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Undid revision 1306255392 by 2001:569:FBB2:6F00:B89E:2E40:905F:CA52 (talk) The literature is more heavy on the neuroIMMUNUE part of ME/CFS, so do not agree nuerological should be so prominent |
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{{Short description|Chronic medical condition}}
{{Distinguish|text=[[Fatigue#Chronic|chronic fatigue]], a symptom experienced in many chronic illnesses, including [[idiopathic chronic fatigue]]}}
{{Featured article}}
{{Use British English|date=March 2024}}
{{Use dmy dates|date=July 2024}}
{{Cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox medical condition
| name = Myalgic encephalomyelitis/chronic fatigue syndrome
| synonyms = Post-viral fatigue syndrome (PVFS), systemic exertion intolerance disease (SEID)<ref name=IOM2015 />{{rp|20}}
| speciality = [[Rheumatology]], [[rehabilitation medicine]], [[endocrinology]], [[infectious disease (medical specialty)|infectious disease]], [[neurology]], [[immunology]], [[general practice]], [[paediatrics]], other specialists in ME/CFS<ref name="NICE2021">{{cite web |title=Myalgic Encephalomyelitis (Or Encephalopathy)/Chronic Fatigue Syndrome: Diagnosis and Management: NICE Guideline|url=https://www.nice.org.uk/guidance/ng206/resources/myalgic-encephalomyelitis-or-encephalopathychronic-fatigue-syndrome-diagnosis-and-management-pdf-66143718094021 |url-status=live |publisher=[[National Institute for Health and Care Excellence]] (NICE) |date=29 October 2021 |access-date=9 March 2024 |archive-url=https://web.archive.org/web/20240208083814/https://www.nice.org.uk/guidance/ng206/resources/myalgic-encephalomyelitis-or-encephalopathychronic-fatigue-syndrome-diagnosis-and-management-pdf-66143718094021 |archive-date=8 February 2024}}</ref>{{Rp|pages=58}}
| image = File:Icons symptoms ME CFS.svg
| caption = The four primary symptoms of ME/CFS according to the [[National Institute for Health and Care Excellence]]
| alt = Icons of the four key ME/CFS symptoms: low battery for profound fatigue, weak muscle for post-exertional malaise, bed for sleep problems and crossed wires in brain for cognitive difficulties.
| symptoms = [[Post-exertional malaise|Worsening of symptoms with activity]], [[Fatigue#Chronic|long-term fatigue]], sleep problems, others<ref name="CDCsym2024" />
| onset = Peaks at 10–19 and 30–39 years old<ref name="pmid31379194" />
| duration = Long-term<ref>{{Cite web |date=29 October 2021 |title=Myalgic Encephalomyelitis (Or Encephalopathy)/Chronic Fatigue Syndrome: Diagnosis and Management: Information for the Public |url=https://www.nice.org.uk/guidance/ng206/informationforpublic |access-date=24 March 2024 |publisher=[[National Institute for Health and Care Excellence]] (NICE) |archive-date=4 April 2024 |archive-url=https://web.archive.org/web/20240404205135/https://www.nice.org.uk/guidance/ng206/informationforpublic |url-status=live }}</ref>
| causes = Unknown<ref name="pmid37793728" />
| risks = Being female, [[genetics|family history]], viral infections<ref name="pmid37793728" />
| diagnosis = Based on symptoms<ref name="pmid37226227" />
| treatment = [[Symptomatic treatment|Symptomatic]]<ref name=CDC2024manage>{{cite web |date=10 May 2024 |title=Manage Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url-status=live |url=https://www.cdc.gov/me-cfs/management/ |archive-url=https://web.archive.org/web/20240518073532/https://www.cdc.gov/me-cfs/management/ |archive-date=18 May 2024 |access-date=18 May 2024|publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref>
| prevalence = About 0.17% to 0.89% (pre-[[COVID-19 pandemic]])<ref name=Lim2020/>
}}
'''Myalgic encephalomyelitis/chronic fatigue syndrome''' ('''ME/CFS''') is a disabling [[Chronic condition|chronic illness]]. People with ME/CFS experience profound [[fatigue]] that does not go away with rest, as well as sleep issues and problems with memory or concentration. The [[Pathognomonic|hallmark]] symptom is [[post-exertional malaise]] (PEM), a worsening of the illness that can start immediately or hours to days after even minor physical or mental activity. This "crash" can last from hours or days to several months. Further common symptoms include [[orthostatic intolerance|dizziness or faintness when upright]] and pain.<ref name="CDCsym2024">{{cite web|title=Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=https://www.cdc.gov/me-cfs/signs-symptoms/|date=10 May 2024|publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)|access-date=17 May 2024|archive-date=17 May 2024|archive-url=https://web.archive.org/web/20240517191603/https://www.cdc.gov/me-cfs/signs-symptoms/|url-status=live}}</ref><ref name="IQWiG-2023" />
<!-- Pathophysiology -->
The cause of the disease is unknown.<ref name="CDC_Clinical2024" /> ME/CFS often starts after an infection, such as [[infectious mononucleosis|mononucleosis]]<ref name="Bateman-2021" /> and it can run in families.<ref name="Dibble McGrath Ponting 2020 p.">{{cite journal |vauthors=Dibble JJ, McGrath SJ, Ponting CP |date=September 2020 |title=Genetic Risk Factors of ME/CFS: A Critical Review |journal=Human Molecular Genetics |volume=29 |issue=R1 |pages=R117–R124 |doi=10.1093/hmg/ddaa169 |pmc=7530519 |pmid=32744306}}</ref> ME/CFS is associated with changes in the nervous and immune systems, as well as in energy production.<ref name="pmid38443223">{{cite journal |vauthors=Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW |date=March 2024 |title=Unravelling Shared Mechanisms: Insights from Recent ME/CFS Research to Illuminate Long COVID Pathologies |url=|journal=Trends in Molecular Medicine |volume=30 |issue=5 |pages=443–458 |doi=10.1016/j.molmed.2024.02.003 |pmid=38443223 |doi-access=free}}</ref> Diagnosis is based on distinctive symptoms, and a [[differential diagnosis]], because no diagnostic test such as a blood test or imaging is available.<ref name="pmid37226227" /><ref>{{Cite web |title=Myalgic encephalomyelitis (Chronic fatigue syndrome) - Symptoms, diagnosis and treatment {{!}} BMJ Best Practice US |url=https://bestpractice.bmj.com/topics/en-us/277 |access-date=2024-10-21 |website=bestpractice.bmj.com |language=en-us}}</ref><ref>{{Cite web |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS) {{!}} Diseases & Conditions {{!}} 5MinuteConsult |url=https://5minuteconsult.com/collectioncontent/1-151513/diseases-and-conditions/myalgic-encephalomyelitis-chronic-fatigue-syndrome-cfs |access-date=2024-11-25 |website=5minuteconsult.com}}</ref><ref name="pmid28033311" />
<!-- Management and epidemiology -->
Symptoms of ME/CFS can sometimes be treated and the illness can improve or worsen over time, but a full recovery is uncommon.<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 |date=November 2021 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management |journal=Mayo Clinic Proceedings |volume=96 |issue=11 |pages=2861–2878 |doi=10.1016/j.mayocp.2021.07.004 |pmid=34454716 |s2cid=237419583 |doi-access=free |title-link=doi}}</ref><ref>{{Cite web |last=CDC |date=2024-05-22 |title=Manage Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=https://www.cdc.gov/me-cfs/management/index.html |access-date=2025-04-08 |website=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |language=en-us}}</ref> No therapies or medications are approved to treat the condition, and management is aimed at relieving symptoms.<ref name="NICE2021" />{{Rp|pages=29}} [[Pacing (activity management)|Pacing of activities]] can help avoid worsening symptoms, and counselling may help in coping with the illness.<ref name=CDC2024manage /> Before the [[COVID-19 pandemic]], ME/CFS affected two to nine out of every 1,000 people, depending on the definition.<ref name="Lim2020">{{cite journal |vauthors=Lim EJ, Ahn YC, Jang ES, Lee SW, Lee SH, Son CG |date=February 2020 |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 |article-number=100 |doi=10.1186/s12967-020-02269-0 |pmc=7038594 |pmid=32093722 |doi-access=free |title-link=doi}}</ref> However, many people fit ME/CFS diagnostic criteria after developing [[long COVID]].<ref name="Davis-2023">{{cite journal |vauthors=Davis HE, McCorkell L, Vogel JM, Topol EJ |date=March 2023 |title=Long COVID: Major Findings, Mechanisms and Recommendations |journal=Nature Reviews. Microbiology |volume=21 |issue=3 |pages=133–146 |doi=10.1038/s41579-022-00846-2 |pmc=9839201 |pmid=36639608}}</ref> ME/CFS occurs more often in women than in men. It is more common in [[middle age]], but can occur at all ages, including childhood.<ref name="CDC_Basics" />
<!-- Society and culture -->
ME/CFS has a large social and economic impact, and the disease can be socially isolating.<ref name="Boulazreg_2024">{{Cite journal | vauthors = Boulazreg, S, Rokach A |date=17 July 2020 |title=The Lonely, Isolating, and Alienating Implications of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |journal=Healthcare |language=en |volume=8 |issue=4 |pages=413–433 |doi=10.3390/healthcare8040413 |issn=2164-1846 |doi-access=free|pmid=33092097 |pmc=7711762 }}</ref> About a quarter of those affected are unable to leave their bed or home.<ref name="IQWiG-2023">{{Cite book |last=Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) |url=https://www.iqwig.de/download/n21-01_me-cfs-aktueller-kenntnisstand_abschlussbericht_v1-0.pdf |title=Myalgische Enzephalomyelitis / Chronic Fatigue Syndrome (ME/CFS): Aktueller Kenntnisstand |date=17 April 2023 |publisher=[[Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen]] |language=de |trans-title=Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): current state of knowledge |issn=1864-2500 |access-date=8 November 2023 |archive-url=https://web.archive.org/web/20231102160213/https://www.iqwig.de/download/n21-01_me-cfs-aktueller-kenntnisstand_abschlussbericht_v1-0.pdf |archive-date=2 November 2023 |url-status=live}}</ref>{{Rp|3}} People with ME/CFS often face stigma in healthcare settings, and care is complicated by [[Controversies related to ME/CFS|controversies around the cause and treatments]] of the illness.<ref name="Hussein-2024">{{Cite journal |last1=Hussein |first1=Said |last2=Eiriksson |first2=Lauren |last3=MacQuarrie |first3=Maureen |last4=Merriam |first4=Scot |last5=Dalton |first5=Maria |last6=Stein |first6=Eleanor |last7=Twomey |first7=Rosie |date=2024 |title=Healthcare System Barriers Impacting the Care of Canadians with Myalgic Encephalomyelitis: A Scoping Review |journal=Journal of Evaluation in Clinical Practice |volume=30 |issue=7 |pages=1337–1360 |language=en |doi=10.1111/jep.14047 |issn=1356-1294|doi-access=free |pmid=39031904 }}</ref> Doctors may be unfamiliar with ME/CFS, as it is often not fully covered in medical school.<ref name="Davis-2023"/> Historically, research funding for ME/CFS has been far below that of diseases with comparable impact.<ref name="Tyson_2022">{{Cite journal |vauthors=Tyson S, Stanley K, Gronlund TA, Leary S, Emmans Dean M, Dransfield C, Baxter H, Elliot R, Ephgrave R, Bolton M, Barclay A, Hoyes G, Marsh B, Fleming R, Crawford J |date=2022 |title=Research Priorities for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): The Results of a James Lind Alliance Priority Setting Exercise |journal=Fatigue: Biomedicine, Health & Behavior |language=en |volume=10 |issue=4 |pages=200–211 |doi=10.1080/21641846.2022.2124775 |issn=2164-1846 |s2cid=252652429 |doi-access=free}}</ref>
== Classification and terminology ==
ME/CFS has been classified as a [[Neurological disorder|neurological disease]] by the [[World Health Organization]] (WHO) since 1969, initially under the name [[History of ME/CFS#Case definitions (1986 onwards)|''benign myalgic encephalomyelitis'']].<ref>{{Cite book |vauthors = Bateman L |title=Neurobiology of Brain Disorders : Biological Basis of Neurological and Psychiatric Disorders |publisher=[[Elsevier]] |year=2022 |isbn=978-0-323-85654-6 | veditors = Zigmond M, Wiley C, Chesselet MF |edition=2nd |chapter=Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome }}</ref>{{rp|564}} The classification of ME/CFS as a neurological disease is based on symptoms which indicate a central role of the nervous system.<ref name="pmid328732972">{{cite journal |vauthors=Shan ZY, Barnden LR, Kwiatek RA, Bhuta S, Hermens DF, Lagopoulos J |date=September 2020 |title=Neuroimaging Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Systematic Review |url=|journal=Journal of Translational Medicine |volume=18 |issue=1 |article-number=335 |doi=10.1186/s12967-020-02506-6 |pmc=7466519 |pmid=32873297 |doi-access=free}}</ref> Alternatively, on the basis of abnormalities in [[White blood cell|immune cells]], ME/CFS is sometimes labelled a [[Neuroimmunology|neuroimmune]] condition.<ref name="Marshall-Gradisnik_2022" /> The disease can further be regarded as a [[post-acute infection syndrome]] (PAIS) or an infection-associated chronic illness.<ref name="CDC_Clinical2024" /><ref name="pmid35585196" /> PAISes such as [[long COVID]] and [[Lyme disease#Post-treatment_Lyme_disease_syndrome|post-treatment Lyme disease syndrome]] share many symptoms with ME/CFS and are suspected to have a similar cause.<ref name="pmid35585196">{{cite journal |vauthors=Choutka J, Jansari V, Hornig M, Iwasaki A |date=May 2022 |title=Unexplained Post-Acute Infection Syndromes |url= |journal=Nature Medicine |volume=28 |issue=5 |pages=911–923 |doi=10.1038/s41591-022-01810-6 |pmid=35585196 |s2cid=248889597 |doi-access=free}}</ref>
Many names have been proposed for the illness. The most commonly used are ''chronic fatigue syndrome'', ''myalgic encephalomyelitis'', and the umbrella term ''myalgic encephalomyelitis/chronic fatigue syndrome'' (''ME/CFS''). Reaching consensus on a name has been challenging because the cause and pathology remain unknown.<ref name="IOM2015">{{cite book |last1=Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=https://www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf |title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness |last2=Board on the Health of Select Populations |author3=Institute of Medicine |date=10 February 2015 |publisher=[[National Academies Press]] |isbn=978-0-309-31689-7 |pmid=25695122 |access-date=28 July 2020 |archive-url=https://web.archive.org/web/20170120175658/https://www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf |archive-date=20 January 2017 |url-status=live}}</ref>{{rp|29–30}} In the WHO's most recent classification, the [[ICD-11]], chronic fatigue syndrome and myalgic encephalomyelitis are named under post-viral fatigue syndrome.<ref name="ICD11">{{cite web |title=8E49 Postviral Fatigue Syndrome |url=https://icd.who.int/browse/2025-01/mms/en#569175314 |access-date=19 May 2025 |website=ICD-11 – Mortality and Morbidity Statistics |publisher=[[World Health Organization]]}}</ref> The term ''post-infectious fatigue syndrome'' was initially proposed as a subset of "chronic fatigue syndrome" with a documented triggering infection, but might also be used as a synonym of ME/CFS or as a broader set of fatigue conditions after infection.<ref name="pmid35585196" />
Many individuals with ME/CFS object to the term ''chronic fatigue syndrome''. They consider the term simplistic and trivialising, which in turn prevents the illness from being taken seriously.<ref name="IOM2015" />{{rp|234}}<ref name="Bhatia-2023">{{Cite journal |vauthors=Bhatia S, Jason LA |date=24 February 2023 |title=Using Data Mining and Time Series to Investigate ME and CFS Naming Preferences |url=http://journals.sagepub.com/doi/10.1177/10442073231154027 |url-status=live |journal=Journal of Disability Policy Studies |volume=35 |pages=65–72 |doi=10.1177/10442073231154027 |issn=1044-2073 |s2cid=257198201 |archive-url=https://web.archive.org/web/20231106033933/https://journals.sagepub.com/doi/10.1177/10442073231154027 |archive-date=6 November 2023 |access-date=15 October 2023|url-access=subscription }}</ref> At the same time, there are also issues with the use of ''myalgic encephalomyelitis'' (myalgia means muscle pain and [[encephalitis|encephalomyelitis]] means brain and spinal cord inflammation), as there is only limited evidence of brain inflammation implied by the name.<ref name="BMJbest_practice3" />{{rp|3}} The umbrella term ''ME/CFS'' would retain the better-known phrase ''CFS'' without trivialising the disease, but some people object to this name too, as they see CFS and ME as distinct illnesses.<ref name="Bhatia-2023" />
A 2015 report from the US Institute of Medicine recommended the illness be renamed ''systemic exertion intolerance disease'' (''SEID'') and suggested new diagnostic criteria.<ref name="IOM2015" /> While the new name was not widely adopted, the diagnostic criteria were taken over by the CDC. Like ''CFS'', the name ''SEID'' only focuses on a single symptom, and opinion from those affected was generally negative.<ref>{{Cite journal |vauthors=Jason LA, Johnson M |date=2 April 2020 |title=Solving the ME/CFS Criteria and Name Conundrum: The Aftermath of IOM |journal=Fatigue: Biomedicine, Health & Behavior |volume=8 |issue=2 |pages=97–107 |doi=10.1080/21641846.2020.1757809 |issn=2164-1846 |s2cid=219011696}}</ref>
== Signs and symptoms ==
ME/CFS causes debilitating fatigue, sleep problems, and [[post-exertional malaise]] (PEM, overall symptoms getting worse after mild activity). In addition, cognitive issues, [[orthostatic intolerance]] (dizziness or nausea when upright) or other physical symptoms may be present (see also {{Section link|2=Diagnostic criteria|nopage=yes}}). Symptoms significantly reduce the ability to function and typically last for three to six months before a diagnosis can be confirmed.<ref name="IQWiG-2023" />{{Rp|page=13}}<ref name="NICE2021" />{{Rp|page=11}} ME/CFS usually starts after an infection. Onset can be sudden or more gradual over weeks to months.<ref name="Bateman-2021" />
=== Core symptoms ===
People with ME/CFS experience persistent debilitating [[fatigue]]. It is made worse by normal physical, mental, emotional, and social activity, and is not a result of ongoing overexertion.<ref name="CDCsym2024" /><ref name="NICE2021" />{{Rp|pages=12}} Rest provides limited relief from fatigue. Particularly in the initial period of illness, this fatigue is described as "flu-like". Individuals may feel "physically drained" and unable to start or finish activities. They may also feel restless while fatigued, describing their experience as "wired but tired". When starting an activity, muscle strength may drop rapidly, which can lead to difficulty with coordination, clumsiness or sudden [[weakness]]. Mental fatigue may also make cognitive efforts difficult.<ref name="NICE2021" />{{Rp|pages=12,57, 95}}<ref>{{Cite journal |last1=Jason |first1=Leonard |last2=Jessen |first2=Tricia |last3=Porter |first3=Nicole |last4=Boulton |first4=Aaron |last5=Gloria-Njoku |first5=Mary |date=2009-07-16 |title=Examining Types of Fatigue Among Individuals with ME/CFS |url=https://dsq-sds.org/index.php/dsq/article/view/938 |journal=Disability Studies Quarterly |language=en |volume=29 |issue=3 |doi=10.18061/dsq.v29i3.938 |issn=2159-8371|doi-access=free }}</ref><ref>{{Cite journal |last1=Jason |first1=Leonard A. |last2=Boulton |first2=Aaron |last3=Porter |first3=Nicole S. |last4=Jessen |first4=Tricia |last5=Njoku |first5=Mary Gloria |last6=Friedberg |first6=Fred |date=2010-02-24 |title=Classification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Types of Fatigue |journal=Behavioral Medicine |language=en |volume=36 |issue=1 |pages=24–31 |doi=10.1080/08964280903521370 |issn=0896-4289 |pmc=4852700 |pmid=20185398}}</ref> The fatigue experienced in ME/CFS is of a longer duration and greater severity than in other conditions characterized by fatigue.<ref name="IQWiG-2023" />{{Rp|page=|pages=5–6}}
The hallmark feature of ME/CFS is a worsening of symptoms after exertion, known as [[post-exertional malaise]] or ''post-exertional symptom exacerbation''.<ref name="pmid37793728" /> PEM involves increased fatigue and is disabling. It can also include flu-like symptoms, pain, cognitive difficulties, gastrointestinal issues, [[nausea]], and sleep problems.<ref name="IQWiG-2023" />{{Rp|page=6}} [[File:Timeframe of PEM from daily activities.jpg|alt=The onset of PEM is usually within two days. Peak PEM occurs within seven, while recovery can take months. |thumb|upright=1.5|Typical time frames of post-exertional malaise after normal daily activities]] All types of activities that require energy, whether physical, cognitive, social, or emotional, can trigger PEM.<ref name="NICE-2021-D" />{{Rp|page=49}} Examples include attending a school event, food shopping, or even taking a shower.<ref name="CDCsym2024" /> For some, being in a stimulating environment can be sufficient to trigger PEM.<ref name="NICE-2021-D" />{{Rp|page=49}} PEM usually starts 12 to 48 hours after the activity,<ref name="CDC_strategies2024">{{cite web |date=10 May 2024 |title=Strategies to Prevent Worsening of Symptoms |url=https://www.cdc.gov/me-cfs/hcp/clinical-care/treating-the-most-disruptive-symptoms-first-and-preventing-worsening-of-symptoms.html |url-status=live |archive-url=https://web.archive.org/web/20240518105522/https://www.cdc.gov/me-cfs/hcp/clinical-care/treating-the-most-disruptive-symptoms-first-and-preventing-worsening-of-symptoms.html |archive-date=18 May 2024 |access-date=18 May 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref> but can also follow immediately after. PEM can last hours, days, weeks, or months.<ref name="IQWiG-2023" />{{Rp|page=6}} Extended periods of PEM, commonly referred to as "crashes" or "flare-ups" by people with the illness, can lead to a prolonged relapse.<ref name="NICE-2021-D" />{{Rp|page=50}}
Unrefreshing sleep is a further core symptom. People wake up exhausted and stiff rather than restored after a night's sleep. This can be caused by a pattern of [[Sleep inversion|sleeping during the day and being awake at night]], shallow sleep, or broken sleep. However, even a full night's sleep is typically non-restorative. Some individuals experience insomnia, [[hypersomnia]] (excessive sleepiness), or vivid nightmares.<ref name="NICE-2021-D"/>{{Rp|page=50}}
[[Cognitive disorder|Cognitive dysfunction]] in ME/CFS can be as disabling as physical symptoms, leading to difficulties at work or school, as well as in social interactions.<ref name="IQWiG-2023" />{{Rp|page=7}} People with ME/CFS sometimes describe it as "[[brain fog]]",<ref name="CDCsym2024" /> and report a slowdown in information processing.<ref name="IQWiG-2023" />{{Rp|page=7}} Individuals may have difficulty speaking, struggling to find words and names. They may have trouble concentrating or [[Human multitasking|multitasking]], or may have difficulties with short-term memory.<ref name="NICE2021" /> Tests often show problems with short-term visual memory, [[Mental chronometry|reaction time]] and [[Reading|reading speed]]. There may also be problems with [[attention]] and [[verbal memory]].<ref name="pmid35140252">{{cite journal |vauthors=Aoun Sebaiti M, Hainselin M, Gounden Y, Sirbu CA, Sekulic S, Lorusso L, Nacul L, Authier FJ |date=February 2022 |title=Systematic Review and Meta-Analysis Of Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) |url=|journal=Scientific Reports |volume=12 |issue=1 |article-number=2157 |doi=10.1038/s41598-021-04764-w |pmc=8828740 |pmid=35140252|bibcode=2022NatSR..12.2157A }}</ref>
People with ME/CFS often experience [[orthostatic intolerance]], symptoms that start or worsen with standing or sitting. Symptoms, which include nausea, lightheadedness, and cognitive impairment, often improve again after lying down.<ref name="Bateman-2021" /> Weakness and vision changes may also be triggered by the upright posture.<ref name="CDCsym2024" /> Some have [[postural orthostatic tachycardia syndrome]] (POTS), an excessive increase in [[heart rate]] after standing up, which can result in [[Syncope (medicine)|fainting]].<ref name="IQWiG-2023" />{{Rp|page=7}} Additionally, individuals may experience [[orthostatic hypotension]], a drop in blood pressure after standing.<ref name="BMJbest_practice3" />{{Rp|page=17}}
=== Other common symptoms ===
Pain and [[hyperalgesia]] (an abnormally increased sensitivity to pain) are common in ME/CFS. The pain is not accompanied by swelling or redness.<ref name="BMJbest_practice3" />{{Rp|page=16}} The pain can be present in muscles ([[myalgia]]) and [[arthralgia|joints]]. Individuals with ME/CFS may have chronic pain behind the eyes and in the neck, as well as [[neuropathic pain]] (related to disorders of the nervous system).<ref name="IQWiG-2023" />{{Rp|page=8}} Headaches and [[migraine]]s that were not present before the illness can occur as well. However, chronic daily headaches may indicate an alternative diagnosis.<ref name="BMJbest_practice3" />{{Rp|page=16}}
Additional common symptoms include [[irritable bowel syndrome]] or other problems with digestion, chills and [[night sweats]], [[shortness of breath]] or an [[Arrhythmia|irregular heartbeat]]. Some experience sore [[lymph node]]s and a sore throat. People may also develop allergies or become sensitive to foods, lights, noise, smells or chemicals.<ref name="CDCsym2024" />
== Illness severity ==
ME/CFS often leads to serious disability, but the degree varies considerably.<ref name="CDC_Clinical2024">{{cite web |date=10 May 2024 |title=Clinical Overview of ME/CFS |url=https://www.cdc.gov/me-cfs/hcp/clinical-overview/ |url-status=live |archive-url=https://web.archive.org/web/20240517192407/https://www.cdc.gov/me-cfs/hcp/clinical-overview/ |archive-date=17 May 2024 |access-date=17 May 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref> ME/CFS is generally classified into four categories of illness severity:<ref name="NICE2021"/>{{Rp|page=8}}<ref name="BMJbest_practice3">{{Cite book |url=https://bestpractice.bmj.com/topics/en-gb/277 |title=BMJ Best Practice: Myalgic Encephalomyelitis (Chronic Fatigue Syndrome) |vauthors=Baraniuk JN, Marshall-Gradisnik S, Eaton-Fitch N |date=January 2024 |publisher=[[BMJ (company)|BMJ Publishing Group]] |access-date=19 January 2024 |url-access=subscription |archive-url=https://web.archive.org/web/20240219120522/https://auth.bmj.com/as/authorization.oauth2?response_type=code&client_id=bmj-bp-client-id&scope=openid%20profile%20bmj_access%20bmj_id&state=ENbX8qK-k7MG_rSrufgtPvjK66pOSygEI5Vm7b_AQQY%3D&redirect_uri=https://bestpractice.bmj.com/login/oauth2/code/bp-client&code_challenge_method=S256&nonce=drW8TQUhsuIuiLIEvrg4WXsMERFsV9emHb-7Yg-SYrQ&code_challenge=Hldf9BnRpXVwaG1wsQNJwmn_zWe8bfqpbf0uUZK8emA&template_name=UNKNOWN_USER&ip=207.241.225.241&acr_values=USER_LOGIN |archive-date=19 February 2024 |url-status=live}}</ref>{{Rp|page=10}}
* People with mild ME/CFS can usually still work and care for themselves, but they will need their free time to recover from these activities rather than engage in social and leisure activities.
* Moderate severity impedes [[activities of daily living]] (self-care activities, such as making a meal). People are usually unable to work and require frequent rest.
* Those with severe ME/CFS are homebound and can do only limited activities of daily living, for instance brushing their teeth. They may be wheelchair-dependent and spend the majority of their time in bed.
* With very severe ME/CFS, people are mostly bed-bound and cannot care for themselves.
[[File:QoL comparison ME-CFS.svg|thumb|upright=1.4|Results of a study on the [[quality of life]] of individuals with ME/CFS, showing it to be lower than in 20 other chronic conditions|alt=A bar graph showing the average quality of life score of those with ME/CFS.]]
Roughly a quarter of those living with ME/CFS fall into the mild category, and half fall into the moderate or moderate-to-severe categories.<ref name="pmid37793728">{{cite journal |vauthors=Grach SL, Seltzer J, Chon TY, Ganesh R |date=October 2023 |title=Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |journal=Mayo Clinic Proceedings |volume=98 |issue=10 |pages=1544–1551 |doi=10.1016/j.mayocp.2023.07.032 |pmid=37793728 |s2cid=263665180 |doi-access=free}}</ref> The final quarter falls into the severe or very severe category.<ref name="IQWiG-2023" />{{Rp|3}} Severity may change over time. Symptoms might get worse, improve, or the illness may go into remission for a period of time.<ref name="CDC_Clinical2024"/> People who feel better for a period of time may overextend their activities, triggering PEM and a worsening of symptoms.<ref name="CDC_strategies2024"/>
Those with severe and very severe ME/CFS experience more extreme and diverse symptoms. They may face severe weakness and greatly limited ability to move. They can lose the ability to speak, swallow, or communicate completely due to cognitive issues. They can further experience severe pain and hypersensitivities to touch, light, sound, and smells.<ref name="NICE2021"/>{{Rp|pages=50}} Minor day-to-day activities can be sufficient to trigger PEM.<ref name="Bateman-2021" />
Individuals with ME/CFS have decreased quality of life when evaluated by the [[SF-36]] questionnaire, especially in the domains of physical and social functioning, general health, and vitality. However, their emotional functioning and mental health are not much lower than those of healthy individuals.<ref name="pmid28033311">{{cite journal |vauthors=Unger ER, Lin JS, Brimmer DJ, Lapp CW, Komaroff AL, Nath A, Laird S, Iskander J |date=December 2016 |title=CDC Grand Rounds: Chronic Fatigue Syndrome – Advancing Research and Clinical Education |url=https://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm655051a4.pdf |url-status=live |journal=MMWR. Morbidity and Mortality Weekly Report |volume=65 |issue=50–51 |pages=1434–1438 |doi=10.15585/mmwr.mm655051a4 |pmid=28033311 |archive-url=https://web.archive.org/web/20170106010408/https://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm655051a4.pdf |archive-date=6 January 2017 |access-date=5 January 2017 |quote= |doi-access=free |title-link=doi}}</ref> Functional impairment in ME/CFS can be greater than [[multiple sclerosis]], [[Cardiovascular disease|heart disease]], or [[lung cancer]].<ref name="Bateman-2021" /> Fewer than half of people with ME/CFS are employed, and roughly one in five have a full-time job.<ref name="Lim2020" />
== Causes ==
The cause of ME/CFS is not yet known.<ref name="Bateman-2021" /> Between 60% and 80% of cases start after an infection, usually a viral infection.<ref name="BMJbest_practice3" />{{rp|5}}<ref name="pmid37793728" /> A genetic factor is believed to contribute, but there is no single gene known to be responsible for increased risk. Instead, many gene variants probably have a small individual effect, but their combined effect can be strong.<ref name="Dibble McGrath Ponting 2020 p." /> Other factors may include problems with the nervous and immune systems, as well as energy metabolism.<ref name="Bateman-2021" /> ME/CFS is a biological disease, not a psychological condition,<ref name="pmid28033311" /><ref name="CDC_Clinical2024" /> and is not due to [[deconditioning]].<ref name="pmid28033311" /><ref name="Bateman-2021" />
Besides viruses, other reported triggers include stress, traumatic events, and environmental exposures such as to [[Mold|mould]].<ref name="IQWiG-2023" />{{Rp|page=21}} Bacterial infections such as [[Q fever|Q-fever]] are other potential triggers.<ref name="BMJbest_practice3" />{{rp|5}} ME/CFS may further occur after physical trauma, such as an accident or surgery.<ref name="CDC_Clinical2024" /> Pregnancy has been reported in around 3% to 10% of cases as a trigger.<ref name="pmid37234076">{{cite journal |vauthors=Pollack B, von Saltza E, McCorkell L, Santos L, Hultman A, Cohen AK, Soares L |date=2023 |title=Female Reproductive Health Impacts of Long COVID and Associated Illnesses Including ME/CFS, POTS, And Connective Tissue Disorders: A Literature Review |url=|journal=Frontiers in Rehabilitation Sciences |volume=4 |issue= |pages=1122673 |doi=10.3389/fresc.2023.1122673 |doi-access=free |pmc=10208411 |pmid=37234076}}</ref> ME/CFS can also begin with multiple minor triggering events, followed by a final trigger that leads to a clear onset of symptoms.<ref name="pmid37793728" />
=== Risk factors ===
ME/CFS can affect people of all ages, ethnicities, and income levels, but it is more common in women than men.<ref name="Lim2020" /> People with a history of frequent infections are more likely to develop it.<ref name="pmid38443223" /> Those with family members who have ME/CFS are also at higher risk, suggesting a genetic factor, however a 2020 review of published gene studies was not able to find strong and reliable correlations of specific genetics with the illness.<ref name="Dibble McGrath Ponting 2020 p." /> In the United States, [[white Americans]] are diagnosed more frequently than other groups,<ref name="CDC_Basics">{{Cite web |date=10 May 2024 |title=ME/CFS Basics |url=https://www.cdc.gov/me-cfs/about/index.html |archive-url=https://web.archive.org/web/20240523214910/https://www.cdc.gov/me-cfs/about/index.html |archive-date=23 May 2024 |access-date=25 May 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |language=en-us}}</ref> but the illness is probably at least as prevalent among African Americans and Hispanics.<ref name="CDCEpide2023">{{cite web |date=21 March 2023 |title=Epidemiology |url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html |url-status=dead |archive-url=https://web.archive.org/web/20240306031847/https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html |archive-date=6 March 2024 |access-date=13 April 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref> It used to be thought that ME/CFS was more common among those with higher incomes. Instead, people in minority groups or lower income groups may have increased risks due to poorer nutrition, lower healthcare access, and increased work stress.<ref name="Lim2020" />
=== Viral infections ===
{{main|Post-acute infection syndrome}}
Viral infections have long been suspected to cause ME/CFS, based on the observation that ME/CFS sometimes occurs in outbreaks and is possibly connected to [[autoimmune disease]]s.<ref name="pmid37898798">{{cite journal |vauthors=Hwang JH, Lee JS, Oh HM, Lee EJ, Lim EJ, Son CG |date=October 2023 |title=Evaluation of Viral Infection as an Etiology of ME/CFS: A Systematic Review and Meta-Analysis |url=|journal=Journal of Translational Medicine |volume=21 |issue=1 |article-number=763 |doi=10.1186/s12967-023-04635-0 |doi-access=free |pmc=10612276 |pmid=37898798}}</ref> How viral infections cause ME/CFS is unclear; it could be via [[Virus latency|viral persistence]] or via a "hit and run" mechanism, in which infections dysregulate the immune system or cause autoimmunity.<ref name="pmid30285773">{{cite journal |vauthors=Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, Prusty BK |date=October 2018 |title=Chronic Viral Infections in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) |url=|journal=Journal of Translational Medicine |volume=16 |issue=1 |article-number=268 |doi=10.1186/s12967-018-1644-y |doi-access=free |pmc=6167797 |pmid=30285773}}</ref>
Different types of viral infection have been implicated in ME/CFS, including airway infections, [[bronchitis]], [[gastroenteritis]], or an acute "[[flu-like illness]]".<ref name="IQWiG-2023" />{{Rp|page=226}} Between 15% and 50% of people with [[long COVID]] also meet the diagnostic criteria for ME/CFS.<ref name="IQWiG-2023" />{{Rp|page=228}} Of people who get [[infectious mononucleosis]], which is caused by the [[Epstein–Barr virus]] (EBV), around 8% to 15% develop ME/CFS, depending on criteria.<ref name="IQWiG-2023" />{{Rp|page=226}} Other viral infections that can trigger ME/CFS are the [[Influenza A virus subtype H1N1|H1N1 influenza virus]], [[Varicella zoster virus|varicella zoster]] (the virus that causes [[chickenpox]] and [[shingles]]), and [[SARS-CoV-1]].<ref name="pmid37433988">{{cite journal |vauthors=Altmann DM, Whettlock EM, Liu S, Arachchillage DJ, Boyton RJ |date=October 2023 |title=The Immunology of Long COVID |journal=Nature Reviews. Immunology |volume=23 |issue=10 |pages=618–634 |doi=10.1038/s41577-023-00904-7 |pmid=37433988 |s2cid=259831825 |doi-access=free}}</ref>
Reactivation of latent viruses, in particular EBV and [[human herpesvirus 6]], has also been hypothesised to drive symptoms. EBV is present in about 90% of people, usually in a latent state.<ref name="pmid37718435">{{cite journal |vauthors=Ruiz-Pablos M, Paiva B, Zabaleta A |date=September 2023 |title=Epstein-Barr Virus-Acquired Immunodeficiency in Myalgic encephalomyelitis-Is It Present in Long COVID? |url=|journal=Journal of Translational Medicine |volume=21 |issue=1 |article-number=633 |doi=10.1186/s12967-023-04515-7 |doi-access=free |pmc=10506247 |pmid=37718435}}</ref><ref>{{Cite report |url=https://www.ninds.nih.gov/sites/default/files/2024-05/Report%20of%20the%20MECFS%20Research%20Roadmap%20Working%20Group%20of%20Council_508C.pdf |title=Report of the ME/CFS Research Roadmap Working Group of Council | vauthors = Bateman L, Hanson M |date=15 May 2024 |publisher=[[National Institutes of Health]] (NIH) |access-date=25 May 2024 |archive-url=https://web.archive.org/web/20240522195146/https://www.ninds.nih.gov/sites/default/files/2024-05/Report%20of%20the%20MECFS%20Research%20Roadmap%20Working%20Group%20of%20Council_508C.pdf |archive-date=22 May 2024 |url-status=live}}</ref>{{Rp|page=13}} The levels of [[Antibody|antibodies]] to EBV are commonly higher in people with ME/CFS, indicating possible viral reactivation.<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 |s2cid=80898744 |quote=}}</ref>
== Pathophysiology ==
ME/CFS is associated with changes in several areas, including the nervous and immune systems, as well as disturbances in energy metabolism.<ref name="CDC_Clinical2024" /><ref name="pmid38443223" /> Neurological differences include [[autonomic nervous system]] dysfunction and a change in brain structure and [[metabolism]].<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 |date=2020 |title=A Systematic Review of Neurological Impairments in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Using Neuroimaging Techniques |journal=PLOS ONE |volume=15 |issue=4 |pages=e0232475 |bibcode=2020PLoSO..1532475M |doi=10.1371/journal.pone.0232475 |pmc=7192498 |pmid=32353033 |doi-access=free |title-link=doi}}</ref> Observed changes in the [[immune system]] include decreased [[natural killer cell]] function and, in some cases, [[autoimmunity]].<ref name="pmid38443223" />
=== Neurological ===
A range of structural, biochemical, and functional abnormalities are found in brain imaging studies of people with ME/CFS.<ref name="Marshall-Gradisnik_2022" /><ref name="Maksoud2020" /> Common findings are changes in the [[brainstem]] and the use of additional brain areas for cognitive tasks. Other consistent findings, based on a smaller number of studies, are low metabolism in some areas, reduced [[serotonin transporter]]s, and problems with [[Neurovascular unit|neurovascular coupling]].<ref name="pmid328732972" />
[[Neuroinflammation]] has been proposed as an underlying mechanism of ME/CFS that could explain a large set of symptoms. Several studies suggest neuroinflammation in the [[brain cortex|cortical]] and [[limbic system|limbic]] regions of the brain. Individuals with ME/CFS, for instance, have higher brain [[lactic acid|lactate]] and [[choline]] levels, which are signs of neuroinflammation. More direct evidence from two small [[positron emission tomography]] studies of [[microglia]], a type of immune cell in the brain, were contradictory, however.<ref name="pmid38016575">{{cite journal |vauthors=Lee JS, Sato W, Son CG |title=Brain-Regional Characteristics and Neuroinflammation in ME/CFS Patients from Neuroimaging: A Systematic Review and Meta-Analysis |journal=Autoimmunity Reviews |volume=23 |issue=2 |article-number=103484 |date=November 2023 |pmid=38016575 |doi=10.1016/j.autrev.2023.103484 |url=|doi-access=free }}</ref><ref>{{cite journal | vauthors = VanElzakker MB, Brumfield SA, Lara Mejia PS | title = Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods | journal = Frontiers in Neurology | volume = 9 | pages = 1033 | date = 2019 | pmid = 30687207 | pmc = 6335565 | doi = 10.3389/fneur.2018.01033 | doi-access = free }}</ref>
ME/CFS affects sleep. Individuals experience decreased [[sleep efficiency]], [[Sleep onset latency|take longer to fall asleep]], and take longer to achieve [[Rapid eye movement sleep|REM sleep]], a phase of sleep characterised by rapid eye movement. Changes to [[Non-rapid eye movement sleep|non-REM sleep]] have also been found, together suggesting a role of the autonomic nervous system.<ref name="pmid36948138">{{cite journal |vauthors=Mohamed AZ, Andersen T, Radovic S, Del Fante P, Kwiatek R, Calhoun V, Bhuta S, Hermens DF, Lagopoulos J, Shan ZY |title=Objective Sleep Measures in Chronic Fatigue Syndrome Patients: A Systematic Review and Meta-Analysis |journal=Sleep Medicine Reviews |volume=69 |issue= |article-number=101771 |date=June 2023 |pmid=36948138 |doi=10.1016/j.smrv.2023.101771 |pmc=10281648 |url=}}</ref> Individuals often have a [[chronotropic incompetence|blunted heart rate response to exercise]], but a higher heart rate during a [[tilt table test]] when the body is rotated from lying flat to an upright position. This again suggests dysfunction in the autonomic nervous system.<ref name="pmid31651868">{{cite journal |vauthors=Nelson MJ, Bahl JS, Buckley JD, Thomson RL, Davison K |date=October 2019 |title=Evidence of Altered Cardiac Autonomic Regulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis |url=|journal=Medicine |volume=98 |issue=43 |pages=e17600 |doi=10.1097/MD.0000000000017600 |pmc=6824690 |pmid=31651868}}</ref>
=== Immunological ===
People with ME/CFS often have immune system abnormalities. A consistent finding in studies is a decreased function of natural killer cells, a type of immune cell that targets virus-infected and tumour cells.<ref name="pmid31727160">{{cite journal |vauthors=Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S |date=November 2019 |title=A Systematic Review of Natural Killer Cells Profile and Cytotoxic Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=|journal=Systematic Reviews |volume=8 |issue=1 |article-number=279 |doi=10.1186/s13643-019-1202-6 |doi-access=free |pmc=6857215 |pmid=31727160}}</ref> They are also more likely to have active viral infections, correlating with cognitive issues and fatigue. [[T cell]]s show less metabolic activity. This may reflect they have reached an exhausted state and cannot respond effectively against [[pathogen]]s.<ref name="pmid38443223" />
Autoimmunity has been proposed to be a factor in ME/CFS. There is a subset of people with ME/CFS with increased levels of [[Autoantibody|autoantibodies]], possibly as a result of [[Molecular mimicry|viral mimicry]].<ref name="Autoimmunity Reviews pp. 601–609" /> Some may have higher levels of autoantibodies to [[muscarinic acetylcholine receptor]]s as well as to [[Beta-2 adrenergic receptor|β2 adrenergic receptors]].<ref name="Autoimmunity Reviews pp. 601–609">{{cite journal |vauthors=Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M |date=June 2018 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an Autoimmune Disease |journal=Autoimmunity Reviews |volume=17 |issue=6 |pages=601–609 |doi=10.1016/j.autrev.2018.01.009 |pmid=29635081 |doi-access=free |collaboration=European Network on ME/CFS (EUROMENE) |title-link=doi}}</ref><ref name="pmid38443223" /> Problems with these receptors can lead to impaired blood flow.<ref name="Autoimmunity Reviews 2020 p.">{{cite journal |vauthors=Wirth K, Scheibenbogen C |date=June 2020 |title=A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the Finding of Autoantibodies Against Β2-Adrenergic Receptors |journal=Autoimmunity Reviews |volume=19 |issue=6 |article-number=102527 |doi=10.1016/j.autrev.2020.102527 |pmid=32247028 |doi-access=free |title-link=doi}}</ref>
=== Energy ===
[[File:Work rate at ventilatory threshold.jpg|thumb|upright=1.35|When people with ME/CFS exercise on consecutive days, their performance declines on the second day, unlike those with [[idiopathic chronic fatigue|unexplained chronic fatigue]] (ICF).|alt=A scatterplot with fifty datapoints. They show that people with ME/CFS score worse in work rate at ventilatory threshold than those with unexplained chronic fatigue on the second day of a 2-day exercise test.]]
Objective signs of PEM have been found with the [[2-day CPET|2-day cardiopulmonary exercise test]].<ref name="pmid33327624">{{cite journal |vauthors=Lim EJ, Kang EB, Jang ES, Son CG |date=December 2020 |title=The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis |url=|journal=Journal of Clinical Medicine |volume=9 |issue=12 |page=4040 |doi=10.3390/jcm9124040 |pmc=7765094 |pmid=33327624 |doi-access=free}}</ref> People with ME/CFS have lower performance compared to healthy controls on the first test. On the second test, healthy people's scores stay roughly the same or increase slightly, while those with ME/CFS have a clinically significant decrease in work rate at the [[Lactate threshold|anaerobic threshold]]. Potential causes include mitochondrial dysfunction, and issues with the transport and use of oxygen.<ref name="Franklin-2022">{{Cite journal | vauthors = Franklin JD, Graham M |date=3 July 2022 |title=Repeated Maximal Exercise Tests of Peak Oxygen Consumption in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis |journal=Fatigue: Biomedicine, Health & Behavior |volume=10 |issue=3 |pages=119–135 |doi=10.1080/21641846.2022.2108628 |s2cid=251636593 |issn=2164-1846|doi-access = free | title-link = doi }}</ref> Some of the usual recovery processes following exercise may be lacking, providing an alternative explanation for PEM.<ref name="pmid38443223" />
Studies have observed [[Mitochondrial disease|mitochondrial abnormalities]] in cellular energy production, but differences between studies make it hard to draw clear conclusions.<ref name="holden2020">{{cite journal |vauthors=Holden S, Maksoud R, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S |date=July 2020 |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 |article-number=290 |doi=10.1186/s12967-020-02452-3 |pmc=7392668 |pmid=32727475 |doi-access=free |title-link=doi}}</ref> [[Adenosine triphosphate|ATP]], the primary energy carrier in cells, is likely more frequently produced from [[lipid]]s and [[amino acid]]s than from [[carbohydrate]]s.<ref name="pmid38443223" />
=== Other ===
Some people with ME/CFS have abnormalities in their [[hypothalamic–pituitary–adrenal axis]] hormones. This can include [[adrenal insufficiency|lower cortisol levels]], less change in cortisol levels throughout the day, and a weaker reaction to stress and stimuli.<ref name="Morris2016rev">{{cite journal |vauthors=Morris G, Anderson G, Maes M |date=November 2017 |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=6806–6819 |doi=10.1007/s12035-016-0170-2 |pmid=27766535 |s2cid=3524276}}</ref> Other proposed abnormalities are reduced [[Cerebral circulation|blood flow to the brain]] under orthostatic stress (as found in a tilt table test), [[Small fiber peripheral neuropathy|small-fibre neuropathy]], and an increase in the amount of [[Gut microbiota|gut microbes]] entering the blood.<ref name="BMJbest_practice3" />{{Rp|page=9}} The diversity of [[Gut microbiota|gut microbes]] is reduced compared to healthy controls.<ref name="pmid38443223" /> Women with ME/CFS are more likely to experience [[endometriosis]], [[Primary ovarian insufficiency|early menopause]], and other menstrual irregularities compared to women without the condition.<ref name="CDC_Clinical2024" />
== Diagnosis ==
Diagnosis of ME/CFS is based on symptoms<ref name="pmid37226227" /> and involves taking a [[medical history]] and a mental and physical examination.<ref name="CDC2020diag" /> No specific lab tests are approved for diagnosis; while physical abnormalities can be found, no single finding is considered sufficient for diagnosis.<ref name="Bateman-2021" /><ref name="pmid37226227">{{cite journal | vauthors = Maksoud R, Magawa C, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S | title = Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review | journal = BMC Medicine | volume = 21 | issue = 1 | article-number = 189 | date = May 2023 | pmid = 37226227 | pmc = 10206551 | doi = 10.1186/s12916-023-02893-9 | doi-access = free }}</ref> Blood and urine tests are used to rule out other conditions that could be responsible for the symptoms.<ref name="CDC2020diag">{{cite web |date=13 May 2024 |title=Diagnosing ME/CFS |url=https://www.cdc.gov/me-cfs/diagnosis/ |url-status=live |archive-url=https://web.archive.org/web/20240517195301/https://www.cdc.gov/me-cfs/diagnosis/ |archive-date=17 May 2024 |access-date=17 May 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC)}}</ref> People with ME/CFS often face significant delays in obtaining a diagnosis, and diagnoses may be missed altogether.<ref name="NICE2021" />{{Rp|pages=66}} Specialists in ME/CFS may be asked to confirm the diagnosis, as primary care physicians often lack a good understanding of the illness.<ref name="NICE2021" />{{Rp|page=68}}
=== Diagnostic criteria ===
{{Main|Clinical descriptions of ME/CFS}}
{| class="wikitable floatright"
|+ ME/CFS symptoms according to five diagnostic criteria<ref name="IQWiG-2023" />{{rp|13}}<ref name="BMJbest_practice3" />{{rp|15}}
! style="text-align: left; font-weight: normal;" |'''Symptom''' {{small|<br> M: Mandatory <br> O: Optional}}
!{{vert header|{{abbr|CDC|Centers for Disease Control and Prevention}}/Fukuda}}
!{{vert header|{{abbr|CCC|Canadian Consensus Criteria}}}}
!{{vert header|{{abbr|ICC|International Consensus Criteria}}}}
!{{vert header|{{abbr|IOM|Institute of Medicine}}}}
!{{vert header|{{abbr|NICE|National Institute for Health and Care Excellence}}}}
|-
|Fatigue
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
|-
|Functional impairment
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
|-
|PEM
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
|-
|Sleep problems
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
|-
|Cognitive issues
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
|-
|Pain or headaches
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #3B7D23; text-align: center;" |<span style="color:white">'''M'''</span>
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|-
|Orthostatic intolerance
|
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
|
|-
|Flu or cold symptoms
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|-
|Nausea
|
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|-
|Cardiovascular problems
|
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|-
|Hypersensitivities
|
| style="background: #8ED973; text-align: center;" |'''O'''
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|-
|Susceptibility to infection
|
|
| style="background: #8ED973; text-align: center;" |'''O'''
|
|
|}
Multiple research and clinical criteria exist to diagnose ME/CFS. These include the [[National Institute for Health and Care Excellence|NICE]] guidelines, [[National Academy of Medicine|Institute of Medicine]] (IOM) criteria, the International Consensus Criteria (ICC), the Canadian Consensus Criteria (CCC), and [[Centers for Disease Control and Prevention|CDC]] criteria. The criteria sets were all developed based on expert consensus and differ in the required symptoms and which conditions preclude a diagnosis of ME/CFS.<ref name="BMJbest_practice3" />{{Rp|page=14}} The definitions differ in their conceptualisation of the cause and mechanisms of ME/CFS.<ref name="Lim_2020">{{cite journal |vauthors=Lim EJ, Son CG |date=July 2020 |title=Review of Case Definitions for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) |journal=Journal of Translational Medicine |volume=18 |issue=1 |article-number=289 |doi=10.1186/s12967-020-02455-0 |pmc=7391812 |pmid=32727489 |doi-access=free |title-link=doi}}</ref>
As there are no verified [[biomarkers]] for ME/CFS, it is not possible to determine which set of criteria is the most accurate. A trade-off must be made between overdiagnosis and missing more diagnoses. The broad Fukuda criteria have a higher risk of overdiagnosis, whereas the strict ICC criteria have a higher risk of missing people. The IOM and NICE criteria fall in the middle.<ref name="NICE-2021-D" />{{Rp|page=|pages=47–48}}
The 1994 CDC criteria, sometimes called the Fukuda criteria, require six months of persistent or relapsing fatigue for diagnosis, as well as the persistent presence of four out of eight other symptoms.<ref name="BMJbest_practice3" />{{Rp|page=35}} While used frequently, the Fukuda criteria have limitations: PEM and cognitive issues are not mandatory. The large variety of optional symptoms can lead to diagnosis of individuals who differ significantly from each other.<ref name="IQWiG-2023" />{{Rp|page=15|pages=}}
The Canadian Consensus Criteria, another commonly used criteria set, was developed in 2003.<ref name="BMJbest_practice3" />{{Rp|page=14}} In addition to PEM, fatigue and sleep problems, pain and neurological or cognitive issues are required for diagnosis. Furthermore, three categories of symptoms are defined (orthostatic, thermal instability, and immunological). At least one symptom in two of these categories needs to be present.<ref name="IQWiG-2023" />{{Rp|page=15}}<ref name="BMJbest_practice3" />{{Rp|page=34}} People diagnosed under the CCC have more severe symptoms compared to those diagnosed under the Fukuda criteria. The 2011 International Consensus Criteria defines ME using symptom clusters and has no minimum duration of symptoms. Similarly to the CCC criteria, ICC is stricter than the Fukuda criteria and selects more severely ill people.<ref name="BMJbest_practice3" />{{Rp|page=14}}
The 2015 IOM criteria share significant similarities with the CCC but were developed to be easy to use for clinicians. Diagnosis requires fatigue, PEM, non-restorative sleep, and either cognitive issues (such as memory impairment) or orthostatic intolerance. Additionally, fatigue must persist for at least six months, substantially impair activities in all areas of life, and have a clearly defined onset.<ref name="IQWiG-2023" />{{Rp|page=|pages=16–17}} Symptoms must be present at least half of the time, and be of moderate severity or worse; previous criteria just required symptoms to be present.<ref name="BMJbest_practice3" />{{Rp|page=14}} In 2021, NICE revised its criteria based on the IOM criteria. The updated criteria require fatigue, PEM, non-restorative sleep, and cognitive difficulties persisting for at least three months.<ref name="IQWiG-2023" />{{Rp|page=|pages=16–17}}
Separate diagnostic criteria have been developed for children and young people. A diagnosis for children often requires a shorter symptom duration. For example, the CCC definition only requires three months of persistent symptoms in children compared to six months for adults.<ref name="IQWiG-2023" />{{Rp|page=|pages=17–18}} NICE requires only four weeks of symptoms to suspect ME/CFS in children, compared to six weeks in adults.<ref name="BMJbest_practice3" />{{Rp|page=15}} Exclusionary diagnoses also differ; for instance, children and teenagers may have [[School refusal|anxiety related to school attendance]], which could explain symptoms.<ref name="IQWiG-2023" />{{Rp|page=|pages=17–18}}
=== Clinical assessment ===
[[File:Could You Have MECFS.webp|thumb|upright=1.35|''Could You Have ME/CFS?'' handout from the US Centers for Disease Control and Prevention|alt=A leaflet from the CDC describing the Institute of Medicine criteria for ME/CFS.]]
Screening can be done using the [[DePaul Symptom Questionnaire]], which assesses the frequency and severity of ME/CFS symptoms.<ref name="BMJbest_practice3" />{{Rp|24}} Individuals may struggle to answer questions related to PEM, if they are unfamiliar with the symptom. To find patterns in symptoms, they may be asked to keep a diary.<ref name="Bateman-2021" />
A [[physical exam]] may appear completely normal, particularly if the individual has rested substantially before a doctor's visit.<ref name="Bateman-2021" /> There may be tenderness in the lymph nodes and abdomen or signs of hypermobility.<ref name="BMJbest_practice3" />{{Rp|17}} Answers to questions may show a temporary difficulty with finding words or other cognitive problems.<ref name="pmid37793728" /> [[Neuropsychological test|Cognitive tests]] and a two-day cardiopulmonary exercise test (CPET) can be helpful to document aspects of the illness, but they may be risky as they can cause severe PEM. They may be warranted to support a disability claim.<ref name="Bateman-2021" /> Orthostatic intolerance can be measured with a tilt table test. If that is unavailable, it can also be assessed with the simpler [[NASA lean test|NASA 10-minute lean test]], which tests the response to prolonged standing.<ref name="pmid37793728" />
Standard laboratory findings are usually normal. Standard tests when suspecting ME/CFS include an HIV test, and blood tests to determine [[Complete blood count|full blood count]], [[Erythrocyte sedimentation rate|red blood cell sedimentation rate]] (ESR), [[C-reactive protein]], blood glucose and [[thyroid-stimulating hormone]]. Tests for [[Antinuclear antibody|antinuclear antibodies]] may come back positive, but below the levels that suggest the individual may have [[lupus]]. C-reactive protein levels are often at the high end of normal. [[Ferritin|Serum ferritin]] levels may be useful to test, as borderline [[Anemia|anaemia]] can make some ME/CFS symptoms worse.<ref name="BMJbest_practice3" />{{Rp|18}}
=== Differential diagnosis ===
Some medical conditions have symptoms similar to ME/CFS. Diagnosis often involves clinical evaluation, testing, and specialist referrals to identify the correct condition. During the time other possible diagnoses are explored, advice can be given on symptom management to help prevent the condition from getting worse.<ref name="NICE2021" />{{Rp|pages=66–67}} Before a diagnosis of ME/CFS is confirmed, a waiting period is used to exclude acute medical conditions or symptoms which may resolve within that time frame.<ref name="Bateman-2021" /><ref>{{Cite journal |last1=Kingdon |first1=Caroline |last2=Lowe |first2=Adam |last3=Shepherd |first3=Charles |last4=Nacul |first4=Luis |date=2022 |title=What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults |journal=Healthcare |language=en |volume=10 |issue=12 |pages=2438 |doi=10.3390/healthcare10122438 |doi-access=free |pmid=36553962 |pmc=9778354 |issn=2227-9032}}</ref>
Possible differential diagnoses span a large set of specialties and depend on the medical history.<ref name="Bateman-2021" /> Examples are [[Infection|infectious diseases]], such as Epstein–Barr virus and [[Lyme disease]], and neuroendocrine disorders, including [[diabetes]] and [[hypothyroidism]]. [[Hematologic disease|Blood disorders]], such as [[Anemia|anaemia]], and some cancers may also present similar symptoms.<ref name="Bateman-2021" /><ref name="NICE-2021-D" />{{Rp|page=57}} Various rheumatological and autoimmune diseases, such as [[fibromyalgia]], [[Sjögren syndrome|Sjögren's syndrome]], lupus, and [[arthritis]], may have overlapping symptoms with ME/CFS. Furthermore, it may be necessary to evaluate [[mental disorder|psychiatric diseases]], such as depression or [[substance use disorder]], as well as neurological disorders, such as [[narcolepsy]], [[multiple sclerosis]], and [[craniocervical instability]].<ref name="Bateman-2021" /><ref name="NICE-2021-D">{{Cite book |last=National Guideline Centre (UK) |url=https://www.ncbi.nlm.nih.gov/books/NBK579530/pdf/Bookshelf_NBK579530.pdf |title=Identifying and Diagnosing ME/CFS: Myalgic Encephalomyelitis (Or Encephalopathy) / Chronic Fatigue Syndrome: Diagnosis and Management: Evidence Review D |date=2021 |publisher=National Institute for Health and Care Excellence (NICE) |isbn=978-1-4731-4221-3 |series=NICE Evidence Reviews Collection |___location=London |pmid=35438857 |access-date=23 September 2023 |archive-url=https://web.archive.org/web/20240219120717/https://www.ncbi.nlm.nih.gov/books/NBK579530/ |archive-date=19 February 2024 |url-status=live}}</ref>{{Rp|page=57}} Finally, sleep disorders, [[coeliac disease]], and side effects of medications may also explain symptoms.<ref name="Bateman-2021" />
Joint and muscle pain without swelling or inflammation is a common feature of ME/CFS, but is more closely associated with [[fibromyalgia]]. Modern definitions of fibromyalgia not only include widespread pain but also fatigue, sleep disturbances, and cognitive issues. This makes it difficult to distinguish ME/CFS from fibromyalgia<ref name="BMJbest_practice">{{Cite book |vauthors=Baraniuk JN |date=January 2022 |title=Myalgic Encephalomyelitis (Chronic Fatigue Syndrome) |url=https://bestpractice.bmj.com/topics/en-us/277/pdf/277/Myalgic%20encephalomyelitis%20(Chronic%20fatigue%20syndrome).pdf |access-date=30 September 2023 |publisher=BMJ Best Practice |url-access=subscription |archive-date=9 October 2023 |archive-url=https://web.archive.org/web/20231009170253/https://bestpractice.bmj.com/topics/en-us/277/pdf/277/Myalgic%20encephalomyelitis%20(Chronic%20fatigue%20syndrome).pdf |url-status=live }}</ref>{{rp|13, 26}} and the two are often co-diagnosed.<ref name="BMJbest_practice3" />{{rp||page=28}}
Another common condition that often co-occurs with ME/CFS is hypermobile [[Ehlers–Danlos syndrome]] (EDS).<ref name="NICE-2021-D" />{{Rp|page=57}} Unlike ME/CFS, EDS is present from birth. People with ME/CFS are more often [[Hypermobility (joints)|hypermobile]] compared to the general population.<ref name="BMJbest_practice3" />{{rp||page=|pages=28–29}} [[Sleep apnea]] may also co-occur with ME/CFS.<ref name="BMJbest_practice3" />{{Rp|page=16}} However, many diagnostic criteria require ruling out sleep disorders before confirming a diagnosis of ME/CFS.<ref name="IQWiG-2023" />{{Rp|page=7}}
Like with other [[Chronic condition|chronic illnesses]], depression and anxiety co-occur frequently with ME/CFS. Depression may be [[Differential diagnosis|differentially diagnosed]] by the presence of feelings of worthlessness, the [[Anhedonia|inability to feel pleasure]], loss of interest, and/or guilt, and the absence of ME/CFS bodily symptoms such as [[autonomic dysfunction]], pain, migraines, and PEM.<ref name="BMJbest_practice3" />{{rp|27}} People with chronic fatigue, which is not due to ME/CFS or other chronic illnesses, may be diagnosed with [[Idiopathic chronic fatigue|idiopathic (unexplained) chronic fatigue]].<ref name="BMJbest_practice3" />{{rp|32}}
== Management ==
{{Main|Management of ME/CFS}}
There is no approved drug treatment or cure for ME/CFS, although some symptoms can be treated or managed. Care for ME/CFS involves multidisciplinary healthcare professionals. Usually, the primary care clinician plays an important role in coordinating health care, social care and educational support for those still in school. This coordinator can help provide access to community resources such as [[occupational therapy]] and [[District nurse|district nursing]]. Management may start with treating the most disabling symptom first, and tackle symptoms one by one in further health care visits.<ref name="BMJbest_practice3" />{{Rp|page=46}}
[[Pacing (activity management)|Pacing]], or managing one's activities to stay within energy limits, can reduce episodes of [[Post-exertional malaise|PEM]]. Addressing sleep problems with good [[sleep hygiene]], or medication if required, may be beneficial. Chronic pain is common in ME/CFS, and the CDC recommends consulting with a pain management specialist if [[over-the-counter]] painkillers are insufficient. For cognitive impairment, adaptations like organisers and calendars may be helpful.<ref name=CDC2024manage />
[[Comorbid|Co-occurring conditions]] that may interact with and worsen ME/CFS symptoms are common, and treating these may help manage ME/CFS.<ref name="Bateman-2021" /> Commonly diagnosed ones include [[fibromyalgia]], irritable bowel syndrome, migraines and [[mast cell activation syndrome]].<ref name="BMJbest_practice3" />{{Rp|page=19}} The debilitating nature of ME/CFS can cause depression, [[anxiety]], or other psychological problems, which can be treated.<ref name="CDC2024manage" /> People with ME/CFS may be unusually sensitive to medications, especially ones that affect the central nervous system.<ref>{{Cite web |date=10 May 2024 |title=Monitoring the Use of Medicines and Supplements |url=https://www.cdc.gov/me-cfs/hcp/clinical-care/monitoring-the-use-of-medicines-and-supplements.html |access-date=25 May 2024 |archive-url=https://web.archive.org/web/20240525121239/https://www.cdc.gov/me-cfs/hcp/clinical-care/monitoring-the-use-of-medicines-and-supplements.html|archive-date=25 May 2024|publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) }}</ref>
=== Pacing and energy management ===
[[File:FitbitIonicMomentDisplay.jpg|upright=1.35|thumb|A heart rate monitor can be helpful for energy management.|alt=A smart watch displaying heart rate on a person's wrist]]
[[Pacing (activity management)|Pacing]], or activity management, involves balancing periods of rest with periods of activity.<ref name="CDC_strategies2024" /> The goal of pacing is to stabilize the illness and avoid triggering PEM.<ref name="Hoffmann_2024" /> This involves staying within an individual's available ''energy envelope'' to reduce the PEM "payback" caused by overexertion.<ref name="Jason2017">{{cite journal |vauthors=O'Connor K, Sunnquist M, Nicholson L, Jason LA, Newton JL, Strand EB |date=March 2019 |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 |doi=10.1177/1742395317746470 |pmc=5750135 |pmid=29231037}}</ref> The technique was developed for ME/CFS in the 1980s.<ref name="Goudsmit2011">{{cite journal | vauthors = Goudsmit EM, Nijs J, Jason LA, Wallman KE | 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 = 1140–1147 | 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 | url-status = live | s2cid = 22457926 | archive-url=https://web.archive.org/web/20200728130945/https://repository.uel.ac.uk/item/85yxz | archive-date = 28 July 2020 }}</ref>
Pacing can involve breaking up large tasks into smaller ones and taking extra breaks, or creating easier ways to do activities. For example, this might include sitting down while doing the laundry. The decision to stop an activity (and rest or change an activity) is determined by self-awareness of a worsening of symptoms. Use of a [[heart rate monitor]] may help some individuals with pacing.<ref name="CDC2024manage" />
Research on pacing and energy envelope theory typically shows positive effects.<ref name="Jason2017" /><ref name="Sanal-Hayes_2023">{{cite journal |vauthors=Sanal-Hayes NE, Mclaughlin M, Hayes LD, Mair JL, Ormerod J, Carless D, Hilliard N, Meach R, Ingram J, Sculthorpe NF |date=October 2023 |title=A Scoping Review of 'Pacing' for Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Lessons Learned for the Long COVID Pandemic |journal=Journal of Translational Medicine |volume=21 |issue=1 |article-number=720 |doi=10.1186/s12967-023-04587-5 |pmc=10576275 |pmid=37838675 |doi-access=free}}</ref> However, these studies have often had a low number of participants and have rarely included methods to check if study participants implemented pacing well.<ref name="Sanal-Hayes_2023" /> Pacing is difficult to apply for people with very severe ME/CFS, as the activities that trigger PEM in this group, such as eating, cannot be avoided completely.<ref name="Hoffmann_2024" />
Those with a stable illness who understand how to "listen to their body" may be able to carefully and flexibly increase their activity levels.<ref name="CDC_strategies2024" /> The goal of an exercise programme would be to increase stamina, while not interfering with everyday tasks or making the illness more severe.<ref name="BMJbest_practice3" />{{Rp|page=56}} In many chronic illnesses, intense exercise is beneficial, but in ME/CFS it is not recommended. The CDC states:<ref name="CDC2024manage" />
{{blockquote|Vigorous aerobic exercise can benefit people with many chronic illnesses. But people 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.}}
[[Graded exercise therapy]] (GET), a proposed treatment for ME/CFS that assumes deconditioning and a fear of activity play important roles in maintaining the illness, is no longer recommended for people with ME/CFS.<ref name="pmid37793728" /><ref name="BMJbest_practice3" />{{Rp|page=38}} Reviews of GET either see weak evidence of a small to moderate effect<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= U.S. [[Centers for Disease Control and Prevention]] |year=2022 |access-date=30 March 2023 |archive-url=https://web.archive.org/web/20240214175237/https://www.cdc.gov/me-cfs/pdfs/systematic-review/file1-final-report-MECFS-Systematic-Review-508.pdf |archive-date=14 February 2024 |url-status=dead}}</ref><ref name="Lar20192">{{cite journal |vauthors=Larun L, Brurberg KG, Odgaard-Jensen J, Price JR |date=October 2019 |title=Exercise Therapy for Chronic Fatigue Syndrome |journal=The Cochrane Database of Systematic Reviews |volume=10 |issue=10 |pages=CD003200 |doi=10.1002/14651858.CD003200.pub8 |pmc=6953363 |pmid=31577366}}</ref> or no evidence of effectiveness.<ref name="Geraghty_2019">{{cite journal |vauthors=Geraghty K, Jason L, Sunnquist M, Tuller D, Blease C, Adeniji C |date=23 April 2019 |title=The 'Cognitive Behavioural Model' of Chronic Fatigue Syndrome: Critique of a Flawed Model |journal=Health Psychology Open |volume=6 |issue=1 |pages=2055102919838907 |doi=10.1177/2055102919838907 |pmc=6482658 |pmid=31041108}}</ref><ref name="Ahmed_2020">{{cite journal |vauthors=Ahmed SA, Mewes JC, Vrijhoef H |date=February 2020 |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 |doi=10.1177/1359105319847261 |pmid=31072121 |s2cid=149443976}}</ref> GET can have serious adverse effects.<ref name="Hoffmann_2024" /> Similarly, a form of [[Cognitive behavioral therapy|cognitive behavioural therapy]] (CBT) that assumed the illness is maintained by unhelpful beliefs about the illness and avoidance of activity is no longer recommended.<ref name="Bateman-2021" />
=== Symptom relief ===
The first management step for sleep problems in ME/CFS is improving sleep habits. If sleep problems remain after implementing sleep hygiene routines, [[Cognitive behavioral therapy for insomnia|cognitive behavioural therapy for insomnia]] can be offered. Avoiding naps during the day can further improve sleep,<ref name="BMJbest_practice3" />{{Rp|page=41}} but there may be a trade-off with needed rest during the day.<ref name="NICE2021" />{{rp|36}} Drugs that help with insomnia in fibromyalgia, such as [[trazodone]] or [[suvorexant]], may help in ME/CFS too.<ref name="pmid37793728" />
Pain is initially managed with over-the-counter pain medication, such as [[ibuprofen]] or [[paracetamol]] ([[Paracetamol|acetaminophen]]). If this is insufficient, referral to a pain specialist or counselling on pain management can be the next step. Heat treatment, [[hydrotherapy]] and gentle massage can sometimes help. In addition, stretching and exercise may help with pain, but a balance must be struck, as they can trigger PEM.<ref name="CDC_strategies2024" /> While there is lack of evidence on pharmaceutical options for pain management in ME/CFS, medication that works for fibromyalgia may be tried, such as [[pregabalin]].<ref name="BMJbest_practice3" />{{Rp|page=42}}<ref name="pmid37793728" />
Like in other chronic illnesses, those with ME/CFS often experience mental health issues like anxiety and depression.<ref name="Bateman-2021" /> [[Psychotherapy]], such as CBT may help manage the stress of being ill and teach self-management strategies.<ref name="NICE2021" />{{Rp|page=42}} Family sessions may be useful to educate people close to those with ME/CFS about the severity of the illness.<ref name="BMJbest_practice3" />{{Rp|page=41}} [[Antidepressant]]s can be useful, but there may be more side effects than in the general population. For instance, it may be difficult to stop weight gain due to exercise intolerance.<ref name="BMJbest_practice3" />{{Rp|page=52}}
Bowel issues are a common symptom of ME/CFS. For some, eliminating specific foods, such as [[caffeine]], [[Health effects of alcohol|alcohol]], [[gluten]], or dairy, can alleviate symptoms.<ref name="Bateman-2021" /> Those with orthostatic intolerance can benefit from increased salt and fluid intake.<ref name="Bateman-2021" /> [[Compression stockings]] can help with orthostatic intolerance.<ref name="Bateman-2021" />
=== Severe ME/CFS ===
People with moderate to severe ME/CFS may benefit from home adaptations and mobility aids, such as [[wheelchair]]s, disability parking, [[Transfer bench|shower chairs]], or [[stair lift]]s. To manage sensitivities to environmental stimuli, these stimuli can be limited. For instance, the surroundings can be made perfume-free, or an [[Blindfold|eye mask]] or [[earplug]]s can be used.<ref name="BMJbest_practice3" />{{Rp|pages=39–40}} Those with severe ME/CFS may have significant trouble getting nutrition. [[Parenteral nutrition|Intravenous feeding]] (via blood) or [[Feeding tube|tube feeding]] may be necessary to address this or to address [[electrolyte imbalance]]s.<ref name="pmid37793728" />
Patients who cannot move easily in bed may need help to prevent [[Pressure ulcer|pressure sores]]. Regular repositioning is important to keep their joints flexible and prevent [[contracture]]s and stiffness. [[Osteoporosis]] may pose a risk over the long term.<ref>{{Cite web |date=13 May 2024 |title=ME/CFS Clinical Care for Severely Affected Patients |url=https://www.cdc.gov/me-cfs/hcp/clinical-care/me-cfs-clinical-care-for-severely-affected-patients.html |archive-url=https://web.archive.org/web/20240528171310/https://www.cdc.gov/me-cfs/hcp/clinical-care/me-cfs-clinical-care-for-severely-affected-patients.html |archive-date=28 May 2024 |access-date=15 June 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |url-status=live}}</ref> Symptoms of severe ME/CFS may be misunderstood as neglect or abuse during well-being evaluations, and NICE recommends that professionals with experience in ME/CFS should be involved in any type of assessment for [[safeguarding]].<ref name="NICE2021" />{{rp|22}}
== Prognosis ==
Information on the [[prognosis]] of ME/CFS is limited. Complete recovery, partial improvement, and worsening are all possible,<ref name="CDC_Clinical2024" /> but full recovery is uncommon.<ref name="IQWiG-2023" />{{Rp|page=11}} Symptoms generally fluctuate over days, weeks, or longer periods, and some people may experience periods of remission. Overall, many will have to adjust to life with ME/CFS.<ref name="NICE2021"/>{{Rp|pages=20}}
An early diagnosis may improve care and prognosis.<ref name="NICE-2021-D" /> Factors that may make the disease worse over days, but also over longer periods, are physical and mental exertion, a new infection, sleep deprivation, and emotional stress.<ref name="IQWiG-2023" />{{Rp|page=11}} Some people who improve need to manage their activities to prevent a relapse.<ref name="CDC_Clinical2024" /> Children and teenagers are more likely to recover or improve than adults.<ref name="CDC_Clinical2024" /><ref name="NICE2021"/>{{Rp|pages=20}} For instance, a study in Australia among 6- to 18-year-olds found that two-thirds reported recovery after 10 years and that the typical duration of illness was five years.<ref name="IQWiG-2023" />{{Rp|page=11}}
The effect of ME/CFS on [[life expectancy]] is poorly studied, and the evidence is mixed. One large retrospective study on the topic found no increase in all-cause mortality due to ME/CFS. Death from suicide was, however, significantly higher among those with ME/CFS.<ref name="BMJbest_practice3" />{{Rp|page=59}} In extreme cases, people can die from the illness.<ref name="Hoffmann_2024">{{cite journal | vauthors = Hoffmann K, Hainzl A, Stingl M, Kurz K, Biesenbach B, Bammer C, Behrends U, Broxtermann W, Buchmayer F, Cavini AM, Fretz GS, Gole M, Grande B, Grande T, Habermann-Horstmeier L, Hackl V, Hamacher J, Hermisson J, King M, Kohl S, Leiss S, Litzlbauer D, Renz-Polster H, Ries W, Sagelsdorff J, Scheibenbogen C, Schieffer B, Schön L, Schreiner C, Thonhofer K, Strasser M, Weber T, Untersmayr E | title = Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-Syndrom | trans-title = Interdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome | language = de | journal = Wiener Klinische Wochenschrift | volume = 136 | issue = Suppl 5 | pages = 103–123 | date = August 2024 | pmid = 38743348 | pmc = 11093804 | doi = 10.1007/s00508-024-02372-y }}</ref>
== Epidemiology ==
[[File:ME-CFS Incidence Rate by Age.png|alt=Graph showing that females have two incidence peaks (teenagers and 30–39 years old), and males' incidence peaks in the teenager years.|thumb|upright=1.35|Incidence rates by age and sex, from a 2014 study in Norway]]
Reported prevalence rates vary widely depending on how ME/CFS is defined and diagnosed. Overall, around one in 150 people has ME/CFS. Based on the 1994 CDC diagnostic criteria, the global prevalence rate for CFS is 0.89%. In comparison, estimates using the stricter 1988 CDC criteria or the 2003 Canadian Consensus Criteria for ME/CFS produced a prevalence rate of only 0.17%.<ref name=Lim2020/>
In England and Wales, over 250,000 people are estimated to be affected.<ref name="NICE2021" />{{Rp|pages=92}} These estimates are based on data before the [[COVID-19 pandemic]]. It is likely that numbers have increased as a large share of people with [[long COVID]] meet the diagnostic criteria of ME/CFS.<ref name="IQWiG-2023" />{{Rp|page=228|pages=}} A 2021–2022 [[National Health Interview Survey|CDC survey]] found that 1.3% of adults in the United States, or 3.3 million, had ME/CFS.<ref>{{Cite report |url=https://www.cdc.gov/nchs/products/databriefs/db488.htm |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021–2022 |date=8 December 2023 |publisher=[[National Center for Health Statistics]] |issue=488 |doi=10.15620/cdc:134504 |pages=1–8 |pmid=38085820 |id=NCHS Data Brief |access-date=8 December 2023 |archive-url=https://web.archive.org/web/20240217000708/https://www.cdc.gov/nchs/products/databriefs/db488.htm |archive-date=17 February 2024 |url-status=live |doi-access=free |vauthors=Vahratian A, Lin JS, Bertolli J, Unger ER}}</ref> <!-- 2020 census US adult population: 258.3M -->
Women are diagnosed with ME/CFS about 1.5 to four times more often than men.<ref name=Lim2020/><ref name="CDCEpide2023" /> The prevalence in children and adolescents is slightly lower than in adults,<ref name="Lim2020" /> and children have it less than adolescents.<ref>{{Cite web |date=31 May 2024 |title=Fast Facts: ME/CFS |url=https://www.cdc.gov/me-cfs/about/fast-facts-about-me-cfs.html |access-date=15 June 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |language=en-us|archive-url=https://web.archive.org/web/20240603101152/https://www.cdc.gov/me-cfs/about/fast-facts-about-me-cfs.html|archive-date=3 June 2024}}</ref> The [[Incidence (epidemiology)|incidence]] rate (the onset of ME/CFS) 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> and the [[prevalence]] is highest in [[middle age]].<ref name="CDC_Basics" />
== History ==
{{Main|History of ME/CFS}}From 1934 onwards, there were multiple outbreaks globally of an unfamiliar illness, initially mistaken for [[polio]]. A 1950s outbreak at London's [[Royal Free Hospital]] led to the term "benign myalgic encephalomyelitis" (ME). Those affected displayed symptoms such as malaise, [[sore throat]], [[pain]], and signs of [[Encephalomyelitis|nervous system inflammation]]. While its infectious nature was suspected, the exact cause remained elusive.<ref name="IOM2015" />{{rp|28–29}} The syndrome appeared in sporadic as well as epidemic cases.<ref>{{cite journal |vauthors=Price JL |date=April 1961 |title=Myalgic Encephalomyelitis |journal=Lancet |volume=1 |issue=7180 |pages=737–738 |doi=10.1016/s0140-6736(61)92893-8 |pmc=1836797 |pmid=13737972}}</ref>
In 1970, two UK psychiatrists proposed that these ME outbreaks were [[psychosocial]] phenomena, suggesting [[Mass psychogenic illness|mass hysteria]] or altered medical perception as potential causes. This theory, though challenged, sparked controversy and cast doubt on ME's legitimacy in the medical community.<ref name="IOM2015" />{{rp|28–29}}
[[Melvin Ramsay]]'s later research highlighted ME's disabling nature, prompting the removal of "benign" from the name and the creation of diagnostic criteria in 1986. These criteria included the tendency of muscles to tire after minor effort and take multiple days to recover, high symptom variability, and chronicity. Despite Ramsay's work and a UK report affirming that ME was not a psychological condition, scepticism persisted within the medical field, leading to limited research.<ref name="IOM2015" />{{rp|28–29}}
In the United States, Nevada and New York State saw outbreaks of what appeared similar to [[Infectious mononucleosis|mononucleosis]] in the middle of the 1980s. People suffered from "chronic or recurrent fatigue", among a large number of other symptoms.<ref name="IOM2015" />{{rp|28–29}} The initial link between elevated antibodies and the Epstein–Barr virus led to the name "chronic Epstein–Barr virus syndrome". The CDC renamed it chronic fatigue syndrome (CFS), as a viral cause could not be confirmed in studies.<ref name="Packard 2004">{{cite book |url=https://books.google.com/books?id=EGNFPZrKIKMC&pg=PA156 |title=Emerging Illnesses and Society: Negotiating the Public Health Agenda |vauthors=Packard RM |publisher=[[Johns Hopkins University Press]] |year=2004 |isbn=978-0-8018-7942-5 |pages= |access-date=6 February 2024 |archive-url=https://web.archive.org/web/20230518113959/https://books.google.com/books?id=EGNFPZrKIKMC&pg=PA156 |archive-date=18 May 2023 |url-status=live}}</ref>{{Rp|155–158}} An initial case definition of CFS was outlined in 1988;<ref name="IOM2015" />{{rp|28–29}} the CDC published new [[Medical diagnosis|diagnostic criteria]] in 1994, which became widely referenced.<ref name="Brurberg2014rev">{{cite journal |vauthors=Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K |date=February 2014 |title=Case Definitions for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): A Systematic Review |journal=BMJ Open |volume=4 |issue=2 |pages=e003973 |doi=10.1136/bmjopen-2013-003973 |pmc=3918975 |pmid=24508851}}</ref>
In the 2010s, ME/CFS began to gain more recognition from health professionals and the public. Two reports proved key in this shift. In 2015, the US [[National Academy of Medicine|Institute of Medicine]] produced a report with new diagnostic criteria that described ME/CFS as a "serious, chronic, complex systemic disease". Following this, the US [[National Institutes of Health]] published their ''Pathways to Prevention'' report, which gave recommendations on research priorities.<ref>{{Cite journal |vauthors=Friedberg F |date=2 January 2020 |title=Legitimizing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Indications of Change over a Decade |url=https://www.tandfonline.com/doi/full/10.1080/21641846.2020.1718292 |journal=Fatigue: Biomedicine, Health & Behavior |volume=8 |issue=1 |pages=24–31 |doi=10.1080/21641846.2020.1718292 |s2cid=214434278 |issn=2164-1846 |access-date=4 February 2024 |archive-date=4 February 2024 |archive-url=https://web.archive.org/web/20240204175310/https://www.tandfonline.com/doi/full/10.1080/21641846.2020.1718292 |url-status=live |url-access=subscription }}</ref>
== Society and culture ==
[[File:Petition presentation by M.E Support in Glamorgan.jpg|thumb|upright=1.35|Presentation of a petition to the [[Senedd|National Assembly for Wales]] relating to ME support in South East Wales|alt=a group of people offering a petition. The group includes a person on a camp bed holding up a placard that says she is in bed 23 hours a day.]]
=== Controversy ===
{{Main|Controversies related to ME/CFS}}
ME/CFS is a contested illness, with debates mainly revolving around the cause of the illness and treatments.<ref name="pmid29971693" /> Historically, there was a heated discussion about whether the condition was psychological or neurological.<ref name="Lim_2020" /> Professionals who subscribed to the psychological model had frequent conflicts with patients, who believed their illness to be organic.<ref name="pmid32601171">{{cite journal |vauthors=O'Leary D |date=December 2020 |title=A Concerning Display of Medical Indifference: Reply to 'Chronic Fatigue Syndrome and an Illness-Focused Approach to Care: Controversy, Morality and Paradox' |url= |journal=Medical Humanities |volume=46 |issue=4 |pages=e4 |doi=10.1136/medhum-2019-011743 |pmid=32601171 |s2cid=220253462}}</ref> While ME/CFS is now generally believed to be a multisystem neuroimmune condition,<ref name="Lim_2020" /> a subset of professionals still see the condition as [[Psychosomatic medicine|psychosomatic]], or an "illness-without-disease".<ref name="pmid32601171" /><ref>{{Cite journal |last=Geraghty |first=Keith |date=2020-07-02 |title=The Negative Impact of the Psychiatric Model of Chronic Fatigue Syndrome on Doctors' Understanding and Management of the Illness |url=https://www.tandfonline.com/doi/full/10.1080/21641846.2020.1834295 |journal=Fatigue: Biomedicine, Health & Behavior |language=en |volume=8 |issue=3 |pages=167–180 |doi=10.1080/21641846.2020.1834295 |issn=2164-1846|url-access=subscription }}</ref>
The possible role of chronic viral infection in ME/CFS has been a subject of disagreement. One study caused considerable controversy by establishing a causal relationship between ME/CFS and a [[retrovirus]] called [[Xenotropic murine leukemia virus–related virus|XMRV]]. Some with the illness began taking [[Management of HIV/AIDS|antiretroviral drugs]] targeted specifically for [[HIV/AIDS]], another retrovirus,<ref>{{Cite web | vauthors = Westly E |date= June 2011 |title=Retrovirus No Longer Thought to Be Cause of Chronic Fatigue Syndrome |url=https://www.scientificamerican.com/article/virus-no-longer-thought-cause-chronic-fatigue-syndrome/ |url-status=live |archive-url=https://web.archive.org/web/20240222054928/https://www.scientificamerican.com/article/virus-no-longer-thought-cause-chronic-fatigue-syndrome/ |archive-date=22 February 2024 |access-date=22 February 2024 |website=Scientific American }}</ref> and national blood supplies were suspected to be tainted with the retrovirus. After several years of study, the XMRV findings were determined to be the result of contamination of the testing materials.<ref name="pmid27358491">{{cite journal |vauthors=Johnson AD, Cohn CS |title=Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and the Safety of the Blood Supply |journal=Clinical Microbiology Reviews |volume=29 |issue=4 |pages=749–57 |date=October 2016 |pmid=27358491 |pmc=5010753 |doi=10.1128/CMR.00086-15 |url=}}</ref>
Treatments based on behavioural and psychological models of the illness have also been the subject of much contention. The largest clinical trial on behavioural interventions, the 2011 [[PACE trial]], concluded that graded exercise therapy and [[Cognitive behavioral therapy|CBT]] are moderately effective. The trial drew heavy criticism.<ref name="pmid29971693">{{cite journal |vauthors=Blease C, Geraghty KJ |date=September 2018 |title=Are ME/CFS Patient Organizations 'Militant'? : Patient Protest in a Medical Controversy |url=|journal=Journal of Bioethical Inquiry |volume=15 |issue=3 |pages=393–401 |doi=10.1007/s11673-018-9866-5 |pmid=29971693 |s2cid=49677273}}</ref> The study authors [[Outcome switching|weakened their definition of recovery]] during the trial: some participants now met a key criterion for recovery before the trial started. A reanalysis under the original [[Protocol (science)|clinical trial protocol]] showed no significant difference in recovery rate between treatment groups and the controls receiving standard care.<ref name="pmid28805517">{{cite journal |vauthors=Geraghty KJ |date=August 2017 |title=Further Commentary on the PACE Trial: Biased Methods and Unreliable Outcomes |url=|journal=Journal of Health Psychology |volume=22 |issue=9 |pages=1209–1216 |doi=10.1177/1359105317714486 |pmid=28805517}}</ref><ref name="pmid31637650">{{cite journal |vauthors=Friedberg F, Sunnquist M, Nacul L |date=March 2020 |title=Rethinking the Standard of Care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome |url=|journal=Journal of General Internal Medicine |volume=35 |issue=3 |pages=906–909 |doi=10.1007/s11606-019-05375-y |pmc=7080939 |pmid=31637650}}</ref>
=== Doctor–patient relations ===
People with ME/CFS often face stigma in healthcare settings,<ref name="Hussein-2024" /> and the majority of individuals report negative healthcare experiences. They may feel that their doctor inappropriately calls their illness psychological or doubts the severity of their symptoms.<ref name="McManimen-2019">{{cite journal |vauthors=McManimen S, McClellan D, Stoothoff J, Gleason K, Jason LA |date=March 2019 |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 |doi=10.1080/07399332.2018.1521811 |pmc=6567989 |pmid=30829147}}</ref> 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=577–590 |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="Bateman-2021" />{{Rp|page=2871}}<ref name="Davis-2023" />
Clinicians may be unfamiliar with ME/CFS, as it is often not fully covered in medical school.<ref name="Davis-2023" /> Due to this unfamiliarity, people may go undiagnosed for years<ref name="Bateman-2021" /> or be misdiagnosed with mental health conditions.<ref name="Davis-2023" /> As individuals gain knowledge about their illness over time, their relationship with treating physicians changes. They may feel on a more equal footing with their doctors and able to work in partnership. At times, relationships may deteriorate instead as the previous asymmetry of knowledge breaks down.<ref name="Shortland_2024">{{Cite journal | vauthors = Shortland D, Fazil Q, Lavis A, Hallett N |date=4 April 2024 |title=A Systematic Scoping Review of How People with ME/CFS Use the Internet |journal=Fatigue: Biomedicine, Health & Behavior |language=en |volume=12 |issue=2 |pages=142–176 |doi=10.1080/21641846.2024.2303887 |issn=2164-1846 |doi-access=free}}</ref>
=== Economic and social impact ===
ME/CFS negatively impacts people's social lives and relationships. Stress can be compounded by disbelief in the illness from the support network, who can be sceptical due to the subjective nature of diagnosis. Many people with the illness feel [[Social isolation|socially isolated]], and [[Suicidal ideation|thoughts of suicide]] are high, especially in those without a supportive care network.<ref name="Shortland_2024" /> ME/CFS interrupts [[Child development|normal development]] in children, making them more dependent on their family for assistance instead of gaining independence as they age.<ref name="pmid28087544">{{cite journal |vauthors=Parslow RM, Harris S, Broughton J, Alattas A, Crawley E, Haywood K, Shaw A |date=January 2017 |title=Children's Experiences of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): A Systematic Review and Meta-Ethnography Of Qualitative Studies |url=|journal=BMJ Open |volume=7 |issue=1 |pages=e012633 |doi=10.1136/bmjopen-2016-012633 |pmc=5253584 |pmid=28087544}}</ref> Caring for somebody with ME/CFS can be a full-time role, and the stress of caregiving is made worse by the lack of effective treatments.<ref>{{cite journal |vauthors=O'Dwyer S, Boothby S, Smith G, Biddle L, Muirhead N, Khot S |date=July 2022 |title=Unpaid Carers Are the Missing Piece in Treatment Guidelines and Research Priorities for ME/CFS |url=https://orca.cardiff.ac.uk/id/eprint/156445/1/bmj.o1691.full.pdf |url-status=live |journal=BMJ |volume=378 |pages=o1691 |doi=10.1136/bmj.o1691 |pmid=35835467 |s2cid=250533596 |archive-url=https://web.archive.org/web/20240306063412/https://orca.cardiff.ac.uk/id/eprint/156445/1/bmj.o1691.full.pdf |archive-date=6 March 2024 |access-date=21 February 2024 |hdl-access=free |hdl=10871/130699}}</ref>
Economic costs due to ME/CFS are significant.<ref>{{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 | title = The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE) | journal = Healthcare | volume = 8 | issue = 2 | pages = 88 | date = April 2020 | pmid = 32272608 | pmc = 7349118 | doi = 10.3390/healthcare8020088 | doi-access = free }}</ref> In the United States, estimates range from $36 to $51 billion per year, 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 |url-status=live |journal=Fatigue: Biomedicine, Health & Behavior |volume=9 |issue=1 |pages=9–13 |doi=10.1080/21641846.2021.1878716 |issn=2164-1846 |s2cid=233745601 |archive-url=https://web.archive.org/web/20230315073408/https://solvecfs.org/wp-content/uploads/2021/02/Jason-Mirin_Prevalence_econ_update.pdf |archive-date=15 March 2023 |access-date=21 January 2023}}</ref> A 2017 estimate for the annual economic burden in the United Kingdom was £3.3 billion.<ref name="Dibble McGrath Ponting 2020 p." />
=== Advocacy ===
[[File:Blue awareness ribbon icon with outline.svg|thumb|The blue ribbon is used for ME/CFS awareness.|alt=see caption]]
Patient organisations have aimed to involve researchers via activism but also by publishing research themselves—similarly to [[HIV/AIDS activism|AIDS activism]] in the 1980s, which also sought to combat underfunding and stigma. [[Citizen science|Citizen scientists]], for example, helped start discussions about weaknesses in trials of psychological treatments.<ref name="pmid29971693" />
[[International May 12th Awareness Day|ME/CFS International Awareness Day]] takes place on 12 May.<ref name="CDC_Awareness">{{cite web |date=10 May 2024 |title=ME/CFS Awareness Day |url=https://www.cdc.gov/me-cfs/awareness-day/ |url-status=live |archive-url=https://web.archive.org/web/20240517200059/https://www.cdc.gov/me-cfs/awareness-day/ |archive-date=17 May 2024 |access-date=17 May 2024 |publisher=U.S. [[Centers for Disease Control and Prevention]]}}</ref> The goal of the day is to raise awareness among the public and health care workers about the diagnosis and treatment of ME/CFS.<ref name="NIH_Awareness">{{cite web |title=Dr. Nancy Lee on International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day|date=12 May 2012|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 |publisher=[[United States Department of Health and Human Services|US Department of Health and Human Services]] |vauthors=Lee N}}</ref> The date was chosen because it is the birthday of [[Florence Nightingale]], who had an unidentified illness similar to ME/CFS.<ref name="CDC_Awareness" />
== 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|upright=1.35|Graph of ME/CFS papers published by year:{{legend|#0062C4|Papers mentioning ME or CFS}}{{legend|#62C400|Papers whose title mentions ME/CFS}}]] Research into ME/CFS seeks to find a better understanding of the disease's causes, biomarkers to aid in diagnosis, and treatments to relieve symptoms.<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 treatment for one may treat the other.<ref name="Marshall-Gradisnik_2022">{{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 | hdl-access = free | s2cid = 252159772 | bibcode = 2022Sci...377.1150M | hdl = 10072/420658 }}</ref><ref name="pmid38443223" />
=== Funding ===
Historical research funding for ME/CFS has been far below that of comparable diseases.<ref name="Tyson_2022" /><ref name="meresearch_funding_2016">{{cite web |date=2016 |title=ME/CFS Research Funding – An Overview Of Activity By Major Institutional Funders Included on the Dimensions Database |url=https://www.meresearch.org.uk/wp-content/uploads/2016/09/mecfs-research-funding-report-2016-final.pdf |url-status=live |archive-url=https://web.archive.org/web/20240204230442/https://www.meresearch.org.uk/wp-content/uploads/2016/09/mecfs-research-funding-report-2016-final.pdf |archive-date=4 February 2024 |access-date=6 April 2023 |publisher=UK CFS/ME Research Collaborative and ÜberResearch |vauthors=Radford G, Chowdhury S}}</ref> In a 2015 report, the US National Academy of Sciences said that "remarkably little research funding" had been dedicated to causes, mechanisms, and treatment.<ref name="IOM2015" />{{Rp|9}} Lower funding levels have led to a smaller number and size of studies.<ref>{{cite journal |vauthors=Scheibenbogen C, Freitag H, Blanco J, Capelli E, Lacerda E, Authier J, Meeus M, Castro Marrero J, Nora-Krukle Z, Oltra E, Strand EB, Shikova E, Sekulic S, Murovska M |date=July 2017 |title=The European ME/CFS Biomarker Landscape Project: An Initiative of the European Network EUROMENE |journal=Journal of Translational Medicine |volume=15 |issue=1 |article-number=162 |doi=10.1186/s12967-017-1263-z |pmc=5530475 |pmid=28747192 |doi-access=free}}</ref> In addition, drug companies have invested very little in the disease.<ref name="pmid33529750">{{cite journal |vauthors=Toogood PL, Clauw DJ, Phadke S, Hoffman D |date=March 2021 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Where Will the Drugs Come From? |journal=Pharmacological Research |volume=165 |issue= |article-number=105465 |doi=10.1016/j.phrs.2021.105465 |pmid=33529750 |s2cid=231787959 |doi-access=free}}</ref>
The US National Institutes of Health (NIH) is the largest biomedical funder worldwide.<ref>{{Cite web |title=Grants & Funding |url=https://www.nih.gov/grants-funding |url-status=live |archive-url=https://web.archive.org/web/20231128044038/https://www.nih.gov/grants-funding |archive-date=28 November 2023 |access-date=22 November 2023 |website= |publisher=[[National Institutes of Health]] (NIH)}}</ref> Using rough estimates of disease burden, a study found NIH funding for ME/CFS was only 3% to 7% of the average disease per [[Disability-adjusted life year|healthy life year lost]] between 2015 and 2019.<ref name="Mirin_2021">{{cite journal |vauthors=Mirin AA |date=July 2021 |title=Gender Disparity in the Funding of Diseases by the U.S. National Institutes of Health |journal=Journal of Women's Health |volume=30 |issue=7 |pages=956–963 |doi=10.1089/jwh.2020.8682 |pmc=8290307 |pmid=33232627}}</ref> Worldwide, [[multiple sclerosis]], which affects fewer people and results in disability no worse than ME/CFS, received 20 times as much funding between 2007 and 2015.<ref name="meresearch_funding_2016" /><ref name="Tyson_2022" /> Funding cuts to [[Columbia University]] during the [[second presidency of Donald Trump|second Trump administration]] forced the closure of a large research program dedicated to the disease.<ref name="j227">{{cite web | last=Cueto | first=Isabella | title=ME/CFS research program shuts down at Columbia after Trump cuts | website=STAT | date=2025-03-19 | url=https://www.statnews.com/2025/03/19/myalgic-encephalomyelitis-chronic-fatigue-syndrome-columbia-program-shutdown/ | access-date=2025-03-19}}</ref>
Multiple reasons have been proposed for the low funding levels. Diseases for which society "blames the victim" are frequently underfunded. This may explain why [[Chronic obstructive pulmonary disease|COPD]], a severe lung disease often caused by smoking, receives low funding per healthy life year lost.<ref>{{cite journal |vauthors=Mirin AA, Dimmock ME, Jason LA |date=2020 |title=Research Update: The Relation Between ME/CFS Disease Burden and Research Funding in the USA |journal=Work |volume=66 |issue=2 |pages=277–282 |doi=10.3233/WOR-203173 |pmid=32568148 |s2cid=219974997 |doi-access=free |veditors=Mooney A}}</ref> Similarly, for ME/CFS, the historical belief that it is caused by psychological factors may have contributed to lower funding. [[Gender disparities in health|Gender bias]] may also play a role; the NIH spends less on diseases that predominantly affect women in relation to disease burden. Less well-funded research areas may also struggle to compete with more mature areas of medicine for the same grants.<ref name="Mirin_2021" />
=== Directions ===
Many biomarkers for ME/CFS have been proposed. Studies on biomarkers have often been too small to draw robust conclusions. Natural killer cells have been identified as an area of interest for biomarker research as they show consistent abnormalities.<ref name="pmid37226227" /> Other proposed markers include [[Electrical impedance|electrical measurements]] of blood cells and [[Raman microscope|Raman microscopy]] of immune cells.<ref name="pmid38443223" /> Several small studies have investigated the genetics of ME/CFS, but none of their findings have been replicated.<ref name="Dibble McGrath Ponting 2020 p." /> A larger study, [[DecodeME]], is currently underway in the United Kingdom.<ref>{{Cite news |date=12 September 2022 |title=Experts Launch World's Largest Genetic Study of ME |work=BBC News |url=https://www.bbc.com/news/uk-scotland-edinburgh-east-fife-62876472 |access-date=20 January 2023 |archive-date=20 January 2023 |archive-url=https://web.archive.org/web/20230120140624/https://www.bbc.com/news/uk-scotland-edinburgh-east-fife-62876472 |url-status=live }}</ref>
Various drug treatments for ME/CFS are being explored. Drugs under investigation often target the nervous system, the immune system, autoimmunity, or pain directly. More recently, there has been a growing interest in drugs targeting energy metabolism.<ref name="pmid33529750" /> In several clinical trials of ME/CFS, [[rintatolimod]] showed a small 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 |date=May 2019 |title=Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-Based Commentary |journal=Clinical Therapeutics |volume=41 |issue=5 |pages=798–805 |doi=10.1016/j.clinthera.2019.02.011 |pmc=6543846 |pmid=30871727}}</ref><ref name="pmid33529750" /> Rintatolimod has been approved in Argentina.<ref name="ADVINAT2019">{{cite book |title=Advances in Nucleic Acid Therapeutics |vauthors=Agrawal S, Kandimalla ER |date=February 2019 |publisher=[[Royal Society of Chemistry]] |isbn=978-1-78801-732-9 |veditors=Agrawal S, Gait MJ |pages=306–338 (310) |chapter=Chapter 14: Synthetic agonists of Toll-like receptors and therapeutic applications. |quote=14.2: Agonists of TLR3 |access-date=20 October 2021 |chapter-url=https://books.google.com/books?id=HsCrDwAAQBAJ&q=Rintatolimod+argentina&pg=PA310 |archive-url=https://web.archive.org/web/20220514015202/https://books.google.com/books?id=HsCrDwAAQBAJ&q=Rintatolimod+argentina&pg=PA310 |archive-date=14 May 2022 |url-status=live}}</ref> [[Rituximab]], a drug that depletes [[B cell]]s, was studied and found to be ineffective.<ref name="pmid38443223" /> Another option targeting autoimmunity is [[Immunoadsorption|immune adsorption]], which removes a large set of (auto)antibodies from the blood.<ref name="pmid33529750" />
=== Challenges ===
Symptoms and their severity can widely differ among people with ME/CFS. This poses a challenge for research into the cause and progression of the disease. Dividing people into subtypes may help manage this heterogeneity.<ref name="pmid38443223" /> The existence of multiple diagnostic criteria and variations in how scientists apply them complicate comparisons between studies.<ref name="IOM2015" />{{Rp|page=53}} Definitions also vary in which co-occurring conditions preclude a diagnosis of ME/CFS.<ref name="IOM2015" />{{Rp|page=52}}
==See also==
* [[List of people with ME/CFS]]
* [[History of ME/CFS]]
== References ==
{{reflist}}
== External links ==
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{{Medical resources
| ICD11 = {{ICD11|8E49}}
| ICD10 = {{ICD10|G93.3}}
| ICD10CM = {{ICD10CM|G93.32}}
| ICD9 = {{ICD9|323.9}} {{ICD9|780.71}}
| ICDO =
| OMIM =
| MeshID = D015673
| DiseasesDB = 1645
| SNOMED CT = 52702003
| Curlie =
| MedlinePlus = 001244
| eMedicineSubj = med
| eMedicineTopic = 3392
| eMedicine_mult = {{eMedicine2|ped|2795}}
| PatientUK =
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| RP = 74341
| AO =
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| Scholia = Q209733
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{{Chronic fatigue syndrome}}
{{CNS diseases of the nervous system}}
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[[Category:Myalgic encephalomyelitis/chronic fatigue syndrome| ]]
[[Category:Immune system disorders]]
[[Category:Neurological disorders]]
[[Category:Sleep disorders]]
[[Category:Syndromes of unknown causes]]
[[Category:Viral diseases]]
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