View source for Medicine:Chronic fatigue syndrome

{{Infobox medical condition (new)
| name       = Chronic fatigue syndrome
| synonyms   = Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS),<ref name=CDC2020/> myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), systemic exertion intolerance disease (SEID), others<ref name=IOM2015 />{{rp|20}}
| speciality = [[Medicine:Rheumatology|Rheumatology]], rehabilitation medicine, [[Biology:Endocrinology|endocrinology]], [[Medicine:Infectious disease (medical specialty)|infectious disease]], [[Biology:Neurology|neurology]], [[Biology:Immunology|immunology]], internal medicine, paediatrics, other specialists in ME/CFS<ref name="NICE diagnosis 2021">{{cite web |title=Recommendations – Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management – Guidance |url=https://www.nice.org.uk/guidance/ng206/chapter/Recommendations#diagnosis |url-status=live |publisher=NICE |date=29 October 2021 |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20211229193427/https://www.nice.org.uk/guidance/ng206/chapter/Recommendations#diagnosis |archive-date=29 December 2021}}</ref>
| image      = ME-CFS Diagnostic Criteria Comparison.webp
| caption    = Chart of the symptoms of CFS according to various definitions
| symptoms   = Worsening of symptoms with activity, [[Medicine:Fatigue#Chronic|long-term fatigue]], others<ref name=CDC2020/>
| onset      = 10 to 30 years old<ref name="pmid29722371"/>
| duration   = Often for years<ref name=CDCWhatIs/>
| causes     = Unknown<ref name=CDC2020/>
| risks      = Female sex, [[Biology:Virus|virus]] and bacterial infections, [[Social:Consanguinity|blood relatives]] with the illness, [[Medicine:Major trauma|major injury]], bodily response to severe [[Medicine:Psychological stress|stress]] and others<ref name="CDC-causes-2020" /><ref name=ICC2011primer />{{Rp|1–2}}
| diagnosis  = Based on symptoms<ref name=CDC2020/>
| treatment  = [[Medicine:Symptomatic treatment|Symptomatic]]<ref name=CDC2020treat/><ref name=Coch2019Oct2 />
| prevalence = About 0.68 to 1% globally<ref name=SandlerLloyd2020>{{cite journal |vauthors=Sandler CX, Lloyd AR |title=Chronic fatigue syndrome: progress and possibilities |journal=The Medical Journal of Australia |volume=212 |issue=9 |pages=428–433 |date=May 2020 |pmid=32248536 |s2cid=214810583 |doi=10.5694/mja2.50553}}</ref><ref name=Lim2020/>
}}
<!-- Definitions and symptoms -->

'''Chronic fatigue syndrome''' ('''CFS'''), also called '''myalgic encephalomyelitis''' ('''ME''') or '''ME/CFS''', is a complex, debilitating, long-term medical condition. The [[Philosophy:Etiology|root cause(s)]] of the disease are unknown and the [[Medicine:Pathophysiology|mechanisms]] are not fully understood.<ref name="Cdc.gov_2018">{{cite web |title=Etiology and Pathophysiology &#124; Presentation and Clinical Course &#124; Healthcare Providers &#124; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) &#124; CDC |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html |publisher=Cdc.gov |date=12 July 2018 |access-date=8 March 2022 |archive-date=18 July 2018 |archive-url=https://web.archive.org/web/20180718174436/https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html |url-status=live}}</ref> Distinguishing core symptoms are lengthy exacerbations or flare-ups of the illness following ordinary minor physical or mental activity, known as post-exertional malaise (PEM);<ref name="CDCINFO2020"/><ref name="Dibble McGrath Ponting 2020 p."/> greatly diminished capacity to accomplish tasks that were routine before the illness; and sleep disturbances.<ref name="CDCINFO2020">{{cite web|title=Information for Healthcare Providers {{!}} CDC|url=https://www.cdc.gov/me-cfs/healthcare-providers/index.html|date=13 April 2020|website=www.cdc.gov|access-date=17 June 2020|archive-date=9 August 2020|archive-url=https://web.archive.org/web/20200809172726/https://www.cdc.gov/me-cfs/healthcare-providers/index.html|url-status=live}}</ref><!-- Quote = Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, debilitating disease with systemic effects. ME/CFS is characterized by reduced ability to perform pre-illness activities that lasts for more than 6 months and is accompanied by profound fatigue, which is not improved by rest... --><ref name=CDCsym2020/><ref name="CDC2020">{{cite web|title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/|date=13 April 2020|website=www.cdc.gov|access-date=20 May 2020|archive-date=22 August 2020|archive-url=https://web.archive.org/web/20200822180244/https://www.cdc.gov/me-cfs/index.html|url-status=live}}</ref><ref name=CDCWhatIs>{{cite web|title=What is ME/CFS? {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/about/index.html|date=12 July 2018|website=www.cdc.gov|access-date=21 May 2020|archive-date=17 August 2020|archive-url=https://web.archive.org/web/20200817094848/https://www.cdc.gov/me-cfs/about/index.html|url-status=live}}</ref><!-- Quote = People with ME/CFS are often not able to do their usual activities. --><ref name=IOM2015>{{cite book|last1=Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|last2=Board on the Health of Select Populations| author3 =Institute of Medicine |date=10 February 2015|title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness|pmid=25695122|url=https://www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf|access-date=28 July 2020|archive-date=20 January 2017|archive-url=https://web.archive.org/web/20170120175658/https://www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf|url-status=live}}</ref>{{Rp|7}} The Center for Disease Control and Prevention’s (CDC) diagnostic criteria also require at least one of the following: (1) [[Medicine:Orthostatic intolerance|Orthostatic intolerance]] (difficulty sitting and standing upright) or (2) impaired memory or attention. Frequently and variably, other common symptoms occur involving numerous body systems, and [[Medicine:Chronic pain|chronic pain]] is very common.<ref name="CDCsym2020">{{cite web|title=Symptoms of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|date=19 November 2019|website=www.cdc.gov|access-date=20 May 2020|archive-date=22 August 2020|archive-url=https://web.archive.org/web/20200822180337/https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|url-status=live}}</ref><ref name="CDC2020b">{{cite web|title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/index.html|date=13 April 2020|website=www.cdc.gov|access-date=20 May 2020|archive-date=22 August 2020|archive-url=https://web.archive.org/web/20200822180244/https://www.cdc.gov/me-cfs/index.html|url-status=live}}</ref> The often incapacitating [[Medicine:Fatigue#Chronic|fatigue]] in CFS is different from that caused by normal strenuous ongoing exertion, is not significantly relieved by rest, and is not due to a previous medical condition.<ref name="CDCsym2020" /> Diagnosis is based on the person's symptoms because no confirmed diagnostic test is available.<ref name="Estévez-López 2020" />

<!-- Cause, impact, and management -->
Proposed mechanisms include biological, [[Biology:Genetics|genetic]], [[Biology:Epigenetics|epigenetic]], infectious, and physical or psychological stress affecting the [[Biology:Biochemistry|biochemistry]] of the body.<ref name="CDC-causes-2020" /><ref name=Af2003>{{cite journal |vauthors=Afari N, Buchwald D |title=Chronic fatigue syndrome: a review |journal=The American Journal of Psychiatry |volume=160 |issue=2 |pages=221–236 |date=February 2003 |pmid=12562565 |s2cid=8210151 |doi=10.1176/appi.ajp.160.2.221}}</ref> Persons with CFS may recover or improve over time, but some will become severely affected and disabled for an extended period.<ref name="CDC-Severe-2019">{{cite web |title=Severely Affected Patients – Clinical Care of Patients – Healthcare Providers – Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) |url=https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/severely-affected-patients.html |url-status=live |publisher=CDC |date=19 November 2019 |access-date=30 November 2020 |archive-date=11 December 2020 |archive-url=https://web.archive.org/web/20201211213025/https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/severely-affected-patients.html}}</ref> No therapies or medications are approved to treat the cause of the illness; treatment is aimed at alleviation of symptoms.<ref name=CDC2020treat>{{cite web|title=Treatment of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/treatment/index.html|date=19 November 2019|website=www.cdc.gov|access-date=22 May 2020|archive-date=20 March 2021|archive-url=https://web.archive.org/web/20210320194421/https://www.cdc.gov/me-cfs/treatment/index.html|url-status=live}} {{PD-notice}}</ref><ref name="NICE21">{{cite web |title=Recommendations – Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management – Guidance |url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#managing-mecfs |url-status=live |publisher=NICE |date=29 October 2021 |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20211229193427/https://www.nice.org.uk/guidance/ng206/chapter/Recommendations#managing-mecfs |archive-date=29 December 2021}}</ref> The CDC recommends pacing (personal activity management) to keep mental and physical activity from making symptoms worse.<ref name=CDC2020treat/> Limited evidence suggests that counseling,<ref name=Smith2015>{{cite journal |type=Systematic review |vauthors=Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD |title=Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop |journal=Annals of Internal Medicine |volume=162 |issue=12 |pages=841–850 |date=June 2015 |pmid=26075755 |doi=10.7326/M15-0114 |doi-access=free}}</ref> personalized activity management,<ref name="NICE21"/> and the use of [[Chemistry:Rintatolimod|rintatolimod]] help improve some patients' functional abilities.

<!-- Epidemiology and controversy -->
About 1% of primary-care patients have CFS; estimates of incidence vary widely because various epidemiological studies have used dissimilar definitions.<ref name=Lim2020/><ref name="Estévez-López 2020">{{cite journal | vauthors = Estévez-López F, Mudie K, Wang-Steverding X, Bakken IJ, Ivanovs A, Castro-Marrero J, Nacul L, Alegre J, Zalewski P, Słomko J, Strand EB, Pheby D, Shikova E, Lorusso L, Capelli E, Sekulic S, Scheibenbogen C, Sepúlveda N, Murovska M, Lacerda E | display-authors = 6 | title = Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology | journal = Journal of Clinical Medicine | volume = 9 | issue = 5 | page = 1557 | date = May 2020 | pmid = 32455633 | pmc = 7290765 | doi = 10.3390/jcm9051557 | publisher = MDPI AG | doi-access = free }}</ref><ref name=SandlerLloyd2020/> It has been estimated that 836,000 to 2.5 million Americans and 250,000 to 1,250,000 people in the United Kingdom have CFS.<ref name="CDC2020"/><ref name="UKDOH_CFS">{{cite web |title= Annex 1: Epidemiology of CFS/ME |publisher= UK Department of Health |date= 6 January 2012 |url= http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/DH_4879305 |archive-url= http://webarchive.nationalarchives.gov.uk/20120106043826/http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/DH_4879305 |url-status= dead |archive-date= 6 January 2012 |access-date=28 July 2017}}</ref> CFS occurs 1.5 to 2 times as often in women as in men.<ref name=Lim2020>{{cite journal | vauthors = Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG | title = Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) | journal = Journal of Translational Medicine | volume = 18 | issue = 1 | page = 100 | date = February 2020 | pmid = 32093722 | pmc = 7038594 | doi = 10.1186/s12967-020-02269-0 }}</ref> It most commonly affects adults between ages 40 and 60 years;<ref name=CDCEpide2018>{{cite web|title=Epidemiology {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html|date=12 July 2018|website=www.cdc.gov|access-date=24 May 2020|archive-date=6 June 2020|archive-url=https://web.archive.org/web/20200606194443/https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html|url-status=live}}</ref> it can occur at other ages, including childhood.<ref name=CDC2020children /> Other studies suggest that about 0.5% of children have CFS, and that it is more common in adolescents than in younger children.<ref name=IOM2015/>{{Rp|182}}<ref name="CDC2020children">{{cite web|title=ME/CFS in Children {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/me-cfs-children/index.html|date=15 May 2019|website=www.cdc.gov|access-date=24 May 2020|quote=ME/CFS is often thought of as a problem in adults, but children (both adolescents and younger children) can also get ME/CFS.|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728135116/https://www.cdc.gov/me-cfs/me-cfs-children/index.html|url-status=live}}</ref> Chronic fatigue syndrome is a major cause of school absence.<ref name="IOM2015" />{{Rp|183}} CFS significantly reduces health, happiness, productivity, and can also cause socio-emotional disruptions such as loneliness and alienation.<ref>{{cite journal | vauthors = Boulazreg S, Rokach A | title = The Lonely, Isolating, and Alienating Implications of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | journal = Healthcare | volume = 8 | issue = 4 | page = 413 | date = October 2020 | pmid = 33092097 | pmc = 7711762 | doi = 10.3390/healthcare8040413 | doi-access = free }}</ref> 

There is [[Unsolved:Controversies related to chronic fatigue syndrome|controversy over many aspects of the disorder]]. Various physicians, researchers, and patient advocates promote different names and diagnostic criteria. Results of studies of proposed causes and treatments are often poor or contradictory.<ref name="CochraneCBT">{{cite journal | vauthors = Price JR, Mitchell E, Tidy E, Hunot V | title = Cognitive behaviour therapy for chronic fatigue syndrome in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 3 | pages = CD001027 | date = July 2008 | pmid = 18646067 | pmc = 7028002 | doi = 10.1002/14651858.CD001027.pub2 | veditors = Price JR }}</ref>

== Signs and symptoms ==
The United States Centers for Disease Control and Prevention (CDC) recommends these criteria for diagnosis:<ref name=CDCsym2020/>
# 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.<ref name="CDCTREATSYMPTOMS2019">{{cite web |date=19 November 2019 |title=Treating the Most Disruptive Symptoms First and Preventing Worsening of Symptoms {{!}} CDC |url=https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/treating-most-disruptive-symptoms.html |url-status=live |archive-url=https://web.archive.org/web/20200807010756/https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/treating-most-disruptive-symptoms.html |archive-date=7 August 2020 |access-date=19 August 2020 |website=www.cdc.gov}}</ref> The 'relapse', or 'crash', may last days, weeks or longer. This is known as post-exertional malaise (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:<ref name=CDCsym2020/>
* Problems with thinking and memory (cognitive dysfunction, sometimes described as "brain fog")<!-- <ref name=CDCsym2020/> -->
* While standing or sitting upright; lightheadedness, dizziness, weakness, fainting or vision changes may occur ([[Medicine:Orthostatic intolerance|orthostatic intolerance]])

===Other common symptoms===
Many, but not all people with ME/CFS report:<ref name=CDCsym2020/>
* Muscle pain, joint pain without swelling or redness, and headache
* Tender lymph nodes in the neck or armpits
* Sore throat
* [[Medicine:Irritable bowel syndrome|Irritable bowel syndrome]]
* Chills and night sweats
* Allergies and sensitivities to foods, odors, chemicals, lights, or noise
* Shortness of breath
* [[Medicine:Arrhythmia|Irregular heartbeat]]

Increased sensitivity to sensory stimuli and pain have also been observed in CFS.<ref name="CDC-Severe-2019" /><ref name="Nijs-2012">{{cite journal |vauthors=Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS |date=February 2012 |title=In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome |journal=European Journal of Clinical Investigation |volume=42 |issue=2 |pages=203–12 |doi=10.1111/j.1365-2362.2011.02575.x |pmid=21793823 |s2cid=13926525}}</ref>

The CDC recommends that people with symptoms of CFS consult a physician to rule out other illnesses, which may be treatable.<ref name="CDCdiagnosis">{{cite web |title=CDC&nbsp;– Chronic Fatigue Syndrome (CFS)&nbsp;– Diagnosis |url=https://www.cdc.gov/cfs/diagnosis/index.html |url-status= |archive-url=https://web.archive.org/web/20120805012528/http://www.cdc.gov/cfs/diagnosis/index.html |archive-date=5 August 2012 |access-date=22 July 2012 |publisher=Cdc.gov}}</ref>

=== Onset ===
The onset of CFS may be gradual or sudden.<ref name="IOM2015" /> When it begins suddenly, it often follows an episode of infectious-like symptoms or a known infection, and between 20 and 80% of patients report an infectious-like onset.<ref name="IOM2015" />{{Rp|page=158}}<ref name="O'Boyle" /> When gradual, the illness may begin over the course of months or years with no apparent trigger.<ref name="CDCPres">{{cite web |date=19 November 2019 |title=Presentation and Clinical Course of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/index.html |url-status=live |archive-url=https://web.archive.org/web/20200728125126/https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/index.html |archive-date=28 July 2020 |access-date=11 July 2020 |website=www.cdc.gov}}</ref> Studies disagree as to which pattern is more common.<ref name=IOM2015 />{{rp|158}}{{rp|181}} CFS may also occur after physical trauma such as a car accident or surgery.<ref name="CDCPres" />

=== Physical functioning ===
[[File:HRQoL of people with ME-CFS.webp|thumb|Results of a study on quality of life of people with CFS, showing it to be lower than in 20 other chronic conditions]]
CFS often causes significant disability, but the degree can vary greatly.<ref name="CDC2020" /><ref name="CDCPres" /> Some people with mild CFS may lead relatively normal lives with vigilant energy management, while moderately affected patients may be unable to work or spend much time upright. People with severe CFS are generally housebound or bedbound, and may be unable to care for themselves.<ref name="CDCPres" /> 

The majority of people with CFS have significant difficulty engaging in work, school, and family activities for extended periods of time.<ref name="CDCsym2020" /><ref name="CDCPres" /> An estimated 75% are unable to work because of their illness, and about 25% are housebound or bedridden for long periods, often decades.<ref name="IOM2015" />{{rp|32}}<ref name="CDCWhatIs" /><ref name="CDCgrandroundsfeb16">{{cite web |date=28 February 2018 |title=Chronic Fatigue Syndrome: Advancing Research and Clinical Education |url=https://www.cdc.gov/grand-rounds/pp/2016/20160216-chronic-fatigue.html |url-status=live |archive-url=https://web.archive.org/web/20200728135224/https://www.cdc.gov/grand-rounds/pp/2016/20160216-chronic-fatigue.html |archive-date=28 July 2020 |access-date=26 May 2020 |website=Centers for Disease Control and Prevention}}</ref> In one review on employment status, more than half of CFS patients were on disability benefits or temporary sick leave, and less than a fifth worked full-time.<ref name="Ross">{{cite journal |vauthors=Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB |date=May 2004 |title=Disability and chronic fatigue syndrome: a focus on function |journal=Archives of Internal Medicine |volume=164 |issue=10 |pages=1098–107 |doi=10.1001/archinte.164.10.1098 |pmid=15159267 |doi-access=free}}</ref> In children, CFS is a major cause of school absence.<ref name="IOM2015" />{{Rp|183}} According to a 1996 study by McCully et al, people with CFS report critical reductions in levels of physical activity, and according to a 2009 study, patients exhibit a reduction in the complexity of their activities.<ref name="PMID_8771284">{{cite journal |vauthors=McCully KK, Sisto SA, Natelson BH |date=January 1996 |title=Use of exercise for treatment of chronic fatigue syndrome |journal=Sports Medicine |volume=21 |issue=1 |pages=35–48 |doi=10.2165/00007256-199621010-00004 |pmid=8771284 |s2cid=239650}}</ref><ref>{{cite journal |vauthors=Burton C, Knoop H, Popovic N, Sharpe M, Bleijenberg G |date=June 2009 |title=Reduced complexity of activity patterns in patients with chronic fatigue syndrome: a case control study |journal=BioPsychoSocial Medicine |volume=3 |issue=1 |page=7 |doi=10.1186/1751-0759-3-7 |pmc=2697171 |pmid=19490619}}</ref> Many people with CFS also experience strongly disabling [[Medicine:Chronic pain|chronic pain]].<ref name="PMID_16843021">{{cite journal |vauthors=Meeus M, Nijs J, Meirleir KD |date=May 2007 |title=Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: a systematic review |journal=European Journal of Pain |volume=11 |issue=4 |pages=377–86 |doi=10.1016/j.ejpain.2006.06.005 |pmid=16843021 |s2cid=21414690}}</ref>

Symptoms can fluctuate over time, making the condition difficult to manage. Persons who feel better for a period may overextend their activities, triggering post-exertional malaise and a worsening of symptoms.<ref name="CDCTREATSYMPTOMS2019" /> Severity may also change over time, with periods of worsening, improvement or remission sometimes occurring.<ref name="CDCPres" />

People with CFS have decreased quality of life according to the [[Social:SF-36|SF-36]] questionnaire, especially in the domains of vitality, physical functioning, general health, physical role, and social functioning. However, their scores in the "role emotional" and mental health domains were not substantially lower than healthy controls.<ref name="pmid28033311">{{cite journal | vauthors = Unger ER, Lin JS, Brimmer DJ, Lapp CW, Komaroff AL, Nath A, Laird S, Iskander J | display-authors = 6 | title = CDC Grand Rounds: Chronic Fatigue Syndrome - Advancing Research and Clinical Education | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 65 | issue = 50–51 | pages = 1434–1438 | date = December 2016 | pmid = 28033311 | doi = 10.15585/mmwr.mm655051a4 | url = https://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm655051a4.pdf | url-status = live | access-date = 5 January 2017 | quote = "The highest prevalence of illness is in persons aged 40–50 years..." | doi-access = free | archive-url = https://web.archive.org/web/20170106010408/https://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm655051a4.pdf | archive-date = 6 January 2017 }}</ref> A 2015 study found that people with CFS had lower health-related quality of life than 20 other chronic conditions, including multiple sclerosis, [[Medicine:Kidney failure|kidney failure]], and lung cancer.<ref>{{cite journal | vauthors = Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, Ehlers L | title = The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) | journal = PLOS ONE | volume = 10 | issue = 7 | pages = e0132421 | date = 2015-07-06 | pmid = 26147503 | pmc = 4492975 | doi = 10.1371/journal.pone.0132421 | bibcode = 2015PLoSO..1032421F | doi-access = free | veditors = Furlan R }}</ref>

=== Cognitive functioning ===
Cognitive dysfunction is one of the most disabling aspects of CFS due to its negative impact on occupational and social functioning. 50 to 80% of people with CFS are estimated to have serious problems with cognition.<ref name="Christley 2013 p=353">{{cite journal |vauthors=Christley Y, Duffy T, Everall IP, Martin CR |date=April 2013 |title=The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma |journal=Current Psychiatry Reports |volume=15 |issue=4 |page=353 |doi=10.1007/s11920-013-0353-8 |pmid=23440559 |s2cid=25790262}}</ref> Cognitive symptoms are mainly due to deficits in attention, memory, and reaction time. Measured cognitive abilities are found to be below projected normal values and likely to affect day-to-day activities, causing increases in common mistakes, forgetting scheduled tasks, or having difficulty responding when spoken to.<ref name="Cvejic 2016"/>

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. Patients who report poorer health status tend to also report more severe cognitive trouble, and better physical functioning is associated with less visuoperceptual difficulty and fewer language-processing complaints.<ref name="Cvejic 2016"/>{{Rp|page=24}}

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.<ref name="Cvejic 2016">{{cite journal | vauthors = Cvejic E, Birch RC, Vollmer-Conna U | title = Cognitive Dysfunction in Chronic Fatigue Syndrome: a Review of Recent Evidence | journal = Current Rheumatology Reports | volume = 18 | issue = 5 | page = 24 | date = May 2016 | pmid = 27032787 | doi = 10.1007/s11926-016-0577-9 | publisher = Springer Science and Business Media LLC | s2cid = 38748839 }}</ref>

==Cause==
The cause of CFS is unknown.<ref name="pmid28033311"/><ref name="Bateman-2021">{{cite journal | vauthors = Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, Dempsey TT, Dimmock ME, Dowell TG, Felsenstein D, Kaufman DL, Klimas NG, Komaroff AL, Lapp CW, Levine SM, Montoya JG, Natelson BH, Peterson DL, Podell RN, Rey IR, Ruhoy IS, Vera-Nunez MA, Yellman BP | display-authors = 6 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management | language = English | journal = Mayo Clinic Proceedings | volume = 96 | issue = 11 | pages = 2861–2878 | date = November 2021 | pmid = 34454716 | doi = 10.1016/j.mayocp.2021.07.004 | s2cid = 237419583 }}</ref> Both genetic and environmental factors are believed to contribute, but the genetic component is unlikely to be a single gene.<ref name="pmid28033311" /> Problems with the nervous and immune systems, and energy metabolism, may be factors.<ref name="Bateman-2021" /> CFS is a biological disease, not a psychiatric or psychological condition,<ref>{{cite web |date=10 July 2018 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome&nbsp;– Etiology and Pathophysiology |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html |url-status=live |archive-url=https://web.archive.org/web/20180718174436/https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html |archive-date=18 July 2018 |access-date=18 July 2018}}</ref><ref name="pmid28033311" /> and is not caused by [[Biology:Deconditioning|deconditioning]].<ref name="pmid28033311" /><ref>{{Cite web |date=2022-07-07 |title=Chronic fatigue syndrome (CFS) |url=http://www.betterhealth.vic.gov.au/health/conditionsandtreatments/chronic-fatigue-syndrome-cfs |access-date=2023-02-01 |website= |publisher=Department of Health, State Government of Victoria, Australia |language=en}}</ref> However, the biological abnormalities found in research are not sensitive or specific enough for diagnosis.<ref name="pmid28033311"/>{{Rp|page=1437}}

Because the illness often follows a known or apparent viral illness, various infectious agents have been proposed, but a single cause has not been found.<ref name="Rosa2018">{{cite journal |vauthors=Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, Prusty BK |title=Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) |journal=J Transl Med |volume=16 |issue=1 |page=268 |date=October 2018 |pmid=30285773 |pmc=6167797 |doi=10.1186/s12967-018-1644-y }}</ref><ref name="IOM2015" /><ref name="pmid28033311" /> Hypothesized infections include mononucleosis, ''[[Biology:Chlamydophila pneumoniae|Chlamydophila pneumoniae]]'', [[Biology:Human herpesvirus 6|human herpesvirus 6]], and [[Unsolved:Lyme disease|Lyme disease]]. Inflammation may be involved.<ref>{{cite journal | vauthors = Gerwyn M, Maes M | s2cid = 11823204 | title = Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings | journal = Current Rheumatology Reports | volume = 19 | issue = 1 | page = 1 | date = January 2017 | pmid = 28116577 | doi = 10.1007/s11926-017-0628-x }}</ref> CFS has been observed to develop after mononucleosis and [[Medicine:Gastroenteritis|gastroenteritis]].<ref>{{cite web | url=https://www.southerncross.co.nz/group/medical-library/chronic-fatigue-syndrome-tapanui-flu | title=Chronic fatigue syndrome (Tapanui flu) | website=www.southerncross.co.nz Southern Cross NZ | date=March 2020 | access-date=3 February 2021 | archive-date=30 January 2021 | archive-url=https://web.archive.org/web/20210130160929/https://www.southerncross.co.nz/group/medical-library/chronic-fatigue-syndrome-tapanui-flu | url-status=live }}</ref>

=== Risk factors ===
All ages, ethnic groups, and income levels are susceptible to the illness. The CDC states that while Caucasians may be diagnosed more frequently than other races in America,<ref name=CDCWhatIs/> the illness is at least as prevalent among African Americans and Hispanics.<ref name=CDCEpide2018/> A 2009 meta-analysis found that Asian Americans (Odds ratio: 0.097; 95%; Confidence interval: 0.004 - 0.65) have a much lower risk of CFS than White Americans, while Native Americans (OR: 11.5; 95% CI: 1.08 - 56.4) have a higher (probably a much higher) risk and African Americans (OR: 2.95; 95% CI: 0.69 - 10.4) probably have a higher risk. The review acknowledged that studies and data were limited.<ref>{{cite journal | vauthors = Dinos S, Khoshaba B, Ashby D, White PD, Nazroo J, Wessely S, Bhui KS | title = A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping | journal = International Journal of Epidemiology | volume = 38 | issue = 6 | pages = 1554–70 | date = December 2009 | pmid = 19349479 | doi = 10.1093/ije/dyp147 |  doi-access = free }}</ref>

More women than men get CFS.<ref name=CDCWhatIs/> 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.<ref name="Lim2020"/> The CDC estimates CFS occurs up to four times more often in women than in men.<ref name=CDCEpide2018/> The illness can occur at any age, but has the highest prevalence in people aged 40 to 60.<ref name=CDCEpide2018/> CFS is less prevalent among children and adolescents than among adults.<ref name=CDC2020children />

People with affected relatives appear to be more likely to get ME/CFS, implying the existence of genetic risk factors. Results of genetic studies have been largely contradictory or unreplicated. One study found an association with mildly deleterious mitochondrial DNA variants, and another found an association with certain variants of human leukocyte antigen genes.<ref name="Dibble McGrath Ponting 2020 p.">{{cite journal | vauthors = Dibble JJ, McGrath SJ, Ponting CP | title = Genetic risk factors of ME/CFS: a critical review | journal = Human Molecular Genetics | volume = 29 | issue = R1 | pages = R117–R124 | date = September 2020 | pmid = 32744306 | pmc = 7530519 | doi = 10.1093/hmg/ddaa169 }}</ref>

===Viral and other infections===
'''Post-viral fatigue syndrome''' (PVFS) or '''post-viral syndrome''' describes a type of chronic fatigue syndrome that occurs following a viral infection.<ref name="O'Boyle">{{cite journal |vauthors=O'Boyle S, Nacul L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM, Lacerda EM |title=A Natural History of Disease Framework for Improving the Prevention, Management, and Research on Post-viral Fatigue Syndrome and Other Forms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |journal= Frontiers in Medicine|volume=8 |issue= |page=688159 |date=2021 |pmid=35155455 |pmc=8835111 |doi=10.3389/fmed.2021.688159 |url=|doi-access=free }}</ref> One review found higher [[Biology:Epstein–Barr virus|Epstein–Barr virus]] (EBV) antibody activity in patients with CFS, and that a subset were likely to have increased EBV activity compared to controls.<ref name="Eriksen">{{cite journal |vauthors=Eriksen W |date=16 August 2018 |title=ME/CFS, case definition, and serological response to Epstein–Barr virus. A systematic literature review |journal=Fatigue: Biomedicine, Health & Behavior |volume=6 |issue=4 |pages=220–34 |doi=10.1080/21641846.2018.1503125 |quote=The levels of antibodies to EBV in ME/CFS patients differed from those in controls in 14 studies. The differences in EBV serology that were revealed, were almost exclusively signs that may indicate higher EBV activity in the patient group. The serological differences between patients and controls were seen in the two studies in which ME/CFS was defined using the Canadian criteria, in 5 of the 9 studies using the Holmes criteria, in 1 of the 2 studies using modified Holmes criteria, in 2 of the 6 studies using the Fukuda criteria, and in 4 of the 7 studies using less known criteria. The single study using the Oxford criteria showed no difference between cases and controls. Conclusions: There seems to be increased EBV activity in subset(s) of ME/CFS patients. |s2cid=80898744}}</ref> 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.<ref>{{cite journal | vauthors = Cleare AJ | title = The HPA axis and the genesis of chronic fatigue syndrome | journal = Trends in Endocrinology and Metabolism | volume = 15 | issue = 2 | pages = 55–59 | date = March 2004 | pmid = 15036250 | doi = 10.1016/j.tem.2003.12.002 | s2cid = 1353041 }}</ref> A systematic review found that fatigue severity was the main predictor of prognosis in CFS, and did not identify psychological factors linked to prognosis.<ref name=Jason2009>{{cite journal | vauthors = Jason LA, Porter N, Brown M, Anderson V, Brown A, Hunnell J, Lerch A | title = CFS: A Review of Epidemiology and Natural History Studies | journal = Bulletin of the IACFS/ME | volume = 17 | issue = 3 | pages = 88–106 | date = 2009 | pmid = 21243091 | pmc = 3021257 }}</ref><!-- Seminal work <ref name=Dubbo>{{cite journal | vauthors = Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A | display-authors = 6 | title = Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study | journal = BMJ | volume = 333 | issue = 7568 | pages = 575 | date = September 2006 | pmid = 16950834 | pmc = 1569956 | doi = 10.1136/bmj.38933.585764.AE }}</ref> --> A review of long COVID research found half of those affected met diagnostic criteria for ME/CFS.<ref name="Davis-2023">{{cite journal | vauthors = Davis HE, McCorkell L, Vogel JM, Topol EJ | title = Long COVID: major findings, mechanisms and recommendations | journal = Nature Reviews. Microbiology | pages = 133–146 | date = January 2023 | volume = 21 | issue = 3 | pmid = 36639608 | pmc = 9839201 | doi = 10.1038/s41579-022-00846-2 }}</ref>

Another review found that risk factors for developing CFS after mononucleosis, [[Medicine:Dengue fever|dengue fever]], or [[Medicine:Q fever|Q-fever]] included 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.<ref name="Hulme" /> The same review found biological factors such as [[Biology:CD4|CD4]] and [[Biology:CD8|CD8]] activation and liver inflammation are predictors of sub-acute fatigue but not CFS.<ref name="Hulme">{{cite journal | vauthors = Hulme K, Hudson JL, Rojczyk P, Little P, Moss-Morris R | title = Biopsychosocial risk factors of persistent fatigue after acute infection: A systematic review to inform interventions | journal = Journal of Psychosomatic Research | volume = 99 | pages = 120–129 | date = August 2017 | pmid = 28712416 | doi = 10.1016/j.jpsychores.2017.06.013 | url = https://eprints.soton.ac.uk/411168/2/Figure_1_v2.pdf }}</ref>

A study analyzing the relationship between diagnostic labels and prognosis found that patients diagnosed with ME had the worst prognosis, and that patients with PVFS had the best. According to a review, it is unclear whether this was because people labeled with ME had a more severe or persistent illness, or because being labelled with ME adversely affects prognosis.<ref name=Brurberg2014rev>{{cite journal | vauthors = Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K | title = Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review | journal = BMJ Open | volume = 4 | issue = 2 | page = e003973 | date = February 2014 | pmid = 24508851 | pmc = 3918975 | doi = 10.1136/bmjopen-2013-003973 }}</ref> The National Academy of Medicine report says it is a misconception that diagnosing ME/CFS worsens prognosis, and that accurate diagnosis is key to appropriate management.<ref name="IOM2015" />{{Rp|page=222}}{{Rp|page=235}}

== Pathophysiology ==
ME/CFS is associated with changes in several areas, including the nervous, immune, and endocrine systems.<ref name="Cdc.gov_2018" /><ref name="Maksoud2020" /> Reported neurological differences include altered brain structure and metabolism, and autonomic nervous system dysfunction.<ref name="Maksoud2020" /> Observed immunological changes include decreased [[Biology:Natural killer cell|natural killer cell]] activity, increased [[Biology:Cytokine|cytokines]], and slightly increased levels of certain antibodies.<ref name="Cdc.gov_2018" /> Endocrine differences, such as modestly low cortisol and HPA axis dysregulation, have been noted as well.<ref name="Cdc.gov_2018" /> Impaired energy production and the possibility of autoimmunity are other areas of interest.<ref name="Bateman-2021" />

===Neurological===
[[File:CFS-brain-activity-salientnetwork.png|left|300 px |upright=1.07|Brain imaging, comparing adolescents with CFS and healthy controls showing abnormal network activity in regions of the brain.|alt=Brain imaging, comparing adolescents with CFS and healthy controls showing abnormal network activity in regions of the brain.|thumb]]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 cortical areas of the brain; these differences are consistent with neurological illness, but not depression or psychological illness.<ref name="ICC2011primer" /><!-- p5-6 quote = Structural and functional abnormalities within the brain and spinal cord are consistent with pathological dysfunction of the regulatory centers and communication networks of the brain, CNS and ANS, and are essential for effective ongoing self-organization.1'75 Reduced brainstem gray matter volume is consistent with insult to the midbrain at fatigue onset...
Greater source activity and more parts of the brain are utilized in cognitive processing, which supports patients' perception of greater effort.73' 77' 78 Reduced duration of uninterrupted sleep may explain reported unrefreshed sleep, pain and overwhelming fatigue. These observed pathological changes are consistent with neurological disorders but not psychiatric conditions.  --> The World Health Organization classes chronic fatigue syndrome as a central nervous system disease.<ref name="ICD11">{{cite web|title=ICD-11 – Mortality and Morbidity Statistics|url=https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f569175314|website=icd.who.int|access-date=20 May 2020|quote=Diseases of the nervous system|archive-date=1 August 2018|archive-url=https://archive.today/20180801205234/https://icd.who.int/browse11/l-m/en%23/http://id.who.int/icd/entity/294762853#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f569175314|url-status=live}}</ref><!-- Disease is not - not disorder - disease means there is an underlying pathology, disorder is only used by WHO in the mental and behavioral section and is not synonyms with illnesses. -->

Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, sample size was limited.<ref name=Maksoud2020/> 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.<ref name="Jason10/2017">{{cite journal | vauthors = Jason LA, Zinn ML, Zinn MA | title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | pages = 701–34 | date = 2 February 2017 | pmid = 26411464 | pmc = 4761639 | doi = 10.2174/1570159X13666150928105725|quote =Decreased frontal grey matter }}</ref><ref name=Maksoud2020>{{cite journal |vauthors=Maksoud R, du Preez S, Eaton-Fitch N, Thapaliya K, Barnden L, Cabanas H, Staines D, Marshall-Gradisnik S |title=A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques |journal=PLOS ONE |volume=15 |issue=4 |page=e0232475 |date=2020 |pmid=32353033 |pmc=7192498|doi=10.1371/journal.pone.0232475|bibcode=2020PLoSO..1532475M|doi-access=free }}</ref>

Tentative evidence suggests a relationship between [[Medicine:Dysautonomia|autonomic nervous system dysfunction]] and diseases such as CFS, [[Medicine:Fibromyalgia|fibromyalgia]], [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]], and [[Medicine:Interstitial cystitis|interstitial cystitis]]. However, it is unknown if this relationship is causative.<ref name=Martinez2014rev>{{cite journal | vauthors = Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M | s2cid = 23799955 | title = Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies | journal = Journal of Clinical Rheumatology | volume = 20 | issue = 3 | pages = 146–50 | date = April 2014 | pmid = 24662556 | doi = 10.1097/RHU.0000000000000089 }}</ref> 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 tests, suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency.<ref>{{cite journal | vauthors = Jackson ML, Bruck D | title = Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review | journal = Journal of Clinical Sleep Medicine | volume = 8 | issue = 6 | pages = 719–28 | date = December 2012 | pmid = 23243408 | pmc = 3501671 | doi = 10.5664/jcsm.2276 }}</ref><ref>{{cite journal | vauthors = Tanaka M, Tajima S, Mizuno K, Ishii A, Konishi Y, Miike T, Watanabe Y | title = Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder | journal = The Journal of Physiological Sciences | volume = 65 | issue = 6 | pages = 483–98 | date = November 2015 | pmid = 26420687 | pmc = 4621713 | doi = 10.1007/s12576-015-0399-y }}</ref><ref>{{cite journal | vauthors = Van Cauwenbergh D, Nijs J, Kos D, Van Weijnen L, Struyf F, Meeus M | title = Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review | journal = European Journal of Clinical Investigation | volume = 44 | issue = 5 | pages = 516–26 | date = May 2014 | pmid = 24601948 | doi = 10.1111/eci.12256 | s2cid = 9722415 }}</ref>

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.<ref name="Nijs-2012" />

===Immunological===
Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found more often in people with CFS and this correlates with severity of symptoms.<ref name="CDC-causes-2020">{{cite web |title=Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC |url=https://www.cdc.gov/me-cfs/about/possible-causes.html |website=www.cdc.gov |access-date=20 May 2020 |date=15 May 2019 |archive-date=22 August 2020 |archive-url=https://web.archive.org/web/20200822180342/https://www.cdc.gov/me-cfs/about/possible-causes.html |url-status=live }}</ref><ref name=CDCgrandround-cause>{{cite web|url=https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf|title=Chronic Fatigue Syndrome: Advancing Research and Clinical Education| vauthors = Lapp CW |date=16 February 2016|series=CDC Public Health Grand Rounds|publisher=Centers for Disease Control and Prevention|access-date=26 May 2020|archive-date=18 October 2020|archive-url=https://web.archive.org/web/20201018051123/https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf|url-status=live}}</ref> People with CFS have an abnormal response to exercise, including increased production of [[Biology:Complement system|complement]] products, increased [[Biology:Oxidative stress|oxidative stress]] combined with decreased antioxidant response, and increased Interleukin 10, and [[Biology:TLR4|TLR4]], some of which correlates with symptom severity.<ref name="pmid 24974723">{{cite journal | vauthors = Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J | title = Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | journal = Exercise Immunology Review | volume = 20 | pages = 94–116 | year = 2014 | pmid = 24974723 }}</ref> Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise;<ref>{{cite journal | vauthors = Armstrong CW, McGregor NR, Butt HL, Gooley PR | title = Metabolism in chronic fatigue syndrome | journal = Advances in Clinical Chemistry | volume = 66 | pages = 121–172 | year = 2014 | pmid = 25344988 | doi = 10.1016/B978-0-12-801401-1.00005-0 | isbn = 978-0-12-801401-1 }}</ref><ref>{{cite journal | vauthors = Morris G, Anderson G, Galecki P, Berk M, Maes M | title = A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior | journal = BMC Medicine | volume = 11 | page = 64 | date = March 2013 | pmid = 23497361 | pmc = 3751187 | doi = 10.1186/1741-7015-11-64 }}</ref> however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found.<ref name="IOM2015"/><ref>{{cite journal | vauthors = Griffith JP, Zarrouf FA | title = A systematic review of chronic fatigue syndrome: don't assume it's depression | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 10 | issue = 2 | pages = 120–128 | date = 2008 | pmid = 18458765 | pmc = 2292451 | doi = 10.4088/pcc.v10n0206 }}</ref> Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of [[Biology:Ribonuclease L|Ribonuclease L]], a protein activated by [[Biology:Interferon|IFN]], and hyperactivity of [[Biology:NF-κB|NF-κB]].<ref>{{cite journal | vauthors = Meeus M, Mistiaen W, Lambrecht L, Nijs J | title = Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? | journal = Anticancer Research | volume = 29 | issue = 11 | pages = 4717–4726 | date = November 2009 | pmid = 20032425 }}</ref>

===Endocrine===
Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels,<ref>{{cite journal | vauthors = Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM | title = Neuroendocrine and immune contributors to fatigue | journal = PM & R | volume = 2 | issue = 5 | pages = 338–46 | date = May 2010 | pmid = 20656615 | pmc = 2933136 | doi = 10.1016/j.pmrj.2010.04.008 }}</ref> a decrease in the variation of [[Chemistry:Cortisol|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 [[Medicine:Post-traumatic stress disorder|post-traumatic stress disorder]]  and some autoimmune conditions.<ref name=Morris2016rev>{{cite journal | vauthors = Morris G, Anderson G, Maes M | s2cid = 3524276 | title = Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways | journal = Molecular Neurobiology | volume = 54 | issue = 9 | pages = 6806–19 | date = November 2017 | pmid = 27766535 | doi = 10.1007/s12035-016-0170-2 }}</ref> It is unclear whether or not decreased cortisol levels of the HPA axis plays a primary role as a cause of CFS,<ref name="PMID_16612182">{{cite journal | vauthors = Cho HJ, Skowera A, Cleare A, Wessely S | s2cid = 12815707 | title = Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology | journal = Current Opinion in Psychiatry | volume = 19 | issue = 1 | pages = 67–73 | date = January 2006 | pmid = 16612182 | doi = 10.1097/01.yco.0000194370.40062.b0 }}</ref><ref name="Papadopoulos AS 2011">{{cite journal | vauthors = Papadopoulos AS, Cleare AJ | s2cid = 22176725 | title = Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 1 | pages = 22–32 | date = September 2011 | pmid = 21946893 | doi = 10.1038/nrendo.2011.153 }}</ref><ref name="PMID 21315796">{{cite journal | vauthors = Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG | s2cid = 206108463 | title = Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders | journal = Biological Psychology | volume = 87 | issue = 2 | pages = 183–94 | date = May 2011 | pmid = 21315796 | doi = 10.1016/j.biopsycho.2011.02.002 }}</ref> or has a secondary role in the continuation or worsening of symptoms later in the illness.<ref name="PMID 17596739">{{cite journal | vauthors = Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ | s2cid = 14956850 | title = Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome | journal = Neuropsychobiology | volume = 55 | issue = 2 | pages = 112–20 | year = 2007 | pmid = 17596739 | doi = 10.1159/000104468 | citeseerx = 10.1.1.626.9632 }}</ref> In most healthy adults, the [[Biology:Cortisol awakening response|cortisol awakening response]] 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.<ref>{{cite journal | vauthors = Powell DJ, Liossi C, Moss-Morris R, Schlotz W | title = Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis | journal = Psychoneuroendocrinology | volume = 38 | issue = 11 | pages = 2405–22 | date = November 2013 | pmid = 23916911 | doi = 10.1016/j.psyneuen.2013.07.004 | doi-access = free }}</ref>

=== Autoimmunity ===
Autoimmunity has been proposed to be a factor in CFS, but there are only a  few relevant findings so far.
There are a subset of patients with increased [[Biology:B cell|B cell]] activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry.<ref>{{cite journal | vauthors = Morris G, Berk M, Galecki P, Maes M | title = The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) | journal = Molecular Neurobiology | volume = 49 | issue = 2 | pages = 741–756 | date = April 2014 | pmid = 24068616 | doi = 10.1007/s12035-013-8553-0 | hdl-access = free | s2cid = 13185036 | hdl = 11343/219795 }}</ref> In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 [[Biology:Muscarinic acetylcholine receptor|muscarinic acetylcholine receptor]]s as well as to ß2 [[Biology:Adrenergic receptor|adrenergic receptor]]s.<ref>{{cite journal | vauthors = Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C | display-authors = 6 | title = Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome | journal = Brain, Behavior, and Immunity | volume = 52 | pages = 32–39 | date = February 2016 | pmid = 26399744 | doi = 10.1016/j.bbi.2015.09.013 | doi-access = free }}</ref><ref name="Autoimmunity Reviews pp. 601–609">{{cite journal | vauthors = Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease | journal = Autoimmunity Reviews | volume = 17 | issue = 6 | pages = 601–609 | date = June 2018 | pmid = 29635081 | doi = 10.1016/j.autrev.2018.01.009 | author8 = European Network on ME/CFS (EUROMENE) | doi-access = free }}</ref><ref name="Autoimmunity Reviews 2020 p.">{{cite journal | vauthors = Wirth K, Scheibenbogen C | title = A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors | journal = Autoimmunity Reviews | volume = 19 | issue = 6 | page = 102527 | date = June 2020 | pmid = 32247028 | doi = 10.1016/j.autrev.2020.102527 | doi-access = free }}</ref> A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors.<ref>{{Cite journal| vauthors = Marshall-Gradisnik S, Smith P, Nilius B, Staines DR |date=1 January 2015|title=Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients|journal=Immunology and Immunogenetics Insights|volume=7|pages=III.S25105|doi=10.4137/III.S25105|issn=1178-6345|doi-access=free}}</ref>{{Primary source inline|date=January 2021}}

===Energy metabolism===
Studies have observed 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.<ref name=holden2020>{{cite journal | vauthors = Holden S, Maksoud R, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S | title = A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease | journal = Journal of Translational Medicine | volume = 18 | issue = 1 | page = 290 | date = July 2020 | pmid = 32727475 | pmc = 7392668 | doi = 10.1186/s12967-020-02452-3 }}</ref>

==Diagnosis==
[[File:Could You Have MECFS.webp|thumb|''Could You Have ME/CFS?'' from US Centers for Disease Control]]
No characteristic laboratory abnormalities are approved to diagnose CFS; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis.<ref name="pmid 14702202">{{cite journal |vauthors=Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER |date=December 2003 |title=Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution |journal=BMC Health Services Research |volume=3 |issue=1 |page=25 |doi=10.1186/1472-6963-3-25 |pmc=317472 |pmid=14702202}}</ref><ref name=ICC2011primer  /> Blood, urine, and other tests are used to rule out other conditions that could be responsible for the symptoms.<ref name=CDC2020diag>{{cite web| url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html| title=Diagnosis of ME/CFS &#124; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) &#124; CDC| date=15 May 2019| access-date=23 May 2020| archive-date=28 July 2020| archive-url=https://web.archive.org/web/20200728145730/https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html| url-status=live}}</ref><ref name=Bansal2016>{{cite journal | vauthors = Bansal AS | title = Investigating unexplained fatigue in general practice with a particular focus on CFS/ME | journal = BMC Family Practice | volume = 17 | issue = 81 | page = 81 | date = July 2016 | pmid = 27436349 | pmc = 4950776 | doi = 10.1186/s12875-016-0493-0 }}</ref><ref name=IOM2015 /> The CDC states that a medical history should be taken and a mental and physical examination should be done to aid diagnosis.<ref name="CDC2020diag" />

===Diagnostic tools===
The CDC recommends considering the questionnaires and tools described in the 2015 Institute of Medicine report, which include:<ref>{{Cite web |last=Institute of Medicine |date=2015 |title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness. Report for Clinicians. |url=https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf |url-status=live |access-date=26 March 2022 |website=Institute of Medicine |archive-date=8 March 2022 |archive-url=https://web.archive.org/web/20220308010033/https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf }}</ref>
* 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<ref name="IOM2015" />{{Rp|270}}

A two-day [[Medicine:Cardiac stress test|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.<ref name="IOM2015" />{{Rp|216}}

=== Definitions ===

Many sets of diagnostic criteria for CFS have been proposed. Required symptoms vary, with post-exertional malaise, fatigue, cognitive impairment, and sleep disruption being the most commonly cited. Notable definitions include:<ref>{{cite journal | vauthors = Lim EJ, Son CG | title = Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) | journal = Journal of Translational Medicine | volume = 18 | issue = 1 | pages = 289 | date = July 2020 | pmid = 32727489 | pmc = 7391812 | doi = 10.1186/s12967-020-02455-0 }}</ref><ref name="Wyller">{{cite journal | vauthors = Wyller VB | title = The chronic fatigue syndrome--an update | journal = Acta Neurologica Scandinavica. Supplementum | volume = 187 | pages = 7–14 | year = 2007 | pmid = 17419822 | doi = 10.1111/j.1600-0404.2007.00840.x | s2cid = 11247547 | doi-access = free }}</ref>
* Centers for Disease Control and Prevention (CDC) definition (1994),<ref name="CDC1994">{{cite journal | vauthors = Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A | s2cid = 510735 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | journal = Annals of Internal Medicine | volume = 121 | issue = 12 | pages = 953–59 | date = December 1994 | pmid = 7978722 | doi = 10.7326/0003-4819-121-12-199412150-00009 }}</ref> the most widely used clinical and research description of CFS,<ref name="Af2003" /> is also called the Fukuda definition and is a revision of the ''Holmes'' or ''CDC 1988'' scoring system.<ref name="Holmes1988">{{cite journal | vauthors = Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S | title = Chronic fatigue syndrome: a working case definition | journal = Annals of Internal Medicine | volume = 108 | issue = 3 | pages = 387–89 | date = March 1988 | pmid = 2829679 | doi = 10.7326/0003-4819-108-3-387 }}</ref> The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.<ref name="NICECG53">{{cite book |publisher= National Institute for Health and Clinical Excellence |title= Guideline 53: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy) |location= London |year= 2007 |isbn= 978-1-84629-453-2 |url= http://guidance.nice.org.uk/CG53 |access-date= 3 September 2007 |archive-date= 1 June 2014 |archive-url= https://web.archive.org/web/20140601090555/http://guidance.nice.org.uk/CG53 |url-status= live }}</ref>
* The 2003 Canadian consensus criteria<ref name="carr">{{cite journal | vauthors = Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles AP, Sherkey JA | display-authors = 6 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |journal=Journal of Chronic Fatigue Syndrome |date=4 December 2011 |volume=11 |issue=1 |pages=7–115 |doi=10.1300/J092v11n01_02 }}</ref> state: "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 clinicians<ref name="ICC2011">{{cite journal | vauthors = Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisnik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S | display-authors = 6 | title = Myalgic encephalomyelitis: International Consensus Criteria | journal = Journal of Internal Medicine | volume = 270 | issue = 4 | pages = 327–38 | date = October 2011 | pmid = 21777306 | pmc = 3427890 | doi = 10.1111/j.1365-2796.2011.02428.x }}</ref><ref name="ICC2011primer">{{cite web | vauthors = Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, 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  | display-authors = 6 | date =2012 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf | title = Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners | collaboration = International Consensus Panel | archive-url = https://web.archive.org/web/20200710004103/http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf | archive-date=10 July 2020 }}</ref> 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.<ref name="ICC2011" /> According to the ICC, patients with post-exertional neuroimmune exhaustion but only partially meeting the criteria should be given the diagnosis of ''atypical myalgic encephalomyelitis''.<ref name="ICC2011primer" />
* The 2015 definition by the National Academy of Medicine (then referred to as the "Institute of Medicine") is not a definition of exclusion (differential diagnosis is still required).<ref name="IOM2015" /> "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."<ref name="IOM2015" />

The 2021 UK [[Organization:National Institute for Health and Care Excellence|NICE]] guidelines employ a definition of ME/CFS that requires severe fatigue, post-exertional malaise, unrefreshing sleep or sleep disturbance, and cognitive difficulties.<ref name="NICE Recommendations 2021">{{cite web |date=29 October 2021 |title=Recommendations - Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management - Guidance |url=https://www.nice.org.uk/guidance/ng206/chapter/Recommendations |url-status=live |archive-url=https://web.archive.org/web/20211229193427/https://www.nice.org.uk/guidance/ng206/chapter/Recommendations |archive-date=29 December 2021 |access-date=15 January 2022 |publisher=NICE}}</ref>

=== Differential diagnosis ===
Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. [[Medicine:Hypothyroidism|Hypothyroidism]], [[Medicine:Anemia|anemia]],<ref name="pmid_11925084" /> [[Medicine:Coeliac disease|coeliac disease]] (that can occur without gastrointestinal symptoms),<ref name=LoganWong2001>{{cite journal | vauthors = Logan AC, Wong C | title = Chronic fatigue syndrome: oxidative stress and dietary modifications | journal = Alternative Medicine Review | volume = 6 | issue = 5 | pages = 450–59 | date = October 2001 | pmid = 11703165 | url = http://www.altmedrev.com/publications/6/5/450.pdf | quote = Finally, recent evidence suggests celiac disease can present with neurological symptoms in the absence of gastrointestinal symptoms; therefore, celiac disease should be included in the differential diagnosis of CFS. | access-date = 12 November 2015 | archive-date = 7 November 2016 | archive-url = https://web.archive.org/web/20161107102229/http://www.altmedrev.com/publications/6/5/450.pdf | url-status = dead }}</ref> [[Medicine:Diabetes|diabetes]] and certain [[Medicine:Mental disorder|psychiatric disorders]] are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.<ref name="NICE Recommendations 2021"/><ref name="CDC1994" /><ref name="pmid_11925084">{{cite journal | vauthors = Craig T, Kakumanu S | title = Chronic fatigue syndrome: evaluation and treatment | journal = American Family Physician | volume = 65 | issue = 6 | pages = 1083–90 | date = March 2002 | pmid = 11925084 | url = http://www.aafp.org/afp/20020315/1083.html | access-date = 25 January 2008 | archive-date = 26 September 2007 | archive-url = https://web.archive.org/web/20070926230745/http://www.aafp.org/afp/20020315/1083.html | url-status = live }}</ref> Other diseases, listed by the Centers for Disease Control and Prevention, include [[Medicine:Infection|infectious diseases]] (such as [[Biology:Epstein–Barr virus|Epstein–Barr virus]], [[Medicine:Influenza|influenza]], HIV infection, [[Medicine:Tuberculosis|tuberculosis]], [[Unsolved:Lyme disease|Lyme disease]]), neuroendocrine diseases (such as [[Medicine:Thyroiditis|thyroiditis]], [[Medicine:Addison's disease|Addison's disease]], adrenal insufficiency, Cushing's disease), hematologic diseases (such as occult malignancy, [[Medicine:Lymphoma|lymphoma]]), rheumatologic diseases (such as [[Medicine:Fibromyalgia|fibromyalgia]], polymyalgia rheumatica, Sjögren's syndrome, [[Medicine:Lupus|lupus]], [[Medicine:Giant-cell arteritis|giant-cell arteritis]], [[Medicine:Polymyositis|polymyositis]], [[Medicine:Dermatomyositis|dermatomyositis]]), [[Medicine:Mental disorder|psychiatric diseases]] (such as [[Medicine:Bipolar disorder|bipolar disorder]], [[Medicine:Schizophrenia|schizophrenia]], [[Medicine:Delusional disorder|delusional disorder]]s, [[Medicine:Dementia|dementia]], [[Medicine:Anorexia nervosa|anorexia]]/[[Medicine:Bulimia nervosa|bulimia nervosa]]), neuropsychologic diseases (such as [[Medicine:Obstructive sleep apnea|obstructive sleep apnea]], [[Medicine:Narcolepsy|narcolepsy]],<ref name="Bateman-2021" /> parkinsonism, multiple sclerosis), and others (such as nasal obstruction from [[Medicine:Allergy|allergies]], [[Medicine:Sinusitis|sinusitis]], anatomic obstruction, [[Medicine:Autoimmune disease|autoimmune disease]]s, [[Medicine:Cancer|cancer]], chronic [[Medicine:Hepatitis|hepatitis]], some [[Medicine:Chronic condition|chronic illness]], alcohol or other substance abuse, pharmacologic [[Medicine:Side effect|side effect]]s, [[Chemistry:Toxic heavy metal|heavy metal exposure and toxicity]], marked body weight fluctuation).<ref name="pmid_11925084" />

Like CFS, [[Medicine:Fibromyalgia|fibromyalgia]] causes muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and extensive tender points in specific locations differentiates fibromyalgia from CFS, although the two diseases often co-occur.<ref>{{cite journal | vauthors = Bradley LA, McKendree-Smith NL, Alarcón GS | s2cid = 2555977 | title = Pain complaints in patients with fibromyalgia versus chronic fatigue syndrome | journal = Current Review of Pain | volume = 4 | issue = 2 | pages = 148–57 | year = 2000 | pmid = 10998728 | doi = 10.1007/s11916-000-0050-2 }}</ref> Ehlers–Danlos syndromes (EDS) may also have similar symptoms.<ref>{{cite journal |vauthors=Hakim A, De Wandele I, O'Callaghan C, Pocinki A, Rowe P |date=March 2017 |title=Chronic fatigue in Ehlers-Danlos syndrome-Hypermobile type |url=https://www.ehlers-danlos.com/2017-eds-classification-non-experts/chronic-fatigue-ehlers-danlos-syndrome-hypermobile-type/ |url-status=live |journal=American Journal of Medical Genetics. Part C, Seminars in Medical Genetics |volume=175 |issue=1 |pages=175–180 |doi=10.1002/ajmg.c.31542 |pmid=28186393 |archive-url=https://web.archive.org/web/20191211020546/https://www.ehlers-danlos.com/2017-eds-classification-non-experts/chronic-fatigue-ehlers-danlos-syndrome-hypermobile-type/ |archive-date=11 December 2019 |access-date=11 December 2019 |doi-access=free}}</ref> Medications can also cause side effects that mimic symptoms of CFS.<ref name="CDCdiagnosis" />

Depressive symptoms, if seen in CFS, may be [[Medicine:Differential diagnosis|differentially diagnosed]] from primary depression by the absence of [[Medicine:Anhedonia|anhedonia]], decreased motivation, or guilt; and the presence of bodily symptoms such as sore throat, swollen lymph nodes, and post-exertional malaise.<ref name="pmid_11925084" />

==Management==

There is no approved pharmacological treatment, therapy or cure for ME/CFS, although some symptoms can be treated or managed.<ref name=CDC2020treat /><ref name="NICE Recommendations 2021"/> According to the CDC, pacing, or managing one's activities to stay within their energy limits, can reduce episodes of post-exertional malaise. Addressing sleep problems with good sleep hygiene, or medication if required, may be beneficial. Chronic pain is common in ME/CFS, and the CDC recommends consulting with a pain management specialist if over-the-counter painkillers are insufficient. The debilitating nature of ME/CFS can cause depression or other psychological problems, which should be treated accordingly. For cognitive impairment, adaptations like organizers and calendars may be helpful. Comorbid conditions are common and should be treated if present.<ref name="CDC2020treat" />

According to the National Institute for Health and Clinical Excellence (NICE), graded exercise therapy (GET) is not an appropriate treatment for ME/CFS. CBT might be offered to help a person manage the difficulties of dealing with chronic illness, but not as a cure for ME/CFS.<ref name="NICE Recommendations 2021" />

The CDC recommends a strategy treating the most disabling symptom first, and the NICE guideline specifies the need for shared decision-making between patients and medical teams.<ref name="CDC2020treat" /> NICE recognized that symptoms of severe ME/CFS may be misunderstood as neglect or abuse and recommends assessment for safeguarding of persons suspected of having ME/CFS be evaluated by professionals with experience and understanding of the illness. Clinical management varies widely, with many patients receiving combinations of therapies.<ref name="Chou_2022">{{Cite book |url=https://www.cdc.gov/me-cfs/pdfs/systematic-review/file1-final-report-MECFS-Systematic-Review-508.pdf |title=Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Updated Systematic Evidence Review |vauthors=Chou R, McDonagh M, Griffins J, Grusing S |publisher=Centers for Disease Control and Prevention |year=2022}}</ref>{{Rp|page=9}}

Prior to publication of the NICE 2021 guideline, Andrew Goddard, president of the Royal College of Physicians, stated there was concern NICE did not adequately consider the experts' support and evidence of the benefits of GET and CBT, and urged they be included in the guideline. Various ME/CFS patient groups disputed the benefits of the therapies and stated that GET can make the illness more severe.<ref name="BBC News 2021">{{cite web | title=Outrage at chronic fatigue syndrome advice update pause | website=BBC News | date=17 August 2021 | url=https://www.bbc.com/news/health-58241864 | access-date=18 August 2021 | archive-date=17 August 2021 | archive-url=https://web.archive.org/web/20210817234405/https://www.bbc.com/news/health-58241864 | url-status=live }}</ref><ref name="Grover 2021">{{cite web | vauthors=Grover N | title=UK health standards body delays new ME guidance in therapy row | website=The Guardian | date=17 August 2021 | url=http://www.theguardian.com/society/2021/aug/17/uk-health-watchdog-nice-delays-new-me-guidance-therapy-row-chronic-fatigue | access-date=19 August 2021 | archive-date=19 August 2021 | archive-url=https://web.archive.org/web/20210819011022/https://www.theguardian.com/society/2021/aug/17/uk-health-watchdog-nice-delays-new-me-guidance-therapy-row-chronic-fatigue | url-status=live }}</ref>

Comorbid conditions that may interact with and worsen ME/CFS symptoms care are common, and appropriate medical intervention for these conditions may be beneficial. The most commonly diagnosed include [[Medicine:Fibromyalgia|fibromyalgia]], [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]], [[Medicine:Depression (mood)|depression]], [[Medicine:Anxiety|anxiety]], allergies, and chemical sensitivities.<ref name=CDCcom2018>{{cite web|title=Comorbid Conditions {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|url=https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/comorbid-conditions.html|date=12 July 2018|website=www.cdc.gov|access-date=29 May 2020|archive-date=7 June 2020|archive-url=https://web.archive.org/web/20200607093320/https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/comorbid-conditions.html|url-status=live}}</ref>

=== Pacing ===
Pacing, or activity management, is an illness management strategy based on the observation that symptoms tend to increase following mental or physical exertion,<ref name=CDC2020treat/> and was recommended for CFS in the 1980s.<ref name=Goudsmit2011>{{cite journal | vauthors = Goudsmit EM, Nijs J, Jason LA, Wallman KE | s2cid = 22457926 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document | journal = Disability and Rehabilitation | volume = 34 | issue = 13 | pages = 1140–47 | date = 19 December 2011 | pmid = 22181560 | doi = 10.3109/09638288.2011.635746 | url = https://repository.uel.ac.uk/item/85yxz | access-date = 23 May 2020 | archive-date = 28 July 2020 | archive-url = https://web.archive.org/web/20200728130945/https://repository.uel.ac.uk/item/85yxz | url-status = live }}</ref> It is now commonly used as a management strategy in chronic illnesses and in chronic pain.<ref name="pmid23247005">{{cite journal | vauthors = Nielson WR, Jensen MP, Karsdorp PA, Vlaeyen JW | s2cid = 28709499 | title = Activity pacing in chronic pain: concepts, evidence, and future directions | journal = The Clinical Journal of Pain | volume = 29 | issue = 5 | pages = 461–68 | date = May 2013 | pmid = 23247005 | doi = 10.1097/AJP.0b013e3182608561 }}</ref>

Its two forms are ''symptom-contingent pacing'', in which the decision to stop (and rest or change an activity) is determined by self-awareness of 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 post-exertional 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.<ref name=Goudsmit2011/><ref name="NICE21"/> Use of a heart-rate monitor with pacing to monitor and manage activity levels is recommended by a number of patient groups,<ref name=MEA-PEM>{{cite web|title=ME Association Summary Review: Assessing PEM (Post-exertional Malaise)|url=https://www.meassociation.org.uk/wp-content/uploads/MEA-Research-Review-Assessing-PEM-in-MECFS-25.03.19.pdf|website=ME Association|date=2019|access-date=23 May 2020|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728162048/https://meassociation.org.uk/wp-content/uploads/MEA-Research-Review-Assessing-PEM-in-MECFS-25.03.19.pdf|url-status=live}}</ref> and the CDC considers it useful for some individuals to help avoid post-exertional malaise.<ref name=CDC2020treat/>

====Energy envelope theory====
Energy envelope theory, considered to be consistent with pacing, is a management strategy suggested in the 2011 international consensus criteria for ME, which refers to using an "energy bank budget". Energy envelope theory was devised by psychologist Leonard Jason, who previously had CFS.<ref name="Jason1999">{{cite journal | vauthors = Jason LA, Melrose H, Lerman A, Burroughs V, Lewis K, King CP, Frankenberry EL | title = Managing chronic fatigue syndrome: overview and case study | journal = AAOHN Journal | volume = 47 | issue = 1 | pages = 17–21 | date = January 1999 | pmid = 10205371 | doi = 10.1177/216507999904700104 | doi-access = free }}</ref> Energy envelope theory states that patients should stay within, and avoid pushing through, the ''envelope'' of energy available to them, so as to reduce the post-exertional malaise "payback" caused by overexertion. This may help them make "modest gains" in physical functioning.<ref name="Jason2013">{{cite journal | vauthors = Jason LA, Brown M, Brown A, Evans M, Flores S, Grant-Holler E, Sunnquist M | title = Energy Conservation/Envelope Theory Interventions to Help Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | journal = Fatigue | volume = 1 | issue = 1–2 | pages = 27–42 | date = January 2013 | pmid = 23504301 | pmc = 3596172 | doi = 10.1080/21641846.2012.733602 }}</ref><ref name=Jason2017 /> 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.<ref name="Jason2008">{{cite journal | vauthors = Jason L, Muldowney K, Torres-Harding S | s2cid = 25558691 | title = The Energy Envelope Theory and myalgic encephalomyelitis/chronic fatigue syndrome | journal = AAOHN Journal | volume = 56 | issue = 5 | pages = 189–95 | date = May 2008 | pmid = 18578185 | doi = 10.3928/08910162-20080501-06 }}</ref><ref name="Brown2011">{{cite journal | vauthors = Brown M, Khorana N, Jason LA | title = The role of changes in activity as a function of perceived available and expended energy in nonpharmacological treatment outcomes for ME/CFS | journal = Journal of Clinical Psychology | volume = 67 | issue = 3 | pages = 253–60 | date = March 2011 | pmid = 21254053 | pmc = 3164291 | doi = 10.1002/jclp.20744 }}</ref><ref name="Jason2017">{{cite journal | vauthors = O'connor K, Sunnquist M, Nicholson L, Jason LA, Newton JL, Strand EB | title = Energy envelope maintenance among patients with myalgic encephalomyelitis and chronic fatigue syndrome: Implications of limited energy reserves | journal = Chronic Illness | volume = 15 | issue = 1 | pages = 51–60 | date = March 2019 | pmid = 29231037 | pmc = 5750135 | doi = 10.1177/1742395317746470 }}</ref> Energy envelope theory does not recommend unilaterally increasing or decreasing activity and is not intended as a therapy or cure for CFS.<ref name=Jason2008 /> It has been promoted by various patient groups.<ref name=SolveMECFS-EET>{{Cite journal| vauthors = Campbell B |url=http://solvecfs.org/wp-content/uploads/2013/06/080505.pdf|title=Managing your energy envelope|journal=The CFIDS Chronicle|date=Winter 2009| pages=28–31|access-date=23 May 2020|archive-date=27 September 2020|archive-url=https://web.archive.org/web/20200927205910/http://solvecfs.org/wp-content/uploads/2013/06/080505.pdf|url-status=live}}</ref><ref>{{Cite web |last=Emerge Australia |date=Nov 2019 |title=Pacing |url=https://www.emerge.org.au/Handlers/Download.ashx?IDMF=9928f57a-7ffd-47ba-997d-4a6bf0ecc552 |url-status=live |archive-url=https://web.archive.org/web/20220717205404/https://www.emerge.org.au/Handlers/Download.ashx?IDMF=9928f57a-7ffd-47ba-997d-4a6bf0ecc552 |archive-date=17 July 2022}}</ref> Some patient groups recommend using a heart rate monitor to increase awareness of exertion and enable patients to stay within their aerobic threshold envelope.<ref name="WhatNursesNeedToKnow">{{Cite book| vauthors = Steefel L |url=https://books.google.com/books?id=e0XGE2D1MJMC&q=energy%20envelope%20pacing&pg=PA54|title=What Nurses Know...Chronic Fatigue Syndrome|date=2011|publisher=Demos Medical Publishing|isbn=978-1-61705-028-2|pages=54–55|access-date=9 November 2020|archive-date=31 May 2021|archive-url=https://web.archive.org/web/20210531205219/https://books.google.com/books?id=e0XGE2D1MJMC&q=energy+envelope+pacing&pg=PA54|url-status=live}}</ref><ref name=PacingByNumbers>{{cite web|title=Pacing by Numbers: using your heart rate to stay inside the energy envelope| vauthors = Campbell B |date=14 November 2009|access-date=23 May 2020|url=https://www.sacfs.asn.au/news/2009/11/11_14_pacing_by_numbers.htm|website=ME/CFS South Australia Inc|archive-date=25 March 2020|archive-url=https://web.archive.org/web/20200325085015/http://sacfs.asn.au/news/2009/11/11_14_pacing_by_numbers.htm|url-status=live}}</ref> Despite a number of studies showing positive results for energy envelope theory, randomized controlled trials are lacking.{{citation needed|date=June 2021}}

=== Exercise ===
Stretching, movement therapies, and toning exercises are recommended for pain in patients with CFS. In many chronic illnesses, aerobic exercise is beneficial, but in chronic fatigue syndrome, the CDC does not recommend it. The CDC states:<ref name=CDC2020treat />{{blockquote|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===
Chronic illness can impact mental health, and depression or anxiety resulting from ME/CFS is common.<ref name="Bateman-2021" /> Psychotherapy may help patients manage the stress of being ill, apply self-management strategies for their symptoms, and cope with physical pain. However, treating co-occurring anxiety or depression will not cure ME/CFS, and talk therapy should not be undertaken in an attempt to cure ME/CFS.<ref name="CDC2020treat" /><ref name="NICE21" />

===Nutrition===
A proper diet is a significant contributor to the health of any individual. Medical consultation about diet and supplements is recommended for persons with CFS.<ref name=CDC2020treat/> 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.<ref name="Castro">{{cite journal |vauthors=Castro-Marrero J, Sáez-Francàs N, Santillo D, Alegre J |title=Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome |journal=Br. J. Pharmacol. |volume=174 |issue=5 |pages=345–69 |date=March 2017 |pmid=28052319 |pmc=5301046 |doi=10.1111/bph.13702 }}</ref><ref name=CDC2020treat />

==Treatment==
There are no approved treatments for ME/CFS. Cognitive behavior therapy (CBT) and graded exercise therapy (GET) have been proposed, but their safety and efficacy are disputed. The drug [[Chemistry:Rintatolimod|rintatolimod]] has been trialed and has been approved in Argentina.

=== Cognitive behavioral therapy ===
Cognitive behavioral therapy for ME/CFS is a variant of CBT that assumes a cognitive-behavioral model of ME/CFS. In this model, people with ME/CFS mistakenly attribute their illness solely to physical causes, and their condition is perpetuated by a fear of triggering symptoms, which leads to a vicious cycle of deconditioning and avoidance of activity. CBT aims to help patients view unhelpful thoughts and behaviors as factors in their illness. This model has been criticized as lacking evidence and being at odds with the biological changes associated with ME/CFS, and the use of this type of CBT has been the subject of much controversy.<ref name="Geraghty_2019">{{cite journal | vauthors = Geraghty K, Jason L, Sunnquist M, Tuller D, Blease C, Adeniji C | title = The 'cognitive behavioural model' of chronic fatigue syndrome: Critique of a flawed model | journal = Health Psychology Open | volume = 6 | issue = 1 | pages = 2055102919838907 | date = 2019-04-23 | pmid = 31041108 | pmc = 6482658 | doi = 10.1177/2055102919838907 }}</ref><ref name="Ahmed_2020">{{cite journal | vauthors = Ahmed SA, Mewes JC, Vrijhoef H | title = Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review | journal = Journal of Health Psychology | volume = 25 | issue = 2 | pages = 240–255 | date = February 2020 | pmid = 31072121 | doi = 10.1177/1359105319847261 | s2cid = 149443976 }}</ref><ref name="Vink2018">{{cite journal | vauthors = Vink M, Vink-Niese A | title = Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review | journal = Health Psychology Open | volume = 5 | issue = 2 | pages = 2055102918805187 | date = 1 July 2018 | pmid = 30305916 | pmc = 6176540 | doi = 10.1177/2055102918805187 | quote = The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome... The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome. }}</ref>

NICE removed their recommendation for this form of CBT in 2021, replacing it with a recommendation to offer patient CBT for help coping with distress that illness causes. The guidelines emphasize that CBT for people with ME/CFS should not assume that unhelpful beliefs cause their illness, and should not be portrayed as curative.<ref name="NICE Recommendations 2021" /> Similarly, the CDC stopped recommending CBT as a treatment in 2017, recommending counseling as a coping method instead.<ref name="Michaeleen_2017">{{Cite news | vauthors = Michaeleen D |date=2017-10-02 |title=For People With Chronic Fatigue Syndrome, More Exercise Isn't Better |url=https://www.npr.org/sections/health-shots/2017/10/02/554369327/for-people-with-chronic-fatigue-syndrome-more-exercise-isnt-better}}</ref><ref name="CDC2020treat" />

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 [[Philosophy:Quality of life|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.<ref name =doi>{{cite journal | vauthors = Green CR, Cowan P, Elk R, O'Neil KM, Rasmussen AL | title = National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | journal = Annals of Internal Medicine | volume = 162 | issue = 12 | pages = 860–65 | date = June 2015 | pmid = 26075757 | doi = 10.7326/M15-0338 | doi-access = free }}</ref> 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|subgroup]]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.<ref name="AHRQ discussion">{{cite journal |vauthors=Smith ME, Nelson HD, Haney E, Pappas M, Daeges M, Wasson N, McDonagh M |date=December 2014 |title=Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=https://www.ncbi.nlm.nih.gov/books/NBK293934 |url-status=live |journal=Evidence Report/Technology Assessment |edition=Evidence Reports/Technology Assessments, No. 219 |publisher=Agency for Healthcare Research and Quality (US) |issue=219 |pages=1–433 |doi=10.23970/AHRQEPCERTA219 |pmid=30313001 |archive-url=https://web.archive.org/web/20160201042204/http://www.ncbi.nlm.nih.gov/books/NBK293934/ |archive-date=1 February 2016 |access-date=22 January 2016 |doi-access=free}}</ref> 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.<ref name=IOM2015 />{{rp|265}}

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.<ref name="PMID 24791749">{{cite journal | vauthors = Adamowicz JL, Caikauskaite I, Friedberg F | s2cid = 13609292 | title = Defining recovery in chronic fatigue syndrome: a critical review | journal = Quality of Life Research | volume = 23 | issue = 9 | pages = 2407–16 | date = November 2014 | pmid = 24791749 | doi = 10.1007/s11136-014-0705-9 }}</ref> In a letter published online in the Lancet in 2016, Charles Shepherd, medical advisor to the ME Association, 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".<ref name="shepherd_2016">{{cite journal | vauthors = Shepherd C | title = Patient reaction to the PACE trial | journal = The Lancet. Psychiatry | volume = 3 | issue = 2 | pages = e7–8 | date = February 2016 | pmid = 26795759 | doi = 10.1016/S2215-0366(15)00546-5 | doi-access = free }}</ref>

A 2020 systematic review did not find CBT to be effective. While most studies claimed positive results, overall evidence quality was low. The use of subjective outcomes in non-blinded trials rendered the results prone to bias, and adverse effects were not reported. When objective outcomes were used, improvements were not seen. Further, the reviewers concluded that the applicability of these studies to modern patient cohorts was dubious because all the studies analyzed used the older Oxford of Fukuda criteria, which did not require PEM.<ref>{{cite journal | vauthors = Ahmed SA, Mewes JC, Vrijhoef H | title = Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review | journal = Journal of Health Psychology | volume = 25 | issue = 2 | pages = 240–255 | date = February 2020 | pmid = 31072121 | doi = 10.1177/1359105319847261 | s2cid = 149443976 }}</ref>

A 2022 evidence review contracted by the CDC found weak evidence supporting a small to moderate positive effect for CBT.<ref name="Chou_2022" />{{Rp|page=23}}

Patient organisations have rebuffed the use of CBT as a treatment for CFS to alter illness beliefs.<ref name="Smith2016">{{cite journal |vauthors=Smith ME, Nelson HD, Haney E, Pappas M, Daeges M, Wasson N, McDonagh M |date=July 2016 |title=July 2016 Addendum. In Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 2014 Dec. |url=https://www.ncbi.nlm.nih.gov/books/NBK379582/ |url-status=live |journal=Evidence Report/Technology Assessment |publisher=Agency for Healthcare Research and Quality (US) |pages=1–433 |archive-url=https://web.archive.org/web/20201101144842/https://www.ncbi.nlm.nih.gov/books/NBK379582/ |archive-date=1 November 2020 |access-date=15 April 2017 |quote=The results are consistent across trials with improvement in function, fatigue, and global improvement and provided moderate strength of evidence for improved function (4 trials, n=607) and global improvement (3 trials, n=539), low strength of evidence for reduced fatigue (4 trials, n=607) and decreased work impairment (1 trial, n=480), and insufficient evidence for improved quality of life (no trials)}}</ref><!-- Smith2016 Quote= Although CBT is a unique approach with disputable underlying rationale regarding the fear avoidance theory contributing to the perpetuation of symptoms in ME/CFS, it has similar aims of improving coping strategies and improving overall well-being.  --><ref name="PMID_11809249">{{cite journal | vauthors = Clark C, Buchwald D, MacIntyre A, Sharpe M, Wessely S | s2cid = 38526912 | title = Chronic fatigue syndrome: a step towards agreement | journal = Lancet | volume = 359 | issue = 9301 | pages = 97–98 | date = January 2002 | pmid = 11809249 | doi = 10.1016/S0140-6736(02)07336-1 }}</ref> The ME Association recommended in 2015, based on the results of an opinion survey of 493 patients who had received CBT treatment in the UK, CBT in its current form should not be used as a primary intervention for people with CFS.<ref name="No decisions about me">{{cite web|last1=The ME Association|title=No decisions about me without me|url=http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf|website=ME Association|publisher=The ME Association|access-date=20 January 2016|archive-date=6 November 2015|archive-url=https://web.archive.org/web/20151106100732/http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf|url-status=live}}</ref> In 2019, a large UK survey of people with ME/CFS reported that CBT was ineffective for more than half of respondents.<ref name="OxfordBrookesSurvey">{{cite web|url=https://www.meassociation.org.uk/2019/04/forward-me-and-oxford-brookes-university-announce-results-of-patient-survey-on-cbt-and-get-in-me-cfs-03-april-2019/|title=Forward-ME and Oxford Brookes University announces results of patient survey on CBT and GET in ME/CFS|date=Apr 2019|website=ME Association|access-date=26 May 2020|archive-date=9 May 2020|archive-url=https://web.archive.org/web/20200509115906/https://www.meassociation.org.uk/2019/04/forward-me-and-oxford-brookes-university-announce-results-of-patient-survey-on-cbt-and-get-in-me-cfs-03-april-2019/|url-status=live}}</ref>

===Graded exercise therapy===
{{Main articles|Medicine:Graded exercise therapy}}
Graded exercise therapy (GET) is a programme of physical therapy that starts at a patient's baseline and gradually increases over time. Like CBT, it assumes that patients' fears of activity and deconditioning play a significant role, and its safety and efficacy are debated.<ref name="Geraghty_2019" /><ref name="Ahmed_2020" /><ref name="Vink2018" />

The 2021 NICE guidelines removed GET as a recommended treatment due to low quality evidence regarding benefit, with the guidelines now telling clinicians not to prescribe ''"''any programme that ... uses fixed incremental increases in physical activity or exercise, for example, graded exercise therapy.''"'' <ref name="NICE21" /> The CDC withdrew their recommendation for GET in 2017.<ref name="Michaeleen_2017" />

A 2022 review contracted by the CDC found that GET may produce small to medium improvements in fatigue, functioning, depression, anxiety, and sleep, based on weak evidence. The authors concluded that trials suffered from methodological limitations, had limited reporting of harms, and generally enrolled patients based on older definitions of ME/CFS that do not require PEM. The CDC does not recommend GET, and there is some evidence of harm.<ref name="Vink2018" /><ref name="Chou_2022" />

A 2019 updated Cochrane review 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 relevance to current definitions of ME/CFS is limited.<ref name="Lar2019">{{cite journal | vauthors = Larun L, Brurberg KG, Odgaard-Jensen J, Price JR | title = Exercise therapy for chronic fatigue syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 10 | page = CD003200 | date = October 2019 | issue = 3 | pmid = 31577366 | pmc = 6953363 | doi = 10.1002/14651858.CD003200.pub8 }}</ref><ref name="Coch2019Oct2">{{cite web|title=Publication of Cochrane Review: 'Exercise therapy for chronic fatigue syndrome'|url=https://www.cochrane.org/news/publication-cochrane-review-exercise-therapy-chronic-fatigue-syndrome |date=21 May 2020|website=www.cochrane.org|access-date=24 May 2020|quote=It now places more emphasis on the limited applicability of the evidence to definitions of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) used in the included studies, the long-term effects of exercise on symptoms of fatigue, and acknowledges the limitations of the evidence about harms that may occur.|archive-date=17 June 2020|archive-url=https://web.archive.org/web/20200617164723/https://www.cochrane.org/news/publication-cochrane-review-exercise-therapy-chronic-fatigue-syndrome|url-status=live}}</ref><!-- Quote =  It now places more emphasis on the limited applicability of the evidence to definitions of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) used in the included studies, the long-term effects of exercise on symptoms of fatigue, and acknowledges the limitations of the evidence about harms that may occur... This amended review is still based on a research question and a set of methods from 2002, and reflects evidence from studies that applied definitions of ME/CFS from the 1990s.
Some support groups have criticized the use of CBT and [[Medicine:Graded exercise therapy|graded exercise therapy]] (GET). Having heard different views expressed about the evidence base for this condition, we acknowledge that the publication of this amended review will not resolve all the ongoing questions about this globally important health topic. --> Cochrane started re-evaluating the effects of exercise therapies in chronic fatigue syndrome in 2020.<ref name="Coch2019Oct2" /><ref name="Elgot_2015">{{Citation | vauthors = Elgot J |title= Chronic fatigue patients criticise study that says exercise can help |newspaper= The Guardian |date= 18 October 2015 |url= https://www.theguardian.com/society/2015/oct/28/chronic-fatigue-patients-criticise-oxford-university-study-exercise-cbt-cfs |access-date= 20 June 2018 |archive-date= 21 June 2018 |archive-url= https://web.archive.org/web/20180621093206/https://www.theguardian.com/society/2015/oct/28/chronic-fatigue-patients-criticise-oxford-university-study-exercise-cbt-cfs |url-status= live }}</ref>

An independent re-analysis of the same studies as the Cochrane review concluded that GET is ineffective and there was no evidence of safety, citing the risk of bias in non-blinded trials with subjective outcome measures, the use of broad inclusion criteria, potential problems with the questionnaires used, and inconsistent dropout rates.<ref name="Vink2018" />

A 2020 systematic review found that GET was not shown to be effective, due to the low quality and high risk of bias of trials. None of the studies analyzed used a definition of ME/CFS that required PEM, and few reported adverse effects. The main outcomes were self-reported and subjective, which may create bias when blinding is impossible.<ref name="Ahmed_2020" />

Patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for ME/CFS.<ref name="PMID_11809249" /><ref name="Geraghty_2019" /> Based on an opinion survey of patients who had received GET, in 2015 the ME Association concluded, GET in its current delivered form should not be recommended as a primary intervention for persons with ME/CFS.<ref name="No decisions about me" />

=== Adaptive pacing therapy ===
APT, not to be confused with pacing,<ref name="JasonAPT">{{cite journal | vauthors = Jason LA | title = The PACE trial missteps on pacing and patient selection | journal = Journal of Health Psychology | volume = 22 | issue = 9 | pages = 1141–45 | date = August 2017 | pmid = 28805518 | doi = 10.1177/1359105317695801 | doi-access = free }}</ref> is a therapy rather than a management strategy.<ref name="APT2004">{{cite web|title=Manual for Participants Adaptive Pacing Therapy (APT) for CFS/ME|url=https://www.qmul.ac.uk/wolfson/media/wolfson/current-projects/2.apt-participant-manual.pdf|date=November 2004|website=Wolfson Institute {{!}} Queen Mary University of London|access-date=23 May 2020|vauthors=Cox D, Ludlam S, Mason L, Wagner S, Sharpe M|collaboration=PACE Trial Management Group|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728143152/https://www.qmul.ac.uk/wolfson/media/wolfson/current-projects/2.apt-participant-manual.pdf|url-status=live}}</ref> 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".<ref name="APT2004" />{{Rp|5}} A large clinical trial known as the PACE trial found APT was no more effective than usual care or specialized medical care.<ref name=PACEtrial>{{cite journal | vauthors = White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M | display-authors = 6 | title = Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial | journal = Lancet | volume = 377 | issue = 9768 | pages = 823–36 | date = March 2011 | pmid = 21334061 | pmc = 3065633 | doi = 10.1016/S0140-6736(11)60096-2 }}</ref> The PACE trial generated much [[Unsolved:Controversies related to chronic fatigue syndrome#PACE trial|criticism]] due to the broad Oxford criteria patient selection, the standards of outcome effectiveness being lowered during the study, and re-analysis of the data not supporting the magnitude of improvements initially reported.<ref name="Wormgoor Rodenburg 2021 p.">{{cite journal | vauthors = Wormgoor ME, Rodenburg SC | title = The evidence base for physiotherapy in myalgic encephalomyelitis/chronic fatigue syndrome when considering post-exertional malaise: a systematic review and narrative synthesis | journal = Journal of Translational Medicine | volume = 19 | issue = 1 | page = 1 | date = January 2021 | pmid = 33397399 | pmc = 7780213 | doi = 10.1186/s12967-020-02683-4 }}</ref>

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.<ref name=AfME-APT>{{cite web|title=Pacing for people with ME|url=https://www.actionforme.org.uk/uploads/pdfs/pacing-for-people-with-me-booklet.pdf | date=2013|website=Action for ME|url-status=dead|archive-url=https://web.archive.org/web/20181105120221/https://www.actionforme.org.uk/uploads/pdfs/pacing-for-people-with-me-booklet.pdf|archive-date=5 November 2018}}</ref> In APT, the patient first establishes a baseline level of activity, which can be carried out consistently without any post-exertional 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.<ref name="APT2004" /> 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.<ref name="JasonAPT" /> 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.<ref name="JasonAPT" /> APT was promoted by Action for ME until 2019. Action for ME was the patient charity involved in the PACE trial.<ref name=AfME-APT />
<!-- Order changed to reflect US and Dutch dropping of CBT and GET plus Smith 2016 downgrading their evidence to low plus Cochrane 2020 announcement about relevance  - PACE trial data release was 2016 -->

=== Rintatolimod ===
Rintatolimod 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.<ref name=Richman2019>{{cite journal |vauthors=Richman S, Morris MC, Broderick G, Craddock TJ, Klimas NG, Fletcher MA |title=Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary |journal=Clin Ther |volume=41 |issue=5 |pages=798–805 |date=May 2019 |pmid=30871727 |pmc=6543846 |doi=10.1016/j.clinthera.2019.02.011 }}</ref> Evidence supporting the use of rintatolimod is deemed low to moderate.<ref name=Smith2015/> 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.<ref name=FDA2015>{{cite web|url=http://www.fda.gov/Drugs/NewsEvents/ucm337750.htm|archive-url=https://wayback.archive-it.org/7993/20161023175013/http://www.fda.gov/Drugs/NewsEvents/ucm337750.htm|url-status=dead|archive-date=23 October 2016|title=FDA Response Letter Regarding Approval of Ampligen for ME/CFS | author = Center for Drug Evaluation and Research |website=www.fda.gov|access-date=12 June 2018}}</ref><ref>{{cite web|url=http://www.medscape.com/viewarticle/778837|title=FDA Nixes Rintatolimod for Chronic Fatigue Syndrome| vauthors = Barclay L |date=5 February 2013|website=[[Medicine:Medscape|Medscape]]|access-date=18 January 2017|archive-date=20 June 2015|archive-url=https://web.archive.org/web/20150620041143/http://www.medscape.com/viewarticle/778837|url-status=live}}</ref> Rintatolimod has been approved for marketing and treatment for persons with CFS in {{wipe|Argentina}},<ref name="ADVINAT2019">{{cite book | vauthors = Agrawal S, Kandimalla ER | chapter = Chapter 14: Synthetic agonists of Toll-like receptors and therapeutic applications. | veditors = Agrawal S, Gait MJ | title = Advances in Nucleic Acid Therapeutics | date = February 2019 | pages = 306–338 (310) | quote = 14.2: Agonists of TLR3 | chapter-url = https://books.google.com/books?id=HsCrDwAAQBAJ&q=Rintatolimod+argentina&pg=PA310 | isbn = 978-1-78801-732-9 | access-date = 20 October 2021 | archive-date = 14 May 2022 | archive-url = https://web.archive.org/web/20220514015202/https://books.google.com/books?id=HsCrDwAAQBAJ&q=Rintatolimod+argentina&pg=PA310 | url-status = live }}</ref> and in 2019, FDA regulatory requirements were met for exportation of rintatolimod to the country.<ref name="rintatolimodArgentina">{{cite web|title=Rintatolimod for severe Chronic Fatigue Syndrome|url=https://search.usa.gov/search?utf8=✓&affiliate=fda1&sort_by=&query=+IND+131114+ORIG+1&commit=Search|date=19 September 2019|website=fda.gov|access-date=26 May 2020|archive-date=29 June 2020|archive-url=https://web.archive.org/web/20200629215032/https://search.usa.gov/search?utf8=%E2%9C%93&affiliate=fda1&sort_by=&query=+IND+131114+ORIG+1&commit=Search|url-status=live}}</ref>

== Prognosis ==
Information on the prognosis of CFS is limited, and the course of the illness is variable.<ref name="CDC-2019">{{Cite web |date=2019-07-23 |title=Prognosis {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/prognosis.html |access-date=2022-07-15 |website=www.cdc.gov |language=en-us}}</ref> According to the NICE guideline, CFS "varies in long-term outlook from person to person."<ref name="NICE-info+support-2021">{{Cite web |title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE |url=https://www.nice.org.uk/guidance/ng206/chapter/Recommendations#information-and-support |access-date=2022-07-15 |website=www.nice.org.uk}}</ref> Complete recovery, partial improvement, and worsening are all possible.<ref name="CDC-2019" /> Symptoms generally fluctuate over days, weeks, or longer periods, and some people may experience periods of remission.<ref name="NICE-info+support-2021" /> Overall, "many will need to adapt to living with ME/CFS."<ref name="NICE-info+support-2021" /> Some people who improve need to manage their activities in order to prevent relapse.<ref name="CDC-2019" /> Children and teenagers are more likely to recover or improve than adults.<ref name="CDC-2019" /><ref name="NICE-info+support-2021" />

A 2005 systematic review found that for untreated CFS, "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%)," and that 8 to 30% of patients were able to return to work. Age at onset, a longer duration of follow-up, less fatigue severity at baseline, and other factors were occasionally, but non consistently, related to outcome.<ref name="Cairns2005">{{cite journal | vauthors = Cairns R, Hotopf M | title = A systematic review describing the prognosis of chronic fatigue syndrome | journal = Occupational Medicine | volume = 55 | issue = 1 | pages = 20–31 | date = January 2005 | pmid = 15699087 | doi = 10.1093/occmed/kqi013 | doi-access = free }}</ref> 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.<ref name="Joyce1997">{{cite journal | vauthors = Joyce J, Hotopf M, Wessely S | title = The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review | journal = QJM | volume = 90 | issue = 3 | pages = 223–33 | date = March 1997 | pmid = 9093600 | doi = 10.1093/qjmed/90.3.223 | doi-access = free }}</ref>

== Epidemiology ==
[[File:ME-CFS Incidence Rate by Age.png|alt=Graph showing that people most frequently get CFS between the ages of 10 and 39, and that it is about 3 times as common in females|thumb|Incidence rates by age and sex, from a 2014 study in Norway]]
Reported prevalence rates vary widely depending on how CFS/ME is defined and diagnosed.<ref name=Lim2020/> Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%.<ref name=Lim2020/>  In comparison, estimates using the 1988 CDC "Holmes" criteria and 2003 Canadian criteria for ME produced an incidence rate of only 0.17%.<ref name=Lim2020/>  Between 836,000 and 2.5 million Americans have ME/CFS, but that 84-91% of these are undiagnosed,<ref name="IOM2015" />{{Rp|page=1}} and over 250,000 people in England and Wales are estimated to be affected.<ref>{{Cite web |title=Context {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE |url=https://www.nice.org.uk/guidance/ng206/chapter/Context |access-date=2023-03-08 |website=www.nice.org.uk}}</ref> The worldwide prevalence is 17 and 24 million.<ref name="Lim2020" />

Females are diagnosed about 1.5 to 2.0 times more often with CFS than males.<ref name=Lim2020/> An estimated 0.5% of children have CFS, and more adolescents are affected with the illness than younger children.<ref name=IOM2015/>{{Rp|182}}<ref name="CDC2020children"/>

The [[Medicine:Incidence (epidemiology)|incidence]] rate according to age has two peaks, one at 10–19 and another at 30–39 years,<ref name="pmid31379194">{{cite journal | vauthors = Collard SS, Murphy J | title = Management of chronic fatigue syndrome/myalgic encephalomyelitis in a pediatric population: A scoping review | journal = Journal of Child Health Care | volume = 24 | issue = 3 | pages = 411–431 | date = September 2020 | pmid = 31379194 | pmc = 7863118 | doi = 10.1177/1367493519864747 }}</ref><ref name="pmid29722371">{{cite journal |vauthors=Crawley E |year=2017 |title=Pediatric chronic fatigue syndrome: current perspectives |journal=Pediatric Health, Medicine and Therapeutics |volume=9 |issue= |pages=27–33 |doi=10.2147/PHMT.S126253 |pmc=5919160 |pmid=29722371 }}</ref> and the rate of [[Prevalence|prevalence]] is highest between ages 40 and 60.<ref name="pmid28033311" /><ref>{{Cite web |date=2021-04-27 |title=Epidemiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html |access-date=2022-07-16 |website=www.cdc.gov |language=en-us}}</ref>

== History ==
{{Main|Medicine:History of chronic fatigue syndrome}}

===Myalgic encephalomyelitis===
* From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors.<ref name="pmid13637100">{{cite journal | vauthors = Acheson ED | title = The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia | journal = The American Journal of Medicine | volume = 26 | issue = 4 | pages = 569–95 | date = April 1959 | pmid = 13637100 | doi = 10.1016/0002-9343(59)90280-3 | citeseerx = 10.1.1.534.4761 }}</ref><ref name="Parish">{{cite journal | vauthors = Parish JG | title = Early outbreaks of 'epidemic neuromyasthenia' | journal = Postgraduate Medical Journal | volume = 54 | issue = 637 | pages = 711–717 | date = November 1978 | pmid = 370810 | pmc = 2425322 | doi = 10.1136/pgmj.54.637.711 }}</ref> Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia".<ref name="Parish" />
* In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London.<ref name=pmid21624573>{{cite journal | vauthors = Wojcik W, Armstrong D, Kanaan R | title = Chronic fatigue syndrome: labels, meanings and consequences | journal = Journal of Psychosomatic Research | volume = 70 | issue = 6 | pages = 500–504 | date = June 2011 | pmid = 21624573 | doi = 10.1016/j.jpsychores.2011.02.002 }}</ref> The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis.<ref>{{cite journal |title = Outbreak at the royal free|journal = The Lancet |date=1955 |volume=266 |issue=6885 |pages=351–352 |doi=10.1016/s0140-6736(55)92344-8}}</ref> 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. [[Biography:Björn Sigurðsson|Björn Sigurðsson]] disapproved of the name, stating that the illness is rarely benign, does not always cause muscle pain, and is possibly never encephalomyelitic.<ref name="pmid13637100" /> The syndrome appeared in sporadic as well as epidemic cases.<ref>{{cite journal | vauthors = Price JL | title = Myalgic encephalomyelitis | journal = Lancet | volume = 1 | issue = 7180 | pages = 737–738 | date = April 1961 | pmid = 13737972 | pmc = 1836797 | doi = 10.1016/s0140-6736(61)92893-8 }}</ref>
* In 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system.<ref name="ICD_8_ME">{{Cite book |title= International Classification of Diseases |publisher= World Health Organization |year= 1969 |volume= I |pages= 158, (vol 2, pp. 173)}}</ref>
* 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.<ref name="ReferenceA">{{cite book | vauthors = Ramsay AM | title = Myalgic encephalomyelitis and postviral fatigue states. | edition = Second | date = 1988 }}</ref>
* By 1988, the continued work of Ramsay had demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling.<ref name=IOM2015 />{{rp|28–29}} Because of this, Ramsay proposed that the prefix "benign" be dropped.<ref name=pmid21624573/><ref>{{cite journal | vauthors = Ramsey AM, David AS, Wessely S, Pelosi AJ, Dowsett EG | title = Myalgic encephalomyelitis, or what? | journal = Lancet | volume = 2 | issue = 8602 | pages = 100–101 | date = July 1988 | pmid = 2898668 | doi = 10.1016/s0140-6736(88)90028-1 | s2cid = 24860444 }}</ref><ref>{{cite journal | vauthors = Ramsay AM, Dowsett EG, Dadswell JV, Lyle WH, Parish JG | title = Icelandic disease (benign myalgic encephalomyelitis or Royal Free disease) | journal = British Medical Journal | volume = 1 | issue = 6072 | pages = 1350 | date = May 1977 | pmid = 861618 | pmc = 1607215 | doi = 10.1136/bmj.1.6072.1350-a }}</ref>

===Chronic fatigue syndrome===
* In the mid-1980s, two large outbreaks of an illness that resembled [[Medicine:Infectious mononucleosis|mononucleosis]] 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, [[Medicine:Myalgia|myalgia]], and [[Medicine:Arthralgia|arthralgia]]s". An initial link to the Epstein-Barr virus had the illness acquire the name "chronic Epstein-Barr virus syndrome".<ref name=IOM2015 />{{rp|29}}<ref name="Holmes1988" />
* 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.<ref>{{cite journal | vauthors = Straus SE | title = History of chronic fatigue syndrome | journal = Reviews of Infectious Diseases | volume = 13 | issue = Suppl. 1 | pages = S2–7 | date = 1991 | pmid = 2020800 | doi = 10.1093/clinids/13.supplement_1.s2 }}</ref> 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.<ref name="Holmes1988" />
* 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.<ref name="CDC1994" />
* The most widely referenced [[Medicine:Medical diagnosis|diagnostic criteria]] and definition of CFS for research and clinical purposes were published in 1994 by the CDC.<ref name=Brurberg2014rev/>
* In 2006, the CDC commenced a national program to educate the American public and health-care professionals about CFS.<ref name="CDCmission">{{cite web |title= Press Briefing Transcripts |publisher= Centers for Disease Control and Prevention |date= 3 November 2006 |url= https://www.cdc.gov/media/transcripts/t061103.htm |access-date= 12 October 2013 |archive-date= 15 October 2013 |archive-url= https://web.archive.org/web/20131015033556/http://www.cdc.gov/media/transcripts/t061103.htm |url-status= live }}</ref>

===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 [[Medicine:Poliomyelitis|poliomyelitis]].<ref name="pmid13637100" /><ref>{{cite journal | vauthors = Shelokov A, Habel K, Verder E, Welsh W | title = Epidemic neuromyasthenia; an outbreak of poliomyelitislike illness in student nurses | journal = The New England Journal of Medicine | volume = 257 | issue = 8 | pages = 345–55 | date = August 1957 | pmid = 13464938 | doi = 10.1056/NEJM195708222570801 }}</ref>
* Iceland disease and Akureyri disease were synonymous terms used for an outbreak of fatigue symptoms in Iceland.<ref>{{cite journal | vauthors = Blattner RJ | title = Benign myalgic encephalomyelitis (Akureyri disease, Iceland disease) | journal = The Journal of Pediatrics | volume = 49 | issue = 4 | pages = 504–06 | date = October 1956 | pmid = 13358047 | doi = 10.1016/S0022-3476(56)80241-2 }}</ref>
* Low natural killer syndrome, a term used mainly in Japan, reflected research showing diminished ''in vitro'' activity of natural killer cells isolated from patients.<ref name="CFS Straus">{{cite book | veditors = Straus SE | title = Chronic Fatigue Syndrome | publisher = Marcel Dekker Inc. | year = 1994 | location = New York, Basel, Hong Kong | page = 227 | isbn = 978-0-8247-9187-2}}</ref><ref name="LNKS">{{cite journal | vauthors = Aoki T, Usuda Y, Miyakoshi H, Tamura K, Herberman RB | title = Low natural killer syndrome: clinical and immunologic features | journal = Natural Immunity and Cell Growth Regulation | volume = 6 | issue = 3 | pages = 116–28 | year = 1987 | pmid = 2442602 }}</ref>
* [[Medicine:Neurasthenia|Neurasthenia]] had been proposed as a historical diagnosis that occupied a similar medical and cultural space to CFS.<ref>{{cite journal | vauthors = Wessely S | s2cid = 12964461 | title = History of postviral fatigue syndrome | journal = British Medical Bulletin | volume = 47 | issue = 4 | pages = 919–41 | date = October 1991 | pmid = 1794091 | doi = 10.1093/oxfordjournals.bmb.a072521 }}</ref>
* 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".<ref name="Ramsay-RF">{{cite book | vauthors = Ramsay AM | title=Postviral Fatigue Syndrome. The saga of Royal Free disease | location=London | year=1986 | isbn=978-0-906923-96-2 | publisher=Gower}}</ref>
* Tapanui flu was a term commonly used in New Zealand, deriving from the name of a town, Tapanui, where numerous people had the syndrome.<ref>{{cite journal | vauthors = Simpson LO | title = Myalgic encephalomyelitis | journal = Journal of the Royal Society of Medicine | volume = 84 | issue = 10 | page = 633 | date = October 1991 | pmid = 1744860 | pmc = 1295578 }}</ref>

== Society and culture ==
[[File:Petition presentation by M.E Support in Glamorgan.jpg|thumb|right|upright=1.25|Presentation of a petition to the National Assembly for Wales relating to ME support in South East Wales]]

===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.<ref name=IOM2015 />{{rp|29–30}}

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.<ref>{{cite journal| vauthors = Jason LA, Richman JA |title=How science can stigmatize: The case of chronic fatigue syndrome|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=4|pages=85–103|doi=10.1080/10573320802092146|year=2008}}</ref> While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness,<ref name="ReferenceA" /><ref>{{cite journal| vauthors = Jason LA, Holbert C, Torres-Harding S, Taylor RR |s2cid=72397898|title=Stigma and the term chronic fatigue syndrome|journal=Journal of Disability Policy Studies|date=2004|volume=14|issue=4|pages=222–28|doi=10.1177/10442073040140040401|citeseerx=10.1.1.486.4577}}</ref> there is resistance amongst some clinicians toward the use of "myalgic encephalomyelitis" on the grounds that the inflammation of the central nervous system ([[Medicine:Myelitis|myelitis]]) implied by the term has not been demonstrated.<ref name="pmid 10583715">{{cite journal | vauthors = Evengård B, Schacterle RS, Komaroff AL | title = Chronic fatigue syndrome: new insights and old ignorance | journal = Journal of Internal Medicine | volume = 246 | issue = 5 | pages = 455–69 | date = November 1999 | pmid = 10583715 | doi = 10.1046/j.1365-2796.1999.00513.x | s2cid = 34123925 | doi-access = free }}</ref><ref name="isbn 1-86016-046-8">{{cite book |title=Chronic fatigue syndrome; Report of a joint working group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners |year= 1996 |publisher=Royal Colleges of Physicians, Psychiatrists and General Practitioners |location=London |isbn=978-1-86016-046-2}}</ref>

A 2015 report from the Institute of Medicine 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.<ref name=IOM2015 /><ref name="Tullar_NYT_2015">{{cite web|url=http://well.blogs.nytimes.com/2015/02/10/chronic-fatigue-syndrome-gets-a-new-name/|title=Chronic Fatigue Syndrome Gets a New Name| vauthors = Tuller D |website= well.blogs.nytimes.com|date=10 February 2015|access-date=3 February 2021|archive-date=11 February 2021|archive-url=https://web.archive.org/web/20210211013039/https://well.blogs.nytimes.com/2015/02/10/chronic-fatigue-syndrome-gets-a-new-name/|url-status=live}}</ref><ref>{{cite web|url=https://www.commondataelements.ninds.nih.gov/Doc/MECFS/04_Post-Exertional_Malaise_Subgroup_CDE_Draft_Recommendations.pdf|title=NIH PEM subgroup CDE draft recommendations|date=Dec 2017|website=NIH Common Data Elements project|access-date=21 April 2018|archive-date=3 February 2018|archive-url=https://web.archive.org/web/20180203213132/https://www.commondataelements.ninds.nih.gov/Doc/MECFS/04_Post-Exertional_Malaise_Subgroup_CDE_Draft_Recommendations.pdf|url-status=live}}</ref>

=== Economic impact ===
Economic costs due to CFS are "significant."<ref name="CDCgrandroundsfeb16" /> A 2021 paper by Leonard Jason and Arthur Mirin estimated the impact in the US to be $36-51 billion per year, or $31,592 to $41,630 per person, considering both lost wages and healthcare costs.<ref>{{Cite journal | vauthors = Jason LA, Mirin AA |date= January 2021 |title=Updating the National Academy of Medicine ME/CFS prevalence and economic impact figures to account for population growth and inflation |url=https://solvecfs.org/wp-content/uploads/2021/02/Jason-Mirin_Prevalence_econ_update.pdf |journal=Fatigue: Biomedicine, Health & Behavior |language=en |volume=9 |issue=1 |pages=9–13 |doi=10.1080/21641846.2021.1878716 |s2cid=233745601 |issn=2164-1846}}</ref> The CDC estimated direct healthcare costs alone at $9-14 billion annually.<ref name="CDCgrandroundsfeb16" /> A 2017 estimate for the annual economic burden in the United Kingdom was £3.3 billion.<ref name="Dibble McGrath Ponting 2020 p." />

=== Awareness day ===
12 May is designated as ME/CFS International Awareness Day.<ref name="CDC_Awareness">{{cite web |title = ME/Chronic Fatigue Syndrome Awareness Day |publisher = Centers for Disease Control and Prevention |url = https://www.cdc.gov/features/cfsawarenessday/ |date = 12 May 2017 |access-date = 12 July 2017 |archive-date = 29 July 2017 |archive-url = https://web.archive.org/web/20170729003809/https://www.cdc.gov/features/cfsawarenessday/ |url-status = live }}</ref> 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."<ref name="NIH_Awareness">{{cite web | vauthors = Lee N |title= Dr. Nancy Lee on International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day |publisher= US Department of Health & Human Services |url=https://www.hhs.gov/advcomcfs/cfsac-cfsa-day.html|archive-url=https://web.archive.org/web/20120708024540/http://www.hhs.gov/advcomcfs/cfsac-cfsa-day.html|archive-date=8 July 2012 |access-date=12 October 2013}}</ref> It was chosen because it is the birthday of Florence Nightingale, who had an illness appearing similar to ME/CFS or fibromyalgia.<ref name="CDC_Awareness"/><ref>{{cite journal | vauthors = Young DA | title = Florence Nightingale's fever | journal = BMJ | volume = 311 | issue = 7021 | pages = 1697–700 | date = 23 December 1995 | pmid = 8541764 | pmc = 2539100 | doi = 10.1136/bmj.311.7021.1697 }}</ref>

=== Doctor–patient relations ===
People with CFS face stigma in healthcare settings, and doctors may have trouble managing an illness that lacks a clear cause or treatment.<ref name="IOM2015" />{{Rp|page=30}}<ref name="McManimen-2019">{{cite journal | vauthors = McManimen S, McClellan D, Stoothoff J, Gleason K, Jason LA | title = Dismissing chronic illness: A qualitative analysis of negative health care experiences | journal = Health Care for Women International | volume = 40 | issue = 3 | pages = 241–258 | date = March 2019 | pmid = 30829147 | pmc = 6567989 | doi = 10.1080/07399332.2018.1521811 }}</ref> There has been much disagreement over proposed causes, diagnosis, and treatment of the illness.<ref name="pmid11446147">{{cite journal | vauthors = Hooge J | title = Chronic fatigue syndrome: cause, controversy and care | journal = British Journal of Nursing | volume = 1 | issue = 9 | pages = 440–41, 443, 445–46 | year = 1992 | pmid = 1446147 | doi = 10.12968/bjon.1992.1.9.440 }}</ref><ref name="pmid8856816">{{cite journal | vauthors = Sharpe M | title = Chronic fatigue syndrome | journal = The Psychiatric Clinics of North America | volume = 19 | issue = 3 | pages = 549–573 | date = September 1996 | pmid = 8856816 | doi = 10.1016/S0193-953X(05)70305-1 }}</ref><ref name="pmid8474729">{{cite journal | vauthors = Denz-Penhey H, Murdoch JC | title = General practitioners acceptance of the validity of chronic fatigue syndrome as a diagnosis | journal = The New Zealand Medical Journal | volume = 106 | issue = 953 | pages = 122–124 | date = April 1993 | pmid = 8474729 }}</ref><ref name="pmid11051301">{{cite journal | vauthors = Greenlee JE, Rose JW | title = Controversies in neurological infectious diseases | journal = Seminars in Neurology | volume = 20 | issue = 3 | pages = 375–386 | year = 2000 | pmid = 11051301 | doi = 10.1055/s-2000-9429 }}</ref> Some doctors believe it is psychological.<ref name="IOM2015" />{{Rp|page=234}}<ref name="Pheby-2020">{{cite journal | vauthors = Pheby DF, Araja D, Berkis U, Brenna E, Cullinan J, de Korwin JD, Gitto L, Hughes DA, Hunter RM, Trepel D, Wang-Steverding X | display-authors = 6 | title = A Literature Review of GP Knowledge and Understanding of ME/CFS: A Report from the Socioeconomic Working Group of the European Network on ME/CFS (EUROMENE) | journal = Medicina | volume = 57 | issue = 1 | pages = 7 | date = December 2020 | pmid = 33374291 | pmc = 7823627 | doi = 10.3390/medicina57010007 | doi-access = free }}</ref> Most patients are convinced their illness is physical instead, straining doctor-patient relationships.<ref name="McManimen-2019" /> Clinicians may be unfamiliar with CFS, as it is often not covered in medical school.<ref name="Davis-2023" /><ref name="McManimen-2019" /> Due to this unfamiliarity, patients may go undiagnosed for years,<ref name="Bateman-2021" />{{Rp|page=2861}}<ref name="IOM2015" />{{Rp|page=1}} or be misdiagnosed with mental conditions.<ref name="Davis-2023" /><ref name="Bateman-2021" />{{Rp|page=2871}} A substantial portion of doctors are uncertain about how to diagnose or manage CFS.<ref name="Pheby-2020" /> In a 2006 survey of GPs in southwest England, 75% accepted it as a "recognisable clinical entity," but 48% did not feel confident in diagnosing it, and 41% in managing it.<ref>{{cite journal | vauthors = Bowen J, Pheby D, Charlett A, McNulty C | title = Chronic Fatigue Syndrome: a survey of GPs' attitudes and knowledge | journal = Family Practice | volume = 22 | issue = 4 | pages = 389–393 | date = August 2005 | pmid = 15805128 | doi = 10.1093/fampra/cmi019 | doi-access = free }}</ref><ref name="Pheby-2020" />

The NAM report refers to CFS as "stigmatized," and the majority of patients report negative healthcare experiences.<ref name="IOM2015" />{{Rp|page=30}}<ref name="McManimen-2019" /> These patients may feel that their doctor inappropriately calls their illness psychological or doubts the severity of their symptoms.<ref name="McManimen-2019" /> They may also feel forced to prove that they are legitimately ill.<ref name="pmid16085344">{{cite journal |vauthors=Dumit J |date=February 2006 |title=Illnesses you have to fight to get: facts as forces in uncertain, emergent illnesses |journal=Social Science & Medicine |volume=62 |issue=3 |pages=577–90 |doi=10.1016/j.socscimed.2005.06.018 |pmid=16085344}}</ref> Some may be given outdated treatments that provoke symptoms or assume their illness is due to unhelpful thoughts and deconditioning.<ref name="IOM2015" />{{Rp|page=25}}<ref name="Bateman-2021" />{{Rp|page=2871}}<ref name="Davis-2023" /> In a 2009 survey, only 35% of patients considered their physicians experienced with CFS and only 23% thought their doctors knew enough to treat it.<ref name="Pheby-2020" />

=== Blood donation ===
In 2010, several national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from [[Medicine:Blood donation|donating blood]], based on concern following the 2009 claim of a link<ref name="Lombardi VC 585–9">{{cite journal | vauthors = Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA | title = Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome | journal = Science | volume = 326 | issue = 5952 | pages = 585–89 | date = October 2009 | pmid = 19815723 | pmc = 3073172 | doi = 10.1126/science.1179052 | bibcode = 2009Sci...326..585L }}{{Retracted|doi=10.1126/science.334.6063.1636-a|intentional=yes}}</ref> between CFS and a [[Biology:Retrovirus|retrovirus]] which was subsequently shown to be unfounded. Organizations adopting these or similar measures included the Canadian Blood Services,<ref>{{cite news|url=http://www.cbc.ca/health/story/2010/04/07/blood-donations-chronic-fatigue-virus.html |title=No blood from chronic fatigue donors: agency |date=7 April 2010 |publisher=CBC |access-date=25 June 2010 |url-status=dead |archive-url=https://web.archive.org/web/20100411035136/http://www.cbc.ca/health/story/2010/04/07/blood-donations-chronic-fatigue-virus.html |archive-date=11 April 2010}}</ref> the [[Medicine:New Zealand Blood Service|New Zealand Blood Service]],<ref>{{cite web |url= http://www.voxy.co.nz/national/chronic-fatigue-set-disqualify-blood-donors/5/45805 |title= Chronic Fatigue Set To Disqualify Blood Donors |access-date= 25 June 2010 |date= 21 April 2010 | vauthors = Atkinson K |publisher= Voxy.co.nz |archive-date= 24 April 2010 |archive-url= https://web.archive.org/web/20100424172954/http://www.voxy.co.nz/national/chronic-fatigue-set-disqualify-blood-donors/5/45805 |url-status= live }}</ref> the [[Medicine:Australian Red Cross Blood Service|Australian Red Cross Blood Service]]<ref>{{cite web|url=http://www.donateblood.com.au/media-centre/latest-national-news/blood-service-updates-cfs-donor-policy |title=Blood Service updates CFS donor policy |publisher=[[Medicine:Australian Red Cross Blood Service|Australian Red Cross Blood Service]] |access-date=7 July 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131014065501/http://www.donateblood.com.au/media-centre/latest-national-news/blood-service-updates-cfs-donor-policy |archive-date=14 October 2013}}</ref> and the American Association of Blood Banks.<ref>{{cite web|url=http://www.aabb.org/pressroom/Pages/cfsrecommendation.aspx |title=Recommendation on Chronic Fatigue Syndrome and Blood Donation |publisher=American Association of Blood Banks |date=18 June 2010 |access-date=25 June 2010 |url-status=dead |archive-url=https://web.archive.org/web/20100625094629/http://www.aabb.org/pressroom/Pages/cfsrecommendation.aspx |archive-date=25 June 2010}}</ref> In November 2010, the UK National Blood Service permanently deferred ME/CFS patients from donating blood to prevent potential harm to the donor.<ref>{{cite web |author=NHS Blood and Transplant |url=http://www.nhsbt.nhs.uk/news-and-media/news-archive/news_2010_10_07.asp |title=ME/CFS sufferers permanently deferred from giving blood |date=5 November 2010 |access-date=9 October 2011 |archive-date=28 November 2015 |archive-url=https://web.archive.org/web/20151128165120/http://www.nhsbt.nhs.uk/news-and-media/news-archive/news_2010_10_07.asp |url-status=live }}</ref> 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."<ref>{{cite web |author=NHS Blood and Transplant |url=http://www.transfusionguidelines.org.uk/dsg/wb/guidelines/ch013-chronic-fatigue-syndrome |title=Chronic Fatigue Syndrome |access-date=11 February 2015 |archive-date=11 February 2015 |archive-url=https://web.archive.org/web/20150211204015/http://www.transfusionguidelines.org.uk/dsg/wb/guidelines/ch013-chronic-fatigue-syndrome |url-status=live }}</ref>

===Controversy===
{{Main|Unsolved:Controversies related to chronic fatigue syndrome}}
Much contention has arisen over the cause, pathophysiology,<ref name="PMID_17892624">{{cite journal | vauthors = Hempel S, Chambers D, Bagnall AM, Forbes C | title = Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies | journal = Psychological Medicine | volume = 38 | issue = 7 | pages = 915–26 | date = July 2008 | pmid = 17892624 | doi = 10.1017/S0033291707001602 | s2cid = 20277129 }}</ref> nomenclature,<ref name="NYTNotYuppieFlu">{{cite news |url= https://www.nytimes.com/ref/health/healthguide/esn-chronicfatigue-ess.html |work= {{wipe|The New York Times}} | vauthors = Tuller D |title= Chronic Fatigue Syndrome No Longer Seen as 'Yuppie Flu' |date= 30 May 2008 |access-date= 29 June 2015 |archive-date= 17 March 2015 |archive-url= https://web.archive.org/web/20150317132227/http://www.nytimes.com/ref/health/healthguide/esn-chronicfatigue-ess.html |url-status= live }}</ref> and diagnostic criteria of CFS.<ref name="pmid11446147" /><ref name="pmid8856816" /> 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.<ref name="pmid1794092">{{cite journal |vauthors=Wallace PG |date=October 1991 |title=Post-viral fatigue syndrome. Epidemiology: a critical review |journal=British Medical Bulletin |volume=47 |issue=4 |pages=942–51 |doi=10.1093/oxfordjournals.bmb.a072522 |pmid=1794092}}</ref><ref name="pmid9231495">{{cite journal |vauthors=Mounstephen A, Sharpe M |date=May 1997 |title=Chronic fatigue syndrome and occupational health |journal=Occupational Medicine |volume=47 |issue=4 |pages=217–27 |doi=10.1093/occmed/47.4.217 |pmid=9231495 |doi-access=free}}</ref><ref>{{cite journal | vauthors = Jason LA, Richman JA, Friedberg F, Wagner L, Taylor R, Jordan KM | title = Politics, science, and the emergence of a new disease. The case of chronic fatigue syndrome | journal = The American Psychologist | volume = 52 | issue = 9 | pages = 973–83 | date = September 1997 | pmid = 9301342 | doi = 10.1037/0003-066X.52.9.973 }}</ref> Some people with CFS reject any psychological component.<ref>{{cite web |title=CFS/ME – The illness and the controversy {{!}} Science Media Centre |url=http://www.sciencemediacentre.org/cfsme-the-illness-and-the-controversy/ |website=www.sciencemediacentre.org |publisher=Science Media Centre |access-date=26 August 2018 |archive-url=https://web.archive.org/web/20180824134956/http://www.sciencemediacentre.org/cfsme-the-illness-and-the-controversy/ |archive-date=24 August 2018 |url-status=dead }}</ref>

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.<ref>{{cite journal | vauthors = McEvedy CP, Beard AW | title = Concept of benign myalgic encephalomyelitis | journal = British Medical Journal | volume = 1 | issue = 5687 | pages = 11–15 | date = January 1970 | pmid = 5411596 | pmc = 1700895 | doi = 10.1136/bmj.1.5687.11 }}</ref> 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 Melvin Ramsay and other staff of the Royal Free Hospital, the center of a significant outbreak.<ref>{{Cite journal|date=19 October 1957|title=An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955|journal=British Medical Journal|volume=2|issue=5050|pages=895–904|issn=0007-1447|pmc=1962472|pmid=13472002|author1=The Medical Staff Of The Royal Free Hospital }}</ref> 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.<ref name="pmid 10583715" /> The specialty that did take a major interest in the illness was psychiatry.<ref name="Speight2013">{{cite journal| vauthors = Speight N |title=Myalgic encephalomyelitis/chronic fatigue syndrome: Review of history, clinical features, and controversies.|journal=Saudi Journal of Medicine & Medical Sciences|date=2013|volume=1|issue=1|pages=11–13|doi=10.4103/1658-631x.112905|doi-access=free}}</ref>

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.<ref name="Speight2013"/> People with disabilities from CFS were often not believed and were accused of being [[Medicine:Malingering|malingerers]].<ref name="Speight2013"/> 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. The term 'yuppie flu' is considered offensive by both patients and clinicians.<ref name="flu">{{Citation | vauthors = Cowley G, Hager M, Joseph N | title = Chronic Fatigue Syndrome | journal = Newsweek | pages = Cover Story | url = https://www.newsweek.com/chronic-fatigue-syndrome-205712 | date = 12 November 1990 | access-date = 24 July 2020 | archive-date = 28 July 2020 | archive-url = https://web.archive.org/web/20200728130943/https://www.newsweek.com/chronic-fatigue-syndrome-205712 | url-status = live }}</ref><ref name="Frumkin2004">{{cite book | vauthors = Frumkin H, Packard RM, Brown P, Berkelman RL |title=Emerging illnesses and society: negotiating the public health agenda |publisher=Johns Hopkins University Press |location=Baltimore |year=2004 |page= [https://books.google.com/books?id=EGNFPZrKIKMC&pg=PA156 156] |isbn=978-0-8018-7942-5 }}</ref>

In 2009, the journal ''Science''<ref name="Lombardi VC 585–9" /> published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding,<ref name="PLoSOne">{{cite journal | vauthors = Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A | title = Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome | journal = PLOS ONE | volume = 5 | issue = 1 | page = e8519 | date = January 2010 | pmid = 20066031 | pmc = 2795199 | doi = 10.1371/journal.pone.0008519 | veditors = Nixon DF | bibcode = 2010PLoSO...5.8519E | doi-access = free }}</ref><ref>{{cite journal | vauthors = Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN | title = Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome | journal = Retrovirology | volume = 7 | issue = 1 | page = 10 | date = February 2010 | pmid = 20156349 | pmc = 2839973 | doi = 10.1186/1742-4690-7-10 }}</ref><ref name="van_Kuppeveld">{{cite journal | vauthors = van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanink CM, Bleijenberg G, Netea MG, Galama JM, van der Meer JW | title = Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort | journal = BMJ | volume = 340 | page = c1018 | date = February 2010 | pmid = 20185493 | pmc = 2829122 | doi = 10.1136/bmj.c1018 }}</ref> and in 2011, the editor of ''Science'' formally retracted its XMRV paper<ref>{{cite journal | vauthors = Alberts B | title = Retraction | journal = Science | volume = 334 | issue = 6063 | page = 1636 | date = December 2011 | pmid = 22194552 | doi = 10.1126/science.334.6063.1636-a | bibcode = 2011Sci...334.1636A | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ | title = Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 1 | page = 346 | date = January 2012 | pmid = 22203980 | pmc = 3252929 | doi = 10.1073/pnas.1119641109 | bibcode = 2012PNAS..109..346. | doi-access = free }}</ref>

===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.<ref name =Brief11>{{cite web|url=https://commonslibrary.parliament.uk/research-briefings/cdp-2019-0014/?doing_wp_cron=1590606661.5333631038665771484375|date=22 January 2019|title=Parliamentary Briefing: Appropriate ME treatment|website=parliament.uk|access-date=27 May 2020|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728125042/https://commonslibrary.parliament.uk/research-briefings/cdp-2019-0014/?doing_wp_cron=1590606661.5333631038665771484375|url-status=live}}</ref><!-- Note that the original material can be used to support the fact that this was said.--> A parliamentary inquiry by an ''ad hoc'' group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into CFS/ME,<ref name=NICE532017>{{cite book |publisher= National Institute for Health and Clinical Excellence |title= Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management |location= London |date= 22 August 2007 |url= https://www.nice.org.uk/guidance/cg53/resources/surveillance-report-2017-chronic-fatigue-syndromemyalgic-encephalomyelitis-or-encephalopathy-diagnosis-and-management-2007-nice-guideline-cg53-4602203537/chapter/how-we-made-the-decision#how-we-made-the-decision |access-date= 3 February 2021 |archive-date= 27 January 2021 |archive-url= https://web.archive.org/web/20210127193109/https://www.nice.org.uk/guidance/cg53/resources/surveillance-report-2017-chronic-fatigue-syndromemyalgic-encephalomyelitis-or-encephalopathy-diagnosis-and-management-2007-nice-guideline-cg53-4602203537/chapter/how-we-made-the-decision#how-we-made-the-decision |url-status= live }}</ref>{{Rp|169–86}}<ref name= Gibson>{{cite web |url=http://www.erythos.com/gibsonenquiry/Docs/ME_Inquiry_Report.pdf |title=ME_Inquiry_Report |website=Erythos.com |access-date=28 January 2011 |archive-date=10 July 2011 |archive-url=https://web.archive.org/web/20110710200941/http://www.erythos.com/gibsonenquiry/Docs/ME_Inquiry_Report.pdf |url-status=live }}</ref> 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.<!-- Gibson report is a parliamentary inquiry referred to by NICE guidelines and its findings have not been disputed. Use appropriate tags to challenge sources rather than ad hoc removals --> 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.<ref name= Gibson/>

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.<ref>{{cite web|url=http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm |title=Chronic Fatigue Syndrome/Myalgic Encephalomyelitis |publisher=MRC.ac.uk |access-date=28 January 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110106010232/http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm |archive-date=6 January 2011}}</ref> 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.<ref>{{cite web |url=http://appgme.org.uk/Downloads/appg_interim_report_v2.pdf |title=APPGME.org.uk |access-date=28 January 2011 |archive-date=11 August 2011 |archive-url=https://web.archive.org/web/20110811150204/http://appgme.org.uk/Downloads/appg_interim_report_v2.pdf |url-status=live }}</ref>

A 2016 report by ME Research looking at UK funding for ME/CFS between Jan 2006 and Dec 2015 found that 99 grants had been funded, totalling £49 million, with the largest number of studies being related to "Biological and endogenous factors".<ref name="meresearch_funding_2016">{{cite web |title=ME/CFS Research Funding AN OVERVIEW OF ACTIVITY BY MAJOR INSTUTIONAL FUNDERS INCLUDED ON THE DIMENSIONS DATABASE |url=https://www.meresearch.org.uk/wp-content/uploads/2016/09/mecfs-research-funding-report-2016-final.pdf}}</ref>

Controversy surrounds psychologically oriented models of the disease and behavioral treatments conducted in the UK.<ref>{{cite journal | vauthors = Cohen J |title=Criticism mounts of a long, controversial chronic fatigue study |journal=Science |date=27 October 2015 |doi=10.1126/science.aad4784 }}</ref>

====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 US 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.<ref name="pmid10932206">{{cite journal | vauthors = Dove A | title = GAO reports on CFS funding controversy | journal = Nature Medicine | volume = 6 | issue = 8 | page = 846 | date = August 2000 | pmid = 10932206 | doi = 10.1038/78579 | s2cid = 1431198 | doi-access = free }}</ref>

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 [[Organization:National Institute of Neurological Disorders and Stroke|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.<ref>{{cite web|url=http://www.nih.gov/news/health/oct2015/od-29.htm|title=NIH takes action to bolster research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=29 October 2015|access-date=29 October 2015|archive-date=31 May 2021|archive-url=https://web.archive.org/web/20210531205218/https://www.nih.gov/news-events/news-releases/nih-takes-action-bolster-research-myalgic-encephalomyelitis/chronic-fatigue-syndrome|url-status=live}}</ref>

=== 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.<ref>{{cite web|url=https://nursingclio.org/2018/09/25/golden-girls-chronic-fatigue-syndrome-and-the-legacies-of-hysteria/|title=Golden Girls, Chronic Fatigue Syndrome, and the Legacies of Hysteria|date=25 September 2018|website=Nursing Clio|access-date=14 November 2019|archive-date=28 July 2020|archive-url=https://web.archive.org/web/20200728124654/https://nursingclio.org/2018/09/25/golden-girls-chronic-fatigue-syndrome-and-the-legacies-of-hysteria/|url-status=live}}</ref> American author Ann Bannon had CFS.<ref name="cain">{{cite book | vauthors = Cain P | date = 2007 | chapter = Ann Bannon | title = Leading the parade: Conversations with America's most influential lesbians and gay men. | publisher = Scarecrow Press, Inc. | pages = 155–63 | isbn = 978-0-8108-5913-5 }}</ref> Laura Hillenbrand, author of the popular book ''Seabiscuit'', has struggled with CFS since age 19.<ref>{{Cite news| vauthors = Hylton WS |date=18 December 2014|title=The Unbreakable Laura Hillenbrand|work=The New York Times|url=https://www.nytimes.com/2014/12/21/magazine/the-unbreakable-laura-hillenbrand.html|access-date=27 June 2020|issn=0362-4331|archive-date=4 March 2020|archive-url=https://web.archive.org/web/20200304010110/https://www.nytimes.com/2014/12/21/magazine/the-unbreakable-laura-hillenbrand.html|url-status=live}}</ref><ref>{{cite web| vauthors = Parker-Pope T |date=4 February 2011|title=An Author Escapes From Chronic Fatigue Syndrome|url=https://well.blogs.nytimes.com/2011/02/04/an-author-escapes-from-chronic-fatigue-syndrome/|access-date=27 June 2020|website=Well|archive-date=4 July 2020|archive-url=https://web.archive.org/web/20200704171813/https://well.blogs.nytimes.com/2011/02/04/an-author-escapes-from-chronic-fatigue-syndrome|url-status=live}}</ref>

==Research==
[[File:ME-CFS Papers by Year.svg|alt=Graph of ME/CFS papers published by year, showing an increasing trend since about 1985|thumb|Graph of CFS papers published by year.{{legend|#0062C4|Papers mentioning ME or CFS}}{{legend|#62C400|Papers whose title mentions ME/CFS}}]]Current research into ME/CFS may lead to a better understanding of the disease's causes, biomarkers to aid in diagnosis, and treatments to relieve symptoms.<ref name="IOM2015" />{{Rp|page=10}} The emergence of long COVID has sparked increased interest in ME/CFS, as the two conditions may share pathology, and a treatment for one may treat the other.<ref>{{cite journal | vauthors = Marshall-Gradisnik S, Eaton-Fitch N | title = Understanding myalgic encephalomyelitis | journal = Science | volume = 377 | issue = 6611 | pages = 1150–1151 | date = September 2022 | pmid = 36074854 | doi = 10.1126/science.abo1261 | bibcode = 2022Sci...377.1150M | hdl = 10072/420658 | s2cid = 252159772 }}</ref>

=== Causes ===
Recent research suggests dysfunction in many biological processes. These changes may share a common cause, but the true relationship between them is currently unknown. Metabolic areas of interest include disruptions in amino acid metabolism, the [[Biology:Citric acid cycle|TCA cycle]], ATP synthesis, and potentially increased [[Biology:Lipid metabolism|lipid metabolism]]. Other research has investigated immune dysregulation and its potential connections to mitochondrial dysfunction. Autoimmunity has been proposed as a cause, but evidence is scant. People with ME/CFS may have abnormal [[Biology:Gut microbiota|gut microbiota]], which has been proposed to affect mitochondria or nervous system function.<ref name="Missailidis-2019">{{cite journal | vauthors = Missailidis D, Annesley SJ, Fisher PR | title = Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | journal = Diagnostics | volume = 9 | issue = 3 | pages = 80 | date = July 2019 | pmid = 31330791 | pmc = 6787592 | doi = 10.3390/diagnostics9030080 | doi-access = free }}</ref>

Several small studies have investigated the genetics of ME/CFS, but none of their findings have been replicated.<ref>{{cite journal | vauthors = Dibble JJ, McGrath SJ, Ponting CP | title = Genetic risk factors of ME/CFS: a critical review | journal = Human Molecular Genetics | volume = 29 | issue = R1 | pages = R117–R124 | date = September 2020 | pmid = 32744306 | pmc = 7530519 | doi = 10.1093/hmg/ddaa169 }}</ref> A larger study, [[Medicine:DecodeME|DecodeME]], is currently underway in the United Kingdom.<ref>{{Cite news |date=2022-09-12 |title=Experts launch world's largest genetic study of ME |language=en-GB |work=BBC News |url=https://www.bbc.com/news/uk-scotland-edinburgh-east-fife-62876472 |access-date=2023-01-20}}</ref>

=== Treatments ===
Various drugs have been or are being investigated for treating ME/CFS.<ref>{{cite journal |vauthors=Smith ME, Nelson HD, Haney E, Pappas M, Daeges M, Wasson N, McDonagh M |date=December 2014 |title=Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=https://www.ncbi.nlm.nih.gov/books/NBK293923/ |url-status=live |journal=Evidence Report/Technology Assessment |edition=Evidence Reports/Technology Assessments, No. 219 |publisher=Agency for Healthcare Research and Quality (US) |issue=219 |pages=1–433 |doi=10.23970/AHRQEPCERTA219 |pmid=30313001 |archive-url=https://web.archive.org/web/20160201042200/http://www.ncbi.nlm.nih.gov/books/NBK293923/ |archive-date=1 February 2016 |access-date=22 January 2016 |doi-access=free}}</ref>

The drug rintatolimod is currently in an experimental trial in the US to treat both ME/CFS and Long COVID.<ref name="CFSCovid">{{cite web |date=29 July 2022 |title=AIM ImmunoTech reports positive Phase III Ampligen data in long COVID |url=https://www.clinicaltrialsarena.com/news/aim-immunotech-covid-ampligen/}}</ref> [[Biology:Low-dose naltrexone|Low-dose naltrexone]] is also being studied as of 2023.<ref name="Tate_2023">{{cite journal | vauthors = Tate WP, Walker MO, Peppercorn K, Blair AL, Edgar CD | title = Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID | journal = International Journal of Molecular Sciences | volume = 24 | issue = 6 | pages = 5124 | date = March 2023 | pmid = 36982194 | pmc = 10048882 | doi = 10.3390/ijms24065124 | doi-access = free }}</ref> [[Chemistry:Rituximab|Rituximab]], a drug that depletes [[Biology:B cell|B cells]], was studied and found to be ineffective.<ref name="Missailidis-2019" />

=== Biomarkers ===
Many biomarkers for ME/CFS have been proposed based on research findings. But due to the use of a number of case definitions in research, some of which are non-specific such as the Sharpe (“Oxford”) and Fukuda (“old CDC”) definitions, no biomarkers have been widely validated or broadly clinically implemented.<ref name="Missailidis-2019" /> Proposed markers include electrical measurements of blood cells and a combination of immune cell death rate and function.<ref name="Tate_2023" />

=== Challenges ===
ME/CFS affects multiple bodily systems, varies widely in severity, and fluctuates over time, creating heterogeneity within patient groups and making it very difficult to identify a singular cause. This variation may also cause treatments that are effective for some patients to have no effect or a negative effect in others.<ref name="Tate_2023" /> Dividing patients into subtypes may help manage this heterogeneity.<ref name="Missailidis-2019" />

The existence of multiple diagnostic criteria, and variations in how scientists apply them, complicate comparisons between studies.<ref name="IOM2015" />{{Rp|page=53}}<ref name="Missailidis-2019" /> Some definitions, like the Oxford and Fukuda criteria, may fail to distinguish between chronic fatigue in general and ME/CFS, which requires PEM in modern definitions.<ref name="Missailidis-2019" /> Definitions also vary in which co-occurring conditions preclude a diagnosis of ME/CFS.<ref name="IOM2015" />{{Rp|page=52}}

==See also==
* ''Unrest'' (2017 film)

== References ==
{{reflist}}

== External links ==
<!-- External links must follow WP:EL
Do not include disputed links unless there is a consensus to do so  -->
* {{cite web |url=https://www.cdc.gov/me-cfs/index.html |title=CDC&nbsp;– Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) |publisher=Centers for Disease Control |access-date=20 May 2020}}
{{Medical resources
| ICD11          = {{ICD11|8E49}}
| ICD10          = {{ICD10|G93.3}}
| ICD10CM        = {{ICD10CM|G93.3}}, {{ICD10CM|R53.82}}
| ICD9           = {{ICD9|323.9}} {{ICD9|780.71}}
| MeshID         = D015673
| DiseasesDB     = 1645
| MedlinePlus    = 001244
| eMedicineSubj  = med
| eMedicineTopic = 3392
| eMedicine_mult = {{eMedicine2|ped|2795}}
}}
{{CNS diseases of the nervous system}}

{{DEFAULTSORT:Chronic fatigue syndrome}}
[[Category:Neurological disorders]]

{{Sourceattribution|Chronic fatigue syndrome|1}}