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Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) and ME/CFS, is a complex, fatiguing, long-term medical condition diagnosed by required primary symptoms and criteria, and often involves a broad range of symptoms. Distinguishing core symptoms are lengthy exacerbations or "flares" of the illness after ordinary minor physical or mental activity, known as
post-exertional malaise Post-exertional malaise (PEM) is one of the main symptoms of Chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM is "a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activ ...
(PEM); greatly diminished capacity to accomplish tasks that were routine before the illness; and
sleep disturbances A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person. Some sleep disorders are serious enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
.
Orthostatic intolerance Orthostatic intolerance (OI) is the development of symptoms when orthostasis, standing upright that are relieved when supine position, reclining. There are many types of orthostatic intolerance. OI can be a subcategory of dysautonomia, a disorder ...
(difficulty sitting and standing upright) and
cognitive dysfunction Cognitive disorders (CDs), also known as neurocognitive disorders (NCDs), are a category of mental health disorders that primarily affect cognitive abilitiesCognitive skills, also called cognitive functions, cognitive abilities or cognitive capac ...
are also diagnostic.
Other common symptoms Other most often refers to: * Other (philosophy), a concept in psychology and philosophy Other or The Other may also refer to: Books * The Other (Tryon novel), ''The Other'' (Tryon novel), a 1971 horror novel by Tom Tryon * The Other (short story ...
may involve numerous body systems, and
chronic pain Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between Acute (medicine), acute and Chronic condition, chronic pain is sometimes determined by the amount of time since onset. Two commonly ...
is common. While the cause is not understood, proposed mechanisms include biological, ,
infectious An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents and the toxin A toxin is a harmful substance produced within living cells ...
, and physical or psychological stress affecting the
biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable explanations and pr ...

biochemistry
of the body. Diagnosis is based on the patient's symptoms because no confirmed diagnostic test is available. The
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

fatigue
in CFS is not due to strenuous ongoing exertion, is not significantly relieved by rest, and is not due to a previous medical condition. Fatigue is a common symptom in many illnesses, but the unexplained fatigue and severity of functional impairment in CFS are relatively rare in these other illnesses. Persons with CFS may recover or improve over time, but some will become severely affected and disabled for an extended period. No therapies or medications are approved to treat the cause of the illness; treatment is aimed at alleviation of symptomatology. The
CDC CDC may refer to: Organizations Government * Centers for Disease Control and Prevention The United States The United States of America (USA), commonly known as the United States (U.S. or US), or America, is a country Contiguous Unite ...
recommends
pacing Pacing may refer to: In sport * Pacing, an athletic technique of spreading one's effort out over longer-distance track and field and swimming (sport), swimming races * Pacing (horse gait), a horse gait used in standardbred horse races * Motor-pace ...
(personal activity management) to keep mental and physical activity from making symptoms worse. Limited evidence suggests that
rintatolimod Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of chronic fatigue syndrome (CFS). Low-strength evidence indicates it can diminish CFS symptoms. It is an immunomodulatory RNA#Double-stranded RNA, double-stra ...
, counseling, and personalized activity management helps improve some patients' functional abilities. About 1% of primary-care patients have CFS; estimates of incidence vary widely because epidemiological studies define the illness dissimilarly. It has been estimated that 836,000 to 2.5 million
Americans Americans are the citizens Citizenship is a relationship between an individual and a state to which the individual owes allegiance and in turn is entitled to its protection. Each state determines the conditions under which it will recogn ...

Americans
and 250,000 to 1,250,000 people in the
United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain,Usage is mixed. The Guardian' and Telegraph' use Britain as a synonym for the United Kingdom. Some prefer to use Britain as shorth ...

United Kingdom
have CFS. CFS occurs 1.5 to 2 times as often in women as in men. It most commonly affects adults between ages 40 and 60 years; it can occur at other ages, including childhood. Other studies suggest that about 0.5% of children have CFS, and that it is more common in adolescents than in younger children. Chronic fatigue syndrome is a major cause of school absence. CFS reduces health, happiness, productivity, and can also cause socio-emotional disruptions such as loneliness and alienation, however, there is controversy over many aspects of the disorder. Physicians, researchers, and patient advocates promote different names and diagnostic criteria; and evidence of proposed causes and treatments is often poor or contradictory.


Signs and symptoms

The United States
Centers for Disease Control and Prevention 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 The United States Department of Heal ...
(CDC) recommends these criteria for diagnosis: # Greatly lowered ability to do activities that were usual before the illness. This drop in activity level occurs along with fatigue and must last six months or longer. # Worsening of symptoms after physical or mental activity that would not have caused a problem before the illness. The amount of activity that might aggravate the illness is difficult for a person to predict, and the decline often presents 12 to 48 hours after the activity. The 'relapse', or 'crash', may last days, weeks or longer. This is known as
post-exertional malaise Post-exertional malaise (PEM) is one of the main symptoms of Chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PEM is "a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activ ...
(PEM). # Sleep problems; people may still feel weary after full nights of sleep, or may struggle to stay awake, fall asleep or stay asleep. Additionally, one of the following symptoms must be present: * Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog") * While standing or sitting upright; lightheadedness, dizziness, weakness,
fainting Syncope, commonly known as fainting, is a loss of consciousness Consciousness, at its simplest, is sentience or awareness of internal and external existence. Despite millennia of analyses, definitions, explanations and debates by philos ...
or vision changes may occur (
orthostatic intolerance Orthostatic intolerance (OI) is the development of symptoms when orthostasis, standing upright that are relieved when supine position, reclining. There are many types of orthostatic intolerance. OI can be a subcategory of dysautonomia, a disorder ...
)


Other common symptoms

Many, but not all people with ME/CFS report: * Muscle pain, joint pain without swelling or redness, and headache * Tender lymph nodes in the neck or armpits * Sore throat * Irritable bowel syndrome * Chills and night sweats * Allergies and sensitivities to foods, odors, chemicals, lights, or noise * Shortness of breath * Irregular heartbeat The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses:
Lyme disease Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia ''Borrelia'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of thing ...
, "
sleep disorder A sleep disorder, or somnipathy, is a medical disorder A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or ...
s,
major depressive disorder Major depressive disorder (MDD), also known simply as depression, is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impai ...
,
alcohol In chemistry, alcohol is an organic compound that carries at least one hydroxyl functional group (−OH) bound to a Saturated and unsaturated compounds, saturated carbon atom. The term alcohol originally referred to the primary alcohol ethan ...
/
substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical composition * Matter, anything that has mass and takes up space * Substance t ...
abuse,
diabetes mellitus Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorders characterized by a hyperglycemia, high blood sugar level over a prolonged period of time. Symptoms often include frequent urination, Polydipsia, increased th ...
,
hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland The thyroid, or thyroid gland, is an endocrine gland in the neck consisting of two ...

hypothyroidism
,
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 adult ...
(mono),
lupus Lupus, technically known as 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 between people and may be mild to severe. Co ...
,
multiple sclerosis Multiple sclerosis (MS), also known as encephalomyelitis disseminata, is the most common demyelinating disease A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impa ...
(MS),
chronic hepatitis Hepatitis is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cell ...

chronic hepatitis
and various
malignancies Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biol ...

malignancies
." Medications can also cause side effects that mimic symptoms of CFS. Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases after exertion, which is opposite to the normal pattern.


Onset

Gradual or sudden onset of the illness may occur, and studies have mixed results as to which occurs more frequently.


Physical functioning

The functional capacity of individuals with CFS varies greatly. Some persons with CFS lead relatively normal lives; others are totally bed-ridden and unable to care for themselves. For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time. The severity of symptoms and disability is the same regardless of gender, and many experience strongly disabling
chronic pain Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between Acute (medicine), acute and Chronic condition, chronic pain is sometimes determined by the amount of time since onset. Two commonly ...
. Persons report critical reductions in levels of physical activity. Also, a reduction in the complexity of activity has been observed. Reported impairment is comparable to other fatiguing medical conditions including late-stage
AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection An infection is the invasion of an organism's body by , their multiplication, and the reaction of ...
,
lupus Lupus, technically known as 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 between people and may be mild to severe. Co ...

lupus
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...
,
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease The lungs are the primary Organ (anatomy), organs of the respiratory system in humans and many other animals including a few fish and some snails. In mammal ...
(COPD), and
end-stage kidney disease Chronic kidney disease (CKD) is a type of kidney disease The kidneys are two reddish-brown bean-shaped organs found in vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukary ...
. CFS affects a person's functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus. Often, courses of remission and relapse of symptoms occur, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness. About 25% of people with CFS are house-bound or bed-ridden for long periods during their illness, often for decades. An estimated 75% are unable to work because of their illness. More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time. Children who become ill with CFS are a major cause of school absence. People with CFS have decreased scores on the
SF-36The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status and an abbreviated variant of it, the SF-6D, is commonly used in health economics Health economics is a branch ...
quality-of-life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role, and social functioning; however, the sub scales for "role emotional" and mental health in CFS patients were consistent with or not substantially lower than healthy controls. Direct healthcare costs are estimated at between $9 and $14 billion annually in the U.S. alone.


Cognitive functioning

Cognitive dysfunction is one of the more disabling aspects of CFS due to its negative impact on occupational and social functioning. 50 to 80% of persons with CFS are estimated to have serious problems with cognition. Cognitive symptoms are mainly due to deficits in attention, memory, and
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; sometimes referred to as "response time") is meas ...
. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities; for example, increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to are observed. Simple and complex information-processing speed, and functions entailing working memory over long time periods are moderately to extensively impaired. These deficits are generally consistent with the patient's perceptions. Perceptual abilities, motor speed, language, reasoning, and intelligence do not appear to be significantly altered. When poorer health status was reported, a person's perception of their cognitive problems was frequently greater. Better physical functioning in people with CFS is associated with less visuoperceptual difficulty and fewer language-processing complaints. Inconsistencies of subjective and observed values of cognitive dysfunction reported across multiple studies are likely caused by a number of factors. Differences of research participants' cognitive abilities pre and post illness onset are naturally variable, and are difficult to measure because of a lack of specialized analytical tools that can consistently quantify the specific cognitive difficulties in CFS. The frequency of neuropsychiatric and neuropsychological symptoms is increased in the population of persons with CFS; the understanding of why this occurs is unresolved. Various hypotheses have been advanced to try to explain the relationship between the cognitive symptoms and the illness. Some researchers believe psychiatric causes underlie or contribute to the illness, while other researchers believe the illness causes biochemical and sociological changes in people that produce the symptoms.


Cause

The cause of CFS is unknown. Genetic and physiological factors are thought to work together to precipitate and perpetuate the condition. A 2016 report by the
Institute of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit A nonprofit organization (NPO), also known as a non-business entity, not-for-profit organization, or nonprofit ...
states that CFS is a biologically based illness, but that the biologic abnormalities are not sensitive or specific enough to be useful as a diagnosis. Because it may begin as an influenza-like illness with a sudden onset, various infectious causes have been proposed, but evidence is insufficient to support such causation. Infections proposed include mononucleosis, ''
Chlamydophila pneumoniae ''Chlamydia pneumoniae'' is a species of ''Chlamydia (genus), Chlamydia'', an Obligate intracellular parasite, obligate intracellular bacterium that infects humans and is a major cause of pneumonia. It was known as the Taiwan acute respiratory ag ...

Chlamydophila pneumoniae
'',
human herpesvirus 6 Human herpesvirus 6 (HHV-6) is the common collective name for ''human betaherpesvirus 6A'' (HHV-6A) and ''human betaherpesvirus 6B'' (HHV-6B). These closely related viruses are two of the nine known human herpesviruses, Herpesviridae, herpesvirus ...
, and
Lyme disease Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia ''Borrelia'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of thing ...
. Inflammation may be involved. Often, the illness will follow a viral illness, such as mononucleosis or
gastroenteritis Gastroenteritis, also known as infectious diarrhea and gastro, is inflammation of the gastrointestinal tract The gastrointestinal tract, (GI tract, GIT, digestive tract, digestion tract, alimentary canal) is the tract from the mouth to the ...

gastroenteritis
.


Risk factors

All ages, ethnic groups, and income levels are susceptible to the illness. The CDC states that Caucasians may be diagnosed more frequently than other races in America, but the illness is at least as prevalent among African Americans and Hispanics. A 2009 meta-analysis showed that compared with Caucasians, African Americans, and Native Americans have a higher risk of CFS, though it specifically excluded other more common ethnicities worldwide, and it acknowledged that studies and data were limited. More women than men get CFS. A large 2020 meta-analysis estimated that between 1.5 and 2.0 times more cases are women. The review acknowledged that different case definitions and diagnostic methods within datasets yielded a wide range of prevalence rates. The CDC estimates CFS occurs up to four times more often in women than in men. The illness can occur at any age, but most frequently in persons between the ages of 40 and 60. CFS is less prevalent among children and adolescents than among adults. Blood relatives of those who have CFS appear to be more predisposed, implying that genetic factors may increase the risk of susceptibility to the illness. According to the CDC, "CFS is a biological illness, not a psychologic disorder", and those affected "are neither
malingering Malingering is the fabrication, feigning, or exaggeration of physical or psychological symptoms designed to achieve a desired outcome, such as relief from duty or work. Malingering is not a medical diagnosis, but may be recorded as a "focus of c ...
nor seeking
secondary gain Primary morbid gain or secondary morbid gain are used in medicine to describe the significant subconscious psychological motivation, motivators patients may have when presenting with symptoms. It is important to note that if these motivators are rec ...
". The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations United Nations Specialized Agencies are autonomous organizations working with the United Nations and each other through the co-ordinating machinery of the Unit ...
(WHO) classifies CFS as a neurological disease in the ICD-11 for Mortality and Morbidity Statistics (
ICD-11 The ICD-11 is the eleventh revision of the International Classification of Diseases The International Classification of Diseases (ICD) is a globally used diagnostic tool for epidemiology Epidemiology is the study and analysis of the distribution ...
).


Viral and other infections

The term post-viral fatigue syndrome (PVFS) is used to describe CFS-like symptoms that occur after a viral infection. A recent review found Epstein-Barr virus (EBV) antibody activity to be higher in patients with CFS, and that a subset of patients with CFS were likely to have increased EBV activity compared to controls. Viral infection is a significant risk factor for CFS, with one study finding 22% of people with EBV experience fatigue six months later, and 9% having strictly defined CFS. A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis. One review found risk factors for developing CFS after mononucleosis,
dengue fever Dengue fever is a mosquito-borne disease, mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin three to fourteen days after infection. These may include a high fever, headache, vomiting, myalgia, muscle and arth ...
or the bacterial infection
Q-fever Q fever or query fever is a disease caused by infection with ''Coxiella burnetii'', a bacterium that affects humans and other animals. This organism is uncommon, but may be found in cattle, sheep, goats, and other domestic mammals, including ...
include longer bed-rest during the illness, poorer pre-illness physical fitness, attributing symptoms to physical illness, belief that a long recovery time is needed, as well as pre-infection distress and fatigue. The same review found biological factors such as CD4 and CD8 activation and liver inflammation are predictors of sub-acute fatigue, but not CFS, however these findings are not generally accepted due to the use of the Oxford criteria in selecting patients. The CDC does not recognize attribution of symptoms as a risk factor. A study comparing diagnostic labels found that people labelled with ME had the worst prognosis, while those with PVFS had the best. Whether this is due to those with more severe or longer lasting symptoms results in a label with the description of ME, or if being labelled with ME adversely causes a more severe or prolonged illness is unclear.


Pathophysiology


Neurological

A range of neurological structural and functional abnormalities is found in people with CFS, including lowered metabolism at the brain stem, and reduced blood flow to areas of the brain; these differences are consistent with neurological illness, but not depression or psychological illness. The World Health Organization classes chronic fatigue syndrome as a central nervous system disease. Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, sample size was limited. Neuroimaging studies in persons with CFS have identified changes in brain structure, and correlations with various symptoms. Results were not consistent across the neuroimaging brain structure studies, and more research is needed to resolve the discrepancies found between the disparate studies. Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS,
fibromyalgia Fibromyalgia (FM) is a medical condition characterized by chronic widespread pain Pain is a distressing feeling often caused by intense or damaging stimuli. The defines pain as "an unpleasant sensory and emotional experience associated wi ...

fibromyalgia
,
irritable bowel syndrome Irritable bowel syndrome (IBS), referred to previously as spastic or nervous colon, and spastic bowel, is a functional gastrointestinal disorder Functional may refer to: * Movements in architecture: ** Functionalism (architecture) In archit ...

irritable bowel syndrome
, and
interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain Chronic pain is classified as pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of P ...
. However, it is unknown if this relationship is causative. Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to
tilt table test A tilt table test (TTT), occasionally called upright tilt testing (UTT), is a medical procedure A medical procedure is a course of action intended to achieve a result in the delivery of healthcare. A medical procedure with the intention of de ...
s suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency.


Immunological

Immunological abnormalities are frequently observed in those with CFS. Decreased
NK cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic Cytotoxicity is the quality of being toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances c ...
activity is found more often in people with CFS and this correlates with severity of symptoms. People with CFS have an abnormal response to exercise, including increased production of
complement A complement is often something that completes something else, or at least adds to it in some useful way. Thus it may be: * Complement (linguistics), a word or phrase having a particular syntactic role ** Subject complement, a word or phrase add ...

complement
products, increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen ...
combined with decreased antioxidant response, and increased
Interleukin 10 Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer ...
, and
TLR4 Toll-like receptor 4 is a protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one location to another. Proteins ...

TLR4
, some of which correlates with symptom severity. Increased levels of
cytokine Cytokines are a broad and loose category of small protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and ...

cytokine
s have been proposed to account for the decreased ATP production and increased lactate during exercise; however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found. Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by
IFN Interferons (IFNs, ) are a group of signaling protein In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, ...

IFN
, and hyperactivity of
NF-κB NF-κB (or NF-kappaB, "nuclear factor kappa-light-chain-enhancer of activated B cells") is a protein complex that controls transcription of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scannin ...

NF-κB
.


Endocrine

Evidence points to abnormalities in the (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels, a decrease in the variation of
cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland. ...

cortisol
levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including
post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental Mental may refer to: * of or relating to the mind Films * Mental (2012 film), ''Mental'' (2012 film), an Australian comedy-drama * Mental (2016 film), ''Mental'' (2016 film), a Bangladeshi ...
and some autoimmune conditions. It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS, or has a secondary role in the continuation or worsening of symptoms later in the illness. In most healthy adults, the
cortisol awakening response The cortisol awakening response (CAR) is an increase between 38% and 75% in cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many a ...
shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, this increase apparently is significantly less, but methods of measuring cortisol levels vary, so this is not certain.


Autoimmunity

Autoimmunity has been proposed to be a factor in CFS, but there are only a few relevant findings so far. A subset of patients with increased
B cell #REDIRECT B cell 3D rendering of a B cell B cells, also known as B lymphocytes, are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a ne ...
activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry. In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4
muscarinic acetylcholine receptor - the natural agonist of muscarinic and nicotinic acetylcholine receptor, nicotinic receptors. - an agonist used to distinguish between these two classes of receptors. Not normally found in the body. Muscarinic acetylcholine receptors, or mAChR ...
s as well as to ß2
adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and ...
s. A 2016 Australian study found that ME/CFS patients had significantly greater numbers of
single nucleotide polymorphism In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interacti ...
s associated with the gene encoding for M3 muscarinic acetylcholine receptors.


Energy metabolism

Studies have observed
mitochondrial A mitochondrion (, plural mitochondria) is a double membrane-bound organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the ide ...

mitochondrial
abnormalities in cellular energy production, but recent focus has concentrated on secondary effects that may result in aberrant mitochondrial function because inherent problems with the mitochondria structure or genetics have not been replicated.


Diagnosis

No characteristic laboratory abnormalities are approved to diagnose CFS; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis. Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms. The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis.


Diagnostic tools

The CDC recommends considering the questionnaires and tools described in the Institute of Medicine report, which include: * The Chalder Fatigue Scale * Multidimensional Fatigue Inventory * Fisk Fatigue Impact Scale * The Krupp Fatigue Severity Scale * DePaul Symptom Questionnaire * CDC Symptom Inventory for CFS * Work and Social Adjustment Scale (WSAS) * SF-36 / RAND-36 A two-day cardiopulmonary exercise test (CPET) is not necessary for diagnosis, although lower readings on the second day may be helpful in supporting a claim for social security disability. A two-day CPET cannot be used to rule out chronic fatigue syndrome.


Definitions

Notable definitions include: * Centers for Disease Control and Prevention (CDC) definition (1994), the most widely used clinical and research description of CFS, is also called the Fukuda definition and is a revision of the ''Holmes'' or ''CDC 1988'' scoring system. The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight. * The ME/CFS 2003 Canadian Clinical working definition states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months". * The Myalgic Encephalomyelitis International Consensus Criteria (ICC) published in 2011 is based on the Canadian working definition and has an accompanying primer for cliniciansCarruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Bell DS, Carlo-Stella N, Chia J, Darragh A, Gerken A, Jo D, Lewis D, Light AR, Light K, Marshall-Gradisnik S, McLaren-Howard J, Mena I, Miwa K, Murovska M, Steven S (2012)
Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners Authors – International Consensus Panel.
The ICC does not have a six months waiting time for diagnosis. The ICC requires ''post-exertional neuroimmune exhaustion'' (PENE) which has similarities with post-exertional malaise, plus at least three neurological symptoms, at least one immune or gastrointestinal or genitourinary symptom, and at least one energy metabolism or ion transportation symptom. Unrefreshing sleep or sleep dysfunction, headaches or other pain, and problems with thinking or memory, and sensory or movement symptoms are all required under the neurological symptoms criterion. According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meet the criteria should be given the diagnosis of ''atypical myalgic encephalomyelitis''. * The 2015 definition by the
National Academy of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit A nonprofit organization (NPO), also known as a non-business entity, not-for-profit organization, or nonprofit ...
(then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required). "Diagnosis requires that the patient have the following three symptoms: 1) A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and 2) post-exertional malaise* 3) Unrefreshing sleep*; At least one of the two following manifestations is also required: 1) Cognitive impairment* 2) Orthostatic intolerance" and notes that "*Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half the time with moderate, substantial, or severe intensity."
Clinical practice guidelines A medical guideline (also called a clinical guideline, standard treatment guideline, or clinical practice line) is a document with the aim of guiding decisions and criteria regarding diagnosis, management, and treatment in specific areas of healt ...
are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in
England England is a Countries of the United Kingdom, country that is part of the United Kingdom. It shares land borders with Wales to its west and Scotland to its north. The Irish Sea lies northwest of England and the Celtic Sea to the southwest. E ...
and
Wales Wales ( cy, Cymru ) is a Countries of the United Kingdom, country that is part of the United Kingdom. It is bordered by England to the Wales–England border, east, the Irish Sea to the north and west, and the Bristol Channel to the south. It ...
, produced in 2007, (presently being updated). Other guidance can be found at the
New York Department of Health The New York State Department of Health (NYSDOH) is the department of the Government of New York (state), New York state government responsible for public health. It is headed by Health Commissioner Mary T. Bassett, who was appointed by Governor ...

New York Department of Health
.


Differential diagnosis

Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given.
Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland The thyroid, or thyroid gland, is an endocrine gland in the neck consisting of two ...

Hypothyroidism
,
anemia Anemia (American and British English spelling differences#ae and oe, also spelled anaemia) is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a lowered ability of the blood to carry oxygen. When anemia c ...

anemia
,
coeliac disease Coeliac disease or celiac disease is a long-term autoimmune disorder An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any bo ...
(that can occur without gastrointestinal symptoms),
diabetes Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients such as proteins, fats, and carbohydrate ...

diabetes
and certain
psychiatric disorders A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing In internal medici ...
are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms. Other diseases, listed by the
Centers for Disease Control and Prevention 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 The United States Department of Heal ...
, include
infectious diseases An infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents and the toxin A toxin is a harmful substance produced within living cells ...

infectious diseases
(such as
Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common virus A virus is a submicroscopic infectious agent I ...
,
influenza Influenza, commonly known as "the flu", is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

influenza
,
HIV infection Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection An infection is the invasion of an organism's body tissues by disease-causing agents, their mult ...
,
tuberculosis Tuberculosis (TB) is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), host tissues to the in ...

tuberculosis
,
Lyme disease Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia ''Borrelia'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of thing ...
), neuroendocrine diseases (such as
thyroiditis Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism. Signs and symptoms There are many different signs and symptom ...
, ,
adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones, primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conserva ...
,
Cushing's disease Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (speci ...
), hematologic diseases (such as occult malignancy,
lymphoma Lymphoma is a group of blood cancer, blood malignancies that develop from lymphocytes (a type of white blood cell). The name often refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include Lymphadenopathy, ...

lymphoma
), rheumatologic diseases (such as
fibromyalgia Fibromyalgia (FM) is a medical condition characterized by chronic widespread pain Pain is a distressing feeling often caused by intense or damaging stimuli. The defines pain as "an unpleasant sensory and emotional experience associated wi ...

fibromyalgia
,
polymyalgia rheumatica Polymyalgia rheumatica (PMR) is a syndrome with pain or stiffness, usually in the neck The neck is the part of the body on many vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellul ...
, Sjögren's syndrome,
giant-cell arteritis Giant cell arteritis (GCA), also called temporal arteritis, is an inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammabili ...
,
polymyositis Polymyositis (PM) is a type of chronic inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that s ...
,
dermatomyositis Dermatomyositis (DM) is a long-term Long-Term Capital Management L.P. (LTCM) was a hedge fund''A financial History of the United States Volume II: 1970–2001'', Jerry W. Markham, Chapter 5: "Bank Consolidation", M. E. Sharpe, Inc., 2002 based i ...

dermatomyositis
),
psychiatric diseases A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitting, or o ...
(such as
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of ...

bipolar disorder
,
schizophrenia Schizophrenia is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may b ...

schizophrenia
,
delusional disorder Delusional disorder is a mental illness A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may ...
s,
dementia Dementia manifests as a set of related symptoms, which usually surface when the brain is damaged by injury or disease. The symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or ...
,
anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder, characterized by underweight, low weight, Calorie restriction, food restriction, fear of gaining weight and a strong desire to be thin. Many people with anorexia see ...
/
bulimia nervosa Bulimia nervosa, also known as simply bulimia, is an eating disorder An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's health, physical or mental health, mental health. Only one eat ...
), neuropsychologic diseases (such as
obstructive sleep apnea Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction Obstruction may refer to: Places * Obstruction Island, in Washington state * Obstr ...
,
parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity and balance disorder, postural instability. These are the four Parkinson's disease#Motor, motor symptoms found in Parkinso ...
,
multiple sclerosis Multiple sclerosis (MS), also known as encephalomyelitis disseminata, is the most common demyelinating disease A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impa ...
), and others (such as nasal obstruction from
allergies Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, ...

allergies
,
sinusitis Sinusitis, also known as rhinosinusitis, is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science ...

sinusitis
, anatomic obstruction,
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of differe ...

autoimmune disease
s, some
chronic illness A chronic condition is a human health Health, according to 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 responsible for ...
, alcohol or other
substance abuse Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder Substance-related disorders, also known as substance use disord ...
, pharmacologic
side effect In medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descriptive knowledge) ...
s, heavy metal exposure and toxicity, marked body weight fluctuation).
Ehlers–Danlos syndromes Ehlers–Danlos syndromes are a group of rare genetic disorders, genetic connective tissue disease, connective-tissue disorders. Symptoms may include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These can be notice ...
(EDS) may also have similar symptoms. Persons with
fibromyalgia Fibromyalgia (FM) is a medical condition characterized by chronic widespread pain Pain is a distressing feeling often caused by intense or damaging stimuli. The defines pain as "an unpleasant sensory and emotional experience associated wi ...

fibromyalgia
(FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of
allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
(abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur. Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of
anhedonia Anhedonia is a diverse array of deficits in hedonic Hedonism refers to a family of theories, all of which have in common that ''pleasure'' plays a central role in them. ''Psychological'' or ''motivational hedonism'' claims that human behavio ...
, decreased motivation, and guilt; and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms.


Management

There is no approved pharmacological treatment, therapy or cure for CFS although various drugs have been or are being investigated. A 2014 report prepared by the
Agency for Healthcare Research and Quality The Agency for Healthcare Research and Quality (AHRQ; pronounced "ark" by initiates and often "A-H-R-Q" by the public) is one of twelve agencies within the United States Department of Health and Human Services The United States Department of He ...
stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and
graded exercise therapy Graded exercise therapy (GET) is an intervention technique that utilizes physical activity as the principal treatment method for addressing the symptoms of chronic fatigue syndrome. It promotes engagement in a program of physical activity that star ...
(GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some. The CDC no longer recommends these interventions, and there is some evidence of patient harm. The CDC guide for the management of CFS states that while there is no cure, a number of methods might improve symptoms. Treatment strategies for sleep problems, pain, (depression, stress, and anxiety) dizziness and lightheadedness (orthostatic Intolerance), and memory and concentration problems are enumerated. Other useful topics mentioned that patients and doctors might discuss include carefully monitoring and managing activity to avoid worsening of symptoms, counseling to cope with the impact the illness may have on quality of life, proper nutrition and nutritional supplements that may support better health, complementary therapies that might help increase energy or decrease pain. The United Kingdom's
National Institute for Health and Clinical Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body In the United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or B ...

National Institute for Health and Clinical Excellence
(NICE) 2007 guideline directed toward clinicians, specifies the need for shared decision-making between the patient and healthcare professionals, and acknowledges the reality and impact of the condition and the symptoms. The NICE guideline covers illness management aspects of
diet Diet may refer to: Food * Diet (nutrition) In nutrition Nutrition is the biochemical Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistr ...
, sleep and sleep disorders, rest, relaxation, and
pacing Pacing may refer to: In sport * Pacing, an athletic technique of spreading one's effort out over longer-distance track and field and swimming (sport), swimming races * Pacing (horse gait), a horse gait used in standardbred horse races * Motor-pace ...
. Referral to specialist care for cognitive behavioural therapy, graded exercise therapy and activity management (pacing) programmes are recommended to be offered as a choice to patients with mild or moderate CFS. In 2017 NICE announced its guidance for CFS/ME needed to be updated, and publication was expected August 18, 2021. On August 17, 2021, NICE chose to pause publication of the new guidance until professional and patient stakeholder groups can agree on the draft recommendations. The proposed draft withdrew the recommendation of GET and CBT for treatment of ME/CFS, but did say CBT might help anxiety caused by the illness.
Andrew Goddard Andrew (Bod) Goddard (born 8 November 1967 in Plymouth Plymouth () is a port city status in the United Kingdom, city in England on the south coast of Devon, approximately south-west of Exeter and west-south-west of London. Enclosing the city ...
, president of the Royal College of Physicians stated there was concern NICE did not adequately consider the expert's support and evidence of the benefits of these therapies, and urged they be included when the guideline is published. Various ME/CFS patient groups dispute the benefits of the therapies, and say that GET can make the illness more severe. Several patient charities issued a joint statement protesting the halting of the publication. On October 28, NICE published the new ME/CFS guideline, and stated GET should not be used as a treatment for ME/CFS. CBT might be offered to help a person manage the difficulties of dealing with a chronic illness, not to cure the illness. Comorbid conditions can occur in CFS which may interact with and exacerbate the symptoms of CFS. Appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include:
fibromyalgia Fibromyalgia (FM) is a medical condition characterized by chronic widespread pain Pain is a distressing feeling often caused by intense or damaging stimuli. The defines pain as "an unpleasant sensory and emotional experience associated wi ...

fibromyalgia
,
irritable bowel syndrome Irritable bowel syndrome (IBS), referred to previously as spastic or nervous colon, and spastic bowel, is a functional gastrointestinal disorder Functional may refer to: * Movements in architecture: ** Functionalism (architecture) In archit ...

irritable bowel syndrome
,
depression Depression may refer to: Mental health * Depression (mood), a state of low mood and aversion to activity * Mood disorders characterized by depression are commonly referred to as simply ''depression'', including: ** Dysthymia ** Major depressive ...
,
anxiety Anxiety is an emotion Emotions are mental state, psychological states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavioural responses, and a degree of pleasure or suffering, disp ...

anxiety
, as well as
allergies Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, ...

allergies
and chemical sensitivities.


Pacing

Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion, and was recommended for CFS in the 1980s. It is now commonly used as a management strategy in chronic illnesses and in chronic pain. Its two forms are: symptom-contingent pacing, where the decision to stop (and rest or change an activity) is determined by a self awareness of an exacerbation of symptoms; and time-contingent pacing, which is determined by a set schedule of activities that a patient estimates he or she is able to complete without triggering postexertional malaise (PEM). Thus, the principle behind pacing for CFS is to avoid overexertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but according to the principle of pacing, must rest or reduce their activity levels if it becomes clear that they have exceeded their limits. Use of a heart-rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups, and the CDC considers it useful for some individuals to help avoid post-exertional malaise.


Energy envelope theory

Energy envelope theory is considered to be consistent with pacing, and is a management strategy suggested in the 2011 international consensus criteria for ME, which referred to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, a former sufferer of CFS. Energy envelope theory states that patients should stay within the ''envelope'' of energy available to them, and avoid pushing through, which will reduce the postexertional malaise "payback" caused by overexerting and may help them make "modest gains" in physical functioning. 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 CFS. Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS. It has been promoted by various patient groups. Some patient groups recommend using a heart rate monitor to increase awareness of exertion, and allow patients to stay within their aerobic threshold envelope. Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking.


Exercise

Stretching, movement therapies, and toning exercises are recommended for pain in patients with CFS, and pain medication is also suggested. In many chronic illnesses, aerobic exercise is beneficial, but in chronic fatigue syndrome, the CDC does not recommend it. The CDC states:
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...


Counseling

The CDC states that counseling may help patients cope with pain caused by CFS, and that talking with a professional counselor or therapist may help people to more effectively manage the symptoms that affect their .


Nutrition

A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements are recommended for persons with CFS. Persons with CFS may benefit from a balanced diet and properly supervised administration of nutritional support if deficiencies are detected by medical testing. Risks of nutritional supplements include interactions with prescribed medications.


Therapies


Cognitive behavioral therapy

The CDC states that speaking with a therapist may help people cope with the illness. A 2015 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for some people, they may not yield improvement in
quality of life Quality of life (QOL) is defined by the World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations United Nations Specialized Agencies are autonomous organizations working with the United N ...

quality of life
, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach. This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in
subgroup In group theory In mathematics Mathematics (from Greek: ) includes the study of such topics as numbers ( and ), formulas and related structures (), shapes and spaces in which they are contained (), and quantities and their changes ...
s of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor. A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients. The rationale behind the use of CBT to change beliefs about the illness is disputed. A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it. Patient organisations have long criticised the use of CBT as a treatment for CFS, and the rationale behind the model is disputed. In 2012 the ME Association (MEA) commenced an opinion survey of 493 patients who had received a CBT treatment in the UK. Based on the finding of this survey, in 2015 the MEA concluded that CBT in its current form should not be recommended as a primary intervention for people with CFS In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS". In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of respondents, and that Graded Exercise Therapy caused deterioration in most respondents.


Graded exercise therapy

Previously, a 2014 National Institutes of Health report concluded that while graded exercise therapy (GET) could produce benefits, it may not yield improvement in quality of life and because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms. A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome. A 2002 Cochrane review updated in 2019 stated that exercise therapy probably has a positive effect on fatigue in adults, and slightly improves sleep, but the long-term effects are unknown, and this has limited relevance to current definitions of ME/CFS. Cochrane have announced that a new review to look at exercise therapies in chronic fatigue syndrome is to start in 2020. As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS. In 2012 the MEA commenced an opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.


Adaptive pacing therapy

APT, not to be confused with pacing, is a therapy rather than a management strategy. APT is based on the idea that CFS involves a person only having a limited amount of available energy, and using this energy wisely will mean the "limited energy will increase gradually". A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care. The PACE trial generated much
criticism Critique is a wikt:method, method of disciplined, systematic study of a written or oral discourse. Although critique is commonly understood as fault finding and negative judgment,Rodolphe Gasché (2007''The honor of thinking: critique, theory, p ...
due to the broad Oxford criteria patient selection, the standards of outcome effectiveness were lowered during the study and that re-analysis of the data did not support the magnitude of improvements initially reported. Unlike pacing, APT is based on the cognitive behavioral model of chronic fatigue syndrome and involves increasing activity levels, which it states may temporarily increase symptoms. In APT, the patient first establishes a baseline level of activity, which can be carried out consistently without any postexertional malaise ("crashes"). APT states that persons should plan to increase their activity, as able. However, APT also requires patients to restrict their activity level to only 70% of what they feel able to do, while also warning against too much rest. This has been described as contradictory, and Jason states that in comparison with pacing, this 70% limit restricts the activities that patients are capable of and results in a lower level of functioning. Jason and Goudsmit, who first described pacing and the energy envelope theory for CFS, have both criticized APT for being inconsistent with the principles of pacing and highlighted significant differences. APT was promoted by Action for ME, the patient charity involved in the PACE trial, until 2019.


Rintatolimod

Rintatolimod Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of chronic fatigue syndrome (CFS). There is some evidence it may improve some CFS symptoms. It is an immunomodulatory RNA#Double-stranded RNA, double-strande ...
is a double-stranded RNA drug developed to modulate an antiviral immune reaction through activation of toll-like receptor 3. In several clinical trials of CFS, the treatment has shown a reduction in symptoms, but improvements were not sustained after discontinuation. Evidence supporting the use of rintatolimod is deemed low to moderate. The US FDA has denied commercial approval, called a new drug application, citing several deficiencies and gaps in safety data in the trials, and concluded that the available evidence is insufficient to demonstrate its safety or efficacy in CFS. Rintatolimod has been approved for marketing and treatment for persons with CFS in
Argentina Argentina (), officially the Argentine Republic ( es, link=no, República Argentina), is a country located mostly in the southern half of South America South America is a continent A continent is any of several large landmasse ...

Argentina
, and in 2019, FDA regulatory requirements were met for exportation of rintatolimod to the country.


Prognosis

A systematic review which looked at the course of CFS without systematic biological or psychological interventions found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome. ... In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." A good outcome was associated with not attributing illness to a physical cause, and having a sense of control over symptoms. Other factors were occasionally, but not consistently, related to outcome, including age at onset, a longer duration of follow-up, and less fatigue severity at baseline. The review concludes that "irrespective of the biology of CFS, patients’ beliefs and attributions about the illness are intricately linked with the clinical presentation, the type of help sought and prognosis" Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up compared to less than 10% of adults returning to pre-illness levels of functioning.


Epidemiology

The prevalence rates for CFS/ME vary widely depending on "case definitions and diagnostic methods". Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%. In comparison, the prevalence rate for the stricter criteria, such as the 1988 CDC "Holmes" criteria for CFS and the 2003 Canadian criteria for ME (both of which, for example, exclude patients with psychiatric diagnoses), produce an incidence rate of only 0.17%. For an example of how these rates impact a nation: the CDC website states that "836,000 to 2.5 million Americans suffer from ME/CFS", but most remain undiagnosed. Females are diagnosed about 1.5 to 2.0 times more often with CFS than males. An estimated 0.5% of children have CFS, and more adolescents are affected with the illness than younger children. The incidence of CFS/ME according to age is
bimodal In statistics, a bimodal distribution is a probability distribution with two different mode (statistics), modes, which may also be referred to as a bimodal distribution. These appear as distinct peaks (local maxima) in the probability densit ...

bimodal
, i.e., it has two peaks, one at 10–19 and one at 30–39 years. The effect is seen both in female and in male data, being more pronounced in the former. It was suggested that it might be due to an increased vulnerability in these age groups.


History


Myalgic encephalomyelitis

* From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors. Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia". * In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London. The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis. The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, symptoms suggesting damage to the nervous system, and to the presumed inflammatory nature of the disorder. Björn Sigurðsson disapproved of the name, stating that the illness is rarely benign, does not always cause muscle pain, and is possibly never encephalomyelitic. The syndrome appeared in sporadic as well as epidemic cases. * In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system. * In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by: 1) muscle fatiguability in which, even after minimal physical effort, three or more days elapse before full muscle power is restored; 2) extraordinary variability or fluctuation of symptoms, even in the course of one day; and 3) chronicity. * By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling. Because of this, Ramsay proposed that the prefix "benign" be dropped.


Chronic fatigue syndrome

* In the mid-1980s, two large outbreaks of an illness that resembled
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 adult ...
drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus had the illness acquire the name "chronic Epstein-Barr virus syndrome". * In 1987, the CDC convened a working group to reach a consensus on the clinical features of the illness. The working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illness's cause and epidemiology. The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world. * In 1988, the first definition of CFS was published. Although the cause of the illness remained unknown, several attempts were made to update this definition, most notably in 1994. * The most widely referenced medical diagnosis, diagnostic criteria and definition of CFS for research and clinical purposes were published in 1994 by the CDC. * In 2006, the CDC commenced a national program to educate the American public and health-care professionals about CFS.


Other medical terms

A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS. These include: * Epidemic neuromyasthenia was a term used for outbreaks with symptoms resembling poliomyelitis. * Iceland disease and Akureyri disease were synonymous terms used for an outbreak of fatigue symptoms in Iceland. * Low natural killer syndrome, a term used mainly in Japan, reflected research showing diminished ''in vitro'' activity of natural killer cells isolated from patients. * Neurasthenia has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS. * Royal Free disease was named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis". * Tapanui flu was a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people had the syndrome.


Society and culture


Naming

Many names have been proposed for the illness. Currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown. The term "chronic fatigue syndrome" has been criticized by some patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research. While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness, there is resistance amongst some clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated. A 2015 report from the
Institute of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit A nonprofit organization (NPO), also known as a non-business entity, not-for-profit organization, or nonprofit ...
recommended the illness be renamed "systemic exertion intolerance disease", (SEID), and suggested new diagnostic criteria, proposing post-exertional malaise, (PEM), impaired function, and sleep problems are core symptoms of ME/CFS. Additionally, they described cognitive impairment and orthostatic intolerance as distinguishing symptoms from other fatiguing illnesses.


Economic impact

Reynolds ''et al.'' (2004) estimated that the illness caused about $20,000 per person with CFS in lost productivity, which totals to $9.1 billion per year in the United States. This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs. A 2008 study calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion. A 2017 estimate for the annual economic burden in the United Kingdom from ME/CFS was 3.3 billion pounds sterling.


Awareness day

May 12 is designated as ME/CFS International Awareness Day. The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and health-care professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness." It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia.


Doctor–patient relations

Some in the medical community do not recognize CFS as a real condition, nor does agreement exist on its prevalence. There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. This uncertainty can significantly affect doctor-patient relations. A 2006 survey of general practitioner, GPs in southwest England found that despite more than two-thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male, and seeing more patients with the condition in the last year. From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health-care providers. In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet were blamed and dismissed. A study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients.


Blood donation

In 2010, several national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from Blood donation, donating blood, based on concern following the 2009 claim of a link, between CFS and a retrovirus which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services, the New Zealand Blood Service, the Australian Red Cross Blood Service and the American Association of Blood Banks, In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm ''to those patients'' that may result from their giving blood. Donation policy in the UK now states, "The condition is relapsing by nature and donation may make symptoms worse, or provoke a relapse in an affected individual."


Controversy

Much contention has arisen over the cause, pathophysiology, nomenclature, and diagnostic criteria of CFS. Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition; nor did agreement exist on its prevalence or seriousness. Some people with CFS reject any psychological component. In 1970, two British psychiatrists, McEvedy and Beard, reviewed the case notes of 15 outbreaks of benign myalgic encephalomyelitis and concluded that it was caused by mass hysteria on the part of patients, or altered medical perception of the attending physicians. Their conclusions were based on previous studies that found many normal physical test results, a lack of a discernible cause, and a higher prevalence of the illness in females. Consequently, the authors recommended that the disease should be renamed "myalgia nervosa". This perspective was rejected in a series of case studies by Dr. Melvin Ramsay and other staff of the Royal Free Hospital, the center of a significant outbreak. The psychological hypothesis posed by McEvedy and Beard created great controversy, and convinced a generation of health professionals in the UK that this could be a plausible explanation for the condition, resulting in neglect by many medical specialties. The specialty that did take a major interest in the illness was psychiatry. Because of the controversy, sociologists hypothesized that stresses of modern living might be a cause of the illness, while some in the media used the term "Yuppie flu" and called it a disease of the middle class. People with disabilities from CFS were often not believed and were accused of being Malingering, malingerers. The November 1990 issue of ''Newsweek'' ran a cover story on CFS, which although supportive of an organic cause of the illness, also featured the term 'yuppie flu', reflecting the stereotype that CFS mainly affected yuppies. The implication was that CFS is a form of Burnout (psychology), burnout. The term 'yuppie flu' is considered List of disability-related terms with negative connotations, offensive by both patients and clinicians. In 2009, the journal ''Science'' published a study that identified the XMRV, XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding, and in 2011, the editor of ''Science'' formally retracted its XMRV paper while the ''Proceedings of the National Academy of Sciences'' similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS.


Research funding


United Kingdom

The lack of research funding and the funding bias towards biopsychosocial studies and against biomedical studies has been highlighted a number of times by patient groups and a number of UK politicians. A parliamentary inquiry by an ''ad hoc'' group of parliamentarians in the United Kingdom, set up and chaired by former MP, Ian Gibson (politician), Dr Ian Gibson, called the Group on Scientific Research into CFS/ME, was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research. The MRC confirmed to the group that from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain. In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding. In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that far too much emphasis in the past had been on psychological research, with insufficient attention to biomedical research, and that further biomedical research must be undertaken to help discover a cause and more effective forms of management for this disease. Controversy surrounds psychologically oriented models of the disease and behavioral treatments conducted in the UK.


United States

In 1998, $13 million for CFS research was found to have been redirected or improperly accounted for by the United States CDC, and officials at the agency misled Congress about the irregularities. The agency stated that they needed the funds to respond to other public-health emergencies. The director of a U.S. national patient advocacy group charged the CDC had a bias against studying the disease. The CDC pledged to improve their practices and to restore the $13 million to CFS research over three years. On 29 October 2015, the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center was to study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke would lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort.


Notable cases

In 1989, ''The Golden Girls'' (1985–1992) featured chronic fatigue syndrome in a two-episode arc, "Sick and Tired: Part 1" and "Part 2", in which protagonist Dorothy Zbornak, portrayed by Bea Arthur, after a lengthy battle with her doctors in an effort to find a diagnosis for her symptoms, is finally diagnosed with CFS. American author Ann Bannon had CFS. Laura Hillenbrand, author of the popular book ''Seabiscuit'', has struggled with CFS since age 19.


Research

The different case definitions used to research the illness influence the types of patients selected for studies, and research also suggests subtypes of patients may exist within a heterogeneous population. In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders. The lack of a single, unifying case definition was criticized in the Institute of Medicine's 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results" (study results). More robust diagnostic methods are being investigated with the aim of identifying unique biomarkers that may be used in clinical testing. In 2019, two different papers were published proposing blood-based biomarkers for CFS. One found that blood cells of CFS patients could be distinguished from healthy controls by their response to Osmotic shock, hyperosmotic stress. Another found that the red blood cells of CFS patients were stiffer, and thus less able to deform in order to pass through Capillary, capilliaries.


See also

* Long COVID


References


External links

* {{DEFAULTSORT:Chronic fatigue syndrome Chronic fatigue syndrome, Ailments of unknown cause Immune system disorders Neurological disorders