chronic Fatigue Syndrome
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling chronic illness. People with ME/CFS experience profound
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
that does not go away with rest, as well as sleep issues and problems with memory or concentration. The
hallmark A hallmark is an official Mark (sign), mark or series of marks struck on items made of metal, mostly to certify the content of noble metals—such as platinum, gold, silver and in some nations, palladium. In a more general sense, the term ''Wikti ...
symptom is
post-exertional malaise Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation (PESE) or post-exertional neuroimmune exhaustion (PENE), is a worsening of symptoms that occurs after minimal exertion. It is the hallmark symptom of m ...
(PEM), a worsening of the illness which can start immediately or hours to days after even minor physical or mental activity. This "crash" can last from hours or days to several months. Further common symptoms include dizziness or faintness when upright and pain. The cause of the disease is unknown. ME/CFS often starts after an infection, such as mononucleosis. It can run in families, but no
genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that contribute to ME/CFS have been confirmed. ME/CFS is associated with changes in the nervous and immune systems, as well as in energy production. Diagnosis is based on distinctive symptoms, and a
differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
, because no diagnostic test such as a blood test or imaging is available. Symptoms of ME/CFS can sometimes be treated and the illness can improve or worsen over time, but a full recovery is uncommon. No therapies or medications are approved to treat the condition, and management is aimed at relieving symptoms. Pacing of activities can help avoid worsening symptoms, and counselling may help in coping with the illness. Before the
COVID-19 pandemic The COVID-19 pandemic (also known as the coronavirus pandemic and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...
, ME/CFS affected two to nine out of every 1,000 people, depending on the definition. However, many people fit ME/CFS diagnostic criteria after developing
long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
. ME/CFS occurs more often in women than in men. It is more common in
middle age Middle age (or middle adulthood) is the age range of the years halfway between childhood and old age. The exact range is subject to public debate, but the term is commonly used to denote the age range from 45 to 65 years. Overall This time span ...
, but can occur at all ages, including childhood. ME/CFS has a large social and economic impact, and the disease can be socially isolating. About a quarter of those affected are unable to leave their bed or home. People with ME/CFS often face stigma in healthcare settings, and care is complicated by controversies around the cause and treatments of the illness. Doctors may be unfamiliar with ME/CFS, as it is often not fully covered in medical school. Historically, research funding for ME/CFS has been far below that of diseases with comparable impact.


Classification and terminology

ME/CFS has been classified as a neurological disease by the
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(WHO) since 1969, initially under the name ''benign myalgic encephalomyelitis''. The classification of ME/CFS as a neurological disease is based on symptoms which indicate a central role of the nervous system. Alternatively, on the basis of abnormalities in
immune cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
, ME/CFS is sometimes labelled a neuroimmune condition. The disease can further be regarded as a post-acute infection syndrome (PAIS) or an infection-associated chronic illness. PAISes such as
long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
and post-treatment Lyme disease syndrome share many symptoms with ME/CFS and are suspected to have a similar cause. 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 has been challenging because the cause and pathology remain unknown. In the WHO's most recent classification, the
ICD-11 The ICD-11 is the eleventh revision of the International Classification of Diseases (ICD). It replaces the ICD-10 as the global standard for recording health information and causes of death. The ICD is developed and annually updated by the World H ...
, chronic fatigue syndrome and myalgic encephalomyelitis are named under post-viral fatigue syndrome. The term ''post-infectious fatigue syndrome'' was initially proposed as a subset of "chronic fatigue syndrome" with a documented triggering infection, but might also be used as a synonym of ME/CFS or as a broader set of fatigue conditions after infection. Many individuals with ME/CFS object to the term ''chronic fatigue syndrome''. They consider the term simplistic and trivialising, which in turn prevents the illness from being taken seriously. 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. 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. A 2015 report from the US Institute of Medicine recommended the illness be renamed ''systemic exertion intolerance disease'' (''SEID'') and suggested new diagnostic criteria. 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 opinion from those affected was generally negative.


Signs and symptoms

ME/CFS causes debilitating fatigue, sleep problems, and
post-exertional malaise Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation (PESE) or post-exertional neuroimmune exhaustion (PENE), is a worsening of symptoms that occurs after minimal exertion. It is the hallmark symptom of m ...
(PEM, overall symptoms getting worse after mild activity). In addition, cognitive issues, orthostatic intolerance (dizziness or nausea when upright) or other physical symptoms may be present (see also ). Symptoms significantly reduce the ability to function and typically last for three to six months before a diagnosis can be confirmed. ME/CFS usually starts after an infection. Onset can be sudden or more gradual over weeks to months.


Core symptoms

People with ME/CFS experience persistent debilitating
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
. It is made worse by normal physical, mental, emotional, and social activity, and is not a result of ongoing overexertion. Rest provides limited relief from fatigue. Particularly in the initial period of illness, this fatigue is described as "flu-like". Individuals may feel "physically drained" and unable to start or finish activities. They may also feel restless while fatigued, describing 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 Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...
. Mental fatigue may also 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. The hallmark feature of ME/CFS is a worsening of symptoms after exertion, known as
post-exertional malaise Post-exertional malaise (PEM), sometimes referred to as post-exertional symptom exacerbation (PESE) or post-exertional neuroimmune exhaustion (PENE), is a worsening of symptoms that occurs after minimal exertion. It is the hallmark symptom of m ...
or ''post-exertional symptom exacerbation''. PEM involves increased fatigue and is disabling. It can also include flu-like symptoms, pain, cognitive difficulties, gastrointestinal issues,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, and sleep problems. All types of activities that require energy, whether physical, cognitive, social, or emotional, can trigger PEM. Examples include attending a school event, food shopping, or even taking a shower. For some, being in a stimulating environment can be sufficient to trigger PEM. PEM usually starts 12 to 48 hours after the activity, but can also follow immediately after. PEM can last hours, days, weeks, or months. Extended periods of PEM, commonly referred to as "crashes" or "flare-ups" by people with the illness, can lead to a prolonged relapse. Unrefreshing sleep is a further core symptom. 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 individuals experience insomnia,
hypersomnia Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...
(excessive sleepiness), or vivid nightmares. Cognitive dysfunction in ME/CFS can be as disabling as physical symptoms, leading to difficulties at work or school, as well as in social interactions. People with ME/CFS sometimes describe it as "
brain fog Clouding of consciousness, also called brain fog or mental fog, occurs when a person is conscious but slightly less wakeful or aware than normal. They are less aware of time and their surroundings, and find it difficult to pay attention. Peopl ...
", and report a slowdown in information processing. Individuals may have difficulty speaking, struggling to find words and names. They may have trouble concentrating or multitasking, or may have difficulties with short-term memory. Tests often show problems with short-term visual memory,
reaction time Mental chronometry is the scientific study of processing speed or reaction time on cognitive tasks to infer the content, duration, and temporal sequencing of mental operations. Reaction time (RT; also referred to as "response time") is measured ...
and
reading speed Reading is the process of taking in the sense or meaning of symbols, often specifically those of a written language, by means of sight or touch. For educators and researchers, reading is a multifaceted process involving such areas as word r ...
. There may also be problems with
attention Attention or focus, is the concentration of awareness on some phenomenon to the exclusion of other stimuli. It is the selective concentration on discrete information, either subjectively or objectively. William James (1890) wrote that "Atte ...
and verbal memory. 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. Weakness and vision changes may also be triggered by the upright posture. Some have
postural orthostatic tachycardia syndrome Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead to a variety of symptoms, ...
(POTS), an excessive increase in
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
after standing up, which can result in
fainting Syncope , commonly known as fainting or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...
. Additionally, individuals may experience
orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
, a drop in blood pressure after standing.


Other common symptoms

Pain and
hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...
(an abnormally increased sensitivity to pain) are common in ME/CFS. The pain is not accompanied by swelling or redness. The pain can be present in muscles (
myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...
) and
joints A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
. Individuals with ME/CFS may have chronic pain behind the eyes and in the neck, as well as
neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...
(related to disorders of the nervous system). Headaches and
migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...
s that were not present before the illness can occur as well. However, chronic daily headaches may indicate an alternative diagnosis. Additional common symptoms include
irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
or other problems with digestion, chills and
night sweats Night sweats or nocturnal hyperhydrosis is the repeated occurrence of excessive sweating during sleep. The person may or may not also perspire excessively while awake. One of the most common causes of night sweats in women over 40 is the horm ...
,
shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...
or an irregular heartbeat. Some experience sore
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s and a sore throat. People may also develop allergies or become sensitive to foods, lights, noise, smells or chemicals.


Illness severity

ME/CFS often leads to serious disability, but the degree varies considerably. ME/CFS is generally classified into four categories of illness severity: * 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 Activities of daily living (ADLs) is a term used in healthcare to refer to an individual's daily self-care activities. Health professionals often use a person's ability or inability to perform ADLs as a measure of their Performance status, functi ...
(self-care activities, such as making a meal). People are usually unable to work and require frequent rest. * Those with severe ME/CFS are homebound and can do only limited activities of daily living, for instance brushing their teeth. They may be wheelchair-dependent and spend the majority of their time in bed. * With very severe ME/CFS, people are mostly bed-bound and cannot care for themselves. Roughly a quarter of those living with ME/CFS fall into the mild category, and half fall into the moderate or moderate-to-severe categories. The final quarter falls into the severe or very severe category. Severity may change over time. Symptoms might get worse, improve, or the illness may go into remission for a period of time. People who feel better for a period of time may overextend their activities, triggering PEM and a worsening of symptoms. Those with severe and very severe ME/CFS experience more extreme and diverse symptoms. They may face severe weakness and greatly limited ability to move. 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. Minor day-to-day activities can be sufficient to trigger PEM. Individuals with ME/CFS have decreased quality of life when evaluated by the SF-36 questionnaire, especially in the domains of physical and social functioning, general health, and vitality. However, their emotional functioning and mental health are not much lower than those of healthy individuals. Functional impairment in ME/CFS can be greater than
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
,
heart disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...
, or
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
. Fewer than half of people with ME/CFS are employed, and roughly one in five have a full-time job.


Causes

The cause of ME/CFS is not yet known. Between 60% and 80% of cases start after an infection, usually a viral infection. A genetic factor is believed to contribute, but there is no single gene known to be responsible for increased risk. Instead, many gene variants probably have a small individual effect, but their combined effect can be strong. Other factors may include problems with the nervous and immune systems, as well as energy metabolism. ME/CFS is a biological disease, not a psychological condition, and is not due to deconditioning. Besides viruses, other reported triggers include stress, traumatic events, and environmental exposures such as to
mould A mold () or mould () is one of the structures that certain fungi can form. The dust-like, colored appearance of molds is due to the formation of spores containing fungal secondary metabolites. The spores are the dispersal units of the fungi ...
. Bacterial infections such as Q-fever are other potential triggers. ME/CFS may further occur after physical trauma, such as an accident or surgery. Pregnancy has been reported in around 3% to 10% of cases as a trigger. ME/CFS can also begin with multiple minor triggering events, followed by a final trigger that leads to a clear onset of symptoms.


Risk factors

ME/CFS can affect people of all ages, ethnicities, and income levels, but it is more common in women than men. People with a history of frequent infections are more likely to develop it. Those with family members who have ME/CFS are also at higher risk, suggesting a genetic factor. In the United States,
white Americans White Americans (sometimes also called Caucasian Americans) are Americans who identify as white people. In a more official sense, the United States Census Bureau, which collects demographic data on Americans, defines "white" as " person hav ...
are diagnosed more frequently than other groups, but the illness is probably at least as prevalent among African Americans and Hispanics. 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.


Viral infections

Viral infections have long been suspected to cause ME/CFS, based on the observation that ME/CFS sometimes occurs in outbreaks and is possibly connected to
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s. 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. Different types of viral infection have been implicated in ME/CFS, including airway infections,
bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...
,
gastroenteritis Gastroenteritis, also known as infectious diarrhea, is an inflammation of the Human gastrointestinal tract, gastrointestinal tract including the stomach and intestine. Symptoms may include diarrhea, vomiting, and abdominal pain. Fever, lack of ...
, or an acute " flu-like illness". Between 15% and 50% of people with
long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
also meet the diagnostic criteria for ME/CFS. Of people who get
infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
, which is caused by the
Epstein–Barr virus The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
(EBV), around 8% to 15% develop ME/CFS, depending on criteria. Other viral infections that can trigger ME/CFS are the H1N1 influenza virus, varicella zoster (the virus that causes
chickenpox Chickenpox, also known as varicella ( ), is a highly contagious disease caused by varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which ...
and
shingles Shingles, also known as herpes zoster or zona, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. T ...
), and
SARS-CoV-1 Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), previously known as severe acute respiratory syndrome coronavirus (SARS-CoV), is a strain (biology), strain of coronavirus that causes severe acute respiratory syndrome (SARS), the ...
. Reactivation of latent viruses, in particular EBV and human herpesvirus 6, has also been hypothesised to drive symptoms. EBV is present in about 90% of people, usually in a latent state. The levels of
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
to EBV are commonly higher in people with ME/CFS, indicating possible viral reactivation.


Pathophysiology

ME/CFS is associated with changes in several areas, including the nervous and immune systems, as well as disturbances in energy metabolism. Neurological differences include
autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...
dysfunction and a change in brain structure and
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
. Observed changes in the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
include decreased
natural killer cell Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...
function and, in some cases,
autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
.


Neurological

A range of structural, biochemical, and functional abnormalities are found in brain imaging studies of people with ME/CFS. Common findings are changes in the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
and the use of additional brain areas for cognitive tasks. Other consistent findings, based on a smaller number of studies, are low metabolism in some areas, reduced serotonin transporters, and problems with neurovascular coupling.
Neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
has been proposed as an underlying mechanism of ME/CFS that could explain a large set of symptoms. Several studies suggest neuroinflammation in the cortical and
limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...
regions of the brain. Individuals with ME/CFS, for instance, have higher brain lactate and
choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...
levels, which are signs of neuroinflammation. More direct evidence from two small
positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
studies of
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
, a type of immune cell in the brain, were contradictory, however. ME/CFS affects sleep. Individuals experience decreased sleep efficiency, take longer to fall asleep, and take longer to achieve
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
, a phase of sleep characterised by rapid eye movement. Changes to non-REM sleep have also been found, together suggesting a role of the autonomic nervous system. Individuals often have a blunted heart rate response to exercise, but a higher heart rate during 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.


Immunological

People with ME/CFS often have immune system abnormalities. A consistent finding in studies is a decreased function of natural killer cells, a type of immune cell that targets virus-infected and tumour cells. They are also more likely to have active viral infections, correlating with cognitive issues and fatigue.
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s show less metabolic activity. This may reflect they have reached an exhausted state and cannot respond effectively against
pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s. 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 An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies. Pr ...
, possibly as a result of viral mimicry. Some may have higher levels of autoantibodies to
muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...
s as well as to β2 adrenergic receptors. Problems with these receptors can lead to impaired blood flow.


Energy

Objective signs of PEM have been found with the 2-day cardiopulmonary exercise test. People with ME/CFS have lower performance compared to healthy controls on the first test. On the second test, healthy people's scores stay roughly the same or increase slightly, while those with ME/CFS have a clinically significant decrease in work rate at the
anaerobic threshold Lactate inflection point (LIP) is the exercise intensity at which the blood concentration of lactate and/or lactic acid begins to increase rapidly. It is often expressed as 85% of maximum heart rate or 75% of maximum oxygen intake. When exercisin ...
. Potential causes include mitochondrial dysfunction, and issues with the transport and use of oxygen. Some of the usual recovery processes following exercise may be lacking, providing an alternative explanation for PEM. Studies have observed mitochondrial abnormalities in cellular energy production, but differences between studies make it hard to draw clear conclusions. ATP, the primary energy carrier in cells, is likely more frequently produced from
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s and
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s than from
carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...
s.


Other

Some people with ME/CFS have abnormalities in their
hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland ( ...
hormones. This can include lower cortisol levels, less change in cortisol levels throughout the day, and a weaker reaction to stress and stimuli. Other proposed abnormalities 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. The diversity of gut microbes is reduced compared to healthy controls. Women with ME/CFS are more likely to experience
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
, early menopause, and other menstrual irregularities compared to women without the condition.


Diagnosis

Diagnosis of ME/CFS is based on symptoms and involves taking a
medical history The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is a set of information the physicians collect over medical interviews. It involves the patient, and ev ...
and a mental and physical examination. No specific lab tests are approved for diagnosis; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis. Blood and urine tests are used to rule out other conditions that could be responsible for the symptoms. People with ME/CFS often face significant delays in obtaining a diagnosis, and diagnoses may be missed altogether. Specialists in ME/CFS may be asked to confirm the diagnosis, as primary care physicians often lack a good understanding of the illness.


Diagnostic criteria

Multiple research and clinical criteria exist to diagnose ME/CFS. These include the
NICE Nice ( ; ) is a city in and the prefecture of the Alpes-Maritimes department in France. The Nice agglomeration extends far beyond the administrative city limits, with a population of nearly one millionInstitute of Medicine The National Academy of Medicine (NAM), known as the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Engineerin ...
(IOM) criteria, the International Consensus Criteria (ICC), the Canadian Consensus Criteria (CCC), and
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, ...
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. The definitions differ in their conceptualisation of the cause and mechanisms of ME/CFS. As there are no verified
biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
for ME/CFS, it is not possible to determine which set of criteria is the most accurate. A trade-off must be made between overdiagnosis and missing more diagnoses. The broad Fukuda criteria have a higher risk of overdiagnosis, whereas the strict ICC criteria have a higher risk of missing people. The IOM and NICE criteria fall in the middle. 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. 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 from each other. The Canadian Consensus Criteria, another commonly used criteria set, was developed in 2003. In addition to PEM, fatigue 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. People diagnosed under the CCC have more severe symptoms compared to those diagnosed under the Fukuda criteria. The 2011 International Consensus Criteria defines ME using symptom clusters and has no minimum duration of symptoms. Similarly to the CCC criteria, ICC is stricter than the Fukuda criteria and selects more severely ill people. The 2015 IOM criteria 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. Symptoms must be present at least half of the time, and be of moderate severity or worse; previous criteria just required symptoms to be present. 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. Separate diagnostic criteria have been developed for children and young people. 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. NICE requires only four weeks of symptoms to suspect ME/CFS in children, compared to six weeks in adults. Exclusionary diagnoses also differ; for instance, children and teenagers may have anxiety related to school attendance, which could explain symptoms.


Clinical assessment

Screening can be done using the DePaul Symptom Questionnaire, which assesses the frequency and severity of ME/CFS symptoms. Individuals may struggle to answer questions related to PEM, if they are unfamiliar with the symptom. To find patterns in symptoms, they may be asked to keep a diary. A
physical exam In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions ...
may appear completely normal, particularly if the individual has rested substantially before a doctor's visit. There may be tenderness in the lymph nodes and abdomen or signs of hypermobility. Answers to questions may show a temporary difficulty with finding words or other cognitive problems.
Cognitive tests Cognitive tests are assessments of the cognitive capabilities of humans and other animals. Tests administered to humans include various forms of IQ tests; those administered to animals include the mirror test (a test of visual self-awareness) and t ...
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. Orthostatic intolerance can be measured with a tilt table test. If that is unavailable, it can also be assessed with the simpler NASA 10-minute lean test, which tests the response to prolonged standing. Standard laboratory findings are usually normal. Standard tests when suspecting ME/CFS include an HIV test, and blood tests to determine
full blood count A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...
, red blood cell sedimentation rate (ESR), C-reactive protein, blood glucose and thyroid-stimulating hormone. Tests for antinuclear antibodies may come back positive, but below the levels that suggest the individual may have
lupus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
. C-reactive protein levels are often at the high end of normal.
Serum ferritin Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. ...
levels may be useful to test, as borderline
anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...
can make some ME/CFS symptoms worse.


Differential diagnosis

Some medical conditions have symptoms similar to ME/CFS. Diagnosis often involves clinical evaluation, testing, and specialist referrals to identify the correct condition. During the time other possible diagnoses are explored, advice can be given on symptom management to help prevent the condition from getting worse. Before a diagnosis of ME/CFS is confirmed, a waiting period is used to exclude acute medical conditions or symptoms which may resolve within that time frame. Possible differential diagnoses span a large set of specialties and depend on the medical history. Examples are
infectious diseases infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
, such as Epstein–Barr virus and
Lyme disease Lyme disease, also known as Lyme borreliosis, is a tick-borne disease caused by species of ''Borrelia'' bacteria, Disease vector, transmitted by blood-feeding ticks in the genus ''Ixodes''. It is the most common disease spread by ticks in th ...
, and neuroendocrine disorders, including
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
and
hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
.
Blood disorders Hematologic diseases are disorders which primarily affect the blood and Blood formation, blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusio ...
, such as
anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...
, and some cancers may also present similar symptoms. Various rheumatological and autoimmune diseases, such as
fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
, Sjögren's syndrome, lupus, and
arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...
, may have overlapping symptoms with ME/CFS. Furthermore, it may be necessary to evaluate psychiatric diseases, such as depression or
substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...
, as well as neurological disorders, such as
narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...
,
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
, and craniocervical instability. Finally, sleep disorders,
coeliac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spelt ...
, and side effects of medications may also explain symptoms. Joint and muscle pain without swelling or inflammation is a common feature of ME/CFS, but is more closely associated with
fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
. Modern definitions of fibromyalgia not only include widespread pain but also fatigue, sleep disturbances, and cognitive issues. This makes it difficult to distinguish ME/CFS from fibromyalgia and the two are often co-diagnosed. Another common condition that often co-occurs with ME/CFS is hypermobile
Ehlers–Danlos syndrome Ehlers–Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Co ...
(EDS). Unlike ME/CFS, EDS is present from birth. People with ME/CFS are more often hypermobile compared to the general population.
Sleep apnea Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...
may also co-occur with ME/CFS. However, many diagnostic criteria require ruling out sleep disorders before confirming a diagnosis of ME/CFS. Like with other
chronic illnesses A chronic condition (also known as chronic disease or chronic illness) is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term ''chronic'' is often applied when the ...
, 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. People with chronic fatigue, which is not due to ME/CFS or other chronic illnesses, may be diagnosed with idiopathic (unexplained) chronic fatigue.


Management

There is no approved drug treatment or cure for ME/CFS, although some symptoms can be treated or managed. Care for ME/CFS involves multidisciplinary healthcare professionals. Usually, the primary care clinician plays an important role in coordinating health care, social care and educational support for those still in school. This coordinator can help provide access to community resources such as
occupational therapy Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek wiktionary:ergon, ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption t ...
and district nursing. Management may start with treating the most disabling symptom first, and tackle symptoms one by one in further health care visits. Pacing, or managing one's activities to stay within energy limits, can reduce episodes of PEM. Addressing sleep problems with good
sleep hygiene Sleep hygiene is a behavioral and environmental practice developed in the late 1970s as a method to help people with mild to moderate insomnia. Clinicians assess the sleep hygiene of people with insomnia and other conditions, such as depressio ...
, 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 Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...
painkillers are insufficient. For cognitive impairment, adaptations like organisers and calendars may be helpful. 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 Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
, irritable bowel syndrome, migraines and mast cell activation syndrome. The debilitating nature of ME/CFS can cause depression,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, or other psychological problems, which can be treated. People with ME/CFS may be unusually sensitive to medications, especially ones that affect the central nervous system.


Pacing and energy management

Pacing, or activity management, involves balancing periods of rest with periods of activity. The goal of pacing is to stabilize the illness and avoid triggering PEM. This involves staying within an individual's available ''energy envelope'' to reduce the PEM "payback" caused by overexertion. The technique was developed for ME/CFS in the 1980s. Pacing can involve breaking up large tasks into smaller ones and taking extra breaks, or creating easier ways to do activities. For example, this might include sitting down while doing the laundry. The decision to stop an activity (and rest or change an activity) is determined by self-awareness of a worsening of symptoms. Use of a
heart rate monitor A heart rate monitor (HRM) is a personal monitoring device that allows one to measure/display heart rate in real time or record the heart rate for later study. It is largely used to gather heart rate data while performing various types of ph ...
may help some individuals with pacing. Research on pacing and energy envelope theory typically shows positive effects. However, these studies have often had a low number of participants and have rarely included methods to check if study participants implemented pacing well. Pacing is difficult to apply for people with very severe ME/CFS, as the activities that trigger PEM in this group, such as eating, cannot be avoided completely. Those with a stable illness who understand how to "listen to their body" may be able to carefully and flexibly increase their activity levels. The goal of an exercise programme would be to increase stamina, while not interfering with everyday tasks or making the illness more severe. In many chronic illnesses, intense exercise is beneficial, but in ME/CFS it is not recommended. The CDC states: 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. Reviews of GET either see weak evidence of a small to moderate effect or no evidence of effectiveness. GET can have serious adverse effects. Similarly, a form of
cognitive behavioural therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...
(CBT) that assumed the illness is maintained by unhelpful beliefs about the illness and avoidance of activity is no longer recommended.


Symptom relief

The first management step for sleep problems in ME/CFS is improving sleep habits. If sleep problems remain after implementing sleep hygiene routines, cognitive behavioural therapy for insomnia can be offered. Avoiding naps during the day can further improve sleep, but there may be a trade-off with needed rest during the day. Drugs that help with insomnia in fibromyalgia, such as
trazodone Trazodone is an antidepressant medication used to treat major depressive disorder, anxiety disorders, and insomnia. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken or ...
or suvorexant, may help in ME/CFS too. Pain is initially managed with over-the-counter pain medication, such as
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It can be taken oral administration, ...
or
paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...
( acetaminophen). If this is insufficient, referral to a pain specialist or counselling on pain management can be the next step. Heat treatment,
hydrotherapy Hydrotherapy, formerly called hydropathy and also called water cure, is a branch of alternative medicine (particularly naturopathy), occupational therapy, and Physical therapy, physiotherapy, that involves the use of water for pain relief and ...
and gentle massage can sometimes help. In addition, stretching and exercise may help with pain, but a balance must be struck, as they can trigger PEM. While there is lack of evidence on pharmaceutical options for pain management in ME/CFS, medication that works for fibromyalgia may be tried, such as
pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, generalized anx ...
. Like in other chronic illnesses, those with ME/CFS often experience mental health issues like anxiety and depression.
Psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of Psychology, psychological methods, particularly when based on regular Conversation, personal interaction, to help a person change behavior, increase hap ...
, such as CBT may help manage the stress of being ill and teach self-management strategies. Family sessions may be useful to educate people close to those with ME/CFS about the severity of the illness.
Antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
s can be useful, but there may be more side effects than in the general population. For instance, it may be difficult to stop weight gain due to exercise intolerance. Bowel issues are a common symptom of ME/CFS. For some, eliminating specific foods, such as
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
,
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
,
gluten Gluten is a structural protein naturally found in certain Cereal, cereal grains. The term ''gluten'' usually refers to the elastic network of a wheat grain's proteins, gliadin and glutenin primarily, that forms readily with the addition of water ...
, or dairy, can alleviate symptoms. Those with orthostatic intolerance can benefit from increased salt and fluid intake. Compression stockings can help with orthostatic intolerance.


Severe ME/CFS

People with moderate to severe ME/CFS may benefit from home adaptations and mobility aids, such as
wheelchair A wheelchair is a mobilized form of chair using two or more wheels, a footrest, and an armrest usually cushioned. It is used when walking is difficult or impossible to do due to illnesses, injury, disabilities, or age-related health conditio ...
s, 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
earplug An earplug is a device that is inserted in the ear canal to protect the user's ears from loud noises, intrusion of water, foreign bodies, dust or excessive wind. Earplugs may be used as well to improve sleep quality or focus in noisy environments ...
s can be used. Those 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 imbalance Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function ...
s. Patients who cannot move easily in bed may need help to prevent pressure sores. Regular repositioning is important to keep their joints flexible and prevent contractures and stiffness.
Osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
may pose a risk over the long term. 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.


Prognosis

Information on the
prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...
of ME/CFS is limited. Complete recovery, partial improvement, and worsening are all possible, but full recovery is uncommon. 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. An early diagnosis may improve care and prognosis. Factors that may make the disease worse over days, but also over longer periods, are physical and mental exertion, a new infection, sleep deprivation, and emotional stress. Some people who improve need to manage their activities to prevent a relapse. Children and teenagers are more likely to recover or improve than adults. For instance, a study in Australia among 6- to 18-year-olds found that two-thirds reported recovery after 10 years and that the typical duration of illness was five years. The effect of ME/CFS on
life expectancy Human life expectancy is a statistical measure of the estimate of the average remaining years of life at a given age. The most commonly used measure is ''life expectancy at birth'' (LEB, or in demographic notation ''e''0, where '' ...
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. In extreme cases, people can die from the illness.


Epidemiology

Reported prevalence rates vary widely depending on how ME/CFS is defined and diagnosed. Overall, around one in 150 people 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/CFS produced a prevalence rate of only 0.17%. In England and Wales, over 250,000 people are estimated to be affected. These estimates are based on data before the
COVID-19 pandemic The COVID-19 pandemic (also known as the coronavirus pandemic and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...
. It is likely that numbers have increased as a large share of people with
long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
meet the diagnostic criteria of ME/CFS. A 2021–2022 CDC survey found that 1.3% of adults in the United States, or 3.3 million, had ME/CFS. Women are diagnosed with ME/CFS about 1.5 to four times more often than men. The prevalence in children and adolescents is slightly lower than in adults, and children have it less than adolescents. The incidence rate (the onset of ME/CFS) has two peaks, one at 10–19 and another at 30–39 years, and the
prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
is highest in
middle age Middle age (or middle adulthood) is the age range of the years halfway between childhood and old age. The exact range is subject to public debate, but the term is commonly used to denote the age range from 45 to 65 years. Overall This time span ...
.


History

From 1934 onwards, there were multiple outbreaks globally of an unfamiliar illness, initially mistaken for
polio Poliomyelitis ( ), commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 75% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe ...
. A 1950s outbreak at London's Royal Free Hospital led to the term "benign myalgic encephalomyelitis" (ME). Those affected displayed symptoms such as malaise,
sore throat Sore throat, also known as throat pain, is pain or irritation of the throat. The majority of sore throats are caused by a virus, for which antibiotics are not helpful. For sore throat caused by bacteria (GAS), treatment with antibiotics may hel ...
,
pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
, and signs of nervous system inflammation. While its infectious nature was suspected, the exact cause remained elusive. The syndrome appeared in sporadic as well as epidemic cases. In 1970, two UK psychiatrists proposed that these ME outbreaks were
psychosocial The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...
phenomena, suggesting
mass hysteria Mass psychogenic illness (MPI), also called mass sociogenic illness, mass psychogenic disorder, epidemic hysteria or mass hysteria, involves the spread of illness symptoms through a population where there is no infectious agent responsible for c ...
or altered medical perception as potential causes. This theory, though challenged, sparked controversy and cast doubt on ME's legitimacy in the medical community. Melvin Ramsay's later research highlighted ME's disabling nature, prompting the removal of "benign" from the name and the creation 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 work and a UK report affirming that ME was not a psychological condition, scepticism persisted within the medical field, leading to limited research. 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. 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. An initial case definition of CFS was outlined in 1988; the CDC published new
diagnostic criteria Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as a diagnosis with the medical context being implicit. The information r ...
in 1994, which became widely referenced. In the 2010s, ME/CFS began to gain more recognition from health professionals and the public. Two reports proved key in this shift. In 2015, the US
Institute of Medicine The National Academy of Medicine (NAM), known as the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Engineerin ...
produced a report with new diagnostic criteria that described ME/CFS as a "serious, chronic, complex systemic disease". Following this, the US
National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
published their ''Pathways to Prevention'' report, which gave recommendations on research priorities.


Society and culture


Controversy

ME/CFS is a contested illness, with debates mainly revolving around the cause of the illness and treatments. Historically, there was a heated discussion about whether the condition was psychological or neurological. Professionals who subscribed to the psychological model had frequent conflicts with patients, who believed their illness to be organic. While ME/CFS is now generally believed to be a multisystem neuroimmune condition, a subset of professionals still see the condition as psychosomatic, or an "illness-without-disease". 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 a
retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase e ...
called XMRV. Some with the illness began taking antiretroviral drugs targeted specifically for
HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
, another retrovirus, 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. 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. The study authors weakened their definition of recovery during the trial: some participants now met a key criterion for recovery before the trial started. A reanalysis under the original
clinical trial protocol In natural and social science research, a protocol is most commonly a predefined procedural method in the design and implementation of an experiment. Protocols are written whenever it is desirable to standardize a laboratory method to ensure su ...
showed no significant difference in recovery rate between treatment groups and the controls receiving standard care.


Doctor–patient relations

People with ME/CFS often face stigma in healthcare settings, and the majority of individuals report negative healthcare experiences. They may feel that their doctor inappropriately calls their illness psychological or doubts the severity of their symptoms. They may also feel forced to prove that they are legitimately ill. Some may be given outdated treatments that provoke symptoms or assume their illness is due to unhelpful thoughts and deconditioning. Clinicians may be unfamiliar with ME/CFS, as it is often not fully covered in medical school. Due to this unfamiliarity, people may go undiagnosed for years or be misdiagnosed with mental health conditions. As individuals 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.


Economic and social impact

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. ME/CFS interrupts normal development in children, making them more dependent on their family for assistance instead of gaining independence as they age. 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. Economic costs due to ME/CFS are significant. In the United States, estimates range from $36 to $51 billion per year, considering both lost wages and healthcare costs. A 2017 estimate for the annual economic burden in the United Kingdom was £3.3 billion.


Advocacy

Patient organisations have aimed to involve researchers via activism but also by publishing research themselves—similarly to AIDS activism in the 1980s, which also sought to combat underfunding and stigma. Citizen scientists, for example, helped start discussions about weaknesses in trials of psychological treatments. ME/CFS International Awareness Day takes place on 12 May. The goal of the day is to raise awareness among the public and health care workers about the diagnosis and treatment of ME/CFS. The date was chosen because it is the birthday of
Florence Nightingale Florence Nightingale (; 12 May 1820 – 13 August 1910) was an English Reform movement, social reformer, statistician and the founder of modern nursing. Nightingale came to prominence while serving as a manager and trainer of nurses during th ...
, who had an unidentified illness similar to ME/CFS.


Research

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. The emergence of long COVID has sparked increased interest in ME/CFS, as the two conditions may share pathology and treatment for one may treat the other.


Funding

Historical research funding for ME/CFS has been far below that of comparable diseases. In a 2015 report, the US National Academy of Sciences said that "remarkably little research funding" had been dedicated to causes, mechanisms, and treatment. Lower funding levels have led to a smaller number and size of studies. In addition, drug companies have invested very little in the disease. The US National Institutes of Health (NIH) is the largest biomedical funder worldwide. 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. Worldwide,
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
, which affects fewer people and results in disability no worse than ME/CFS, received 20 times as much funding between 2007 and 2015. Funding cuts to
Columbia University Columbia University in the City of New York, commonly referred to as Columbia University, is a Private university, private Ivy League research university in New York City. Established in 1754 as King's College on the grounds of Trinity Churc ...
during the second Trump administration forced the closure of a large research program dedicated to the disease. Multiple reasons have been proposed for the low funding levels. Diseases for which society "blames the victim" are frequently underfunded. This may explain why
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
, a severe lung disease often caused by smoking, receives low funding per healthy life year lost. Similarly, for ME/CFS, the historical belief that it is caused by psychological factors may have contributed to lower funding.
Gender bias Gender bias is the tendency to prefer one gender over another. It is a form of unconscious bias, or implicit bias, which occurs when one individual unconsciously attributes certain attitudes and stereotypes to another person or group of people ...
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.


Directions

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. Other proposed markers include electrical measurements of blood cells and
Raman microscopy The Raman microscope is a laser-based microscope, microscopic device used to perform Raman spectroscopy.''Microscopical techniques in the use of the molecular optics laser examiner Raman microprobe'', by M. E. Andersen, R. Z. Muggli, Analytical C ...
of immune cells. Several small studies have investigated the genetics of ME/CFS, but none of their findings have been replicated. A larger study,
DecodeME DecodeME is an ongoing genome-wide association study searching for genetic risk factors for Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With a planned recruitment of 25,000 patients, it is expected to be the largest such stud ...
, is currently underway in the United Kingdom. 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. In several clinical trials of ME/CFS, rintatolimod showed a small reduction in symptoms, but improvements were not sustained after discontinuation. Rintatolimod has been approved in Argentina.
Rituximab Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
, a drug that depletes
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s, was studied and found to be ineffective. Another option targeting autoimmunity is immune adsorption, which removes a large set of (auto)antibodies from the blood.


Challenges

Symptoms and their severity can widely differ among people with ME/CFS. This poses a challenge for research into the cause and progression of the disease. Dividing people into subtypes may help manage this heterogeneity. The existence of multiple diagnostic criteria and variations in how scientists apply them complicate comparisons between studies. Definitions also vary in which co-occurring conditions preclude a diagnosis of ME/CFS.


See also

* List of people with ME/CFS * History of ME/CFS


References


External links

{{DEFAULTSORT:Myalgic encephalomyelitis/chronic fatigue syndrome Immune system disorders Neurological disorders Syndromes of unknown causes