 8E49 code post-viral fatigue syndrome, classified under other disorders of the nervous system.^[22]

The cause of the illness is unknown and the classification is based on symptoms which indicate a central role of the nervous system.^[23] Alternatively, based on abnormalities in immune cells, ME/CFS may better fit into a classification of a neuroimmune condition.^[24]

A share of people with post-acute infection syndrome (PAIS) meet the criteria of ME/CFS. PAISs such as long COVID and post-treatment Lyme disease syndrome share many symptoms with ME/CFS and are suspected to have a similar cause. The term post-infectious fatigue syndrome describes severe fatigue after an infection, often with additional signs and symptoms. It was initially considered a subset of chronic fatigue syndrome with a documented triggering infection. In current use, there is no agreement on which conditions the term should encompass.^[25]

Signs and symptoms[edit]

The illness causes debilitating fatigue, sleep problems, and post-exertional malaise (overall symptoms getting worse after mild activity). In addition, cognitive issues, orthostatic intolerance (dizziness or nausea when upright), or other symptoms, may be present (see also § Diagnostic criteria). Symptoms significantly reduce the ability to function compared to pre-illness, can not be caused by a different illness and typically last for three to six months before a diagnosis can be confirmed.^[10]^: 13^[2]^: 11

Debilitating fatigue[edit]

People with ME/CFS experience debilitating fatigue, which is made worse by activity. It is not caused by cognitive, physical, social, or emotional overexertion. Rest does not ease the fatigue much. Particularly in the initial period of illness, this fatigue is described as "flu-like". People with ME/CFS may feel restless and describe their experience as "wired but tired". When starting an activity, muscle strength may drop rapidly, which can lead to difficulty with coordination, clumsiness or sudden weakness.^[2]^: 12, 57 Mental fatigue may make cognitive efforts difficult. The fatigue experienced in ME/CFS is of a longer duration and greater severity than in other conditions characterized by fatigue.^[10]^: 5–6

Post-exertional malaise[edit]

The hallmark feature of ME/CFS is a worsening of symptoms after activity.^[10]^: 6 This is called post-exertional malaise (PEM), or more accurately, post-exertional symptom exacerbation. The term malaise may be considered outdated, as it gives the impression of "vague discomfort".^[26]^: 49 PEM involves a decline in function and increased fatigue. It can also include heightened flu-like symptoms, pain, cognitive difficulties, gastrointestinal issues, nausea, or sleep disturbances. The crash can last hours, days, weeks, or months.^[10]^: 6 Extended periods of PEM are commonly referred to as "crashes" or "flare-ups" and can provoke a prolonged relapse.^[26]^: 50

All types of activities that require energy can trigger PEM. It can be physical or cognitive, but also social or emotional.^[26]^: 49 Examples are attending a school event, a grocery run, or even taking a shower.^[3] The decline often presents 12 to 48 hours after the activity,^[27] but can also follow immediately after.^[10]^: 6

Sleep problems[edit]

There is a wide variety of sleep problems in the ME/CFS population. People wake up exhausted and stiff rather than restored after a night's sleep. This can be caused by a pattern of sleeping during the day and being awake at night, shallow sleep, or broken sleep. However, even a full night's sleep is typically non-restorative. Some people with ME/CFS experience insomnia, hypersomnia (excessive sleepiness), or vivid nightmares.^[26]^: 50

Cognitive dysfunction[edit]

Cognitive dysfunction is one of the most disabling aspects of ME/CFS due to its negative impact on occupational and social functioning.^[28] This is sometimes described as "brain fog".^[3] Short-term visual memory, reaction time and reading speed are most consistently impaired. There may also be problems with attention and verbal memory.^[29] People may struggle to find words.^[10]^: 7 Simple and complex information-processing speed can be extensively impaired. Perceptual abilities, motor speed, reasoning, and intelligence are not different.^[30]

Orthostatic intolerance[edit]

People with ME/CFS often experience orthostatic intolerance, symptoms that start or worsen with standing or sitting. Symptoms, which include nausea, lightheadedness, and cognitive impairment, often improve again after lying down.^[12] Weakness and vision changes may also be triggered by the upright posture.^[3] Postural orthostatic tachycardia syndrome (POTS), an excessive increase in heart rate after standing up, is the most common form of orthostatic intolerance in ME/CFS. Sometimes, POTS can result in fainting.^[10]^: 7 Individuals can also have orthostatic hypotension, a drop in blood pressure after standing.^[31]^: 17

Other common symptoms[edit]

Pain and hyperalgesia (an abnormally increased sensitivity to pain) are common in ME/CFS. The pain is not accompanied by swelling or redness.^[31]^: 16 The pain can be present in muscles (as myalgia) and joints, in the lymph nodes, and as a sore throat. Individuals with ME/CFS may have chronic pain behind the eyes and in the neck, as well as neuropathic pain (related to disorders of the nervous system).^[10]^: 8 Headaches and migraines that were not present before the illness can be present as well. However, chronic daily headaches may indicate an alternative diagnosis.^[31]^: 16 PEM frequently makes pain worse.^[10]^: 8

Additional common symptoms include irritable bowel syndrome or other problems with digestion, chills and night sweats, shortness of breath or an irregular heartbeat. People may also become allergic or sensitive to foods, lights, noise, smells or chemicals.^[3]

Severity[edit]

ME/CFS often causes significant disability, but the degree varies considerably, and symptom severity and duration can fluctuate substantially for an individual.^[32] People with ME/CFS are divided into four categories of illness severity:^[2]^: 8^[31]^: 10

People with mild ME/CFS can usually still work and care for themselves, but they will need their free time to recover from these activities rather than engage in social and leisure activities.
Moderate severity impedes activities of daily living (self-care activities, such as feeding and washing oneself). People are usually unable to work and require frequent rest.
People with severe ME/CFS are homebound and can do only limited activities of daily living.
With very severe ME/CFS, people are mostly bedbound and cannot independently care for themselves.

Roughly a quarter of people with ME/CFS fall into the mild category, and half fall into the moderate or moderate-to-severe categories.^[6] The final quarter falls into the severe or very severe category.^[10]^: 3 Severity may change over time, with periods of worsening, improvement, or remission sometimes occurring.^[32] People who feel better for a period may overextend their activities, triggering PEM and a worsening of symptoms.^[27]

People with severe and very severe ME/CFS experience more or more severe symptoms. They may face severe weakness and be unable to move at times.^[33] They can lose the ability to speak, swallow, or communicate completely due to cognitive issues. They can further experience severe pain and hypersensitivities to touch, light, sound, and smells.^[2]^: 50 The activities that can trigger PEM in the severely ill are very minor, such as sitting or going to the toilet.^[33]

People with ME/CFS have decreased quality of life according to the SF-36 questionnaire, especially in the domains of vitality, physical functioning, general health, physical role, and social functioning. However, their scores in the "role emotional" and mental health domains were not substantially lower than healthy controls.^[34] Functional impairment can be greater than multiple sclerosis, heart disease, or lung cancer.^[12] Less than 50% of people with ME/CFS are employed, and 19% have a full-time job.^[9]

Causes[edit]

The cause of ME/CFS is not yet known.^[12] It often starts after a viral infection.^[14] A genetic factor is believed to contribute, but there is not a single gene responsible for increased risk.^[13] Problems with the nervous and immune systems and energy metabolism may be factors.^[12] ME/CFS is a biological disease, not a psychological condition,^[34]^[11] and is not caused by deconditioning.^[34]^[12]

The onset of ME/CFS may be gradual or sudden.^[1] When it begins suddenly, it often follows an episode of infectious-like symptoms or a known infection. Estimates differ on what share of cases start after an infection: some report a wide range of between 25% and 80%,^[1]^: 158 whereas others indicate that a majority of cases start with an infection, for instance, 60% to 70%^[31]^: 5 or over 80%.^[12] When starting gradually, the illness may begin over the course of months or years with no apparent trigger.^[32] It is also frequent for ME/CFS to begin with multiple triggering events that initially cause minor symptoms and culminate in a final trigger leading to a noticeable onset.^[6]

Viral infections are the most frequently cited triggers of ME/CFS, but other factors, including stress, traumatic events, and environmental exposures like mould, have also been reported.^[10]^: 21 Bacterial infections such as Q-fever are another potential trigger.^[31]^: 5 ME/CFS may also occur after physical trauma, such as a car accident or surgery.^[32] Pregnancy has been reported in around 3% to 10% of cases as a trigger.^[35]

Risk factors[edit]

All ages, ethnic groups, and income levels are susceptible to ME/CFS, but women are more likely to develop it than men.^[9] People with a history of frequent infections are also more prone to developing it.^[14] In the United States, white Americans are diagnosed more frequently than other groups,^[36] but the illness is thought to be at least as prevalent among African Americans and Hispanics.^[16] It used to be thought that ME/CFS was more common among those with higher incomes. Instead, people in minority groups or lower income groups may have increased risks due to poorer nutrition, lower healthcare access, and increased work stress.^[9]

People with affected relatives appear to be more likely to get ME/CFS, implying the existence of genetic risk factors.^[13] People with a family history of neurological or autoimmune diseases also seem to be at increased risk, as do those with pre-existing neurological, autoimmune, or multisystem diseases.^[6] The results of genetic studies have been largely contradictory or unreplicated. One study found an association with mildly deleterious mitochondrial DNA variants, and another found an association with certain variants of human leukocyte antigen genes.^[13]

Viral infections[edit]

Viral infections have long been suspected to cause ME/CFS, based on the observation that ME/CFS sometimes occurs in outbreaks and is connected to autoimmune diseases.^[37] How viral infections cause ME/CFS is unclear; it could be via viral persistence or via a "hit and run" mechanism, in which infections dysregulate the immune system or cause autoimmunity.^[38]

Different types of viral infection have been implicated in ME/CFS, including airway infections, bronchitis, gastroenteritis, or an acute "flu-like illness".^[10]^: 226 Between 15% and 50% of people with long COVID also meet the diagnostic criteria for ME/CFS.^[10]^: 228 Of people who get infectious mononucleosis, which is caused by the Epstein–Barr virus (EBV), around 8% to 15% develop ME/CFS, depending on criteria.^[10]^: 226 Other viral infections that can trigger ME/CFS are the H1N1 influenza virus, varicella zoster (the virus that causes chickenpox), and SARS-CoV-1.^[39]

Reactivation of latent viruses, in particular EBV, has also been hypothesised to drive symptoms. EBV is present in about 90% of people, usually in a latent state.^[40] EBV antibody activity is often higher in people with ME/CFS, indicating possible viral reactivation.^[41]

Pathophysiology[edit]

ME/CFS is associated with changes in several areas, including the nervous and immune systems, as well as disturbances in energy production.^[11]^[14] Neurological differences include altered brain structure and metabolism and autonomic nervous system dysfunction.^[42] Observed immunological changes include decreased natural killer cell activity and, in some cases, autoimmunity.^[14]

Neurological[edit]

A range of structural, biochemical, and functional abnormalities are found in brain imaging studies of people with ME/CFS.^[24]^[42] Consistent and frequent findings are the recruitment of additional brain areas for cognitive tasks and changes in the brainstem. Other consistent findings, based on a small number of studies, are regionally low metabolism, reduced serotonin transporters, and problems with neurovascular coupling.^[23]

Neuroinflammation has been proposed as an underlying mechanism of ME/CFS that could explain a large set of symptoms. A number of studies suggest neuroinflammation in the cortical and limbic regions of the brain in people with ME/CFS. People with ME/CFS, for instance, have higher brain lactate and choline levels, which are signs of neuroinflammation. More direct evidence from two small PET studies of microglia, a type of immune cell in the brain, were contradictory, however.^[43]^[44]

ME/CFS affects sleep. People with ME/CFS experience decreased sleep efficiency, take longer to fall asleep, and take longer to achieve REM sleep, a phase of sleep characterised by rapid eye movement. Changes to non-rapid eye movement sleep have also been found, together suggesting a role of the autonomic nervous system.^[45] People with ME/CFS often have an abnormal heart rate response to exercise, or to a tilt table test when the body is rotated from lying flat to an upright position. This again suggests dysfunction in the autonomic nervous system.^[46]

Immunological[edit]

People with ME/CFS often have immunological abnormalities. A consistent finding in studies is a decreased activity of natural killer cells, a type of immune cell that targets virus-infected and tumour cells.^[47] T cells show less metabolic activity. This may reflect they have reached an exhausted state and cannot respond effectively against pathogens.^[14] People with ME/CFS have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with a decreased antioxidant response, and increased interleukin 10 and TLR4, some of which correlate with symptom severity.^[48]

Autoimmunity has been proposed to be a factor in ME/CFS. There is a subset of people with ME/CFS with increased levels of autoantibodies, possibly as a result of viral mimicry.^[49] Some people with ME/CFS may have elevated autoantibodies to muscarinic acetylcholine receptors as well as to β2 adrenergic receptors.^[49]^[14] Problems with these receptors can lead to impaired blood flow.^[50]

Energy metabolism[edit]

Objective signs of PEM have been found with the 2-day cardiopulmonary exercise test.^[51] People with ME/CFS have lower performance compared to healthy controls on the first test. On the second test, healthy people's scores stay the roughly the same or increase slightly, while people with ME/CFS have a clinically significant decrease in work rate at the anaerobic threshold. Potential causes include impaired oxygen transport, impaired aerobic metabolism, and mitochondrial dysfunction.^[52]

Studies have observed mitochondrial abnormalities in cellular energy production, but heterogeneity among studies makes it difficult to draw any conclusions. ME/CFS is likely not a mainly mitochondrial disorder, based on genetic evidence.^[53] ATP, the primary energy carrier in cells, is likely more frequently produced from lipids and amino acids than from carbohydrates.^[14]

Other[edit]

Some people with ME/CFS have abnormalities in their hypothalamic-pituitary-adrenal axis (HPA axis), which may include lower cortisol levels, a decrease in the variation of cortisol levels throughout the day, and decreased responsiveness of the HPA axis.^[54] Other abnormalities that have been proposed are reduced blood flow to the brain under orthostatic stress (as found in a tilt table test), small-fibre neuropathy, and an increase in the amount of gut microbes entering the blood.^[31]^: 9 The diversity of gut microbes is reduced compared to healthy controls.^[14]

Diagnosis[edit]

Diagnosis of ME/CFS is based on symptoms^[7] and involves taking a medical history and a mental and physical examination.^[55] No characteristic laboratory abnormalities are approved for diagnosis; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis.^[12]^[7] Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms.^[55]

People with ME/CFS often face significant delays in obtaining a diagnosis for appropriate care.^[2]^{: 66–68, 92} Specialists in ME/CFS may be asked to confirm the diagnosis, as primary care physicians often lack a good understanding of the illness.^[2]^: 68

Diagnostic criteria[edit]

Multiple research and clinical criteria exist to diagnose ME/CFS. These include the NICE guidelines, IOM criteria, the International Consensus Criteria (ICC), the Canadian Consensus Criteria (CCC), and CDC criteria. The criteria sets were all developed based on expert consensus and differ in the required symptoms and which conditions preclude a diagnosis of ME/CFS.^[31]^: 14 The definitions also differ in their conceptualisation of the cause and mechanisms of ME/CFS.^[56]

The 1994 CDC criteria, sometimes called the Fukuda criteria, require six months of persistent or relapsing fatigue for diagnosis, as well as the persistent presence of four out of eight other symptoms.^[31]^: 35 While used frequently, the Fukuda criteria have limitations: PEM and cognitive issues are not mandatory. The large variety of optional symptoms can lead to diagnosis of individuals who differ significantly.^[10]^: 15 This can lead to higher rates of misdiagnoses and overdiagnoses compared to modern definitions of ME/CFS.^[10]^: 19

The Canadian Consensus Criteria, another commonly used criteria set, was developed in 2003.^[31]^: 14 In addition to PEM and sleep problems, pain and neurological or cognitive issues are required for diagnosis. Furthermore, three categories of symptoms are defined (orthostatic, thermal instability, and immunological). At least one symptom in two of these categories needs to be present.^[10]^: 15^[31]^: 34 People diagnosed under the CCC have more severe symptoms compared to those diagnosed under the 1994 CDC criteria. Similarly, the International Consensus Criteria are stricter than the Fukuda criteria and select more severely ill people.^[31]^: 14

The 2015 criteria by the Institute of Medicine share significant similarities with the CCC but were developed to be easy to use for clinicians. Diagnosis requires fatigue, PEM, non-restorative sleep, and either cognitive issues (such as memory impairment) or orthostatic intolerance. Additionally, fatigue must persist for at least six months, substantially impair activities in all areas of life, and have a clearly defined onset. In 2021, NICE revised its criteria based on the IOM criteria. The updated criteria require fatigue, PEM, non-restorative sleep, and cognitive difficulties persisting for at least three months.^[10]^: 16–17

Separate diagnostic criteria have been developed for children and young people with ME/CFS. A diagnosis for children often requires a shorter symptom duration. For example, the CCC definition only requires three months of persistent symptoms in children compared to six months for adults.^[10]^: 17–18 NICE requires only four weeks of symptoms to suspect ME/CFS in children, compared to six weeks in adults.^[31]^: 15 Exclusionary diagnoses also differ; for instance, children and teenagers may have anxiety related to school attendance, which could explain symptoms.^[10]^: 17–18

Clinical assessment[edit]

Screening can be done using the DePaul Symptom Questionnaire, which assesses the frequency and severity of ME/CFS symptoms.^[31]^: 24 Individuals may struggle to answer questions related to PEM, as they are unfamiliar with the symptom. To find patterns in symptoms, they may be asked to keep a diary. Distinctive elements of PEM are strange symptoms after exercise (cognitive issues or a sore throat), a disproportionate response to exertion and a delayed response.^[12]

A physical exam may appear completely normal, particularly if the individual has rested substantially before a doctor’s visit.^[12] There may be tenderness in the lymph nodes and abdomen or signs of hypermobility.^[31]^: 17 Answers to questions may show a temporary difficulty with finding words or other cognitive problems.^[6] Cognitive tests and a two-day cardiopulmonary exercise test (CPET) can be helpful to document aspects of the illness, but they may be risky as they can cause severe PEM. They may be warranted to support a disability claim.^[12] However, a two-day CPET cannot be used to rule out ME/CFS.^[1]^: 216 Orthostatic intolerance can be measured with a tilt table test, or if that is unavailable, using the simpler NASA 10-minute lean test.^[12]

Standard laboratory findings are usually normal. Standard tests when suspecting ME/CFS include a full blood count, a HIV test, red blood cell sedimentation rate, C-reactive protein, blood glucose and thyroid-stimulating hormone. Tests for antinuclear antibodies may come back positive, but below the levels that indicate the individual has lupus. C-reactive protein levels are often at the high end of normal. Serum ferritin levels may be useful to test, as borderline anaemia can make some ME/CFS symptoms worse.^[31]^: 18

Differential diagnosis[edit]

Certain medical conditions have similar symptoms as ME/CFS, and healthcare professionals use their clinical experience, testing and referrals to specialists, to determine an appropriate diagnosis. During the time alternative diagnoses are explored, advice can be given on symptom management that may help prevent a worsening of the condition.^[2]^: 66–67 An appropriate waiting period, before ME/CFS is confirmed, is used to exclude acute medical conditions or symptoms which may resolve within that time frame.^[12]

Possible differential diagnoses span a large set of specialties and depend on the patient's history.^[12] Examples are infectious diseases (such as Epstein–Barr virus, HIV infection, and Lyme disease), neuroendocrine disorders (such as diabetes, hypothyroidism and Addison's disease), blood disorders (such as anaemia), and some cancers. Various rheumatological and autoimmune diseases may also have overlapping symptoms with ME/CFS, such as Sjögren's syndrome, lupus, and arthritis. Furthermore, evaluation of psychiatric diseases (such as depression or substance use disorder) and neurological disorders (such as narcolepsy, multiple sclerosis, and craniocervical instability) may be warranted.^[12]^[26] Finally, sleep disorders, coeliac disease, connective tissue disorders, and side effects of medications may also explain symptoms.^[57]

Joint and muscle pain without swelling or inflammation is a feature of ME/CFS but is more associated with fibromyalgia. Modern definitions of fibromyalgia not only include widespread pain but also fatigue, sleep disturbances, and cognitive issues, making the two syndromes difficult to distinguish.^[58]^: 13, 26 The two are often co-diagnosed.^[31]^: 28 Ehlers–Danlos syndromes (EDS) may also have similar symptoms.^[59] Sleep apnoea may be present as a co-occurring condition.^[31]^: 16 However, many diagnostic criteria state that sleep disorders must be excluded before a diagnosis of ME/CFS is confirmed.^[10]^: 7

Like with other chronic illnesses, depression and anxiety co-occur frequently with ME/CFS. Depression may be differentially diagnosed by the presence of feelings of worthlessness, the inability to feel pleasure, loss of interest, and/or guilt, and the absence of ME/CFS bodily symptoms such as autonomic dysfunction, pain, migraines, and PEM.^[31]^: 27 People with chronic fatigue, which is not due to ME/CFS or other chronic illnessess, may be diagnosed with idiopathic (unexplained) chronic fatigue.^[31]^: 32

Management[edit]

There is no approved drug treatment or cure for ME/CFS, although some symptoms can be treated or managed. The CDC recommends a strategy of treating the most disabling symptoms first.^[8] Clinical management varies widely, with many patients receiving combinations of therapies.^[60]^: 9

Pacing, or managing one's activities to stay within energy limits, can reduce episodes of post-exertional malaise. Addressing sleep problems with good sleep hygiene, or medication if required, may be beneficial. Chronic pain is common in ME/CFS, and the CDC recommends consulting with a pain management specialist if over-the-counter painkillers are insufficient. For cognitive impairment, adaptations like organisers and calendars may be helpful.^[8]

Symptoms of severe ME/CFS may be misunderstood as neglect or abuse during well-being evaluations, and NICE recommends that professionals with experience in ME/CFS should be involved in any type of assessment for safeguarding.^[2]^: 22

Co-occurring conditions that may interact with and worsen ME/CFS symptoms are common, and treating these may help manage ME/CFS. Commonly diagnosed ones include fibromyalgia, irritable bowel syndrome, allergies, and chemical sensitivities.^[61] The debilitating nature of ME/CFS can cause depression, anxiety, or other psychological problems, which should be treated accordingly.^[8] People with ME/CFS may be unusually sensitive to medications, especially ones that affect the central nervous system.^[62]

Pacing and energy envelope[edit]

Pacing, or activity management, is a management strategy based on the observation that symptoms tend to increase following mental or physical exertion.^[8] It was developed for ME/CFS in the 1980s^[63] and is now commonly used as a management strategy for chronic illnesses and chronic pain.^[64]

The goal of pacing, in ME/CFS, is to help stabilize the illness and avoid triggering post-exertional malaise (PEM). Its two forms are symptom-contingent pacing, in which the decision to stop (and rest or change an activity) is determined by self-awareness of a worsening of symptoms, and time-contingent pacing, which is determined by a set schedule of activities that can likely be completed without an exacerbation of symptoms. People with stable illness may then try to carefully and flexibly increase activity and exercise using the technique.^[63]^[2]^{: 15, 30, 56}

Energy envelope theory, consistent with pacing, states that people with ME/CFS should stay within and avoid pushing through the envelope of energy available to them so as to reduce the PEM "payback" caused by overexertion.^[65]^[66] Use of a heart rate monitor may help some individuals with pacing.^[8]

Several studies have found energy envelope theory to be a helpful management strategy, noting that it reduces symptoms and may increase the level of functioning in ME/CFS.^[66] Most trials on pacing find positive effects, but they have typically been small and have rarely included a way to ascertain if study participants implemented pacing well.^[67]

Exercise[edit]

Stretching, movement therapies, and toning exercises are recommended for pain in people with ME/CFS. In many chronic illnesses, aerobic exercise is beneficial, but in ME/CFS it is not recommended. The CDC states:^[8]

Any activity or exercise plan for people with ME/CFS needs to be carefully designed with input from each patient. While vigorous aerobic exercise can be beneficial for many chronic illnesses, patients with ME/CFS do not tolerate such exercise routines. Standard exercise recommendations for healthy people can be harmful for patients with ME/CFS. However, it is important that patients with ME/CFS undertake activities that they can tolerate.

Short periods of low-intensity exercise to improve stamina may be possible in a subset of people with ME/CFS. An exercise programme can be offered after pacing has been implemented effectively.^[12] The goal of the exercise programme would be to increase stamina, while not interfering with everyday tasks or making the illness more severe.^[31]^: 56

Graded exercise therapy (GET), a proposed treatment for ME/CFS that assumes deconditioning and a fear of activity play important roles in maintaining the illness, is no longer recommended for people with ME/CFS.^[6]^[31]^: 38 Reviews of GET either see weak evidence of a small to moderate effect^[60]^[68] or no evidence of effectiveness.^[69]^[70] There are reports of serious adverse effects from GET,^[10]^: 160 and few clinical trials contain enough detail about adverse effects.^[60] NICE removed their recommendation for this treatment in 2021.^[2]^: 33, 93

Counselling[edit]

Chronic illness often impacts mental health.^[12] Psychotherapy may help people with ME/CFS manage the stress of being ill, apply self-management strategies for their symptoms, and cope with physical pain.^[2]^: 42^[8] Cognitive behavioural therapy (CBT) may be offered to people with a new ME/CFS diagnosis to give them tools to cope with the disease and help with rehabilitation. A mindfulness approach is sometimes also chosen.^[31]^: 41

If sleep problems remain after implementing sleep hygiene routines, cognitive behavioural therapy for insomnia can be offered. Family sessions may be useful to educate people close to those with ME/CFS about the severity of the illness.^[31]^: 41 Depression or anxiety resulting from ME/CFS is common,^[12] and CBT may be a useful treatment.^[31]^: 41

In the past, a form of CBT was offered that assumed the illness was maintained by unhelpful beliefs about the illness and avoidance of activity.^[12] According to this model, fear of triggering symptoms can prolong the condition, creating a harmful cycle of avoiding activity and becoming less physically active. This model has been criticized as lacking evidence and being at odds with the biological changes associated with ME/CFS.^[69]^[70]

Diet and nutrition[edit]

A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements is recommended for people with ME/CFS.^[8] People with ME/CFS may also benefit from nutritional support if deficiencies are detected by medical testing. However, nutritional supplements may interact with prescribed medication.^[8] Those with orthostatic intolerance can benefit from increased salt and fluid intake.^[12]

Bowel issues are a common symptom of ME/CFS. For some, eliminating specific foods, such as caffeine, alcohol, gluten, or dairy, can alleviate symptoms.^[12] People with severe ME/CFS may have significant trouble getting nutrition. Intravenous feeding (via blood) or tube feeding may be necessary to address this or to address electrolyte imbalances.^[6]

Aids and adaptations[edit]

People with moderate to severe ME/CFS may benefit from home adaptations and mobility aids, such as wheelchairs, disability parking, shower chairs, or stair lifts. To manage sensitivities to environmental stimuli, these stimuli can be limited. For instance, the surroundings can be made perfume-free, or an eye mask or earplugs can be used.^[31]^: 39–40 Compression stockings can help with orthostatic intolerance.^[12]

Prognosis[edit]

Information on the prognosis of ME/CFS is limited. Complete recovery, partial improvement, and worsening are all possible,^[71] but full recovery is rare.^[10]^: 11 Symptoms generally fluctuate over days, weeks, or longer periods, and some people may experience periods of remission. Overall, many will have to adjust to life with ME/CFS.^[2]^: 20

An early diagnosis may improve care and prognosis.^[26] Factors that may make the disease worse over days, but also over longer time periods, are physical and mental exertion, a new infection, sleep deprivation, and emotional stress.^[10]^: 11 Some people who improve need to manage their activities in order to prevent relapse.^[71] Children and teenagers are more likely to recover or improve than adults.^[71]^[2]^: 20 For instance, a study in Australia among 6- to 18-year-olds found that two-thirds reported recovery after ten years, and that the typical duration of illness was five years.^[10]^: 11

The effect of ME/CFS on life expectancy is poorly studied, and the evidence is mixed. One large retrospective study on the topic found no increase in all-cause mortality due to ME/CFS. Death from suicide was, however, significantly higher among those with ME/CFS.^[31]^: 59

Epidemiology[edit]

Reported prevalence rates vary widely depending on how ME/CFS is defined and diagnosed. Overall, around 1 in 150 have ME/CFS. Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%. In comparison, estimates using the stricter 1988 CDC criteria or the 2003 Canadian consensus criteria for ME produced a prevalence rate of only 0.17%.^[9]

As of 2015, between 836,000 and 2.5 million Americans were estimated to have ME/CFS, with 84–91% of these being undiagnosed.^[1]^: 1 In England and Wales, over 250,000 people are estimated to be affected.^[2]^: 92 These estimates are based on data before the COVID-19 pandemic. It is likely that numbers have increased as a large share of people with long COVID meet the diagnostic criteria of ME/CFS.^[10]^: 228 A 2021–2022 CDC survey found that 1.3% of adults in the United States, or 3.3 million, had ME/CFS.^[72]

Women are diagnosed about 1.5 to 4 times more often with ME/CFS than men.^[9]^[16] An estimated 0.2%–0.5% of children have ME/CFS, and more adolescents are affected by the illness than younger children.^[1]^: 182^[73] The incidence rate according to age has two peaks, one at 10–19 and another at 30–39 years,^[4] and the prevalence is highest between ages 40 and 60.^[34]^[16]

History[edit]

From 1934 onwards, there were multiple outbreaks globally of an unfamiliar illness, initially mistaken for polio. A 1950s outbreak at London's Royal Free Hospital led to the term "benign myalgic encephalomyelitis" (ME). Patients displayed symptoms such as malaise, sore throat, pain, and signs of nervous system inflammation. While its infectious nature was suspected, the exact cause remained elusive.^[1]^: 28–29 The syndrome appeared in sporadic as well as epidemic cases.^[74]

In 1970, two UK psychiatrists proposed that these ME outbreaks were psychosocial phenomena, suggesting mass hysteria or altered medical perception as potential causes. This theory, though challenged, sparked controversy and cast doubt on ME's legitimacy in the medical community.^[1]^: 28–29

Melvin Ramsay's subsequent research emphasised ME's disabling nature, prompting the removal of "benign" from the name and the establishment of diagnostic criteria in 1986. These criteria included the tendency of muscles to tire after minor effort and take multiple days to recover, high symptom variability, and chronicity. Despite Ramsay's efforts and a UK report acknowledging ME as not psychological, scepticism persisted within the medical field, leading to limited research.^[1]^: 28–29

In the United States, Nevada and New York State saw outbreaks of what appeared similar to mononucleosis in the middle of the 1980s. People suffered from "chronic or recurrent fatigue", among a large number of other symptoms.^[1]^: 28–29 The initial link between elevated antibodies and the Epstein–Barr virus led to the name "chronic Epstein–Barr virus syndrome". The CDC renamed it chronic fatigue syndrome (CFS), as a viral cause could not be confirmed in studies.^[75]^{: 155–158} An initial case definition of CFS was outlined in 1988;^[1]^: 28–29 the CDC published new diagnostic criteria in 1994, which became widely referenced.^[76]

In the 2010s, ME/CFS gained increasing recognition from health professionals and the public. Two reports proved key in this shift. In 2015, the Institute of Medicine produced a report with new diagnostic criteria that described ME/CFS as a "serious, chronic, complex systemic disease". The US National Institutes of Health subsequently published their Pathways to Prevention report, which gave recommendations on research priorities.^[77]

Society and culture[edit]

Naming[edit]

Many names have been proposed for the illness. The most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "myalgic encephalomyelitis/chronic fatigue syndrome" (ME/CFS). Reaching consensus on a name is challenging because the cause and pathology remain unknown.^[1]^: 29–30

Many patients object to the term "chronic fatigue syndrome". They consider the term simplistic and trivialising, which in turn prevents the illness from being taken seriously.^[1]^: 234^[78] At the same time, there are also issues with the use of "myalgic encephalomyelitis" (myalgia means muscle pain and encephalomyelitis means brain and spinal cord inflammation), as there is only limited evidence of brain inflammation implied by the name.^[31]^: 3 The umbrella term ME/CFS would retain the better-known phrase CFS without trivialising the disease, but some people object to this name too, as they see CFS and ME as distinct illnesses.^[78]

A 2015 report from the Institute of Medicine recommended the illness be renamed "systemic exertion intolerance disease" (SEID) and suggested new diagnostic criteria, proposing that post-exertional malaise (PEM), impaired function, and sleep problems are core symptoms of ME/CFS.^[1] While the new name was not widely adopted, the diagnostic criteria were taken over by the CDC. Like CFS, the name SEID only focuses on a single symptom, and patient opinions have generally been negative.^[79]

Economic and social impact[edit]

ME/CFS negatively impacts people's social lives and relationships. Stress can be compounded by disbelief in the illness from the support network, who can be sceptical due to the subjective nature of diagnosis. Many people with the illness feel socially isolated, and thoughts of suicide are high, especially in those without a supportive care network. Compared to other patient groups, people with ME/CFS engage more in peer-to-peer support online.^[17]

For children, normal development becomes interrupted due to ME/CFS as they increasingly rely on their family for assistance rather than becoming more independent with age.^[80] Unpaid carers also face challenges. Caring for somebody with ME/CFS can be a full-time role, and the stress of caregiving is made worse by the lack of effective treatments and historical biases.^[81]

Economic costs due to ME/CFS are significant.^[82] A 2021 paper by Leonard Jason and Arthur Mirin estimated the impact in the US to be $36–51 billion per year, or $31,592 to $41,630 per person, considering both lost wages and healthcare costs.^[83] The CDC estimated direct healthcare costs alone at $9–14 billion annually.^[82] A 2017 estimate for the annual economic burden in the United Kingdom was £3.3 billion.^[13]

Advocacy[edit]

12 May is designated as ME/CFS International Awareness Day.^[84] The goal of the day is to raise awareness among the public and health care workers about the diagnosis and treatment of ME/CFS.^[85] It was chosen because it is the birthday of Florence Nightingale, who had an unidentified illness that appeared similar to ME/CFS.^[86]

Advocacy and research organisations include MEAction,^[87] the Open Medicine Foundation,^[88] and the Solve ME/CFS Initiative in the US;^[87] the ME Association in the UK;^[89] and the European ME Coalition.^[87]

Doctor–patient relations[edit]

The NAM report refers to ME/CFS as "stigmatized", and the majority of patients report negative healthcare experiences.^[1]^: 30 These patients may feel that their doctor inappropriately calls their illness psychological or doubts the severity of their symptoms.^[90] They may also feel forced to prove that they are legitimately ill.^[91] Some may be given outdated treatments that provoke symptoms or assume their illness is due to unhelpful thoughts and deconditioning.^[12]^: 2871^[15]

Clinicians may be unfamiliar with ME/CFS, as it is often not covered in medical school.^[15] Due to this unfamiliarity, people may go undiagnosed for years^[12]^: 2861^[1]^: 1 or be misdiagnosed with mental conditions.^[15]^[12]^: 2871 As people with ME/CFS gain knowledge about their illness over time, their relationship with treating physicians changes. They may feel on a more equal footing with their doctors and able to work in partnership. At times, relationships may deteriorate instead as the previous asymmetry of knowledge breaks down.^[17]

Controversy[edit]

ME/CFS is a contested illness, with debates mainly revolving around the cause of the illness and treatments.^[92] Historically, there was a heated discussion about whether the condition was psychological or neurological.^[56] Professionals who subscribed to the psychological model had frequent conflicts with patients, who believed their illness to be organic.^[18] While ME/CFS is now generally believed to be a multisystem neuroimmune condition,^[56] a subset of professionals still see the condition as psychosomatic, or an "illness-without-disease".^[18]

The possible role of chronic viral infection in ME/CFS has been a subject of disagreement. One study caused considerable controversy by establishing a causal relationship between ME/CFS and the xenotropic murine leukemia virus–related virus (XMRV), a retrovirus. Some with the illness began taking antiretroviral drugs targeted specifically for HIV/AIDS, another retrovirus,^[93] and national blood supplies were suspected to be tainted with the retrovirus. After several years of study, the XMRV findings were determined to be the result of contamination of the testing materials.^[94]

Treatments based on behavioural and psychological models of the illness have also been the subject of much contention. The largest clinical trial on behavioural interventions, the 2011 PACE trial, concluded that graded exercise therapy and CBT are moderately effective. The trial drew heavy criticism.^[92] The study authors weakened their definition of recovery during the trial: even some participants who reported a worsening of physical function were counted as recovered. A reanalysis under the original clinical trial protocol showed no significant difference in recovery rate between treatment groups and healthy control subjects.^[95]^[96]

Research[edit]

Research into ME/CFS seeks to find a better understanding of the disease's causes, biomarkers to aid in diagnosis, and treatments to relieve symptoms.^[1]^: 10 The emergence of long COVID has sparked increased interest in ME/CFS, as the two conditions may share pathology and a treatment, for one may treat the other.^[24]^[14]

Research funding[edit]

Historical research funding for ME/CFS has been far below that of comparable diseases.^[19]^[97] In a 2015 report, the US National Academy of Sciences said that "remarkably little research funding" had been dedicated to causes, mechanisms, and treatment.^[1]^: 9 Lower funding levels have led to a smaller number and size of studies.^[98] In addition, drug companies have invested very little in the disease.^[99]

The US National Institutes of Health (NIH) is the largest biomedical funder worldwide.^[100] Using rough estimates of disease burden, a study found NIH funding for ME/CFS was only 3% to 7% of the average disease per healthy life year lost between 2015 and 2019.^[101] Worldwide, multiple sclerosis, which affects fewer people and results in disability no worse than ME/CFS, received 20 times as much funding between 2007 and 2015.^[97]^[19]

Multiple reasons have been proposed for the low funding levels. Diseases for which society "blames the victim" are frequently underfunded. This may explain why a severe lung disease often caused by smoking receives low funding per healthy life year lost.^[102] Similarly, for ME/CFS, the historical belief that it is caused by psychological factors may have contributed to lower funding. Gender bias may also play a role; the NIH spends less on diseases that predominantly affect women in relation to disease burden. Less well-funded research areas may also struggle to compete with more mature areas of medicine for the same grants.^[101]

Research directions[edit]

Many biomarkers for ME/CFS have been proposed. Studies on biomarkers have often been too small to draw robust conclusions. Natural killer cells have been identified as an area of interest for biomarker research as they show consistent abnormalities.^[7] Other proposed markers include electrical measurements of blood cells and Raman microscopy of immune cells.^[14] Several small studies have investigated the genetics of ME/CFS, but none of their findings have been replicated.^[13] A larger study, DecodeME, is currently underway in the United Kingdom.^[103]

Various drug treatments for ME/CFS are being explored. Drugs under investigation often target the nervous system, the immune system, autoimmunity, or pain directly. More recently, there has been a growing interest in drugs targeting energy metabolism.^[99] In several clinical trials of ME/CFS, rintatolimod showed a small reduction in symptoms, but improvements were not sustained after discontinuation.^[104]^[99] Rintatolimod has been approved in Argentina.^[105] Rituximab, a drug that depletes B cells, was studied and found to be ineffective.^[14] Other options targeting autoimmunity are immune absorption, whereby a large set of (auto)antibodies is removed from the blood.^[99]

Challenges[edit]

People with ME/CFS can widely differ in which symptoms they have and how severe these symptoms are. This poses a challenge for research into the cause and progression of the disease. Dividing people with ME/CFS into subtypes may help manage this heterogeneity.^[14]

The existence of multiple diagnostic criteria and variations in how scientists apply them complicate comparisons between studies.^[1]^: 53 Definitions also vary in which co-occurring conditions preclude a diagnosis of ME/CFS.^[1]^: 52

References[edit]

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Classification	D ICD-11: 8E49 ICD-10: G93.3 ICD-10-CM: G93.3, R53.82 ICD-9-CM: 323.9 780.71 MeSH: D015673 DiseasesDB: 1645
External resources	MedlinePlus: 001244 eMedicine: med/3392 ped/2795 Patient UK: Myalgic encephalomyelitis/chronic fatigue syndrome

v t e Myalgic encephalomyelitis/chronic fatigue syndrome
Medical issues	Clinical descriptions Treatment Post-exertional malaise 2-day CPET
Research	DecodeME
Society and history	History Controversies Notable patients
Organizations	Action for ME ME Association ME Research UK Open Medicine Foundation Solve ME/CFS Initiative Whittemore Peterson Institute

Authority control databases
International	FAST
National	France BnF data Israel United States Latvia Japan Czech Republic