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Myalgic encephalomyelitis

2024-06-27T13:51:12Z

Yannlk:grammar error in lead sentence

'''Myalgic encephalomyelitis''' (ME) is a chronic, [[Inflammation|inflammatory]], physical and [[nervous system|neurological]] and immune-mediated disease that presents with symptoms involving multiple bodily systems. It is frequently triggered by a [[viral infection]] or a [[flu-like illness]].<ref name="ICC2011primer" /><ref name="CDC-causes" /> ME presents with symptoms in the [[central nervous system]] (CNS), [[autonomic nervous system]] (ANS), [[immune system]], [[cardiovascular system]], [[endocrine system]], [[digestive system]], and [[musculoskeletal system]].<ref name="ICC2011primer" /><ref name="CDC-symptoms" />

Myalgic encephalomyelitis was first classified as a [[nervous system|neurological]] disease by the [[World Health Organization]] (WHO) in 1969, with the publication of the [[World Health Organization#icd8|World Health Organization's ICD-8]] manual.<ref name="ICD-8">{{Cite book |url=https://apps.who.int/iris/bitstream/handle/10665/70934/ICD_10_1969_eng_v2a.pdf | title=Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death Based on the Recommendations of the Eighth Revision Conference | last = World Health Organization | first = | authorlink = World Health Organization|publisher=WHO| year = 1969|isbn=|editor-link=|edition=8th|volume=2|location=Geneva | page = 173|chapter=|quote=Encephalomyelitis (chronic), (myalgic, benign) 323}}</ref>

ME has occurred in both [[Epidemic myalgic encephalomyelitis|epidemic]] and [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|sporadic]] forms.

According to the [[Centers for Disease Control|CDC]] the hallmark symptom of myalglc encephalomyelitis is [[post-exertional malaise]] (PEM), which is the worsening of ME/CFS symptoms after minimal physical, mental, or emotional [[exertion|effort]].<ref name="CDC-doctors">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/index.html | title = Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = Dec 27, 2021 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2022-03-28}}</ref><ref name="Friedman2021">{{Cite journal | title = Our Evolving Understanding of ME/CFS | date = Mar 2021|url=https://www.mdpi.com/1648-9144/57/3/200/htm|journal=Medicina|volume=57|issue=3|pages=200 | last = Friedman | first = Kenneth J. | authorlink = Kenneth Friedman | last2 = Murovska | first2 = Modra | authorlink2 = Modra Murovska | last3 = Pheby | first3 = Derek F.H. | authorlink3 = Derek Pheby | last4 = Zalewski | first4 = Paweł | authorlink4 = Paweł Zalewski|language=en|doi=10.3390/medicina57030200|pmc=|pmid=33652622|access-date=|issn=1648-9144|quote=|via=}}</ref><ref name="Carruthers, 2003" /><ref name="Speight2013">{{Cite journal|url=https://www.sjmms.net/article.asp?issn=1658-631X;year=2013;volume=1;issue=1;spage=11;epage=13;aulast=Speight | title = Myalgic encephalomyelitis/chronic fatigue syndrome: Review of history, clinical features, and controversies | last = Speight | first = Nigel | authorlink=Nigel Speight | date = 2013|pages=11-13|doi=10.4103/1658-631x.112905|archive-url=|archive-date=|url-status=|access-date=|volume=1|issue=1|journal=Saudi J Med Med Sci}}</ref><ref name="CDC-symptoms" /> Other key symptoms include [[muscle weakness]] and easy [[muscle fatigability]], [[sleep dysfunction|sleep disturbance]], plus either [[orthostatic intolerance]] or [[cognitive dysfunction]]. Orthostic intolerance is [[autonomic nervous system]] dysfunction causing the worsening of symptoms when standing or sitting upright, and may include feeling [[syncope|faint]], [[dizziness]], feeling weak, [[blurred vision]], [[postural orthostatic tachycardia]] (POTS), reduced [[heart rate variability]] at night, and both [[Body temperature|cold and heat intolerance]]. Other ME/CFS common symptoms include [[myalgia|muscle pain]], [[neuralgia|nerve pain]], neck and spine stiffness, and sensory symptoms including [[sensitivity to light]], [[Hyperacusis|sound]], [[touch]], [[Paresthesia|skin tingling or numbness]] and hyperaesthesia (skin sensitivity and pain, and [[allodynia]]). There is a progressive form of ME, but it is rarer than the relapsing-remitting type.<ref name="Howes2015">{{Cite journal|url=http://www.meassociation.org.uk/wp-content/uploads/fulltext_pmr-v2-id10521.pdf | title=Progressive Myalgic Encephalomyelitis (ME) or A New Disease? A Case Report | last = Howes | first = S | authorlink = Sandra Howes | last2 = Goudsmit | first2 = EM | authorlink2 = Ellen Goudsmit | date = Jul 7, 2015 |journal=Physical Medicine and Rehabilitation - International|volume=2|issue=6|pages=1052|doi=}}</ref>

Among adults, ME is [[Female predominant diseases|more common in women]] than men.<ref name="CDC-causes">{{Cite web|url=https://www.cdc.gov/me-cfs/about/possible-causes.html | title = Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-13}}</ref> [[Onset of ME/CFS|New onset]] has been [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|observed in children]]<ref name="CDC-children">{{Cite web|url=https://www.cdc.gov/me-cfs/me-cfs-children/index.html | title = ME/CFS in Children {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-13}}</ref> and in adults usually between the ages of 40-60.<ref name="what-is">{{Cite web|url=https://www.cdc.gov/me-cfs/about/index.html | title = What is ME/CFS? {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-13}}</ref> [[Inger Johanne Bakken|Bakken]] et. al notes two age peaks for [[CFS/ME]]; age group 10 to 19 years and a second peak in the age group 30 to 39 years.<ref name="Bakken2014">{{Cite journal | last1 = Bakken | first1 = Inger Johanne | authorlink=Inger Johanne Bakken | last2 = Tveito | first2 = Kari | last3 = Gunnes | first3 = Nina | last4 = Ghaderi | first4 = Sara | last5 = Stoltenberg | first5 = Camilla | last6 = Trogstad | first6 = Lill | last7 = Håberg | first7 = Siri Eldevik | last8 = Magnus | first8 = Per | date = 2014-10-01 | title = Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012|url=https://doi.org/10.1186/s12916-014-0167-5|journal=BMC Medicine|volume=12|issue=1|pages=167|doi=10.1186/s12916-014-0167-5|issn=1741-7015|pmc=4189623|pmid=25274261}}</ref>

There are no approved pharmacological treatments for ME anywhere in the world except in [[Argentina]], which has approved the immunomodulator [[Ampligen]] (rintatolimod) for [[Severe and very severe ME|severe ME/CFS]] as of August 23, 2016.<ref name="Hemispherx">{{Cite news | title = Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic|url=http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html|work=GlobeNewswire News Room|access-date=2018-08-12|language=en-US | first = | last = Hemispherx Biopharma, Inc | date = Aug 23, 2016|archive-url=|archive-date=|url-status=}}</ref>[[File:Linda Crowhurst.JPG|thumb|[[Linda Crowhurst]] is married to [[Greg Crowhurst]]; they reside in Belfast, [[Northern Ireland]]. Greg is Linda's full-time carer as she is [[Severe and very severe ME|very severely ill with ME]]. As of June 2018, Linda has been ill for 25 years. Image source: [https://www.youtube.com/watch?v=Z1z5O_cgQ7I Wasteland (video)] which visually documents Linda's very severe ME. Greg posted a [https://www.youtube.com/watch?v=rVsOeZjhMFY YouTube video in 2006 (reposted in 2007)] of Linda speaking of her condition and showing her [[Nervous system|neurological]] symptoms which are the first known public visual document of very severe ME. She is now bedbound barely able to move and unable to feed herself.]]

[[File:Jenny Spotlia.jpg|300px|thumb|right|[[Jennie Spotila]] is an American ME patient who fell ill on October 6, 1994. Jennie is [[Severe and very severe ME|disabled, mostly housebound, and uses a wheelchair]] but has been an [[ME/CFS]] advocate for many years. She writes the blog [[Occupy M.E.]] She served on the Board of Directors of [[Solve ME/CFS Initiative|The CFIDS Association of America]] and testified before the [[Chronic Fatigue Syndrome Advisory Committee|CFSAC]]]]

== History ==
Myalgic encephalomyelitis was first classified as a [[nervous system|neurological]] disease by the [[World Health Organization]] in 1969, with the publication of the [[World_Health_Organization#icd8|ICD-8]] manual.<ref name="ICD-8" />
[[File:Hillary Johnson.jpg|200px|thumb|[[Hillary Johnson]] is an [[United States|American]] journalist and while ill herself, wrote the book [[Osler's Web]] which is the historical account of the early years of a "new" illness that had an outbreak at [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]] which she shared the same symptoms. The illness came to be known as [[chronic fatigue syndrome]] (CFS). Johnson spent nine years investigating the outbreak and the [[Centers for Disease Control and Prevention|CDC]]'s refusal to acknowledge a devastating disease (deeming sufferers of Incline Village as having [[mass hysteria|"mass hysteria"]]) that can be spread through casual contact and she appears in the documentary [[Forgotten Plague]].]]

The World Health Organization's [[World Health Organization#icd8|ICD-8]] manual did not include any alternative names for myalgic encephalomyelitis although postinfectious encephalomyelitis and all other encephalomyelitis diseases were classified under the same code; fatigue-related alternative names were not added in any later revisions.<ref name="ICD-8" /><ref name="icd10-2016">{{Cite web|url=https://icd.who.int/browse10/2016/en#/G93 | title = G93 Other diseases of the nervous system - ICD-10 Version:2016 | last = World Health Organization | first = | authorlink = World Health Organization | date = 2016 | website = World Health Organization|archive-url=|archive-date=|url-status=|access-date=2019-04-13}}</ref> The alternative name [[chronic fatigue syndrome]] (CFS) was not in use at this time; it was proposed in 1987 by the [[Centers for Disease Control]], which adopted [[Holmes criteria|new diagnostic criteria]] the following year.<ref name="IOM-full" />{{Rp|29}}

In the ICD-9, which was published in 1989, the entry for myalglc encephalomyelitis is uses code 323.9:<ref name="ICD-9">{{Cite book |url=https://apps.who.int/iris/bitstream/handle/10665/40492/9241540052_eng_v2_p1.pdf?sequence=3&isAllowed=y| title = Manual of the international statistical classification of diseases, injuries, and causes of death : based on the recommendations of the ninth revision conference, 1975, and adopted by the Twenty-ninth World Health Assembly, 1975 revision: alphabetic index | first = | last = World Health Organization & International Conference for the Ninth Revision of the International Classification of Diseases|publisher=World Health Organization | year = 1978|isbn=9241540044|editor-link=|edition=9th|volume=2|location=Geneva | page = 182|chapter=|quote=}}</ref>
{{Main article | page_name =History of myalgic encephalomyelitis and chronic fatigue syndrome}}

ME has occurred in both epidemic and sporadic form since at least the 1930s, although it has likely been occurring much longer but was not formally named. The first recorded outbreak of [[epidemic myalgic encephalomyelitis]] was in [[1934 Los Angeles atypical polio outbreak|1934 in Los Angeles]] and was thought to be an outbreak of atypical [[polio]]. After the outbreak in [[Akureyri]], Iceland in 1946, the disease came to be called [[1948-49 Akureyri outbreak|''Akureyri Disease'']] or ''Icelandic disease'' through much of the 1940s and 1950s. It was named ME after London's [[Royal Free Hospital outbreak]] in 1955. Other names included benign myalgic encephalomyelitis and [[Epidemic myalgic encephalomyelitis|epidemic neuromyasthenia]].

After the [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]] outbreak in Nevada in 1984, the disease came to be called and redefined as [[chronic fatigue syndrome]] (CFS). The most recent myalgic encephalomyelitis outbreak was caused by the [[2019-2022 Coronavirus pandemic outbreak]].{{clear|both}}

==Disease name==
{{Main article |page_name = Names of myalgic encephalomyelitis and chronic fatigue syndrome}}
[[File:Myalgic Encephalomyelitis awareness.png|thumb|right|alt=Poster of breakdown of parts of the name myalgic encephalomyelitis]]
* '''Myalgic''' - of or relating to [[myalgia]] (muscle pain).<ref name="Terminology" />

* '''Encephalo''': Refers to the [[brain]].<ref name="Terminology" />

* '''-myel''': relating to the [[spinal cord]].<ref name="Terminology" />

* '''-itis''': [[Inflammation]].<ref name="Terminology" />
The name '''myalgic encephalomyelitis''' was first used in 1956 in an article in the ''Lancet'' medical journal to describ findings from the [[1955 Royal Free Hospital outbreak]] in London, UK.<ref name="MyalgicEncephalomyelitis-first-coines">{{Cite journal | journal = Lancet|volume=1|issue= | pages = 789–790 | date = 1956 | title = A new clinical entity?|url=https://mecfsj.files.wordpress.com/2019/05/lancet_e383a9e383b3e382bbe38383e383881956_me.pdf}}</ref><ref name="Terminology" /><ref name="Ramsay1965">{{Cite journal | last = Ramsay | first = A. Melvin | authorlink = Melvin Ramsay | date = 1965-10-30 | title = Hysteria and “Royal Free Disease.”|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847119/|journal=British Medical Journal|volume=2|issue=5469|pages=1062|doi=|issn=0007-1447|pmc=1847119|pmid=|access-date=|quote=|via=}}</ref> The term myalgic encephalomyelitis is a portmanteau of several of the key signs and symptoms of the disease: myalgic (muscle pain), encephalo (brain), myel (spinal cord), itis (inflammation).<ref name="Terminology">{{Cite web|url=https://www.investinme.org/Article%20010-Encephalopathy%20Hooper.shtml | title = The Terminology of ME & CFS | first = Malcolm | last = Hooper | authorlink = Malcolm Hooper}}</ref><ref name="Smith1989">{{Cite book | title = Understanding M.E.: The Phenomenon of Myalgic Encephalomyelitis and Acute Onset Post Viral Fatigue Syndrome | page = 20 | last = Smith | first = David G | date = 1989}}</ref> The [[central nervous system]] (brain and spinal cord) are inflamed.<ref name="Terminology"/>
===Benign myalgic encephalomyelitis ===
''Benign'' myalgic encephalomyelitis was the term used by the [[World Health Organization]] from 1969,<ref name="ICD-8" /> with the prefix "benign" used to denote that M.E. was not fatal, the prefix benign was later dropped since M.E. can [[causes of death|cause death]], for example the deaths of [[Merryn Crofts]] and [[Sophia Mirza]].<ref name="Terminology" /><ref name="Vindication" /><ref name="ICD-11">{{Cite web|url=https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/569175314 | title = 8E49 Postviral fatigue syndrome {{!}} ICD-11 - Mortality and Morbidity Statistics | last = World Health Organization | first = | authorlink = World Health Organization | date = |website=World Health Organization|language=en|archive-url=|archive-date=|access-date=2022-03-19|quote='''8E49 Postviral fatigue syndrome''' Other disorders of the nervous system Inclusions chronic fatigue syndrome myalgic encephalomyelitis Exclusions Fatigue (MG22)}}</ref>
[[Merryn Crofts]] had [[Severe and very severe ME#verysevere|very severe ME]], was bedbound and unable to eat. Merryn weighed under six stone (84 lbs) at her death, and was just 21 years-old. Merryn's death certificate was the second in the [[United Kingdom|UK]] to attribute a death to ME.<ref name="Vindication">{{Cite web |url=https://www.bbc.co.uk/news/health-44969741 | title = 'Vindication' for woman who wanted ME on death certificate | first = Jim | last = Taylor|publisher=BBC Radio 5 Live | date = Jul 27, 2018}}</ref>
===Disease of a thousand names ===
Myalgic Encephalomyelitis has been referred to as the ''"disease of a thousand names"''.<ref name="Bell1991">{{Cite book | last = Bell | first = David S. | authorlink = David Bell | title = Chronic Fatigue/Immune Dysfunction Syndrome. CFIDS: The disease of a thousand names|location = Lyndonville, NY|publisher=Pollard Publications | date = 1991 | url=https://books.google.com/books/about/Chronic_Fatigue_immune_Dysfunction_Syndr.html?id=QYvkugAACAAJ|archive-url=https://archive.org/details/cfidsdiseaseofth00bell|archive-date=2010-02-16}}</ref> Other names used or proposed in the history of the myalgic encephalomyelitis include [[atypical polio]], [[Icelandic disease]], benign ME, [[epidemic neuromyasthenia]], [[chronic fatigue syndrome]], [[Chronic Fatigue Immune Dysfunction Syndrome]] (CFIDS), and [[systemic exertion intolerance disease]] (SEID).<ref name="Bell1991" /><ref name="IOM-full" /> This has lead to much confusion as a variety of names have been used at different times to describe discrete outbreaks as well as a larger and potentially more heterogenous population of sporadic cases, defined by a wide variety of [[Definitions of myalgic encephalomyelitis and chronic fatigue syndrome|diagnostic criteria]]. Some names have emphasized particular symptoms or pathology, including chronic fatigue syndrome and myalgic encephalomyelitis.<ref name="Terminology" />

A survey by [[The MEAction Network]] in 2016 found that the majority of patients prefer the name ME to other names including chronic fatigue syndrome.<ref>{{Cite news | url=http://www.meaction.net/2016/08/07/meaction-rfi-poll-report-1-of-3/ | title = #MEAction RFI Poll Report (Part 1 of 3) - #MEAction | date = 2016-08-07|work=#MEAction|access-date=2018-09-08|language=en-US}}</ref>

Myalgic encephalomyelitis (ME) was the original name for [[chronic fatigue syndrome]] (CFS); the names are sometimes used interchangeably or with the acronym [[ME/CFS]].<ref name="Smith1989" />

== Onset ==
{{Main article |page_name =Onset of ME/CFS}}
According to Dr [[Byron Hyde]], after an incubation period of 4 to 7 days, the prodromal phase generally involve a [[flu-like illness]] with [[low-grade fever]].<ref name="Evans2018" /> In the majority but not all cases, an [[infection]] or infectious process is evident.<ref name="Evans2018">{{Cite journal | last = Evans | first = Meredyth | authorlink = Meredyth Evans | last2 = Jason | first2 =Leonard | authorlink2 = Leonard Jason | date = 2018 | title = Onset patterns of chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.openaccessjournals.com/articles/Onset%20patterns%20of%20chronic%20fatigue%20syndrome%20and%20myalgic%20encephalomyelitis.pdf | journal=Research on Chronic diseases|volume=2|issue=1|pages=2-3|quote=|via=}}</ref> Two to seven days later, a chronic phase commences, characterized by a measurable diffuse change in the function of the CNS. It is this second phase, persistent phase that most characterizes ME.<ref name="Nightingale">{{Citation | title = The Nightingale Research Foundation Definition of Myalgic Encephalomyelitis (M.E.)|pages=|language=en|title-link=Nightingale Research Foundation definition | date = 2016 | publisher=IACFS/ME | last = Hyde | first = Byron | authorlink = Byron Hyde|others=|oclc=|quote=|location=}}</ref><ref name="Evans2018" />

==Signs and symptoms==
Myalgic encephalomyelitis is a [[neurological disorder|neurological disease]] that affects multiple bodily systems, causing a widespread combination of symptoms.<ref name="ICC" /> Symptoms can range from mild to very severe and can include:

<div style="column-count:2;">
* [[ataxia|ataxia (coordination difficulties)]]
* [[cognitive dysfunction]]
* [[Chronic fatigue|fatigability]]
* [[gastrointestinal]] symptoms
* [[headache]]
*[[low-grade fever]], [[Temperature dysregulation|temperature instability]]
*[[muscle]] [[Muscle weakness|weakness]] and [[Muscle fatigability|fatiguability]]
*[[myalgia|myalgia (muscle pain)]]
*neck and back or [[spinal cord]] stiffness
*[[neuralgia|neuralgia (nerve pain)]]
*[[Orthostatic intolerance|othostatic intolerance]]
*[[post-exertional malaise]]
*sensitivity to [[Temperature sensitivity|heat or cold]]
*sensitivity to [[Light sensitivity|light]], [[Hyperacusis|sound]] and/or [[Allodynia|touch]]
*[[sleep dysfunction]]<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | authorlink = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | authorlink8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14 = Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23 = Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24 = Modra Murovska | last25 = Pall | first25 = Martin | author-link25 = Martin Pall | last26 = Stevens | first26 = Staci | author-link26 = Staci Stevens | date = 2011-08-22 | title=Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365q-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref>
</div>
[[File:ME CFS.png|alt=Myalgic encephalomyelitis is an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features. - International Consensus Criteria|thumb|upright=1.6|left]]

Symptom presentation and [[:Category:Severity definitions|severity]] can vary considerably day to day and even hour to hour.<ref name="CDC-symptoms" /><ref name="Primer2014">{{Citation | date = 2014 |url=https://www.massmecfs.org/images/pdf/Primer_2014.pdf | title=Chronic Fatigue Syndrome Myalgic Encephalomyelitis Primer for Clinical Practitioners | last1 = ((International Association for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis)) | author-link = International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | last2 = Friedberg | first2 = Fred | authorlink2 = Fred Friedberg | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Bested | first4 = Alison C | authorlink4 = Alison Bested | last5 = Davenport | first5 = Todd | authorlink5 = Todd Davenport | last6 = Friedman | first6 = Kenneth J | authorlink6 = Kenneth Friedman | last7 = Gurwitt | first7 = Alan R | authorlink7 = Alan Gurwitt | last8 = Jason | first8 = Leonard A | authorlink8 = Leonard Jason | last9 = Lapp | first9 = Charles W | authorlink9 = Charles Lapp | last10 = Stevens | first10 = Staci R | authorlink10 = Staci Stevens | last11 = Underhill | first11 = Rosemary A | authorlink11 = Rosemary Underhill | last12 = Vallings | first12 = Rosamund | authorlink12 = Rosamund Vallings|location=Chicago, USA|publisher= International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis |quote=The illness can vary from mild to severe, with symptoms that may fluctuate significantly from hour to hour and day to day.}}</ref> Overexertion can exacerbate all symptoms, and [[post-exertional malaise]] is often [[Delayed onset of post-exertional symptoms|delayed by 24 hours or more]].<ref name="CDC-symptoms" /> The US [[National Institutes of Health]] (NIH) notes that sensitivity to noise, light and [[multiple chemical sensitivity|chemical]]s may force patients to withdraw from society.<ref name="P2P2016">{{Cite web|url=https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs | title = ME/CFS - Pathways to Prevention - Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last = | first = | date = Dec 8, 2016 | website = [[National Institutes of Health]]|access-date=2022-03-28|quote=Effects of the illness can range from moderate to debilitating, and can substantially impact everyday functioning. Routine daily activities such as cooking meals, brushing teeth, and caring for children become difficult. Additionally, sensitivity to environmental factors (e.g., noise, light, chemicals) may force many individuals with ME/CFS into seclusion or withdrawal from society.|archive-url=|archive-date=|url-status=|language=en}}</ref>

=== Post-exertional malaise ===
{{Main article | page_name =Post-exertional malaise}}
A core symptom, [[post-exertional malaise]] (PEM), is intolerance to previously trivial mental or physical effort such as attending a child's school event, running an errand or grocery shopping, taking a shower or brushing teeth; this causes a worsening of symptoms, and deterioration of health from persistent or repeated exertion.<ref name="ICC2011primer" /><ref name="CDC-symptoms" />
[[File:J Brea TED.JPG|200px|thumb|right|[[Jen Brea|Jennifer Brea]] is an American who was studying at Harvard; while on a trip to [[Kenya]] she became very ill with what would eventually be diagnosed as [[ME/CFS]]. Brea began experiencing [[Nervous system|neurological]] problems. Her neurologist diagnosed her with "conversion disorder" ([[hysteria]]). When walking home from his office, she collapsed. [[Severe and very severe ME|Jen needed to use a wheelchair]] to keep her legs up due to [[Postural orthostatic tachycardia syndrome|POTS]] as her blood pools into her legs. View her TED Talk ''[https://www.ted.com/talks/jen_brea_what_happens_when_you_have_a_disease_doctors_can_t_diagnose What happens when you have a disease doctors can't diagnose]'']]
Some studies show that patients who have been ill for longer are more likely to uave [[severe and very severe ME|severe ME/CFS]]. ME/CFS oftens becomes more severe when patients try to [[pushing through symptoms|push through]] their symptoms and continue to repeatedly exceed their personal ''physical'' or ''cognitive'' [[energy limit|limits]], for instance by attempting to keep working, which typically entails [[anaerobic]] activity.<ref name="Vink2015LA"/><ref name="Vink2019">{{Cite journal | last = Vink | last2 = Vink-Niese | date = 2019-09-20 | title = Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies|url=https://www.mdpi.com/2075-4418/9/4/124|journal=Diagnostics|language=en|volume=9|issue=4|pages=124|doi=10.3390/diagnostics9040124|issn=2075-4418 | first = Mark | first2 = Alexandra|pmc=|pmid= | author-link = Mark Vink | authorlink2 = Alexandra Vink-Niese|access-date=|quote=People with ME/CFS often feel under pressure to continue working when they first become ill or when their symptoms worsen. Unfortunately, trying to push through this illness is counterproductive, potentially causing longer sickness absences and slower recovery.}}</ref>

== Clinical findings ==
{{Main article|1=List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis|label1=List of abnormal findings}}
[[File:Alem Matthee.png|200px|thumb|right|[[Alem Matthees]] is an [[Australia|Australian]] ME patient that filed an FOI request for data from the [[PACE trial]]. At a [[Severe and very severe ME|great cost to his health]], Alem appealed the denial of the data and won. This data proved the results published in [[The Lancet|''The Lancet'']] were untrue. Alem's health suffered significantly in part from the efforts required for the FOI request and tribunal]]
Although there is no definitive [[biomarker]], several signs and findings have been frequently observed in clinical settings:<div style="column-count:2;">
*high [[:Category:Antibodies|antibody]] titers to specific infections (including [[Epstein-Barr virus|EBV]],<ref>{{Cite journal | last = Schmaling | first = K.B. | last2 = Jones | first2 = J.F. | date = Jan 1996 | title = MMPI profiles of patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8730646|journal=Journal of Psychosomatic Research|volume=40|issue=1 | pages = 67–74|issn=0022-3999|pmid=8730646}}</ref> [[Human herpesvirus 6|HHV-6]],<ref name="Cuende1997">{{cite journal| vauthors=Cuende JI, Civeira P, Diez N, Prieto J| title=[High prevalence without reactivation of herpes virus 6 in subjects with chronic fatigue syndrome]. | journal=An Med Interna | year= 1997 | volume= 14 | issue= 9 | pages = 441-4 | pmid=9453750 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/pubmed/9453750}}</ref><ref name="Komaroff2006">{{cite journal | last=Komaroff | first = AL | authorlink = Anthony Komaroff | title=Is human herpesvirus-6 a trigger for chronic fatigue syndrome? | journal=J Clin Virol | year= 2006 | volume= 37 | issue= Suppl 1 | pages = S39-46 | pmid=17276367 | doi=10.1016/S1386-6532(06)70010-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/pubmed/17276367}}</ref> and [[Coxsackie B virus|Coxsackie B]]<ref>{{Cite journal | last = Landay | first = AL | date = September 1991 | title = Chronic fatigue syndrome: clinical condition associated with immune activation | url =https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name="Chia2005">{{Cite journal | last = Chia | first = John | date = November 2005 | title = The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref> among others)
*[[Hormone]] imbalance<ref name="Ruiz-Núñez, 2018">{{Cite journal | last1 = Ruiz-Núñez | first1 = Begoña | authorlink1 = | last2 = Tarasse | first2 = Rabab | authorlink2 = | last3 = Vogelaar | first3 = Emar F. | authorlink3 = | last4 = Janneke Dijck-Brouwer | first4 = D.A. | authorlink4 = | last5 =Muskiet | first5 = Frits A. J. | authorlink5 = | title = Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study | url = https://doi.org/10.3389%2Ffendo.2018.00097 | journal = Frontiers in Endocrinology | volume = 9 | issue = | page = 97 | date = 2018 | pmid = 29615976 | doi = 10.3389/fendo.2018.00097}}</ref>
*[[Immune system|immunological abnormalities]]<ref name="ICC" /><ref name="Brenu2014">{{Cite journal | last = Brenu | first = Ekua Weba | last2 = Huth | first2 = Teilah K. | last3 = Hardcastle | first3 = Sharni L. | last4 = Fuller | first4 = Kirsty | last5 = Kaur | first5 = Manprit | last6 = Johnston | first6 = Samantha | last7 = Ramos | first7 = Sandra B. | last8 = Staines | first8 = Don R. | last9 = Marshall-Gradisnik | first9 = Sonya M. | date = Apr 2014 | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis|url=http://www.ncbi.nlm.nih.gov/pubmed/24343819|journal=International Immunology|volume=26|issue=4|pages=233–242|doi=10.1093/intimm/dxt068|issn=1460-2377|pmid=24343819}}</ref><ref name="CDC-etiology"/>
*[[Natural Killer Cell (NKC) function|low natural killer cell function]]<ref name="Brenu2014" />
*low red blood cell [[magnesium]]<ref name="Cox1991">{{Cite journal | title = Red blood cell magnesium and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1672392|journal=Lancet (London, England) | date = 1991-03-30|issn=0140-6736|pmid=1672392 | pages = 757–760|volume=337|issue=8744 | first = I.M. | last=Cox | first2 = M.J. | last2 = Campbell | first3 = D. | last3 = Dowson}}</ref>
*[[Postural orthostatic tachycardia syndrome|postural orthostatic tachychardia]] (POTS)<ref name="ICC2011primer" /><ref>{{Cite web|url=https://ammes.org/overlapping-conditions/ | title = Overlapping Conditions – American ME and CFS Society|website=ammes.org|language=en-US|access-date=2018-08-12}}</ref>
*[[Post-exertional malaise|physical and mental exertion, sensory input cause relapse]] (PEM)<ref name="ICC2011primer" /><ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | authorlink = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref><ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>
</div>

==Diagnosis==
[[File:Tom Kindlon.png|300px|thumb|[[Tom Kindlon]] became [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|ill at 16]] and never recovered. He is an ME/CFS advocate with published works in Research Gate and PubMed. Kindlon lives in [[Ireland]] and is Assistant Chairperson of the [[Irish ME/CFS Association]]. Tom and others analyzed the data for the PACE trial proving out that its published results were untrue. He uses a [[Severe and very severe ME|wheelchair and his full-time carer]] is his mother, Vera]]
{{Main article | page_name =Definitions of myalgic encephalomyelitis and chronic fatigue syndrome}}

There are several proposed criteria for diagnosing ME including the [[International Consensus Criteria]] (ICC) and the [[Canadian Consensus Criteria]] (CCC). The original criteria developed by [[Melvin Ramsay]], the [[Ramsay definition]], is not used for diagnosing ME today.

===Generally accepted criteria for diagnosing ME/CFS and ME===
*[[Canadian Consensus Criteria]] (CCC)<ref name="Carruthers, 2003">{{Citation | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 = Joshi | first9 = Pradip | authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols | journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid = | doi = 10.1300/J092v11n01_02 | url = http://phoenixrising.me/wp-content/uploads/Canadian-definition.pdf }}</ref> A diagnosis of moderate and severe forms of [[ME/CFS]] are accurately made using this criterion. Adults can be diagnosed at 6 months while pediatric cases are diagnosed at three months.
*[[International Consensus Criteria]] (ICC)<ref name="ICC" /><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012
| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf }}</ref> This criteria will accurately diagnose myalgic encephalomyelitis (ME). There is no requirement that the individual have symptoms for a specified period of time for diagnosis, as opposed to CCC, [[Fukuda criteria|Fukuda]], and [[Systemic Exertion Intolerance Disease|SEID]], which all require 6 months in adults.
*[[Systemic Exertion Intolerance Disease]] (SEID)<ref name="IOM-full">{{Cite book | last = Institute of Medicine | first = | authorlink = Institute of Medicine | date = 2015 | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.|location = Washington, DC|publisher =The National Academies Press|doi=10.17226/19012 | url = http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx}}</ref>

ME/CFS ([[Systemic Exertion Intolerance Disease|SEID]]) is accurately diagnosed when the [[Systemic Exertion Intolerance Disease#Diagnostic criteria|core symptoms]] are met. The [[Institute of Medicine report]] is a whole is a comprehensive review of the medical literature available at time of publication (2015). Adults can be diagnosed at 6 months while pediatric cases are diagnosed at three months.

=== Other diagnostic criteria ===
Several, overly broad criteria have been proposed and are in use. These criteria likely capture some patients with the disease characterized in the medical literature on [[Epidemic myalgic encephalomyelitis|epidemic ME]], exclude others, and also include patients with a wide range of other undiagnosed conditions including cancer, depression, and a range of autoimmune diseases. The United Kingdom's [[Oxford criteria|Oxford criteria for chronic fatigue syndrome]] is the broadest and likely least discerning definition and has been retired due to the risk of many different fatiguing illnesses being [[misdiagnosis of myalgic encephalomyelitis and chronic fatigue syndrome|misdiagnosed]] as [[chronic fatigue syndrome]].<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> The US [[Centers for Disease Control and Prevention|Centers for Disease Control]]'s (CDC) [[Fukuda criteria]], in use since 1994, is also overly broad. The Institute of Medicine report developed the criteria of [[Systemic Exertion Intolerance Disease]] (SEID) and although it can diagnose ME patients [[Systemic Exertion Intolerance Disease#Diagnostic criteria|with the minimum core symptoms]],<ref name="IOM-flowchart">{{Cite web|url=http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2015/MECFS/MECFS_DiagnosticAlgorithm | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - Diagnostic Algorithm | last = | first = | authorlink = | date = 2015 | website = nationalacademies.org|archive-url=|archive-date=|url-status=|access-date=}}</ref><ref name="IOM-clinicians">{{Cite web|url=http://iom.nationalacademies.org/~/media/Files/Report%20Files/2015/MECFS/MECFScliniciansguide.pdf | title=Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness: Clinicians' Guide | last = | first = | date = 2015 | website = National Academies|archive-url=|archive-date=|url-status=|access-date=}}</ref> it does not describe the array of symptoms those suffering with ME experience. Symptoms such as [[Nervous system|neurological]], [[Immune system|immune]]/[[Gastrointestinal system|gastrointestinal]]/genitourinary impairment, and [[Portal:Energy metabolism|energy metabolism]]/[[Ion transportation|ion transport]] impairment; these [[International Consensus Criteria#Criteria|symptoms are necessary for a diagnosis]] under the [[International Consensus Criteria|ICC]].<ref name="ICC" /> The [[Canadian Consensus Criteria|CCC]] requires neurological, [[Autonomic nervous system|autonomic]], neuroendocrine, immune system, and [[myalgia]] symptoms to meet [[Canadian Consensus Criteria#Definition|its ME/CFS diagnostic criteria]].<ref name="Carruthers, 2003" />

===Differential diagnosis===
The signs and symptoms of myalgic encephalomyelitis can be similar to other medical illnesses, including cancer, [[multiple sclerosis]], [[Systemic lupus erythematosus|lupus]], [[Hashimoto's thyroiditis (hypothyroidism)]], [[diabetes|diabetes mellitus]], [[brucellosis]], [[anemia]] and others.<ref name="CDC-differentialdiagnosis">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/other-conditions.html | title = Other Conditions for Evaluation {{!}} Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = Jul 12, 2018 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2022-03-28}}</ref><ref name="Carruthers, 2003" /> Standard medical tests are needed to help distinguish ME from these other illnesses, and additional testing may also be needed.<ref name="IOM-clinicians" /><ref name="CDC-differentialdiagnosis"/><ref name="CDC-medicaltests">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/evaluation.html | title = Evaluation {{!}} Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = Apr 28, 2021 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2022-04-01}}</ref>

==Course and prognosis ==

{{Main article|page_name =Prognosis for myalgic encephalomyelitis and chronic fatigue syndrome}}

The [[prognosis for myalgic encephalomyelitis and chronic fatigue syndrome]] (ME and CFS) is considered to be poor with only a small minority (a median estimate of 5%) returning to pre-morbid levels of functioning.<ref name="Cairns2005">{{Cite journal | last = Cairns | first = R. | last2 = Hotopf | first2 = M. | date = Jan 2005 | title = A systematic review describing the prognosis of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/15699087|journal=Occupational Medicine (Oxford, England)|volume=55|issue=1|pages=20–31|doi=10.1093/occmed/kqi013|issn=0962-7480|pmid=15699087}}</ref> The majority of patients remains significantly impaired. A substantial improvement however is noted in an estimated 40% of patients<ref name="Joyce1997">{{Cite journal | last= Joyce | first = J. | last2 = Hotopf | first2 = M. | last3 = Wessely | first3 = S. | date = Mar 1997 | title = The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review | url =https://www.ncbi.nlm.nih.gov/pubmed/9093600|journal=QJM: monthly journal of the Association of Physicians|volume=90|issue=3|pages=223–233|issn=1460-2725|pmid=9093600|doi=|pmc=|quote= | authorlink2 = Matthew Hotopf|access-date= | authorlink3 = Simon Wessely|via=}}</ref> and the prognosis in [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|adolescents]] is considered to be better than in adults.<ref name="CDC-prognosis">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/prognosis.html | title = Prognosis {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-10-28}}</ref><ref name="Rowe2017>{{Cite journal | last = Rowe | first = Peter C. | last2 = Underhill | first2 = Rosemary A. | last3 = Friedman | first3 = Kenneth J. | last4 = Gurwitt | first4 = Alan | last5 = Medow | first5 = Marvin S. | last6 = Schwartz | first6 = Malcolm S. | last7 = Speight | first7 = Nigel | last8 = Stewart | first8 = Julian M. | last9 = Vallings | first9 = Rosamund | date = 2017 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url =https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref>

==Pathophysiology==
[[File:Vanessa Li.jpg|thumb|right|[[Vanessa Li]] lived in Hong Kong, the UK, and the US. She became ill with a [[flu-like illness]] while skiing in [[Italy]] and never recovered. Vanessa founded a crowdfund for the [[Microbe Discovery Project]]. She was in [[Severe and very severe ME|excruciating pain, suffered from breathing issues, and occasional paralysis]] for 15 years. She took her own life in 2015]]
{{Main article | page_name =List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}

ME is a multi-system disease. Numerous biological abnormalities have been found in multiple bodily system, however no common, central cause or mechanism has yet been elucidated.

=== Central nervous system ===
[[File:Sophia mirza.jpg|thumb|right|[[Sophia Mirza]] was a [[Severe and very severe ME|very severely ill]] ME patient who lived in the UK. Sophia's death came not long after a forced entry into her mother's home and being forcibly taken to a mental hospital in 2003. An independent neuropathologist found Sophia's [[spine]] contained a massive inflammation. Her death certificate was the first in the UK to attribute a death to CFS.<ref name="Vink2015LA">{{Cite journal | last = Vink | first = Mark | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology (ISSN 2379-7150)|volume=1|doi=10.16966/2379-7150.112}}</ref>]]
{{Main article |page_name =Central nervous system}}

=== Autonomic nervous system ===
{{Main article |page_name =Autonomic nervous system}}

=== Cardiovascular ===
{{Main article |page_name =Cardiovascular system}}

=== Gastrointestinal system ===
{{Main article |page_name = Gastrointestinal system}}

=== Immune system ===

{{Main article |page_name =Immune system}}

=== Musculoskeletal system ===
{{Main article |page_name =Muscle}}

=== Peripheral nervous system ===
{{Main article |page_name =Peripheral nervous system}}

== Sex differences ==
[[File:Florence Nightingale.png|200px|thumb|right|[[Florence Nightingale]] was a British citizen and pioneer of modern nursing. Nightingale was stationed in Crimea when she developed "Crimean fever" (a bacterial infection now known as [[brucellosis]]) and never recovered. She remained [[Severe and very severe ME|mostly bedbound]] the rest of her life. Although ME and CFS were not defined in her lifetime, many current physicians and medical historians believe she developed ME/CFS as a result of a chronic brucellosis infection]]

{{Main article |page_name = Sex differences in myalgic encephalomyelitis and chronic fatigue syndrome}}
A Norwegian [[CFS/ME]] study shows that the disease affects all ages, with two peak ages of 10-19 years and 30-39 years; it is more common in women than in men.<ref name="Bakken2014" /> Research by the [[Open Medicine Foundation]] cited in its paper, [[Metabolic features of chronic fatigue syndrome|''Metabolic features of chronic fatigue syndrome'']] which studied severe [[chronic fatigue syndrome|CFS]], found that the disease is different in men and women but this is not related to testosterone or estrogen. [[Michael VanElzakker]] notes there are [[Michael_VanElzakker#Male_and_female_differences_in_neuropathic_pain|male and female differences in neuropathic pain]]. A study of UK and Dutch cohorts found "younger children had a more equal gender balance compared to adolescents and adults."<ref name="Collin2015">{{Cite journal | last = Collin | first = Simon M. | last2 = Nuevo | first2 = Roberto | last3 = van de Putte | first3 = Elise M. | last4 = Nijhof | first4 = Sanne L. | last5 = Crawley | first5 = Esther | date = 2015-10-28 | title = Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts|url=https://www.ncbi.nlm.nih.gov/pubmed/26510728|journal=BMJ open|volume=5|issue=10| pages = e008830|doi=10.1136/bmjopen-2015-008830|issn=2044-6055|pmid=26510728|via=}}</ref>

==Risk factors and potential causes==

{{Main article | page_name =Epidemiology of myalgic encephalomyelitis and chronic fatigue syndrome}}

===Genetic risks===

Myalgic encephalomyelitis and chronic fatigue syndrome have been reported to run in families, although ME and CFS are not considered inherited illnesses, there is evidence of a genetic predisposition.<ref name="Schlauch, 2016" /><ref name="Dibble2020">{{Cite journal | title = Genetic risk factors of ME/CFS: a critical review | date = 2020-08-03|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530519/|journal=Human Molecular Genetics|volume=29|issue=R1|pages=R117–R124 | last = Dibble | first = Joshua J | author-link = | last2 = McGrath | first2 = Simon J | authorlink2 = Simon McGrath | last3 = Ponting | first3 = Chris P | authorlink3 = Chris Ponting|doi=10.1093/hmg/ddaa169|pmc=7530519|pmid=32744306|access-date=|issn=0964-6906|quote=|via=}}</ref><ref name="Hajdarevic2022">{{Cite journal | title = Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci | date = 2022-05-01|url=https://www.sciencedirect.com/science/article/pii/S0889159122000782|journal=Brain, Behavior, and Immunity|volume=102|issue=|pages=362–369 | last = Hajdarevic | first = Riad | authorlink = Riad Hajdarevic | last2 = Lande | first2 = Asgeir | authorlink2 = Asgeir Lande | last3 = Mehlsen | first3 = Jesper | authorlink3 = | last4 = Rydland | first4 = Anne | authorlink4 = | last5 = Sosa | first5 = Daisy D. | authorlink5 = | last6 = Strand | first6 = Elin B. | authorlink6 = Elin Strand | last7 = Mella | first7 = Olav | authorlink7 = Olav Mella | last8 = Pociot | first8 = Flemming | last9 = Fluge | first9 = Øystein | authorlink9 = Øystein Fluge | last10 = Lie | first10 = Benedicte A. | last11 = Viken | first11 = Marte K.|language=en|doi=10.1016/j.bbi.2022.03.010|pmc=|pmid=|access-date=|issn=0889-1591|quote=|via=}}</ref>

{{Main article|page_name = Genetics of chronic fatigue syndrome}}

===Potential causes===
Although risk factors for myalgic encephalomyelitis have been identified, no single [[Vagus nerve infection hypothesis|definitive virus]] has been found in all cases, which has led to the claim that ME is a common end path of a variety of infectious insults.<ref name="Rasa2018">{{Cite journal | last = Rasa | first = Santa | authorlink = Santa Rasa | last2 = Nora-Krukle | first2 = Zaiga | authorlink2 = Zaiga Nora-Krukle | last3 = Henning | first3 = Nina | authorlink3 = | last4 = Eliassen | first4 = Eva | authorlink4 = | last5 = Shikova | first5 = Evelina | authorlink5 = Evelina Shikova | last6 = Harrer | first6 = Thomas | authorlink6 = Thomas Harrer | last7 = Scheibenbogen | first7 = Carmen | authorlink7 = Carmen Scheibenbogen | last8 = Murovska | first8 = Modra | authorlink8 = Modra Murovska | last9 = Prusty | first9 = Bhupesh K. | authorlink9 = Bhupesh Prusty | last10 = European Network on ME/CFS (EUROMENE) | first10 = | authorlink10 = EUROMENE | date = 2018-10-01 | title = Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1644-y|journal=Journal of Translational Medicine|language=en|volume=16|issue=1|pages=|doi=10.1186/s12967-018-1644-y|issn=1479-5876|pmc=|pmid=30285773|quote=|via=}}</ref><ref name="Magnus2015">{{Cite journal | last = Magnus | first = Per | last2 = Gunnes | first2 = Nina | last3 = Tveito | first3 = Kari | last4 = Bakken | first4 = Inger Johanne | last5 = Ghaderi | first5 = Sara | last6 = Stoltenberg | first6 = Camilla | last7 = Hornig | first7 = Mady | last8 = Lipkin | first8 = W. Ian | last9 = Trogstad | first9 = Lill | date = 2015-11-17 | title = Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine|url=https://www.ncbi.nlm.nih.gov/pubmed/26475444/|journal=Vaccine|volume=33|issue=46 | pages = 6173–6177|doi=10.1016/j.vaccine.2015.10.018|issn=1873-2518|pmid=26475444}}</ref> It is still possible ME involves some combination of both environmental and genetic factors. Various theories try to combine the known data into plausible explanations.<ref>{{Cite journal | last = Underhill | first = R.A. | date = 2015 | title=Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease|url=https://www.ncbi.nlm.nih.gov/pubmed/26604026|journal=Medical Hypotheses|volume=85|issue=6 | pages = 765–773|doi=10.1016/j.mehy.2015.10.011|issn=1532-2777|pmid=26604026|via=}}</ref><ref name="Schlauch, 2016">{{Cite journal | last1 = Schlauch | first1 = Karen A. | authorlink1 = Karen Schlauch | last2 = Khaiboullina | first2 = Svetlana F. | authorlink2 = Svetlana Khaiboullina | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny de Meirleir | last4 = Rawat | first4 = Shanti | authorlink4 = Shanti Rawat | last5 = Petereit | first5 = J | authorlink5 = | last6 = Rizvanov | first6 = Albert A | authorlink6 = Albert Rizvanov | last7 = Blatt | first7 = Nataliya | authorlink7 = Nataliya Blatt | last8 = Mijatovic | first8 = Tatjana | authorlink8 = Tatjana Mijatovic | last9 = Kulick | first9 = D | authorlink9 = | last10 = Palotás | first10 = András | authorlink10 = András Palotás | last11 = Lombardi | first11 = Vincent C. | authorlink11 = Vincent Lombardi | title = Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome | journal = Translational Psychiatry | volume = 6 | issue = 2 | page = e730 | date = 2016 | pmid = | doi = 10.1038/tp.2015.208 }}</ref> Several theories suggest that ME is an inappropriate immune response to an infection, a theory bolstered by the observation that there is sometimes a family history of [[autoimmune disease]].<ref name="Sotzny, 2018">{{Cite journal | last1 = Sotzny | first1 = Franziska | authorlink1 = Franziska Sotzny | last2 = Blanco | first2 = Julià | authorlink2 = Julià Blanco | last3 = Capelli | first3 = Enrica | authorlink3 = Enrica Capelli | last4 = Castro-Marrero | first4 = Jesús | authorlink4 = Jesús Castro-Marrero | last5 =Steiner | first5 = Sophie | authorlink5 = | last6 = Murovska | first6 = Modra | authorlink6 = Modra Murovska | last7 = Scheibenbogen | first7 = Carmen | authorlink7 = Carmen Scheibenbogen| title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease | url = https://www.sciencedirect.com/science/article/pii/S1568997218300880 | journal = Autoimmunity Reviews | volume = 17 | issue = 6 | page = 601-609 | date = 2018 | pmid = | doi = 10.1016/j.autrev.2018.01.009}}</ref><ref>{{Cite web|url=https://www.facebook.com/permalink.php?story_fbid=564532390371988&id=564526123705948 | title = Klimas ME CFS Genes Study | last = | first = | date = Nov 23, 2015 | website = facebook.com|language=en|archive-url=|archive-date=|url-status=|access-date=2018-09-08}}</ref> There is also a shift from the [[Th1]] type of helper [[T cell]]s, which fight infection, to the [[Th2]] type, which are more active in [[allergy]] and more likely to attack the body.<ref>{{Cite journal | date = 2015-03-01 | title = Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis|url=https://www.sciencedirect.com/science/article/abs/pii/S1043466614006024|journal=Cytokine|language=en|volume=72|issue=1|pages=1–8|doi=10.1016/j.cyto.2014.11.019|issn=1043-4666}}</ref><ref name="Hardcastle2014">{{Cite journal|url=http://www.m-hikari.com/bmgt/bmgt2014/bmgt1-4-2014/hardcastleBMGT1-4-2014.pdf | title=Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and the Potential Role of T Cells | last = Hardcastle | first = S.L. | last2 = Brenu | first2 = E.W. | last3 = Staines | first3 = D.R. | authorlink3 = Donald Staines | last4 = Marshall-Gradisnik | first4 = S. | authorlink4 = Sonya Marshall-Gradisnik| date = 2014 |journal=Biological Markers and Guided Therapy|volume=1|issue=1=|pages=25|doi=10.12988/bmgt.2014.3122}}</ref>

[[File:Naomi Whittingham .png|300px|thumb|[[Naomi Whittingham]] lives in the UK with a [[Severe and very severe ME|severe case of ME]]. Naomi became ill at [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|age 12]] with a routine virus and never recovered. She advocates for ME by doing interviews, writing the blog [[A Life Hidden]], and supporting her brother [[Tom Whittingham]]'s marathon fund raising for [[ME Research UK]]]]

===Viruses===
{{Main article |page_name = Virus}}

Other theories describe ME as an immune response to a chronic infection. The association between ME and the [[Coxsackie B]], [[Human herpesvirus 6]], and [[HHV-7]] viruses<ref>{{Cite journal | last = Bell | first = E.J. | last2 = McCartney | first2 = R.A. | last3 = Riding | first3 = M.H. | date = 1988 | title = Coxsackie B viruses and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/2841461|journal=Journal of the Royal Society of Medicine|volume=81|issue=6|pages=329–331|doi=10.1177/014107688808100609|issn=0141-0768|pmid=2841461|via=}}</ref><ref>{{Cite news | url=http://solvecfs.org/ramsay-research-team-5-the-potential-role-of-hhv-6-in-mecfs/ | title = Ramsay Research Team 5 – The Potential Role of HHV-6 in ME/CFS - Solve ME/CFS Initiative | last = | first = | date = 2016-12-16|work=Solve ME/CFS Initiative|access-date=2018-09-08|archive-url=|archive-date=|url-status=|publisher=VOLKMEDIA|language=en-US}}</ref><ref name="Chapenko2012">{{Cite journal | last = Chapenko | first = Svetlana | last2 = Krumina | first2 = Angelika | last3 = Logina | first3 = Inara | last4 = Rasa | first4 = Santa | last5 = Chistjakovs | first5 = Maksims | last6 = Sultanova | first6 = Alina | last7 = Viksna | first7 = Ludmila | last8 = Murovska | first8 = Modra | date = 2012 | title = Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/22927850|journal=Advances in Virology|volume=|pages=205085|doi=10.1155/2012/205085|issn=1687-8647|pmid=22927850|via=}}</ref> suggests a potential viral contribution in at least some individuals. Some researchers have stated that evidence from [[epidemic myalgic encephalomyelitis]] strongly point to an enterovirus, however, in most outbreaks, no virus was successfully isolated.<ref name="Chia2005"/><ref name="Hanson2021">{{Cite journal | title = The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review | date = 2021 | url=https://www.frontiersin.org/article/10.3389/fmed.2021.688486|journal=Frontiers in Medicine|volume=8|issue= | pages = 688486 | last = O'Neal | first = Adam J. | authorlink = | last2 = Hanson | first2 = Maureen R. | authorlink2 = Maureen Hanson|doi=10.3389/fmed.2021.688486/abstract|pmc=|pmid=|access-date=|issn=2296-858X|quote=|via=}}</ref>

=== Bacteria ===
{{Main article |page_name = Bacteria}}

Others believe ME may sometimes result from a chronic infection with spirochetal bacteria, such as [[lyme disease]]. Another bacterium that has been implicated in ME is [[chlamydia pneumoniae]].<ref name="Tovey2018">{{Cite journal | date = 2018-09-05 | last = Tovey | first = JE | title = Chlamydia pneumoniae infection a treatable cause of Chronic Fatigue Syndrome|url=https://www.bmj.com/rapid-response/2011/11/01/chlamydia-pneumoniae-infection-treatable-cause-chronic-fatigue-syndrome|journal=The BMJ|language=en|volume=|pages=|via=}}</ref><ref>{{Cite news | url=https://www.prohealth.com/library/new-me-cfs-study-at-stanford-dr-montoya-to-test-for-scores-of-infections-27346 | title = New ME/CFS Study at Stanford: Dr. Montoya to test for scores of Infections - Prohealth | date = 2010-06-04|work=Prohealth|access-date=2018-09-08|language=en-US}}</ref> Protein findings relating to several infections have seen found in the oligoclonal bands ME of patients.<ref name="Nicholson2009">{{Cite journal|url=http://www.bjmp.org/content/role-chronic-bacterial-and-viral-infections-neurodegenerative-neurobehavioral-psychiatric-au | title = Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioral, Psychiatric, Autoimmune and Fatiguing Illnesses: Part 1 | first = Garth L. | last=Nicolson | first2 = Jörg | last2 = Haier | date = 2009|journal=British Journal of Medical Practitioners|volume=2|issue=4|pages = 20-28|doi=|pmid=}}</ref>

The [[vagus nerve infection hypothesis]] (VNIH) accounts for why so many different infectious onsets could be responsible. The [[vagus nerve]] runs from the brain stem and throughout the body and has an impact on many body systems.{{citation needed|date=2023-11-17}}

===Transmission via blood===
{{Main article|Blood donation}}
Given the uncertainty regarding the cause, ME and CFS patients are barred from [donating blood or organs in the [[United Kingdom]] (even after recovery),<ref name="BloodUK">{{Cite web | url = https://my.blood.co.uk/KnowledgeBase | title = Knowledgebase|website=My Donor Record - Health, Eligibility & Travel | last = | first = | authorlink = |archive-url=|archive-date=|url-status=|access-date=2021-10-08}}</ref> most of [[Canada]],<ref name="Wilson2014">{{Cite journal | title = The Use of Preliminary Scientific Evidence in Public Health: A Case Study of XMRV | date = 2014-04-08 | url = https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001623|journal=PLOS Medicine|volume=11|issue=4| pages = e1001623 | last = Wilson | first = Kumanan | last2 = Atkinson | first2 = Katherine | last3 = Keelan | first3 = Jennifer|language=en|doi=10.1371/journal.pmed.1001623|pmc=PMC3979645|pmid=24714396|issn=1549-1676}}</ref> [[Australia]],<ref name="RedCrossAus">{{cite web | url = https://www.lifeblood.com.au/faq/eligibility/medical-conditions-and-procedures/chronic-fatigue-syndrome| website = Australian Red Cross|title = Chronic Fatigue Syndrome|access-date=2023-11-17}}</ref><ref name="donate">{{Cite web|url = https://www.donateblood.com.au/faq/chronic-fatigue-syndrome |title=Chronic fatigue syndrome – I have/had chronic fatigue syndrome. Can I donate?|access-date=2022-05-25|website = Australian Red Cross}}</ref> [[New Zealand]] (while symptoms persist), and and for a time also in the [[United States]].<ref name="post">{{Cite web | url = http://voices.washingtonpost.com/checkup/2010/12/red_cross_bars_chronic_fatique.html | title = Red Cross bars chronic fatigue patients from donating blood | last = Stein | first = Rob | authorlink = | date = Dec 3, 2010 | website = Washington Post|archive-url=|archive-date=|access-date=2022-05-25}}</ref><ref name="USblood">{{Cite news | url=http://www.washingtonpost.com/wp-dyn/content/article/2010/12/03/AR2010120305888.html | title = Chronic fatigue patients barred from blood donation|publisher=Washington Post | last = Stein | first = Rob | date = 2010-12-03|access-date=2018-09-08|language=en-US|issn=0190-8286}}</ref><ref name="NZblood">{{Cite web|url=http://www.nzblood.co.nz/Give-blood/Donating/Detailed-eligibility-criteria#C | title = Detailed eligibility criteria|website=NZ Blood|language=en-NZ|access-date=2018-09-08}}</ref>

In the US, the American Association of Blood Banks advises to either accept or defer ME/CFS donors based on "clinical judgment of the donor's health status".<ref name="AABBOct2012">{{Cite web | last = American Association of Blood Banks | url = https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2 | date = October 2012 | title = Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV)|pages = 3 |quote=An updated AABB Association Bulletin #12-05 (November 2012) states that individual collectors of blood and cellular therapy products should accept or defer donors with a history of CFS based on their clinical judgment of the donor's health status.|access-date=2022-05-25}}</ref> Patient charities discourage ME/CFS patients from donating blood,<ref name="MassBlood2015">{{Cite web | url = https://www.massmecfs.org/research/recent-research/19-xmrv/237-aabbs-recommendation-on-cfidsme-and-blood-donation | title = AABB's recommendation on ME/CFS and blood donation | date = Nov 25, 2015 |website=[[Massachusetts ME/CFS & FM Association]]|access-date=2022-05-25}}</ref>

==Treatments==
[[File:Karina Hansen.jpg|200px|thumb|right|[[Karina Hansen]] became [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|ill as an adult teenager]] and is [[Severe and very severe ME|severely ill]] with ME. She was forcibly institutionalized for 3 1/2 years as the [[Denmark]] healthcare system designates ME as psychosomatic. Karina is now home with her family where she received cards from well-wishers from around the world. Karina's Danish High Court case and return home were featured in the documentary film [[Unrest|''Unrest'']]]]
{{Main article |page_name=Treatments|Potential treatments for myalgic encephalomyelitis and chronic fatigue syndrome}}

There is no cure for ME and no country has approved any pharmacological treatment for the disease except, [[Argentina]] which has approved [[Ampligen]] for the treatment of severe ME/CFS.<ref name="Hemispherx" /> However the effectiveness of Ampligen is under dispute.<ref name="FDA-2009">{{Cite web|url=https://www.bizjournals.com/philadelphia/stories/2009/11/30/daily23.html | title = FDA rejects Hemispherx’s chronic fatigue drug Ampligen | website = bizjournals.com|access-date=2018-08-12 | date =Dec 2, 2009 | last = George | first = John|archive-url=|archive-date=|url-status=}}</ref> Other medications have been used off-label for ME with varying effectiveness in some patients.<ref name="Carruthers, 2003" /><ref name="ICC" />

Treatments for sleep problems, headaches, pain or other symptoms are utilized by some doctors for some patients although these are treating symptoms and not ME itself.<ref name="ICC" />

Success of treating symptoms of ME is not well researched or documented.

An immune system modulator drug called [[Rituximab]] has failed in a phase III clinical trial.<ref>{{Cite news | url=http://simmaronresearch.com/2017/11/norwegian-rituximab-chronic-fatigue-syndrome-mecfs-trial-fails/ | title = Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails - Simmaron Research | last = Johnson | first =Cort | date = 2017-11-26|work=Simmaron Research|access-date=2018-09-07|archive-url=|archive-date=|url-status=|language=en-US}}</ref> The antiviral Valganciclovir failed in a controlled nine month study against ME patients positive for Herpes Simplex 6 and Epstein Barr viral infections.<ref>{{Cite journal | last = Montoya | first = Jose G. | last2 = Kogelnik | first2 = Andreas M. | last3 = Bhangoo | first3 = Munveer | last4 = Lunn | first4 = Mitchell R. | last5 = Flamand | first5 = Louis | last6 = Merrihew | first6 = Lindsey E. | last7 = Watt | first7 = Tessa | last8 = Kubo | first8 = Jessica T. | last9 = Paik | first9 = Jane | date = Dec 2013 | title = Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23959519|journal=Journal of Medical Virology|volume=85|issue=12|pages=2101–2109|doi=10.1002/jmv.23713|issn=1096-9071|pmid=23959519|pmc=|quote= | author-link = Jose Montoya | authorlink2 = Andreas Kogelnik|access-date=|via=}}</ref>

==Epidemiology ==
{{Main article |page_name = Epidemiology of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome}}
ME has been found world-wide, in at least 75 [[Outbreaks|epidemics]] documented in published papers from the 1930s to the 1980s.<ref name="HFME">{{Cite web|url=http://www.hfme.org/methemedicalfacts.htm | title = M.E.: The medical facts | last = Bassett | first = Jodi | authorlink=Jodi Bassett | date = Sep 2010 | website = The Hummingbirds' Foundation for M.E.|archive-url=|archive-date=|url-status=|access-date=2018-09-08}}</ref> Epidemics often occur in enclosed communities such as schools and hospitals.

As observed in many autoimmune disorders, ME is more common in females than males; the mean sex ratio is approximately 2-3 females for every male.<ref name="Bakken2014" /> In children the sex ratio is approximately equal.<ref name="Collin2015" />

== Co-morbidities ==
[[File:Chronically_Hopeful_Char_Profile_Pic.jpg|250px|thumb|right|Char, author at [[Chronically Hopeful]], must use sunglasses due to light sensitivity ([[photophobia]]) and noise canceling ear protection due to sound sensitivity ([[hyperacusis]])]]
{{main article|Comorbidities of Myalgic Encephalomyelitis}}
Clinicians have observed several predisposing conditions, co-morbidities, overlapping conditions, and increased risks for secondary diseases in patients with ME.<ref name="Carruthers, 2003" /><ref name="CDC-symptoms" /> However, as no large-scale [[Epidemiology of myalgic encephalomyelitis and chronic fatigue syndrome|epidemiological]] studies, genetic studies, or family studies have been done, there is little that can be said definitively about the rate or underlying biological reasons for these potentially related conditions. Overlapping [[:Category:Definitions|diagnostic criteria]] and the lack of a [[Diagnostic biomarker|biomarker]] in many of these conditions add to the confusion and diagnostic uncertainty. Moreover, certain conditions such as [[postural orthostatic tachycardia syndrome]] (POTS) and [[neurally mediated hypotension]] (NMH) and idiopathic [[intracranial hypertension]] (IIH/IH) and [[fibromyalgia]] (FM/FMS) can occur in or be co-morbid with numerous conditions, including ME.<ref name="CDC-etiology">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html | title = Etiology and Pathophysiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-11-08 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-02-17}}</ref><ref name="Dankaerts2018">{{Cite web|url=https://www.dovepress.com/the-link-between-idiopathic-intracranial-hypertension-fibromyalgia-and-peer-reviewed-article-JPR | title = The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology | last = Dankaerts | first = Wim | last2 = Bruyninckx | first2 = Frans | date = 2018-12-10 | website = Journal of Pain Research|language=English|access-date=2019-02-17 | last3 = Stalmans | first3 = Ingeborg | last4 = Vansant | first4 = Greet | last5 = Rasschaert | first5 = Ricky | last6 = Hulens | first6 = Mieke}}</ref>

The following are some syndromes and diseases that have been associated with or misdiagnosed as ME:
<div style="column-count:2;">
*[[fibromyalgia]]<ref name="CDC-comorbid">{{Cite web|url=https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/comorbid-conditions.html | title = Comorbid Conditions {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-11-08 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-02-26}}</ref>
* [[Lyme disease]] and [[Chronic lyme disease|chronic Lyme disease]]<ref name="ICC" />
*[[Intracranial hypertension|idiopathic intracranial hypertension]]<ref name="Dankaerts2018" />
*[[Postural orthostatic tachycardia syndrome|postural orthostatic tachychardia syndrome]]<ref name="ICC" /><ref name="Hoad2008">{{Cite journal | last = Hoad | first = A. | authorlink = | last2 = Spickett | first2 = G. | authorlink2 = Gavin Spickett‎ | last3 = Elliott | first3 = J. | authorlink3 = | last4 = Newton | first4 = J. | authorlink4 = Julia Newton | date = 2008 | title = Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/18805903|journal=QJM: monthly journal of the Association of Physicians|volume=101|issue=12 | pages = 961–965|doi=10.1093/qjmed/hcn123|issn=1460-2393|pmid=18805903|quote=|via=}}</ref>
*[[irritable bowel syndrome]]<ref name="CDC-comorbid" /><ref name="Carruthers, 2003" />
*[[Hashimoto's thyroiditis (hypothyroidism)]]<ref name="CDC-differentialdiagnosis" />
*[[Ehlers-Danlos syndrome]]<ref name="CDC-differentialdiagnosis" />
*[[Sjögren's syndrome]]<ref name="CDC-differentialdiagnosis" />
*[[multiple chemical sensitivity]]<ref name="CDC-comorbid" /><ref name="ICC2011primer" />
</div>

A Swedish study of 234 ME/CFS patients meeting the [[Canadian Consensus Criteria]] found that 13.2% had tonsillar herniations severe enough to be considered a [[Chiari malformation|Chiari Malformation]]. 49% had hypermobility and 20% met criteria for hEDS (Ehlers-Danlos syndrome with hypermobility), while 96% had fibromyalgia trigger point pain, with 67% meeting the diagnostic criteria for fibromyalgia.<ref name="Bragee2020">{{Cite journal | last = Bragée | first = Björn | authorlink = Björn Bragée | last2 = Michos | first2 = Anastasios | authorlink2 = | last3 = Drum | first3 = Brandon | authorlink3 = | last4 = Fahlgren | first4 = Mikael | authorlink4 = | last5 = Szulkin | first5 = Robert | authorlink5 = | last6 = Bertilson | first6 = Bo C. | authorlink6 = | date = 2020 | title=Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.00828/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.00828|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref>

== Notable studies ==
{{Main article |page_name = Notable studies}}
Due to lack of [[funding]] by governments around the world there has been little biological research into [[ME/CFS]]. There are studies which do reveal [[Nervous system|neurological]] involvement, [[metabolic]] features, and other abnormalities.
* 2016, [[Metabolic features of chronic fatigue syndrome]]
* 2016, [[CDC Multi-site Clinical Assessment of CFS]]
* 2019, [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy]]
* [[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis]]

==News and articles==
*2015, [http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped] - The Argus Report
* 2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder - New York Times: Well (2014)|Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder]]
*2010, [http://www.washingtonpost.com/wp-dyn/content/article/2010/12/03/AR2010120305888.html Chronic fatigue patients barred from blood donation] - Washington Post
*1987, [https://www.nytimes.com/1987/07/28/science/fatigue-virus-has-experts-more-baffled-and-skeptical-than-ever.html Fatigue 'Virus' Has Experts More Baffled And Skeptical Than Ever] - The New York Times

== See also ==
* [[Chronic fatigue syndrome]]
* [[Misdiagnosis of myalgic encephalomyelitis and chronic fatigue syndrome]]
* [[ME/CFS]]
* [[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome]]
* [[Severe and very severe ME]]
*[[Systemic Exertion Intolerance Disease]]

== Learn more ==
*[https://www.cdc.gov/me-cfs/about/index.html What is ME/CFS?] - CDC
*[https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/other-conditions.html Diagnosis - Other conditions for evaluation] - CDC
*[https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/evaluation.html Evaluation] - medical tests needed to rule out other illnesses from ME/CFS - CDC
*[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x M.E. International Consensus Criteria]

== References ==
{{reflist}}

[[Category:Diagnoses]]
[[Category:Disease names]]
[[Category:Disease names and definitions]]
[[Category:Neurological diseases and disorders]]

Post-exertional malaise

2024-06-27T13:43:30Z

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[[File:Cfs woman sketch.jpg|435x435px|thumb|Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more.<ref name="Chu2018" />]]

In [[ME/CFS]], '''Post-exertional malaise (PEM)''' refers to a ''worsening'' of the illness after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /><ref name=":0">Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (17 April 2023). ''Myalgische Enzephalomyelitis / Chronic Fatigue Syndrome (ME/CFS): Aktueller Kenntnisstand'' [''Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): current state of knowledge''] (PDF) (in German). Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. [[ISSN (identifier)|ISSN]] 1864-2500. Archived(PDF) from the original on 2 November 2023. Retrieved 8 November 2023.</ref> This can include a [[post-exertional symptom exacerbation|worsening of ME/CFS symptoms]], the appearance of new symptoms, and a worsening of “baseline” (capacity for exertion).<ref name="Stussman2020" /><ref name=":0" /> These characteristics are often delayed 24-72 hours or more after the triggering event.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" />

While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> When in PEM, people with ME/CFS have a lower capacity for exertion and the baseline for tiggering more PEM is lower.<ref name="Stussman2020" />

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer.<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> PEM can lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref> Some people with ME refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|thumb|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Post-exertional malaise

2024-06-23T12:33:20Z

Yannlk:link

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

In [[ME/CFS]], '''Post-exertional malaise (PEM)''' refers to a ''worsening'' of the illness after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /><ref name=":0">Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (17 April 2023). ''Myalgische Enzephalomyelitis / Chronic Fatigue Syndrome (ME/CFS): Aktueller Kenntnisstand'' [''Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): current state of knowledge''] (PDF) (in German). Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. [[ISSN (identifier)|ISSN]] 1864-2500. Archived(PDF) from the original on 2 November 2023. Retrieved 8 November 2023.</ref> This can include a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]], the appearance of new symptoms, and a worsening of “baseline” (capacity for exertion).<ref name="Stussman2020" /><ref name=":0" /> These characteristics are often delayed 24-72 hours or more after the triggering event.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" />

While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> When in PEM, people with ME/CFS have a lower capacity for exertion and the baseline for tiggering more PEM is lower.<ref name="Stussman2020" />

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer.<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> PEM can lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref> Some people with ME refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|thumb|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Post-exertional malaise

2024-06-23T12:26:48Z

Yannlk:Reformed the base definition (lead) to be more inline with modern defintions of PEM.

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

In ME/CFS, '''Post-exertional malaise (PEM)''' refers to a ''worsening'' of the illness after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /><ref name=":0">Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (17 April 2023). ''Myalgische Enzephalomyelitis / Chronic Fatigue Syndrome (ME/CFS): Aktueller Kenntnisstand'' [''Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): current state of knowledge''] (PDF) (in German). Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. [[ISSN (identifier)|ISSN]] 1864-2500. Archived(PDF) from the original on 2 November 2023. Retrieved 8 November 2023.</ref> This can include a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]], the appearance of new symptoms, and a worsening of “baseline” (capacity for exertion).<ref name="Stussman2020" /><ref name=":0" /> These characteristics are often delayed 24-72 hours or more after the triggering event.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" />

While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> When in PEM, people with ME/CFS have a lower capacity for exertion and the baseline for tiggering more PEM is lower.<ref name="Stussman2020" />

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer.<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> PEM can lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref> Some people with ME refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|thumb|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Low dose naltrexone

2024-06-07T10:23:59Z

Yannlk:/* VLDN and ULDN */ No medical advice, no advertising

'''Low Dose Naltrexone''' (LDN) refers to very small doses of the drug '''naltrexone hydrochloride''', which at higher doses treats drug or [[alcohol]] dependence. Low dose naltrexone may reduce [[pain]], or potentially [[Nervous system|neurological]] symptoms. Brand names of naltrexone include '''ReViva''', '''Depade''', and '''Vivitrol'''.<ref name="brands">{{Cite web|url=https://www.drugs.com/ingredient/naltrexone.html | title = Naltrexone - brand name list from Drugs.com|website=Drugs.com|language=en|access-date=2022-01-17}}</ref>
LDN use other for treating drug dependence is considered off-label. Some patients report that LDN helps reduce their symptoms of [[ME/CFS]], [[multiple sclerosis]] (MS), [[fibromyalgia]] (FMS), or [[autoimmune disease]]. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory.<ref name="Younger2014" />

==Prescription forms ==
LDN is typically prescribed using generic naltrexone hydrochloride or branded naltrexone, divided into much smaller doses. LDN may be taken in the form of liquid solution/syrup, sublingual doses or 1.5mg capsules, or a compounding pharmacy can create smaller sized capsules or tablets. LDN in the form of naltrexone cream, subcutaneous injections, IV naltrexone and eye drops (for [[Sjögren's syndrome|dry eyes]]) are also available.<ref name="forms">{{Cite web|url=https://ldnresearchtrust.org/types-of-ldn | title = Types of LDN | last = | first = | authorlink = | date = | website = LDN Research Trust |language=en|archive-url=|archive-date=|url-status=|access-date=2022-01-17}}</ref>

== VLDN and ULDN ==
'''Very Low Dose Naltrexone''' (VLDN) and '''Ultra-Low Dose Naltrexone''' (ULDN) have recently been used in limited trials, both VLDN and ULDN involve doses of naltrexone significantly below 1mg.<ref>{{Cite journal | last = Toljan | first = Karlo | author-link =Karlo Toljan | last2 = Vrooman | first2 = Bruce | authorlink2 = Bruce Vrooman | date = Sep 21, 2018 | title = Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313374/|journal=Medical Sciences|volume=6|issue=4|pages=|doi=10.3390/medsci6040082|issn=2076-3271|pmc=|pmid=30248938|quote=|via=}}</ref>

Very Low Dose Naltrexone is increasingly being used under 1mg for people who cannot titrate from 0.5mg to find their individual optimal dose.
==Evidence==
[[File:LDN-Fibro2014.jpg|alt=Data shows a graph with 10% worse after treatment, 57% improved or much improved, and 12% very much improved. Darker colors are the most improved sections.|thumb|350x350px|Low Dose Naltrexone results for 29 patients with [[Fibromyalgia]]. Fibromyalgia participants’ (N = 29) self-reported improvement in symptoms after daily LDN treatment.
Source: Clin Rheumatol 2014; 33(4):452-459. Fig 1.<ref name="Younger2014" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/figure/Fig1/ PMC3962576] ]]

[[Jarred Younger]] published a small study that concluded "...low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia".<ref name="Younger2009" /><ref name="Mackey2009" />

A second study concluded that "specific and clinically beneficial impact on fibromyalgia pain".<ref name="Younger2013" /><ref>{{Cite web|url=https://med.stanford.edu/pain/snapl/completed-research/naltrexone2.html | title = Low Dose Naltrexone for Fibromyalgia|website=Systems Neuroscience and Pain Lab {{!}} Stanford Medicine|language=en|access-date=2018-10-04 | date = |last = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>

A 2014 review by Stanford researchers suggests that "LDN may operate as a novel anti-inflammatory agent in the [[central nervous system]], via action on [[microglia]]l cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on [[opioid]] receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated."<ref name="Younger2014" />
[[File:LDN-Fibro-ESR.jpg|thumb|420x420px|Relationship between ESR, a marker inflammation, and LDN treatment in 29 patients with [[Fibromyalgia]]. ]]
The [[FDA]] approved naltrexone HCL in 1984 to treat opioid addiction. Low-dose naltrexone is typically given at about 1/10th the typical dose of naltrexone. By blocking opioid receptors, naltrexone can increase pain, but at very low doses naltrexone has both pain-reducing ([[analgesic]]) and anti-inflammatory properties.

In 2012 [[Solve ME/CFS Initiative]] contracted [[Biovista]] to use drug models to identify existing drugs that may be worth investigating for treatment. The results suggested Naltrexone was worth considering.<ref>{{Cite web|url=http://solvecfs.org/biovista-work-released | title = Biovista work released|last = Solve ME/CFS Initiative | first = | authorlink = Solve ME/CFS Initiative | date = |website=|archive-url=|archive-date=|access-date=|url-status=live}}</ref>

Jarred Younger's research suggests that people with an [[Erythrocyte sedimentation rate|Erythrocyte Sedimentation Rate]] (ESR) over 40 millimeters an hour, tend to be strong responders to LDN, and that there may be other predictive factors for success.<ref name="Younger20160329sh" />

==News articles==
* 2019, [https://www.npr.org/sections/health-shots/2019/09/23/741783834/in-tiny-doses-an-addiction-medication-moonlights-as-a-treatment-for-chronic-pain In Tiny Doses, An Addiction Medication Moonlights As A Treatment For Chronic Pain] - NPR, All Things Considered
* September 9, 2021<nowiki/>https://www.empr.com/home/news/drugs-in-the-pipeline/low-dose-naltrexone-designated-orphan-drug-for-complex-regional-pain-syndrome/

==Clinical use==

Naltrexone is a prescription drug in many countries including the [[United States]].<ref name="naltrexonecompliance">{{Cite journal | last = Feeney|first = G. F. X. | last2 = Connor | first2 = J.P. | last3 = Young | first3 = R. McD | last4 = Tucker | first4 = J. | last5 = Czajkowski | first5 = F. | date = 2001 | title = Adherence with naltrexone prescription advice in hospital outpatient alcohol rehabilitation programme|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2710.2001.00326.x|journal=Journal of Clinical Pharmacy and Therapeutics|language=en|volume=26|issue=1 | pages = 73–79|doi=10.1111/j.1365-2710.2001.00326.x|issn=1365-2710}}</ref>Compounding chemists or compounding pharmacists can mix naltrexone with a powder filler or dilute in into a liquid to create the lower dose.

=== Fast-release fillers only ===
The LDN Research Trust advises that:
"Pharmacies should be instructed NOT to provide LDN in an "SR" or slow-release or timed-release form. Unless the low dose of naltrexone is in an unaltered form, which permits it to reach a prompt "spike" in the blood stream, its therapeutic effects may be inhibited."<ref name="leaflet2014" /> and states that calcium carbonate filler should NOT be used because they reduce absorption, instead Avicel, lactose, or sucrose fillers as alternative fast-release fillers."<ref name="leaflet2014">{{Cite web|url=https://ldnresearchtrust.org/sites/default/files/Doctors-info-pack-US.pdf | title=Low-dose Naltrexone (LDN) Fact Sheet 2014 | website = LDN Research Trust | date = 2014}}</ref>

===Do not take with===
In general, Low Dose Naltrexone (LDN) should not be taken concurrently with opioid-containing drugs (opioid receptors in brain are blocked by LDN), alcohol, immunosuppressive drugs, or immunomodulator drugs.{{citation needed | date = 2021}} LDN blocks the effect of opioid drugs.<ref name="chronicpain">{{Cite web|url=https://www.ldnresearchtrust.org/content/low-dose-naltrexone-and-chronic-pain-pradeep-chopra-md | title = Low Dose Naltrexone and chronic pain | first = Pradeep |last =Chopra|website=LDN Research Trust|access-date=2019-01-31}}</ref> Some opioid drugs are [[codeine]], [[tramadol]], [[oxycodone]], [[vicodin]], [[hydrocodone]], [[fentanyl]] and [[morphine]].
==Pharmacies ==

=== Australia ===
''Compounding Pharmacies'' are able to fill these prescriptions, and post if needed.

=== UK ===
LDN suppliers in the UK include '''Dickson Chemist''' in Glasgow, Roseway Labs, and Specialist Pharmacy (The London Specialist Pharmacy Ltd). All these are compounding pharmacies and require a perscription, they are usually able to put patients in contact with private doctors who will consider writing a prescription, and can post medications to you.<ref name="RosewayLabs">{{Cite web |url = https://rosewaylabs.com/compounding-processes-regulations | title = Compounding processes regulations/|website =Roseway Labs}}</ref> Compounding pharmacies are regulated by the UK's General Pharmaceutical Council.<ref name="RosewayLabs" />

===United States===
Neighborhood ''Compounding Pharmacies'' are able to fill these prescriptions and mail if needed. Your prescribing doctor can help you locate a compounding pharmacy in your area/state or you can look online.<ref>[http://www.wikihow.com/Find-a-Compounding-Pharmacy Finding a Compounding Pharmacy - WIKI How]</ref>

===Other countries ===
The LDN Research Trust lists pharmacies in multiple countries.<ref name="sources">{{Cite web |url = https://ldnresearchtrust.org/ldn-pharmacists|website=LDN Research Trust|title =LDN Pharmacists |access-date =}}</ref>

== Clinical trials ==
A large number of clinical trials have been completed for LDN recently, although none have looked at the effect of LDN on symptoms of [[myalgic encephalomyelitis]]/[[chronic fatigue syndrome]]. Research has been carried out on patients with MS, [[Chronic Regional Pain Syndrome]], FMS, [[Irritable bowel syndrome|Irritable Bowel Syndrome]] (IBS), Ulcerative Colitis, Skin Disorders and a range of other illnesses.<ref name="trials">{{Cite web|url=https://www.ldnresearchtrust.org/ldn-clinical-trials | title = Clinical Trials|website=LDN Research Trust|access-date=2019-01-21}}</ref>

==When, How To Take ==
Dr Whitaker states that the ideal dose is different for each person. Some doctors recommend starting at 1mg.<ref name="LDN-now">{{Cite web|url=http://www.ldnnow.com/48591/90512.html | title = LDN Dosing|last = LDN Now|first = | authorlink = | date = | website = |access-date=2018-02-01}}</ref> Common dosages are 1.5mg, 3mg, 4.5mg.<ref>{{Cite web|url=https://www.amymyersmd.com/2017/05/low-dose-naltrexone/ | title = Low-Dose Naltrexone for Autoimmunity? | last = Myers | date = 2017-05-02 | website = Amy Myers MD|language=en-US|access-date=2019-02-02|first = Amy | authorlink = |archive-url=|archive-date=|url-status=}}</ref><ref name=":1">{{Cite web|url=https://www.drwhitaker.com/what-is-low-dose-naltrexone | title = What is Low-Dose Naltrexone?|last = Dr Whitaker | first = | authorlink = | date = | website = drwhitaker.com|language=en|archive-url=|archive-date=|access-date=2019-01-21}}</ref><ref name="chronicpain" /> When beginning use of LDN, the drug must be stepped up over 6-8+ weeks as it may keep you awake; discuss how best to do this with your doctor and pharmacist.<ref name=":1" /><ref>{{Cite web|url=https://collierdrug.com/low-dose-naltrexone-ldn/ | title = Low Dose Naltrexone (LDN) – Collier Drug Store|last = | first = | authorlink = | date = | website = collierdrug.com|at=What dose of Low Dose Naltrexone (LDN) is best?|archive-url=|archive-date=|access-date=2019-02-02}}</ref><ref name="chronicpain" />

LDN is usually taken at bedtime. Some people take LDN in the morning to minimize [[Sleep dysfunction|sleep disturbance]], [[insomnia]], and vivid dreams.<ref name="chronicpain" />

== Talks and webinars==
*2012, [https://www.youtube.com/watch?v=z0p0ykSzy9o LDNscience® Presents - How LDN (Low Dose Naltrexone) Works]<ref>{{Cite web|url=https://www.youtube.com/watch?v=z0p0ykSzy9o | title = LDNscience® Presents - How LDN (Low Dose Naltrexone) Works|last = | first = | authorlink = | date = Dec 20, 2012 | website = YouTube|publisher=LDNscience|archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''LDNscience® Presents - How LDN (Low Dose Naltrexone) Works'' By LDNscience">https://www.youtube.com/watch?v=z0p0ykSzy9o</embedvideo>

*2015, [https://www.youtube.com/watch?v=8a-ULCaarCQ Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez]<ref>{{Cite web|url=https://www.youtube.com/watch?v=8a-ULCaarCQ | title = Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez|last = Carnahan | first = Jill | authorlink= | last2 = Vasquez | first2 = Alex | authorlink2 = | date = Nov 30, 2015 | website = YouTube|publisher=Alex Vasquez|archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez '' By Alex Vasquez">https://www.youtube.com/watch?v=8a-ULCaarCQ</embedvideo>

*2015, [https://www.youtube.com/watch?v=Qnr51yU9ih8 Is Low Dose Naltrexone (LDN) for you?]<ref>{{Cite web|url=https://www.youtube.com/watch?v=Qnr51yU9ih8 | title = 1:05 / 7:05 Is Low Dose Naltrexone (LDN) for you?|last = | first = | authorlink = | date = Oct 11, 2015 | website = YouTube | archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''Is Low Dose Naltrexone (LDN) for you?'' By Integrative Health Solutions">https://www.youtube.com/watch?v=Qnr51yU9ih8</embedvideo>

==Notable studies==
* 2009, Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study<ref>{{Cite journal|last = Younger | first = Jarred | authorlink = Jarred Younger | last2 = Mackey | first2 = Sean | authorlink2 = | date = May 2009 | title = Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study|url=https://academic.oup.com/painmedicine/article-lookup/doi/10.1111/j.1526-4637.2009.00613.x|journal=Pain Medicine|language=en|volume=10|issue=4 | pages = 663–672|doi=10.1111/j.1526-4637.2009.00613.x|issn=1526-2375|pmc=2891387|pmid=19453963|access-date=|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891387/ (Full text)]
* 2013, Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels<ref name="Younger2013" /> - [https://onlinelibrary.wiley.com/doi/full/10.1002/art.37734 (Full text)]
* 2014, The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain<ref name="Younger2014" /> - [http://link.springer.com/article/10.1007%2Fs10067-014-2517-2 (Full text)]
*2018, Double-blinded placebo-controlled cross-over pilot trial of naltrexone to treat [[Gulf War Illness]]<ref name="Brewer, 2018" /> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2018.1477034 (Abstract)]

* 2018, Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization<ref>{{Cite journal | last = Toljan | first = Karlo | last2 = Vrooman | first2 = Bruce | date = 2018-09-21 | title = Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization | url = http://www.mdpi.com/2076-3271/6/4/82|journal=Medical Sciences|language=en|volume=6|issue=4 | pages = 82|doi=10.3390/medsci6040082|issn=2076-3271|pmc=6313374|pmid=30248938}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313374/#!po=19.1057 (Full text)]

* 2019, Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)<ref name="Polo2019">{{Cite journal | last = Polo|first = Olli | authorlink = Olli Polo | last2 = Pesonen | first2 = Pia | authorlink2 = | last3 = Tuominen | first3 = Essi | authorlink3 = | date = 2019-11-19 | title = Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2019.1692770|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=7|issue=4|pages=207-217|doi=10.1080/21641846.2019.1692770|issn=2164-1846|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.tandfonline.com/doi/abs/10.1080/21641846.2019.1692770?journalCode=rftg20 (Abstract)]
* 2020, Low-dose naltrexone as a treatment for chronic fatigue syndrome<ref>{{Cite journal|last = Bolton | first = Monica Jane | authorlink = | last2 = Chapman | first2 = Bryan Paul | authorlink2 = | last3 = Van Marwijk | first3 = Harm | authorlink3 = | date = Jan 2020 | title = Low-dose naltrexone as a treatment for chronic fatigue syndrome|url=http://casereports.bmj.com/lookup/doi/10.1136/bcr-2019-232502|journal=BMJ Case Reports|language=en|volume=13|issue=1| pages = e232502|doi=10.1136/bcr-2019-232502|issn=1757-790X|pmc=6954765|pmid=31911410|access-date=|quote=|via=}}</ref> - [https://casereports.bmj.com/content/bmjcr/13/1/e232502.full.pdf (Full text)]
*2021, Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment<ref name="Cabanas2021">{{Cite journal | title = Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment | date = 2021|url=https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806|journal=Frontiers in Immunology|volume=12|issue= | pages = 687806|last = Cabanas | first = Helene | authorlink = Hélène Cabanas | last2 = Muraki | first2 = Katsuhiko | authorlink2 = | last3 = Eaton-Fitch | first3 = Natalie | authorlink3 = Natalie Eaton-Fitch | last4 = Staines | first4 = Donald Ross | authorlink4 = Donald Staines | last5 = Marshall-Gradisnik | first5 = Sonya | authorlink5 = Sonya Marshall-Gradisnik|doi=10.3389/fimmu.2021.687806|pmc=PMC8313851|pmid=34326841|access-date=|issn=1664-3224|quote=|via=}}</ref> - [https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806/full (Full text)]

==See also==
*[[Endorphin]]
*[[Brain#Microglia|Microglia]]
*[[Oxymatrine]]
*[[The LDN Book]]

==Learn more==
*[https://ldnresearchtrust.org/sites/default/files/Doctors-info-pack-US.pdf Low-dose Naltrexone (LDN) Doctor's Fact Sheet 2014] - LDN Research Trust
*[https://www.ldnresearchtrust.org LDN Research Trust]<ref>{{Cite web|url=https://www.ldnresearchtrust.org/ | title = Low Dose Naltrexone {{!}}|website=LDN Research Trust|access-date=2019-02-02}}</ref>
*[https://www.ldnresearchtrust.org/content/low-dose-naltrexone-and-chronic-pain-pradeep-chopra-md Low Dose Naltrexone and chronic pain]<ref name="chronicpain" />
*[https://en.wikipedia.org/wiki/Naltrexone Wikipedia - Naltrexone]
*[http://www.ldnnow.com/ LDN Now]
*[https://www.ldnscience.org/ LDN Science - MedInsight Research Institute]
*2015, [https://www.ncbi.nlm.nih.gov/books/NBK390569/ The Use of Naltrexone in Low Doses Beyond the Approved Indication]<ref name="NBK390569">{{Citation | url = https://www.ncbi.nlm.nih.gov/books/NBK390569/ | title = The Use of Naltrexone in Low Doses Beyond the Approved Indication|last = Ringerike | first = Tove | last2 = Pike | first2 = Eva | last3 = Nevjar | first3 = Janicke | last4 = Klemp | first4 = Marianne|publisher=NIPH| year = 2015 |isbn=|location=}}</ref>
* [https://selfhacked.com/2016/06/20/top-22-scientific-health-benefits-low-dose-naltrexone/ Top 15 Scientific Health Benefits of Low Dose Naltrexone] (2016)
*[https://www.healthrising.org/treating-chronic-fatigue-syndrome/drugs/low-dose-naltrexone-ldn-fibromyalgia-chronic-fatigue-syndrom/ Low Dose Naltrexone Resource Center for Fibromylgia and ME/CFS] (2019)
*2016, [http://www.rheumatologyadvisor.com/fibromyalgia/using-low-dose-naltrexone-in-fibromyalgia/article/478182/ Low-Dose Naltrexone as Adjunctive Pharmacotherapy for Fibromyalgia]
*[[The LDN Book]] - Lisa Elsegood (2016)
*[http://www.cortjohnson.org/blog/2016/02/04/low-dose-naltrexone-combo-chronic-fatigue/ 2016, Low Dose Naltrexone Drug Combination Proposed for Chronic Fatigue Syndrome] - Health Rising, by [[Cort Johnson]] (2016)
*[https://cfsremission.wordpress.com/2016/03/19/review-of-low-dose-naltrexone/ Low dose naltrexone: side effects and efficacy in gastrointestinal disorders] by [[CFS Remission]] (2016)
*Opioid blocking and alcohol - [http://www.well.com/user/woa/revia/reviafaq.htm FAQ About Naltrexone Treatment for Alcoholism - 10.]
*[https://www.cfspharmacy.pharmacy/blog/post/low-dose-naltrexone-for-fibromyalgia Low Dose Naltrexone for Fibromyalgia] (2018)
* [https://www.cfspharmacy.pharmacy/blog/post/low-dose-naltrexone-therapy-for-crohn-s-disease Low Dose Naltrexone Therapy for Crohn's Disease] (2018)
* [https://www.facebook.com/groups/200010163370187 LDN LOW DOSE NALTREXONE FOR ME/CFS MYALGIC ENCEPHALOMYELITIS & FIBROMYALGIA]

==References==
<references>
<ref name="Brewer, 2018">{{Cite journal | last1 = Brewer | first1 = Kori L. | authorlink1 = | last2 = Mainhart | first2 = Allison | authorlink2 = | last3 = Meggs | first3 = William J. | authorlink3 = | title = Double-blinded placebo-controlled cross-over pilot trial of naltrexone to treat Gulf War Illness | journal = Fatigue: Biomedicine, Health & Behavior | volume = 6 | issue = 3 | pages = 132-140 | date = 2018 | pmid = | url = https://ldnresearchtrust.org/double-blinded-placebo-controlled-cross-over-pilot-trial-naltrexone-treat-gulf-war-illness-abstract | doi = 10.1080/21641846.2018.1477034}}</ref>
<ref name="Younger2009">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Mackey | first2 = Sean | authorlink2 = Sean Mackey | title = Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study | journal = Pain Med | volume = 10 | issue = 4 | pages = 663–672 | date = Apr 22, 2009 | pmid = 2891387 | doi = 10.1111/j.1526-4637.2009.00613.x | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891387/ }}</ref>
<ref name="Younger2013">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Noor | first2 = Noorulain | authorlink2 = Noorulain Noor | last3 = McCue | first3 = Rebecca| authorlink3 = Rebecca McCue | last4 = Mackey | first4 = Sean | authorlink4 = Sean Mackey | title = Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels | journal = Arthritis Rheum | volume = 65 | issue = 2 | pages = 529-38 | date = Jan 28, 2013 | pmid = 23359310 | doi = 10.1002/art.37734 | url = http://onlinelibrary.wiley.com/enhanced/doi/10.1002/art.37734/}}</ref>
<ref name="Mackey2009">{{Cite web | last1 = Mackey | first1 = Sean | authorlink1 = Sean Mackey | title = An Update on Fibromyalgia
| publisher = Research Channel (USA) | date = May 1, 2009 | url = https://www.youtube.com/watch?v=jtc2JARVpPw}}</ref>
<ref name="Younger2014">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Parkitny | first2 = Luke | authorlink2 = Luke Parkitny | last3 = McLain | first3 = David | authorlink3 = David McLain | title = The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain | journal = Clin Rheumatol | volume = 33 | issue = 4 | pages = 451-459 | date = Feb 15, 2014 | pmid = 24526250 | doi = 10.1007/s10067-014-2517-2 | url = http://link.springer.com/article/10.1007%2Fs10067-014-2517-2}}</ref>
<ref name="Younger20160329sh">{{Cite web | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Cohen | first2 = Joseph M | authorlink2 = Joseph Cohen | title = Dr. Jarred Younger: Cutting Edge Research on CFS, Neuroinflammation, Pain, and Fatigue
| type = video interview with transcript
| publisher = Self Hacked Blog | date = Mar 29, 2016 | url = http://selfhacked.com/2016/03/29/dr-jared-younger-cutting-edge-research-on-cfs-neuroinflammation-pain-and-fatigue/#Leptin_and_Chronic_Fatigue_Syndrome}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Anti-inflammatories]]
[[Category:Analgesics]]

Low dose naltrexone

2024-06-07T10:21:13Z

Yannlk:

'''Low Dose Naltrexone''' (LDN) refers to very small doses of the drug '''naltrexone hydrochloride''', which at higher doses treats drug or [[alcohol]] dependence. Low dose naltrexone may reduce [[pain]], or potentially [[Nervous system|neurological]] symptoms. Brand names of naltrexone include '''ReViva''', '''Depade''', and '''Vivitrol'''.<ref name="brands">{{Cite web|url=https://www.drugs.com/ingredient/naltrexone.html | title = Naltrexone - brand name list from Drugs.com|website=Drugs.com|language=en|access-date=2022-01-17}}</ref>
LDN use other for treating drug dependence is considered off-label. Some patients report that LDN helps reduce their symptoms of [[ME/CFS]], [[multiple sclerosis]] (MS), [[fibromyalgia]] (FMS), or [[autoimmune disease]]. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory.<ref name="Younger2014" />

==Prescription forms ==
LDN is typically prescribed using generic naltrexone hydrochloride or branded naltrexone, divided into much smaller doses. LDN may be taken in the form of liquid solution/syrup, sublingual doses or 1.5mg capsules, or a compounding pharmacy can create smaller sized capsules or tablets. LDN in the form of naltrexone cream, subcutaneous injections, IV naltrexone and eye drops (for [[Sjögren's syndrome|dry eyes]]) are also available.<ref name="forms">{{Cite web|url=https://ldnresearchtrust.org/types-of-ldn | title = Types of LDN | last = | first = | authorlink = | date = | website = LDN Research Trust |language=en|archive-url=|archive-date=|url-status=|access-date=2022-01-17}}</ref>

== VLDN and ULDN ==
'''Very Low Dose Naltrexone''' (VLDN) and '''Ultra-Low Dose Naltrexone''' (ULDN) have recently been used in limited trials, both VLDN and ULDN involve doses of naltrexone significantly below 1mg.<ref>{{Cite journal | last = Toljan | first = Karlo | author-link =Karlo Toljan | last2 = Vrooman | first2 = Bruce | authorlink2 = Bruce Vrooman | date = Sep 21, 2018 | title = Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313374/|journal=Medical Sciences|volume=6|issue=4|pages=|doi=10.3390/medsci6040082|issn=2076-3271|pmc=|pmid=30248938|quote=|via=}}</ref>

Very Low Dose Naltrexone is increasingly being used under 1mg for people who cannot titrate from 0.5mg to find their individual optimal dose.

'''Dr. John Kim has great experience with LDN and shares his latest results in combining ULDN (Ultra-Low Dose Naltrexone) with acupuncture and Vitamin C. shares his latest results in combining ULDN (Ultra-Low Dose Naltrexone)''' [https://www.youtube.com/watch?v=npYPfLs4-kM&fbclid=IwAR2EJwyKp-Pyxqg9vjsW0QWV1e4pfwQ6aYus6MMRseih1nIGl64NrudJsro Dr. John Kim has great experience with LDN and shares his latest results in combining ULDN (Ultra-Low Dose Naltrexone) with acupuncture and Vitamin C.]

'''An Archived LDN Presentation- ULDN, Micro Dosing with Dr John Kim'''

[https://the-ldn-radio-show.captivate.fm/episode/an-ldn-prescribers-experience-uldn-micro-dosing-with-dr-john-kim?fbclid=IwAR09ptgFzkxG17UfZ0R0kBtGx98iYWq3hv8HTO5MWeN8ZtQc_zA1X-O_g0c https://the-ldn-radio-show.captivate.fm/.../an-ldn...]

'''Dr John Kim on The LDN Trust site''' [https://ldnresearchtrust.org/search/exclude?keys=John%20kim&page=1&fbclid=IwAR1H3xMKog5OAONnAl9kb0ufdKSZXGJrenYVNPaA84MQiOa_jUxysRE62m0 https://ldnresearchtrust.org/search/exclude?keys=John%20kim&page=1]

Patients who wish to cease opioids use and transition onto LDN can first use ULDN using facebook group and explainer document below.

'''[https://www.facebook.com/groups/1593950197487522/permalink/1594322687450273 Using Ultra Low Dose Naltrexone to reduce opiate use and transition to LDN].''' - Using Ultra Low Dose Naltrexone to transition to Low Dose Naltrexone by Michael D Robinson. Link to https://www.scribd.com/document/195139174/ULDN-Inverse-Titration-Protocol-FINAL?fbclid=IwAR3qG2YSjrl6WB2dpiNi4fKw96Loj8yC8x79TVp5tGX3_PR2itFyrNWjbiY

==Evidence==
[[File:LDN-Fibro2014.jpg|alt=Data shows a graph with 10% worse after treatment, 57% improved or much improved, and 12% very much improved. Darker colors are the most improved sections.|thumb|350x350px|Low Dose Naltrexone results for 29 patients with [[Fibromyalgia]]. Fibromyalgia participants’ (N = 29) self-reported improvement in symptoms after daily LDN treatment.
Source: Clin Rheumatol 2014; 33(4):452-459. Fig 1.<ref name="Younger2014" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/figure/Fig1/ PMC3962576] ]]

[[Jarred Younger]] published a small study that concluded "...low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia".<ref name="Younger2009" /><ref name="Mackey2009" />

A second study concluded that "specific and clinically beneficial impact on fibromyalgia pain".<ref name="Younger2013" /><ref>{{Cite web|url=https://med.stanford.edu/pain/snapl/completed-research/naltrexone2.html | title = Low Dose Naltrexone for Fibromyalgia|website=Systems Neuroscience and Pain Lab {{!}} Stanford Medicine|language=en|access-date=2018-10-04 | date = |last = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>

A 2014 review by Stanford researchers suggests that "LDN may operate as a novel anti-inflammatory agent in the [[central nervous system]], via action on [[microglia]]l cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on [[opioid]] receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated."<ref name="Younger2014" />
[[File:LDN-Fibro-ESR.jpg|thumb|420x420px|Relationship between ESR, a marker inflammation, and LDN treatment in 29 patients with [[Fibromyalgia]]. ]]
The [[FDA]] approved naltrexone HCL in 1984 to treat opioid addiction. Low-dose naltrexone is typically given at about 1/10th the typical dose of naltrexone. By blocking opioid receptors, naltrexone can increase pain, but at very low doses naltrexone has both pain-reducing ([[analgesic]]) and anti-inflammatory properties.

In 2012 [[Solve ME/CFS Initiative]] contracted [[Biovista]] to use drug models to identify existing drugs that may be worth investigating for treatment. The results suggested Naltrexone was worth considering.<ref>{{Cite web|url=http://solvecfs.org/biovista-work-released | title = Biovista work released|last = Solve ME/CFS Initiative | first = | authorlink = Solve ME/CFS Initiative | date = |website=|archive-url=|archive-date=|access-date=|url-status=live}}</ref>

Jarred Younger's research suggests that people with an [[Erythrocyte sedimentation rate|Erythrocyte Sedimentation Rate]] (ESR) over 40 millimeters an hour, tend to be strong responders to LDN, and that there may be other predictive factors for success.<ref name="Younger20160329sh" />

==News articles==
* 2019, [https://www.npr.org/sections/health-shots/2019/09/23/741783834/in-tiny-doses-an-addiction-medication-moonlights-as-a-treatment-for-chronic-pain In Tiny Doses, An Addiction Medication Moonlights As A Treatment For Chronic Pain] - NPR, All Things Considered
* September 9, 2021<nowiki/>https://www.empr.com/home/news/drugs-in-the-pipeline/low-dose-naltrexone-designated-orphan-drug-for-complex-regional-pain-syndrome/

==Clinical use==

Naltrexone is a prescription drug in many countries including the [[United States]].<ref name="naltrexonecompliance">{{Cite journal | last = Feeney|first = G. F. X. | last2 = Connor | first2 = J.P. | last3 = Young | first3 = R. McD | last4 = Tucker | first4 = J. | last5 = Czajkowski | first5 = F. | date = 2001 | title = Adherence with naltrexone prescription advice in hospital outpatient alcohol rehabilitation programme|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2710.2001.00326.x|journal=Journal of Clinical Pharmacy and Therapeutics|language=en|volume=26|issue=1 | pages = 73–79|doi=10.1111/j.1365-2710.2001.00326.x|issn=1365-2710}}</ref>Compounding chemists or compounding pharmacists can mix naltrexone with a powder filler or dilute in into a liquid to create the lower dose.

=== Fast-release fillers only ===
The LDN Research Trust advises that:
"Pharmacies should be instructed NOT to provide LDN in an "SR" or slow-release or timed-release form. Unless the low dose of naltrexone is in an unaltered form, which permits it to reach a prompt "spike" in the blood stream, its therapeutic effects may be inhibited."<ref name="leaflet2014" /> and states that calcium carbonate filler should NOT be used because they reduce absorption, instead Avicel, lactose, or sucrose fillers as alternative fast-release fillers."<ref name="leaflet2014">{{Cite web|url=https://ldnresearchtrust.org/sites/default/files/Doctors-info-pack-US.pdf | title=Low-dose Naltrexone (LDN) Fact Sheet 2014 | website = LDN Research Trust | date = 2014}}</ref>

===Do not take with===
In general, Low Dose Naltrexone (LDN) should not be taken concurrently with opioid-containing drugs (opioid receptors in brain are blocked by LDN), alcohol, immunosuppressive drugs, or immunomodulator drugs.{{citation needed | date = 2021}} LDN blocks the effect of opioid drugs.<ref name="chronicpain">{{Cite web|url=https://www.ldnresearchtrust.org/content/low-dose-naltrexone-and-chronic-pain-pradeep-chopra-md | title = Low Dose Naltrexone and chronic pain | first = Pradeep |last =Chopra|website=LDN Research Trust|access-date=2019-01-31}}</ref> Some opioid drugs are [[codeine]], [[tramadol]], [[oxycodone]], [[vicodin]], [[hydrocodone]], [[fentanyl]] and [[morphine]].
==Pharmacies ==

=== Australia ===
''Compounding Pharmacies'' are able to fill these prescriptions, and post if needed.

=== UK ===
LDN suppliers in the UK include '''Dickson Chemist''' in Glasgow, Roseway Labs, and Specialist Pharmacy (The London Specialist Pharmacy Ltd). All these are compounding pharmacies and require a perscription, they are usually able to put patients in contact with private doctors who will consider writing a prescription, and can post medications to you.<ref name="RosewayLabs">{{Cite web |url = https://rosewaylabs.com/compounding-processes-regulations | title = Compounding processes regulations/|website =Roseway Labs}}</ref> Compounding pharmacies are regulated by the UK's General Pharmaceutical Council.<ref name="RosewayLabs" />

===United States===
Neighborhood ''Compounding Pharmacies'' are able to fill these prescriptions and mail if needed. Your prescribing doctor can help you locate a compounding pharmacy in your area/state or you can look online.<ref>[http://www.wikihow.com/Find-a-Compounding-Pharmacy Finding a Compounding Pharmacy - WIKI How]</ref>

===Other countries ===
The LDN Research Trust lists pharmacies in multiple countries.<ref name="sources">{{Cite web |url = https://ldnresearchtrust.org/ldn-pharmacists|website=LDN Research Trust|title =LDN Pharmacists |access-date =}}</ref>

== Clinical trials ==
A large number of clinical trials have been completed for LDN recently, although none have looked at the effect of LDN on symptoms of [[myalgic encephalomyelitis]]/[[chronic fatigue syndrome]]. Research has been carried out on patients with MS, [[Chronic Regional Pain Syndrome]], FMS, [[Irritable bowel syndrome|Irritable Bowel Syndrome]] (IBS), Ulcerative Colitis, Skin Disorders and a range of other illnesses.<ref name="trials">{{Cite web|url=https://www.ldnresearchtrust.org/ldn-clinical-trials | title = Clinical Trials|website=LDN Research Trust|access-date=2019-01-21}}</ref>

==When, How To Take ==
Dr Whitaker states that the ideal dose is different for each person. Some doctors recommend starting at 1mg.<ref name="LDN-now">{{Cite web|url=http://www.ldnnow.com/48591/90512.html | title = LDN Dosing|last = LDN Now|first = | authorlink = | date = | website = |access-date=2018-02-01}}</ref> Common dosages are 1.5mg, 3mg, 4.5mg.<ref>{{Cite web|url=https://www.amymyersmd.com/2017/05/low-dose-naltrexone/ | title = Low-Dose Naltrexone for Autoimmunity? | last = Myers | date = 2017-05-02 | website = Amy Myers MD|language=en-US|access-date=2019-02-02|first = Amy | authorlink = |archive-url=|archive-date=|url-status=}}</ref><ref name=":1">{{Cite web|url=https://www.drwhitaker.com/what-is-low-dose-naltrexone | title = What is Low-Dose Naltrexone?|last = Dr Whitaker | first = | authorlink = | date = | website = drwhitaker.com|language=en|archive-url=|archive-date=|access-date=2019-01-21}}</ref><ref name="chronicpain" /> When beginning use of LDN, the drug must be stepped up over 6-8+ weeks as it may keep you awake; discuss how best to do this with your doctor and pharmacist.<ref name=":1" /><ref>{{Cite web|url=https://collierdrug.com/low-dose-naltrexone-ldn/ | title = Low Dose Naltrexone (LDN) – Collier Drug Store|last = | first = | authorlink = | date = | website = collierdrug.com|at=What dose of Low Dose Naltrexone (LDN) is best?|archive-url=|archive-date=|access-date=2019-02-02}}</ref><ref name="chronicpain" />

LDN is usually taken at bedtime. Some people take LDN in the morning to minimize [[Sleep dysfunction|sleep disturbance]], [[insomnia]], and vivid dreams.<ref name="chronicpain" />

== Talks and webinars==
*2012, [https://www.youtube.com/watch?v=z0p0ykSzy9o LDNscience® Presents - How LDN (Low Dose Naltrexone) Works]<ref>{{Cite web|url=https://www.youtube.com/watch?v=z0p0ykSzy9o | title = LDNscience® Presents - How LDN (Low Dose Naltrexone) Works|last = | first = | authorlink = | date = Dec 20, 2012 | website = YouTube|publisher=LDNscience|archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''LDNscience® Presents - How LDN (Low Dose Naltrexone) Works'' By LDNscience">https://www.youtube.com/watch?v=z0p0ykSzy9o</embedvideo>

*2015, [https://www.youtube.com/watch?v=8a-ULCaarCQ Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez]<ref>{{Cite web|url=https://www.youtube.com/watch?v=8a-ULCaarCQ | title = Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez|last = Carnahan | first = Jill | authorlink= | last2 = Vasquez | first2 = Alex | authorlink2 = | date = Nov 30, 2015 | website = YouTube|publisher=Alex Vasquez|archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''Functional Medicine & LDN (low-dose naltrexone) with Drs Carnahan and Vasquez '' By Alex Vasquez">https://www.youtube.com/watch?v=8a-ULCaarCQ</embedvideo>

*2015, [https://www.youtube.com/watch?v=Qnr51yU9ih8 Is Low Dose Naltrexone (LDN) for you?]<ref>{{Cite web|url=https://www.youtube.com/watch?v=Qnr51yU9ih8 | title = 1:05 / 7:05 Is Low Dose Naltrexone (LDN) for you?|last = | first = | authorlink = | date = Oct 11, 2015 | website = YouTube | archive-url=|archive-date=|access-date=}}</ref>
<embedvideo service="youtube" dimensions="400" alignment="center" container="frame" description="''Is Low Dose Naltrexone (LDN) for you?'' By Integrative Health Solutions">https://www.youtube.com/watch?v=Qnr51yU9ih8</embedvideo>

==Notable studies==
* 2009, Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study<ref>{{Cite journal|last = Younger | first = Jarred | authorlink = Jarred Younger | last2 = Mackey | first2 = Sean | authorlink2 = | date = May 2009 | title = Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study|url=https://academic.oup.com/painmedicine/article-lookup/doi/10.1111/j.1526-4637.2009.00613.x|journal=Pain Medicine|language=en|volume=10|issue=4 | pages = 663–672|doi=10.1111/j.1526-4637.2009.00613.x|issn=1526-2375|pmc=2891387|pmid=19453963|access-date=|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891387/ (Full text)]
* 2013, Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels<ref name="Younger2013" /> - [https://onlinelibrary.wiley.com/doi/full/10.1002/art.37734 (Full text)]
* 2014, The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain<ref name="Younger2014" /> - [http://link.springer.com/article/10.1007%2Fs10067-014-2517-2 (Full text)]
*2018, Double-blinded placebo-controlled cross-over pilot trial of naltrexone to treat [[Gulf War Illness]]<ref name="Brewer, 2018" /> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2018.1477034 (Abstract)]

* 2018, Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization<ref>{{Cite journal | last = Toljan | first = Karlo | last2 = Vrooman | first2 = Bruce | date = 2018-09-21 | title = Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization | url = http://www.mdpi.com/2076-3271/6/4/82|journal=Medical Sciences|language=en|volume=6|issue=4 | pages = 82|doi=10.3390/medsci6040082|issn=2076-3271|pmc=6313374|pmid=30248938}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313374/#!po=19.1057 (Full text)]

* 2019, Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)<ref name="Polo2019">{{Cite journal | last = Polo|first = Olli | authorlink = Olli Polo | last2 = Pesonen | first2 = Pia | authorlink2 = | last3 = Tuominen | first3 = Essi | authorlink3 = | date = 2019-11-19 | title = Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2019.1692770|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=7|issue=4|pages=207-217|doi=10.1080/21641846.2019.1692770|issn=2164-1846|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.tandfonline.com/doi/abs/10.1080/21641846.2019.1692770?journalCode=rftg20 (Abstract)]
* 2020, Low-dose naltrexone as a treatment for chronic fatigue syndrome<ref>{{Cite journal|last = Bolton | first = Monica Jane | authorlink = | last2 = Chapman | first2 = Bryan Paul | authorlink2 = | last3 = Van Marwijk | first3 = Harm | authorlink3 = | date = Jan 2020 | title = Low-dose naltrexone as a treatment for chronic fatigue syndrome|url=http://casereports.bmj.com/lookup/doi/10.1136/bcr-2019-232502|journal=BMJ Case Reports|language=en|volume=13|issue=1| pages = e232502|doi=10.1136/bcr-2019-232502|issn=1757-790X|pmc=6954765|pmid=31911410|access-date=|quote=|via=}}</ref> - [https://casereports.bmj.com/content/bmjcr/13/1/e232502.full.pdf (Full text)]
*2021, Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment<ref name="Cabanas2021">{{Cite journal | title = Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment | date = 2021|url=https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806|journal=Frontiers in Immunology|volume=12|issue= | pages = 687806|last = Cabanas | first = Helene | authorlink = Hélène Cabanas | last2 = Muraki | first2 = Katsuhiko | authorlink2 = | last3 = Eaton-Fitch | first3 = Natalie | authorlink3 = Natalie Eaton-Fitch | last4 = Staines | first4 = Donald Ross | authorlink4 = Donald Staines | last5 = Marshall-Gradisnik | first5 = Sonya | authorlink5 = Sonya Marshall-Gradisnik|doi=10.3389/fimmu.2021.687806|pmc=PMC8313851|pmid=34326841|access-date=|issn=1664-3224|quote=|via=}}</ref> - [https://www.frontiersin.org/articles/10.3389/fimmu.2021.687806/full (Full text)]

==See also==
*[[Endorphin]]
*[[Brain#Microglia|Microglia]]
*[[Oxymatrine]]
*[[The LDN Book]]

==Learn more==
*[https://ldnresearchtrust.org/sites/default/files/Doctors-info-pack-US.pdf Low-dose Naltrexone (LDN) Doctor's Fact Sheet 2014] - LDN Research Trust
*[https://www.ldnresearchtrust.org LDN Research Trust]<ref>{{Cite web|url=https://www.ldnresearchtrust.org/ | title = Low Dose Naltrexone {{!}}|website=LDN Research Trust|access-date=2019-02-02}}</ref>
*[https://www.ldnresearchtrust.org/content/low-dose-naltrexone-and-chronic-pain-pradeep-chopra-md Low Dose Naltrexone and chronic pain]<ref name="chronicpain" />
*[https://en.wikipedia.org/wiki/Naltrexone Wikipedia - Naltrexone]
*[http://www.ldnnow.com/ LDN Now]
*[https://www.ldnscience.org/ LDN Science - MedInsight Research Institute]
*2015, [https://www.ncbi.nlm.nih.gov/books/NBK390569/ The Use of Naltrexone in Low Doses Beyond the Approved Indication]<ref name="NBK390569">{{Citation | url = https://www.ncbi.nlm.nih.gov/books/NBK390569/ | title = The Use of Naltrexone in Low Doses Beyond the Approved Indication|last = Ringerike | first = Tove | last2 = Pike | first2 = Eva | last3 = Nevjar | first3 = Janicke | last4 = Klemp | first4 = Marianne|publisher=NIPH| year = 2015 |isbn=|location=}}</ref>
* [https://selfhacked.com/2016/06/20/top-22-scientific-health-benefits-low-dose-naltrexone/ Top 15 Scientific Health Benefits of Low Dose Naltrexone] (2016)
*[https://www.healthrising.org/treating-chronic-fatigue-syndrome/drugs/low-dose-naltrexone-ldn-fibromyalgia-chronic-fatigue-syndrom/ Low Dose Naltrexone Resource Center for Fibromylgia and ME/CFS] (2019)
*2016, [http://www.rheumatologyadvisor.com/fibromyalgia/using-low-dose-naltrexone-in-fibromyalgia/article/478182/ Low-Dose Naltrexone as Adjunctive Pharmacotherapy for Fibromyalgia]
*[[The LDN Book]] - Lisa Elsegood (2016)
*[http://www.cortjohnson.org/blog/2016/02/04/low-dose-naltrexone-combo-chronic-fatigue/ 2016, Low Dose Naltrexone Drug Combination Proposed for Chronic Fatigue Syndrome] - Health Rising, by [[Cort Johnson]] (2016)
*[https://cfsremission.wordpress.com/2016/03/19/review-of-low-dose-naltrexone/ Low dose naltrexone: side effects and efficacy in gastrointestinal disorders] by [[CFS Remission]] (2016)
*Opioid blocking and alcohol - [http://www.well.com/user/woa/revia/reviafaq.htm FAQ About Naltrexone Treatment for Alcoholism - 10.]
*[https://www.cfspharmacy.pharmacy/blog/post/low-dose-naltrexone-for-fibromyalgia Low Dose Naltrexone for Fibromyalgia] (2018)
* [https://www.cfspharmacy.pharmacy/blog/post/low-dose-naltrexone-therapy-for-crohn-s-disease Low Dose Naltrexone Therapy for Crohn's Disease] (2018)
* [https://www.facebook.com/groups/200010163370187 LDN LOW DOSE NALTREXONE FOR ME/CFS MYALGIC ENCEPHALOMYELITIS & FIBROMYALGIA]

==References==
<references>
<ref name="Brewer, 2018">{{Cite journal | last1 = Brewer | first1 = Kori L. | authorlink1 = | last2 = Mainhart | first2 = Allison | authorlink2 = | last3 = Meggs | first3 = William J. | authorlink3 = | title = Double-blinded placebo-controlled cross-over pilot trial of naltrexone to treat Gulf War Illness | journal = Fatigue: Biomedicine, Health & Behavior | volume = 6 | issue = 3 | pages = 132-140 | date = 2018 | pmid = | url = https://ldnresearchtrust.org/double-blinded-placebo-controlled-cross-over-pilot-trial-naltrexone-treat-gulf-war-illness-abstract | doi = 10.1080/21641846.2018.1477034}}</ref>
<ref name="Younger2009">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Mackey | first2 = Sean | authorlink2 = Sean Mackey | title = Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study | journal = Pain Med | volume = 10 | issue = 4 | pages = 663–672 | date = Apr 22, 2009 | pmid = 2891387 | doi = 10.1111/j.1526-4637.2009.00613.x | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891387/ }}</ref>
<ref name="Younger2013">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Noor | first2 = Noorulain | authorlink2 = Noorulain Noor | last3 = McCue | first3 = Rebecca| authorlink3 = Rebecca McCue | last4 = Mackey | first4 = Sean | authorlink4 = Sean Mackey | title = Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels | journal = Arthritis Rheum | volume = 65 | issue = 2 | pages = 529-38 | date = Jan 28, 2013 | pmid = 23359310 | doi = 10.1002/art.37734 | url = http://onlinelibrary.wiley.com/enhanced/doi/10.1002/art.37734/}}</ref>
<ref name="Mackey2009">{{Cite web | last1 = Mackey | first1 = Sean | authorlink1 = Sean Mackey | title = An Update on Fibromyalgia
| publisher = Research Channel (USA) | date = May 1, 2009 | url = https://www.youtube.com/watch?v=jtc2JARVpPw}}</ref>
<ref name="Younger2014">{{Cite journal | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Parkitny | first2 = Luke | authorlink2 = Luke Parkitny | last3 = McLain | first3 = David | authorlink3 = David McLain | title = The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain | journal = Clin Rheumatol | volume = 33 | issue = 4 | pages = 451-459 | date = Feb 15, 2014 | pmid = 24526250 | doi = 10.1007/s10067-014-2517-2 | url = http://link.springer.com/article/10.1007%2Fs10067-014-2517-2}}</ref>
<ref name="Younger20160329sh">{{Cite web | last1 = Younger | first1 = Jarred | authorlink1 = Jarred Younger | last2 = Cohen | first2 = Joseph M | authorlink2 = Joseph Cohen | title = Dr. Jarred Younger: Cutting Edge Research on CFS, Neuroinflammation, Pain, and Fatigue
| type = video interview with transcript
| publisher = Self Hacked Blog | date = Mar 29, 2016 | url = http://selfhacked.com/2016/03/29/dr-jared-younger-cutting-edge-research-on-cfs-neuroinflammation-pain-and-fatigue/#Leptin_and_Chronic_Fatigue_Syndrome}}</ref>
</references>

[[Category:Potential treatments]]
[[Category:Anti-inflammatories]]
[[Category:Analgesics]]

Draft:Primer for Journalists

2024-06-06T11:04:38Z

Yannlk:

''Note: This page is currently being discussed [https://www.s4me.info/threads/the-mepedia-primer-for-journalists.38819/ here].''

'''Myalgic encephalomyelitis (ME)''', sometimes referred to as '''chronic fatigue syndrome (CFS)''' is a serious and long-term illness. The hallmark symptom is '''post-exertional malaise (PEM)''' marked worsening of the illness after exertion. People with ME/CFS experience debilitating fatigue, non-refreshing sleep, and problems with memory or concentration. Other common symptoms include pain, gut issues, sensitivity to light and sound, and orthostatic intolerance.

{{Table of contents}}

'''Not chronic fatigue'''

ME/CFS is not the same as chronic fatigue and it is important not to confuse both conditions. ME/CFS patients are severely ill not, fatigued. Most people with chronic fatigue do not meet ME/CFS diagnostic criteria and for many ME/CFS patients, fatigue is not their most debilitating symptom. It is therefore inaccurate to shorten ME/CFS to ‘chronic fatigue’ in the body of an article or its headline.

'''Representative images'''

The quality of life of persons with ME/CFS is severely reduced. The National Academy of Medicine estimates that at least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives. Functional impairment of ME/CFS can be greater than in disabling conditions such as multiple sclerosis, end-stage renal disease or congestive heart failure.

Most patients with ME/CFS can no longer work or study and are forced to reduce their social activities. It is therefore inappropriate to use stock images of models in business clothing who are yawning or looking fatigued. This is not a good representation of ME/CFS.

The German association ‘Deutsche Gesellschaft für ME/CFS’ has provided 32 professional photos for press use that adequately depict the reality of people living with ME/CFS.

<nowiki>https://www.mecfs.de/stockphotos/</nowiki>

'''Disease burden and low funding'''

ME/CFS affects approximately 0.4% of the population or 1 in 250 people.

Economic costs due to ME/CFS are high. In the United States, estimates range from $36 to $51 billion per year, considering both lost wages and healthcare costs. In Europe, the illness affects approximately 2 European citizens and the annual burden of ME/CFS is estimated to be 40 billion euros annually.

Despite its high disease burden, research on ME/CFS remains underfunded. One analysis of NIH funding found that ME/CFS research only receives 7% of the amount commensurate with its disease burden. A study contracted by the European Commission also identified ME/CFS as a high-burden, under-researched medical condition.

'''Cause and pathology'''

The cause and pathology of ME/CFS remain largely unknown. The illness is much more common in women than in men: approximately 75% of patients are female.

Infections are also considered a risk factor. Longitudinal studies have shown that infectious diseases such as mononucleosis increase the chances of developing ME/CFS. Increased incidence has also been reported following Q-fever, Ross River Virus, giardiasis, and several other infections. Sars-Cov-2 leads to a higher risk of ME/CFS and a substantial proportion of patients with Long Covid meet ME/CFS diagnostic criteria.

ME/CFS is suspected to have a genetic component. The DecodeME project in the UK has collected samples of more than 20,000 ME/CFS patients to perform a genome-wide analysis.

Researchers have reported abnormalities in the immune system, metabolism, cardiovascular system, brain signalling, endothelial function, and other bodily functions of ME/CFS patients. However, most of these findings are not specific to ME/CFS (they are also found in other conditions) or have not been replicated by multiple research groups.

'''Not a mental disorder'''

Because there is no biomarker or diagnostic test, ME/CFS was incorrectly believed to be a mental disorder, an illness without disease, or a collection of symptoms that are ‘all in the mind’. This view is in contrast with scientific evidence and expert opinion. The Centers for Disease Control and Prevention (CDC), for example, states: ''"ME/CFS is a biological illness, not a psychologic disorder.”''

The World Health Organization classifies ME and CFS as Diseases of the Nervous System, using code 8E49 Postviral fatigue syndrome in the International Classiciation of Diseases.

'''Treatment'''

There are no Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved treatments for ME/CFS. Physicians aim to reduce the impact of ME/CFS by managing or treating individual symptoms. The European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) and the US Clinician's Coaltion have issued guidelines and advice on symptom management.

In the past, graded exercise therapy (GET) was a popular treatment for ME/CFS. This was based on the idea that ME/CFS is perpetuated by deconditioning and avoidance of activity. In randomized trials, however, GET failed to increase employment rates and fitness levels of ME/CFS patients. Multiple reviews have evaluated the evidence supporting GET as low quality. In surveys, ME/CFS patients reported a worsening of their health following GET. The National Institutes of Health and Care Excellence (NICE) therefore actively recommends against GET and other exercise programs for ME/CFS.

Cognitive behavioral therapy (CBT) may be offered to people with a new ME/CFS diagnosis to help them cope with the disease. CBT that assumes patients have 'abnormal' illness beliefs and behaviors as an underlying cause of their ME/CFS is no longer recommended by NICE.

Surveys indicate that ME/CFS patients often find pacing useful. Pacing is a self-management strategy where activities are dosed so that patients can remain as active as possible without causing postexertional malaise.

'''Psychosomatic theories and stigma'''

Because blood tests often return normal and most patients are women, ME/CFS has historically been minimalized. The illness has inappropriately been called ‘yuppie flu’ and was once dismissed as hysteria. Patients have reported harm from psychosomatic theories that assume ME/CFS to be caused by abnormal illness beliefs and excessive resting behavior. This has been considered a barrier to appropriate patient care.

'''12 May: World ME Day'''

ME/CFS organizations have advocated against stigma and for more recognition of the illness in research and the healthcare system. On 12 May, World ME/CFS Day, various awareness events are organized worldwide to highlight the millions of ME/CFS patients who have disappeared from public life because of their illness. These are often called ‘Millions Missing’ events, a campaign coordinated by the US-based ME Action Network.

'''Reports and guidelines'''

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - PubMed (nih.gov)

Overview | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management | Guidance | NICE

ME/CFS: The current state of knowledge | IQWiG.de

ME/CFS Basics | ME/CFS | CDC

'''Patient organizations'''

Home - World ME Alliance

Home - #MEAction Network

The ME Association - The ME Association

Start — Deutsche Gesellschaft für ME/CFS (mecfs.de)

European ME Alliance - Home Page - A Voice for People with ME in Europe

'''ME/CFS experts'''

Luis Nacul

Carmen Scheibenbogen

Lucinda Bateman

Nancy Klimas

Anthony Komaroff

Chris Ponting

Karl Tronstad

'''Examples of excellent reporting'''

‘You don’t want to get better’: the outdated treatment of ME/CFS patients is a national scandal | George Monbiot | The Guardian

Fatigue Is So Much More Than Being Tired - The Atlantic

When the doctor doesn’t listen - Coda Story

Draft:Primer for Journalists

2024-06-06T10:58:24Z

Yannlk:

''Note: This page is currently being discussed [https://www.s4me.info/threads/the-mepedia-primer-for-journalists.38819/ here].''

'''Myalgic encephalomyelitis (ME)''', sometimes referred to as '''chronic fatigue syndrome (CFS)''' is a serious and long-term illness. The hallmark symptom is '''post-exertional malaise (PEM)''' marked worsening of the illness after exertion. People with ME/CFS experience debilitating fatigue, non-refreshing sleep, and problems with memory or concentration. Other common symptoms include pain, gut issues, sensitivity to light and sound, and orthostatic intolerance.

'''Not chronic fatigue'''

ME/CFS is not the same as chronic fatigue and it is important not to confuse both conditions. ME/CFS patients are severely ill not, fatigued. Most people with chronic fatigue do not meet ME/CFS diagnostic criteria and for many ME/CFS patients, fatigue is not their most debilitating symptom. It is therefore inaccurate to shorten ME/CFS to ‘chronic fatigue’ in the body of an article or its headline.

'''Representative images'''

The quality of life of persons with ME/CFS is severely reduced. The National Academy of Medicine estimates that at least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives. Functional impairment of ME/CFS can be greater than in disabling conditions such as multiple sclerosis, end-stage renal disease or congestive heart failure.

Most patients with ME/CFS can no longer work or study and are forced to reduce their social activities. It is therefore inappropriate to use stock images of models in business clothing who are yawning or looking fatigued. This is not a good representation of ME/CFS.

The German association ‘Deutsche Gesellschaft für ME/CFS’ has provided 32 professional photos for press use that adequately depict the reality of people living with ME/CFS.

<nowiki>https://www.mecfs.de/stockphotos/</nowiki>

'''Disease burden and low funding'''

ME/CFS affects approximately 0.4% of the population or 1 in 250 people.

Economic costs due to ME/CFS are high. In the United States, estimates range from $36 to $51 billion per year, considering both lost wages and healthcare costs. In Europe, the illness affects approximately 2 European citizens and the annual burden of ME/CFS is estimated to be 40 billion euros annually.

Despite its high disease burden, research on ME/CFS remains underfunded. One analysis of NIH funding found that ME/CFS research only receives 7% of the amount commensurate with its disease burden. A study contracted by the European Commission also identified ME/CFS as a high-burden, under-researched medical condition.

'''Cause and pathology'''

The cause and pathology of ME/CFS remain largely unknown. The illness is much more common in women than in men: approximately 75% of patients are female.

Infections are also considered a risk factor. Longitudinal studies have shown that infectious diseases such as mononucleosis increase the chances of developing ME/CFS. Increased incidence has also been reported following Q-fever, Ross River Virus, giardiasis, and several other infections. Sars-Cov-2 leads to a higher risk of ME/CFS and a substantial proportion of patients with Long Covid meet ME/CFS diagnostic criteria.

ME/CFS is suspected to have a genetic component. The DecodeME project in the UK has collected samples of more than 20,000 ME/CFS patients to perform a genome-wide analysis.

Researchers have reported abnormalities in the immune system, metabolism, cardiovascular system, brain signalling, endothelial function, and other bodily functions of ME/CFS patients. However, most of these findings are not specific to ME/CFS (they are also found in other conditions) or have not been replicated by multiple research groups.

'''Not a mental disorder'''

Because there is no biomarker or diagnostic test, ME/CFS was incorrectly believed to be a mental disorder, an illness without disease, or a collection of symptoms that are ‘all in the mind’. This view is in contrast with scientific evidence and expert opinion. The Centers for Disease Control and Prevention (CDC), for example, states: ''"ME/CFS is a biological illness, not a psychologic disorder.”''

The World Health Organization classifies ME and CFS as Diseases of the Nervous System, using code 8E49 Postviral fatigue syndrome in the International Classiciation of Diseases.

'''Treatment'''

There are no Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved treatments for ME/CFS. Physicians aim to reduce the impact of ME/CFS by managing or treating individual symptoms. The European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) and the US Clinician's Coaltion have issued guidelines and advice on symptom management.

In the past, graded exercise therapy (GET) was a popular treatment for ME/CFS. This was based on the idea that ME/CFS is perpetuated by deconditioning and avoidance of activity. In randomized trials, however, GET failed to increase employment rates and fitness levels of ME/CFS patients. Multiple reviews have evaluated the evidence supporting GET as low quality. In surveys, ME/CFS patients reported a worsening of their health following GET. The National Institutes of Health and Care Excellence (NICE) therefore actively recommends against GET and other exercise programs for ME/CFS.

Cognitive behavioral therapy (CBT) may be offered to people with a new ME/CFS diagnosis to help them cope with the disease. CBT that assumes patients have 'abnormal' illness beliefs and behaviors as an underlying cause of their ME/CFS is no longer recommended by NICE.

Surveys indicate that ME/CFS patients often find pacing useful. Pacing is a self-management strategy where activities are dosed so that patients can remain as active as possible without causing postexertional malaise.

'''Psychosomatic theories and stigma'''

Because blood tests often return normal and most patients are women, ME/CFS has historically been minimalized. The illness has inappropriately been called ‘yuppie flu’ and was once dismissed as hysteria. Patients have reported harm from psychosomatic theories that assume ME/CFS to be caused by abnormal illness beliefs and excessive resting behavior. This has been considered a barrier to appropriate patient care.

'''12 May: World ME Day'''

ME/CFS organizations have advocated against stigma and for more recognition of the illness in research and the healthcare system. On 12 May, World ME/CFS Day, various awareness events are organized worldwide to highlight the millions of ME/CFS patients who have disappeared from public life because of their illness. These are often called ‘Millions Missing’ events, a campaign coordinated by the US-based ME Action Network.

'''Reports and guidelines'''

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - PubMed (nih.gov)

Overview | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management | Guidance | NICE

ME/CFS: The current state of knowledge | IQWiG.de

ME/CFS Basics | ME/CFS | CDC

'''Patient organizations'''

Home - World ME Alliance

Home - #MEAction Network

The ME Association - The ME Association

Start — Deutsche Gesellschaft für ME/CFS (mecfs.de)

European ME Alliance - Home Page - A Voice for People with ME in Europe

'''ME/CFS experts'''

Luis Nacul

Carmen Scheibenbogen

Lucinda Bateman

Nancy Klimas

Anthony Komaroff

Chris Ponting

Karl Tronstad

'''Examples of excellent reporting'''

‘You don’t want to get better’: the outdated treatment of ME/CFS patients is a national scandal | George Monbiot | The Guardian

Fatigue Is So Much More Than Being Tired - The Atlantic

When the doctor doesn’t listen - Coda Story

Draft:Primer for Journalists

2024-06-06T10:50:15Z

Yannlk:Created page with "''Note: This page is currently being discussed [https://www.s4me.info/threads/the-mepedia-primer-for-journalists.38819/ here].'' Myalgic encephalomyelitis (ME), sometimes referred to as chronic fatigue syndrome (CFS) is a serious and long-term illness. People with ME/CFS experience debilitating fatigue, non-refreshing sleep, and problems with memory or concentration. Other common symptoms include pain, gut issues, sensitivity to light and sound, and orthostatic intoler..."

''Note: This page is currently being discussed [https://www.s4me.info/threads/the-mepedia-primer-for-journalists.38819/ here].''

Myalgic encephalomyelitis (ME), sometimes referred to as chronic fatigue syndrome (CFS) is a serious and long-term illness. People with ME/CFS experience debilitating fatigue, non-refreshing sleep, and problems with memory or concentration. Other common symptoms include pain, gut issues, sensitivity to light and sound, and orthostatic intolerance (dizziness or nausea when upright). The hallmark symptom of ME/CFS is a marked worsening of the illness after exertion, often referred to as post-exertional malaise (PEM).

'''Not chronic fatigue'''

ME/CFS is not the same as chronic fatigue and it is important not to confuse both conditions. ME/CFS patients are severely ill not, fatigued. Most people with chronic fatigue do not meet ME/CFS diagnostic criteria and for many ME/CFS patients, fatigue is not their most debilitating symptom. It is therefore inaccurate to shorten ME/CFS to ‘chronic fatigue’ in the body of an article or its headline.

'''Representative images'''

The quality of life of persons with ME/CFS is severely reduced. The National Academy of Medicine estimates that at least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives. Functional impairment of ME/CFS can be greater than in disabling conditions such as multiple sclerosis, end-stage renal disease or congestive heart failure.

Most patients with ME/CFS can no longer work or study and are forced to reduce their social activities. It is therefore inappropriate to use stock images of models in business clothing who are yawning or looking fatigued. This is not a good representation of ME/CFS.

The German association ‘Deutsche Gesellschaft für ME/CFS’ has provided 32 professional photos for press use that adequately depict the reality of people living with ME/CFS.

<nowiki>https://www.mecfs.de/stockphotos/</nowiki>

'''Disease burden and low funding'''

ME/CFS affects approximately 0.4% of the population or 1 in 250 people.

Economic costs due to ME/CFS are high. In the United States, estimates range from $36 to $51 billion per year, considering both lost wages and healthcare costs. In Europe, the illness affects approximately 2 European citizens and the annual burden of ME/CFS is estimated to be 40 billion euros annually.

Despite its high disease burden, research on ME/CFS remains underfunded. One analysis of NIH funding found that ME/CFS research only receives 7% of the amount commensurate with its disease burden. A study contracted by the European Commission also identified ME/CFS as a high-burden, under-researched medical condition.

'''Cause and pathology'''

The cause and pathology of ME/CFS remain largely unknown. The illness is much more common in women than in men: approximately 75% of patients are female.

Infections are also considered a risk factor. Longitudinal studies have shown that infectious diseases such as mononucleosis increase the chances of developing ME/CFS. Increased incidence has also been reported following Q-fever, Ross River Virus, giardiasis, and several other infections. Sars-Cov-2 leads to a higher risk of ME/CFS and a substantial proportion of patients with Long Covid meet ME/CFS diagnostic criteria.

ME/CFS is suspected to have a genetic component. The DecodeME project in the UK has collected samples of more than 20,000 ME/CFS patients to perform a genome-wide analysis.

Researchers have reported abnormalities in the immune system, metabolism, cardiovascular system, brain signalling, endothelial function, and other bodily functions of ME/CFS patients. However, most of these findings are not specific to ME/CFS (they are also found in other conditions) or have not been replicated by multiple research groups.

'''Not a mental disorder'''

Because there is no biomarker or diagnostic test, ME/CFS was incorrectly believed to be a mental disorder, an illness without disease, or a collection of symptoms that are ‘all in the mind’. This view is in contrast with scientific evidence and expert opinion. The Centers for Disease Control and Prevention (CDC), for example, states: ''"ME/CFS is a biological illness, not a psychologic disorder.”''

The World Health Organization classifies ME and CFS as Diseases of the Nervous System, using code 8E49 Postviral fatigue syndrome in the International Classiciation of Diseases.

'''Treatment'''

There are no Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved treatments for ME/CFS. Physicians aim to reduce the impact of ME/CFS by managing or treating individual symptoms. The European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) and the US Clinician's Coaltion have issued guidelines and advice on symptom management.

In the past, graded exercise therapy (GET) was a popular treatment for ME/CFS. This was based on the idea that ME/CFS is perpetuated by deconditioning and avoidance of activity. In randomized trials, however, GET failed to increase employment rates and fitness levels of ME/CFS patients. Multiple reviews have evaluated the evidence supporting GET as low quality. In surveys, ME/CFS patients reported a worsening of their health following GET. The National Institutes of Health and Care Excellence (NICE) therefore actively recommends against GET and other exercise programs for ME/CFS.

Cognitive behavioral therapy (CBT) may be offered to people with a new ME/CFS diagnosis to help them cope with the disease. CBT that assumes patients have 'abnormal' illness beliefs and behaviors as an underlying cause of their ME/CFS is no longer recommended by NICE.

Surveys indicate that ME/CFS patients often find pacing useful. Pacing is a self-management strategy where activities are dosed so that patients can remain as active as possible without causing postexertional malaise.

'''Psychosomatic theories and stigma'''

Because blood tests often return normal and most patients are women, ME/CFS has historically been minimalized. The illness has inappropriately been called ‘yuppie flu’ and was once dismissed as hysteria. Patients have reported harm from psychosomatic theories that assume ME/CFS to be caused by abnormal illness beliefs and excessive resting behavior. This has been considered a barrier to appropriate patient care.

'''12 May: World ME Day'''

ME/CFS organizations have advocated against stigma and for more recognition of the illness in research and the healthcare system. On 12 May, World ME/CFS Day, various awareness events are organized worldwide to highlight the millions of ME/CFS patients who have disappeared from public life because of their illness. These are often called ‘Millions Missing’ events, a campaign coordinated by the US-based ME Action Network.

'''Reports and guidelines'''

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - PubMed (nih.gov)

Overview | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management | Guidance | NICE

ME/CFS: The current state of knowledge | IQWiG.de

ME/CFS Basics | ME/CFS | CDC

'''Patient organizations'''

Home - World ME Alliance

Home - #MEAction Network

The ME Association - The ME Association

Start — Deutsche Gesellschaft für ME/CFS (mecfs.de)

European ME Alliance - Home Page - A Voice for People with ME in Europe

'''ME/CFS experts'''

Luis Nacul

Carmen Scheibenbogen

Lucinda Bateman

Nancy Klimas

Anthony Komaroff

Chris Ponting

Karl Tronstad

'''Examples of excellent reporting'''

‘You don’t want to get better’: the outdated treatment of ME/CFS patients is a national scandal | George Monbiot | The Guardian

Fatigue Is So Much More Than Being Tired - The Atlantic

When the doctor doesn’t listen - Coda Story

Primer for journalists

2024-06-06T10:44:58Z

Yannlk:added note

{{mbox|text= Editors: Edits to this Primer may require the same edits to the other [[:Category:Primers|Primers]].}}
''Note: This page is slightly outdated, long, and slightly disordered. We are working on revamping it at [[draft:Primer for Journalists]].''

[[Myalgic encephalomyelitis]] (ME), sometimes referred to as [[chronic fatigue syndrome|myalgic encephalomyelits/chronic fatigue syndrome]] (ME/CFS), and not to be confused with [[chronic fatigue]] (CF), is widely misunderstood. In this '''Primer for journalists''', we provide evidence-based statements (with links to further reading & sources) to support journalists writing about the disease. '''Chronic Fatigue Syndrome''' must never be shortened to ''Chronic Fatigue'' in the body of an article or its headline. This has caused much confusion for readers who do not understand ME/CFS is a debilitating lifelong illness and it is not the same as [[chronic fatigue]] (CF); CF is a symptom of many different illnesses. Although the [[Fukuda criteria|Fukuda]]<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | authorlink = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959 |issn=0003-4819|pmid=7978722|via=|doi=10.7326/0003-4819-121-12-199412150-00009|publisher=American College of Physicians}}</ref> and the [[Oxford criteria|Oxford Criteria]]<ref name="PMC1293107">{{Cite journal | title = A report--chronic fatigue syndrome: guidelines for research. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/|journal=Journal of the Royal Society of Medicine | date = Feb 1991|issn=0141-0768|pmc=1293107|pmid=1999813 | pages = 118–121 |volume=84|issue=2 | first = MC | last = Sharpe | first2 = LC | last2 = Archard | first3 = JE | last3 = Banatvala | first4 = LK | last4 = Borysiewicz | first5 = AW | last5 = Clare | first6 = A | last6 = David | first7 = RH | last7 = Edwards | first8 = KE | last8 = Hawton | first9 = HP | last9 = Lambert}}</ref> were previously used for diagnosing ME/CFS, they are now regarded as overly broad, there being criticism that patients were being [[misdiagnosis of myalgic encephalomyelitis and chronic fatigue syndrome|misdiagnosed]] in both clinical and research settings as having ME/CFS when in fact they were suffering from the symptom CF or another fatiguing diagnosis.<ref name="Vink2019">{{Cite journal | last = Vink | last2 = Vink-Niese | date = 2019-09-20 | title = Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies | url = https://www.mdpi.com/2075-4418/9/4/124|journal=Diagnostics|language=en|volume=9|issue=4|page=124|doi=10.3390/diagnostics9040124|issn=2075-4418 | first = Mark | first2 = Alexandra|pmc=|pmid=|quote= | author-link = Mark Vink | authorlink2 = Alexandra Vink-Niese|access-date=|via=}}</ref><ref name="Carruthers, 2003" /><ref name="ICC2011primer" /><ref>{{Cite web | title = What Does a True ME Definition Look Like? | url = https://www.meadvocacy.org/what_does_a_true_me_definition_look_like|website=MEadvocacy.org|access-date=2019-01-25 | first = | last = }}</ref><ref name="fukuda1994" /><ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped - The Argus Report By: Penny Swift]</ref><ref>{{Cite web | url = http://occupyme.net/2016/08/16/ahrq-evidence-review-changes-its-conclusions/|website=occupyme.net|access-date=2019-01-25 | title = AHRQ Evidence Review Changes Its Conclusions | date = Aug 16, 2016 | last = Spotila | first=Jennie | authorlink=Jennie Spotila | last2 = Dimmock | first2 = Mary | authorlink2 = Mary Dimmock|archive-url=|archive-date=}}</ref>

In the past, there have been media reports of athletes diagnosed with ME or CFS who have recovered in a relatively short period of time after rest, supplementation, and diet changes;<ref name="Inews2018">{{Cite news |url = https://inews.co.uk/news/health/marathon-runner-quit-work-me-cfs-diet-change/ | title = Marathon runner forced to quit work after developing ME claims diet change gave him his life back | first = Claudia | last = Tanner|publisher =iNews | date = 2018}}</ref><ref name="Times2017">{{Cite news | url = https://www.thetimes.co.uk/article/muslim-fighter-with-me-who-left-an-arranged-marriage-to-win-world-title-svxhhzt57 | title = Muslim fighter with ME who left an arranged marriage to win world | last = Broadbent | first = Rick | date = 2017-12-02|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref><ref name="ABC2018">{{Cite news |url = http://www.abc.net.au/7.30/committee-reviews-potentially-harmful-and-old/10010408 |at=6mins 18s| title = Committee reviews 'potentially harmful and old fashioned' chronic fatigue treatments|publisher =ABC News | first =Andy|last = Park | first2 = Clare | last2 = O'Halloran}}</ref><ref name="London2019">{{Cite news | url = https://www.thetimes.co.uk/article/nathan-douglas-london-2012-was-the-darkest-period-of-my-life-vxt5gftcx | title = Nathan Douglas: London 2012 was the darkest period of my life | last = Broadbent | first = Rick | date = 2019-02-27|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref> these athletes may have had [[overtraining syndrome]] (which has the symptom of [[chronic fatigue]]) and not ME or CFS,<ref name="spence"/> while people with adrenal failure, [[idiopathic chronic fatigue]] or other fatiguing illnesses may be erroneously diagnosed with CFS.<ref name="recovery"/><ref name="Anoop2012"/><ref name="ICC" /> ME and CFS in professional athletes is normally a career-ending diagnosis.<ref name="Squash" /><ref name="Annadale"/><ref name="Shattered"/><ref name="Olympian"/><ref name="FIFA"/><ref name="olaf"/><ref name="LA"/>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''What is ME/CFS'' By Open Medicine Foundation - OMF. Linda Tannenbaum, Founder & CEO/President, talks about ME/CFS and how OMF is leading research and delivering hope (2018)">https://www.youtube.com/watch?v=pqDubEeIBtA</embedvideo>

The core [[List of symptoms in ME CFS|ME/CFS symptoms]] are: [[post-exertional malaise]] (PEM); [[chronic fatigue]] (CF); [[unrefreshing sleep]]/[[Sleep dysfunction|sleep problems]]; and [[Cognitive dysfunction|cognitive impairment]]/[[brain fog]] and/or [[orthostatic intolerance]] (OI).<ref name="symptoms"/><ref name="clinicians">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness {{!}} Clinicians Guide | last = | first = | date = 2015 | publisher=Nation Academies Press|archive-url=|archive-date=|access-date= | authorlink = }}</ref>{{Rp|9-10}} A patient can have many more symptoms<ref name="what-is">{{Cite web | url = https://www.omf.ngo/what-is-mecfs/ | title = What is ME/CFS? | last = | first = | date = |archive-url=|archive-date=|access-date= | authorlink = |website=[[Open Medicine Foundation]]}}</ref> and meet different criteria. [[Systemic Exertion Intolerance Disease]] (SEID), an ME/CFS criterion, allows for a patient to be [[Systemic Exertion Intolerance Disease#Diagnostic criteria|diagnosed with the minimum core symptoms]]<ref name="DiagnosticAlgorithm">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - Diagnostic Algorithm | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190528223706/https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg|archive-date=2019-05-28|access-date=}}</ref> and the patient may have other symptoms.<ref name="clinicians"/<ref name="IOM2015">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgid Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness - Clinician's Guide | date = 2015 | access-date=|website=nap.edu | last = | first = | authorlink = |archive-url=|archive-date= | page = 9}}</ref> The [[Canadian Consensus Criteria]] (CCC) requires the core symptoms and [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]], [[Neuroendocrine system|neuroendocrine]], [[immune system]], and [[myalgia]] symptoms to meet [[Canadian Consensus Criteria#Definition|its ME/CFS diagnostic criteria]].<ref name="Carruthers, 2003">{{Cite journal | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 =Joshi | first9 = Pradip | authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols | journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid = | doi = 10.1300/J092v11n01_02
| url = http://phoenixrising.me/wp-content/uploads/Canadian-definition.pdf }}</ref> The [[International Consensus Criteria]] (ICC) is used to diagnose [[myalgic encephalomyelitis]] (ME) which requires the core symptoms and neurological, immune/[[Gastrointestinal system|gastrointestinal]]/genitourinary impairment, and [[portal:Energy metabolism|energy metabolism]]/[[Ion transportation|ion transport]] impairment [[International Consensus Criteria#Criteria|symptoms for a diagnosis]].<ref name="ICC">{{Cite journal | last = Carruthers | first=Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | authorlink8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | author-link12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14 = Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23 = Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24 = Modra Murovska | last25 = Pall | first25 = Martin | author-link25 = Martin Pall | last26 = Stevens | first26 = Staci | author-link26 = Staci Stevens | date = 2011-08-22 | title=Myalgic encephalomyelitis: International Consensus Criteria | url = https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref>

The acronym ME/CFS is widely used in research, by clinicians, patient organizations, and patients.

"The most common overlapping condition with ME/CFS is [[fibromyalgia]]."<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25 = Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012 | isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref><ref name="Primer2014"/><ref name="Jason2001">{{Cite journal | last= Jason | first = Leonard | last2 = Taylor | first2 = R.R. | last3 = Kennedy | first3 = C.L. | last4 = Song | first4 = S | last5 = Johnson | first5 = D | last6 = Torres | first6 = S.R. | date = 2001-01-01 | title = Chronic fatigue syndrome: Comorbidity with fibromyalgia and psychiatric illness | url = https://www.researchgate.net/publication/285787383_Chronic_fatigue_syndrome_Comorbidity_with_fibromyalgia_and_psychiatric_illness|journal=Medicine and Psychiatry|volume=4 | pages = 29–34}}</ref> While some have posited ME/CFS and fibromyalgia are variants of the same illness, [[Benjamin Natelson]], MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiologic processes leading to different treatments.<ref>{{Cite journal | last = Natelson | first = Benjamin H. | date = 2019-02-19 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: Definitions, Similarities, and Differences | url = https://www.clinicaltherapeutics.com/article/S0149-2918(19)30003-7/abstract|journal=Clinical Therapeutics|language=English|volume=41|issue=4 | page = 612|doi=10.1016/j.clinthera.2018.12.016|issn=0149-2918|pmid=30795933}}</ref>

While ME/CFS is recognised as a physical disease by researchers, a [[Psychologization|psychiatric approach]] was taken with ME/CFS in the past, and some clinicians are still using this practice. At this time there are no approved drug treatments. In the past, [[Graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT) were used for ME/CFS. They are now discouraged or banned by major health guidelines as they were based on a psychological view of the illness and have lead to patient harm.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206|title=Overview {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-19}}</ref><ref name="etiology" />The [[Centers for Disease Control and Prevention]] (CDC) website states "ME/CFS is a '''biological illness''', not a psychologic disorder" and impacts multiple body systems.<ref name="etiology">{{Cite web | title = Etiology and Pathophysiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08| access-date = 2019-01-22 |language=en-us}}</ref> The CDC recognizes the hallmark symptom of PEM which is a worsening of symptoms after physical, mental or emotional exertion<ref name="symptoms">{{Cite web | title = Symptoms of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-22|language=en-us}}</ref> and says [[ME/CFS]] is a "disabling and complex disease."<ref name="whatis">{{Cite web | url = https://www.cdc.gov/me-cfs/about/index.html | title = What is ME/CFS? {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-12}}</ref>

[[File:SEID algorithm.JPG|400px|thumb|right|Diagnostic Algorithm for [[Systemic Exertion Intolerance Disease|SEID]]'s minimum [[List of symptoms in ME CFS#Systemic Exertion Intolerance Disease (SEID) symptom list|ME/CFS core symptoms]]]]

==What do we know?==
ME is a debilitating illness that has been recognized as a neurological disease by the [[World Health Organization]] (WHO) since 1969.<ref name="icd10">{{Cite book | url = https://apps.who.int/iris/bitstream/handle/10665/70934/ICD_10_1969_eng_v2a.pdf?sequence=3&isAllowed=y | title = International Classification of Diseases | last = World Health Organization | first = |publisher=WHO| year = 1969|isbn=|editor-link=|edition=Eighth revision|volume=2|location=Geneva|pages=173|chapter=|quote=Encephalomyelitis (chronic), (myalgic, benign) 323|editor-last2=|editor-link2=}}</ref>

It is a systemic [[Neuro-immune disease|neuroimmune]] disease characterized by [[post-exertional malaise]] (PEM) (a severe worsening of symptoms after even minimal [[exertion]]). It causes dysregulation of both the [[immune system]] and the [[nervous system]]. The effects of ME are devastating enough to leave [[Severe and very severe ME|25% of patients housebound or bedbound]]. For moderate to severe patients, the disability of living with ME is like living with late-stage cancer, advanced stage AIDS, or congestive heart failure for decades.

[[ME/CFS]] costs the US economy up to $24 billion per year in direct medical costs, and lost production.<ref name="IOM2015MECFS" /> Despite this, funding for research is not commensurate with the level of disease burden. In the 2015 financial year, the [[National Institutes of Health]] (NIH) provided only $5 million in research funding for ME/CFS, which is less funding than hayfever. This is in stark contrast to funding levels for other similarly disabling illnesses, like [[multiple sclerosis]] ($105 million) and HIV/AIDS ($3 billion).{{Citation needed|reason=Reference needed for NIH funding levels | date = 4 November 2019}} The [[Institute of Medicine]], a special advisory committee of the [[U.S. Department of Health and Human Services]] (HHS) (ref: [[Chronic Fatigue Syndrome Advisory Committee|CFSAC]] recommendations) and [[NIH]] expert advisory panel agree that it is imperative to increase research funding into ME/CFS.<ref name="NIHP2PFIN" />

== Disease onset and course of illness==
[[Onset of ME/CFS|ME/CFS can begin]] from many acute/sudden<ref name="Chu2019">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | authorlink5 = | date = Jan 14, 2019 | title = Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome | url = https://www.frontiersin.org/articles/10.3389/fped.2019.00012/abstract|journal=Frontiers in Pediatrics|volume=|issue=|pages=|doi=10.3389/fped.2019.00012|quote=|via=}}</ref> events: usually [[Viral onset hypothesis|viral]] or [[Bacterial disease onset|bacterial]] infections, but also [[trauma]], surgery or childbirth, [[anaphylaxis|allergic reaction]], and [[stress]].<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=[[Centers for Disease Control and Prevention]] | page = 6|archive-url=|archive-date=|access-date=}}</ref> There is also a gradual onset in some people,<ref name="Chu2019" /><ref name="clinical">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/index.html | title = Presentation and Clinical Course of ME/CFS {{!}} Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS | date = 2018-12-12 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-02-07}}</ref> that is not attributed to any one event. Occasionally, ME/CFS has been triggered by [[Environmentally acquired illness|environmental toxins]] or the receipt of an [[Vaccine|immunizing injection]].<ref>[https://www.masscfids.org/images/pdf/Primer_2014.pdf Chronic Fatigue Syndrome Myalgic Encephalomyelitis - Primer for Clinical Practitioners - 2014 Edition - Massachusettes CFIDS/FM Assoc]</ref> Some say that the disease [[Myalgic encephalomyelitis|ME]] always has an acute/sudden [[Infection|infectious]] onset.<ref name="Evans2018">{{Cite journal | last = Evans | first = Meredyth | authorlink = Meredyth Evans | authorlink2 = Leonard Jason | date = 2018 | title = Onset patterns of chronic fatigue syndrome and myalgic encephalomyelitis | url = https://www.openaccessjournals.com/articles/Onset%20patterns%20of%20chronic%20fatigue%20syndrome%20and%20myalgic%20encephalomyelitis.pdf|journal=Research on Chronic Diseases|volume=|issue=|pages=2|quote=|via= | last2 = Jason | first2 = Leonard}}</ref>

The disease [[ME/CFS]] is often diagnosed when a person does not recover from a [[flu-like illness]], [[mononucleosis]] or another [[HHV|herpesvirus]], [[Q fever]], an unidentified [[virus]], or [[:Category:Infectious agents|other infection]], and meets one or more [[Definitions of myalgic encephalomyelitis and chronic fatigue syndrome|diagnostic criteria for either ME, CFS, or ME/CFS]].<ref name="IOM2015"/>{{Rp|157-158}}<ref>[http://www.cortjohnson.org/blog/2014/01/09/lipkin-study-vagus-nerve-hhv-6-loomis-hhv-6-foundation/ The Lipkin Study, The Vagus Nerve Infection Hypothesis and HHV-6: Kristin Loomis of the HHV-6 Foundation Talks – Pt. I - Health Rising - By: Cort Johnson - June 2014]</ref> Patients experience [[List of symptoms in ME CFS|numerous symptoms]] and disease severity which fluctuate from day to day, week to week, month to month, year to year, and even decade to decade. Furthermore, symptoms and disease severity vary among patients.<ref name="Primer2014"/><ref name="WebMD">[http://www.webmd.com/chronic-fatigue-syndrome/chronic-fatigue-syndrome-symptoms Chronic Fatigue Syndrome - Symptoms - Web MD]</ref>

The CDC recognizes that there can be different causes and it is possible that two or more things could cause the illness. Areas of research include infections, [[immune system]] changes, physical or psychological [[stress]] affecting body chemistry, changes in [[Metabolic|energy production]], and a possible [[Genetics of chronic fatigue syndrome|genetic link]].<ref name="causes">{{Cite web | title = Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/about/possible-causes.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-27|language=en-us}}</ref><ref name="etiology" /> The CDC notes there are abnormalities with the immune system, [[Metabolic|cellular metabolism]], neuroendocrine disturbances, and [[blood pressure]] or heart rate regulation.<ref name="etiology" />
===Not a mental health disorder===
In the past, CFS was believed to be a mental health disorder. This is why the CDC now states: "ME/CFS is a biological illness, not a psychologic disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have multiple pathophysiological changes that affect multiple systems."<ref name="etiology" />

===No clear evidence that ME/CFS is contagious===
[[:Category:Infectious agents|Infectious episodes]] have led to [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreaks]] over the years and 72% of ME/CFS patients report an [[Onset of ME/CFS|onset]] of a viral or bacterial infection.<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=cdc.gov | page = 6|archive-url=|archive-date=|access-date=}}</ref> Nowadays, the vast majority of ME/CFS cases are sporadic rather than epidemic - although some outbreaks have been caused by known viruses such as the [[2003 Hong Kong outbreak|SARS pandemic]] and [[2019 Coronavirus pandemic outbreak|COVID-19]] - there is no clear evidence that sporadic ME/CFS cases are contagious.<ref name="pediatricprimer">{{Cite journal | last = Rowe | first = Katherine S. | last2 = Vallings | first2 = Rosamund | last3 = Stewart | first3 = Julian M. | last4 = Speight | first4 = Nigel | last5 = Schwartz | first5 = Malcolm S. | last6 = Medow | first6 = Marvin S. | last7 = Gurwitt | first7 = Alan | last8 = Friedman | first8 = Kenneth J. | last9 = Underhill | first9 = Rosemary A. | date = 2017 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref>

Families, partners, and friends do not report contracting ME/CFS from someone with the disease nor do patients report passing it on to others.<ref>{{Cite web | url = http://forums.prohealth.com/forums/index.php?threads/is-cfs-contagious.189664/ | title = Is CFS contagious? |website = ProHealth Forums|access-date=2019-02-13}}</ref> However, [[Rosemary Underhill|Underhill]] and O'Gorman (2006) researched 219 patients with ME/CFS, and concluded that close household contact and genetics were both risk factors for CFS, finding 3.2% of spouses/partners of those with CFS also had the illness.<ref name="UnderhillInfectious">{{Cite journal | last = Underhill | first = Rosemary A. | last2 = O'Gorman | first2 = Ruth | date = 2006-01-01 | title = Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families of CFS Patients | url = https://doi.org/10.1300/J092v13n01_02|journal=Journal of Chronic Fatigue Syndrome|volume=13|issue=1|pages=3–13|doi=10.1300/J092v13n01_02|issn=1057-3321}}</ref> This was a higher prevalence than all genetic relatives except children of patients. Because ME/CFS can run in families, a [[Genetics of chronic fatigue syndrome|genetic link]] is a line of research recommended by the CDC.<ref name="causes" /> 

[[Michael Sikora]] and collaborators at the [[Open Medicine Foundation]] hope that their research on the role of [[T cell]]s and immune-related [[Genetics of chronic fatigue syndrome|genes]] will help address "whether ME/CFS is an autoimmune or infectious disease, or simply an activation of the immune system".<ref name="omf-funded">{{Cite web | url = https://www.omf.ngo/2018/06/04/omf-funded-research/ | title = OMF funded research | date = Jun 4, 2018 | website = [[Open Medicine Foundation]]}}</ref>

====Blood donation and organ transplant====
A [[Blood donation|tissue and blood donation]] ban is in force for ME/CFS in the [[United Kingdom]] (even if recovered),<ref name="BloodUK">{{Cite web | url = https://my.blood.co.uk/KnowledgeBase | title = Knowledgebase|website=My Donor Record - Health, Eligibility & Travel | last = | first = | authorlink = |archive-url=|archive-date=|url-status=|access-date=2021-10-08}}</ref> [[Australia]],<ref name="donate">{{Cite web|url = https://www.donateblood.com.au/faq/chronic-fatigue-syndrome |title=Chronic fatigue syndrome – I have/had chronic fatigue syndrome. Can I donate?|access-date=2022-05-25|website = Australian Red Cross}}</ref> [[New Zealand]],<ref name="NZBlood">{{Cite web |url = https://www.nzblood.co.nz/become-a-donor/am-i-eligible/detailed-eligibility-criteria/ | title = Detailed Eligibility Criteria|access-date=2022-05-25 | date = |website=NZ Blood|quote=}}</ref> most of [[Canada]],<ref name="Wilson2014">{{Cite journal | title = The Use of Preliminary Scientific Evidence in Public Health: A Case Study of XMRV | date = 2014-04-08 | url = https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001623|journal=PLOS Medicine|volume=11|issue=4| pages = e1001623 | last = Wilson | first = Kumanan | last2 = Atkinson | first2 = Katherine | last3 = Keelan | first3 = Jennifer|language=en|doi=10.1371/journal.pmed.1001623|pmc=PMC3979645|pmid=24714396|issn=1549-1676}}</ref> and for a time also in the [[United States]],<ref name="post">{{Cite web | url = http://voices.washingtonpost.com/checkup/2010/12/red_cross_bars_chronic_fatique.html | title = Red Cross bars chronic fatigue patients from donating blood | last = Stein | first = Rob | authorlink = | date = Dec 3, 2010 | website = Washington Post|archive-url=|archive-date=|access-date=2022-05-25}}</ref> initially due to the research on [[Xenotropic murine leukemia virus-related virus|XMRV]] as being the likely infectious trigger of CFS<ref>{{Cite web | url = https://www.meassociation.org.uk/2010/04/xmrv-testing-in-the-uk/ | title = XMRV testing in the UK | last = | first = | author-link =| date = 2010 | website = [[ME Association]]|language=en-US|archive-url=|archive-date=|access-date=2019-02-13}}</ref> and showing that patients carried the virus.<ref name="post" /> Two papers on XMRV were retracted as the result was caused by laboratory contamination,<ref name="Redaction2012">{{Cite journal | date = Dec 2012 | title = Redaction, retraction and reaction | url = https://www.nature.com/articles/nrmicro2928|journal=Nature Reviews Microbiology|language=en|volume=10|issue=12 | pages = 799|doi=10.1038/nrmicro2928|issn=1740-1534}}</ref><ref name="transfusion">{{Cite web | url = https://transfusionnews.com/2012/10/05/multicenter-study-finds-no-correlation-between-chronic-fatigue-syndrome-and-xmrv/ | title = Multicenter Study Finds No Correlation between Chronic Fatigue Syndrome and XMRV|website=transfusionnews.com|access-date=2019-02-13}}</ref> but many blood donation bans remain.<ref name="Wilson2014"/>

The US American Red Cross no longer has statements barring transfusions or transplants for CFS,<ref name="redcross">{{Cite web | url = https://www.redcrossblood.org/faq.html#eligibility-health|access-date=2019-02-13 | title = Frequently Asked Questions | date = | last = | first = | authorlink = |archive-url=|archive-date=|website=American Red Cross|quote=Your search for "Chronic fatigue syndrome" returned no results.}}</ref> but patients are expected to be in "good health" which would exclude most.<ref name="redcross"/> The American Association of Blood Banks advises to either accept or defer ME/CFS donors based on "clinical judgment of the donor's health status".<ref name="AABBOct2012">{{Cite web | last = American Association of Blood Banks | url = https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2 | date = October 2012 | title = Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV)|pages = 3 |quote=An updated AABB Association Bulletin #12-05 (November 2012) states that individual collectors of blood and cellular therapy products should accept or defer donors with a history of CFS based on their clinical judgment of the donor's health status.|access-date=2022-05-25}}</ref> Patient charities discourage ME/CFS patients from donating blood,<ref name="MassBlood2015">{{Cite web | url = https://www.massmecfs.org/research/recent-research/19-xmrv/237-aabbs-recommendation-on-cfidsme-and-blood-donation | title = AABB's recommendation on ME/CFS and blood donation | date = Nov 25, 2015 |website=[[Massachusetts ME/CFS & FM Association]]|access-date=2022-05-25}}</ref>

== Mini-Docs ==
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Jen Brea/TED (2016)">https://www.youtube.com/watch?v=Fb3yp4uJhq0</embedvideo>
[[What happens when you have a disease doctors can't diagnose - TED Talk (2016)|''What happens when you have a disease doctors can't diagnose'']] By [[Jennifer Brea|Jen Brea]]/TED

Five years ago, TED Fellow Jen Brea became progressively ill with myalgic encephalomyelitis, commonly known as chronic fatigue syndrome, a debilitating illness that severely impairs normal activities and on bad days makes even the rustling of bed sheets unbearable. In this poignant talk, Brea describes the obstacles she's encountered in seeking treatment for her illness, whose root causes and physical effects we don't fully understand, as well as her mission to document through film the lives of patients that medicine struggles to treat.<ref>{{Cite web | url = https://www.youtube.com/watch?v=Fb3yp4uJhq0 | title = What happens when you have a disease doctors can't diagnose | date = Jan 17, 2017|access-date=|website=YouTube | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=|publisher=TED}}</ref><ref>{{Cite web | url = https://www.ted.com/talks/jen_brea_what_happens_when_you_have_a_disease_doctors_can_t_diagnose | title = What happens when you have a disease doctors can't diagnose | date = Jun 2016|access-date=|website=TED | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Veronica Weber/Palo Alto Online (2015)">https://www.youtube.com/watch?v=9_HwOUiImvw</embedvideo>

[[Invisible Illness - Stories of Chronic Fatigue Syndrome|''Invisible Illness - Stories of Chronic Fatigue Syndrome'']] By Veronica Weber/Palo Alto Online

This mini documentary reveals 3 stories of people who have been impacted by [[Chronic Fatigue Syndrome]] - a little known disease that affects roughly 836,000-2.5 million people in the U.S. and receives little research funding. They share emotions of treating loved ones with the disease, their frustrations of being ignored by members of society and the healthcare industry and express hopes of treatment and research. Video by Veronica Weber/Palo Alto Online<ref>{{Cite web | url = https://www.youtube.com/watch?v=9_HwOUiImvw | title = Invisible Illness - Stories of Chronic Fatigue Syndrome | date = Jul 10, 2015 |access-date=|website=YouTube | last = Weber | first = Veronica | authorlink=|archive-url=|archive-date=|publisher=Palo Alto Online}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Dr. David Kaufman/Unrest (2018)">https://www.youtube.com/watch?v=RC9TjgE_PlU</embedvideo>

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module''', made available through the American Medical Women’s Association and Indiana University School of Medicine, and in partnership with #MEAction. US medical providers can visit: https://www.unrest.film/cme to register to watch [[Unrest]] online for free and receive Continuing Education credit.<ref>{{Cite web | url = https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = | first = | authorlink = David Kaufman|archive-url=|archive-date=|publisher=Unrest Film}}</ref>

==Epidemiology ==
In the [[United States]], 836,000 - 2.5 million people suffer from ME/CFS. "The total economic costs of ME/CFS are estimated at $17 to $24 billion annually."<ref name="clinicians" /> Some CFS patients can work with [https://www.dol.gov/general/topic/disability/jobaccommodations job accommodations] but 1/3 to 1/2 become unemployed and [[Disability|many rely on SSDI/SSI]].<ref>[https://www.masscfids.org/job-accommodations Job Accommodations - MASS CFIDS]</ref>
*[[Epidemiology of myalgic encephalomyelitis and chronic fatigue syndrome|Epidemiology]]
:All races and cultures are afflicted with ME/CFS.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-91 Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care - July 2011]</ref><ref name="epidemiology">{{Cite web | title = Epidemiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-29|language=en-us}}</ref> Children and adolescents are also diagnosed.<ref>{{Cite web | title = ME/CFS in Children {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/me-cfs-children/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-29|language=en-us}}</ref><ref>{{Cite web | title = Pediatric ME/CFS Home Page | url = https://www.massmecfs.org/pediatric-me-cfs-home-page|website=massmecfs.org|access-date=2019-01-29}}</ref>
*[[Female predominant diseases]]
:Like many [[Autoimmune disease|autoimmune]] and [[Neuro-immune disease|neuro-immune]] diseases where mostly women are afflicted,<ref>[http://www.rightdiagnosis.com/artic/fact_sheet_autoimmune_disease_in_women_nwhic.htm Fact Sheet Autoimmune Disease in Women: NWHIC - Right Diagnosis - Aug 2015]</ref> the ME/CFS female/male patient ratio per Capelli et al. is 6:1<ref>{{Cite journal | title = Chronic fatigue syndrome/myalgic encephalomyelitis: an update | url = https://www.ncbi.nlm.nih.gov/pubmed/21244747|journal=International Journal of Immunopathology and Pharmacology | date = Oct 2010|issn=0394-6320|pmid=21244747 | pages = 981–989|volume=23|issue=4|doi=10.1177/039463201002300402 | first = E. | last=Capelli | first2 = R. | last2 = Zola | first3 = L. | last3 = Lorusso | first4 = L. | last4 = Venturini | first5 = F. | last5 = Sardi | first6 = G. | last6 = Ricevuti}}</ref> while the CDC states 4:1.<ref name="epidemiology"/>
*[[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|Pediatric]]
:Pediatric ME/CFS is defined by the CDC<ref>{{Cite web | url = https://www.cdc.gov/me-cfs/me-cfs-children/factsheet-healthcare-professional.html | title = Pediatric ME/CFS: Fact Sheet for Healthcare Professionals {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2017-10-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-10-13}}</ref> and the [[National Academy of Medicine]] (NAM)<ref name="IOM2015"/>{{Rp|181}} although it is usually diagnosed in adults.<ref name="whatis"/> "Children below the age of 8 or 9 do not have the symptom pattern of adolescents past puberty. If the onset of the disease occurs during adolescence, the most common time of onset, the pattern is similar to that of adults."<ref>{{Cite web | url = https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children - by David S. Bell, MD | date = 2016-06-25|publisher=[[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US | last = Bell | first = David | authorlink = David Bell}}</ref> The prognosis in adolescents is considered to be better than in adults.<ref name="prognosis">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/prognosis.html | title = Prognosis {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = 2018-11-08 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-01-31}}</ref><ref>{{Cite journal | last = Rowe | first = Peter C. | last2 = Underhill | first2 = Rosemary A. | last3 = Friedman | first3 = Kenneth J. | last4 = Gurwitt | first4 = Alan | last5 = Medow | first5 = Marvin S. | last6 = Schwartz | first6 = Malcolm S. | last7 = Speight | first7 = Nigel | last8 = Stewart | first8 = Julian M. | last9 = Vallings | first9 = Rosamund | date = 2017 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref> Children are diagnosed with ME/CFS at three months of illness under SEID and CCC and ME is diagnosed immediately under ICC.<ref>{{Cite web | url = https://www.masscfids.org/pediatric-me-cfs-links | title = Pediatric ME/CFS links|website=[[Massachusetts ME/CFS & FM Association]]|language=en-GB|access-date=2018-08-11}}</ref><ref name="clinicians" /><ref name="Carruthers, 2003" /><ref name="ICC" />
*[[Prevalence of myalgic encephalomyelitis and chronic fatigue syndrome|Prevalence]]
:"Worldwide, there may be as many as 17 – 24 million people with ME/CFS."<ref>{{Cite web | url = https://ammes.org/how-many-people-have-mecfs/ | title = How Many People Have ME/CFS?|website = [[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|access-date=2019-01-31}}</ref> 25% of ME/CFS patients are [[Severe and very severe ME|housebound or bedbound]] at some point in their illness.<ref name="keyfacts">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf | title = Myalgic Encelphalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Key Facts | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190327085836/https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf|archive-date=2019-03-27|url-status=dead|access-date=}}</ref><ref name="IOM2015"/>{{Rp|32}} 90% of patients are undiagnosed.<ref name="whatis"/>
*[[Prognosis for myalgic encephalomyelitis and chronic fatigue syndrome|Prognosis]]
:The prognosis for a patient diagnosed with ME/CFS is considered to be poor with only a minority (a median estimate of 5%) returning to pre-morbid levels of functioning.<ref name="Cairns2005">{{Cite journal | last = Cairns | first = R. | author-link = | last2 = Hotopf | first2 = M. | authorlink2 = Matthew Hotopf | date = Jan 2005 | title = A systematic review describing the prognosis of chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/15699087|journal=Occupational Medicine (Oxford, England)|volume=55|issue=1|pages=20–31|doi=10.1093/occmed/kqi013|issn=0962-7480|pmid=15699087|quote=|via=}}</ref> The majority of patients remains significantly impaired. A substantial improvement however is noted in an estimated 40% of patients.<ref name="Cairns2005" /><ref name="Joyce1997">{{Cite journal | last= Joyce | first = J. | last2 = Hotopf | first2 = M. | last3 = Wessely | first3 = S. | date = Mar 1997 | title = The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review | url = https://www.ncbi.nlm.nih.gov/pubmed/9093600|journal=QJM: monthly journal of the Association of Physicians|volume=90|issue=3|pages=223–233|issn=1460-2725|pmid=9093600}}</ref>

==ME vs CFS vs CF==

The name myalgic encephalomyelitis (ME) was coined following an [[Epidemic myalgic encephalomyelitis|outbreak]] of an illness at the [[1955 Royal Free Hospital outbreak|Royal Free Hospital]] in the UK, in 1955. The name chronic fatigue syndrome (CFS) was coined by the [[Centers for Disease Control and Prevention]] (CDC) following an [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreak]] of a [[flu-like illness]] at [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]], at Lake Tahoe, in the 1980s. There is disagreement as to whether ME and CFS are the same disease, entirely separate illnesses, or whether ME constitutes a more severe subset of CFS. Adding to the confusion, the diagnostic name given to patients is more often dependent on the country in which they live, than differing characteristics of their illness, as some countries use CFS (eg: US, [[Australia]]), and other countries (particularly in Europe) use ME. At this point in time, there is no clear biological evidence to resolve whether the illnesses are the same or different, and there is unlikely to be a resolution until firm [[diagnostic biomarker|biomarkers]] have been identified. As such, many patients and researchers use the term ME/CFS.<ref name="Klimas20140621video" /> See: [[Definitions of ME and CFS]].

The name Chronic Fatigue Syndrome is itself controversial, as many consider it [[stigma and discrimination|stigmatizing]]. In February 2016, Dr [[Anthony Komaroff]], who was part of the CDC group of clinicians who coined the name Chronic Fatigue Syndrome, said of it:
<blockquote>"I think that was a big mistake because the name, in my opinion, and the opinion of a lot of people, it both trivializes and stigmatizes the illness. It makes it seem unimportant, maybe not even real"<ref name="Komaroff20160217video" /></blockquote>

It is important to distinguish between ME/CFS and chronic fatigue (CF), which is a symptom of many different medical conditions (e.g.: anemia, [[hepatitis]], [[multiple sclerosis]], [[Thyroid disease|hypothyroidism]], [[depression]], ME/CFS). "Chronic fatigue" is not an illness in its own right and it is incorrect and misleading to refer to ME/CFS as "chronic fatigue". While [[fatigue]] is a component of ME/CFS, many consider [[post-exertional malaise]] (PEM) to be the cardinal feature of ME/CFS.<ref name="Carruthers, 2003" /><ref name="IOM2015MECFS" />

==Evidence of a disease==

=== Symptoms ===
[[List of symptoms in ME CFS|Symptom presentation varies enormously]] between individuals. Symptom presentation also varies within individuals, as individuals often report that symptoms change over time (increasing or decreasing) and new symptoms may appear while others disappear.<ref>{{Cite web | title = Symptoms and Diagnosis of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-02-01|language=en-us}}</ref> There are many symptoms which people with ME/CFS experience, though those listed below are the core symptoms found in all patients.

[[File:Cfs woman sketch.jpg|435x435px|thumb|[[Post-exertional malaise]] (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|physical, mental or emotional exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]], [[brain fog]]/[[cognitive dysfunction]], and [[word-finding problems]], [[unrefreshing sleep]], [[headache]]s and [[migraine]]s, [[chronic pain]], [[Myalgia|muscle pain]] and [[muscle fatigability]], [[orthostatic intolerance]], [[neurally mediated hypotension]], or [[Postural orthostatic tachycardia syndrome|POTS]] and more. The [[Delayed onset of post-exertional symptoms|onset of PEM can be delayed 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months]]

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about [[Post-exertional malaise|PEM]] and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her illness worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM.]]

[[File:Brian vastag.png|thumb|left|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]

[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #[[ME/CFS|MEcfs]] research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.<ref>{{Cite web | url = https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #MEcfs research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = @JackCroxall|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair on a rare trip out]]. Second photo, the inevitable crash. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak, etc. #TwoFacesofME<ref>{{Cite web | url = https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak, etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = @hopeforMEyet|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = @Authorportrait | date = 2019-01-17|access-date=2019-01-17|language=en | first = Henry | last = Köhler}}</ref>]]

*[[Post-exertional malaise]] (PEM) is the hallmark symptom of ME/CFS. After physical, mental or emotional [[exertion]] (which for some patients can be a shower or making out a to-do list, others grocery shopping, socializing or reading a news article, while some just walking to the mailbox, getting to the doctor or mentally following a T.V. program)<ref name="what-is" /><ref name="symptoms"/><ref name="Cairns2005" /> there is a payback of significant '''worsening''' [[List of symptoms in ME CFS|ME/CFS symptoms]] which can be [[Delayed onset of post-exertional symptoms|delayed for 24-72 hours or more]]<ref name="symptoms"/><ref name="Lindheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise | url = https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref><ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> and can last 24 hours and even days, weeks, or months.<ref name="VanNess2010">{{Cite journal | last = VanNess | first=J. Mark | last2 = Stevens | first2 = Staci R. | last3 = Bateman | first3 = Lucinda | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health (2002)|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref><ref>[https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf The Voice of the Patient.] A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative. September 2013</ref> The patient will experience even greater fatigue as well as exasperate the [[flu-like symptoms]] and body [[pain]]. Every patient experiences different symptoms and symptom severity from different activities and exertion output according to how sick he or she is with the disease.<ref name="prognosis" /><ref name="what-is" /><ref name="Cairns2005" /> Regarding PEM the [[CFIDS Association of America]] states:
<blockquote>This is a term which describes a symptom in which exercise or exertion can bring on [[malaise]] (illness). In the case of people with ME/CFS, malaise often occurs during a period some 24-72 hours after exertion. For example, in some cases, a short walk can worsen ME/CFS symptoms two days later. This lack of understanding about the delayed onset of symptoms has, in the past, made it harder to test for ME/CFS. Follow up tests, taken less than 24 hours after an initial exercise test, may show that the patient can still perform activities at the same level (before post exertional malaise has a chance to take hold).<ref>[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html What Health - International CFS/ME Awareness Day 2017 - CFIDS Association of America]</ref></blockquote>
*[[chronic fatigue]]
*[[cognitive dysfunction]]

*[[orthostatic intolerance]] (OI) such as [[postural orthostatic tachycardia syndrome]] (POTS) or [[neurally mediated hypotension]] (NMH)
*[[unrefreshing sleep]]/[[sleep dysfunction|sleep disturbance]] <ref name="DiagnosticAlgorithm" /><ref name="clinicians" />
==== Other possible symptoms ====
*[[chronic pain]]
*[[immune system]]
*[[:Category:Neurological signs and symptoms|neurological signs and symptoms]] See also: [[neuroinflammation]].
*[[List of symptoms in ME CFS|List of symptoms in ME/CFS]]

=== Comorbids ===
*[[fibromyalgia]] (FMS)
*[[irritable bowel syndrome]] (IBS)
*[[multiple chemical sensitivity]] (MCS)
*[[temporomandibular joint disorder]] (TMJ) <ref>[http://solvecfs.org/what-is-mecfs/ What is ME/CFS? - Solve ME/CFS Initiative]</ref>

=== Government guides on symptoms ===
'''US Government guides on symptoms'''
*[https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf Clinicians Guide] via The [[Institute of Medicine report]] (IOM)
*[https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html CDC - ME/CFS Symptoms]

'''Canada guides on symptoms'''
*[http://linkis.com/org/tUheh Alberta Clinicians Guide]

===Biological abnormalities===
Because there is currently no biomedical test for ME/CFS, many have incorrectly assumed that there are no medical abnormalities found in people with the illness. As a result, ME/CFS symptoms are often considered to be [[Medically unexplained physical symptoms|medically unexplained]], and therefore [[Psychologization|psychological]] in origin. While it is true that the illness is poorly understood, many biological abnormalities have been found in a range of different body systems, particularly in the [[central nervous system]], [[autonomic nervous system]], [[immune system]], and [[Metabolic|energy metabolism]].<ref name="IOM2015MECFS" /> Unfortunately, none have yet proved to be specific enough to ME/CFS as to be useful as a [[Diagnostic biomarker|biomarker]] of the disease, and many were identified in small studies, which need replication. Whilst there have been [[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis|many abnormalities identified]] found to be associated with the disease, it cannot yet be determined whether these are a cause or consequence.
* [[Gastrointestinal system]]
* [[Natural killer cell]]

==== Notable studies ====
* [[Cytokine#Notable_studies|Cytokine ("Notable studies")]]
*Immune findings by [[Mady Hornig]] & [[Ian Lipkin]]<ref name="Hornig20150201immune" />
*[[List of enterovirus infection studies]]

*2014, [[Neuroinflammation]] Japanese Neuroinflammation study<ref name="NakatomiY2014" />
*2015, Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology<ref name="stanfordleptin">{{Cite journal | last1 = Stringer | first1 = EA | last2 = Baker | first2 = KS | last3 = Carrol | first3 = IR | last4 = Montoya | first4 = JG | authorlink4 = Jose Montoya | last5 = Chu | first5 = L | authorlink5 = Lily Chu | last6 = Maeker | first6 = HT | last7 = Younger | first7 = JW | authorlink7 = Jarred Younger| title = Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology | journal = J Transl Med.| date = Apr 9, 2013 | pmid = 23570606 | pmc = 3637529 | doi = 10.1186/1479-5876-11-93| url = http://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 }}</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 (Full text)]
::Younger's Leptin study
*2014, Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome<ref name="Zeineh2014">{{Cite journal | last = Zeineh | first = Michael M. | author-link = Michael Zeineh | last2 = Kang | first2 = James | last3 = Atlas | first3 = Scott W. | last4 = Raman | first4 = Mira M. | last5 = Reiss | first5 = Allan L. | last6 = Norris | first6 = Jane L. | last7 = Valencia | first7 = Ian | last8 = Montoya | first8 = Jose G. | date = 2014-10-29 | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome | url = https://pubs.rsna.org/doi/10.1148/radiol.14141079|journal=Radiology|volume=274|issue=2 | pages = 517–526|doi=10.1148/radiol.14141079|issn=0033-8419}}</ref>
<blockquote>Bilateral [[white matter]] atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a [[Diagnostic biomarker|biomarker]] for CFS.</blockquote>
:*2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder - New York Times: Well (2014)|Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder By David Tuller - New York Times: Well]]
[[File:ME-CFS Brain Images.jpg|500px|thumb|center|Top scans: Healthy control patient; Bottom scans: chronic fatigue syndrome (CFS) patient. Image By: [[Michael Zeineh]]]]
*2016, [[Metabolic features of chronic fatigue syndrome]]

*2019, [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy]]<ref name="Mueller2019">{{Cite journal | url = https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink= | last2 = Lin | first2 = Joanne | authorlink2 = | date = 2019 | journal=Brain Imaging and Behavior|volume=14|issue= | pages = 562–572|doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|access-date=2019-01-17 | last3 = Sheriff | first3 =Sulaiman | authorlink3 = | last4 = Maudsley | first4 = Andrew | authorlink4 = | last5 = Younger | first5 = Jarred | authorlink5 = Jarred Younger}}</ref>
**2018, [https://www.youtube.com/watch?v=rxdzaWD5wfU ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study]<ref>{{Cite web | url = https://www.youtube.com/watch?v=rxdzaWD5wfU | title = ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study | date = Dec 14, 2018|access-date=|website=YouTube | last = Younger | first=Jarred | authorlink=Jarred Younger|archive-url=|archive-date=|publisher=SolveCFS}}</ref> (TALK)

===Causes & triggers===

*Outbreaks - see [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|List of outbreaks]]
*Possible infectious triggers: [[Enterovirus]]es, [[Epstein-Barr virus]]<ref name="Hickie2006" />, [[Q fever]]<ref name="Hickie2006" />, [[Ross River virus]]<ref name="Hickie2006" />, [[mononucleosis]]<ref name="Jason, Katz, 2017" />, ([[Ebola virus disease|Ebola]]?)<ref name="Hickie2006" />
*Non-viral triggers - [[trauma]], chemical

== Tests ==
* [[Natural killer cell]] (NKC) Blood Test
* Sleep study for [[sleep apnea]], [[Restless legs syndrome|restless leg syndrome]], and other sleep disturbances.
* [[Tilt table test]] for [[Orthostatic intolerance|OI]] or [[Postural orthostatic tachycardia syndrome|POTS]].

==Treatments==
There are currently no [[U.S. Food and Drug Administration|Food and Drug Administration]] (FDA) approved treatments for ME/CFS. Treatments consist mostly of symptom management, rather than treatment of the underlying cause of the disease, which is not yet understood.<ref name="Primer2014" /> There are many [[:Category:Potential_treatments|potential treatments]], though their evidence-base is limited, as most research into treatments has gone into psychological approaches to treatment.

=== Drugs ===
[[File:Ampligen.jpg|200px|thumb|right|Ampligen]]
Two treatments that have garnered much attention are [[Ampligen]], produced by [[AIM ImmunoTech]] (formerly Hemispherx Biopharma), and [[Rituximab]]. Many people have reported improvements from Ampligen, and a few recovered but relapsed when they stopped taking it.<ref name="TownCFS">{{Cite web | url = https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue | title = A Town for People with Chronic Fatigue Syndrome|website=New Yorker | date = Sep 3, 2019 | first = Mike | last = Mariani|access-date=2022-04-13}}</ref>

Attempts to obtain FDA approval for Ampligen in the US have failed, but it is available to some people on [[compassionate use]].<ref name="experimental">{{Cite web | url = https://ammes.org/experimental-treatments/ | title = Experimental treatments | last = | first = | date = |website=[[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|archive-url=|archive-date=|access-date=2021-03-18}}</ref> [[Argentina]] approved the use of Ampligen for [[Severe and very severe ME|severe ME/CFS]] in 2016.<ref>{{Cite news | url = http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html | title = Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic | last = Hemispherx Biopharma, Inc. | date = Aug 23, 2016|work=GlobeNewswire News Room|access-date=2018-08-13|archive-url=|archive-date=|language=en-US}}</ref><ref>{{Cite news | url = http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf | title = Hemispherx Biopharma, Inc. Executive Informational Overview | last = | first = | date = Nov 27, 2016|work=Crystal Research Associates|access-date=|archive-url=|archive-date=|format=PDF}}</ref> Also in 2016, it was made available on a limited basis in Europe.<ref>{{Cite web | url = https://www.bizjournals.com/philadelphia/news/2016/07/25/hemispherx-ships-ampligen-for-european-chronic.html | title = Hemispherx ships Ampligen for European chronic fatigue syndrome program | last = George | first = John | date = Jul 25, 2016 | website = bizjournals.com|archive-url=|archive-date=|access-date=2018-08-13}}</ref> In July 2018, AIM ImmunoTech announced the expansion of its US [[compassionate use]] program, '''AMP-511''', to new ME/CFS patients for the first time in over a year.<ref>[http://www.4-traders.com/HEMISPHERX-BIOPHARMA-INC-31148494/news/Hemispherx-BioPharma-Opens-FDA-Approved-Reimbursement-Based-Expanded-Access-Treatment-Program-for-26862569/ Hemispherx BioPharma : Opens FDA-Approved Reimbursement Based Expanded Access Treatment Program for ME/CFS to New Enrollees - 4 Traders]</ref><ref>{{Cite web | url = https://finance.yahoo.com/news/hemispherx-biopharma-inc-announces-advancement-133000883.html | title = Hemispherx Biopharma Inc. Announces Advancement in Expanded Access Program for Ampligen in the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last = | first = | author-link =| date = Jan 2, 2019|website=finance.yahoo.com|publisher=GlobeNewswire|language=en-US|archive-url=|archive-date=|access-date=2019-02-10}}</ref>

[[Rituximab]], a lymphoma drug, had shown promising results in initial trials in Norway,<ref>{{Cite journal | last = Fluge | first = Øystein | authorlink = Øystein Fluge | last2 = Risa | first2 = Kristin | authorlink2 = | last3 = Lunde | first3 = Sigrid | author-link3 = | last4 = Alme | first4 = Kine | authorlink4 = | last5 = Rekeland | first5 = Ingrid Gurvin | authorlink5 = | last6 = Sapkota | first6 = Dipak | authorlink6 = | last7 = Kristoffersen | first7 = Einar Kleboe | last8 = Sørland | first8 = Kari | last9 = Bruland | first9 = Ove | date = 2015-07-01 | editor-last = van der Feltz-Cornelis|editor-first = Christina | title = B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment | url = http://dx.plos.org/10.1371/journal.pone.0129898|journal=PLOS ONE|language=en|volume=10|issue=7| pages = e0129898|doi=10.1371/journal.pone.0129898|issn=1932-6203|pmc=4488509|pmid=26132314|access-date=|quote=|via=}}</ref> and there were groups crowdsourcing funding for further trials in other countries. In 2017, Drs. [[Øystein Fluge]] and [[Olav Mella]] announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab.<ref>{{Cite web | url = https://www.simmaronresearch.com/blog/2017/11/norwegian-rituximab-chronic-fatigue-syndrome-mecfs-trial-fails | title = Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails|website=Simmaron Research|language=en-US|access-date=2021-11-21}}</ref> A phase III trial published in 2019 showed Rituximab does not improve ME/CFS.<ref name="phase3-2019">{{Cite journal | last = Fluge | first = Øystein | last2 = Rekeland | first2 = Ingrid G. | last3 = Lien | first3 = Katarina | last4 = Thürmer | first4 = Hanne | last5 = Borchgrevink | first5 = Petter C. | last6 = Schäfer | first6 = Christoph | last7 = Sørland | first7 = Kari | last8 = Aßmus | first8 = Jörg | last9 = Ktoridou-Valen | first9 = Irini | date = 2019-04-02 | title = B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial | url = https://www.ncbi.nlm.nih.gov/pubmed/30934066|journal=Annals of Internal Medicine|doi=10.7326/M18-1451|issn=1539-3704|pmid=30934066}}</ref> 

[[Jarred Younger]] announced in March 2016 that he will be undertaking a trial of [[low dose naltrexone]] (LDN) in ME/CFS.<ref name="younger-research">{{Cite web | last = Younger | first=Jarred | authorlink = Jarred Younger | title = Research. Neuroinflammation Pain and Fatigue Laboratory|access-date= Nov 21, 2021 | url = https://sites.uab.edu/younger/research/}}</ref>

=== Treating other conditions ===
Different forms of [[Orthostatic intolerance|OI]] are treated with beta-blockers (Metopropol), [[Fludrocortisone]] (Florinef), and [[Mestinon|Pyridostigmine]].<ref name="Carruthers, 2003" /> When treating other diseases, illnesses, and conditions, and ME/CFS comorbidities or overlapping conditions such as sleep difficulties, cognitive problems, pain, and other symptoms it is important to remember that patients are [[Medicine sensitivities|sensitive to medications]].<ref name="monitor">{{Cite web | title = Monitoring the Use of All Medicines and Supplements {{!}} Clinical Care of Patients {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/monitoring-medication.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-27|language=en-us}}</ref> The CDC advice to health care practitioners is to be aware that because all drugs can cause side effects, ME/CFS patient symptoms can worsen. "This is particularly true of any medication that acts on the [[central nervous system]], such as sedating medications: therapeutic benefits can often be achieved at lower-than-standard doses. Patients with ME/CFS might tolerate or need only a fraction of the usual recommended doses for medications. After initial management with lower dosing, one or more gradual increases may be considered as necessary and as tolerated by the patient."<ref name="prognosis" /> For instance, tricyclic drugs can improve mood and help with sleep and pain. However, in some in can worsen OI.<ref name="prognosis" />
===Exercise as treatment===
[[File:J Brea TED.JPG|200px|thumb|right|[[Jen Brea|Jennifer Brea]] is an [[United States|American]] who was studying at Harvard; while on a trip to [[Kenya]] she became very ill with what would eventually be diagnosed as [[ME/CFS]]. Brea began experiencing [[Nervous system|neurological]] problems. Her neurologist diagnosed her with "conversion disorder" ([[hysteria]]). When walking home from his office, she collapsed. [[Severe and very severe ME|Jen then needed to use a wheelchair]] keeping her legs up due to [[Postural orthostatic tachycardia syndrome|POTS]] as her blood pooled into her legs]].
Previously, two common treatment recommendations for ME/CFS were [[graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT). These treatments are based on disproven the hypothesis that the disease might have begun with a viral infection but has been perpetuated by [[deconditioning]] from lack of activity, and [[illness beliefs|fear and avoidance]] of activity. GET and CBT are aimed at addressing these hypothesized causes by challenging the proposed unhelpful thoughts that result in avoidance of activity and reconditioning through a gradual increase in exercise. These treatments are controversial and are at odds with much of the research literature, which suggests that exercise is harmful to people with ME/CFS. A large patient survey of treatment responses found that 74% of people who had tried GET, reported that their symptoms subsequently worsened,<ref name="MEASSUK20150529survey" /> which is consistent with other patient surveys and many research findings.<ref name="Phoenix20160222Norway2012" /><ref name="OxfordBrookesSurvey">{{Cite web|url = https://www.meassociation.org.uk/wp-content/uploads/NICE-Patient-Survey-Outcomes-CBT-and-GET-Final-Consolidated-Report-03.04.19.pdf| title = Evaluation of a survey exploring the experiences of adults and children with ME/CFS who have participated in CBT and GET interventional programmes. FINAL REPORT | last = Oxford Clinical Allied Technology and Trials Services Unit (OxCATTS)|location=Oxford Brookes University | date = Feb 27, 2019}}</ref>

The [[PACE trial]], published in 2011, is the largest GET trial ever conducted. It has received much publicity as a result of its recovery rate claims, though it has come under strong criticism from within both the scientific and patient community for significant flaws in its design, and for overstating (and in some cases misrepresenting) outcomes in both the initial trial, and follow-up studies.<ref>{{Cite journal | last = Coyne | first = James Charles | last2 = Laws | first2 = Keith R | date = 2016 | title=Results of the PACE follow-up study are uninterpretable | url = http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00551-9/fulltext|journal=The Lancet Psychiatry|language=English|volume=3|issue=2| pages = e6–e7|doi=10.1016/S2215-0366(15)00551-9|issn=2215-0366|via=}}</ref> From 2015 to present day, the study was the subject of a series of investigative pieces that were highly critical of the trial by journalist Dr. [[David Tuller]]<ref name="viroblogMECFS" />, science writer [[Julie Rehmeyer]], patient advocate [[Tom Kindlon]], Dr. [[Keith Geraghty]]<ref name="Geraghty, 2017">{{Cite journal | last1 = Geraghty | first1 = Keith | authorlink1 = Keith Geraghty| title = Further Commentary on the PACE Trial: Biased Methods and Unreliable Outcomes| journal = Journal of Health Psychology | volume = | issue = | page = | date = May 2017 | doi = 10.1177/1359105317714486}}</ref>, psychologist [[Carolyn Wilshire]]<ref name="Wilshire C, et al, 2017">{{Cite journal | last1 = Wilshire | first1 = C | authorlink1 = Carolyn Wilshire | last2 = Kindlon | first2 = T | authorlink2 = Tom Kindlon | last3 = McGrath | first3 = S | authorlink3 = Simon McGrath | title = PACE trial claims of recovery are not justified by the data: a rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White | journal = Fatigue: Biomedicine, Health & Behavior | volume = 5 | issue = 1 | page = 62-67 | date = 2017 | doi = 10.1080/21641846.2017.1259724}}</ref> and others. A petition signed by almost 12,000 ME/CFS patients and allies,<ref name="MEACTIONpacepetition" /> and an open letter signed by 42 ME/CFS experts from around the world,<ref name="openletrLANCET2">{{Cite web | last1 = Davis | first1 = Ronald W | authorlink1 = Ronald Davis | last2 = Edwards | first2 = Jonathan C W | authorlink2 = Jonathan Edwards | last3 = Jason | first3 = Leonard A | authorlink3 = Leonard Jason | last4 = Levin | first4 = Bruce | authorlink4 = Bruce Levin | last5 = Racaniello | first5 = Vincent R | authorlink5 = Vincent Racaniello | last6 = Reingold | first6 = Arthur L | authorlink6 = Arthur Reingold | last7 = Ablashi | first7 = Dharam V | authorlink7 = Dharam Ablashi | last8 = Baraniuk | first8 = James N | authorlink8 = James Baraniuk | last9 = Barcellos | first9 = Lisa F | authorlink9 = Lisa Barcellos | last10 = Bateman | first10 = Lucinda | authorlink10 = Lucinda Bateman | last11 = Bell | first11 = David S | authorlink11 = David Bell | last12 = Bested | first12 = Alison C | authorlink12= Alison Bested | last13 = Broderick | first13 = Gordon | authorlink13 = Gordon Broderick | last14 = Chia | first14 = John | authorlink14 = John Chia | last15 = Chu | first15 = Lily | authorlink15 = Lily Chu | last16 = Enlander | first16 = Derek | authorlink16 = Derek Enlander | last17 = Fletcher | first17 = Mary Ann | authorlink17 = Mary Ann Fletcher | last18 = Friedman | first18 = Kenneth | authorlink18 = Kenneth Friedman | last19 = Kaufman | first19 = David L | authorlink19 = David Kaufman | last20 = Klimas | first20 = Nancy | authorlink20 = Nancy Klimas | last21 = Lapp | first21 = Charles W | authorlink21 = Charles Lapp | last22 = Levine | first22 = Susan | authorlink22 = Susan Levine | last23 = Light | first23 = Alan R | authorlink23 = Alan Light | last24 = Marshall-Gradisnik | first24 = Sonya | authorlink24 = Sonya Marshall-Gradisnik | last25 = Medveczky | first25 = Peter G | authorlink25= Peter Medveczky | last26 = Nahle | first26 = Zaher | authorlink26 = Zaher Nahle | last27 = Oleske | first27 = James M | authorlink27= James Oleske | last28 = Podell | first28 = Richard N | authorlink28= Richard Podell | last29 = Shepherd | first29 = Charles | authorlink29= Charles Shepherd | last30 = Snell | first30 = Christopher R | authorlink30 = Christopher Snell | last31 = Speight | first31 = Nigel | authorlink31= Nigel Speight | last32 = Staines | first32 = Donald | authorlink32= Donald Staines | last33 = Stark | first33 = Philip B | authorlink33= Philip Stark | last34 = Stein | first34 = Eleanor | authorlink34= Eleanor Stein | last35 = Swartzberg | first35 = John | authorlink35= John Swartzberg | last36 = Tompkins | first36 = Ronald G | authorlink36= Ronald Tompkins | last37 = Underhill | first37 = Rosemary | authorlink37= Rosemary Underhill | last38 = Vallings | first38 = Rosamund | authorlink38= Rosamund Vallings | last39 = VanElzakker | first39 = Michael | authorlink39= Michael VanElzakker | last40 = Weir | first40 = William | authorlink40= William Weir | last41 = Zinn | first41 = Marcie L | authorlink41= Marcie Zinn | last42 = Zinn | first42 = Mark A | authorlink42= Mark Zinn | title = An open letter to the Lancet - again | date = Feb 10, 2016
| website = Virology Blog| url = http://www.virology.ws/2016/02/10/another-request-for-data-from-the-pace-trial/ }}</ref> were sent to The Lancet, both calling for the data to be reanalysed. Twenty-four ME/CFS organizations from 14 different countries have written to Queen Mary University London requesting that the trial data be released for reanalysis.<ref name="MEACTION20160313openletr" /> To date, the authors of the trial and editor of The Lancet have refused such requests. Despite such criticism, the PACE trial continues to influence both government and the medical profession's approach to the treatment of ME/CFS in many countries.

One of the reasons that exercise may be harmful to people with ME/CFS, is the presence of [[post-exertional malaise]] (PEM), which is an exacerbation of symptoms following physical, mental or even emotional [[exertion]]. Studies have revealed immunological, muscular, [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]] and [[Cardiovascular system|cardiovascular]] abnormalities in response to exercise in people with ME/CFS. As these results are not also found in healthy sedentary controls, the adverse effects of exercise cannot be said to be due to deconditioning.<ref name="TwiskF2015">{{Cite journal | last1 = Twisk | first1 = Frank NM | authorlink1 = Frank Twisk | last2 = Geraghty | first2 = Keith J | authorlink2 = Keith Geraghty | title = Deviant Cellular and Physiological Responses to Exercise in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome| journal = Jacobs Journal of Physiology | volume = 1 | issue =2 | pages = 007 | date = Jul 11, 2015 | url = http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf}}</ref>{{citation needed|reason=VanNess2010 / Workwell Foundation studies need to be cited here.}}{{citation needed|reason=The Lights epigenetic changes post-exercise study needs to be cited here.}}

People with ME/CFS should approach [[exercise]] with caution, as there is much evidence of potential for harm.<ref name="OxfordBrookesSurvey"/><ref name="ICC2011primer"/>

[[Anaerobic threshold]], use of heart rate monitors for activity and [[pacing]]. Analeptic, not aerobic. [[Energy Envelope Theory|Energy envelope]]/pacing - people do better if stay within their envelope, than push to increase activity

====Graded exercise therapy & Cognitive behavioral therapy ====
[[File:Emma Shorter.JPG|400px|thumb|right|[[Emma Shorter]], is a citizen of [[Scotland]]. Here, she gives testimony before Parliament's Petitions Committee on [[graded exercise therapy|GET]] and how it put her in a wheelchair]].
GET and CBT have been recently abandoned in the [[United Kingdom|UK]], [[Ireland]] and many parts of Europe by ME Clinics.<ref name="niceng206">{{Cite web | url = https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref> They are highly controversial and not recommended by patients, most patient advocates, and research organizations nor by many doctors or researchers outside of the UK. Based on the flawed [[PACE trial]] which used the flawed [[Oxford criteria]] to diagnose and recruit patients, GET and CBT found its way into treating people with ME/CFS.

[[Exercise]], especially GET, can harm an ME/CFS patient further.<ref name="OxfordBrookesSurvey"/>

*[[Jennifer Brea]] walked home from her Neurologist's office and became [[severe and very severe ME|wheelchair-bound]].
*This is an experience of serious harm due to GET shared [https://twitter.com/TomKindlon/status/846425974052966400 by K. Miles, via Tom Kindlon on Twitter].
*[[Emma Shorter]] was able to walk a few minutes a day until GET put her in a wheelchair.
*[[Maik Speedy|Dr Maik Speedy]] was also seriously injured by GET and has been bedbound since.
*British MP [[Brynmor John]] collapsed outside the House of Commons gym in 1998 and [[Causes of death|died]], as a result of following his doctor's advice to exercise back to health.

==== Claims of recovery and cures ====
Charlatans claim they can cure CFS (per the CDC "there is no cure"<ref name="treatments">{{Cite web | url = https://www.cdc.gov/me-cfs/treatment/index.html | title = Treatment {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last = | first = | date = 2018-07-03 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|access-date=2021-11-22}}</ref>) when in reality they may be able to treat [[chronic fatigue]] (CF). ME/CFS patients experience an ongoing improper immune response and other abnormalities for at least 6 months straight with a reduction in activity with a specific symptom set for at least 50% of the time.<ref name="etiology" /><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html | title = IOM 2015 Diagnostic Criteria {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-09-07}}</ref><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/approach-to-diagnosis.html | title = Proposed Approach to ME/CFS Diagnosis in Children and Adults {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-12 | website = [[Centers for Disease Control and Prevention]] |language=en-us|access-date=2018-09-07}}</ref>

Additionally, there have been media reports of some athletes―usually amateur athletes,―diagnosed with CFS that recovered after a relatively short period of time with rest, supplementation, and diet changes,<ref name="Inews2018" /><ref name="Times2017" /><ref name="ABC2018" /><ref name="London2019" /> but they may have had [[overtraining syndrome]],<ref name="spence">{{Cite web | last = Spence | first = Vance | authorlink = Vance Spence|website=Irish M.E. Association| title = Snippets {{!}} A presentation by MERGE Chairman Dr Vance Spence on 12 November 2005 at the Oak Tree Court Conference Centre, Coventry, at the invitation of the Warwickshire Network for ME|url = https://www.imet.ie/imet_website/snippets/7th_december_2005_snippets.html|quote=(Mommersteeg et al, 2005) shows that the "burnout" experienced by athletes differs from CFS, and is certainly not ME as described in earlier literature. This is just one example of many media stories - thrown out into the public arena - which have an uncertain meaning in the context of ME/CFS}}</ref> while some people with adrenal failure, [[idiopathic chronic fatigue]] or another fatiguing illness may be erroneously diagnosed with CFS<ref name="ICC"/><ref name="recovery">{{Cite web | url = https://www.researchgate.net/profile/Diane_Cox2/publication/257764167_Severe_Chronic_Fatigue_Syndrome_CFSME_Recovery_is_possible/links/00b49525d3a11018ad000000/Severe-Chronic-Fatigue-Syndrome-CFS-ME-Recovery-is-possible.pdf | title = Severe Chronic Fatigue Syndrome: Recovery is Possible | last = Burley | first = Lucy | authorlink=Lucy Burley | last2 = Cox | first2 = Diane | authorlink2 = Diane Cox | date = Aug 1, 2007|pages=339-344|language=en|doi=10.1177/030802260707000803|archive-url=|archive-date=|url-status=|access-date=2019-02-11 | last3 = Findley | first3 = Leslie|journal=British Journal of Occupational Therapy|volume=70|issue=8 | authorlink3 = Leslie Findley}}</ref><ref name="Anoop2012">{{Cite journal | last = Devasahayam | first = Anoop | author-link = | last2 = Lawn | first2 = Tara | authorlink2 = | last3 = Murphy | first3 = Maurice | authorlink3 = | last4 = White | first4 = Peter D | authorlink4 = Peter White | date = Jan 2012 | title = Alternative Diagnoses to Chronic Fatigue Syndrome in Referrals to a Specialist Service: Service Evaluation Survey | url = https://journals.sagepub.com/doi/epub/10.1258/shorts.2011.011127|journal=JRSM Short Reports|volume=3|issue=1|pages=1–5|doi=10.1258/shorts.2011.011127|issn=2042-5333|pmc=PMC3269106|pmid=22299071|access-date=|quote=Half of all the referred patients to a specialist CFS clinic had alternative medical and psychiatric diagnoses.|via=}}</ref> ME and CFS in professional athletes normally results in very premature retirement.<ref name="Squash">{{Cite news | title = Illness robbed Marshall of crowning glory | first = Sam | last = Murley | date = Apr 10, 2019 | url = https://www.royalgazette.com/sport/article/20190410/illness-robbed-marshall-of-crowning-glory/|publisher =Royal Gazette}}</ref><ref name="Annadale">{{Cite web| title = Annadale Striders Interview - Derek Graham | url = http://annadalestriders.co.uk/derek-graham-interview/|website=Annadale Striders}}</ref><ref name="Shattered">{{Cite book |url = https://books.google.co.uk/books/about/Shattered.html?id=mkbxPAAACAAJ&redir_esc=y | title = Shattered: A Champion's Fight Against a Mystery Illness | first=Peter | last= Marshall | first2 = Nick | last2 = Kehoe | date = 2001|publisher =Mainstream}}</ref><ref name="Olympian">{{Cite news | date = May 4, 2012| title = Linley Frame: Olympian and Chronic Fatigue Syndrome sufferer|url = https://www.abc.net.au/local/audio/2012/05/04/3495770.htm|website =Australian Broadcasting Corporation}}</ref><ref name="FIFA">{{Cite web|url = http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-url=https://web.archive.org/web/20150610042710/http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-date = 2015-06-10| title = Michelle Akers USA|website=FIFA}}</ref><ref name="olaf">{{Cite news | url = https://www.welt.de/sport/gallery118782921/Benefizspiel-fuer-den-schwer-kranken-Olaf-Bodden.html | title = Benefizspiel für den schwer kranken Olaf Bodden | last = | first = | date = 2021 | website = Die Welt|archive-url=|archive-date=|url-status=|access-date=2021-11-17}}</ref><ref name="LA">{{Cite news | title = Garton enjoying life after United in LA | first = Andy | last = Mitten | date = Jul 24, 2014 | url = https://www.manchestereveningnews.co.uk/sport/football/football-news/andy-mitten-billy-garton-enjoying-7508558.amp|website =Manchester Evening News}}</ref>

==Severely ill patients==
Considerable variation exists in the severity of the disease. The [[International Consensus Criteria]] lists the following severity levels (it should be noted that even "mild" ME/CFS consists of significant debility):

*Mild = 50% reduction in pre-illness activity levels
*Moderate = mostly housebound
*Severe = mostly bedridden
*Very Severe = totally bedridden, and needing help with basic functions.

At least [[Severe and very severe ME|25% of people with ME/CFS are bedbound or housebound]], often for years or even decades, so are largely an invisible population.<ref name="IOM2015MECFS" /><ref name="DerekPrisk2009" /><ref>[http://iacfsme.org/PDFS/2017JanNewsletter/8-Japan-2014-Patient-Survey.aspx ME/CFS Patient Survey Report: Ministry of Health Survey Reveals Harsh Reality of ME/CFS Patients in Japan - IACFSME - By Mieko Shinohara]</ref> So invisible in fact, that they have rarely been included as part of research because their level of debility precludes them from traveling to laboratories for required testing. The [[Open Medicine Foundation]]'s [[ME/CFS Severely Ill, Big Data Study]] will be the first in-depth study of people with a severe form of ME/CFS. This study has so far produced the groundbreaking paper [[Metabolic features of chronic fatigue syndrome]].
It is estimated that 25% of ME/CFS patients are severely ill and are housebound or bedbound.

Notable patients with severe or very severe ME/CFS include [[Whitney Dafoe]], [[Karina Hansen]], [[Lynn Gilderdale]], [[Laura Hillenbrand]], [[Tom Kindlon]], [[Vanessa Li]], [[Doctor Speedy]], [[Naomi Whittingham]], [[Jamison Hill]] and [[Jessica Taylor-Bearman]].

Though uncommon, there have been [[causes of death|instances of deaths]] which have been attributed to the disease (see [[Sophia Mirza]], [[Merryn Crofts]]). National Statistics report an average of 10 - 12 deaths per year in England and Wales [[Causes of death|partly or fully caused by ME/CFS]], with almost all patients dying being of working age.
<ref name="ONS2018">{{Cite web | url = https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/adhocs/008461mentionsofpostviralfatiguesyndromebenignmyalgicencephalomyelitisdeathsregisteredinenglandandwales2001to2016 | title = Mentions of postviral fatigue syndrome (benign myalgic encephalomyelitis), deaths registered in England and Wales, 2001 to 2016 | website = Office for National Statistics|access-date=2019-03-06}}</ref>

==Patients and psychiatry/psychology==

*Objections and scope
*Mind-body dualism
*[[Psychologization]]
*[[Cognitive behavioral therapy]]
*The [[PACE trial]]. See [http://www.meaction.net/wp-content/uploads/2015/05/MEAction%E2%80%93patient-view-of-the-PACE-Trial-Controversy.pdf Patient view of the PACE Trial controversy]
*[[Ethical issues]]
*[[Patient mental health]]

===Stigmatization===

*Pretty young women slumped on desk
*[[Yuppie Flu]]
*Accusations of laziness/lethargy
*Epidemiological evidence - age, gender, demographic, racial/cultural
*[[Stigma and discrimination]]

===Accusations of harassment===

*No arrests or convictions<ref>{{Cite web | url = http://www.virology.ws/2016/02/01/trial-by-error-continued-a-few-words-about-harassment/ | title = Trial By Error, Continued: A Few Words About “Harassment” | last = Tuller | first = David | authorlink = David Tuller | date = Feb 1, 2016 | website = [[Virology blog]]|archive-url=|archive-date=|access-date=2019-01-21}}</ref>
* Potential harassment and "wild speculations" about threats to researchers were unsuccessful arguments used in [[Queen Mary University of London]]'s failed attempt to deny access to the [[PACE trial]] data at the 2015 tribunal. The tribunal judgement stated that the only evidence of harassment provided was a single heckler in a single seminar.<ref name="FirstTierTribunal2015">{{Cite news | title = First-tier tribunal: Information Rights Appeal EA/2015/0269. | url = https://informationrights.decisions.tribunals.gov.uk//DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF | page = 40 | last = Kennedy | first = Brian | last2 = Stephenson | first2 = Darryl | last3 = Watson | first3 = Nigel|quote=The evidence of <nowiki>[expert witness]</nowiki> Professor Anderson that third parties could not identify participants from the information alone and that, when pressed, he said that the chance of an "activist" being able to discover information that would lead to individual identification was remote, it was clear that his assessment of activist behaviour was, in our view, grossly exaggerated and the only actual evidence was that an individual at a seminar had heckled Professor Chalder. The identity of those questioning the research, who had signed an open letter or supported it, was impressive.}}</ref>

*Mistreatment of patients, including forced harmful treatment of children, is not mentioned. E.g., the story of "B", aged 8,<ref name="StoryofB">{{cite web | title = The Story of B - Children with ME. Appropriate ME Treatment Parliament debate | date = Jan 24, 2018 | url = https://www.youtube.com/watch?v=5HzZ4U6yU6o&autoplay=0}}</ref> and [[Ean Proctor]] and others "The Mental Health Movement: Persecution of Patients?"<ref>[http://www.theoneclickgroup.co.uk/documents/ME-CFS_docs/The%20Mental%20Health%20Movement%20-%20Persecution%20of%20Patients.pdf The Mental Health Movement: Persecution of Patients?]</ref>

* A pattern of [[intimidation and bullying of PACE trial critics]] has included targeting scientists' employers, professional bodies, politicians including the [[Countess of Mar]], and smear tactics in the national press.

== Working with government to move forward ==

Advocates met with senate staffers the week of March 16, 2016, and discussed research and drug development by the [[NIH]], the [[Centers for Disease Control and Prevention|CDC]] reinstating and increasing funding and education based on [[IOM]] recommendations and the [[HHS]] funding to develop Centers of Excellence.<ref>[http://www.meaction.net/2016/03/16/meaction-meets-with-senate-staffers/ #MEAction meets with Senate staffers]</ref> [[The MEAction Network]] reports on this ongoing process.

====CDC Website updates====
*Jul 3, 2017, the CDC's Chronic Fatigue Syndrome page has been changed to [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] (ME/CFS) and GET and CBT recommendations have been removed.<ref>{{Cite web|url = http://www.virology.ws/2017/07/10/trial-by-error-the-cdc-drops-cbtget/ | title = Trial By Error: The CDC Drops CBT/GET - Virology Blog | last = Tuller | first = David | authorlink = David Tuller | date = Jul 10, 2017 | website = [[Virology blog]]}}</ref><ref>[https://www.cdc.gov/me-cfs/index.html Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - CDC.gov]</ref>

*Jul 12, 2018, the "Information for Healthcare Providers" tab and its sub-tabs were updated.<ref>[https://www.cdc.gov/me-cfs/healthcare-providers/index.html Information for Healthcare Providers - ME/CFS - CDC]</ref><ref>[https://www.cdc.gov/media/releases/2018/a0712-new-website-me-cfs.html New ME/CFS Web Content for Healthcare Providers - CDC - Jul 12, 2018]</ref>

* Feb 25, 2019, Dr. [[Elizabeth Unger]], Chief of CDC's Chronic Viral Disease Branch (CVDB), that houses the ME/CFS program, in collaboration between ''Medscape'' and the CDC put out brief video and commentary page with links to the CDC's July 12th, 2018 updates for medical professionals: ''[https://www.medscape.com/viewarticle/908622?src=rss Chronic Fatigue Syndrome: It's Real, and We Can Do Better].''<ref>{{Cite web | title = Chronic Fatigue Syndrome: It's Real, and We Can Do Better |url = https://www.medscape.com/viewarticle/908622?src=rss| website = Medscape |access-date=2019-02-25 | date = Feb 25, 2019 | last = Unger | first=Elizabeth | authorlink = Elizabeth Unger | last2 = Medscape | first2 = | authorlink2 = |archive-url=|archive-date=}}</ref>
'''MEAction input'''
*Jul 29, 2018, [https://www.meaction.net/2018/07/29/cdc-revises-its-information-on-me/ CDC Revises its Information on ME] #[[MEAction]] report on the CDC July 2017 and July 2018 website updates. Recommendations for the CDC's ME/CFS page have been created from patient feedback on the updates as well as asking for further patient input.

==Expert opinions==

===Quotes from ME/CFS experts and patients===
*[[Individual quotes]]
*[http://thoughtsaboutme.com/quotes/ Thoughts About ME - List of Quotes]

===Doctors===
'''UK'''
*[[Jonathan Edwards]]
*[[Charles Shepherd]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">

*[[Lucinda Bateman]]
*[[Lily Chu]]
*[[David Kaufman]]
*[[Nancy Klimas]]
*[[Anthony Komaroff]]
*[[Susan Levine]]
*[[Jose Montoya]]
*[[Benjamin Natelson]]
*[[Daniel Peterson]]
*[[Alan Pocinki]]
*[[Peter Rowe]]
*[[Ronald Tompkins]]
*[[David Tuller]]

</div>

===Researchers===
'''Australia'''
*[[Neil McGregor]]

'''UK'''
*[[Keith Geraghty]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">
*[[Ron Davis]]
*[[Gunnar Gottschalk]]
*[[Maureen Hanson]]
*[[Mady Hornig]]
*[[Leonard Jason]]
*[[Betsy Keller]]
*[[Ian Lipkin]]
*[[Staci Stevens]]
*[[Suzanne Vernon]]
*[[Jarred Younger]]

</div>

===Patients===
====Australia====

===== Canada =====
*[[Scott Simpson]]

====Scotland====
*[[Emma Shorter]]

====US====
<div style="column-count:2;">
*[[Jennifer Brea]]
*[[Carol Head]]
*[[Ryan Prior]]
*[[Julie Rehmeyer]]
*[[Jaime Seltzer]]
</div>

====UK====
*[[Adam Lowe]]
*[[Graham McPhee]]
*[[Jessica Taylor-Bearman]]

====Ireland====
*[[Tom Kindlon]]

===Patient groups & charities===

'''[[:Category:Patient groups|Patient groups]]'''
<div style="column-count:3">
*[[:Category:American patient groups|American patient groups]]
*[[:Category:Australian patient groups|Australian patient groups]]
*[[:Category:Belgian patient groups|Belgian patient groups]]
*[[:Category:British patient groups|British patient groups]]
*[[:Category:Canadian patient groups|Canadian patient groups]]
*[[:Category:Dutch patient groups|Dutch patient groups]]
*[[:Category:Irish patient groups|Irish patient groups]]
*[[:Category:Italian patient groups|Italian patient groups]]
*[[:Category:New Zealand patient groups|New Zealand patient groups]]
*[[:Category:Norwegian patient groups|Norwegian patient groups]]
*[[:Category:Scottish patient groups|Scottish patient groups]]
*[[:Category:Swedish patient groups|Swedish patient groups]]
</div>

==Photos==
*[https://phoenixrising.me/stock-photography Stock photographs suitable for ME/CFS articles] - curated by [[Phoenix Rising]]
*[https://forums.phoenixrising.me/threads/the-real-me-a-stock-photography-resource-for-the-media.43734/ Advice on photograph choice]

==History==
*[[Osler's Web|''Osler's Web'']] is a book by [[Hillary Johnson]] on the early history of CFS.
*[[Thirty Years of Disdain|''Thirty Years of Disdain'']] by [[Mary Dimmock]] and Matthew Lazell-Fairman picks up on the ME/CFS history where Osler's Web leaves off.

=== Deaths of ME/CFS patients ===
*[[Causes of death]]
*[[Suicide]]

'''Death certificates with ME or CFS'''
*[[Merryn Crofts]]' death is attributed to ME.
*[[Sophia Mirza]]'s death is attributed to CFS.

In the UK, United States, and Australia there are further reports of loved ones who have died due to ME/CFS.<ref>[https://www.newscientist.com/letter/mg19125620-600-not-sadly-the-first/ Sadly, not the first (Comment Section)]</ref> See Editor's Note<ref>[https://www.newscientist.com/article/dn9342-first-official-uk-death-from-chronic-fatigue-syndrome/ First official UK death from chronic fatigue syndrome - New Scientist]</ref>

==Other tips and articles for journalists==
*2021, [https://www.theopennotebook.com/2021/01/26/how-to-report-with-accuracy-and-sensitivity-on-contested-illnesses/ How to Report with Accuracy and Sensitivity on Contested Illnesses] - by ME/CFS patient and science writer Julie Rehmeyer, Open Notebook
*Always interview a patient
*Interview more than one researcher (not just from the psychological etiology view)
*Avoid using derogatory, outdated & incorrect term "[[Yuppie Flu]]"
*Never shorten the disease name [[chronic fatigue syndrome]] (CFS) to the symptom [[chronic fatigue]] (CF). [[Chronic fatigue syndrome|CFS]], [[myalgic encephalomyelitis|ME]] or [[ME/CFS]] can be used to save print space.
*Use photographic imagery that represents the reality for patients - serious illness & disability - not well-groomed & slightly tired office workers at their computer or students with a pile of books sleeping at their desk. [[Solve ME/CFS Initiative]]'s [https://www.youtube.com/watch?v=cF2OuYFDriY Times Square Public Awareness Ad] shows the reality of the disease ME/CFS. Using photos of patients whether chronically ill yet functioning or a severely ill patient or stock photos that reflect life with this disease is necessary.
{{See also|Long_COVID#Articles_for_journalists_covering_Long_COVID|Articles for journalists covering Long COVID}}

==Learn more==
'''Key facts'''
*[https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf Key Facts] - Institute of Medicine (2015)

'''Research'''
*[[Institute of Medicine report]] (2015) The CDC based its updated [https://www.cdc.gov/me-cfs/index.html ME/CFS page] on information in this report.
*[[Notable studies]]

'''Films'''
*''[[Forgotten Plague]]'' is a US documentary about [[Ryan Prior]], an afflicted journalist who investigates the disease and its history and why the CDC has left millions sidelined from life; available for [http://www.forgottenplague.com/ streaming and DVD purchase]. (2015)
[[File:Forgotten Plague.jpeg|200px|thumb|center]]
*''[[Unrest]]'' is a US documentary film that aired on PBS's ''Independent Lens'' in 2018 and is available for [https://www.unrest.film/watch/#digital streaming] and [https://www.unrest.film/store/ DVD purchase]. [[Jennifer Brea]], a person with [[myalgic encephalomyelitis|ME]], directs. (2017)
[[File:Unrest.jpg|400px|thumb|center]]

'''ME/CFS organization and researchers material'''
*[https://www.youtube.com/watch?v=hRdn4A2SGic Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education] (The CDC's Dr. [[John Iskander]] interviews Dr. [[Anthony Komaroff]]. Video, 2016)
*[https://drive.google.com/file/d/1h_ZwdR4567k-mSoWahnC_id0F_fAA3Fb/view Caring for People with Myalgic Encephalomyelitis] (2018) Guide for Caretakers
*[http://youtu.be/c2vIQ92wU9Y ME/CFS Diagnosis and Name with Dr Nancy Klimas (video)]
*[http://www.openmedicinefoundation.org/what-is-mecfs/ What is ME/CFS?] By the [[Open Medicine Foundation]]

'''[[Patient mental health]]'''

:Patients that had been deemed as suffering from mental health and not a biological illness:
:*[[Karina Hansen]] is a young [[Denmark|Danish]] woman taken from her family for 3 1/2 years due to [[Per Fink]]'s insistence her ME was due to mental health issues.
:*[[Sophia Mirza]] was taken forcibly from her home to a mental hospital only to be returned shortly after; she then died of ME.
:*[[Ean Proctor]] was taken from his parents as a young boy and he was told his "parents were letting him die." He had become [[paralysis|paralyzed]] and mute and was let go in the deep end of a pool to make him swim and another time put him on a scary theme park ride to scare him into moving.

'''More mental health information'''
*ME/CFS is not [[depression]]. It causes a lack of energy, not a lack of desire.<ref name="Griffith, 2008">{{Cite journal | last1 = Griffith | first1 = J.P. | authorlink1 = | last2 = Zarrouf | first2 = F.A. | authorlink2 = | title = A Systematic Review of Chronic Fatigue Syndrome: Don’t Assume It’s Depression| url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292451/| pmc =2292451| journal = Primary Care Companion to The Journal of Clinical Psychiatry | volume = 10 | issue = 2 | page = 120–128| date = 2008 | pmid = 18458765 | doi = 10.4088/pcc.v10n0206 }}</ref><ref name="Hawk, 2006">{{Cite journal | last1 = Hawk | first1 = C | authorlink1 = | last2 = Jason | first2 = L | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = S | authorlink3 = Susan Torres-Harding| title = Differential diagnosis of chronic fatigue syndrome and major depressive disorder | journal = International Journal of Behavioral Medicine | volume = 13 | issue = 3 | page = 244-51 | date = 2006 | pmid = 17078775 | doi = 10.1207/s15327558ijbm1303_8
| url = http://www.healthrising.org/wp-content/uploads/2014/04/Hawk.-Jason.-Differential-Diagnosis-of-Chronic-Fatigue-Syndrome-and-Major-Depressive-Disorder.pdf }}</ref><ref name="myhill">{{Cite web|url = http://drmyhill.co.uk/wiki/CFS_or_depression_-_what_are_the_differences| title = CFS or depression - what are the differences | last = Myhill | first = Sarah | authorlink = Sarah Myhill | website = DrMyhill|access-date = 2021-03-22}}</ref>

==See also==
*[[Primer for the public#Disease_names_and_acronyms_around_the_world|Primer for the public (''Disease names and acronyms around the world'' section)]]

==References==
<references>

<ref name="Hickie2006">{{Cite journal | last1 = Hickie | first1 = Ian | authorlink1 = Ian Hickie | last2 = Davenport | first2 = Tracey | authorlink2 = Tracey Davenport | last3 = Wakefield | first3 = Denis | authorlink3 = Denis Wakefield | last4 = Vollmer-Conna | first4 = Ute | authorlink4 = Ute Vollmer-Conna | last5 = Cameron | first5 = Barbara | authorlink5 = Barbara Cameron | last6 = Vernon | first6 = Suzanne D | authorlink6 = Suzanne Vernon | last7 = Reeves | first7 = William C | authorlink7 = William Reeves | last8 = Lloyd | first8 = Andrew | authorlink8 = Andrew Lloyd | last9 = Dubbo Infection Outcomes Study Group | title = Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study | journal = BMJ | volume = 333 | issue =575 | date = Sep 14, 2006 | pmid = 16950834 | doi = 10.1136/bmj.38933.585764.AE| url = http://www.bmj.com/content/333/7568/575.long}}</ref>
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<ref name="Primer2014">{{Cite web | last1 = ((International Association for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis)) | authorlink = International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | last2 = Friedberg | first2 = Fred | authorlink2 = Fred Friedberg | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Bested | first4 = Alison C | authorlink4 = Alison Bested | last5 = Davenport | first5 = Todd | authorlink5 = Todd Davenport | last6 = Friedman | first6 = Kenneth J | authorlink6 = Kenneth Friedman | last7 = Gurwitt | first7 = Alan R | authorlink7 = Alan Gurwitt | last8 = Jason | first8 = Leonard A | authorlink8 = Leonard Jason | last9 = Lapp | first9 = Charles W | authorlink9 = Charles Lapp | last10 = Stevens | first10 = Staci R | authorlink10 = Staci Stevens | last11 = Underhill | first11 = Rosemary A | authorlink11 = Rosemary Underhill | last12 = Vallings | first12 = Rosamund | authorlink12= Rosamund Vallings | date = 2014 | url=https://www.massmecfs.org/images/pdf/Primer_2014.pdf | title =Chronic Fatigue Syndrome Myalgic Encephalomyelitis Primer for Clinical Practitioners }}</ref>
<ref name="IOM2015MECFS">{{Cite web | last1 = Institute of Medicine (US) | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness| publisher = The National Academies Press | location = Washington, DC, US| date = Feb 10, 2015 | isbn = 978-0-309-31689-7| url = https://pubmed.ncbi.nlm.nih.gov/25695122/}}</ref>
<ref name="Jason, Katz, 2017">{{Cite journal | last1 = Jason | first1 = Leonard A | authorlink1 = Leonard Jason | last2 = Katz | first2 = Ben | authorlink2 = Ben Katz | last3 = Gleason | first3 = Kristen | authorlink3 = | last4 = McManimen | first4 = Stephanie | authorlink4 = Stephanie McManimen | last5 = Sunnquist | first5 = Madison | authorlink5 = Madison Sunnquist | last6 = Thorpe | first6 = Taylor | authorlink6 = | title = A Prospective Study of Infectious Mononucleosis in College Students | journal = International Journal of Psychiatry | volume = 2 | issue = 1 | page = | date = 2017| doi = | url = https://www.researchgate.net/profile/Leonard_Jason/publication/312936696_A_prospective_study_of_Infectious_Mononucleosis_in_college_students/links/588a23cc92851c2779b2568c/A-prospective-study-of-Infectious-Mononucleosis-in-college-students.pdf }}</ref>
<ref name="Klimas20140621video">{{Cite web | last1 = Klimas | first1 = Nancy | authorlink1 = Nancy Klimas | title = ME/CFS Diagnosis and Name with Dr. Nancy Klimas (video)| date = Jun 21, 2014 | url = http://youtu.be/c2vIQ92wU9Y}}</ref>
<ref name="Komaroff20160217video">{{citation | last1 = Komaroff | first1 = Anthony | authorlink1 = Anthony Komaroff | last2 = Iskander | first2 = John | authorlink2 = John Iskander | title = Interview with Dr Anthony Komaroff | journal = CDC Public Health Ground Rounds - Beyond the Data - Chronic Fatigue Syndrome: Advancing Research and Clinical Education | date = Feb 17, 2016 | url = https://youtu.be/hRdn4A2SGic}}</ref>
<ref name="MEACTIONpacepetition">{{Cite web | last1 = #MEAction | authorlink1 = #MEAction | title = Petition: Misleading Claims Should Be Retracted| website = #MEAction | date = Oct 2015 | url = http://my.meaction.net/petitions/pace-trial-needs-review-now}}</ref>
<ref name="MEACTION20160313openletr">{{Cite web | last1 = #MEAction | authorlink1 = #MEAction | title = 24 organisations in 14 countries tell QMUL: Release the PACE data | date = Mar 13, 2016| url = http://www.meaction.net/2016/03/13/24-organisations-in-14-countries-tell-qmul-release-pace-data/#comment-2518}}</ref>
<ref name="MEASSUK20150529survey">{{Cite web | last1 = ME Association (UK) | authorlink1 = ME Association | date = May 29, 2015 | title = Our CBT, GET and Pacing Report calls for major changes to therapies offered for ME/CFS| url = http://www.meassociation.org.uk/2015/05/23959/ }}</ref>
<ref name="NakatomiY2014">{{Cite journal | last1 = Nakatomi | first1 = Yasuhito | authorlink1 = Yasuhito Nakatomi | last2 = Mizuno | first2 = Kei | authorlink2 = Kei Mizuno | last3 = Ishii | first3 = Ishii | authorlink3 = Akira Ishii | last4 = Yasuhiro | first4 = Wada | authorlink4 = Yasuhiro Wada | last5 = Masaaki | first5 = Tanaka | authorlink5 = Masaaki Tanaka | last6 = Shusaku | first6 = Tazawa | authorlink6 = Shusaku Tazawa | last7 = Kayo | first7 = Onoe | authorlink7 = Kayo Onoe | last8 = Sanae | first8 = Fukuda | authorlink8 = Sanae Fukuda | last9 = Joji | first9 = Kawabe | authorlink9 = Joji Kawabe | last10 = Kazuhiro | first10 = Takahashi | authorlink10 = Kazuhiro Takahashi | last11 = Yosky | first11 = Kataoka | authorlink11 = Yosky Kataoka | last12 = Susumu | first12 = Shiomi | authorlink12= Susumu Shiomi | last13 = Kouzi | first13 = Yamaguti | authorlink13 = Kouzi Yamaguti | last14 = Masaaki | first14 = Inaba | authorlink14 = Masaaki Inaba | last15 = Hirohiko | first15 = Kuratsune | authorlink15 = Hirohiko Kuratsune | last16 = Yasuyoshi | first16 = Watanabe | authorlink16 = Yasuyoshi Watanabe | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study| journal = Journal of Nuclear Medicine | volume = 55 | issue =6 | page = 945-50 | date = Mar 24, 2014 | pmid = 24665088 | doi = 10.2967/jnumed.113.131045| url = http://jnm.snmjournals.org/content/55/6/945.long}}</ref>
<ref name="NIHP2PFIN">{{citation | author = National Institutes of Health (US)| title = NIH Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = Dec 9, 2014| url = https://prevention.nih.gov/docs/programs/mecfs/ODP-P2P-MECFS-FinalReport.pdf}}</ref>

<ref name="Phoenix20160222Norway2012">{{Citation | title = Norwegian patient survey: Experiences of therapeutic approaches (2012) | journal = Phoenix Rising Forum | date = Feb 22, 2016| url = http://forums.phoenixrising.me/index.php?threads/norwegian-patient-survey-experiences-of-therapeutic-approaches-2012-update.43193/ }}</ref>
<ref name="viroblogMECFS">{{Cite web | title = List of ME/CFS articles published at Virology Blog| url = http://www.virology.ws/mecfs/ }}</ref>
<ref name="DerekPrisk2009">{{Cite journal | last1 = Pheby | first1 = D | authorlink1 = Derek Pheby | last2 = Saffron | first2 = L | authorlink2 = | title = Risk factors for severe ME/CFS | journal = Biology and Medicine | volume = 1 | issue = 4 | date = 2009
| eissn = 09748369 | doi = | url = http://biolmedonline.com/Articles/vol1_4_50-74.pdf}}</ref>

</references>
[[Category:Primers]]

Primer for journalists

2024-06-05T11:45:08Z

Yannlk:small edits

{{mbox|text= Editors: Edits to this Primer may require the same edits to the other [[:Category:Primers|Primers]].}}
[[myalgic encephalomyelitis|Myalgic encephalomyelitis]] (ME), sometimes referred to as [[chronic fatigue syndrome|myalgic encephalomyelits/chronic fatigue syndrome]] (ME/CFS), and not to be confused with [[chronic fatigue]] (CF), is widely misunderstood. In this '''Primer for journalists''', we provide evidence-based statements (with links to further reading & sources) to support journalists writing about the disease. '''Chronic Fatigue Syndrome''' must never be shortened to ''Chronic Fatigue'' in the body of an article or its headline. This has caused much confusion for readers who do not understand ME/CFS is a debilitating lifelong illness and it is not the same as [[chronic fatigue]] (CF); CF is a symptom of many different illnesses. Although the [[Fukuda criteria|Fukuda]]<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | authorlink = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959 |issn=0003-4819|pmid=7978722|via=|doi=10.7326/0003-4819-121-12-199412150-00009|publisher=American College of Physicians}}</ref> and the [[Oxford criteria|Oxford Criteria]]<ref name="PMC1293107">{{Cite journal | title = A report--chronic fatigue syndrome: guidelines for research. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/|journal=Journal of the Royal Society of Medicine | date = Feb 1991|issn=0141-0768|pmc=1293107|pmid=1999813 | pages = 118–121 |volume=84|issue=2 | first = MC | last = Sharpe | first2 = LC | last2 = Archard | first3 = JE | last3 = Banatvala | first4 = LK | last4 = Borysiewicz | first5 = AW | last5 = Clare | first6 = A | last6 = David | first7 = RH | last7 = Edwards | first8 = KE | last8 = Hawton | first9 = HP | last9 = Lambert}}</ref> were previously used for diagnosing ME/CFS, they are now regarded as overly broad, there being criticism that patients were being [[misdiagnosis of myalgic encephalomyelitis and chronic fatigue syndrome|misdiagnosed]] in both clinical and research settings as having ME/CFS when in fact they were suffering from the symptom CF or another fatiguing diagnosis.<ref name="Vink2019">{{Cite journal | last = Vink | last2 = Vink-Niese | date = 2019-09-20 | title = Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies | url = https://www.mdpi.com/2075-4418/9/4/124|journal=Diagnostics|language=en|volume=9|issue=4|page=124|doi=10.3390/diagnostics9040124|issn=2075-4418 | first = Mark | first2 = Alexandra|pmc=|pmid=|quote= | author-link = Mark Vink | authorlink2 = Alexandra Vink-Niese|access-date=|via=}}</ref><ref name="Carruthers, 2003" /><ref name="ICC2011primer" /></div><ref>{{Cite web | title = What Does a True ME Definition Look Like? | url = https://www.meadvocacy.org/what_does_a_true_me_definition_look_like|website=MEadvocacy.org|access-date=2019-01-25 | first = | last = }}</ref><ref name="fukuda1994"/><ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped - The Argus Report By: Penny Swift]</ref><ref>{{Cite web | url = http://occupyme.net/2016/08/16/ahrq-evidence-review-changes-its-conclusions/|website=occupyme.net|access-date=2019-01-25 | title = AHRQ Evidence Review Changes Its Conclusions | date = Aug 16, 2016 | last = Spotila | first=Jennie | authorlink=Jennie Spotila | last2 = Dimmock | first2 = Mary | authorlink2 = Mary Dimmock|archive-url=|archive-date=}}</ref>

In the past, there have been media reports of athletes diagnosed with ME or CFS who have recovered in a relatively short period of time after rest, supplementation, and diet changes;<ref name="Inews2018">{{Cite news |url = https://inews.co.uk/news/health/marathon-runner-quit-work-me-cfs-diet-change/ | title = Marathon runner forced to quit work after developing ME claims diet change gave him his life back | first = Claudia | last = Tanner|publisher =iNews | date = 2018}}</ref><ref name="Times2017">{{Cite news | url = https://www.thetimes.co.uk/article/muslim-fighter-with-me-who-left-an-arranged-marriage-to-win-world-title-svxhhzt57 | title = Muslim fighter with ME who left an arranged marriage to win world | last = Broadbent | first = Rick | date = 2017-12-02|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref><ref name="ABC2018">{{Cite news |url = http://www.abc.net.au/7.30/committee-reviews-potentially-harmful-and-old/10010408 |at=6mins 18s| title = Committee reviews 'potentially harmful and old fashioned' chronic fatigue treatments|publisher =ABC News | first =Andy|last = Park | first2 = Clare | last2 = O'Halloran}}</ref><ref name="London2019">{{Cite news | url = https://www.thetimes.co.uk/article/nathan-douglas-london-2012-was-the-darkest-period-of-my-life-vxt5gftcx | title = Nathan Douglas: London 2012 was the darkest period of my life | last = Broadbent | first = Rick | date = 2019-02-27|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref> these athletes may have had [[overtraining syndrome]] (which has the symptom of [[chronic fatigue]]) and not ME or CFS,<ref name="spence"/> while people with adrenal failure, [[idiopathic chronic fatigue]] or other fatiguing illnesses may be erroneously diagnosed with CFS.<ref name="recovery"/><ref name="Anoop2012"/><ref name="ICC" /> ME and CFS in professional athletes is normally a career-ending diagnosis.<ref name="Squash" /><ref name="Annadale"/><ref name="Shattered"/><ref name="Olympian"/><ref name="FIFA"/><ref name="olaf"/><ref name="LA"/>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''What is ME/CFS'' By Open Medicine Foundation - OMF. Linda Tannenbaum, Founder & CEO/President, talks about ME/CFS and how OMF is leading research and delivering hope (2018)">https://www.youtube.com/watch?v=pqDubEeIBtA</embedvideo>

The core [[List of symptoms in ME CFS|ME/CFS symptoms]] are: [[post-exertional malaise]] (PEM); [[chronic fatigue]] (CF); [[unrefreshing sleep]]/[[Sleep dysfunction|sleep problems]]; and [[Cognitive dysfunction|cognitive impairment]]/[[brain fog]] and/or [[orthostatic intolerance]] (OI).<ref name="symptoms"/><ref name="clinicians">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness {{!}} Clinicians Guide | last = | first = | date = 2015 | publisher=Nation Academies Press|archive-url=|archive-date=|access-date= | authorlink = }}</ref>{{Rp|9-10}} A patient can have many more symptoms<ref name="what-is">{{Cite web | url = https://www.omf.ngo/what-is-mecfs/ | title = What is ME/CFS? | last = | first = | date = |archive-url=|archive-date=|access-date= | authorlink = |website=[[Open Medicine Foundation]]}}</ref> and meet different criteria. [[Systemic Exertion Intolerance Disease]] (SEID), an ME/CFS criterion, allows for a patient to be [[Systemic Exertion Intolerance Disease#Diagnostic criteria|diagnosed with the minimum core symptoms]]<ref name="DiagnosticAlgorithm">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - Diagnostic Algorithm | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190528223706/https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg|archive-date=2019-05-28|access-date=}}</ref> and the patient may have other symptoms.<ref name="clinicians"/<ref name="IOM2015">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgid Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness - Clinician's Guide | date = 2015 | access-date=|website=nap.edu | last = | first = | authorlink = |archive-url=|archive-date= | page = 9}}</ref> The [[Canadian Consensus Criteria]] (CCC) requires the core symptoms and [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]], [[Neuroendocrine system|neuroendocrine]], [[immune system]], and [[myalgia]] symptoms to meet [[Canadian Consensus Criteria#Definition|its ME/CFS diagnostic criteria]].<ref name="Carruthers, 2003">{{Cite journal | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 =Joshi | first9 = Pradip | authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols | journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid = | doi = 10.1300/J092v11n01_02
| url = http://phoenixrising.me/wp-content/uploads/Canadian-definition.pdf }}</ref> The [[International Consensus Criteria]] (ICC) is used to diagnose [[myalgic encephalomyelitis]] (ME) which requires the core symptoms and neurological, immune/[[Gastrointestinal system|gastrointestinal]]/genitourinary impairment, and [[portal:Energy metabolism|energy metabolism]]/[[Ion transportation|ion transport]] impairment [[International Consensus Criteria#Criteria|symptoms for a diagnosis]].<ref name="ICC">{{Cite journal | last = Carruthers | first=Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | authorlink8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | author-link12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14 = Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23 = Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24 = Modra Murovska | last25 = Pall | first25 = Martin | author-link25 = Martin Pall | last26 = Stevens | first26 = Staci | author-link26 = Staci Stevens | date = 2011-08-22 | title=Myalgic encephalomyelitis: International Consensus Criteria | url = https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref>

The acronym ME/CFS is widely used in research, by clinicians, patient organizations, and patients.

"The most common overlapping condition with ME/CFS is [[fibromyalgia]]."<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25 = Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012 | isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref><ref name="Primer2014"/><ref name="Jason2001">{{Cite journal | last= Jason | first = Leonard | last2 = Taylor | first2 = R.R. | last3 = Kennedy | first3 = C.L. | last4 = Song | first4 = S | last5 = Johnson | first5 = D | last6 = Torres | first6 = S.R. | date = 2001-01-01 | title = Chronic fatigue syndrome: Comorbidity with fibromyalgia and psychiatric illness | url = https://www.researchgate.net/publication/285787383_Chronic_fatigue_syndrome_Comorbidity_with_fibromyalgia_and_psychiatric_illness|journal=Medicine and Psychiatry|volume=4 | pages = 29–34}}</ref> While some have posited ME/CFS and fibromyalgia are variants of the same illness, [[Benjamin Natelson]], MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiologic processes leading to different treatments.<ref>{{Cite journal | last = Natelson | first = Benjamin H. | date = 2019-02-19 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: Definitions, Similarities, and Differences | url = https://www.clinicaltherapeutics.com/article/S0149-2918(19)30003-7/abstract|journal=Clinical Therapeutics|language=English|volume=41|issue=4 | page = 612|doi=10.1016/j.clinthera.2018.12.016|issn=0149-2918|pmid=30795933}}</ref>

While ME/CFS is recognised as a physical disease by researchers, a [[Psychologization|psychiatric approach]] was taken with ME/CFS in the past, and some clinicians are still using this practice. At this time there are no approved drug treatments. In the past, [[Graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT) were used for ME/CFS. They are now discouraged or banned by major health guidelines as they were based on a psychological view of the illness and have lead to patient harm.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206|title=Overview {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-19}}</ref><ref name="etiology" />The [[Centers for Disease Control and Prevention]] (CDC) website states "ME/CFS is a '''biological illness''', not a psychologic disorder" and impacts multiple body systems.<ref name="etiology">{{Cite web | title = Etiology and Pathophysiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08| access-date = 2019-01-22 |language=en-us}}</ref> The CDC recognizes the hallmark symptom of PEM which is a worsening of symptoms after physical, mental or emotional exertion<ref name="symptoms">{{Cite web | title = Symptoms of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-22|language=en-us}}</ref> and says [[ME/CFS]] is a "disabling and complex disease."<ref name="whatis">{{Cite web | url = https://www.cdc.gov/me-cfs/about/index.html | title = What is ME/CFS? {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-12}}</ref>

[[File:SEID algorithm.JPG|400px|thumb|right|Diagnostic Algorithm for [[Systemic Exertion Intolerance Disease|SEID]]'s minimum [[List of symptoms in ME CFS#Systemic Exertion Intolerance Disease (SEID) symptom list|ME/CFS core symptoms]]]]

==What do we know?==
ME is a debilitating illness that has been recognized as a neurological disease by the [[World Health Organization]] (WHO) since 1969.<ref name="icd10">{{Cite book | url = https://apps.who.int/iris/bitstream/handle/10665/70934/ICD_10_1969_eng_v2a.pdf?sequence=3&isAllowed=y | title = International Classification of Diseases | last = World Health Organization | first = |publisher=WHO| year = 1969|isbn=|editor-link=|edition=Eighth revision|volume=2|location=Geneva|pages=173|chapter=|quote=Encephalomyelitis (chronic), (myalgic, benign) 323|editor-last2=|editor-link2=}}</ref>

It is a systemic [[Neuro-immune disease|neuroimmune]] disease characterized by [[post-exertional malaise]] (PEM) (a severe worsening of symptoms after even minimal [[exertion]]). It causes dysregulation of both the [[immune system]] and the [[nervous system]]. The effects of ME are devastating enough to leave [[Severe and very severe ME|25% of patients housebound or bedbound]]. For moderate to severe patients, the disability of living with ME is like living with late-stage cancer, advanced stage AIDS, or congestive heart failure for decades.

[[ME/CFS]] costs the US economy up to $24 billion per year in direct medical costs, and lost production.<ref name="IOM2015MECFS" /> Despite this, funding for research is not commensurate with the level of disease burden. In the 2015 financial year, the [[National Institutes of Health]] (NIH) provided only $5 million in research funding for ME/CFS, which is less funding than hayfever. This is in stark contrast to funding levels for other similarly disabling illnesses, like [[multiple sclerosis]] ($105 million) and HIV/AIDS ($3 billion).{{Citation needed|reason=Reference needed for NIH funding levels | date = 4 November 2019}} The [[Institute of Medicine]], a special advisory committee of the [[U.S. Department of Health and Human Services]] (HHS) (ref: [[Chronic Fatigue Syndrome Advisory Committee|CFSAC]] recommendations) and [[NIH]] expert advisory panel agree that it is imperative to increase research funding into ME/CFS.<ref name="NIHP2PFIN" />

== Disease onset and course of illness==
[[Onset of ME/CFS|ME/CFS can begin]] from many acute/sudden<ref name="Chu2019">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | authorlink5 = | date = Jan 14, 2019 | title = Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome | url = https://www.frontiersin.org/articles/10.3389/fped.2019.00012/abstract|journal=Frontiers in Pediatrics|volume=|issue=|pages=|doi=10.3389/fped.2019.00012|quote=|via=}}</ref> events: usually [[Viral onset hypothesis|viral]] or [[Bacterial disease onset|bacterial]] infections, but also [[trauma]], surgery or childbirth, [[anaphylaxis|allergic reaction]], and [[stress]].<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=[[Centers for Disease Control and Prevention]] | page = 6|archive-url=|archive-date=|access-date=}}</ref> There is also a gradual onset in some people,<ref name="Chu2019" /><ref name="clinical">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/index.html | title = Presentation and Clinical Course of ME/CFS {{!}} Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS | date = 2018-12-12 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-02-07}}</ref> that is not attributed to any one event. Occasionally, ME/CFS has been triggered by [[Environmentally acquired illness|environmental toxins]] or the receipt of an [[Vaccine|immunizing injection]].<ref>[https://www.masscfids.org/images/pdf/Primer_2014.pdf Chronic Fatigue Syndrome Myalgic Encephalomyelitis - Primer for Clinical Practitioners - 2014 Edition - Massachusettes CFIDS/FM Assoc]</ref> Some say that the disease [[Myalgic encephalomyelitis|ME]] always has an acute/sudden [[Infection|infectious]] onset.<ref name="Evans2018">{{Cite journal | last = Evans | first = Meredyth | authorlink = Meredyth Evans | authorlink2 = Leonard Jason | date = 2018 | title = Onset patterns of chronic fatigue syndrome and myalgic encephalomyelitis | url = https://www.openaccessjournals.com/articles/Onset%20patterns%20of%20chronic%20fatigue%20syndrome%20and%20myalgic%20encephalomyelitis.pdf|journal=Research on Chronic Diseases|volume=|issue=|pages=2|quote=|via= | last2 = Jason | first2 = Leonard}}</ref>

The disease [[ME/CFS]] is often diagnosed when a person does not recover from a [[flu-like illness]], [[mononucleosis]] or another [[HHV|herpesvirus]], [[Q fever]], an unidentified [[virus]], or [[:Category:Infectious agents|other infection]], and meets one or more [[Definitions of myalgic encephalomyelitis and chronic fatigue syndrome|diagnostic criteria for either ME, CFS, or ME/CFS]].<ref name="IOM2015"/>{{Rp|157-158}}<ref>[http://www.cortjohnson.org/blog/2014/01/09/lipkin-study-vagus-nerve-hhv-6-loomis-hhv-6-foundation/ The Lipkin Study, The Vagus Nerve Infection Hypothesis and HHV-6: Kristin Loomis of the HHV-6 Foundation Talks – Pt. I - Health Rising - By: Cort Johnson - June 2014]</ref> Patients experience [[List of symptoms in ME CFS|numerous symptoms]] and disease severity which fluctuate from day to day, week to week, month to month, year to year, and even decade to decade. Furthermore, symptoms and disease severity vary among patients.<ref name="Primer2014"/><ref name="WebMD">[http://www.webmd.com/chronic-fatigue-syndrome/chronic-fatigue-syndrome-symptoms Chronic Fatigue Syndrome - Symptoms - Web MD]</ref>

The CDC recognizes that there can be different causes and it is possible that two or more things could cause the illness. Areas of research include infections, [[immune system]] changes, physical or psychological [[stress]] affecting body chemistry, changes in [[Metabolic|energy production]], and a possible [[Genetics of chronic fatigue syndrome|genetic link]].<ref name="causes">{{Cite web | title = Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/about/possible-causes.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-27|language=en-us}}</ref><ref name="etiology" /> The CDC notes there are abnormalities with the immune system, [[Metabolic|cellular metabolism]], neuroendocrine disturbances, and [[blood pressure]] or heart rate regulation.<ref name="etiology" />
===Not a mental health disorder===
In the past, CFS was believed to be a mental health disorder. This is why the CDC now states: "ME/CFS is a biological illness, not a psychologic disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have multiple pathophysiological changes that affect multiple systems."<ref name="etiology" />

===No clear evidence that ME/CFS is contagious===
[[:Category:Infectious agents|Infectious episodes]] have led to [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreaks]] over the years and 72% of ME/CFS patients report an [[Onset of ME/CFS|onset]] of a viral or bacterial infection.<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=cdc.gov | page = 6|archive-url=|archive-date=|access-date=}}</ref> Nowadays, the vast majority of ME/CFS cases are sporadic rather than epidemic - although some outbreaks have been caused by known viruses such as the [[2003 Hong Kong outbreak|SARS pandemic]] and [[2019 Coronavirus pandemic outbreak|COVID-19]] - there is no clear evidence that sporadic ME/CFS cases are contagious.<ref name="pediatricprimer">{{Cite journal | last = Rowe | first = Katherine S. | last2 = Vallings | first2 = Rosamund | last3 = Stewart | first3 = Julian M. | last4 = Speight | first4 = Nigel | last5 = Schwartz | first5 = Malcolm S. | last6 = Medow | first6 = Marvin S. | last7 = Gurwitt | first7 = Alan | last8 = Friedman | first8 = Kenneth J. | last9 = Underhill | first9 = Rosemary A. | date = 2017 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref>

Families, partners, and friends do not report contracting ME/CFS from someone with the disease nor do patients report passing it on to others.<ref>{{Cite web | url = http://forums.prohealth.com/forums/index.php?threads/is-cfs-contagious.189664/ | title = Is CFS contagious? |website = ProHealth Forums|access-date=2019-02-13}}</ref> However, [[Rosemary Underhill|Underhill]] and O'Gorman (2006) researched 219 patients with ME/CFS, and concluded that close household contact and genetics were both risk factors for CFS, finding 3.2% of spouses/partners of those with CFS also had the illness.<ref name="UnderhillInfectious">{{Cite journal | last = Underhill | first = Rosemary A. | last2 = O'Gorman | first2 = Ruth | date = 2006-01-01 | title = Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families of CFS Patients | url = https://doi.org/10.1300/J092v13n01_02|journal=Journal of Chronic Fatigue Syndrome|volume=13|issue=1|pages=3–13|doi=10.1300/J092v13n01_02|issn=1057-3321}}</ref> This was a higher prevalence than all genetic relatives except children of patients. Because ME/CFS can run in families, a [[Genetics of chronic fatigue syndrome|genetic link]] is a line of research recommended by the CDC.<ref name="causes" /> 

[[Michael Sikora]] and collaborators at the [[Open Medicine Foundation]] hope that their research on the role of [[T cell]]s and immune-related [[Genetics of chronic fatigue syndrome|genes]] will help address "whether ME/CFS is an autoimmune or infectious disease, or simply an activation of the immune system".<ref name="omf-funded">{{Cite web | url = https://www.omf.ngo/2018/06/04/omf-funded-research/ | title = OMF funded research | date = Jun 4, 2018 | website = [[Open Medicine Foundation]]}}</ref>

====Blood donation and organ transplant====
A [[Blood donation|tissue and blood donation]] ban is in force for ME/CFS in the [[United Kingdom]] (even if recovered),<ref name="BloodUK">{{Cite web | url = https://my.blood.co.uk/KnowledgeBase | title = Knowledgebase|website=My Donor Record - Health, Eligibility & Travel | last = | first = | authorlink = |archive-url=|archive-date=|url-status=|access-date=2021-10-08}}</ref> [[Australia]],<ref name="donate">{{Cite web|url = https://www.donateblood.com.au/faq/chronic-fatigue-syndrome |title=Chronic fatigue syndrome – I have/had chronic fatigue syndrome. Can I donate?|access-date=2022-05-25|website = Australian Red Cross}}</ref> [[New Zealand]],<ref name="NZBlood">{{Cite web |url = https://www.nzblood.co.nz/become-a-donor/am-i-eligible/detailed-eligibility-criteria/ | title = Detailed Eligibility Criteria|access-date=2022-05-25 | date = |website=NZ Blood|quote=}}</ref> most of [[Canada]],<ref name="Wilson2014">{{Cite journal | title = The Use of Preliminary Scientific Evidence in Public Health: A Case Study of XMRV | date = 2014-04-08 | url = https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001623|journal=PLOS Medicine|volume=11|issue=4| pages = e1001623 | last = Wilson | first = Kumanan | last2 = Atkinson | first2 = Katherine | last3 = Keelan | first3 = Jennifer|language=en|doi=10.1371/journal.pmed.1001623|pmc=PMC3979645|pmid=24714396|issn=1549-1676}}</ref> and for a time also in the [[United States]],<ref name="post">{{Cite web | url = http://voices.washingtonpost.com/checkup/2010/12/red_cross_bars_chronic_fatique.html | title = Red Cross bars chronic fatigue patients from donating blood | last = Stein | first = Rob | authorlink = | date = Dec 3, 2010 | website = Washington Post|archive-url=|archive-date=|access-date=2022-05-25}}</ref> initially due to the research on [[Xenotropic murine leukemia virus-related virus|XMRV]] as being the likely infectious trigger of CFS<ref>{{Cite web | url = https://www.meassociation.org.uk/2010/04/xmrv-testing-in-the-uk/ | title = XMRV testing in the UK | last = | first = | author-link =| date = 2010 | website = [[ME Association]]|language=en-US|archive-url=|archive-date=|access-date=2019-02-13}}</ref> and showing that patients carried the virus.<ref name="post" /> Two papers on XMRV were retracted as the result was caused by laboratory contamination,<ref name="Redaction2012">{{Cite journal | date = Dec 2012 | title = Redaction, retraction and reaction | url = https://www.nature.com/articles/nrmicro2928|journal=Nature Reviews Microbiology|language=en|volume=10|issue=12 | pages = 799|doi=10.1038/nrmicro2928|issn=1740-1534}}</ref><ref name="transfusion">{{Cite web | url = https://transfusionnews.com/2012/10/05/multicenter-study-finds-no-correlation-between-chronic-fatigue-syndrome-and-xmrv/ | title = Multicenter Study Finds No Correlation between Chronic Fatigue Syndrome and XMRV|website=transfusionnews.com|access-date=2019-02-13}}</ref> but many blood donation bans remain.<ref name="Wilson2014"/>

The US American Red Cross no longer has statements barring transfusions or transplants for CFS,<ref name="redcross">{{Cite web | url = https://www.redcrossblood.org/faq.html#eligibility-health|access-date=2019-02-13 | title = Frequently Asked Questions | date = | last = | first = | authorlink = |archive-url=|archive-date=|website=American Red Cross|quote=Your search for "Chronic fatigue syndrome" returned no results.}}</ref> but patients are expected to be in "good health" which would exclude most.<ref name="redcross"/> The American Association of Blood Banks advises to either accept or defer ME/CFS donors based on "clinical judgment of the donor's health status".<ref name="AABBOct2012">{{Cite web | last = American Association of Blood Banks | url = https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2 | date = October 2012 | title = Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV)|pages = 3 |quote=An updated AABB Association Bulletin #12-05 (November 2012) states that individual collectors of blood and cellular therapy products should accept or defer donors with a history of CFS based on their clinical judgment of the donor's health status.|access-date=2022-05-25}}</ref> Patient charities discourage ME/CFS patients from donating blood,<ref name="MassBlood2015">{{Cite web | url = https://www.massmecfs.org/research/recent-research/19-xmrv/237-aabbs-recommendation-on-cfidsme-and-blood-donation | title = AABB's recommendation on ME/CFS and blood donation | date = Nov 25, 2015 |website=[[Massachusetts ME/CFS & FM Association]]|access-date=2022-05-25}}</ref>

== Mini-Docs ==
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Jen Brea/TED (2016)">https://www.youtube.com/watch?v=Fb3yp4uJhq0</embedvideo>
[[What happens when you have a disease doctors can't diagnose - TED Talk (2016)|''What happens when you have a disease doctors can't diagnose'']] By [[Jennifer Brea|Jen Brea]]/TED

Five years ago, TED Fellow Jen Brea became progressively ill with myalgic encephalomyelitis, commonly known as chronic fatigue syndrome, a debilitating illness that severely impairs normal activities and on bad days makes even the rustling of bed sheets unbearable. In this poignant talk, Brea describes the obstacles she's encountered in seeking treatment for her illness, whose root causes and physical effects we don't fully understand, as well as her mission to document through film the lives of patients that medicine struggles to treat.<ref>{{Cite web | url = https://www.youtube.com/watch?v=Fb3yp4uJhq0 | title = What happens when you have a disease doctors can't diagnose | date = Jan 17, 2017|access-date=|website=YouTube | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=|publisher=TED}}</ref><ref>{{Cite web | url = https://www.ted.com/talks/jen_brea_what_happens_when_you_have_a_disease_doctors_can_t_diagnose | title = What happens when you have a disease doctors can't diagnose | date = Jun 2016|access-date=|website=TED | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Veronica Weber/Palo Alto Online (2015)">https://www.youtube.com/watch?v=9_HwOUiImvw</embedvideo>

[[Invisible Illness - Stories of Chronic Fatigue Syndrome|''Invisible Illness - Stories of Chronic Fatigue Syndrome'']] By Veronica Weber/Palo Alto Online

This mini documentary reveals 3 stories of people who have been impacted by [[Chronic Fatigue Syndrome]] - a little known disease that affects roughly 836,000-2.5 million people in the U.S. and receives little research funding. They share emotions of treating loved ones with the disease, their frustrations of being ignored by members of society and the healthcare industry and express hopes of treatment and research. Video by Veronica Weber/Palo Alto Online<ref>{{Cite web | url = https://www.youtube.com/watch?v=9_HwOUiImvw | title = Invisible Illness - Stories of Chronic Fatigue Syndrome | date = Jul 10, 2015 |access-date=|website=YouTube | last = Weber | first = Veronica | authorlink=|archive-url=|archive-date=|publisher=Palo Alto Online}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Dr. David Kaufman/Unrest (2018)">https://www.youtube.com/watch?v=RC9TjgE_PlU</embedvideo>

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module''', made available through the American Medical Women’s Association and Indiana University School of Medicine, and in partnership with #MEAction. US medical providers can visit: https://www.unrest.film/cme to register to watch [[Unrest]] online for free and receive Continuing Education credit.<ref>{{Cite web | url = https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = | first = | authorlink = David Kaufman|archive-url=|archive-date=|publisher=Unrest Film}}</ref>

==Epidemiology ==
In the [[United States]], 836,000 - 2.5 million people suffer from ME/CFS. "The total economic costs of ME/CFS are estimated at $17 to $24 billion annually."<ref name="clinicians" /> Some CFS patients can work with [https://www.dol.gov/general/topic/disability/jobaccommodations job accommodations] but 1/3 to 1/2 become unemployed and [[Disability|many rely on SSDI/SSI]].<ref>[https://www.masscfids.org/job-accommodations Job Accommodations - MASS CFIDS]</ref>
*[[Epidemiology of myalgic encephalomyelitis and chronic fatigue syndrome|Epidemiology]]
:All races and cultures are afflicted with ME/CFS.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-91 Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care - July 2011]</ref><ref name="epidemiology">{{Cite web | title = Epidemiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-29|language=en-us}}</ref> Children and adolescents are also diagnosed.<ref>{{Cite web | title = ME/CFS in Children {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/me-cfs-children/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-29|language=en-us}}</ref><ref>{{Cite web | title = Pediatric ME/CFS Home Page | url = https://www.massmecfs.org/pediatric-me-cfs-home-page|website=massmecfs.org|access-date=2019-01-29}}</ref>
*[[Female predominant diseases]]
:Like many [[Autoimmune disease|autoimmune]] and [[Neuro-immune disease|neuro-immune]] diseases where mostly women are afflicted,<ref>[http://www.rightdiagnosis.com/artic/fact_sheet_autoimmune_disease_in_women_nwhic.htm Fact Sheet Autoimmune Disease in Women: NWHIC - Right Diagnosis - Aug 2015]</ref> the ME/CFS female/male patient ratio per Capelli et al. is 6:1<ref>{{Cite journal | title = Chronic fatigue syndrome/myalgic encephalomyelitis: an update | url = https://www.ncbi.nlm.nih.gov/pubmed/21244747|journal=International Journal of Immunopathology and Pharmacology | date = Oct 2010|issn=0394-6320|pmid=21244747 | pages = 981–989|volume=23|issue=4|doi=10.1177/039463201002300402 | first = E. | last=Capelli | first2 = R. | last2 = Zola | first3 = L. | last3 = Lorusso | first4 = L. | last4 = Venturini | first5 = F. | last5 = Sardi | first6 = G. | last6 = Ricevuti}}</ref> while the CDC states 4:1.<ref name="epidemiology"/>
*[[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|Pediatric]]
:Pediatric ME/CFS is defined by the CDC<ref>{{Cite web | url = https://www.cdc.gov/me-cfs/me-cfs-children/factsheet-healthcare-professional.html | title = Pediatric ME/CFS: Fact Sheet for Healthcare Professionals {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2017-10-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-10-13}}</ref> and the [[National Academy of Medicine]] (NAM)<ref name="IOM2015"/>{{Rp|181}} although it is usually diagnosed in adults.<ref name="whatis"/> "Children below the age of 8 or 9 do not have the symptom pattern of adolescents past puberty. If the onset of the disease occurs during adolescence, the most common time of onset, the pattern is similar to that of adults."<ref>{{Cite web | url = https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children - by David S. Bell, MD | date = 2016-06-25|publisher=[[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US | last = Bell | first = David | authorlink = David Bell}}</ref> The prognosis in adolescents is considered to be better than in adults.<ref name="prognosis">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/prognosis.html | title = Prognosis {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = 2018-11-08 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-01-31}}</ref><ref>{{Cite journal | last = Rowe | first = Peter C. | last2 = Underhill | first2 = Rosemary A. | last3 = Friedman | first3 = Kenneth J. | last4 = Gurwitt | first4 = Alan | last5 = Medow | first5 = Marvin S. | last6 = Schwartz | first6 = Malcolm S. | last7 = Speight | first7 = Nigel | last8 = Stewart | first8 = Julian M. | last9 = Vallings | first9 = Rosamund | date = 2017 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref> Children are diagnosed with ME/CFS at three months of illness under SEID and CCC and ME is diagnosed immediately under ICC.<ref>{{Cite web | url = https://www.masscfids.org/pediatric-me-cfs-links | title = Pediatric ME/CFS links|website=[[Massachusetts ME/CFS & FM Association]]|language=en-GB|access-date=2018-08-11}}</ref><ref name="clinicians" /><ref name="Carruthers, 2003" /><ref name="ICC" />
*[[Prevalence of myalgic encephalomyelitis and chronic fatigue syndrome|Prevalence]]
:"Worldwide, there may be as many as 17 – 24 million people with ME/CFS."<ref>{{Cite web | url = https://ammes.org/how-many-people-have-mecfs/ | title = How Many People Have ME/CFS?|website = [[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|access-date=2019-01-31}}</ref> 25% of ME/CFS patients are [[Severe and very severe ME|housebound or bedbound]] at some point in their illness.<ref name="keyfacts">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf | title = Myalgic Encelphalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Key Facts | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190327085836/https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf|archive-date=2019-03-27|url-status=dead|access-date=}}</ref><ref name="IOM2015"/>{{Rp|32}} 90% of patients are undiagnosed.<ref name="whatis"/>
*[[Prognosis for myalgic encephalomyelitis and chronic fatigue syndrome|Prognosis]]
:The prognosis for a patient diagnosed with ME/CFS is considered to be poor with only a minority (a median estimate of 5%) returning to pre-morbid levels of functioning.<ref name="Cairns2005">{{Cite journal | last = Cairns | first = R. | author-link = | last2 = Hotopf | first2 = M. | authorlink2 = Matthew Hotopf | date = Jan 2005 | title = A systematic review describing the prognosis of chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/15699087|journal=Occupational Medicine (Oxford, England)|volume=55|issue=1|pages=20–31|doi=10.1093/occmed/kqi013|issn=0962-7480|pmid=15699087|quote=|via=}}</ref> The majority of patients remains significantly impaired. A substantial improvement however is noted in an estimated 40% of patients.<ref name="Cairns2005" /><ref name="Joyce1997">{{Cite journal | last= Joyce | first = J. | last2 = Hotopf | first2 = M. | last3 = Wessely | first3 = S. | date = Mar 1997 | title = The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review | url = https://www.ncbi.nlm.nih.gov/pubmed/9093600|journal=QJM: monthly journal of the Association of Physicians|volume=90|issue=3|pages=223–233|issn=1460-2725|pmid=9093600}}</ref>

==ME vs CFS vs CF==

The name myalgic encephalomyelitis (ME) was coined following an [[Epidemic myalgic encephalomyelitis|outbreak]] of an illness at the [[1955 Royal Free Hospital outbreak|Royal Free Hospital]] in the UK, in 1955. The name chronic fatigue syndrome (CFS) was coined by the [[Centers for Disease Control and Prevention]] (CDC) following an [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreak]] of a [[flu-like illness]] at [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]], at Lake Tahoe, in the 1980s. There is disagreement as to whether ME and CFS are the same disease, entirely separate illnesses, or whether ME constitutes a more severe subset of CFS. Adding to the confusion, the diagnostic name given to patients is more often dependent on the country in which they live, than differing characteristics of their illness, as some countries use CFS (eg: US, [[Australia]]), and other countries (particularly in Europe) use ME. At this point in time, there is no clear biological evidence to resolve whether the illnesses are the same or different, and there is unlikely to be a resolution until firm [[diagnostic biomarker|biomarkers]] have been identified. As such, many patients and researchers use the term ME/CFS.<ref name="Klimas20140621video" /> See: [[Definitions of ME and CFS]].

The name Chronic Fatigue Syndrome is itself controversial, as many consider it [[stigma and discrimination|stigmatizing]]. In February 2016, Dr [[Anthony Komaroff]], who was part of the CDC group of clinicians who coined the name Chronic Fatigue Syndrome, said of it:
<blockquote>"I think that was a big mistake because the name, in my opinion, and the opinion of a lot of people, it both trivializes and stigmatizes the illness. It makes it seem unimportant, maybe not even real"<ref name="Komaroff20160217video" /></blockquote>

It is important to distinguish between ME/CFS and chronic fatigue (CF), which is a symptom of many different medical conditions (e.g.: anemia, [[hepatitis]], [[multiple sclerosis]], [[Thyroid disease|hypothyroidism]], [[depression]], ME/CFS). "Chronic fatigue" is not an illness in its own right and it is incorrect and misleading to refer to ME/CFS as "chronic fatigue". While [[fatigue]] is a component of ME/CFS, many consider [[post-exertional malaise]] (PEM) to be the cardinal feature of ME/CFS.<ref name="Carruthers, 2003" /><ref name="IOM2015MECFS" />

==Evidence of a disease==

=== Symptoms ===
[[List of symptoms in ME CFS|Symptom presentation varies enormously]] between individuals. Symptom presentation also varies within individuals, as individuals often report that symptoms change over time (increasing or decreasing) and new symptoms may appear while others disappear.<ref>{{Cite web | title = Symptoms and Diagnosis of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-02-01|language=en-us}}</ref> There are many symptoms which people with ME/CFS experience, though those listed below are the core symptoms found in all patients.

[[File:Cfs woman sketch.jpg|435x435px|thumb|[[Post-exertional malaise]] (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|physical, mental or emotional exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]], [[brain fog]]/[[cognitive dysfunction]], and [[word-finding problems]], [[unrefreshing sleep]], [[headache]]s and [[migraine]]s, [[chronic pain]], [[Myalgia|muscle pain]] and [[muscle fatigability]], [[orthostatic intolerance]], [[neurally mediated hypotension]], or [[Postural orthostatic tachycardia syndrome|POTS]] and more. The [[Delayed onset of post-exertional symptoms|onset of PEM can be delayed 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months]]

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about [[Post-exertional malaise|PEM]] and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her illness worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM.]]

[[File:Brian vastag.png|thumb|left|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]

[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #[[ME/CFS|MEcfs]] research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.<ref>{{Cite web | url = https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #MEcfs research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = @JackCroxall|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair on a rare trip out]]. Second photo, the inevitable crash. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak, etc. #TwoFacesofME<ref>{{Cite web | url = https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak, etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = @hopeforMEyet|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = @Authorportrait | date = 2019-01-17|access-date=2019-01-17|language=en | first = Henry | last = Köhler}}</ref>]]

*[[Post-exertional malaise]] (PEM) is the hallmark symptom of ME/CFS. After physical, mental or emotional [[exertion]] (which for some patients can be a shower or making out a to-do list, others grocery shopping, socializing or reading a news article, while some just walking to the mailbox, getting to the doctor or mentally following a T.V. program)<ref name="what-is" /><ref name="symptoms"/><ref name="Cairns2005" /> there is a payback of significant '''worsening''' [[List of symptoms in ME CFS|ME/CFS symptoms]] which can be [[Delayed onset of post-exertional symptoms|delayed for 24-72 hours or more]]<ref name="symptoms"/><ref name="Lindheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise | url = https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref><ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> and can last 24 hours and even days, weeks, or months.<ref name="VanNess2010">{{Cite journal | last = VanNess | first=J. Mark | last2 = Stevens | first2 = Staci R. | last3 = Bateman | first3 = Lucinda | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health (2002)|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref><ref>[https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf The Voice of the Patient.] A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative. September 2013</ref> The patient will experience even greater fatigue as well as exasperate the [[flu-like symptoms]] and body [[pain]]. Every patient experiences different symptoms and symptom severity from different activities and exertion output according to how sick he or she is with the disease.<ref name="prognosis" /><ref name="what-is" /><ref name="Cairns2005" /> Regarding PEM the [[CFIDS Association of America]] states:
<blockquote>This is a term which describes a symptom in which exercise or exertion can bring on [[malaise]] (illness). In the case of people with ME/CFS, malaise often occurs during a period some 24-72 hours after exertion. For example, in some cases, a short walk can worsen ME/CFS symptoms two days later. This lack of understanding about the delayed onset of symptoms has, in the past, made it harder to test for ME/CFS. Follow up tests, taken less than 24 hours after an initial exercise test, may show that the patient can still perform activities at the same level (before post exertional malaise has a chance to take hold).<ref>[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html What Health - International CFS/ME Awareness Day 2017 - CFIDS Association of America]</ref></blockquote>
*[[chronic fatigue]]
*[[cognitive dysfunction]]

*[[orthostatic intolerance]] (OI) such as [[postural orthostatic tachycardia syndrome]] (POTS) or [[neurally mediated hypotension]] (NMH)
*[[unrefreshing sleep]]/[[sleep dysfunction|sleep disturbance]] <ref name="DiagnosticAlgorithm" /><ref name="clinicians" />
==== Other possible symptoms ====
*[[chronic pain]]
*[[immune system]]
*[[:Category:Neurological signs and symptoms|neurological signs and symptoms]] See also: [[neuroinflammation]].
*[[List of symptoms in ME CFS|List of symptoms in ME/CFS]]

=== Comorbids ===
*[[fibromyalgia]] (FMS)
*[[irritable bowel syndrome]] (IBS)
*[[multiple chemical sensitivity]] (MCS)
*[[temporomandibular joint disorder]] (TMJ) <ref>[http://solvecfs.org/what-is-mecfs/ What is ME/CFS? - Solve ME/CFS Initiative]</ref>

=== Government guides on symptoms ===
'''US Government guides on symptoms'''
*[https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf Clinicians Guide] via The [[Institute of Medicine report]] (IOM)
*[https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html CDC - ME/CFS Symptoms]

'''Canada guides on symptoms'''
*[http://linkis.com/org/tUheh Alberta Clinicians Guide]

===Biological abnormalities===
Because there is currently no biomedical test for ME/CFS, many have incorrectly assumed that there are no medical abnormalities found in people with the illness. As a result, ME/CFS symptoms are often considered to be [[Medically unexplained physical symptoms|medically unexplained]], and therefore [[Psychologization|psychological]] in origin. While it is true that the illness is poorly understood, many biological abnormalities have been found in a range of different body systems, particularly in the [[central nervous system]], [[autonomic nervous system]], [[immune system]], and [[Metabolic|energy metabolism]].<ref name="IOM2015MECFS" /> Unfortunately, none have yet proved to be specific enough to ME/CFS as to be useful as a [[Diagnostic biomarker|biomarker]] of the disease, and many were identified in small studies, which need replication. Whilst there have been [[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis|many abnormalities identified]] found to be associated with the disease, it cannot yet be determined whether these are a cause or consequence.
* [[Gastrointestinal system]]
* [[Natural killer cell]]

==== Notable studies ====
* [[Cytokine#Notable_studies|Cytokine ("Notable studies")]]
*Immune findings by [[Mady Hornig]] & [[Ian Lipkin]]<ref name="Hornig20150201immune" />
*[[List of enterovirus infection studies]]

*2014, [[Neuroinflammation]] Japanese Neuroinflammation study<ref name="NakatomiY2014" />
*2015, Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology<ref name="stanfordleptin">{{Cite journal | last1 = Stringer | first1 = EA | last2 = Baker | first2 = KS | last3 = Carrol | first3 = IR | last4 = Montoya | first4 = JG | authorlink4 = Jose Montoya | last5 = Chu | first5 = L | authorlink5 = Lily Chu | last6 = Maeker | first6 = HT | last7 = Younger | first7 = JW | authorlink7 = Jarred Younger| title = Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology | journal = J Transl Med.| date = Apr 9, 2013 | pmid = 23570606 | pmc = 3637529 | doi = 10.1186/1479-5876-11-93| url = http://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 }}</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 (Full text)]
::Younger's Leptin study
*2014, Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome<ref name="Zeineh2014">{{Cite journal | last = Zeineh | first = Michael M. | author-link = Michael Zeineh | last2 = Kang | first2 = James | last3 = Atlas | first3 = Scott W. | last4 = Raman | first4 = Mira M. | last5 = Reiss | first5 = Allan L. | last6 = Norris | first6 = Jane L. | last7 = Valencia | first7 = Ian | last8 = Montoya | first8 = Jose G. | date = 2014-10-29 | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome | url = https://pubs.rsna.org/doi/10.1148/radiol.14141079|journal=Radiology|volume=274|issue=2 | pages = 517–526|doi=10.1148/radiol.14141079|issn=0033-8419}}</ref>
<blockquote>Bilateral [[white matter]] atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a [[Diagnostic biomarker|biomarker]] for CFS.</blockquote>
:*2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder - New York Times: Well (2014)|Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder By David Tuller - New York Times: Well]]
[[File:ME-CFS Brain Images.jpg|500px|thumb|center|Top scans: Healthy control patient; Bottom scans: chronic fatigue syndrome (CFS) patient. Image By: [[Michael Zeineh]]]]
*2016, [[Metabolic features of chronic fatigue syndrome]]

*2019, [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy]]<ref name="Mueller2019">{{Cite journal | url = https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink= | last2 = Lin | first2 = Joanne | authorlink2 = | date = 2019 | journal=Brain Imaging and Behavior|volume=14|issue= | pages = 562–572|doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|access-date=2019-01-17 | last3 = Sheriff | first3 =Sulaiman | authorlink3 = | last4 = Maudsley | first4 = Andrew | authorlink4 = | last5 = Younger | first5 = Jarred | authorlink5 = Jarred Younger}}</ref>
**2018, [https://www.youtube.com/watch?v=rxdzaWD5wfU ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study]<ref>{{Cite web | url = https://www.youtube.com/watch?v=rxdzaWD5wfU | title = ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study | date = Dec 14, 2018|access-date=|website=YouTube | last = Younger | first=Jarred | authorlink=Jarred Younger|archive-url=|archive-date=|publisher=SolveCFS}}</ref> (TALK)

===Causes & triggers===

*Outbreaks - see [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|List of outbreaks]]
*Possible infectious triggers: [[Enterovirus]]es, [[Epstein-Barr virus]]<ref name="Hickie2006" />, [[Q fever]]<ref name="Hickie2006" />, [[Ross River virus]]<ref name="Hickie2006" />, [[mononucleosis]]<ref name="Jason, Katz, 2017" />, ([[Ebola virus disease|Ebola]]?)<ref name="Hickie2006" />
*Non-viral triggers - [[trauma]], chemical

== Tests ==
* [[Natural killer cell]] (NKC) Blood Test
* Sleep study for [[sleep apnea]], [[Restless legs syndrome|restless leg syndrome]], and other sleep disturbances.
* [[Tilt table test]] for [[Orthostatic intolerance|OI]] or [[Postural orthostatic tachycardia syndrome|POTS]].

==Treatments==
There are currently no [[U.S. Food and Drug Administration|Food and Drug Administration]] (FDA) approved treatments for ME/CFS. Treatments consist mostly of symptom management, rather than treatment of the underlying cause of the disease, which is not yet understood.<ref name="Primer2014" /> There are many [[:Category:Potential_treatments|potential treatments]], though their evidence-base is limited, as most research into treatments has gone into psychological approaches to treatment.

=== Drugs ===
[[File:Ampligen.jpg|200px|thumb|right|Ampligen]]
Two treatments that have garnered much attention are [[Ampligen]], produced by [[AIM ImmunoTech]] (formerly Hemispherx Biopharma), and [[Rituximab]]. Many people have reported improvements from Ampligen, and a few recovered but relapsed when they stopped taking it.<ref name="TownCFS">{{Cite web | url = https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue | title = A Town for People with Chronic Fatigue Syndrome|website=New Yorker | date = Sep 3, 2019 | first = Mike | last = Mariani|access-date=2022-04-13}}</ref>

Attempts to obtain FDA approval for Ampligen in the US have failed, but it is available to some people on [[compassionate use]].<ref name="experimental">{{Cite web | url = https://ammes.org/experimental-treatments/ | title = Experimental treatments | last = | first = | date = |website=[[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|archive-url=|archive-date=|access-date=2021-03-18}}</ref> [[Argentina]] approved the use of Ampligen for [[Severe and very severe ME|severe ME/CFS]] in 2016.<ref>{{Cite news | url = http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html | title = Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic | last = Hemispherx Biopharma, Inc. | date = Aug 23, 2016|work=GlobeNewswire News Room|access-date=2018-08-13|archive-url=|archive-date=|language=en-US}}</ref><ref>{{Cite news | url = http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf | title = Hemispherx Biopharma, Inc. Executive Informational Overview | last = | first = | date = Nov 27, 2016|work=Crystal Research Associates|access-date=|archive-url=|archive-date=|format=PDF}}</ref> Also in 2016, it was made available on a limited basis in Europe.<ref>{{Cite web | url = https://www.bizjournals.com/philadelphia/news/2016/07/25/hemispherx-ships-ampligen-for-european-chronic.html | title = Hemispherx ships Ampligen for European chronic fatigue syndrome program | last = George | first = John | date = Jul 25, 2016 | website = bizjournals.com|archive-url=|archive-date=|access-date=2018-08-13}}</ref> In July 2018, AIM ImmunoTech announced the expansion of its US [[compassionate use]] program, '''AMP-511''', to new ME/CFS patients for the first time in over a year.<ref>[http://www.4-traders.com/HEMISPHERX-BIOPHARMA-INC-31148494/news/Hemispherx-BioPharma-Opens-FDA-Approved-Reimbursement-Based-Expanded-Access-Treatment-Program-for-26862569/ Hemispherx BioPharma : Opens FDA-Approved Reimbursement Based Expanded Access Treatment Program for ME/CFS to New Enrollees - 4 Traders]</ref><ref>{{Cite web | url = https://finance.yahoo.com/news/hemispherx-biopharma-inc-announces-advancement-133000883.html | title = Hemispherx Biopharma Inc. Announces Advancement in Expanded Access Program for Ampligen in the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last = | first = | author-link =| date = Jan 2, 2019|website=finance.yahoo.com|publisher=GlobeNewswire|language=en-US|archive-url=|archive-date=|access-date=2019-02-10}}</ref>

[[Rituximab]], a lymphoma drug, had shown promising results in initial trials in Norway,<ref>{{Cite journal | last = Fluge | first = Øystein | authorlink = Øystein Fluge | last2 = Risa | first2 = Kristin | authorlink2 = | last3 = Lunde | first3 = Sigrid | author-link3 = | last4 = Alme | first4 = Kine | authorlink4 = | last5 = Rekeland | first5 = Ingrid Gurvin | authorlink5 = | last6 = Sapkota | first6 = Dipak | authorlink6 = | last7 = Kristoffersen | first7 = Einar Kleboe | last8 = Sørland | first8 = Kari | last9 = Bruland | first9 = Ove | date = 2015-07-01 | editor-last = van der Feltz-Cornelis|editor-first = Christina | title = B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment | url = http://dx.plos.org/10.1371/journal.pone.0129898|journal=PLOS ONE|language=en|volume=10|issue=7| pages = e0129898|doi=10.1371/journal.pone.0129898|issn=1932-6203|pmc=4488509|pmid=26132314|access-date=|quote=|via=}}</ref> and there were groups crowdsourcing funding for further trials in other countries. In 2017, Drs. [[Øystein Fluge]] and [[Olav Mella]] announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab.<ref>{{Cite web | url = https://www.simmaronresearch.com/blog/2017/11/norwegian-rituximab-chronic-fatigue-syndrome-mecfs-trial-fails | title = Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails|website=Simmaron Research|language=en-US|access-date=2021-11-21}}</ref> A phase III trial published in 2019 showed Rituximab does not improve ME/CFS.<ref name="phase3-2019">{{Cite journal | last = Fluge | first = Øystein | last2 = Rekeland | first2 = Ingrid G. | last3 = Lien | first3 = Katarina | last4 = Thürmer | first4 = Hanne | last5 = Borchgrevink | first5 = Petter C. | last6 = Schäfer | first6 = Christoph | last7 = Sørland | first7 = Kari | last8 = Aßmus | first8 = Jörg | last9 = Ktoridou-Valen | first9 = Irini | date = 2019-04-02 | title = B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial | url = https://www.ncbi.nlm.nih.gov/pubmed/30934066|journal=Annals of Internal Medicine|doi=10.7326/M18-1451|issn=1539-3704|pmid=30934066}}</ref> 

[[Jarred Younger]] announced in March 2016 that he will be undertaking a trial of [[low dose naltrexone]] (LDN) in ME/CFS.<ref name="younger-research">{{Cite web | last = Younger | first=Jarred | authorlink = Jarred Younger | title = Research. Neuroinflammation Pain and Fatigue Laboratory|access-date= Nov 21, 2021 | url = https://sites.uab.edu/younger/research/}}</ref>

=== Treating other conditions ===
Different forms of [[Orthostatic intolerance|OI]] are treated with beta-blockers (Metopropol), [[Fludrocortisone]] (Florinef), and [[Mestinon|Pyridostigmine]].<ref name="Carruthers, 2003" /> When treating other diseases, illnesses, and conditions, and ME/CFS comorbidities or overlapping conditions such as sleep difficulties, cognitive problems, pain, and other symptoms it is important to remember that patients are [[Medicine sensitivities|sensitive to medications]].<ref name="monitor">{{Cite web | title = Monitoring the Use of All Medicines and Supplements {{!}} Clinical Care of Patients {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/monitoring-medication.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-27|language=en-us}}</ref> The CDC advice to health care practitioners is to be aware that because all drugs can cause side effects, ME/CFS patient symptoms can worsen. "This is particularly true of any medication that acts on the [[central nervous system]], such as sedating medications: therapeutic benefits can often be achieved at lower-than-standard doses. Patients with ME/CFS might tolerate or need only a fraction of the usual recommended doses for medications. After initial management with lower dosing, one or more gradual increases may be considered as necessary and as tolerated by the patient."<ref name="prognosis" /> For instance, tricyclic drugs can improve mood and help with sleep and pain. However, in some in can worsen OI.<ref name="prognosis" />
===Exercise as treatment===
[[File:J Brea TED.JPG|200px|thumb|right|[[Jen Brea|Jennifer Brea]] is an [[United States|American]] who was studying at Harvard; while on a trip to [[Kenya]] she became very ill with what would eventually be diagnosed as [[ME/CFS]]. Brea began experiencing [[Nervous system|neurological]] problems. Her neurologist diagnosed her with "conversion disorder" ([[hysteria]]). When walking home from his office, she collapsed. [[Severe and very severe ME|Jen then needed to use a wheelchair]] keeping her legs up due to [[Postural orthostatic tachycardia syndrome|POTS]] as her blood pooled into her legs]].
Previously, two common treatment recommendations for ME/CFS were [[graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT). These treatments are based on disproven the hypothesis that the disease might have begun with a viral infection but has been perpetuated by [[deconditioning]] from lack of activity, and [[illness beliefs|fear and avoidance]] of activity. GET and CBT are aimed at addressing these hypothesized causes by challenging the proposed unhelpful thoughts that result in avoidance of activity and reconditioning through a gradual increase in exercise. These treatments are controversial and are at odds with much of the research literature, which suggests that exercise is harmful to people with ME/CFS. A large patient survey of treatment responses found that 74% of people who had tried GET, reported that their symptoms subsequently worsened,<ref name="MEASSUK20150529survey" /> which is consistent with other patient surveys and many research findings.<ref name="Phoenix20160222Norway2012" /><ref name="OxfordBrookesSurvey">{{Cite web|url = https://www.meassociation.org.uk/wp-content/uploads/NICE-Patient-Survey-Outcomes-CBT-and-GET-Final-Consolidated-Report-03.04.19.pdf| title = Evaluation of a survey exploring the experiences of adults and children with ME/CFS who have participated in CBT and GET interventional programmes. FINAL REPORT | last = Oxford Clinical Allied Technology and Trials Services Unit (OxCATTS)|location=Oxford Brookes University | date = Feb 27, 2019}}</ref>

The [[PACE trial]], published in 2011, is the largest GET trial ever conducted. It has received much publicity as a result of its recovery rate claims, though it has come under strong criticism from within both the scientific and patient community for significant flaws in its design, and for overstating (and in some cases misrepresenting) outcomes in both the initial trial, and follow-up studies.<ref>{{Cite journal | last = Coyne | first = James Charles | last2 = Laws | first2 = Keith R | date = 2016 | title=Results of the PACE follow-up study are uninterpretable | url = http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00551-9/fulltext|journal=The Lancet Psychiatry|language=English|volume=3|issue=2| pages = e6–e7|doi=10.1016/S2215-0366(15)00551-9|issn=2215-0366|via=}}</ref> From 2015 to present day, the study was the subject of a series of investigative pieces that were highly critical of the trial by journalist Dr. [[David Tuller]]<ref name="viroblogMECFS" />, science writer [[Julie Rehmeyer]], patient advocate [[Tom Kindlon]], Dr. [[Keith Geraghty]]<ref name="Geraghty, 2017">{{Cite journal | last1 = Geraghty | first1 = Keith | authorlink1 = Keith Geraghty| title = Further Commentary on the PACE Trial: Biased Methods and Unreliable Outcomes| journal = Journal of Health Psychology | volume = | issue = | page = | date = May 2017 | doi = 10.1177/1359105317714486}}</ref>, psychologist [[Carolyn Wilshire]]<ref name="Wilshire C, et al, 2017">{{Cite journal | last1 = Wilshire | first1 = C | authorlink1 = Carolyn Wilshire | last2 = Kindlon | first2 = T | authorlink2 = Tom Kindlon | last3 = McGrath | first3 = S | authorlink3 = Simon McGrath | title = PACE trial claims of recovery are not justified by the data: a rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White | journal = Fatigue: Biomedicine, Health & Behavior | volume = 5 | issue = 1 | page = 62-67 | date = 2017 | doi = 10.1080/21641846.2017.1259724}}</ref> and others. A petition signed by almost 12,000 ME/CFS patients and allies,<ref name="MEACTIONpacepetition" /> and an open letter signed by 42 ME/CFS experts from around the world,<ref name="openletrLANCET2">{{Cite web | last1 = Davis | first1 = Ronald W | authorlink1 = Ronald Davis | last2 = Edwards | first2 = Jonathan C W | authorlink2 = Jonathan Edwards | last3 = Jason | first3 = Leonard A | authorlink3 = Leonard Jason | last4 = Levin | first4 = Bruce | authorlink4 = Bruce Levin | last5 = Racaniello | first5 = Vincent R | authorlink5 = Vincent Racaniello | last6 = Reingold | first6 = Arthur L | authorlink6 = Arthur Reingold | last7 = Ablashi | first7 = Dharam V | authorlink7 = Dharam Ablashi | last8 = Baraniuk | first8 = James N | authorlink8 = James Baraniuk | last9 = Barcellos | first9 = Lisa F | authorlink9 = Lisa Barcellos | last10 = Bateman | first10 = Lucinda | authorlink10 = Lucinda Bateman | last11 = Bell | first11 = David S | authorlink11 = David Bell | last12 = Bested | first12 = Alison C | authorlink12= Alison Bested | last13 = Broderick | first13 = Gordon | authorlink13 = Gordon Broderick | last14 = Chia | first14 = John | authorlink14 = John Chia | last15 = Chu | first15 = Lily | authorlink15 = Lily Chu | last16 = Enlander | first16 = Derek | authorlink16 = Derek Enlander | last17 = Fletcher | first17 = Mary Ann | authorlink17 = Mary Ann Fletcher | last18 = Friedman | first18 = Kenneth | authorlink18 = Kenneth Friedman | last19 = Kaufman | first19 = David L | authorlink19 = David Kaufman | last20 = Klimas | first20 = Nancy | authorlink20 = Nancy Klimas | last21 = Lapp | first21 = Charles W | authorlink21 = Charles Lapp | last22 = Levine | first22 = Susan | authorlink22 = Susan Levine | last23 = Light | first23 = Alan R | authorlink23 = Alan Light | last24 = Marshall-Gradisnik | first24 = Sonya | authorlink24 = Sonya Marshall-Gradisnik | last25 = Medveczky | first25 = Peter G | authorlink25= Peter Medveczky | last26 = Nahle | first26 = Zaher | authorlink26 = Zaher Nahle | last27 = Oleske | first27 = James M | authorlink27= James Oleske | last28 = Podell | first28 = Richard N | authorlink28= Richard Podell | last29 = Shepherd | first29 = Charles | authorlink29= Charles Shepherd | last30 = Snell | first30 = Christopher R | authorlink30 = Christopher Snell | last31 = Speight | first31 = Nigel | authorlink31= Nigel Speight | last32 = Staines | first32 = Donald | authorlink32= Donald Staines | last33 = Stark | first33 = Philip B | authorlink33= Philip Stark | last34 = Stein | first34 = Eleanor | authorlink34= Eleanor Stein | last35 = Swartzberg | first35 = John | authorlink35= John Swartzberg | last36 = Tompkins | first36 = Ronald G | authorlink36= Ronald Tompkins | last37 = Underhill | first37 = Rosemary | authorlink37= Rosemary Underhill | last38 = Vallings | first38 = Rosamund | authorlink38= Rosamund Vallings | last39 = VanElzakker | first39 = Michael | authorlink39= Michael VanElzakker | last40 = Weir | first40 = William | authorlink40= William Weir | last41 = Zinn | first41 = Marcie L | authorlink41= Marcie Zinn | last42 = Zinn | first42 = Mark A | authorlink42= Mark Zinn | title = An open letter to the Lancet - again | date = Feb 10, 2016
| website = Virology Blog| url = http://www.virology.ws/2016/02/10/another-request-for-data-from-the-pace-trial/ }}</ref> were sent to The Lancet, both calling for the data to be reanalysed. Twenty-four ME/CFS organizations from 14 different countries have written to Queen Mary University London requesting that the trial data be released for reanalysis.<ref name="MEACTION20160313openletr" /> To date, the authors of the trial and editor of The Lancet have refused such requests. Despite such criticism, the PACE trial continues to influence both government and the medical profession's approach to the treatment of ME/CFS in many countries.

One of the reasons that exercise may be harmful to people with ME/CFS, is the presence of [[post-exertional malaise]] (PEM), which is an exacerbation of symptoms following physical, mental or even emotional [[exertion]]. Studies have revealed immunological, muscular, [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]] and [[Cardiovascular system|cardiovascular]] abnormalities in response to exercise in people with ME/CFS. As these results are not also found in healthy sedentary controls, the adverse effects of exercise cannot be said to be due to deconditioning.<ref name="TwiskF2015">{{Cite journal | last1 = Twisk | first1 = Frank NM | authorlink1 = Frank Twisk | last2 = Geraghty | first2 = Keith J | authorlink2 = Keith Geraghty | title = Deviant Cellular and Physiological Responses to Exercise in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome| journal = Jacobs Journal of Physiology | volume = 1 | issue =2 | pages = 007 | date = Jul 11, 2015 | url = http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf}}</ref>{{citation needed|reason=VanNess2010 / Workwell Foundation studies need to be cited here.}}{{citation needed|reason=The Lights epigenetic changes post-exercise study needs to be cited here.}}

People with ME/CFS should approach [[exercise]] with caution, as there is much evidence of potential for harm.<ref name="OxfordBrookesSurvey"/><ref name="ICC2011primer"/>

[[Anaerobic threshold]], use of heart rate monitors for activity and [[pacing]]. Analeptic, not aerobic. [[Energy Envelope Theory|Energy envelope]]/pacing - people do better if stay within their envelope, than push to increase activity

====Graded exercise therapy & Cognitive behavioral therapy ====
[[File:Emma Shorter.JPG|400px|thumb|right|[[Emma Shorter]], is a citizen of [[Scotland]]. Here, she gives testimony before Parliament's Petitions Committee on [[graded exercise therapy|GET]] and how it put her in a wheelchair]].
GET and CBT have been recently abandoned in the [[United Kingdom|UK]], [[Ireland]] and many parts of Europe by ME Clinics.<ref name="niceng206">{{Cite web | url = https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref> They are highly controversial and not recommended by patients, most patient advocates, and research organizations nor by many doctors or researchers outside of the UK. Based on the flawed [[PACE trial]] which used the flawed [[Oxford criteria]] to diagnose and recruit patients, GET and CBT found its way into treating people with ME/CFS.

[[Exercise]], especially GET, can harm an ME/CFS patient further.<ref name="OxfordBrookesSurvey"/>

*[[Jennifer Brea]] walked home from her Neurologist's office and became [[severe and very severe ME|wheelchair-bound]].
*This is an experience of serious harm due to GET shared [https://twitter.com/TomKindlon/status/846425974052966400 by K. Miles, via Tom Kindlon on Twitter].
*[[Emma Shorter]] was able to walk a few minutes a day until GET put her in a wheelchair.
*[[Maik Speedy|Dr Maik Speedy]] was also seriously injured by GET and has been bedbound since.
*British MP [[Brynmor John]] collapsed outside the House of Commons gym in 1998 and [[Causes of death|died]], as a result of following his doctor's advice to exercise back to health.

==== Claims of recovery and cures ====
Charlatans claim they can cure CFS (per the CDC "there is no cure"<ref name="treatments">{{Cite web | url = https://www.cdc.gov/me-cfs/treatment/index.html | title = Treatment {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last = | first = | date = 2018-07-03 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|access-date=2021-11-22}}</ref>) when in reality they may be able to treat [[chronic fatigue]] (CF). ME/CFS patients experience an ongoing improper immune response and other abnormalities for at least 6 months straight with a reduction in activity with a specific symptom set for at least 50% of the time.<ref name="etiology" /><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html | title = IOM 2015 Diagnostic Criteria {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-09-07}}</ref><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/approach-to-diagnosis.html | title = Proposed Approach to ME/CFS Diagnosis in Children and Adults {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-12 | website = [[Centers for Disease Control and Prevention]] |language=en-us|access-date=2018-09-07}}</ref>

Additionally, there have been media reports of some athletes―usually amateur athletes,―diagnosed with CFS that recovered after a relatively short period of time with rest, supplementation, and diet changes,<ref name="Inews2018" /><ref name="Times2017" /><ref name="ABC2018" /><ref name="London2019" /> but they may have had [[overtraining syndrome]],<ref name="spence">{{Cite web | last = Spence | first = Vance | authorlink = Vance Spence|website=Irish M.E. Association| title = Snippets {{!}} A presentation by MERGE Chairman Dr Vance Spence on 12 November 2005 at the Oak Tree Court Conference Centre, Coventry, at the invitation of the Warwickshire Network for ME|url = https://www.imet.ie/imet_website/snippets/7th_december_2005_snippets.html|quote=(Mommersteeg et al, 2005) shows that the "burnout" experienced by athletes differs from CFS, and is certainly not ME as described in earlier literature. This is just one example of many media stories - thrown out into the public arena - which have an uncertain meaning in the context of ME/CFS}}</ref> while some people with adrenal failure, [[idiopathic chronic fatigue]] or another fatiguing illness may be erroneously diagnosed with CFS<ref name="ICC"/><ref name="recovery">{{Cite web | url = https://www.researchgate.net/profile/Diane_Cox2/publication/257764167_Severe_Chronic_Fatigue_Syndrome_CFSME_Recovery_is_possible/links/00b49525d3a11018ad000000/Severe-Chronic-Fatigue-Syndrome-CFS-ME-Recovery-is-possible.pdf | title = Severe Chronic Fatigue Syndrome: Recovery is Possible | last = Burley | first = Lucy | authorlink=Lucy Burley | last2 = Cox | first2 = Diane | authorlink2 = Diane Cox | date = Aug 1, 2007|pages=339-344|language=en|doi=10.1177/030802260707000803|archive-url=|archive-date=|url-status=|access-date=2019-02-11 | last3 = Findley | first3 = Leslie|journal=British Journal of Occupational Therapy|volume=70|issue=8 | authorlink3 = Leslie Findley}}</ref><ref name="Anoop2012">{{Cite journal | last = Devasahayam | first = Anoop | author-link = | last2 = Lawn | first2 = Tara | authorlink2 = | last3 = Murphy | first3 = Maurice | authorlink3 = | last4 = White | first4 = Peter D | authorlink4 = Peter White | date = Jan 2012 | title = Alternative Diagnoses to Chronic Fatigue Syndrome in Referrals to a Specialist Service: Service Evaluation Survey | url = https://journals.sagepub.com/doi/epub/10.1258/shorts.2011.011127|journal=JRSM Short Reports|volume=3|issue=1|pages=1–5|doi=10.1258/shorts.2011.011127|issn=2042-5333|pmc=PMC3269106|pmid=22299071|access-date=|quote=Half of all the referred patients to a specialist CFS clinic had alternative medical and psychiatric diagnoses.|via=}}</ref> ME and CFS in professional athletes normally results in very premature retirement.<ref name="Squash">{{Cite news | title = Illness robbed Marshall of crowning glory | first = Sam | last = Murley | date = Apr 10, 2019 | url = https://www.royalgazette.com/sport/article/20190410/illness-robbed-marshall-of-crowning-glory/|publisher =Royal Gazette}}</ref><ref name="Annadale">{{Cite web| title = Annadale Striders Interview - Derek Graham | url = http://annadalestriders.co.uk/derek-graham-interview/|website=Annadale Striders}}</ref><ref name="Shattered">{{Cite book |url = https://books.google.co.uk/books/about/Shattered.html?id=mkbxPAAACAAJ&redir_esc=y | title = Shattered: A Champion's Fight Against a Mystery Illness | first=Peter | last= Marshall | first2 = Nick | last2 = Kehoe | date = 2001|publisher =Mainstream}}</ref><ref name="Olympian">{{Cite news | date = May 4, 2012| title = Linley Frame: Olympian and Chronic Fatigue Syndrome sufferer|url = https://www.abc.net.au/local/audio/2012/05/04/3495770.htm|website =Australian Broadcasting Corporation}}</ref><ref name="FIFA">{{Cite web|url = http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-url=https://web.archive.org/web/20150610042710/http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-date = 2015-06-10| title = Michelle Akers USA|website=FIFA}}</ref><ref name="olaf">{{Cite news | url = https://www.welt.de/sport/gallery118782921/Benefizspiel-fuer-den-schwer-kranken-Olaf-Bodden.html | title = Benefizspiel für den schwer kranken Olaf Bodden | last = | first = | date = 2021 | website = Die Welt|archive-url=|archive-date=|url-status=|access-date=2021-11-17}}</ref><ref name="LA">{{Cite news | title = Garton enjoying life after United in LA | first = Andy | last = Mitten | date = Jul 24, 2014 | url = https://www.manchestereveningnews.co.uk/sport/football/football-news/andy-mitten-billy-garton-enjoying-7508558.amp|website =Manchester Evening News}}</ref>

==Severely ill patients==
Considerable variation exists in the severity of the disease. The [[International Consensus Criteria]] lists the following severity levels (it should be noted that even "mild" ME/CFS consists of significant debility):

*Mild = 50% reduction in pre-illness activity levels
*Moderate = mostly housebound
*Severe = mostly bedridden
*Very Severe = totally bedridden, and needing help with basic functions.

At least [[Severe and very severe ME|25% of people with ME/CFS are bedbound or housebound]], often for years or even decades, so are largely an invisible population.<ref name="IOM2015MECFS" /><ref name="DerekPrisk2009" /><ref>[http://iacfsme.org/PDFS/2017JanNewsletter/8-Japan-2014-Patient-Survey.aspx ME/CFS Patient Survey Report: Ministry of Health Survey Reveals Harsh Reality of ME/CFS Patients in Japan - IACFSME - By Mieko Shinohara]</ref> So invisible in fact, that they have rarely been included as part of research because their level of debility precludes them from traveling to laboratories for required testing. The [[Open Medicine Foundation]]'s [[ME/CFS Severely Ill, Big Data Study]] will be the first in-depth study of people with a severe form of ME/CFS. This study has so far produced the groundbreaking paper [[Metabolic features of chronic fatigue syndrome]].
It is estimated that 25% of ME/CFS patients are severely ill and are housebound or bedbound.

Notable patients with severe or very severe ME/CFS include [[Whitney Dafoe]], [[Karina Hansen]], [[Lynn Gilderdale]], [[Laura Hillenbrand]], [[Tom Kindlon]], [[Vanessa Li]], [[Doctor Speedy]], [[Naomi Whittingham]], [[Jamison Hill]] and [[Jessica Taylor-Bearman]].

Though uncommon, there have been [[causes of death|instances of deaths]] which have been attributed to the disease (see [[Sophia Mirza]], [[Merryn Crofts]]). National Statistics report an average of 10 - 12 deaths per year in England and Wales [[Causes of death|partly or fully caused by ME/CFS]], with almost all patients dying being of working age.
<ref name="ONS2018">{{Cite web | url = https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/adhocs/008461mentionsofpostviralfatiguesyndromebenignmyalgicencephalomyelitisdeathsregisteredinenglandandwales2001to2016 | title = Mentions of postviral fatigue syndrome (benign myalgic encephalomyelitis), deaths registered in England and Wales, 2001 to 2016 | website = Office for National Statistics|access-date=2019-03-06}}</ref>

==Patients and psychiatry/psychology==

*Objections and scope
*Mind-body dualism
*[[Psychologization]]
*[[Cognitive behavioral therapy]]
*The [[PACE trial]]. See [http://www.meaction.net/wp-content/uploads/2015/05/MEAction%E2%80%93patient-view-of-the-PACE-Trial-Controversy.pdf Patient view of the PACE Trial controversy]
*[[Ethical issues]]
*[[Patient mental health]]

===Stigmatization===

*Pretty young women slumped on desk
*[[Yuppie Flu]]
*Accusations of laziness/lethargy
*Epidemiological evidence - age, gender, demographic, racial/cultural
*[[Stigma and discrimination]]

===Accusations of harassment===

*No arrests or convictions<ref>{{Cite web | url = http://www.virology.ws/2016/02/01/trial-by-error-continued-a-few-words-about-harassment/ | title = Trial By Error, Continued: A Few Words About “Harassment” | last = Tuller | first = David | authorlink = David Tuller | date = Feb 1, 2016 | website = [[Virology blog]]|archive-url=|archive-date=|access-date=2019-01-21}}</ref>
* Potential harassment and "wild speculations" about threats to researchers were unsuccessful arguments used in [[Queen Mary University of London]]'s failed attempt to deny access to the [[PACE trial]] data at the 2015 tribunal. The tribunal judgement stated that the only evidence of harassment provided was a single heckler in a single seminar.<ref name="FirstTierTribunal2015">{{Cite news | title = First-tier tribunal: Information Rights Appeal EA/2015/0269. | url = https://informationrights.decisions.tribunals.gov.uk//DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF | page = 40 | last = Kennedy | first = Brian | last2 = Stephenson | first2 = Darryl | last3 = Watson | first3 = Nigel|quote=The evidence of <nowiki>[expert witness]</nowiki> Professor Anderson that third parties could not identify participants from the information alone and that, when pressed, he said that the chance of an "activist" being able to discover information that would lead to individual identification was remote, it was clear that his assessment of activist behaviour was, in our view, grossly exaggerated and the only actual evidence was that an individual at a seminar had heckled Professor Chalder. The identity of those questioning the research, who had signed an open letter or supported it, was impressive.}}</ref>

*Mistreatment of patients, including forced harmful treatment of children, is not mentioned. E.g., the story of "B", aged 8,<ref name="StoryofB">{{cite web | title = The Story of B - Children with ME. Appropriate ME Treatment Parliament debate | date = Jan 24, 2018 | url = https://www.youtube.com/watch?v=5HzZ4U6yU6o&autoplay=0}}</ref> and [[Ean Proctor]] and others "The Mental Health Movement: Persecution of Patients?"<ref>[http://www.theoneclickgroup.co.uk/documents/ME-CFS_docs/The%20Mental%20Health%20Movement%20-%20Persecution%20of%20Patients.pdf The Mental Health Movement: Persecution of Patients?]</ref>

* A pattern of [[intimidation and bullying of PACE trial critics]] has included targeting scientists' employers, professional bodies, politicians including the [[Countess of Mar]], and smear tactics in the national press.

== Working with government to move forward ==

Advocates met with senate staffers the week of March 16, 2016, and discussed research and drug development by the [[NIH]], the [[Centers for Disease Control and Prevention|CDC]] reinstating and increasing funding and education based on [[IOM]] recommendations and the [[HHS]] funding to develop Centers of Excellence.<ref>[http://www.meaction.net/2016/03/16/meaction-meets-with-senate-staffers/ #MEAction meets with Senate staffers]</ref> [[The MEAction Network]] reports on this ongoing process.

====CDC Website updates====
*Jul 3, 2017, the CDC's Chronic Fatigue Syndrome page has been changed to [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] (ME/CFS) and GET and CBT recommendations have been removed.<ref>{{Cite web|url = http://www.virology.ws/2017/07/10/trial-by-error-the-cdc-drops-cbtget/ | title = Trial By Error: The CDC Drops CBT/GET - Virology Blog | last = Tuller | first = David | authorlink = David Tuller | date = Jul 10, 2017 | website = [[Virology blog]]}}</ref><ref>[https://www.cdc.gov/me-cfs/index.html Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - CDC.gov]</ref>

*Jul 12, 2018, the "Information for Healthcare Providers" tab and its sub-tabs were updated.<ref>[https://www.cdc.gov/me-cfs/healthcare-providers/index.html Information for Healthcare Providers - ME/CFS - CDC]</ref><ref>[https://www.cdc.gov/media/releases/2018/a0712-new-website-me-cfs.html New ME/CFS Web Content for Healthcare Providers - CDC - Jul 12, 2018]</ref>

* Feb 25, 2019, Dr. [[Elizabeth Unger]], Chief of CDC's Chronic Viral Disease Branch (CVDB), that houses the ME/CFS program, in collaboration between ''Medscape'' and the CDC put out brief video and commentary page with links to the CDC's July 12th, 2018 updates for medical professionals: ''[https://www.medscape.com/viewarticle/908622?src=rss Chronic Fatigue Syndrome: It's Real, and We Can Do Better].''<ref>{{Cite web | title = Chronic Fatigue Syndrome: It's Real, and We Can Do Better |url = https://www.medscape.com/viewarticle/908622?src=rss| website = Medscape |access-date=2019-02-25 | date = Feb 25, 2019 | last = Unger | first=Elizabeth | authorlink = Elizabeth Unger | last2 = Medscape | first2 = | authorlink2 = |archive-url=|archive-date=}}</ref>
'''MEAction input'''
*Jul 29, 2018, [https://www.meaction.net/2018/07/29/cdc-revises-its-information-on-me/ CDC Revises its Information on ME] #[[MEAction]] report on the CDC July 2017 and July 2018 website updates. Recommendations for the CDC's ME/CFS page have been created from patient feedback on the updates as well as asking for further patient input.

==Expert opinions==

===Quotes from ME/CFS experts and patients===
*[[Individual quotes]]
*[http://thoughtsaboutme.com/quotes/ Thoughts About ME - List of Quotes]

===Doctors===
'''UK'''
*[[Jonathan Edwards]]
*[[Charles Shepherd]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">

*[[Lucinda Bateman]]
*[[Lily Chu]]
*[[David Kaufman]]
*[[Nancy Klimas]]
*[[Anthony Komaroff]]
*[[Susan Levine]]
*[[Jose Montoya]]
*[[Benjamin Natelson]]
*[[Daniel Peterson]]
*[[Alan Pocinki]]
*[[Peter Rowe]]
*[[Ronald Tompkins]]
*[[David Tuller]]

</div>

===Researchers===
'''Australia'''
*[[Neil McGregor]]

'''UK'''
*[[Keith Geraghty]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">
*[[Ron Davis]]
*[[Gunnar Gottschalk]]
*[[Maureen Hanson]]
*[[Mady Hornig]]
*[[Leonard Jason]]
*[[Betsy Keller]]
*[[Ian Lipkin]]
*[[Staci Stevens]]
*[[Suzanne Vernon]]
*[[Jarred Younger]]

</div>

===Patients===
====Australia====

===== Canada =====
*[[Scott Simpson]]

====Scotland====
*[[Emma Shorter]]

====US====
<div style="column-count:2;">
*[[Jennifer Brea]]
*[[Carol Head]]
*[[Ryan Prior]]
*[[Julie Rehmeyer]]
*[[Jaime Seltzer]]
</div>

====UK====
*[[Adam Lowe]]
*[[Graham McPhee]]
*[[Jessica Taylor-Bearman]]

====Ireland====
*[[Tom Kindlon]]

===Patient groups & charities===

'''[[:Category:Patient groups|Patient groups]]'''
<div style="column-count:3">
*[[:Category:American patient groups|American patient groups]]
*[[:Category:Australian patient groups|Australian patient groups]]
*[[:Category:Belgian patient groups|Belgian patient groups]]
*[[:Category:British patient groups|British patient groups]]
*[[:Category:Canadian patient groups|Canadian patient groups]]
*[[:Category:Dutch patient groups|Dutch patient groups]]
*[[:Category:Irish patient groups|Irish patient groups]]
*[[:Category:Italian patient groups|Italian patient groups]]
*[[:Category:New Zealand patient groups|New Zealand patient groups]]
*[[:Category:Norwegian patient groups|Norwegian patient groups]]
*[[:Category:Scottish patient groups|Scottish patient groups]]
*[[:Category:Swedish patient groups|Swedish patient groups]]
</div>

==Photos==
*[https://phoenixrising.me/stock-photography Stock photographs suitable for ME/CFS articles] - curated by [[Phoenix Rising]]
*[https://forums.phoenixrising.me/threads/the-real-me-a-stock-photography-resource-for-the-media.43734/ Advice on photograph choice]

==History==
*[[Osler's Web|''Osler's Web'']] is a book by [[Hillary Johnson]] on the early history of CFS.
*[[Thirty Years of Disdain|''Thirty Years of Disdain'']] by [[Mary Dimmock]] and Matthew Lazell-Fairman picks up on the ME/CFS history where Osler's Web leaves off.

=== Deaths of ME/CFS patients ===
*[[Causes of death]]
*[[Suicide]]

'''Death certificates with ME or CFS'''
*[[Merryn Crofts]]' death is attributed to ME.
*[[Sophia Mirza]]'s death is attributed to CFS.

In the UK, United States, and Australia there are further reports of loved ones who have died due to ME/CFS.<ref>[https://www.newscientist.com/letter/mg19125620-600-not-sadly-the-first/ Sadly, not the first (Comment Section)]</ref> See Editor's Note<ref>[https://www.newscientist.com/article/dn9342-first-official-uk-death-from-chronic-fatigue-syndrome/ First official UK death from chronic fatigue syndrome - New Scientist]</ref>

==Other tips and articles for journalists==
*2021, [https://www.theopennotebook.com/2021/01/26/how-to-report-with-accuracy-and-sensitivity-on-contested-illnesses/ How to Report with Accuracy and Sensitivity on Contested Illnesses] - by ME/CFS patient and science writer Julie Rehmeyer, Open Notebook
*Always interview a patient
*Interview more than one researcher (not just from the psychological etiology view)
*Avoid using derogatory, outdated & incorrect term "[[Yuppie Flu]]"
*Never shorten the disease name [[chronic fatigue syndrome]] (CFS) to the symptom [[chronic fatigue]] (CF). [[Chronic fatigue syndrome|CFS]], [[myalgic encephalomyelitis|ME]] or [[ME/CFS]] can be used to save print space.
*Use photographic imagery that represents the reality for patients - serious illness & disability - not well-groomed & slightly tired office workers at their computer or students with a pile of books sleeping at their desk. [[Solve ME/CFS Initiative]]'s [https://www.youtube.com/watch?v=cF2OuYFDriY Times Square Public Awareness Ad] shows the reality of the disease ME/CFS. Using photos of patients whether chronically ill yet functioning or a severely ill patient or stock photos that reflect life with this disease is necessary.
{{See also|Long_COVID#Articles_for_journalists_covering_Long_COVID|Articles for journalists covering Long COVID}}

==Learn more==
'''Key facts'''
*[https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf Key Facts] - Institute of Medicine (2015)

'''Research'''
*[[Institute of Medicine report]] (2015) The CDC based its updated [https://www.cdc.gov/me-cfs/index.html ME/CFS page] on information in this report.
*[[Notable studies]]

'''Films'''
*''[[Forgotten Plague]]'' is a US documentary about [[Ryan Prior]], an afflicted journalist who investigates the disease and its history and why the CDC has left millions sidelined from life; available for [http://www.forgottenplague.com/ streaming and DVD purchase]. (2015)
[[File:Forgotten Plague.jpeg|200px|thumb|center]]
*''[[Unrest]]'' is a US documentary film that aired on PBS's ''Independent Lens'' in 2018 and is available for [https://www.unrest.film/watch/#digital streaming] and [https://www.unrest.film/store/ DVD purchase]. [[Jennifer Brea]], a person with [[myalgic encephalomyelitis|ME]], directs. (2017)
[[File:Unrest.jpg|400px|thumb|center]]

'''ME/CFS organization and researchers material'''
*[https://www.youtube.com/watch?v=hRdn4A2SGic Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education] (The CDC's Dr. [[John Iskander]] interviews Dr. [[Anthony Komaroff]]. Video, 2016)
*[https://drive.google.com/file/d/1h_ZwdR4567k-mSoWahnC_id0F_fAA3Fb/view Caring for People with Myalgic Encephalomyelitis] (2018) Guide for Caretakers
*[http://youtu.be/c2vIQ92wU9Y ME/CFS Diagnosis and Name with Dr Nancy Klimas (video)]
*[http://www.openmedicinefoundation.org/what-is-mecfs/ What is ME/CFS?] By the [[Open Medicine Foundation]]

'''[[Patient mental health]]'''

:Patients that had been deemed as suffering from mental health and not a biological illness:
:*[[Karina Hansen]] is a young [[Denmark|Danish]] woman taken from her family for 3 1/2 years due to [[Per Fink]]'s insistence her ME was due to mental health issues.
:*[[Sophia Mirza]] was taken forcibly from her home to a mental hospital only to be returned shortly after; she then died of ME.
:*[[Ean Proctor]] was taken from his parents as a young boy and he was told his "parents were letting him die." He had become [[paralysis|paralyzed]] and mute and was let go in the deep end of a pool to make him swim and another time put him on a scary theme park ride to scare him into moving.

'''More mental health information'''
*ME/CFS is not [[depression]]. It causes a lack of energy, not a lack of desire.<ref name="Griffith, 2008">{{Cite journal | last1 = Griffith | first1 = J.P. | authorlink1 = | last2 = Zarrouf | first2 = F.A. | authorlink2 = | title = A Systematic Review of Chronic Fatigue Syndrome: Don’t Assume It’s Depression| url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292451/| pmc =2292451| journal = Primary Care Companion to The Journal of Clinical Psychiatry | volume = 10 | issue = 2 | page = 120–128| date = 2008 | pmid = 18458765 | doi = 10.4088/pcc.v10n0206 }}</ref><ref name="Hawk, 2006">{{Cite journal | last1 = Hawk | first1 = C | authorlink1 = | last2 = Jason | first2 = L | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = S | authorlink3 = Susan Torres-Harding| title = Differential diagnosis of chronic fatigue syndrome and major depressive disorder | journal = International Journal of Behavioral Medicine | volume = 13 | issue = 3 | page = 244-51 | date = 2006 | pmid = 17078775 | doi = 10.1207/s15327558ijbm1303_8
| url = http://www.healthrising.org/wp-content/uploads/2014/04/Hawk.-Jason.-Differential-Diagnosis-of-Chronic-Fatigue-Syndrome-and-Major-Depressive-Disorder.pdf }}</ref><ref name="myhill">{{Cite web|url = http://drmyhill.co.uk/wiki/CFS_or_depression_-_what_are_the_differences| title = CFS or depression - what are the differences | last = Myhill | first = Sarah | authorlink = Sarah Myhill | website = DrMyhill|access-date = 2021-03-22}}</ref>

==See also==
*[[Primer for the public#Disease_names_and_acronyms_around_the_world|Primer for the public (''Disease names and acronyms around the world'' section)]]

==References==
<references>

<ref name="Hickie2006">{{Cite journal | last1 = Hickie | first1 = Ian | authorlink1 = Ian Hickie | last2 = Davenport | first2 = Tracey | authorlink2 = Tracey Davenport | last3 = Wakefield | first3 = Denis | authorlink3 = Denis Wakefield | last4 = Vollmer-Conna | first4 = Ute | authorlink4 = Ute Vollmer-Conna | last5 = Cameron | first5 = Barbara | authorlink5 = Barbara Cameron | last6 = Vernon | first6 = Suzanne D | authorlink6 = Suzanne Vernon | last7 = Reeves | first7 = William C | authorlink7 = William Reeves | last8 = Lloyd | first8 = Andrew | authorlink8 = Andrew Lloyd | last9 = Dubbo Infection Outcomes Study Group | title = Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study | journal = BMJ | volume = 333 | issue =575 | date = Sep 14, 2006 | pmid = 16950834 | doi = 10.1136/bmj.38933.585764.AE| url = http://www.bmj.com/content/333/7568/575.long}}</ref>
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<ref name="Primer2014">{{Cite web | last1 = ((International Association for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis)) | authorlink = International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | last2 = Friedberg | first2 = Fred | authorlink2 = Fred Friedberg | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Bested | first4 = Alison C | authorlink4 = Alison Bested | last5 = Davenport | first5 = Todd | authorlink5 = Todd Davenport | last6 = Friedman | first6 = Kenneth J | authorlink6 = Kenneth Friedman | last7 = Gurwitt | first7 = Alan R | authorlink7 = Alan Gurwitt | last8 = Jason | first8 = Leonard A | authorlink8 = Leonard Jason | last9 = Lapp | first9 = Charles W | authorlink9 = Charles Lapp | last10 = Stevens | first10 = Staci R | authorlink10 = Staci Stevens | last11 = Underhill | first11 = Rosemary A | authorlink11 = Rosemary Underhill | last12 = Vallings | first12 = Rosamund | authorlink12= Rosamund Vallings | date = 2014 | url=https://www.massmecfs.org/images/pdf/Primer_2014.pdf | title =Chronic Fatigue Syndrome Myalgic Encephalomyelitis Primer for Clinical Practitioners }}</ref>
<ref name="IOM2015MECFS">{{Cite web | last1 = Institute of Medicine (US) | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness| publisher = The National Academies Press | location = Washington, DC, US| date = Feb 10, 2015 | isbn = 978-0-309-31689-7| url = https://pubmed.ncbi.nlm.nih.gov/25695122/}}</ref>
<ref name="Jason, Katz, 2017">{{Cite journal | last1 = Jason | first1 = Leonard A | authorlink1 = Leonard Jason | last2 = Katz | first2 = Ben | authorlink2 = Ben Katz | last3 = Gleason | first3 = Kristen | authorlink3 = | last4 = McManimen | first4 = Stephanie | authorlink4 = Stephanie McManimen | last5 = Sunnquist | first5 = Madison | authorlink5 = Madison Sunnquist | last6 = Thorpe | first6 = Taylor | authorlink6 = | title = A Prospective Study of Infectious Mononucleosis in College Students | journal = International Journal of Psychiatry | volume = 2 | issue = 1 | page = | date = 2017| doi = | url = https://www.researchgate.net/profile/Leonard_Jason/publication/312936696_A_prospective_study_of_Infectious_Mononucleosis_in_college_students/links/588a23cc92851c2779b2568c/A-prospective-study-of-Infectious-Mononucleosis-in-college-students.pdf }}</ref>
<ref name="Klimas20140621video">{{Cite web | last1 = Klimas | first1 = Nancy | authorlink1 = Nancy Klimas | title = ME/CFS Diagnosis and Name with Dr. Nancy Klimas (video)| date = Jun 21, 2014 | url = http://youtu.be/c2vIQ92wU9Y}}</ref>
<ref name="Komaroff20160217video">{{citation | last1 = Komaroff | first1 = Anthony | authorlink1 = Anthony Komaroff | last2 = Iskander | first2 = John | authorlink2 = John Iskander | title = Interview with Dr Anthony Komaroff | journal = CDC Public Health Ground Rounds - Beyond the Data - Chronic Fatigue Syndrome: Advancing Research and Clinical Education | date = Feb 17, 2016 | url = https://youtu.be/hRdn4A2SGic}}</ref>
<ref name="MEACTIONpacepetition">{{Cite web | last1 = #MEAction | authorlink1 = #MEAction | title = Petition: Misleading Claims Should Be Retracted| website = #MEAction | date = Oct 2015 | url = http://my.meaction.net/petitions/pace-trial-needs-review-now}}</ref>
<ref name="MEACTION20160313openletr">{{Cite web | last1 = #MEAction | authorlink1 = #MEAction | title = 24 organisations in 14 countries tell QMUL: Release the PACE data | date = Mar 13, 2016| url = http://www.meaction.net/2016/03/13/24-organisations-in-14-countries-tell-qmul-release-pace-data/#comment-2518}}</ref>
<ref name="MEASSUK20150529survey">{{Cite web | last1 = ME Association (UK) | authorlink1 = ME Association | date = May 29, 2015 | title = Our CBT, GET and Pacing Report calls for major changes to therapies offered for ME/CFS| url = http://www.meassociation.org.uk/2015/05/23959/ }}</ref>
<ref name="NakatomiY2014">{{Cite journal | last1 = Nakatomi | first1 = Yasuhito | authorlink1 = Yasuhito Nakatomi | last2 = Mizuno | first2 = Kei | authorlink2 = Kei Mizuno | last3 = Ishii | first3 = Ishii | authorlink3 = Akira Ishii | last4 = Yasuhiro | first4 = Wada | authorlink4 = Yasuhiro Wada | last5 = Masaaki | first5 = Tanaka | authorlink5 = Masaaki Tanaka | last6 = Shusaku | first6 = Tazawa | authorlink6 = Shusaku Tazawa | last7 = Kayo | first7 = Onoe | authorlink7 = Kayo Onoe | last8 = Sanae | first8 = Fukuda | authorlink8 = Sanae Fukuda | last9 = Joji | first9 = Kawabe | authorlink9 = Joji Kawabe | last10 = Kazuhiro | first10 = Takahashi | authorlink10 = Kazuhiro Takahashi | last11 = Yosky | first11 = Kataoka | authorlink11 = Yosky Kataoka | last12 = Susumu | first12 = Shiomi | authorlink12= Susumu Shiomi | last13 = Kouzi | first13 = Yamaguti | authorlink13 = Kouzi Yamaguti | last14 = Masaaki | first14 = Inaba | authorlink14 = Masaaki Inaba | last15 = Hirohiko | first15 = Kuratsune | authorlink15 = Hirohiko Kuratsune | last16 = Yasuyoshi | first16 = Watanabe | authorlink16 = Yasuyoshi Watanabe | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study| journal = Journal of Nuclear Medicine | volume = 55 | issue =6 | page = 945-50 | date = Mar 24, 2014 | pmid = 24665088 | doi = 10.2967/jnumed.113.131045| url = http://jnm.snmjournals.org/content/55/6/945.long}}</ref>
<ref name="NIHP2PFIN">{{citation | author = National Institutes of Health (US)| title = NIH Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = Dec 9, 2014| url = https://prevention.nih.gov/docs/programs/mecfs/ODP-P2P-MECFS-FinalReport.pdf}}</ref>

<ref name="Phoenix20160222Norway2012">{{Citation | title = Norwegian patient survey: Experiences of therapeutic approaches (2012) | journal = Phoenix Rising Forum | date = Feb 22, 2016| url = http://forums.phoenixrising.me/index.php?threads/norwegian-patient-survey-experiences-of-therapeutic-approaches-2012-update.43193/ }}</ref>
<ref name="viroblogMECFS">{{Cite web | title = List of ME/CFS articles published at Virology Blog| url = http://www.virology.ws/mecfs/ }}</ref>
<ref name="DerekPrisk2009">{{Cite journal | last1 = Pheby | first1 = D | authorlink1 = Derek Pheby | last2 = Saffron | first2 = L | authorlink2 = | title = Risk factors for severe ME/CFS | journal = Biology and Medicine | volume = 1 | issue = 4 | date = 2009
| eissn = 09748369 | doi = | url = http://biolmedonline.com/Articles/vol1_4_50-74.pdf}}</ref>

</references>
[[Category:Primers]]

Green tea

2024-06-05T11:34:19Z

Yannlk:/* Theory */

{{Cleanup|reason=Contains information pasted from elsewhere, rephrase and add citations.}}
[[File:Green tea box.jpg|alt=Box of green tea bags|thumb|400x400px]]
Green tea is a type of tea that is made from Camellia sinensis leaves that have not undergone the same withering and oxidation process used to make oolong teas and black teas.

Some of the extracts of Green tea inhibit the activity of the Murine leukemia virus<ref>[https://journals.lww.com/aidsonline/fulltext/2002/04120/polyphenolic_antioxidant.20.aspx Polyphenolic antioxidant (–)-epigallocatechin-3-gallate from green tea as a candidate anti-HIV agent]</ref>.

Green tea contains [[Epigallocatechin gallate|epigallocatechin gallate (EGCG)]] which is a strong [[antioxidant]].

== Evidence ==
There exists no evidence green tea is an effective treatment for ME/CFS in humans. A 2016 study claimed that green tea may improve some biological abnormalities in rats theorised to have ME/CFS. This study has not been reproduced.<ref name=":0" />

==Potential Mechanism==

Regular green tea is 99.9% water, provides 1 Calorie per 100 ml serving, is devoid of significant nutrient content (table) and contains phytochemicals, such as polyphenols and caffeine. Polyphenols found in green tea include epigallocatechin gallate (EGCG), epicatechin gallate, epicatechins and flavanols,{{Citation needed}} which have antioxidant, anticarcinogen, anti-inflammatory, and anti-radiation biochemical effects in vitro. Other components include three kinds of flavonoids, known as kaempferol, quercetin, and myricetin.

==Risks and side effects==

In high doses green tea supplements can cause permanent liver damage in some people.<ref>{{Cite news | url = https://www.bbc.com/news/stories-45971416 | title = 'The food supplement that ruined my liver' | date = 2018-10-25|work=BBC News|access-date=2018-10-25|language=en-GB}}</ref> However, EGCG doses <800mg/day have not shown any hepatotoxic effects according to the European Food Safety Authority<ref>{{Cite journal | last = Younes | first = Maged | last2 = Aggett | first2 = Peter | last3 = Aguilar | first3 = Fernando | last4 = Crebelli | first4 = Riccardo | last5 = Dusemund | first5 = Birgit | last6 = Filipič | first6 = Metka | last7 = Frutos | first7 = Maria Jose | last8 = Galtier | first8 = Pierre | last9 = Gott | first9 = David | date = 2018 | title = Scientific opinion on the safety of green tea catechins| url = https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/j.efsa.2018.5239|journal=EFSA Journal|language=en|volume=16|issue=4| pages = e05239|doi=10.2903/j.efsa.2018.5239|issn=1831-4732}}</ref>

==Costs and availability==
It is nutritional supplement so its available without prescription. In Germany a 250mg capsule costs only about 0,14€ (approx. 0.17 US-$).

== Research studies ==
* Therapeutic Effect and Metabolic Mechanism of A Selenium-Polysaccharide from ''Ziyang'' Green Tea on Chronic Fatigue Syndrome<ref name=":0">{{Cite journal | last = Shao | first = Changzhuan | authorlink = | last2 = Song | first2 = Jing | authorlink2 = | last3 = Zhao | first3 = Shanguang | authorlink3 = | last4 = Jiang | first4 = Hongke | authorlink4 = | last5 = Wang | first5 = Baoping | authorlink5 = | last6 = Chi | first6 = Aiping | date = 2018-11-15 | title = Therapeutic Effect and Metabolic Mechanism of A Selenium-Polysaccharide from Ziyang Green Tea on Chronic Fatigue Syndrome| url = http://www.mdpi.com/2073-4360/10/11/1269|journal=Polymers|language=en|volume=10|issue=11 | pages = 1269|doi=10.3390/polym10111269|issn=2073-4360|pmc=|pmid=30961194|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401680/ (Full text)]

It is used in the treatment regime against ME of Ms Voss to prevent the use of [[Raltegravir]]
*[http://meversuscfs.blogspot.com/2018/06/arztanfragen-mein-therapieregime-fur.html My antiretroviral Regime for Antiretroviral Treatment of Myalgic Encephalomyelitis (Deutsch: #Arztanfragen - Mein Therapieregime für die antiretrovirale Behandlung bei Myalgischer Enzephalomyelitis)]
*[https://www.bbc.co.uk/news/stories-45971416 The health supplement that ruined my liver]

==Costs and availability ==
You can drink it as tea but green tea extracts is also available as supplements.

==See also==
* [[Epigallocatechin gallate]] (EGCG)
* [[:Category:Supplements|Supplements]]
* [[Antioxidant]]

==Learn more==
*[https://www.nccih.nih.gov/health/green-tea Green tea] - National Center for Complimentary and Integrative Health
*[https://www.drugs.com/mtm/green-tea.html Green Tea] - drugs.com
==References==
{{Reflist}}

[[Category:Potential treatments]]
[[Category:Medicinal foods]]
[[Category:Supplements]]
[[Category:Herbs]]
[[Category:Flavonoids]]
[[Category:Depression alternative treatments]]

Sarah Myhill

2024-06-05T10:46:13Z

Yannlk:

[[File:Sarahmyhill.jpg|right]]
Doctor '''Sarah Myhill''' is a British naturopath running her own specialist [[Myalgic encephalomyelitis|M.E.]] clinic in Knighton, [[Wales|Wales,]] [[United Kingdom]]. Her website is an extensive resource of articles and information based on her treatment of patients, it runs to 920 webpages and has had over six million individual visits.{{Citation needed|reason=data/numbers need citation|date=5 June 2024}}

Dr Myhill's view is that [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] is characterized by a cellular metabolic [[Mitochondrion|mitochondria]]l dysfunction and has published several studies.<ref name="Myhill2013" /><ref name="Booth2012" /><ref name="Myhill2009" /><ref>{{Cite web|url=http://drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure| title = CFS - The Central Cause: Mitochondrial Failure - DoctorMyhill|website=drmyhill.co.uk|access-date=2019-02-20}}</ref> Dr Myhill has attempted to treat over 10,000 ME/CFS sufferers over her 30-year career.{{Citation needed|reason=data/numbers need citation|date=5 June 2024}}

Dr Myhill explains her philosophy of medicine [http://www.doctormyhill.co.uk/wiki/About_my_practice here]. Sarah Myhill is currently suspended from the GMC register and is not allowed to practice as a doctor in the United Kingdom.<ref>{{Cite web|url=https://www.gmc-uk.org/doctors/2734668|title=Sarah Barbara Myhill - General Medical Council|website=General Medical Council|archive-url=https://www.gmc-uk.org/doctors/2734668|access-date=02/11/2023}}</ref>

==Clinical Practice==
Dr Myhill has an experienced staff supporting her clinical practice. For individuals unable to visit in person staff will coordinate with the individual's primary care provider, will send lab kits for blood draw to be analyzed by Dr Myhill. She produces detailed analysis of blood work, provides recommendations and will discuss cases by telephone. Blood test analysis provides measures of [[Adenosine triphosphate|ATP]] production and mitochondrial efficiency based upon her published research. While other physicians seem to understand her analytical methods, few, if any, are comfortable commenting on their significance. For decades, Dr Myhill has prioritized patient support and treatment results over independent corroboration.{{Citation needed}}

Dr Myhill also supports Miss Voss's Regime for Antiretroviral Treatment of Myalgic Encephalomyelitis<ref>{{Cite web|url=http://meversuscfs.blogspot.com/2018/06/arztanfragen-mein-therapieregime-fur.html| title = ME versus CFS: #Arztanfragen - Mein Therapieregime für die antiretrovirale Behandlung bei Myalgischer Enzephalomyelitis | last = Voss | first = Katharina | authorlink=Katharina Voss | date = 2018-06-09 | website = ME versus CFS|archive-url=|archive-date=|url-status=|access-date=2019-02-20}}</ref><ref>{{Cite web|url=http://www.drmyhill.co.uk/wiki/A_Regime_for_Antiretroviral_Treatment_of_Myalgic_Encephalomyelitis| title = A Regime for Antiretroviral Treatment of Myalgic Encephalomyelitis - DoctorMyhill|website=drmyhill.co.uk|access-date=2019-02-20}}</ref>: [[A Regime for Antiretroviral Treatment of Myalgic Encephalomyelitis]].

==Complaints==
Dr Myhill has been the subject of complaints to the [[General Medical Council]].<ref name="Myhill201004BBC" /> A recent Freedom of Information Act request confirmed that Dr Myhill is the most investigated doctor in the history of the GMC. She has been subject to 38 investigations before she gave up her GMC license in resignation; all investigations were found in her favour.<ref>Myhill & Robinson, The Underactive Thyroid, 2023 edition, pages 0-25</ref> None of the complainants against Dr Myhill were patients.{{Citation needed|reason= | date = 3 October 2020}}

A non-compliance Hearing was held from Sep 28th - Oct 2nd 2020 found in favor of Dr Myhill and no restrictions were placed on her practice.<ref name=":0" /> The non-compliance issue was about Dr Myhill's refusal to provide the GMC with the medical records of a patient who did not consent to them being shared. The GMC requested the records after the patient's GP made a complaint to the GMC, which the patient refused to support.<ref name=":0">{{Cite web|url=https://www.drmyhill.co.uk/wiki/Press_Release_re_my_Non_Compliance_Hearing_-_MPTS_-_Myhill_vs_GMC_Sept_28_to_Oct_1_2020?| title = Press Release re my Non Compliance Hearing - MPTS - Myhill vs GMC Sept 28 to Oct 1 2020 - DoctorMyhill|website=drmyhill.co.uk|access-date=2020-10-03}}</ref><ref name=":1">{{Cite web|url=https://www.mpts-uk.org/-/media/mpts-rod-files/dr-sarah-myhill-01-oct-20.pdf| title = Medical Practice Tribunal - Dr Sarah Myhill | last = Medical Practitioners Tribunal Service | first= | authorlink = | date = 2020-10-01 | website = |archive-url=|archive-date=|url-status=|access-date=}}</ref> A further complaint was made against her and Dr Myhill was brought to Tribunal in February 2023.<ref name=":2">{{Cite web|url=https://www.bmj.com/content/bmj/380/bmj.p278.full.pdf|title=GP suspended for nine months after promoting vitamins and iodine
for covid-19|last=Dyer|first=Claire|date=03/02/2023|website=British Medical Journal|access-date=02/11/2023}}</ref> The tribunal found that Myhill, who practises in Powys, promoted and endorsed the use of high doses of vitamins C and D and the inhalation of iodine through a salt pipe for the treatment of bacterial and viral infections including covid.<ref name=":2" /> The tribunal found that Myhill “does not practise evidence based medicine and may encourage false reassurance in her patients who may believe that they will not catch covid-19 or other infections if they follow her advice.” Myhill was also found guilty of serious misconduct in failing to reconsider her treatment plan after she failed to diagnose a fractured hip in a patient who had a fall, and in not recommending his admission to hospital when his condition had not improved. Dr Myhill was suspended for 9 month as a result of this Tribunal, with a review scheduled for the end which has not yet taken place.<ref name=":2" />

==Advocacy ==
Dr Myhill is a vocal critic of the [[PACE trial]] and [[biopsychosocial model]] of [[ME/CFS]]. Dr Myhill's [[General Medical Council |GMC]] complaint regarding a number of PACE trial authors was first rejected without investigation by the GMC, after Dr Myhill appealed the GMC stated they would reconsider.{{citation needed}} Dr Myhill's action against the GMC for failing to provide reasoning for not investigating the PACE trial authors is still continuing, and began a number of months before the most recent GMC instigation of her practice started.<ref name=":0" /><ref name=":1" />

Dr Myhill is also the creator of the Medical Abuse In ME Sufferers (MAIMES) petition.

===Medical Abuse in ME Sufferers===
Dr Sarah Myhill's [[Medical Abuse In ME Sufferers (MAIMES)]] petition calls for a UK public enquiry into the medical abuse and neglect experienced by British patients with [[myalgic encephalomyelitis]] (often called [[chronic fatigue syndrome]] or [[CFS/ME]] in the UK).<ref>{{Cite web|url=http://drmyhill.co.uk/wiki/Medical_Abuse_In_ME_Sufferers_(MAIMES)| title = Medical Abuse In ME Sufferers (MAIMES) | last = Myhill | first = Sarah | authorlink = Sarah Myhill | date = 2019-02-10 | website = |archive-url=|archive-date=|url-status=|access-date=}}</ref>

==Mitochondrial Energy Score test ==
[[Cara Tomas|Tomas]] et al. (2019) attempted to replicate the findings of Myhill, Booth and McClaren-Howard in a study of just ten ME patients, but were unable to distinguish between patients and healthy controls. Myhill responsed highlighting differences in their methods that could have accounted for their results, and stating they incorrectly referred to the test as a diagnostic test for [[CFS/ME]].<ref name="Myhill2019">{{Cite web|url=https://www.drmyhill.co.uk/wiki/Response_to_the_paper_%27Assessing_cellular_energy_dysfunction_in_CFS/ME_using_a_commercially_available_laboratory_test%27_by_Cara_Tomas_et_al| title = Response to the paper 'Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test' by Cara Tomas et al | last = Myhill | first = Sarah | authorlink = Sarah Myhill | date = Aug 2019 | website = drmyhill.co.uk|archive-url=|archive-date=|url-status=|access-date=2019-08-16}}</ref>
* [https://www.drmyhill.co.uk/wiki/Response_to_the_paper_%27Assessing_cellular_energy_dysfunction_in_CFS/ME_using_a_commercially_available_laboratory_test%27_by_Cara_Tomas_et_al Dr Myhill's response to "Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test"]

==Notable studies==
*2009, [[Chronic fatigue syndrome]] and [[mitochondrion|mitochondrial]] dysfunction<ref name="Myhill2009" /> [http://www.ijcem.com/files/IJCEM812001.pdf (Full Text)]
*2012, [[mitochondrion|Mitochondrial]] dysfunction and the pathophysiology of [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] ([[ME/CFS]])<ref name="Booth2012" /> [http://www.ijcem.com/files/IJCEM1204005.pdf (Full Text)]
*2013, Targeting mitochondrial dysfunction in the treatment of [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] ([[ME/CFS]])<ref name="Myhill2013" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515971/ (Full Text)]

==Book==
*2014, updated 2018 - ''[[Diagnosis and Treatment of Chronic Fatigue Syndrome: It's Mitochondria, Not Hypochondria]]'' by Sarah Myhill. Edited by, and with a chapter by [[Craig Robinson]].

==Talks and interviews==
(More talks and interviews can be found on [https://www.youtube.com/playlist?list=PLcy0gKHd07NUYlup5f9POdK9GDua8ecSm YouTube playlist for Dr Myhill])
*2007, Speaker at the 2nd [[Invest in ME International ME Conference]] on ''Treatments and Diagnosis – A GP’s Perspective''<ref>{{Cite web|url=http://www.investinme.org/IIMEC2.shtml#agenda | title = 2nd International ME Conference Agenda - IIMEC2 | last = Invest in ME Research | first = | authorlink = Invest in ME Research | date = 2007 | website = [[Invest in ME Research]]|archive-url=|archive-date=|url-status=|access-date=2019-02-20}}</ref> - [https://www.youtube.com/watch?v=Ye31fXTS-DM (Video)]
*2015, [http://www.doctormyhill.co.uk/wiki/Biocare_Summer_2015_Conference Biocare Summer 2015 Conference]
*2016, [http://www.drmyhill.co.uk/wiki/OMEGA_AGM_Seminar_2016 OMEGA AGM Seminar 2016]
*2018, [https://www.youtube.com/watch?v=UYOLVruElJU Dr. Myhill Calls For The GMC To Investigate The PACE Trial Authors]
*Mar 04, 2019 - Interviewed on [[The ME Show]] by [[Gary Burgess]] on her understanding and experience of treating people with ME and CFS, as well as her own ongoing battles with the General Medical Council<ref>{{Citation| title = Episode Six - Dr Sarah Myhill - The ME Show | url =http://www.buzzsprout.com/172265/967163-episode-six-dr-sarah-myhill|access-date=2019-08-13}}</ref> - [https://www.buzzsprout.com/172265/967163-episode-six-dr-sarah-myhill (Episode Link)]

=Online presence=
*[http://www.drmyhill.co.uk/ Website]
*[https://www.facebook.com/groups/108048875899603/ Support Dr Sarah Myhill public Facebook group]
*[https://www.facebook.com/groups/435645003161721/ Support for followers of Dr Myhill's protocol closed Facebook group]
*[https://www.facebook.com/Supporters-of-Dr-Sarah-Myhill-230752230289407/ Supporters of Dr Sarah Myhill Facebook page]
*[https://twitter.com/MyhillNews Twitter]
*[https://www.youtube.com/playlist?list=PLcy0gKHd07NUYlup5f9POdK9GDua8ecSm YouTube playlist]
*Address: Upper Weston, Knighton LD7 1SL, Wales, United Kingdom ({{Coord|52.326276|-3.155665|display=title}})

==Learn more==
*2012, [http://www.prohealth.com/library/showarticle.cfm?libid=17086 "Booth, Myhill, McLaren-Howard Comment on ME/CFS Mitochondrial Dysfunction Paper" by Norman E. Booth, Sarah Myhill, John McLaren-Howard for] [[ProHealth]]
*[http://drmyhill.co.uk/wiki/Medical_Abuse_In_ME_Sufferers_(MAIMES) MAIMES petition - Medical Abuse of ME Sufferers]
*[http://www.doctormyhill.co.uk/wiki/CFS_Checklist_-_start_off_and_check_your_treatment_regime_here CFS Checklist - start off and check your treatment regime here]

==See also==
*[[John McLaren-Howard]]
*[[Ethical issues]]
*[[Medical Abuse In ME Sufferers (MAIMES)]]

==References==
<references>
<ref name="Booth2012">{{Cite journal | last1 = Booth | first1 = NE | last2 = Myhill | first2 = S | authorlink2 = Sarah Myhill | last3 = McLaren-Howard | first3 = J | authorlink3 = John McLaren-Howard | title = Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | journal = International Journal of Clinical Experimental Medicine | volume = 5 | issue = 3| pages = 208–220 | date = Jun 15, 2012 | pmid = 22837795
| url = http://www.ncbi.nlm.nih.gov/pubmed/22837795
|quote= | author-link = Norman Booth | authorlink4 = | authorlink5 = |via=}}</ref>
<ref name="Myhill2009">{{Cite journal | last1 = Myhill | first1 = S | last2 = Booth | first2 = NE | authorlink2 = Norman Booth | last3 = McLaren-Howard | first3 = J | authorlink3 = John McLaren-Howard | title = Chronic fatigue syndrome and mitochondrial dysfunction | journal = International Journal of Clinical Experimental Medicine | volume = 2 | issue = 1| pages = 1–16 | date = Jan 15, 2009 | pmid = 19436827
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/
|quote= | author-link = Sarah Myhill | authorlink4 = | authorlink5 = |via=}}</ref>
<ref name="Myhill2013">{{Cite journal | last1 = Myhill | first1 = S | last2 = Booth | first2 = NE | last3 = McLaren-Howard | first3 = J | authorlink3 = John McLaren-Howard | title = Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit | journal = International Journal of Clinical Experimental Medicine | volume = 6 | issue = 1| pages = 1–15 | date = 2013 | pmid = 23236553
| url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515971/
|quote= | author-link = Sarah Myhill | authorlink4 = | authorlink5 = |via=|pmc=3515971 | authorlink2 = Norman Booth}}</ref>
<ref name="Myhill201004BBC">{{Cite news | title = Dr. Myhill on BBC News
| publisher = [[BBC news]]
| type = video | date = Apr 29, 2010
| url = https://www.youtube.com/watch?v=gW_GMCcuUcU }}</ref>
</references>

[[Category:Researchers]]
[[Category:UK researchers]]
[[Category:Clinicians]]
[[Category:British clinicians]]
[[Category:Authors]]
[[Category:Psychological paradigm critics]]
[[Category:PACE trial critics]]
[[Category:Advocates or allies]]
[[Category:British advocates or allies]]

Neurology of ME/CFS

2024-06-05T10:36:07Z

Yannlk:added intro paragraph

Myalgic encephalomyelitis/chronic fatigue syndrome ([[ME/CFS]]) is a complex disease, that is often considered to be neurological or [[Neuroimmune disease|neuro-immune]]. Myriad [[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis|neurological abnormalities]] have been found, such as changes in brain structure and metabolism, and [[autonomic nervous system]] dysfunction. [[Neuroinflammation]], indicated by elevated brain [[lactate]] and choline, is suggested as a key mechanism, though evidence is mixed.<ref>{{Cite journal|title=Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2023-10|url=https://doi.org/10.1016/j.mayocp.2023.07.032|journal=Mayo Clinic Proceedings|volume=98|issue=10|pages=1544–1551|last=Grach|first=Stephanie L.|last2=Seltzer|first2=Jaime|last3=Chon|first3=Tony Y.|last4=Ganesh|first4=Ravindra|doi=10.1016/j.mayocp.2023.07.032|issn=0025-6196}}</ref><ref>{{Cite journal|title=Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis|date=2024-02|url=https://doi.org/10.1016/j.autrev.2023.103484|journal=Autoimmunity Reviews|volume=23|issue=2|pages=103484|last=Lee|first=Jin-Seok|last2=Sato|first2=Wakiro|last3=Son|first3=Chang-Gue|doi=10.1016/j.autrev.2023.103484|issn=1568-9972}}</ref>[[File:Progressive Brain Changes Longitudinal MRI Study (2016).jpeg|400px|thumb|right|Progressive Brain Changes Six-year Longitudinal MRI Study of Chronic Fatigue Syndrome patients (2016) Source: J Magnetic Res Imaging.<ref name="Shan2016" /> License: [https://creativecommons.org/licenses/by-nc/4.0/ CC-BY-NC-4.0] https://doi.org/10.1002/jmri.25283]]

==Brain imaging==
{{Main article|page_name=Brain}}
{{Main article|Neuroinflammation}}
[[File:Grey and white matter differences in Chronic Fatigue Syndrome (2017).jpeg|400px|thumb|Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study (2018) Source: Finkelmeyer et al. NeuroImage: Clinical 17 pp.24-30. https://doi.org/10.1016/j.nicl.2017.09.024]]

[[File:Brain-scan-CFS-basal-ganglia.png|thumb|Reduced Activation in Basal Ganglia Structures in CFS compared to Controls for the Win-Lose Contrast.<ref name="Finkelmeyer, 2017" /> Source: Miller et al. (2014). PLoS ONE 9(5): e98156. doi:10.1371/journal.pone.0098156]]

==Spine==
<div role="note" class="hatnote navigation-not-searchable">{{Main article|page_name=Spine}}</div>

== Neural strain ==
{{Main article|page_name=Neural strain}}

In a study of neuromuscular strain in ME/CFS, 60 people with ME/CFS and 20 healthy controls randomly were assigned to undergo a neuromuscular strain maneuver or sham maneuver. Those with ME/CFS in the strain condition group had significantly increased symptoms for up to 24 hours.<ref>{{Cite journal | last = Violand | first = Richard L. | last2 = Thompson | first2 = Carol B. | last3 = Moni | first3 = Malini | last4 = Marden | first4 = Colleen L. | last5 = Jasion | first5 = Samantha E. | last6 = Lauver | first6 = Megan | last7 = Fontaine | first7 = Kevin R. | last8 = Rowe | first8 = Peter C. | date = 2016-07-18 | title = Neuromuscular Strain Increases Symptom Intensity in Chronic Fatigue Syndrome|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159386|journal=PLOS ONE|language=en|volume=11|issue=7| pages = e0159386|doi=10.1371/journal.pone.0159386|issn=1932-6203}}</ref>

==Causes of neurological symptoms==
[[File:MECFS-neuroeffects-brain.jpg|alt=Sketch of a brain with words inside saying intracranial hypertension, impaired cerebral blood flow, hyperventilation/hypocapnia, and adrenergic hyperactivity.|thumb|Key neurological pathomechanisms in ME/CFS are intracranial hypertension, impaired cerebral blood flow, hyperventilation/hypocapnia, and adrenergic hyperactivity. '''Source:''' Wirth, K.J., Scheibenbogen, C. & Paul, F. [https://doi.org/10.1186/s12967-021-03143-3 An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.] J Transl Med 19, 471 (2021). https://doi.org/10.1186/s12967-021-03143-3]]

Causes of neurological symptoms in ME/CFS include:
*hyperventilation/hypnocapnia (reduced carbon dioxide levels in the blood)
*[[intracranial hypertension]] (increased pressure within the skull and around brain)
* reduced blood flow to the brain
* [[Neuroinflammation|brain inflammation]] may also be a factor<ref name="Wirth2021b" />

These can explain cognitive impairment, brain fog, headache, psychomotor slowing, ataxia and loss of coordination of movements, hypersensitivity, sleep disturbances and dysautonomia.<ref name="Wirth2021b" />

==Notable studies ==
*2021, An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Wirth2021b">{{Cite journal | last = Wirth | first = Klaus J. | authorlink = | last2 = Scheibenbogen | first2 = Carmen | authorlink2 = Carmen Scheibenbogen | last3 = Paul | first3 = Friedemann | authorlink3 = | date = 2021-11-22 | title = An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://doi.org/10.1186/s12967-021-03143-3|journal=Journal of Translational Medicine|volume=19|issue=1 | pages = 471|doi=10.1186/s12967-021-03143-3|issn=1479-5876|pmc=PMC8607226|pmid=34809664|access-date=|quote=|via=}}</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03143-3 (Full text)]
==Talks and interviews==
* 2016, [https://www.youtube.com/watch?v=pnWinDtPurY 77. ME & the brain, part 1 / ME & de hersenen, deel 1 - Dr. Neil Harrison]<ref>{{Cite web|url=https://www.youtube.com/watch?v=pnWinDtPurY | title = 77. ME & the brain, part 1 / ME & de hersenen, deel 1 - Dr. Neil Harrison | last = | first = | authorlink = Neil Harrison | date = Apr 5, 2016 | website = YouTube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|url-status=|access-date=}}</ref>
* 2016, [https://www.youtube.com/watch?v=q4SsixfuYKE&feature=youtu.be 78. ME & the brain, part 2 / ME & de hersenen, deel 2 - Dr. Neil Harrison]<ref>{{Cite web|url=https://www.youtube.com/watch?v=q4SsixfuYKE&feature=youtu.be | title = 78. ME & the brain, part 2 / ME & de hersenen, deel 2 - Dr. Neil Harrison | last = | first = | authorlink = Neil Harrison | date = Apr 19, 2016 | website = YouTube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|url-status=|access-date=}}</ref>

*2016, [https://www.youtube.com/watch?v=K4br0X7CJE0&feature=youtu.be 79. ME & inflammation, part 1 / ME & inflammatie, deel 1 - Dr Harrison]<ref>{{Cite web|url=https://www.youtube.com/watch?v=K4br0X7CJE0&feature=youtu.be | title = 79. ME & inflammation, part 1 / ME & inflammatie, deel 1 - Dr Harrison | last = Harrison | first = Neil | authorlink=Neil Harrison | date = May 3, 2016 | website = YouTube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|url-status=|access-date=}}</ref>
*2018, [https://www.youtube.com/watch?v=rxdzaWD5wfU ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study], sponsored by [[Solve ME/CFS Initiative]]<ref>{{Cite web|url=https://www.youtube.com/watch?v=rxdzaWD5wfU | title = ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study | last = | first = | authorlink = Jarred Younger | date = Dec 14, 2018 | website = YouTube|publisher=SolveCFS|archive-url=|archive-date=|url-status=|access-date=}}</ref>

==See also==
*[[Brain]]
*[[Basal ganglia]]
*[[Microglia]]
*[[QEEG]]
*[[Neuroinflammation]]
*[[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis]]

=== Researchers ===
* [[Neil Harrison]]
* [[Jose Montoya]]
* [[Jarred Younger]]

==Learn more==
* 2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder - New York Times: Well (2014)|Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder]]

*2016, [http://www.healthrising.org/blog/2016/07/25/chronic-fatigue-syndrome-brain-under-functioning/ Laggard: Is an Under-Active Brain the Problem in Chronic Fatigue Syndrome (ME/CFS)]<ref>{{Cite news | url=http://www.healthrising.org/blog/2016/07/25/chronic-fatigue-syndrome-brain-under-functioning/ | title = Laggard: Is an Under-Active Brain the Problem in Chronic Fatigue Syndrome (ME/CFS) | last = Johnson | first =Cort | date = 2016-07-25|work=Health Rising|access-date=2018-11-29|archive-url=|archive-date=|url-status=|language=en-GB|quote= | author-link = Cort Johnson}}</ref>
*2017, [https://www.dropbox.com/s/u0ynbse2xb2hao6/Reference%20List%20of%20Neurology%20studies%20%20ME%20CFS%202017.pdf Reference List of Neurology studies ME CFS 2017.pdf]<ref>{{Cite web|url=https://www.dropbox.com/s/u0ynbse2xb2hao6/Reference%20List%20of%20Neurology%20studies%20%20ME%20CFS%202017.pdf | title = Reference List of Neurology studies - ME CFS 2017 | last = Chapman | first = Suzy | authorlink= | date = 2017 | website = Dropbox|language=en|archive-url=|archive-date=|url-status=|access-date=2018-11-29}}</ref>
*2018, [https://www.healthrising.org/blog/2018/09/24/brain-fire-neuroinflammation-found-chronic-fatigue-syndrome-me-cfs/ Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS)]<ref>{{Cite news | url=https://www.healthrising.org/blog/2018/09/24/brain-fire-neuroinflammation-found-chronic-fatigue-syndrome-me-cfs/ | title = Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS) | last = Johnson | first =Cort | date = 2018-09-24|work=Health Rising|access-date=2018-11-29|archive-url=|archive-date=|url-status=|language=en-GB|quote= | author-link = Cort Johnson}}</ref>
*2019, [http://go.solvecfs.org/webmail/192652/97033877/74d435097e87231f24cffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1 ''Brain Imaging and Behavior'' publication from Dr. Jarred Younger’s SMCI Ramsay pilot study supports involvement of neuroinflammation in ME/CFS]<ref name=":1">{{Cite web|url=http://go.solvecfs.org/webmail/192652/97033877/74d435097e87231f24cffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1 | title = Brain Imaging and Behavior publication from Dr. Jarred Younger’s SMCI Ramsay pilot study supports involvement of neuroinflammation in ME/CFS|website=go.solvecfs.org|access-date=2019-01-17 | date = | last = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>

==References==
<references>
<ref name="Finkelmeyer, 2017">{{Citation | last1 = Finkelmeyer | first1 = Andreas | authorlink1 = Andreas Finkelmeyer | last2 = He | first2 = Jiabao | authorlink2 = | last3 = Maclachlan | first3 = Laura | authorlink3 = | last4 = Watson | first4 = Stuart | authorlink4 = | last5 = Gallagher | first5 = Peter | authorlink5 = | last6 = Newton | first6 = Julia L. | authorlink6 = Julia Newton | last7 = Blamire | first7 = Andrew M. | authorlink7 = | title = Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study | journal = NeuroImage: Clinical | volume = 17 | issue = | page = 24-30 | date = 2018 | pmid = 29021956 | doi = 10.1016/j.nicl.2017.09.024 | url = http://www.sciencedirect.com/science/article/pii/S221315821730236X }}</ref>
<ref name="Shan2016">{{citation | last1 = Shan | first1 = ZY | authorlink1 = | last2 = Kwiatek | first2 = R | authorlink2 = Richard Kwiatek | last3 = Burnet | first3 = R | authorlink3 = Richard Burnet | last4 = Del Fante | first4 = P | authorlink4 = Peter Del Fante | last5 = Staines | first5 = DR | authorlink5 = Donald Staines | last6 = Marshall-Gradisnik | first6 = SM | authorlink6 = Sonya Marshall-Gradisnik | last7 = Barnden | first7 = LR | authorlink7 = Leighton Barnden | title = Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study | journal = Journal of magnetic resonance imaging: JMRI | date = 2016-04-28 | pmid = 27123773 | doi = 10.1002/jmri.25283 | url = http://onlinelibrary.wiley.com/doi/10.1002/jmri.25283/abstract;jsessionid=070BE1111DE3D52AC62FD00B68E96028.f03t01 }}</ref>
</references>
[[Category:Neurology]]

Marcie Zinn

2024-06-05T10:23:11Z

Yannlk:

'''Marcie Lynn Zinn''' Ph.D. (May 6, 1951- Dec 28, 2019) was a research psychologist in Psychophysiology, Rehabilitation, Cognitive Neuroscience and Data Science conducting [[myalgic encephalomyelitis]]/[[chronic fatigue syndrome]] (ME/CFS) research with her husband, [[Mark Zinn]], at their nonprofit, the [[Neurocognitive Research Institute]]. Dr Zinn's research interests included the study of brain dysfunction in chronic disease, such as [[myalgic encephalomyelitis]] (M.E.). Marcie and her husband, Mark Zinn, also founded the NeuroCognitive Research Institute. Marcie Zinn passed away suddenly from sudden heart failure<ref>{{Cite web|url=https://www.kaminskifamilyfuneralhomes.com/obituary/dr-marcie-zinn-phd | title = Dr. Marcie Zinn, Ph.D. {{!}} Kaminski Family | website = kaminskifamilyfuneralhomes.com|language=en|access-date=2020-01-10}}</ref> while working to establish the NeuroCognitive Research Institute.<ref>{{Cite web|url=https://www.gofundme.com/f/the-ncri-needs-your-support | title = Click here to support Marcie Zinn Memorial Fund organized by Mark Zinn, Ph.D. |website=gofundme.com|language=en|access-date=2020-01-09}}</ref>

Dr Zinn's early research and career interests were in Performance Neuroscience and Psychology, but after being diagnosed in 2009 with herpes viral encephalitis which developed into [[Myalgic Encephalomyelitis]], her interest turned toward using her extensive [[QEEG|qEEG]] and neuroscience skills for research in [[myalgic encephalomyelitis|M.E.]]. Under the leadership of Dr. [[Jose Montoya]], she conducted a pilot study to look at cognitive dysfunction using [[QEEG|qEEG]] methods. While continuing to collaborate with Jose Montoya at Stanford, she and her husband [[Mark Zinn|Mark]] published research using brain network modeling in the study of M.E. [[brain]] dysfunction.<ref name="meet">{{Cite web
|work=MEE Medical|publisher =[[ME Association]]|url = https://meassociation.org.uk/wp-content/uploads/MEE-MEDICAL-MAGAZINE-AUTUMN-2021.pdf | pages=12-13| title = Meet the Scientist: Central Autonomic Network Disturbance in people with ME/CFS {{!}} A conversation with Dr. Mark Zinn | first = Dylan |last =Murphy | date =Autumn 2021}}</ref>

==ME/CFS Common Data Element (CDE) Project==
Marcie Zinn was a member of the Pain Working Group and the Neurologic/Cognitive/CNS Imaging Working Group of the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Common Data Element (CDE) Project sponsored by the [[National Institute of Neurological Disorders and Stroke]] and the [[Centers for Disease Control and Prevention]].<ref>{{Cite web|url=https://www.commondataelements.ninds.nih.gov/Myalgic%20Encephalomyelitis/Chronic%20Fatigue%20Syndrome#pane-138 | title = Complete Myalgic Encephalomyelitis/Chronic Fatigue Syndrome CDE Roster | last = | first = | authorlink = | date = | website = NIH|archive-url=|archive-date=|url-status=|access-date=2019-10-11}}</ref>

==Advocacy==
* Dr. Zinn signed the second and third [[open letter to the Lancet|open letters to the editor of ''The Lancet'']] urging the editor to commission a fully independent review of the [[PACE trial]], which the journal published in 2011.<ref>{{Cite web|url=http://www.virology.ws/2016/02/10/open-letter-lancet-again/ | title = An open letter to The Lancet, again|website=[[Virology blog]]|access-date=2019-12-03}}</ref><ref>{{Cite web|url=http://www.virology.ws/2018/06/19/trial-by-error-an-open-letter-to-the-lancet-two-years-on/ | title = Trial By Error: An Open Letter to The Lancet, Two Years On|website=[[Virology blog]]|language=en-US|access-date=2019-12-03}}</ref>
* Feb 10, 2016, [http://www.virology.ws/2016/02/10/open-letter-lancet-again/ An open letter to The Lancet, again - Virology blog]
* Jun 19, 2018, [http://www.virology.ws/2018/06/19/trial-by-error-an-open-letter-to-the-lancet-two-years-on/ Trial By Error: An Open Letter to The Lancet, Two Years On - Virology blog]

==Notable studies==
* June, 2004: ''Development of a Self-Report Inventory to Assess Cognitive Dysfunction in Musicians.'' ProQuest Information and Learning Company, Ann Arbor, Michigan.
* March, 2005: ''The Hippocampus in Music Learning and Performance'' (March, 2005). Presentation at the annual Brain Awareness Week event sponsored by Dana Alliance for Brain Initiatives, Dublin, CA.
* Mar 2014, Cortical hypoactivation during resting eLORETA suggests central nervous system pathology in patients with chronic fatigue syndrome (Conference paper, 2014 Stanford Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Symposium: Advances in Clinical Care and Translational Research for health care providers, Stanford School of Medicine, Palo Alto, CA<ref>{{Cite journal|last = Zinn | first = Mark | authorlink = Mark Zinn | last2 = Zinn | first2 = Marcie | authorlink2 = Marcie Zinn | last3 = Maldonado | first3 = Jose R | authorlink3 = | last4 = Norris | first4 = Jane L | authorlink4 = Jane Norris | last5 = Valencia | first5 = Ian J. | authorlink5 = Ian Valencia | last6 = Montoya | first6 = Jose G | authorlink6 = Jose Montoya | date = 2014-03-18 | title = Cortical hypoactivation during resting eLORETA suggests central nervous system pathology in patients with chronic fatigue syndrome|url=https://www.researchgate.net/publication/290628295_Cortical_hypoactivation_during_resting_eLORETA_suggests_central_nervous_system_pathology_in_patients_with_chronic_fatigue_syndrome|journal=2014 Stanford Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Symposium Conference Paper|volume=|issue=|pages=|doi=|pmc=|pmid=|access-date=2019-12-03|quote=|via=}}</ref> - [https://www.researchgate.net/publication/290628295_Cortical_hypoactivation_during_resting_eLORETA_suggests_central_nervous_system_pathology_in_patients_with_chronic_fatigue_syndrome (Abstract - full text on request)]
* Mar 2014, ''EEG peak alpha frequency is associated with chronic fatigue syndrome: a case-control observational study''. Invited presentation at the 2014 Stanford Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symposium : Advances in Clinical Care and Translational Research; March 19, 2014, Stanford University Dept. of Medicine, Palo Alto, CA.
*2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref>{{Cite web|url=http://www.eurekaselect.com/135207/article | title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | last = Jason | first = Leonard A. | authorlink = Leonard Jason | last2 = Zinn | first2 = Marcie L. | authorlink2 = Marcie Zinn | date = 2015-08-31 | website = Current Neuropharmacology|language=en|doi=10.2174/1570159x13666150928105725|pmc=4761639|pmid=26411464|archive-url=|archive-date=|url-status=|access-date=2019-12-03 | last3 = Zinn | first3 = Mark A. | authorlink3 = Mark Zinn}}</ref> - [http://www.ncbi.nlm.nih.gov/pubmed/26411464 (Full Text)]
*2015, Zinn, M.L. & Zinn, M.A. Psychophysiology for Performing Artists. In M. S. Schwartz & F. Andrasik, Eds: Biofeedback: A Practitioners Guide (4th ed.), New York: Guilford.
*2016, Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with [[Myalgic Encephalomyelitis]]: A Pilot Study<ref>{{Cite journal|last = Zinn | first = Marcie L. | authorlink = Marcie Zinn | last2 = Zinn | first2 = Mark A. | authorlink2 = Mark Zinn | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | date = Sep 2016 | title = Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study|url=http://link.springer.com/10.1007/s10484-016-9331-3|journal=Applied Psychophysiology and Biofeedback|language=en|volume=41|issue=3|pages=283–300|doi=10.1007/s10484-016-9331-3|issn=1090-0586|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.researchgate.net/publication/294258397_Intrinsic_Functional_Hypoconnectivity_in_Core_Neurocognitive_Networks_Suggests_Central_Nervous_System_Pathology_in_Patients_with_Myalgic_Encephalomyelitis_A_Pilot_Study (Full Text)]
*2016, [[QEEG|qEEG]] / LORETA in Assessment of Neurocognitive Impairment in a Patient with Chronic Fatigue Syndrome: A Case Report<ref>{{Cite journal|last = Marcie L | first = Zinn | authorlink = Marcie Zinn | last2 = Zinn | first2 = Mark A | authorlink2 = Mark Zinn | last3 = Jason | first3 = Leonard A | authorlink3 = Leonard Jason | date = 2016 | title=qEEG / LORETA in Assessment of Neurocognitive Impairment in a Patient with Chronic Fatigue Syndrome: A Case Report|url=https://www.sciforschenonline.org/journals/clinical-research/CLROA-2-110.php|journal=Clinical Research: Open Access ( ISSN 2469-6714 )|volume=2|issue=1|pages=|doi=10.16966/2469-6714.110|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://sciforschenonline.org/journals/clinical-research/CLROA-2-110.php (Full Text)]
*2016, Functional Neural Network Connectivity in Myalgic Encephalomyelitis<ref>{{Cite journal|last = Zinn | first = Marcie | authorlink = Marcie Zinn | last2 = Zinn | first2 = Mark | authorlink2 = Mark Zinn | last3 = Jason | first3 = Leonard | authorlink3 = Leonard Jason | date = 2016-03-09 | title = Functional Neural Network Connectivity in Myalgic Encephalomyelitis|url=http://www.neuroregulation.org/article/view/16018|journal=NeuroRegulation|volume=3|issue=1|pages=28–50|doi=10.15540/nr.3.1.28|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [https://www.researchgate.net/publication/297453164_NeuroRegulation_httpwwwisnrorg_Functional_Neural_Network_Connectivity_in_Myalgic_Encephalomyelitis (Full Text)]
*2017, Small-world network analysis of cortical connectivity in [[Chronic Fatigue Syndrome]] using quantitative [[EEG]]<ref>{{Cite journal|last = Zinn | first = Mark Alan | authorlink = Mark Zinn | last2 = Zinn | first2 = Marcie L. | authorlink2 = Marcie Zinn | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | date = 2017-12-07 | title = Small-World Network Analysis of Cortical Connectivity in Chronic Fatigue Syndrome Using Quantitative EEG|url=http://www.neuroregulation.org/article/view/17838|journal=NeuroRegulation|language=en|volume=4|issue=3-4|pages=125|doi=10.15540/nr.4.3-4.125|issn=2373-0587|via=}}</ref> - [https://www.researchgate.net/publication/321717868_Small-World_Network_Analysis_of_Cortical_Connectivity_in_Chronic_Fatigue_Syndrome_Using_Quantitative_EEG (Full Text)]
*2018, Cortical hypoactivation during resting EEG suggests central nervous system pathology in patients with [[chronic fatigue syndrome]]<ref>{{Cite journal|last = Zinn | first = M.A. | authorlink = Mark Davis | last2 = Zinn | first2 = M.L. | authorlink2 = Marcie Zinn | last3 = Valencia | first3 = I. | authorlink3 = Ian Valencia | last4 = Jason | first4 = L.A. | authorlink4 = Leonard Jason | last5 = Montoya | first5 = J.G. | authorlink5 = Jose Montoya | date = Jul 2018 | title = Cortical hypoactivation during resting EEG suggests central nervous system pathology in patients with chronic fatigue syndrome|url=https://linkinghub.elsevier.com/retrieve/pii/S0301051118304071|journal=Biological Psychology|language=en|volume=136|issue= | pages = 87–99|doi=10.1016/j.biopsycho.2018.05.016|pmc=|pmid=29802861|quote=|via=}}</ref> - [https://www.sciencedirect.com/science/article/pii/S0301051118304071 (Abstract)]

==Talks and interviews==
*2016, [https://www.youtube.com/watch?v=aN0Fh0kiUiI "qEEG LORETA CFS Case study - Sci Forschen Inc."]

==Online presence==
*[https://www.ncbi.nlm.nih.gov/pubmed/?term=Zinn%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=26869373 PubMed]
*[https://www.researchgate.net/profile/Dr_Marcie_Zinn ResearchGate]
*[https://www.linkedin.com/in/marcie-zinn-795083a8/ LinkedIn]

==Learn more==
*[https://meassociation.org.uk/wp-content/uploads/MEE-MEDICAL-MAGAZINE-AUTUMN-2021.pdf Meet the Scientist: Central Autonomic Network Disturbance in people with ME/CFS {{!}} A conversation with Dr. Mark Zinn] (p. 12-13)
*[http://www.selfgrowth.com/experts/marcie_zinn.html "Marcie Zinn Ph.D., NCTM" bio]
*[https://www.thencri.org NeuroCognitive Research Institute]

==See also==
*[[Mark Zinn]]
*[[qEEG|eLORETA]]

==References==
{{reflist}}

[[Category:Researchers]]
[[Category:Clinicians]]
[[Category:US researchers]]
[[Category:People with ME, CFS, and/or FMS]]
[[Category:Psychological paradigm critics]]
[[Category:PACE trial critics]]
[[Category:Deceased people with ME, CFS, and/or FMS]]
[[Category:Famous people with ME, CFS, and/or FMS]]
[[Category:American famous people with ME, CFS, and/or FMS]]

Adrenaline rush

2024-06-04T20:26:22Z

Yannlk:/* Symptom recognition */

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described in some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used for the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.)

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020" /><ref name="Bested2015" /><ref name=":0" />
==Co-Occurring Symptoms==
Some patients report Adrenaline rushes co-occurring with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==
In a 2020 [[Cardiopulmonary exercise test|CPET]]-based study of 44 patients diagnosed with ME/CFS, 25% reported experiencing an adrenaline rush during the study and also in their personal lives during and/or after overexertion.<ref name="Stussman2020" />

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref>

It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==

* Stussman B, Williams A, Snow J, Gavin A, Scott R, Nath A and Walitt B (2020) Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. ''Front. Neurol.'' 11:1025. doi: 10.3389/fneur.2020.01025

==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Adrenaline rush

2024-06-04T20:21:00Z

Yannlk:/* Prevalence */

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described in some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used for the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.)

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020" /><ref name="Bested2015" /><ref name=":0" />
==Co-Occurring Symptoms==
Some patients report Adrenaline rushes co-occurring with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==
In a 2020 [[Cardiopulmonary exercise test|CPET]]-based study of 44 patients diagnosed with ME/CFS, 25% reported experiencing an adrenaline rush during the study and also in their personal lives during and/or after overexertion.<ref name="Stussman2020" />

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref> It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==

* Stussman B, Williams A, Snow J, Gavin A, Scott R, Nath A and Walitt B (2020) Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. ''Front. Neurol.'' 11:1025. doi: 10.3389/fneur.2020.01025

==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Adrenaline rush

2024-06-04T16:18:39Z

Yannlk:/* Prevalence */

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described in some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used for the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.)

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020" /><ref name="Bested2015" /><ref name=":0" />
==Co-Occurring Symptoms==
Some patients report Adrenaline rushes co-occurring with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==
In a 2020 study of 44 patients with post-exertional malaise, 25% reported having experienced adrenaline rush during and or after overexertion.<ref name="Stussman2020" />

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref> It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==

* Stussman B, Williams A, Snow J, Gavin A, Scott R, Nath A and Walitt B (2020) Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. ''Front. Neurol.'' 11:1025. doi: 10.3389/fneur.2020.01025

==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Adrenaline rush

2024-06-04T16:14:15Z

Yannlk:

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described in some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used for the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.)

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020" /><ref name="Bested2015" /><ref name=":0" />
==Co-Occurring Symptoms==
Some patients report Adrenaline rushes co-occurring with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref> It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==
==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Adrenaline rush

2024-06-04T16:12:48Z

Yannlk:

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described in some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used to describe the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.)

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020" /><ref name="Bested2015" /><ref name=":0" />
==Co-Occurring Symptoms==
Some patients report Adrenaline rushes co-occurs with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref> It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==
==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Science Media Centre

2024-06-02T17:28:48Z

Yannlk:controversy

The '''Science Media Centre''' (or SMC) is an organisation formed in 2000 to encourage more accurate reporting of science in the media. When notable scientific papers are published, the Science Media Centre will often publish a page of "expert opinion" which journalists will then commonly re-purpose in their published work. The Science Media Centre has published a number of expert opinions on ME/CFS.<ref>[http://www.sciencemediacentre.org/?s=cfs/me&cat= Search results for (cfs/me)]</ref> It is a controversial organisation that has received significant criticism.

==Controversy==

=== "Militant" patient ===
The Science Media Centre has played a role in placing articles with the angle that a small group of "abusive" ME patients are driving researchers, namely psychiatrists studying cognitive behavioral therapy and graded exercise therapy, from the field. This story has been repeated in the UK media for nearly a decade, chiefly via reporting by [[Kate Kelland]] (Reuters), [[Tom Feilden]] (BBC), and [[Rod Liddle]] (Sunday Times).

The SMC claims to have been the source of Feilden's original 2011 reporting on threats and harassment to Chronic Fatigue Syndrome researchers. Feilden won an award from the UK Press Gazette for this reporting, and was nominated by the SMC.<ref>{{Cite web|url=http://www.sciencemediacentre.org/wp-content/uploads/2013/03/Review-of-the-first-three-years-of-the-mental-health-research-function-at-the-Science-Media-Centre.pdf | title = Review of the first three years of the mental health research function at the Science Media Centre | last = | first = | author-link =| date = |website=|access-date=}}</ref><ref>{{Cite web|url=https://mrtopple.com/2019/03/18/the-media-is-waging-a-coordinated-war-against-chronically-ill-and-disabled-people/ | title = The media is waging a coordinated war against chronically ill and disabled people | last = Topple | first = Steve | date = 2019-03-18 | website = Mr Topple|language=en|access-date=2019-03-21}}</ref> Prof. [[Simon Wessely]] of Kings College London, a colleague of [[PACE trial]] co-author and Oxford University professor, [[Michael Sharpe]], was the source and subject Feilden's story, and is on the SMC board of trustees.<ref>{{Cite web|url=http://www.sciencemediacentre.org/about-us/governance/ | title = governance {{!}} Science Media Centre|language=en-US|access-date=2019-03-21}}</ref> Kelland is featured in the Science Media Centre's promotional materials.<ref>{{Cite web|url=http://www.sciencemediacentre.org/film/ | title = a short film about the SMC {{!}} Science Media Centre|language=en-US|access-date=2019-03-21}}</ref><ref>{{Cite web|url=http://www.sciencemediacentre.org/wp-content/uploads/2012/10/SMC-Views-from-the-front-line-essays-on-the-SMC.pdf | title = Views from the front line {{!}} Essays on the Science Media Center | last= | first = | author-link =| date = Oct 2010 | website = |access-date=}}</ref>
{| class="wikitable"
!Month
!Day
!Year
!Author
!Headline
!Publication
|-
|March
|19
|2019
|Kate Kelland
|"[https://www.reuters.com/investigates/special-report/science-socialmedia/ Online activists are silencing us, scientists say]"
|Reuters
|-
|March
|18
|2019
|Tom Feilden
|
|BBC Radio 4 Today
|-
|March
|17
|2019
|Rod Liddle
|"[https://www.thetimes.co.uk/article/always-fatigued-yet-they-never-tire-of-claiming-their-malady-really-is-a-virus-d7s7qlvbk Always fatigued — yet they never tire of claiming their malady really is a virus]"
|The Sunday Times
|-
|October
|17
|2018
|Kate Kelland
|"[https://whbl.com/news/articles/2018/oct/17/exclusive-science-journal-to-withdraw-chronic-fatigue-review-amid-patient-activist-complaints/ Science journal to withdraw chronic fatigue review amid patient activist complaints]"
|Reuters
|-
|November
|7
|2015
|Rod Liddle
|"[https://www.spectator.com.au/2015/11/the-me-lobby-is-just-a-symptom-of-our-stupidity-about-mental-illness/ The ME lobby is just a symptom of our stupidity about mental illness]"
|The Spectator
|-
|July
|29
|2011
|Tom Feilden
|"'[http://www.bbc.co.uk/news/mobile/science-environment-14326514 Torrent of abuse' hindering ME research]"
|BBC Radio 4 Today
|-
|July
|27
|2011
|Rod Liddle
|"[https://www.thetimes.co.uk/article/shoot-the-medical-messenger-see-if-thatll-cure-you-8k88fv6w9wv Shoot the medical messenger – see if that'll cure you]"
|The Sunday Times
|}
===Other criticism===
The Science Media Centre has been criticized for being a "lobby group".<ref>{{Cite news | url=https://www.theguardian.com/science/2002/jun/02/gm.observersciencepages | title = Lobby group 'led GM thriller critics' | last = McKie | first = Robin | date = 2002-06-02|work=The Observer|access-date=2019-02-28|language=en-GB|issn=0029-7712|quote=}}</ref>

Patients with [[ME/CFS]] have criticised the Science Media Centre for focusing its output on psychological and psychiatric expert opinions on ME/CFS and the fact that they house the disease within their Mental Health section.<ref>{{Cite web|url=http://voicesfromtheshadowsfilm.co.uk/welcome/reflections/ | title = Reflections on "Voices from the Shadows" | last = Voices from the Shadows | first = | authorlink = Voices from the Shadows | date = |website=voicesfromtheshadowsfilm.co.uk|access-date=2019-02-28}}</ref><ref>{{Cite web|url=http://www.investinme.org/Article418%20The%20Media%20and%20ME.htm | title = The Media and ME | last = Williams | first = Margaret | authorlink=Margaret Williams | date = |website=[[Invest in ME Research]]|access-date=2019-02-28}}</ref>

It has also been criticised for [[bias]] toward corporate interests.<ref>{{Cite web|url=http://www.scidev.net/index.cfm?originalUrl=/global/journalism/feature/uk-s-science-media-centre-lambasted-for-pushing-corporate-science.html& | title = UK’s Science Media Centre lambasted for pushing corporate science | last = SciDev.Net|website=SciDev.Net|language=en|access-date=2019-02-28}}</ref>

[[Fiona Fox]], director of the SMC, has debated a critic about the value of the SMC.<ref>{{Cite web|url=http://www.cjr.org/the_observatory/science_media_centers_the_pres.php | title = Science media centers & the press, part 1 | website = Columbia Journalism Review|language=en|access-date=2019-02-28}}</ref>

Professor [[James Coyne]] has criticized the Science Media Centre for what he sees as lobbying against open-data in science.<ref>{{Cite web|url=https://jcoynester.wordpress.com/2016/01/31/further-insights-into-the-war-against-data-sharing-the-science-media-centres-letter-writing-campaign-to-uk-parliament/ | title = Further insights into war against data sharing: Science Media Centre’s letter writing campaign to UK Parliament | last = Coyne | first=James C. | authorlink = James Coyne | date = 2016-01-31 | website = Quick Thoughts|language=en|access-date=2019-02-28}}</ref>

Professor [[Malcolm Hooper]] has criticized the Science Media Centre coverage of the disease.<ref>[http://www.meactionuk.org.uk/The-SMC-and-its-campaign-against-MECFS.pdf The Role of the Science Media Centre and the Insurance Industry in ME/CFS: the facts behind the fiction]</ref>

It was found upon investigation that the Science Media Centre were behind the media publicity blitz in 2011 of allegations of harassment of researchers by patients during the year when the [[PACE trial]] results were published and criticised. <ref>{{Cite web|url=http://www.sciencemediacentre.org/wp-content/uploads/2013/03/Review-of-the-first-three-years-of-the-mental-health-research-function-at-the-Science-Media-Centre.pdf | title = Supporting experts targeted by extremists | last = Science Media Centre | first= | authorlink = Science Media Centre | date = Mar 2013 | website = web.archive.org|archive-url=https://web.archive.org/web/20160418232134/http://www.sciencemediacentre.org/wp-content/uploads/2013/03/Review-of-the-first-three-years-of-the-mental-health-research-function-at-the-Science-Media-Centre.pdf|archive-date=2016-04-18|url-status=dead|access-date=2019-02-28}}</ref><ref>{{Cite web|url=http://www.sciencemediacentre.org/wp-content/uploads/2011/10/SMC-Anniversary-Brochure.pdf | title = Threats of Persecution {{!}} SMC Anniversary Brochure | last = Science Media Centre | first= | authorlink = Science Media Centre | date = Oct 2011 | website = web.archive.org|archive-url=https://web.archive.org/web/20140106032125/http://www.sciencemediacentre.org/wp-content/uploads/2011/10/SMC-Anniversary-Brochure.pdf|archive-date=2014-01-06|url-status=dead|access-date=2019-02-28}}</ref>

In August 2017, [[David Tuller]] criticized the Science Media Centre's published "expert opinions" in relation to criticism of the [[PACE trial]].<ref>{{Cite web|url=http://www.virology.ws/2017/08/02/trial-by-error-the-science-media-centres-desperate-efforts-to-defend-pace/ | title = Trial by Error: The Science Media Centre’s Desperate Efforts to Defend PACE | last = Tuller | first = David | authorlink = David Tuller | date = Aug 2, 2017 | website = [[Virology blog]]|language=en-US|access-date=2019-02-28}}</ref>

A blog criticising and questioning Fiona Fox was published by [[John Peters]] in response to her 'Inconvenient Truths' blogpost <ref>{{Cite news | url=https://johnthejack.com/2017/10/20/a-response-to-fiona-fox/ | title = A Response to Fiona Fox | date = 2017-10-20|work=johnthejack|access-date=2018-10-15|language=en-US | last = Peters | first = John|quote= | author-link = John Peters}}</ref>.

==Notable people==
*[[Fiona Fox]] (Chief Executive)<ref>{{Cite web|url=http://www.sciencemediacentre.org/about-us/staff/ | title = staff {{!}} Science Media Centre|website=sciencemediacentre.org|language=en-US|access-date=2018-10-15}}</ref>
*[[Edward Sykes]] (Senior Press Manager & Head of Mental Health and Neuroscience)
*[[Simon Wessely]] (Board of Trustees)<ref>{{Cite web|url=http://www.sciencemediacentre.org/about-us/governance/ | title = governance {{!}} Science Media Centre|website=sciencemediacentre.org|language=en-US|access-date=2018-10-15}}</ref>

==Learn more==
*[http://www.investinme.org/Article418%20The%20Media%20and%20ME.htm The Media and ME] - Margaret Williams
*[http://www.virology.ws/2017/08/02/trial-by-error-the-science-media-centres-desperate-efforts-to-defend-pace/ Trial by Error: The Science Media Centre's Desperate Attempts to Defend PACE] - David Tuller
*[https://en.wikipedia.org/wiki/Science_Media_Centre Wikipedia - Science Media Centre]

==See also==
*[[Sense About Science]]
*[[PACE trial]]
*[[UK CFS/ME Research Collaborative]]
*[[Wessely school|The Wessely school]]
*[[Intimidation and bullying of PACE trial critics]]
*[[Simon Wessely]]
*[[Kate Kelland]]
*[[Rod Liddle]]
*[[Tom Feilden]]
== References ==
{{Reflist}}

[[Category:Organizations]]
[[Category:Organizations based in the United Kingdom]]

Peter Wostyn

2024-06-02T12:15:21Z

Yannlk:

{{NeedsImage}}
'''Peter Wostyn''', MD, works in the Department of Psychiatry, Psychiatrisch Centrum Sint-Amandus, Beernem, [[Belgium]]<ref>{{Cite web|url=https://www.linkedin.com/in/peter-wostyn-a43a07171/ | title = Peter Wostyn | last = | first = | authorlink = | date = 2019-10-22 | website = LinkedIn|archive-url=|archive-date=|url-status=|access-date=}}</ref> and is a co-founder of P&X Medical, a biotech company focused on the treatment of intracranial pressure, cerebrospinal fluid turnover and glymphatic flow in neurodegenerative disorders, with a primary focus on glaucoma.<ref>{{Cite web|url=https://www.px-medical.be/en/ | title = Technology - P&X Medical|website=px-medical.be|language=en|access-date=2019-10-22}}</ref>

Dr Wostyn developed the unproven glymphatic dysfunction hypothesis which postulates that a dysfunction of the waste clearance system, called the glymphatic system, causes a build-up of toxins within the central nervous system, which he hypothesised precipitates at least some cases of ME/CFS.<ref name=":0" />

==Notable studies==
* 2018, Can cerebrospinal fluid diversion be beneficial in the treatment of chronic fatigue syndrome?<ref>{{Cite journal | last = Wostyn | first = Peter | author-link = | last2 = De Deyn | first2 = Peter Paul | authorlink2 = | date = Sep 2018 | title = Can cerebrospinal fluid diversion be beneficial in the treatment of chronic fatigue syndrome?|url=https://linkinghub.elsevier.com/retrieve/pii/S0306987718302895|journal=Medical Hypotheses|language=en|volume=118|issue=|pages=174|doi=10.1016/j.mehy.2018.04.020|pmc=|pmid=|access-date=|quote=|via=}}</ref>
* 2018, The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy<ref name=":0">{{Cite journal | last = Wostyn | first = Peter | author-link = | last2 = De Deyn | first2 = Peter Paul | authorlink2 = | date = Sep 2018 | title = The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy|url=https://linkinghub.elsevier.com/retrieve/pii/S0306987718305486|journal=Medical Hypotheses|language=en|volume=118|issue=|pages=142–145|doi=10.1016/j.mehy.2018.07.007|pmc=|pmid=|access-date=|quote=|via=}}</ref> - [[pubmed:30037603|(Abstract)]]

*2019, Retinal nerve fiber layer thinning in chronic fatigue syndrome as a possible ocular biomarker of underlying glymphatic system dysfunction<ref>{{Cite journal | last = Wostyn | first = Peter| date = 2019-10-04 | title = Retinal nerve fiber layer thinning in chronic fatigue syndrome as a possible ocular biomarker of underlying glymphatic system dysfunction|url=https://www.ncbi.nlm.nih.gov/pubmed/31622921|journal=Medical Hypotheses|volume=134|pages=109416|doi=10.1016/j.mehy.2019.109416|issn=1532-2777|pmid=31622921}}</ref>

==Talks and interviews==

==Online presence==

==See also==
* [[Glymphatic dysfunction hypothesis]]

==Learn more==

==References==
{{reflist}}

[[Category:Researchers]]
[[Category:Belgium researchers]]

Adrenaline rush

2024-06-01T15:00:32Z

Yannlk:/* Prevalence */ co-occuring symptoms

'''Adrenaline rush''', also called '''adrenaline crash''', and '''adrenaline surge''' is a physiological state described by some people with [[ME/CFS]] and [[Long COVID]]. 
Although the word "adrenaline" is used by patients to describe the phenomenon, it is unknown if the release of [[Epinephrine|adrenaline]] (epinephrine) is the cause of the phenomenon, which is described as being characterised by:<ref name="Stussman2020">{{Cite journal|title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|date=2020-09-18|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530890/|journal=Frontiers in Neurology|volume=11|pages=1025|last=Stussman|first=Barbara|last2=Williams|first2=Ashley|last3=Snow|first3=Joseph|last4=Gavin|first4=Angelique|last5=Scott|first5=Remle|last6=Nath|first6=Avindra|last7=Walitt|first7=Brian|doi=10.3389/fneur.2020.01025|pmc=7530890|pmid=33071931|issn=1664-2295}}</ref><ref name="Bested2015">{{Cite journal|title=Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians|date=Aug 18, 2015|url=https://www.degruyter.com/document/doi/10.1515/reveh-2015-0026/pdf|journal=Review of Environmental Health|volume=30|issue=4|pages=223-249|last=Bested|first=Alison|last2=Marshall|first2=Lynn}}</ref><ref>{{Cite web|url=https://medicine.wustl.edu/news/podcast-loss-of-smell-heart-problems-common-symptoms-for-long-haulers/|title=Podcast: Loss of smell, heart problems common symptoms for long-haulers|last=Dryden|first=Jim|date=2021-03-10|website=Washington University School of Medicine in St. Louis|language=en|access-date=2024-05-02}}</ref>

* A temporary increase in energy levels compared to baseline
* [[restlessness|Inability to rest]] and [[anxiety]]
* Lessening of some symptoms
* [[Autonomic dysfunction]] ([[Tachycardia|fast heart rate]], jittering / [[muscle spasm]]s, low [[heart rate variability]] etc.

==Co-Occurring Symptoms==
An adrenaline rush often co-occurs with [[temperature dysregulation]], specifically a feeling described as “overheating” in various parts of the body.<ref name=":0">{{Cite journal|title=Extremely Severe ME/CFS-A Personal Account|date=2021-04-27|url=https://pubmed.ncbi.nlm.nih.gov/33925566|journal=Healthcare (Basel, Switzerland)|volume=9|issue=5|pages=504|last=Dafoe|first=Whitney|doi=10.3390/healthcare9050504|pmc=8145314|pmid=33925566|issn=2227-9032}}</ref>

==Prevalence==

==Symptom recognition==
An adrenaline rush is similar to the state of being "[[wired but tired]]", however tiredness is not necessarily a feature of an adrenaline rush.<ref>{{Cite web|url=https://www.springermedizin.de/praevention-und-gesundheitsfoerderung-in-der-paediatrie/fatigue/chronische-erschoepfung-bedeutet-nicht-einfach-nur-muede-zu-sein/23172132?fulltextView=true&doi=10.1007%2Fs15014-022-4043-z|title=Chronische Erschöpfung bedeutet nicht, einfach nur müde zu sein|website=springermedizin.de|language=de|doi=10.1007/s15014-022-4043-z|pmc=PMC9203140|access-date=2024-05-02}}</ref> It is not to be confused with a [[panic attack]], as a panic attack has a psychological cause, whilst an adrenaline rush has an organic cause.<ref>{{Cite web|url=https://www.nimh.nih.gov/health/publications/panic-disorder-when-fear-overwhelms|title=Panic Disorder: When Fear Overwhelms|website=National Institute of Mental Health|language=en|access-date=2024-05-02}}</ref>

==Notable studies==

==Possible causes==
Adrenaline rushes have been described in some patients during and after overexertion, but before [[post-exertional malaise]] (or a [[crash]]) begins.<ref name="Stussman2020"/><ref name="Bested2015" /><ref name=":0" />

==See also==
* [[Post-exertional malaise]]
* [[Adrenaline]]

==Learn more==


==References==
{{reflist}}


[[Category:Signs and symptoms]]
[[Category:Allergy signs and symptoms]]
[[Category:Aural signs and symptoms]]‎
[[Category:Cardiac signs and symptoms]]‎
[[Category:Cognitive signs and symptoms]]‎
[[Category:Digestive signs and symptoms]]‎
[[Category:Endocrine signs and symptoms]]‎
[[Category:Energy production or transportation symptoms]]‎
[[Category:Food intolerances‎]]
[[Category:Genitourinary signs and symptoms]]‎
[[Category:Immune signs and symptoms]]‎
[[Category:Long COVID signs and symptoms]]‎
[[Category:Muscular signs and symptoms]]‎
[[Category:Neurological signs and symptoms]]‎
[[Category:Ocular signs and symptoms]]‎
[[Category:Oral signs and symptoms]]‎
[[Category:Pain signs and symptoms]]‎
[[Category:Post-exertional neuroimmune signs and symptoms]]‎
[[Category:Psychological signs and symptoms]]‎
[[Category:Pulmonary signs and symptoms]]‎
[[Category:Sensitivity signs and symptoms]]‎
[[Category:Sleep signs and symptoms]]‎

Sleep dysfunction

2024-06-01T09:50:15Z

Yannlk:various improvments

[[File:Insomnia_sleep_remedies.jpg|alt="Sleep easy" tea bags containing valerian, lemon balm capsules and a bottle of melatonin.|thumb]]
'''Sleep dysfunction''' is very common in [[ME/CFS]] and can take a very wide range of forms, with [[unrefreshing sleep]] being particularly common.<ref name="CDC-symptoms">{{Cite web|url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|website=[[Centers for Disease Control and Prevention]] | date = Jan 27, 2021|access-date = 2021-02-25}}</ref> Sleep disorders affect around one in two people with ME/CFS, a similar rate is found in [[Long COVID|long covid]].<ref>{{Cite journal | date = 2018-07-01 | title = Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties|url=https://www.sciencedirect.com/science/article/pii/S2173580818300038|journal=Neurología (English Edition)|language=en|volume=33|issue=6|pages=385–394|doi=10.1016/j.nrleng.2015.11.020|issn=2173-5808}}</ref><ref name="ICC2011primer" /><ref name="canadianconsensus-CCC" /><ref name="CDC-symptoms" /><ref>{{Cite journal|title=Prevalence of sleep disturbances in patients with long COVID assessed by standardised questionnaires and diagnostic criteria: A systematic review and meta-analysis|date=December 2023|url=https://pubmed.ncbi.nlm.nih.gov/37898059|journal=Journal of Psychosomatic Research|volume=175|pages=111535|last=Chinvararak|first=Chotiman|last2=Chalder|first2=Trudie|doi=10.1016/j.jpsychores.2023.111535|pmid=37898059|issn=1879-1360}}</ref> [[Fibromyalgia]] patients also suffer from sleep disorders.<ref name="ACR2010">{{Cite journal|url=https://www.rheumatology.org/Portals/0/Files/2010_Preliminary_Diagnostic_Criteria.pdf | title = American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia | last = Wolfe | first = Frederick | date = May 2010|volume =62 | issue = 5 | pages = 600–610| doi = 10.1002/acr.20140|type=PDF|archive-url=|archive-date=|access-date= | author-link =| last2 = Clauw | first2 = Daniel | authorlink2 = |journal=Arthritis Care & Research | last3 = Fitzcharles | first3=Mary-Ann | first4 = Don| last5 = Katz | last4 = Goldenberg | first5 = Robert | last6 = Mease | first6 = Philip | last7 = Russel | first7 = Anthony | last8 = Russel | first8 = I. Jon | first9 = John | last9 = Winfield | first10 = Muhammad | last10 = Yunus|quote=}}</ref>

== Types of sleep dysfunction ==
Some of these sleep dysfunctions or disorders include:
*[[dysania]]<ref>{{Cite web|url=https://ammes.org/symptoms-of-mecfs/ | title = Symptoms of ME/CFS – American ME and CFS Society|website=[[American ME and CFS Society]]|language=en-US|access-date=2018-08-29}}</ref> (a state of finding it hard to get out of bed in the morning; in [[ME/CFS]] it can an extended period lasting several hours after awakening [assuming the patient is not bedridden from the illness])
*[[hypersomnia]] (excessive sleeping, inability to stay awake)
*[[agogia]] (transitional state from wakefulness to sleep during which lucid thought, lucid dreaming, hallucinations and, sleep paralysis can occur)
*[[insomnia]]<ref>{{Cite journal | date = 2015-05-01 | title = The role of insomnia in the treatment of chronic fatigue|url=https://www.sciencedirect.com/science/article/pii/S002239991400422X|journal=Journal of Psychosomatic Research|language=en|volume=78|issue=5 | pages = 427–432|doi=10.1016/j.jpsychores.2014.11.022|issn=0022-3999}}</ref> (difficulty falling asleep, staying asleep, and/or waking up too early in the morning)
*[[light sleep]] (a non-REM stage and the easiest sleep stage to awaken from)
*[[Periodic limb movement disorder]]/nocturnal myoclonus - involuntary jerking or leg movements when sleeping or when falling asleep<ref name="UScoal-2020">{{Cite web | title = Diagnosing and Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last=U.S. ME/CFS Clinician Coalition
|edition=2 | date = July 2020 | url= https://bridgesandpathways.org.au/wp-content/uploads/2021/02/DiagnosingAndTreatingMECFSV2_USCoalition_2020.pdf
| pages = 4}}</ref>
*[[nightmare]]s (a frightening or unpleasant dream)
*[[night sweat]]s (excessive sweating while you sleep)
*[[Restless legs syndrome]]<ref>{{Cite journal | last = Viola-Saltzman | first = Mari | last2 = Watson | first2 = Nathaniel F. | last3 = Bogart | first3=Andy | last4 = Goldberg | first4 = Jack| last5 = Buchwald | first5 = Dedra | date = 2010-10-15 | title = High prevalence of restless legs syndrome among patients with fibromyalgia: a controlled cross-sectional study|url=https://www.ncbi.nlm.nih.gov/pubmed/20957840|journal=Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine|volume=6|issue=5 | pages = 423–427|issn=1550-9389|pmid=20957840|via=}}</ref> (a strong urge to move one's legs)
*[[Sleep apnea]] (pauses in breathing or periods of shallow breathing)
*[[Reversed or chaotic diurnal sleep rhythms|sleep phase shifting]] or [[sleep reversal]]<ref name="Cambras2018">{{Cite journal | last = Cambras | first=Trinitat | last2 = Castro-Marrero | first2 = Jesús | last3 = Zaragoza | first3=Maria Cleofé | last4 = Díez-Noguera | first4 = Antoni| last5 = Alegre | first5 = José | date = 2018-06-06 | title = Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis|url=https://doi.org/10.1371/journal.pone.0198106|journal=PLOS ONE|language=en|volume=13|issue=6| pages = e0198106|doi=10.1371/journal.pone.0198106|issn=1932-6203|pmid=29874259|via=}}</ref> ([[reversed or chaotic diurnal sleep rhythms]]) (circadian abnormalities: delayed sleep phase, non-24hr sleep cycle, loss of rhythm)
*[[somnolence]] (sleepiness)
*[[unrefreshing sleep]] (poor-quality sleep that doesn't relieve fatigue)<ref name="ICC2011primer" /><ref name="canadianconsensus-CCC">{{Citation | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 = Joshi | first9 = Pradip| authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols| journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid =
| doi = 10.1300/J092v11n01_02| url = http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf}}</ref>

==Prevalence==
*Depending on the criteria used for diagnosis, prevalence can vary greatly.

*In a 2001 Belgian study, 91.9% of patients meeting the [[Fukuda criteria]] and 94.8% of patients meeting the [[Holmes criteria]], in a cohort of 2073 [[chronic fatigue syndrome|CFS]] patients, reported sleep disturbances.<ref>{{Cite journal | last = De Becker | first=Pascale | authorlink = Pascale De Becker | last2 = McGregor | first2 = Neil | authorlink2 = Neil McGregor | last3 = De Meirleir | first3=Kenny | author-link3 = Kenny De Meirleir | date = December 2001 | title = A definition‐based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2796.2001.00890.x?sid=nlm%3Apubmed|journal=Journal of Internal Medicine|volume=250|issue=3|pages=234–240|doi=10.1046/j.1365-2796.2001.00890.x|quote=|via=}}</ref>
*A 2017 study by Davidson, et al, found up to 96.8% of people with CFS report [[unrefreshing sleep]] and many describe changes in sleep over the course of their illness.<ref name="Davidson, 2017" />
According to the published evidence, the mean prevalence of sleep disorders in patients with CFS is '''estimated at 56%.'''<ref>{{Cite journal | date = 2018-07-01 | title = Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties|url=https://www.sciencedirect.com/science/article/pii/S2173580818300038|journal=Neurología (English Edition)|language=en|volume=33|issue=6|pages=385–394|doi=10.1016/j.nrleng.2015.11.020|issn=2173-5808}}</ref>
{| class="wikitable"
!
!Year
!N
!Prevalence
!Sleep disorders included
|-
|Krupp et al.<ref>{{Cite journal | last = Krupp | first = Lauren B. | last2 = Jandorf | first2 = L. | last3 = Coyle | first3 = P.K. | last4 = Mendelson | first4 = W.B. | date = 1993-05-01 | title = Sleep disturbance in chronic fatigue syndrome|url=http://www.sciencedirect.com/science/article/pii/0022399993901342|journal=Journal of Psychosomatic Research|language=en|volume=37|issue=4|pages=325–331|doi=10.1016/0022-3999(93)90134-2|issn=0022-3999}}</ref>
|1993
|16
|62%
|OSAHS, PLMD, narcolepsy, hypersomnia
|-
|Morriss et al.<ref>{{Cite journal | last = Morriss | first = R. | last2 = Sharpe | first2 = M. | last3 = Sharpley | first3 = A.L. | last4 = Cowen | first4 = P.J. | last5 = Hawton | first5 = K. | last6 = Morris | first6 = J. | date = 1993-05-01 | title = Abnormalities of sleep in patients with the chronic fatigue syndrome.|url=https://www.bmj.com/content/306/6886/1161|journal=British Medical Journal|language=en|volume=306|issue=6886|pages=1161–1164|doi=10.1136/bmj.306.6886.1161|issn=0959-8138|pmid=8499816}}</ref>
|1993
|12
|58%
|Maintenance insomnia
|-
|Buchwald et al.<ref>{{Cite journal | last = Buchwald | first=Dedra | last2 = Pascualy | first2 = Ralph | last3 = Bombardier | first3=Charles | last4 = Kith | first4 = Phalla | date = 1994-01-01 | title = Sleep Disorders in Patients with Chronic Fatigue|url=https://doi.org/10.1093/clinids/18.Supplement_1.S68|journal=Clinical Infectious Diseases|volume=18|issue=Supplement_1|pages=S68–S72|doi=10.1093/clinids/18.supplement_1.s68|issn=1537-6591}}</ref>
|1994
|59
|81%
|OSAHS, hypersomnia
|-
|Le Bon et al.<ref>{{Cite journal | last = Le Bon | first = O. | last2 = Fischler | first2 = B. | last3 = Hoffmann | first3=G. | last4 = Murphy | first4 = J.R. | last5 = De Meirleir | first5 = K. | last6 = Cluydts | first6 = R. | last7 = Pelc | first7 = I. | date = 2000 | title=How significant are primary sleep disorders and sleepiness in the chronic fatigue syndrome?|url=https://pubmed.ncbi.nlm.nih.gov/11382899/|journal=Sleep research online: SRO|volume=3|issue=2 | pages = 43–48|issn=1096-214X|pmid=11382899}}</ref>
|2000
|53
|46%
|OSAHS
|-
|Fossey et al.<ref>{{Cite journal | last = Fossey | first = Myrtis | last2 = Libman | first2 = Eva | last3 = Bailes | first3=Sally | last4 = Baltzan | first4 = Marc| last5 = Schondorf | first5 = Ronald | last6 = Amsel | first6 = Rhonda | last7 = Fichten | first7 = Catherine S. | date = 2004-12-01 | title = Sleep Quality and Psychological Adjustment in Chronic Fatigue Syndrome|url=https://doi.org/10.1007/s10865-004-0004-y|journal=Journal of Behavioral Medicine|language=en|volume=27|issue=6|pages=581–605|doi=10.1007/s10865-004-0004-y|issn=1573-3521}}</ref>
|2004
|37
|58%
|OSAHS, narcolepsy
|-
|Reeves et al.<ref>{{Cite journal | last = Reeves | first=William C. | last2 = Heim | first2 = Christine | last3 = Maloney | first3 = Elizabeth M. | last4 = Youngblood | first4 = Laura Solomon| last5 = Unger | first5 = Elizabeth R. | last6 = Decker | first6 = Michael J. | last7 = Jones | first7 = James F. | last8 = Rye | first8 = David B. | date = 2006-11-16 | title = Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study|url=https://doi.org/10.1186/1471-2377-6-41|journal=BMC Neurology|language=en|volume=6|issue=1 | pages = 41|doi=10.1186/1471-2377-6-41|issn=1471-2377|pmc = 1660569|pmid=17109739}}</ref>
|2006
|43
|25%
|OSAHS, PLMD
|-
|Majer et al.<ref>{{Cite journal | last = Majer | first = Matthias | last2 = Jones | first2 = James F. | last3 = Unger | first3=Elizabeth R. | last4 = Youngblood | first4 = Laura Solomon| last5 = Decker | first5 = Michael J. | last6 = Gurbaxani | first6 = Brian | last7 = Heim | first7 = Christine | last8 = Reeves | first8 = William C. | date = 2007-12-05 | title = Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study|url=https://doi.org/10.1186/1471-2377-7-40|journal=BMC Neurology|language=en|volume=7|issue=1 | pages = 40|doi=10.1186/1471-2377-7-40|issn=1471-2377|pmc = 2231384|pmid=18053240}}</ref>
|2007
|35
|30%
|OSAHS, PLMD, ISS
|-
|Libman et al.<ref>{{Cite journal | last = Libman | first = Eva | last2 = Creti | first2 = Laura | last3 = Baltzan | first3=Marcel | last4 = Rizzo | first4 = Dorrie| last5 = Fichten | first5 = Catherine S. | last6 = Bailes | first6 = Sally | date = 2009-10-26 | title = Sleep Apnea and Psychological Functioning in Chronic Fatigue Syndrome|url=https://journals.sagepub.com/doi/10.1177/1359105309344895|journal=Journal of Health Psychology|language=en|doi=10.1177/1359105309344895}}</ref>
|2009
|66
|68%
|OSAHS
|-
|Creti et al.<ref>{{Cite journal | last = Creti | first = Laura | last2 = Libman | first2 = Eva | last3 = Baltzan | first3=Marcel | last4 = Rizzo | first4 = Dorrie| last5 = Bailes | first5 = Sally | last6 = Fichten | first6 = Catherine S. | date = 2010-05-11 | title = Impaired Sleep in Chronic Fatigue Syndrome: How Is It Best Measured?|url=https://journals.sagepub.com/doi/10.1177/1359105309355336|journal=Journal of Health Psychology|language=en|doi=10.1177/1359105309355336}}</ref>
|2010
|49
|69%
|OSAHS, PLMD
|-
|
|
|
|65%
|Chronic insomnia
|-
|''Mean''
|
|
|''56.2%''
|
|}

==Symptom recognition==
Sleep dysfunction is a core diagnostic symptom required in the 2003 [[Canadian Consensus Criteria]] diagnostic criteria for [[ME/CFS]],<ref name="CCC">{{Cite journal | last = Carruthers | first=Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3=Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = 2003 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://doi.org/10.1300%2Fj092v11n01_02 |journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321|via=}}</ref> the 2007 [[Nightingale definition]],<ref>{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Byron%20Hyde%20Definition%20Booklet.pdf | title = The Nightingale, Myalgic Encephalomyelitis (M.E.) Definition | last = | first = | date = Jan 2007 | website = investinme.org|archive-url=|archive-date=|url-status=|access-date=}}</ref> and the 2015 [[Systemic Exertion Intolerance Disease|Institute of Medicine report]].<ref>{{Cite web|url=http://iom.nationalacademies.org/~/media/Files/Report%20Files/2015/MECFS/MECFS_ProposedDiagnosticCriteria?_ga=1.14761526.1865741811.1437002921 | title = Proposed Diagnostic Criteria for ME/CFS | last = | first = | date = 2015 | website = nationalacademies.org|archive-url=|archive-date=|url-status=|access-date=}}</ref>

Sleep dysfunction is an optional symptom in the 1988 [[Holmes criteria]],<ref>{{Cite journal | last = Holmes | first=G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. |last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679|via=}}</ref> the 1991 [[Oxford criteria]],<ref>{{Cite journal | last = Sharpe | first = M. C. | last2 = Archard | first2 = L.C. | last3 = Banatvala | first3 = J.E. | last4 = Borysiewicz | first4 = L.K. | last5 = Clare | first5 = A.W. | last6 = David | first6 = A. | last7 = Edwards | first7 = R.H. | last8 = Hawton | first8 = K.E. | last9 = Lambert | first9 = H.P. | date = 1991 | title = A report--chronic fatigue syndrome: guidelines for research|url=https://www.ncbi.nlm.nih.gov/pubmed/1999813|journal=Journal of the Royal Society of Medicine|volume=84|issue=2|pages=118–121|issn=0141-0768|pmid=1999813|via=}}</ref> the 1994 [[Fukuda criteria]],<ref>{{Cite journal | last = Fukuda | first = K. | last2 = Straus | first2 = S.E. | last3 = Hickie | first3 = I. | last4 = Sharpe | first4 = M.C. | last5 = Dobbins | first5 = J.G. |last6 = Komaroff | first6 = A. | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.ncbi.nlm.nih.gov/pubmed/7978722|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722}}</ref> the 2005 [[Reeves criteria]],<ref>{{Cite journal | last = Reeves | first=William C. | last2 = Wagner | first2 = Dieter | last3 = Nisenbaum | first3 = Rosane | last4 = Jones | first4 = James F. | last5 = Gurbaxani | first5 = Brian | last6 = Solomon | first6 = Laura | last7 = Papanicolaou | first7 = Dimitris A. | last8 = Unger | first8 = Elizabeth R. | last9 = Vernon | first9 = Suzanne D. | date = 2005-12-15 | title = Chronic fatigue syndrome--a clinically empirical approach to its definition and study|url=https://www.ncbi.nlm.nih.gov/pubmed/16356178|journal=BMC medicine|volume=3|pages=19|doi=10.1186/1741-7015-3-19|issn=1741-7015|pmid=16356178|via=}}</ref> the 2007 [[NICE guidelines]],<ref>{{Cite web|url=https://www.nice.org.uk/guidance/CG53/chapter/1-Guidance#diagnosis | title = Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management {{!}} Guidance and guidelines {{!}} NICE | last = | first = | date = Aug 2007 | website = nice.org.uk|language=en-GB|archive-url=|archive-date=|url-status=|access-date=2018-08-29}}</ref> the 2012 [[International Consensus Criteria]].<ref>{{Cite journal | last = Carruthers | first=B. M. | last2 = Sande | first2 = M. I. van de | last3 = Meirleir | first3=K. L. De | last4 = Klimas | first4 = N.G. | last5 = Broderick | first5 = G. | last6 = Mitchell | first6 = T. | last7 = Staines | first7 = D. | last8 = Powles | first8 = A.C.P. | last9 = Speight | first9 = N. | date = 2011-10-01 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|doi=10.1111/j.1365-2796.2011.02428.x/full|issn=1365-2796}}</ref>, and the 2014 [[London criteria]].<ref>{{Cite web|url=http://www.axfordsabode.org.uk/me/mecrit2014.htm | title = ME/CFS Medical Update (Layman's version) Winter 2001 | website = axfordsabode.org.uk|access-date=2018-08-29}}</ref>

Sleep dysfunction is not a criteria listed for diagnosis with the 1986 [[Ramsay definition]].<ref>{{Cite web|url=http://www.cfids-me.org/ramsay86.html | title = Ramsay's Definition of M.E., 1986 | website = cfids-me.org|access-date=2018-08-29}}</ref>

==Notable studies==
*2007, Paradoxical NREMS Distribution in “Pure” Chronic Fatigue Patients: A Comparison with Sleep Apnea-Hypopnea Patients and Healthy Control Subjects<ref>{{Cite journal | last = Bon | first = Olivier Le | last2 = Neu | first2 = Daniel | last3 = Valente | first3 = Filomena | last4 = Linkowski | first4 = Paul | date = 2007 | title=Paradoxical NREMS Distribution in “Pure” Chronic Fatigue Patients|url=https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_05|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=14|issue=2 | pages = 45–59|doi=10.1300/j092v14n02_05|issn=1057-3321|via=}}</ref> - [https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_05 (Abstract)]
*2012, Sleep Abnormalities in [[ME/CFS|Chronic Fatigue Syndrome/Myalgic Encephalomyelitis]]: A Review<ref name="Jackson, 2012" /> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501671/ (Full Text)]
*2017, Sleep Quality in Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)<ref>{{Cite journal | last= Josev | first = Elisha K. | author-link = Elisha Josev | last2 = Jackson | first2 = Melinda L. | authorlink2 = Melinda Jackson | last3 = Bei | first3 = Bei | author-link3 = | last4 = Trinder | first4 = John | author-link4 = | last5 = Harvey | first5 = Adrienne | authorlink5 = | last6 = Clarke | first6 = Cathriona | last7 = Snodgrass | first7 = Kelli | last8 = Scheinberg | first8 = Adam | authorlink8 = | last9 = Knight | first9 = Sarah J. | authorlink9 = Sarah Knight | date = 2017-09-15 | title = Sleep Quality in Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)|url=http://jcsm.aasm.org/ViewAbstract.aspx?pid=31079|journal=Journal of Clinical Sleep Medicine|language=en|volume=13|issue=09|pages=1057–1066|doi=10.5664/jcsm.6722|issn=1550-9389|pmc=5566461|pmid=28760189|quote=|via=}}</ref> - [[pubmed:28760189|(Full text)]]
*2018, Circadian rhythm abnormalities and [[autonomic dysfunction]] in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis<ref name="Cambras, 2018" /> - [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198106 (Full Text)]
*2018, The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and [[multiple sclerosis]]<ref name="Morris, 2018" /> - [https://www.ncbi.nlm.nih.gov/pubmed/29759891 (Abstract)]
*2018, Association of sleep disorders, chronic pain, and fatigue with survival in patients with chronic kidney disease: A meta-analysis of clinical trials<ref>{{Cite journal | last = Yang | first = Xiu Hong | last2 = Zhang | first2 = Bao Long | last3 = Gu | first3 = Yan Hong | last4 = Zhan | first4 = Xiao Li| last5 = Guo | first5 = Li Li | last6 = Jin | first6 = Hui Min | date = 2018 | title=Association of sleep disorders, chronic pain, and fatigue with survival in patients with chronic kidney disease: a meta-analysis of clinical trials|url=https://www.sleep-journal.com/article/S1389-9457(18)30397-6/abstract|journal=Sleep Medicine|language=English|volume=51|pages=59–65|doi=10.1016/j.sleep.2018.06.020|issn=1389-9457|via=}}</ref> - ([https://www.sleep-journal.com/article/S1389-9457(18)30397-6/abstract Abstract])
*2021, Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Maksoud2021">{{Cite journal | last = Maksoud | first = Rebekah | authorlink = | last2 = Eaton-Fitch | first2 = Natalie | authorlink2 = Natalie Eaton-Fitch | last3 = Matula | first3=Michael | authorlink3 = | last4 = Cabanas | first4 = Hélène | authorlink4 = Hélène Cabanas| last5 = Staines | first5 = Donald | authorlink5 = Donald Staines | last6 = Marshall-Gradisnik | first6 = Sonya | author-link6 = Sonya Marshall-Gradisnik | date = May 2021 | title = Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.mdpi.com/2227-9032/9/5/568|journal=Healthcare|language=en|volume=9|issue=5|pages=568|doi=10.3390/healthcare9050568|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.mdpi.com/2227-9032/9/5/568 (Full text)]

==Treatment==
Treatment can include:
*perscription drugs
*[[Cannabinoid|cannabiniods]] (CBD)
*alternative natural remedies including [[chamomile]], [[kava]], [[hops]], [[lavender]], [[lemon balm]], and [[passiflora]] (passion flower), and [[valerian]]; kava and valerian have the most evidence
*over-the-counter [[melatonin]] or sedating anti-histamines like [[diphenhydramine]]
*[[vitamin B12]]
*relaxation techniques e.g., [[meditation]]
*good [[sleep hygiene]] practices.<ref name="Gyllenhaal2000">{{Cite journal|title=Efficacy and safety of herbal stimulants and sedatives in sleep disorders|date=2000-06-01|url=https://www.sciencedirect.com/science/article/pii/S108707929990093X|journal=Sleep Medicine Reviews|volume=4|issue=3|pages=229–251|last=Gyllenhaal|first=Charlotte|last2=Merritt|first2=Sharon L.|last3=Peterson|first3=Sara Davia|last4=Block|first4=Keith I.|last5=Gochenour|first5=Tom|doi=10.1053/smrv.1999.0093|issn=1087-0792}}</ref><ref name="Chaudhury2019">{{Cite journal|title=Chronic Insomnia: A Review|date=May 2019|url=https://journals.lww.com/mjdy/Fulltext/2019/12030/Chronic_Insomnia__A_Review.3.aspx|journal=Medical Journal of Dr. D.Y. Patil University|volume=12|issue=3|pages=193|last=Chaudhury|first=Suprakash|last2=Singh|first2=Rakesh Kumar|last3=Kumari|first3=Dolly|last4=Diwan|first4=Chetan|last5=Mujawar|first5=Swaleha|last6=Saldanha|first6=Daniel|language=en-US|doi=10.4103/mjdrdypu.mjdrdypu_76_19|issn=2589-8302}}</ref>

Medications, including:
*[[:Category:Benzodiazepines|Benzodiazepines]] (benzos), e.g. [[temazepam]], [[Valium]] (diazepam)<ref name="SACFS-survey">{{Cite web|url=https://www.sacfs.asn.au/news/2014/02/02_28_survey_results_insomnia.htm | website = ME/CFS South Australia Inc | title = Survey results - insomnia |access-date=2021-02-11}}</ref>
*[[:Category:Non-benzodiazepine hypnotics|Non-benzodiazepine hypnotics]], commonly known as z-drugs, e.g. [[zopiclone]], [[Ambien]] (zolpidem)
*Sedating [[antidepressant]]s, particularly [[amitriptyline]]
*Sedating [[:Category:Antihistamines|anti-histamines]], e.g., [[diphenhydramine]] (Benadryl)
*[[Melatonin]], either on prescription or as a supplement<ref>{{Cite web|url=https://www.hopkinsmedicine.org/health/wellness-and-prevention/melatonin-for-sleep-does-it-work | title = Melatonin for Sleep: Does It Work?|website=hopkinsmedicine.org|language=en|access-date=2021-02-11}}</ref>
*Anticonvulsants, such as gabapentin and valproic acid
*Other medications, when used off-label<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf }}</ref>

Supplements and natural remedies include:<dynamicpagelist>
category = Sleep aids and hypnotics
category = Supplements
ordermethod=sortkey
order=ascending
mode=inline-list
</dynamicpagelist>

== See also ==
* [[Buspirone challenge test]] (the degree of prolactin released by buspirone in ME/CFS patients correlates to the degree of shift in their sleep/wake cycle).
* [[Hypersomnia]]
* [[Insomnia]]
* [[Unrefreshing sleep]]

==Learn more==
*[https://www.drugs.com/condition/insomnia.html Medications for insomnia] - drugs.com

==References==
<references>
<ref name="Cambras, 2018">{{Citation | last1 = Cambras | first1 = T. | authorlink1 = | last2 = Castro-Marrero | first2 = J. | authorlink2 = Jesús Castro-Marrero | last3 = Zaragoza | first3 = MC. | authorlink3 = | last4 = Díez-Noguera | first4 = A. | authorlink4 = | last5 = Alegre | first5 = J. | authorlink5 = José Alegre | title = Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | journal = PLoS ONE | volume = 13 | issue = 6 | page = e0198106 | date = 2018 | pmid = | doi = 10.1371/journal.pone.0198106 }}</ref>
<ref name="Davidson, 2017">{{Citation | last1 = Davidson | first1 = Sean L. | authorlink1 = | last2 = Gotts | first2 = Zoe M. | authorlink2 = Zoe Gotts | last3 = Ellis | first3 = Jason G. | authorlink3 = | last4 = Newton | first4 = Julia L. | authorlink4 = Julia Newton | title = Two year follow-up of sleep diaries and polysomnography in chronic fatigue syndrome: a cohort study | journal = Fatigue: Biomedicine, Health & Behavior | volume = | issue = | page = | date = Mar 2017 | pmid = | doi = 10.1080/21641846.2017.1297280 }}</ref>
<ref name="Jackson, 2012">{{Citation | last1 = Jackson | first1 = ML | authorlink1 = Melinda Jackson | last2 = Bruck | first2 = D | authorlink2 = Dorothy Bruck | title = Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review, Journal of Clinical Sleep Medicine | journal = Journal of Clinical Sleep Medicine | volume = 8 | issue = 6 | page = 719-28 | date = 2012
| doi = 10.5664/jcsm.2276 }}</ref>
<ref name="Morris, 2018">{{Citation | last1 = Morris | first1 = Gerwyn | authorlink1 = Gerwyn Morris | last2 = Stubbs | first2 = Brendon | authorlink2 = | last3 = Köhler | first3 = Cristiano A. | authorlink3 = | last4 = Walder | first4 = Ken | authorlink4 = | last5 = Slyepchenko | first5 = Anastasiya | authorlink5 = | last6 = Berk | first6 = Michael| authorlink6 = Michael Berk | last7 = Carvalho | first7 = André F. | authorlink7 = | title = The putative role of Oxidative Stress and Inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders : Focus on Chronic Fatigue Syndrome, Bipolar Disorder and Multiple Sclerosis | journal = Sleep Med Reviews | volume = | issue = | page = | date = 2018 | pmid = 29759891
| doi = 10.1016/j.smrv.2018.03.007 }}</ref>
</references>

[[Category:Signs and symptoms]]
[[Category:Sleep signs and symptoms]]

Sleep dysfunction

2024-06-01T09:42:33Z

Yannlk:/ patient

[[File:Insomnia_sleep_remedies.jpg|alt="Sleep easy" tea bags containing valerian, lemon balm capsules and a bottle of melatonin.|thumb]]
'''Sleep dysfunction''' is very common in [[ME/CFS]] and can take a very wide range of forms, with [[unrefreshing sleep]] being particularly common.<ref name="CDC-symptoms">{{Cite web|url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|website=[[Centers for Disease Control and Prevention]] | date = Jan 27, 2021|access-date = 2021-02-25}}</ref> The prevalence of sleep disorders in ME/CFS is estimated at 56%.<ref>{{Cite journal | date = 2018-07-01 | title = Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties|url=https://www.sciencedirect.com/science/article/pii/S2173580818300038|journal=Neurología (English Edition)|language=en|volume=33|issue=6|pages=385–394|doi=10.1016/j.nrleng.2015.11.020|issn=2173-5808}}</ref><ref name="ICC2011primer" /><ref name="canadianconsensus-CCC" /><ref name="CDC-symptoms" />

[[Fibromyalgia]] patients also suffer from sleep disorders.<ref name="ACR2010">{{Cite journal|url=https://www.rheumatology.org/Portals/0/Files/2010_Preliminary_Diagnostic_Criteria.pdf | title = American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia | last = Wolfe | first = Frederick | date = May 2010|volume =62 | issue = 5 | pages = 600–610| doi = 10.1002/acr.20140|type=PDF|archive-url=|archive-date=|access-date= | author-link =| last2 = Clauw | first2 = Daniel | authorlink2 = |journal=Arthritis Care & Research | last3 = Fitzcharles | first3=Mary-Ann | first4 = Don| last5 = Katz | last4 = Goldenberg | first5 = Robert | last6 = Mease | first6 = Philip | last7 = Russel | first7 = Anthony | last8 = Russel | first8 = I. Jon | first9 = John | last9 = Winfield | first10 = Muhammad | last10 = Yunus|quote=}}</ref>

== Types of sleep dysfunction ==
Some of these sleep dysfunctions or disorders include:
*[[dysania]]<ref>{{Cite web|url=https://ammes.org/symptoms-of-mecfs/ | title = Symptoms of ME/CFS – American ME and CFS Society|website=[[American ME and CFS Society]]|language=en-US|access-date=2018-08-29}}</ref> (a state of finding it hard to get out of bed in the morning; in [[ME/CFS]] it can an extended period lasting several hours after awakening)
*[[hypersomnia]] (excessive sleeping, inability to stay awake)
*[[agogia]] (transitional state from wakefulness to sleep during which lucid thought, lucid dreaming, hallucinations and, sleep paralysis can occur)
*[[insomnia]]<ref>{{Cite journal | date = 2015-05-01 | title = The role of insomnia in the treatment of chronic fatigue|url=https://www.sciencedirect.com/science/article/pii/S002239991400422X|journal=Journal of Psychosomatic Research|language=en|volume=78|issue=5 | pages = 427–432|doi=10.1016/j.jpsychores.2014.11.022|issn=0022-3999}}</ref> (difficulty falling asleep, staying asleep, and/or waking up too early in the morning)
*[[light sleep]] (a non-REM stage and the easiest sleep stage to awaken from)
*[[Periodic limb movement disorder]]/nocturnal myoclonus - involuntary jerking or leg movements when sleeping or when falling asleep<ref name="UScoal-2020">{{Cite web | title = Diagnosing and Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last=U.S. ME/CFS Clinician Coalition
|edition=2 | date = July 2020 | url= https://bridgesandpathways.org.au/wp-content/uploads/2021/02/DiagnosingAndTreatingMECFSV2_USCoalition_2020.pdf
| pages = 4}}</ref>
*[[nightmare]]s (a frightening or unpleasant dream)
*[[night sweat]]s (excessive sweating while you sleep)
*[[Restless legs syndrome]]<ref>{{Cite journal | last = Viola-Saltzman | first = Mari | last2 = Watson | first2 = Nathaniel F. | last3 = Bogart | first3=Andy | last4 = Goldberg | first4 = Jack| last5 = Buchwald | first5 = Dedra | date = 2010-10-15 | title = High prevalence of restless legs syndrome among patients with fibromyalgia: a controlled cross-sectional study|url=https://www.ncbi.nlm.nih.gov/pubmed/20957840|journal=Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine|volume=6|issue=5 | pages = 423–427|issn=1550-9389|pmid=20957840|via=}}</ref> (a strong urge to move one's legs)
*[[Sleep apnea]] (pauses in breathing or periods of shallow breathing)
*[[Reversed or chaotic diurnal sleep rhythms|sleep phase shifting]] or [[sleep reversal]]<ref name="Cambras2018">{{Cite journal | last = Cambras | first=Trinitat | last2 = Castro-Marrero | first2 = Jesús | last3 = Zaragoza | first3=Maria Cleofé | last4 = Díez-Noguera | first4 = Antoni| last5 = Alegre | first5 = José | date = 2018-06-06 | title = Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis|url=https://doi.org/10.1371/journal.pone.0198106|journal=PLOS ONE|language=en|volume=13|issue=6| pages = e0198106|doi=10.1371/journal.pone.0198106|issn=1932-6203|pmid=29874259|via=}}</ref> ([[reversed or chaotic diurnal sleep rhythms]]) (circadian abnormalities: delayed sleep phase, non-24hr sleep cycle, loss of rhythm)
*[[somnolence]] (sleepiness)
*[[unrefreshing sleep]] (poor-quality sleep that doesn't relieve fatigue)<ref name="ICC2011primer" /><ref name="canadianconsensus-CCC">{{Citation | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 = Joshi | first9 = Pradip| authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols| journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid =
| doi = 10.1300/J092v11n01_02| url = http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf}}</ref>

==Prevalence==
*Depending on the criteria used for diagnosis, prevalence can vary greatly.

*In a 2001 Belgian study, 91.9% of patients meeting the [[Fukuda criteria]] and 94.8% of patients meeting the [[Holmes criteria]], in a cohort of 2073 [[chronic fatigue syndrome|CFS]] patients, reported sleep disturbances.<ref>{{Cite journal | last = De Becker | first=Pascale | authorlink = Pascale De Becker | last2 = McGregor | first2 = Neil | authorlink2 = Neil McGregor | last3 = De Meirleir | first3=Kenny | author-link3 = Kenny De Meirleir | date = December 2001 | title = A definition‐based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2796.2001.00890.x?sid=nlm%3Apubmed|journal=Journal of Internal Medicine|volume=250|issue=3|pages=234–240|doi=10.1046/j.1365-2796.2001.00890.x|quote=|via=}}</ref>
*A 2017 study by Davidson, et al, found up to 96.8% of people with CFS report [[unrefreshing sleep]] and many describe changes in sleep over the course of their illness.<ref name="Davidson, 2017" />
According to the published evidence, the mean prevalence of sleep disorders in patients with CFS is '''estimated at 56%.'''<ref>{{Cite journal | date = 2018-07-01 | title = Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties|url=https://www.sciencedirect.com/science/article/pii/S2173580818300038|journal=Neurología (English Edition)|language=en|volume=33|issue=6|pages=385–394|doi=10.1016/j.nrleng.2015.11.020|issn=2173-5808}}</ref>
{| class="wikitable"
!
!Year
!N
!Prevalence
!Sleep disorders included
|-
|Krupp et al.<ref>{{Cite journal | last = Krupp | first = Lauren B. | last2 = Jandorf | first2 = L. | last3 = Coyle | first3 = P.K. | last4 = Mendelson | first4 = W.B. | date = 1993-05-01 | title = Sleep disturbance in chronic fatigue syndrome|url=http://www.sciencedirect.com/science/article/pii/0022399993901342|journal=Journal of Psychosomatic Research|language=en|volume=37|issue=4|pages=325–331|doi=10.1016/0022-3999(93)90134-2|issn=0022-3999}}</ref>
|1993
|16
|62%
|OSAHS, PLMD, narcolepsy, hypersomnia
|-
|Morriss et al.<ref>{{Cite journal | last = Morriss | first = R. | last2 = Sharpe | first2 = M. | last3 = Sharpley | first3 = A.L. | last4 = Cowen | first4 = P.J. | last5 = Hawton | first5 = K. | last6 = Morris | first6 = J. | date = 1993-05-01 | title = Abnormalities of sleep in patients with the chronic fatigue syndrome.|url=https://www.bmj.com/content/306/6886/1161|journal=British Medical Journal|language=en|volume=306|issue=6886|pages=1161–1164|doi=10.1136/bmj.306.6886.1161|issn=0959-8138|pmid=8499816}}</ref>
|1993
|12
|58%
|Maintenance insomnia
|-
|Buchwald et al.<ref>{{Cite journal | last = Buchwald | first=Dedra | last2 = Pascualy | first2 = Ralph | last3 = Bombardier | first3=Charles | last4 = Kith | first4 = Phalla | date = 1994-01-01 | title = Sleep Disorders in Patients with Chronic Fatigue|url=https://doi.org/10.1093/clinids/18.Supplement_1.S68|journal=Clinical Infectious Diseases|volume=18|issue=Supplement_1|pages=S68–S72|doi=10.1093/clinids/18.supplement_1.s68|issn=1537-6591}}</ref>
|1994
|59
|81%
|OSAHS, hypersomnia
|-
|Le Bon et al.<ref>{{Cite journal | last = Le Bon | first = O. | last2 = Fischler | first2 = B. | last3 = Hoffmann | first3=G. | last4 = Murphy | first4 = J.R. | last5 = De Meirleir | first5 = K. | last6 = Cluydts | first6 = R. | last7 = Pelc | first7 = I. | date = 2000 | title=How significant are primary sleep disorders and sleepiness in the chronic fatigue syndrome?|url=https://pubmed.ncbi.nlm.nih.gov/11382899/|journal=Sleep research online: SRO|volume=3|issue=2 | pages = 43–48|issn=1096-214X|pmid=11382899}}</ref>
|2000
|53
|46%
|OSAHS
|-
|Fossey et al.<ref>{{Cite journal | last = Fossey | first = Myrtis | last2 = Libman | first2 = Eva | last3 = Bailes | first3=Sally | last4 = Baltzan | first4 = Marc| last5 = Schondorf | first5 = Ronald | last6 = Amsel | first6 = Rhonda | last7 = Fichten | first7 = Catherine S. | date = 2004-12-01 | title = Sleep Quality and Psychological Adjustment in Chronic Fatigue Syndrome|url=https://doi.org/10.1007/s10865-004-0004-y|journal=Journal of Behavioral Medicine|language=en|volume=27|issue=6|pages=581–605|doi=10.1007/s10865-004-0004-y|issn=1573-3521}}</ref>
|2004
|37
|58%
|OSAHS, narcolepsy
|-
|Reeves et al.<ref>{{Cite journal | last = Reeves | first=William C. | last2 = Heim | first2 = Christine | last3 = Maloney | first3 = Elizabeth M. | last4 = Youngblood | first4 = Laura Solomon| last5 = Unger | first5 = Elizabeth R. | last6 = Decker | first6 = Michael J. | last7 = Jones | first7 = James F. | last8 = Rye | first8 = David B. | date = 2006-11-16 | title = Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study|url=https://doi.org/10.1186/1471-2377-6-41|journal=BMC Neurology|language=en|volume=6|issue=1 | pages = 41|doi=10.1186/1471-2377-6-41|issn=1471-2377|pmc = 1660569|pmid=17109739}}</ref>
|2006
|43
|25%
|OSAHS, PLMD
|-
|Majer et al.<ref>{{Cite journal | last = Majer | first = Matthias | last2 = Jones | first2 = James F. | last3 = Unger | first3=Elizabeth R. | last4 = Youngblood | first4 = Laura Solomon| last5 = Decker | first5 = Michael J. | last6 = Gurbaxani | first6 = Brian | last7 = Heim | first7 = Christine | last8 = Reeves | first8 = William C. | date = 2007-12-05 | title = Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study|url=https://doi.org/10.1186/1471-2377-7-40|journal=BMC Neurology|language=en|volume=7|issue=1 | pages = 40|doi=10.1186/1471-2377-7-40|issn=1471-2377|pmc = 2231384|pmid=18053240}}</ref>
|2007
|35
|30%
|OSAHS, PLMD, ISS
|-
|Libman et al.<ref>{{Cite journal | last = Libman | first = Eva | last2 = Creti | first2 = Laura | last3 = Baltzan | first3=Marcel | last4 = Rizzo | first4 = Dorrie| last5 = Fichten | first5 = Catherine S. | last6 = Bailes | first6 = Sally | date = 2009-10-26 | title = Sleep Apnea and Psychological Functioning in Chronic Fatigue Syndrome|url=https://journals.sagepub.com/doi/10.1177/1359105309344895|journal=Journal of Health Psychology|language=en|doi=10.1177/1359105309344895}}</ref>
|2009
|66
|68%
|OSAHS
|-
|Creti et al.<ref>{{Cite journal | last = Creti | first = Laura | last2 = Libman | first2 = Eva | last3 = Baltzan | first3=Marcel | last4 = Rizzo | first4 = Dorrie| last5 = Bailes | first5 = Sally | last6 = Fichten | first6 = Catherine S. | date = 2010-05-11 | title = Impaired Sleep in Chronic Fatigue Syndrome: How Is It Best Measured?|url=https://journals.sagepub.com/doi/10.1177/1359105309355336|journal=Journal of Health Psychology|language=en|doi=10.1177/1359105309355336}}</ref>
|2010
|49
|69%
|OSAHS, PLMD
|-
|
|
|
|65%
|Chronic insomnia
|-
|''Mean''
|
|
|''56.2%''
|
|}

==Symptom recognition==
Sleep dysfunction is a core diagnostic symptom required in the 2003 [[Canadian Consensus Criteria]] diagnostic criteria for [[ME/CFS]],<ref name="CCC">{{Cite journal | last = Carruthers | first=Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3=Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = 2003 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://doi.org/10.1300%2Fj092v11n01_02 |journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321|via=}}</ref> the 2007 [[Nightingale definition]],<ref>{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Byron%20Hyde%20Definition%20Booklet.pdf | title = The Nightingale, Myalgic Encephalomyelitis (M.E.) Definition | last = | first = | date = Jan 2007 | website = investinme.org|archive-url=|archive-date=|url-status=|access-date=}}</ref> and the 2015 [[Systemic Exertion Intolerance Disease|Institute of Medicine report]].<ref>{{Cite web|url=http://iom.nationalacademies.org/~/media/Files/Report%20Files/2015/MECFS/MECFS_ProposedDiagnosticCriteria?_ga=1.14761526.1865741811.1437002921 | title = Proposed Diagnostic Criteria for ME/CFS | last = | first = | date = 2015 | website = nationalacademies.org|archive-url=|archive-date=|url-status=|access-date=}}</ref>

Sleep dysfunction is an optional symptom in the 1988 [[Holmes criteria]],<ref>{{Cite journal | last = Holmes | first=G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. |last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679|via=}}</ref> the 1991 [[Oxford criteria]],<ref>{{Cite journal | last = Sharpe | first = M. C. | last2 = Archard | first2 = L.C. | last3 = Banatvala | first3 = J.E. | last4 = Borysiewicz | first4 = L.K. | last5 = Clare | first5 = A.W. | last6 = David | first6 = A. | last7 = Edwards | first7 = R.H. | last8 = Hawton | first8 = K.E. | last9 = Lambert | first9 = H.P. | date = 1991 | title = A report--chronic fatigue syndrome: guidelines for research|url=https://www.ncbi.nlm.nih.gov/pubmed/1999813|journal=Journal of the Royal Society of Medicine|volume=84|issue=2|pages=118–121|issn=0141-0768|pmid=1999813|via=}}</ref> the 1994 [[Fukuda criteria]],<ref>{{Cite journal | last = Fukuda | first = K. | last2 = Straus | first2 = S.E. | last3 = Hickie | first3 = I. | last4 = Sharpe | first4 = M.C. | last5 = Dobbins | first5 = J.G. |last6 = Komaroff | first6 = A. | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.ncbi.nlm.nih.gov/pubmed/7978722|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722}}</ref> the 2005 [[Reeves criteria]],<ref>{{Cite journal | last = Reeves | first=William C. | last2 = Wagner | first2 = Dieter | last3 = Nisenbaum | first3 = Rosane | last4 = Jones | first4 = James F. | last5 = Gurbaxani | first5 = Brian | last6 = Solomon | first6 = Laura | last7 = Papanicolaou | first7 = Dimitris A. | last8 = Unger | first8 = Elizabeth R. | last9 = Vernon | first9 = Suzanne D. | date = 2005-12-15 | title = Chronic fatigue syndrome--a clinically empirical approach to its definition and study|url=https://www.ncbi.nlm.nih.gov/pubmed/16356178|journal=BMC medicine|volume=3|pages=19|doi=10.1186/1741-7015-3-19|issn=1741-7015|pmid=16356178|via=}}</ref> the 2007 [[NICE guidelines]],<ref>{{Cite web|url=https://www.nice.org.uk/guidance/CG53/chapter/1-Guidance#diagnosis | title = Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management {{!}} Guidance and guidelines {{!}} NICE | last = | first = | date = Aug 2007 | website = nice.org.uk|language=en-GB|archive-url=|archive-date=|url-status=|access-date=2018-08-29}}</ref> the 2012 [[International Consensus Criteria]].<ref>{{Cite journal | last = Carruthers | first=B. M. | last2 = Sande | first2 = M. I. van de | last3 = Meirleir | first3=K. L. De | last4 = Klimas | first4 = N.G. | last5 = Broderick | first5 = G. | last6 = Mitchell | first6 = T. | last7 = Staines | first7 = D. | last8 = Powles | first8 = A.C.P. | last9 = Speight | first9 = N. | date = 2011-10-01 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|doi=10.1111/j.1365-2796.2011.02428.x/full|issn=1365-2796}}</ref>, and the 2014 [[London criteria]].<ref>{{Cite web|url=http://www.axfordsabode.org.uk/me/mecrit2014.htm | title = ME/CFS Medical Update (Layman's version) Winter 2001 | website = axfordsabode.org.uk|access-date=2018-08-29}}</ref>

Sleep dysfunction is not a criteria listed for diagnosis with the 1986 [[Ramsay definition]].<ref>{{Cite web|url=http://www.cfids-me.org/ramsay86.html | title = Ramsay's Definition of M.E., 1986 | website = cfids-me.org|access-date=2018-08-29}}</ref>

==Notable studies==
*2007, Paradoxical NREMS Distribution in “Pure” Chronic Fatigue Patients: A Comparison with Sleep Apnea-Hypopnea Patients and Healthy Control Subjects<ref>{{Cite journal | last = Bon | first = Olivier Le | last2 = Neu | first2 = Daniel | last3 = Valente | first3 = Filomena | last4 = Linkowski | first4 = Paul | date = 2007 | title=Paradoxical NREMS Distribution in “Pure” Chronic Fatigue Patients|url=https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_05|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=14|issue=2 | pages = 45–59|doi=10.1300/j092v14n02_05|issn=1057-3321|via=}}</ref> - [https://www.tandfonline.com/doi/abs/10.1300/J092v14n02_05 (Abstract)]
*2012, Sleep Abnormalities in [[ME/CFS|Chronic Fatigue Syndrome/Myalgic Encephalomyelitis]]: A Review<ref name="Jackson, 2012" /> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501671/ (Full Text)]
*2017, Sleep Quality in Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)<ref>{{Cite journal | last= Josev | first = Elisha K. | author-link = Elisha Josev | last2 = Jackson | first2 = Melinda L. | authorlink2 = Melinda Jackson | last3 = Bei | first3 = Bei | author-link3 = | last4 = Trinder | first4 = John | author-link4 = | last5 = Harvey | first5 = Adrienne | authorlink5 = | last6 = Clarke | first6 = Cathriona | last7 = Snodgrass | first7 = Kelli | last8 = Scheinberg | first8 = Adam | authorlink8 = | last9 = Knight | first9 = Sarah J. | authorlink9 = Sarah Knight | date = 2017-09-15 | title = Sleep Quality in Adolescents With Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)|url=http://jcsm.aasm.org/ViewAbstract.aspx?pid=31079|journal=Journal of Clinical Sleep Medicine|language=en|volume=13|issue=09|pages=1057–1066|doi=10.5664/jcsm.6722|issn=1550-9389|pmc=5566461|pmid=28760189|quote=|via=}}</ref> - [[pubmed:28760189|(Full text)]]
*2018, Circadian rhythm abnormalities and [[autonomic dysfunction]] in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis<ref name="Cambras, 2018" /> - [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198106 (Full Text)]
*2018, The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and [[multiple sclerosis]]<ref name="Morris, 2018" /> - [https://www.ncbi.nlm.nih.gov/pubmed/29759891 (Abstract)]
*2018, Association of sleep disorders, chronic pain, and fatigue with survival in patients with chronic kidney disease: A meta-analysis of clinical trials<ref>{{Cite journal | last = Yang | first = Xiu Hong | last2 = Zhang | first2 = Bao Long | last3 = Gu | first3 = Yan Hong | last4 = Zhan | first4 = Xiao Li| last5 = Guo | first5 = Li Li | last6 = Jin | first6 = Hui Min | date = 2018 | title=Association of sleep disorders, chronic pain, and fatigue with survival in patients with chronic kidney disease: a meta-analysis of clinical trials|url=https://www.sleep-journal.com/article/S1389-9457(18)30397-6/abstract|journal=Sleep Medicine|language=English|volume=51|pages=59–65|doi=10.1016/j.sleep.2018.06.020|issn=1389-9457|via=}}</ref> - ([https://www.sleep-journal.com/article/S1389-9457(18)30397-6/abstract Abstract])
*2021, Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Maksoud2021">{{Cite journal | last = Maksoud | first = Rebekah | authorlink = | last2 = Eaton-Fitch | first2 = Natalie | authorlink2 = Natalie Eaton-Fitch | last3 = Matula | first3=Michael | authorlink3 = | last4 = Cabanas | first4 = Hélène | authorlink4 = Hélène Cabanas| last5 = Staines | first5 = Donald | authorlink5 = Donald Staines | last6 = Marshall-Gradisnik | first6 = Sonya | author-link6 = Sonya Marshall-Gradisnik | date = May 2021 | title = Systematic Review of Sleep Characteristics in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.mdpi.com/2227-9032/9/5/568|journal=Healthcare|language=en|volume=9|issue=5|pages=568|doi=10.3390/healthcare9050568|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.mdpi.com/2227-9032/9/5/568 (Full text)]

==Treatment==
Treatment can include:
*perscription drugs
*[[Cannabinoid|cannabiniods]] (CBD)
*alternative natural remedies including [[chamomile]], [[kava]], [[hops]], [[lavender]], [[lemon balm]], and [[passiflora]] (passion flower), and [[valerian]]; kava and valerian have the most evidence
*over-the-counter [[melatonin]] or sedating anti-histamines like [[diphenhydramine]]
*[[vitamin B12]]
*relaxation techniques e.g., [[meditation]]
*good [[sleep hygiene]] practices.<ref name="Gyllenhaal2000">{{Cite journal|title=Efficacy and safety of herbal stimulants and sedatives in sleep disorders|date=2000-06-01|url=https://www.sciencedirect.com/science/article/pii/S108707929990093X|journal=Sleep Medicine Reviews|volume=4|issue=3|pages=229–251|last=Gyllenhaal|first=Charlotte|last2=Merritt|first2=Sharon L.|last3=Peterson|first3=Sara Davia|last4=Block|first4=Keith I.|last5=Gochenour|first5=Tom|doi=10.1053/smrv.1999.0093|issn=1087-0792}}</ref><ref name="Chaudhury2019">{{Cite journal|title=Chronic Insomnia: A Review|date=May 2019|url=https://journals.lww.com/mjdy/Fulltext/2019/12030/Chronic_Insomnia__A_Review.3.aspx|journal=Medical Journal of Dr. D.Y. Patil University|volume=12|issue=3|pages=193|last=Chaudhury|first=Suprakash|last2=Singh|first2=Rakesh Kumar|last3=Kumari|first3=Dolly|last4=Diwan|first4=Chetan|last5=Mujawar|first5=Swaleha|last6=Saldanha|first6=Daniel|language=en-US|doi=10.4103/mjdrdypu.mjdrdypu_76_19|issn=2589-8302}}</ref>

Medications, including:
*[[:Category:Benzodiazepines|Benzodiazepines]] (benzos), e.g. [[temazepam]], [[Valium]] (diazepam)<ref name="SACFS-survey">{{Cite web|url=https://www.sacfs.asn.au/news/2014/02/02_28_survey_results_insomnia.htm | website = ME/CFS South Australia Inc | title = Survey results - insomnia |access-date=2021-02-11}}</ref>
*[[:Category:Non-benzodiazepine hypnotics|Non-benzodiazepine hypnotics]], commonly known as z-drugs, e.g. [[zopiclone]], [[Ambien]] (zolpidem)
*Sedating [[antidepressant]]s, particularly [[amitriptyline]]
*Sedating [[:Category:Antihistamines|anti-histamines]], e.g., [[diphenhydramine]] (Benadryl)
*[[Melatonin]], either on prescription or as a supplement<ref>{{Cite web|url=https://www.hopkinsmedicine.org/health/wellness-and-prevention/melatonin-for-sleep-does-it-work | title = Melatonin for Sleep: Does It Work?|website=hopkinsmedicine.org|language=en|access-date=2021-02-11}}</ref>
*Anticonvulsants, such as gabapentin and valproic acid
*Other medications, when used off-label<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf }}</ref>

Supplements and natural remedies include:<dynamicpagelist>
category = Sleep aids and hypnotics
category = Supplements
ordermethod=sortkey
order=ascending
mode=inline-list
</dynamicpagelist>

== See also ==
* [[Buspirone challenge test]] (the degree of prolactin released by buspirone in ME/CFS patients correlates to the degree of shift in their sleep/wake cycle).
* [[Hypersomnia]]
* [[Insomnia]]
* [[Unrefreshing sleep]]

==Learn more==
*[https://www.drugs.com/condition/insomnia.html Medications for insomnia] - drugs.com

==References==
<references>
<ref name="Cambras, 2018">{{Citation | last1 = Cambras | first1 = T. | authorlink1 = | last2 = Castro-Marrero | first2 = J. | authorlink2 = Jesús Castro-Marrero | last3 = Zaragoza | first3 = MC. | authorlink3 = | last4 = Díez-Noguera | first4 = A. | authorlink4 = | last5 = Alegre | first5 = J. | authorlink5 = José Alegre | title = Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | journal = PLoS ONE | volume = 13 | issue = 6 | page = e0198106 | date = 2018 | pmid = | doi = 10.1371/journal.pone.0198106 }}</ref>
<ref name="Davidson, 2017">{{Citation | last1 = Davidson | first1 = Sean L. | authorlink1 = | last2 = Gotts | first2 = Zoe M. | authorlink2 = Zoe Gotts | last3 = Ellis | first3 = Jason G. | authorlink3 = | last4 = Newton | first4 = Julia L. | authorlink4 = Julia Newton | title = Two year follow-up of sleep diaries and polysomnography in chronic fatigue syndrome: a cohort study | journal = Fatigue: Biomedicine, Health & Behavior | volume = | issue = | page = | date = Mar 2017 | pmid = | doi = 10.1080/21641846.2017.1297280 }}</ref>
<ref name="Jackson, 2012">{{Citation | last1 = Jackson | first1 = ML | authorlink1 = Melinda Jackson | last2 = Bruck | first2 = D | authorlink2 = Dorothy Bruck | title = Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review, Journal of Clinical Sleep Medicine | journal = Journal of Clinical Sleep Medicine | volume = 8 | issue = 6 | page = 719-28 | date = 2012
| doi = 10.5664/jcsm.2276 }}</ref>
<ref name="Morris, 2018">{{Citation | last1 = Morris | first1 = Gerwyn | authorlink1 = Gerwyn Morris | last2 = Stubbs | first2 = Brendon | authorlink2 = | last3 = Köhler | first3 = Cristiano A. | authorlink3 = | last4 = Walder | first4 = Ken | authorlink4 = | last5 = Slyepchenko | first5 = Anastasiya | authorlink5 = | last6 = Berk | first6 = Michael| authorlink6 = Michael Berk | last7 = Carvalho | first7 = André F. | authorlink7 = | title = The putative role of Oxidative Stress and Inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders : Focus on Chronic Fatigue Syndrome, Bipolar Disorder and Multiple Sclerosis | journal = Sleep Med Reviews | volume = | issue = | page = | date = 2018 | pmid = 29759891
| doi = 10.1016/j.smrv.2018.03.007 }}</ref>
</references>

[[Category:Signs and symptoms]]
[[Category:Sleep signs and symptoms]]

MEpedia:Discussion forum and Help desk

2024-05-20T18:03:14Z

Yannlk:-- 198.144.121.43 02:34, Februarh 12, 2022 (UTC) */

__NEWSECTIONLINK__ {{NOINDEX}}
[[Category:MEpedia help]]
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==Questions==

===Request for science help re: gancyclovir===
{{collapse top}}
I'm wondering if any more scientifically knowledgeable folks can help me with [[Gancyclovir]]. It's one of many pages that have no references at all and probably I'm best equipped just to tag them for cleanup, but since the entry only contains two claims, I thought I could track down refs to verify them. Ha ha. I found these studies which (''if'' I understand them correctly) make opposing claims about its effect on microglial: "[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597339/ The antiviral drug ganciclovir does not inhibit microglial proliferation and activation]" (2015) versus "[https://www.ncbi.nlm.nih.gov/pubmed/24493798 Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation]" (2014). Is anyone available to help either revise the page (if I'm correct that maybe these are conflicting results that require qualification on the page) or confirm for me that the latter ref (or some other ref?) suffices to verify the entry's current claim that gancyclovir "also reduces microglial activation." Thanks much. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 17:45, 15 April 2019 (EDT)
:Excellent question. I answer your question [https://forums.phoenixrising.me/threads/drs-who-treat-with-low-dose-valcyte.39092/page-2#post-1023199 here]. (Spoiler: it doesn’t reduce microglial activation after all.)
:[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 18:17, 15 April 2019 (EDT)
::Oh, thank you so much [[User:Pyrrhus|Pyrrhus]]! Ok, I've updated both the [[gancyclovir]] and [[valgancyclovir]]. If you have a chance to look over and make sure I've presented it accurately, I'd be grateful! (Whew, glad we're fixing this! Def the kind of thing that argues for working hard to recruit and retain a lot more folks to comb the 2500+ pages for such issues...) [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:57, 15 April 2019 (EDT)
:::Ah belatedly reading down the rest of that thread to see the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806703/ follow-up STING paper] from the first authors. I'm pretty well in over my head scientifically at this point. If you have guidance about if/how it should be incorporated, that'd be greatly appreciated but I don't want to assign you work (!); I can also just add it as a "Learn more" and eventually someone else can incorporate as far as explaining its implications. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 21:42, 15 April 2019 (EDT)
::::You covered the two papers very well in the two pages- succinctly, accurately, and objectively. I'll summarize the STING paper and then you can decide whether to include my summary in the page(s).
::::"The authors of the original 2014 paper published a follow-up paper which described in-vitro and in-vivo experiments where they observed evidence that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. Although this pro-inflammatory finding might appear to contradict the authors 2014 paper, the authors explain the contradiction by saying:
::::<blockquote>We show that GCV can exhibit dual function in microglia (Figure S10): in naïve state, GCV induces microglia to be “primed”; on the other hand, GCV reduces inflammation in active microglia. </blockquote>"
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 00:07, 16 April 2019 (EDT)
:::::Oh fab. For those of us with limited neuroscience background, can I take a stab at restating your explanation and you tell me if I understood it correctly?

::::::The authors of the 2014 paper later published a follow-up paper (2017) based on in-vitro and in-vivo experiments using ganciclovir. This time they found a potentially pro-inflammatory response, specifically that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. While this result might appear to contradict their earlier anti-neuroinflammatory finding, they suggest it could indicate ganciclovir (GCV) "can exhibit dual function in microglia [...]: in naïve state, GCV induces microglia to be 'primed'; on the other hand, GCV reduces inflammation in active microglia."

:::::If my lay-ified paraphrase gets it wrong tho, I say let's use yours; it does seem like a finding worth flagging for researchers even if some less scientifically literate readers (ha, yours truly) may not get it (although also you're definitely better qualified than I to judge whether the study rates mention. So whatever you think is best.) [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:01, 16 April 2019 (EDT)
:::::: I‘ve made a few small changes to your text. Mainly, we have to be careful about our phrasing because there is currently a vicious fight over the very definition of “inflammation”. The old-timers stick stubbornly to the ancient greco-roman definition of inflammation, which does not recognize either the interferon response or neuroinflammation to have anything to do with what they consider to be “real” inflammation. Additionally, this is a hard paper to summarize because the authors themselves seem confused about their findings. Since you ask for my opinion, I don’t think their paper introduces anything new since their findings are perfectly consistent with the known toxicity of ganciclovir at high doses. But, in the interest of completeness, let’s include it. Hope this helps.
::::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 21:15, 16 April 2019 (EDT)
:::::::Ah thank you so much for your edits and your explanation [[User:Pyrrhus|Pyrrhus]]. This sounds like a good solution to me: the lay reader will def get the key take away that no, there's not firm evidence for this effect as the initial study suggested; and any scientist readers who want to get in the weeds will learn this study exists and they can go delve into its particulars if they wish. Cool! Thanks! Successful first use of the editor help desk! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 22:07, 16 April 2019 (EDT)
{{collapse bottom}}
{{done}} Resolved and copied to relevant entry's talk page for future reference. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:24, 17 April 2019 (EDT)

=== Broken citation template? ===
{{collapse top}}
Hi all. I'm suddenly having trouble using the "Cite web" template. In particular I'm trying to add https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Polymyalgia-Rheumatica as the reference for all the material I've added so far to the [[Polymyalgia rheumatica]] page I just started. But both in Visual Editor and in source code editing, I can't get the "Cite web" template to populate as a reference--it doesn't work at all in VE now and when I try source code, it adds all the info to the prose of the entry, rather than creating a footnote. Anybody have an idea what might be going on? I've used this extensively before (just for one example, see the [[HIV/AIDS]] page) and those references remain properly formatted so I am really stumped. Thanks for any advice! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 15:21, July 5, 2019 (EDT)
:With [[User:Notjusttired|Njt]]'s help, I copied pre-formatted source code and successfully inserted the ref, but in VE, even the Manual tab is still not recognizing the "Cite web" template (even though [[Template:Cite web]] is there!), and it doesn't seem to vary based either on the entry I'm editing or on the link I'm trying to add (e.g. no luck adding https://www.britannica.com/science/glucocorticoid to the [[Glucocorticoid]] page even tho Britannica is [[MediaWiki:Captcha-addurl-whitelist|whitelisted]]). Does anyone have any idea what's up with that? [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 22:05, July 5, 2019 (EDT)
::You’re not the only one to notice citation problems recently. It’s currently unclear to what extent the problems are on our side or on the side of the Citoid server. If it’s on our side , there are some things we can try. If it’s on the side of the Citoid server, then all wikis using that Citoid server should be seeing the same problems.
::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 00:59, July 6, 2019 (EDT)
:::[[User:JenB]] has also reported pubmed links not being looked up, even ones that previously worked, and this appears to be related (they use the journal template). [[User:Kmdenmark]] [[User:Canele]] [[User:Pyrrhus]] What's happening is that Citoid, which generates the references, and/or the VisualEditor can't find the '''templateData''' so doesn't know what fields are in the template to fill out. This seems to have happened when the Citation, Cite web and other templates were accidentally then restored. I've copied the templateData from [[Template:Cite web/doc]] to [[Template:Cite web]] so the web one is working, but this isn't much of a solution since it means there's duplicate data there. Cite news still isn't working (Insert, Template, Cite news brings up no boxes to fill out). Looking elsewhere, a purge of the Citation json has been suggested (which basically means delete old versions) but I don't have access to do this. [[User:Kmdenmark]] You might see a purge option on [[MediaWiki:Citoid-template-type-map.json]] to click - if not try clicking once on this [https://me-pedia.org/w/api.php?action=purge&titles=MediaWiki:Citoid-template-type-map.json link to purge the page] - I get "file not found" when I try, probably because the page is protected or I don't have edit access - it might need unprotecting first. (Purge instructions suggested at bottom of [https://phabricator.wikimedia.org/T106938 this page)]. I don't know how or why but the citoid tool or visual editor or both don't seem to see the templateData and/or some other values that exist. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 08:20, July 6, 2019 (EDT)
::::”Purging” refers simply to refreshing the cache, not removing old versions. You don’t need any special permissions to purge the cache. Since the [[MediaWiki:Citoid-template-type-map.json]] page hasn’t recently been changed, I don’t think that purging the cache will have any effect.
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 13:54, July 6, 2019 (EDT)
:::::I think it's worth trying, although editing and saving without changing first is probably a good idea. Purging involves clearing old versions from the cache (temporary memory) in this case - but can also mean deleting old copies (I don't think mediawiki allows that). Normally to clear the cache online you just refresh the page, but I think it's the server cache that's the issue not our local cache. We are on web hosting do no physical server to restart. At the moment I'm trying to guess what might help since I don't know exactly where the problem is. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 15:23, July 6, 2019 (EDT)
:::Thank you both for the updates, it's very helpful to know at least it's not just me! Most of this punches well above my technical-skills weightclass so I'm afraid I don't have much to add, but if I'm reading [https://www.mediawiki.org/wiki/Citoid/Where_citoid_is_enabled this] correctly, it looks like Citoid is enabled on en-Wikipedia, and I can confirm the ref issue is not happening there. Just in case that helps! Thanks again. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 16:45, July 6, 2019 (EDT)
::::Yeah, the “edit and save without changing” trick works for TemplateData, and may work on Template pages in general, but it might be less applicable in other scenarios. MediaWiki uses a number of different caches, but most of the time, people refer to the MediaWiki server’s Page Cache when they say “purging the cache”. To purge the server’s Page Cache for a specific page, simply append <nowiki>?action=purge</nowiki> to the end of the page’s URL. (See https://www.mediawiki.org/wiki/Manual:Purge ). Hope this helps!
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 19:08, July 6, 2019 (EDT)
::::You probably already know this, but there is a [https://phabricator.wikimedia.org/T52372 known bug] where TemplateData in the doc subpage doesn’t show up in the main Template page. I encountered this recently. Although there are workarounds, this problem seems to show up surprisingly often. I think it might be better practice for us to consider storing all TemplateData in the main Template pages, and remove all TemplateData from doc subpages. This way we won’t have to worry about this bug anymore...
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 21:20, July 6, 2019 (EDT)
::::Okay, the TemplateData for all CS1 templates (<nowiki>{{Cite x}}</nowiki>) and the CS2 template (<nowiki>{{Citation}}</nowiki>) has been moved from the /doc subpages to the main Template pages. This should clear up everything on our end. If problems continue, it's probably on the side of the Citoid server. (Unless our TemplateData is wrong!)
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 22:49, July 6, 2019 (EDT)
:::::Thank you!! So after purging the cache on [[Glucocorticoid]] (just for instance), the Cite Web template does how populate in the Manual tab--however, automatic ref generating still isn't working even for sources we use all the time, like PubMed (I was trying to add https://www.ncbi.nlm.nih.gov/pubmed/10990237 without having to fill in every author manually). Just an update on where it stands, I know all this debugging is a ton of work. It's very greatly appreciated! Definitely affects how much content I am able to add, whether or not the refs can be largely automated or if all of it needs to be copied by hand. Thank you! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 23:14, July 6, 2019 (EDT)
::::::[[User:Notjusttired]] The news and web citations are now being generated, plus doi links and everything but pubmed works as far as I know. I tried the purge suggested by [[User:Pyrrhus]] on all relevant modules and templates plus a trivial edit to the Cite journal template and a purge. I didn't know about the templateData bug but the solution sounds better than having duplicate templatedata like before. But pubmed generation still isn't working. I don't know how Citoid links with Cite journal, or Zotero - it's Zotero that generates the references apparently. Can't think what else to try. [[User:Canele]] Either a non-pubmed link to the article, or a doi link will generate a reference as a workaround. There's no question that if is just here, I'm also sure it was caused by the accidental delete of templates that were restored very soon after. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 17:17, July 7, 2019 (EDT)
:::::::So it sounds like we fixed the problem that we had on our side. Now there's just the remaining problem on the side of the Citoid server. The Zotero software that runs on the Citoid server must continually be updated to keep pace with the website changes on journal websites, pubmed website, etc. Sometimes the Zotero software on the Citoid server might fall behind, and will fail to automatically produce a citation based on a URL. In this case, you just have to try different URL's until you find one that can successfully be converted into a citation. Hope this helps.
:::::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 20:56, July 7, 2019 (EDT)
::::::::Yes thank you both, that helps a lot and I agree that's where we are--just tried en-Wikipedia and encountered the same PubMed-specific problem. In this case it's an old text so I don't have a great option for different links to it (and predictably PMID is also down when PubMed URL is down) but that should be a good workaround for most things until they update Citoid/Zotero. A million thanks! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 21:04, July 7, 2019 (EDT)
{{done}} Resolved as best as we could. [[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 20:27, July 12, 2019 (EDT)
:Citations from pubmed are fully working now - I haven't made any change since I last posted here. [[User:Canele]] [[User:JenB]] [[User:Pyrrhus]] if you find any examples of them not working please tag me and I will take a look. Canele's original [https://www.ncbi.nlm.nih.gov/pubmed/10990237 pmc ref] works for me on my user page. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 16:13, July 14, 2019 (EDT)
{{collapse bottom}}
{{done}} Now working.

===Auto-signing section headers===
Hi, starting a new section on a talk page automatically adds a signature to the header, with no possibility to remove it during the same edit. This is a very annoying feature. Can we get rid of it? [[User:Guido den Broeder|Guido den Broeder]] ([[User talk:Guido den Broeder|talk]]) 19:18, September 15, 2019 (EDT)

=== http to Secure https -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 17:58, October 21, 2020 (UTC) ===
{{Collapse top|Added to MEpedia suggested tasks}}
Hello,

There is a technical website issue that needs to be resolved. Currently, http and https are both being used in the URLs throughout the website.

This means that some users will land on non-secure pages (http w/out "s").

All pages need automatically redirect from http to https. This will keep everything secure, and improve SEO and organic search traffic.

I am not very familiar with the wiki platform, so I can't give specific details on where to make the changes. However, it looks like it's covered on here...

https://www.mediawiki.org/wiki/Manual:HTTPS

The above link goes over the dangers of having "http" URLs, and also talks about settings to auto-redirect everything to https (secure).

Thanks
:This is a great idea. I've added this to the [[MEpedia:Suggested_tasks#Developer_suggestions MEpedia suggested tasks], under Developer suggestions - feel free to edit or add it this page any time. ~[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 11:58, October 22, 2020 (UTC)
{{collapse bottom}}
=== Create and submit XML sitemap -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 18:22, October 21, 2020 (UTC) ===
{{collapse top |Added to MEpedia suggested tasks}}
A technical site improvement involving XML sitemap. This is a file that shows all the pages on a website. You then submit it to Google (Google Search Console) so Google can do a better job of displaying the website's pages/content in search results.

I don't believe me-pedia currently has an XML sitemap, because it would likely be found here - https://me-pedia.org/sitemap.xml

It looks like the instructions are here - https://www.mediawiki.org/wiki/Extension:AutoSitemap

After there's a sitemap file created, we will need to submit this file in Google Search Console. To do this, go here - https://search.google.com/search-console/welcome, in the URL Prefix section, add "https://me-pedia.org". Then verify using one of the methods provided. After that, you will see a Sitemaps section on the left. Here you will be able to add the URL where Google can find the XML sitemap.

After this, you'll want to create a second property in Google Search Console. This time, add the URL "http://me-pedia.org" (<<< w/out the "s"). Then do the same steps as above.

Let me know if there are any questions.
:This is a great find! I previously suggested adding a sitemap but this extension would be a better method - although we need to update the MediaWiki version first (this should happen later this year). I've added the to [[MEpedia:Suggested_tasks]].

Are you interested in joining the Slack channel, where we discuss things like developer agegroup suggestions? ~[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 12:09, October 22, 2020 (UTC)
{{collapse bottom}}

== Duplicate Citations: Merge these together -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 21:38, November 21, 2020 (UTC) ==

There are a lot of instances where the Reference section will show the exact same citation (word for word) multiple times. I've even seen the same citation listed 5 or 6 times.

For instance, the Myalgic encephalomyelitis: International Consensus Criteria citation is listed (3) times in the Reference section of the Immune system page - [[https://me-pedia.org/wiki/Immune_system]]

Supposedly, there's a tool to fix these...

https://en.wikipedia.org/wiki/Wikipedia:Citing_sources#Duplicate_citations
https://en.wikipedia.org/wiki/Wikipedia:AutoWikiBrowser

== Can I just delete the consequential symptoms page? -- [[Special:Contributions/198.144.121.43|198.144.121.43]] 02:34, February 12, 2022 (UTC) ==

I do not have the health capacity to read the rules or search dark-ish references that could support the claim. I added to Talk but I fear the page will sit there for years potentially doing harm.

* [[Consequential Symptoms]] - I agree, I don't really know what that page is even talking about. [[User:Forestglip|Forestglip]] ([[User talk:Forestglip|talk]]) 23:16, May 19, 2024 (UTC)

** Given there are no references on that page, and that a quick google search reveals it may be slightly misleading, I would agree. The term “consequential symptoms” does exist in medicine for conditions which arise as a result of an underlying condition. However, I’ve never heard this being used in relation to worsening from PEM as this page suggests. Maybe, in the slim likelihood that someone would in the future like to invest some time into the page, we could send it back to “draft” state? [[User:Yannlk]]

== Adding mobile-friendly skins -- [[Special:Contributions/104.193.135.218|104.193.135.218]] 22:34, May 19, 2024 (UTC) -- [[Special:Contributions/104.193.135.218|104.193.135.218]] 22:34, May 19, 2024 (UTC) ==

Someone on [https://s4me.info/threads/read-first-welcome-to-the-mepedia-subforum.5306/page-2#post-533134 S4ME] was commenting on the editor being buggy on mobile:

"Is there a recommended browser to use when editing mepedia on mobile? I’ve managed a couple edits, but atleast on my safari browser on my phone it’s very clonky and the ui has some obvious bugs. Am unable to use tablet or laptop due to severity."

Maybe consider installing a more [https://m.mediawiki.org/wiki/Manual:Mobiles,_tablets_and_responsive_design mobile-friendly skin]. This doesn't require changing the default, but it allows users to select a custom skin if they would like.

MEpedia:Discussion forum and Help desk

2024-05-20T18:02:24Z

Yannlk:/* Can I just delete the consequential symptoms page? -- 198.144.121.43 02:34, February 12, 2022 (UTC) */ reply

__NEWSECTIONLINK__ {{NOINDEX}}
[[Category:MEpedia help]]
This '''Discussion Forum''' and '''Help Desk''' is a centralized place for the MEpedia community to discuss, seek advice, and give advice on the MEpedia project.
 
To ask a question or make a comment:
# Click on the "Add topic" tab at the top of the window, which will bring up the [[MEpedia:Source editor|Source Editor]]. (If you are not familiar with using the Source Editor, see [[Help:Discussion]].)
# Then add your question or comment. Be sure to sign your question/comment with four tildes: <code><nowiki>~~~~</nowiki></code>
# Keep an eye on your [[MEpedia:Watchlist|watchlist]] to see when someone has responded. (If you are not familiar with watchlists, see [[MEpedia:Watchlist]].)
You can also raise questions on the [[Help:Discussion|discussion]] (talk) page for a specific page or on another user's talk page. Since editor availability can vary, though, you may wish to ask your question here in order to get advice from whoever might see it soonest.
 
''Note:'' Editors willing to participate in community discussions, or to offer guidance to other editors, should please add this page to their [[MEpedia:Watchlist|watchlist]]. When a question/comment is resolved, mark it as ‘done’ with the “done” template tag, and collapse the discussion with the “collapse top” and “collapse bottom” template tags.

==Questions==

===Request for science help re: gancyclovir===
{{collapse top}}
I'm wondering if any more scientifically knowledgeable folks can help me with [[Gancyclovir]]. It's one of many pages that have no references at all and probably I'm best equipped just to tag them for cleanup, but since the entry only contains two claims, I thought I could track down refs to verify them. Ha ha. I found these studies which (''if'' I understand them correctly) make opposing claims about its effect on microglial: "[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597339/ The antiviral drug ganciclovir does not inhibit microglial proliferation and activation]" (2015) versus "[https://www.ncbi.nlm.nih.gov/pubmed/24493798 Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation]" (2014). Is anyone available to help either revise the page (if I'm correct that maybe these are conflicting results that require qualification on the page) or confirm for me that the latter ref (or some other ref?) suffices to verify the entry's current claim that gancyclovir "also reduces microglial activation." Thanks much. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 17:45, 15 April 2019 (EDT)
:Excellent question. I answer your question [https://forums.phoenixrising.me/threads/drs-who-treat-with-low-dose-valcyte.39092/page-2#post-1023199 here]. (Spoiler: it doesn’t reduce microglial activation after all.)
:[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 18:17, 15 April 2019 (EDT)
::Oh, thank you so much [[User:Pyrrhus|Pyrrhus]]! Ok, I've updated both the [[gancyclovir]] and [[valgancyclovir]]. If you have a chance to look over and make sure I've presented it accurately, I'd be grateful! (Whew, glad we're fixing this! Def the kind of thing that argues for working hard to recruit and retain a lot more folks to comb the 2500+ pages for such issues...) [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:57, 15 April 2019 (EDT)
:::Ah belatedly reading down the rest of that thread to see the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806703/ follow-up STING paper] from the first authors. I'm pretty well in over my head scientifically at this point. If you have guidance about if/how it should be incorporated, that'd be greatly appreciated but I don't want to assign you work (!); I can also just add it as a "Learn more" and eventually someone else can incorporate as far as explaining its implications. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 21:42, 15 April 2019 (EDT)
::::You covered the two papers very well in the two pages- succinctly, accurately, and objectively. I'll summarize the STING paper and then you can decide whether to include my summary in the page(s).
::::"The authors of the original 2014 paper published a follow-up paper which described in-vitro and in-vivo experiments where they observed evidence that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. Although this pro-inflammatory finding might appear to contradict the authors 2014 paper, the authors explain the contradiction by saying:
::::<blockquote>We show that GCV can exhibit dual function in microglia (Figure S10): in naïve state, GCV induces microglia to be “primed”; on the other hand, GCV reduces inflammation in active microglia. </blockquote>"
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 00:07, 16 April 2019 (EDT)
:::::Oh fab. For those of us with limited neuroscience background, can I take a stab at restating your explanation and you tell me if I understood it correctly?

::::::The authors of the 2014 paper later published a follow-up paper (2017) based on in-vitro and in-vivo experiments using ganciclovir. This time they found a potentially pro-inflammatory response, specifically that ganciclovir, in sufficient doses, might stimulate a type-I interferon response in microglia. The authors attributed this response to a DNA-sensing protein called STING. While this result might appear to contradict their earlier anti-neuroinflammatory finding, they suggest it could indicate ganciclovir (GCV) "can exhibit dual function in microglia [...]: in naïve state, GCV induces microglia to be 'primed'; on the other hand, GCV reduces inflammation in active microglia."

:::::If my lay-ified paraphrase gets it wrong tho, I say let's use yours; it does seem like a finding worth flagging for researchers even if some less scientifically literate readers (ha, yours truly) may not get it (although also you're definitely better qualified than I to judge whether the study rates mention. So whatever you think is best.) [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:01, 16 April 2019 (EDT)
:::::: I‘ve made a few small changes to your text. Mainly, we have to be careful about our phrasing because there is currently a vicious fight over the very definition of “inflammation”. The old-timers stick stubbornly to the ancient greco-roman definition of inflammation, which does not recognize either the interferon response or neuroinflammation to have anything to do with what they consider to be “real” inflammation. Additionally, this is a hard paper to summarize because the authors themselves seem confused about their findings. Since you ask for my opinion, I don’t think their paper introduces anything new since their findings are perfectly consistent with the known toxicity of ganciclovir at high doses. But, in the interest of completeness, let’s include it. Hope this helps.
::::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 21:15, 16 April 2019 (EDT)
:::::::Ah thank you so much for your edits and your explanation [[User:Pyrrhus|Pyrrhus]]. This sounds like a good solution to me: the lay reader will def get the key take away that no, there's not firm evidence for this effect as the initial study suggested; and any scientist readers who want to get in the weeds will learn this study exists and they can go delve into its particulars if they wish. Cool! Thanks! Successful first use of the editor help desk! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 22:07, 16 April 2019 (EDT)
{{collapse bottom}}
{{done}} Resolved and copied to relevant entry's talk page for future reference. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 20:24, 17 April 2019 (EDT)

=== Broken citation template? ===
{{collapse top}}
Hi all. I'm suddenly having trouble using the "Cite web" template. In particular I'm trying to add https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Polymyalgia-Rheumatica as the reference for all the material I've added so far to the [[Polymyalgia rheumatica]] page I just started. But both in Visual Editor and in source code editing, I can't get the "Cite web" template to populate as a reference--it doesn't work at all in VE now and when I try source code, it adds all the info to the prose of the entry, rather than creating a footnote. Anybody have an idea what might be going on? I've used this extensively before (just for one example, see the [[HIV/AIDS]] page) and those references remain properly formatted so I am really stumped. Thanks for any advice! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 15:21, July 5, 2019 (EDT)
:With [[User:Notjusttired|Njt]]'s help, I copied pre-formatted source code and successfully inserted the ref, but in VE, even the Manual tab is still not recognizing the "Cite web" template (even though [[Template:Cite web]] is there!), and it doesn't seem to vary based either on the entry I'm editing or on the link I'm trying to add (e.g. no luck adding https://www.britannica.com/science/glucocorticoid to the [[Glucocorticoid]] page even tho Britannica is [[MediaWiki:Captcha-addurl-whitelist|whitelisted]]). Does anyone have any idea what's up with that? [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 22:05, July 5, 2019 (EDT)
::You’re not the only one to notice citation problems recently. It’s currently unclear to what extent the problems are on our side or on the side of the Citoid server. If it’s on our side , there are some things we can try. If it’s on the side of the Citoid server, then all wikis using that Citoid server should be seeing the same problems.
::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 00:59, July 6, 2019 (EDT)
:::[[User:JenB]] has also reported pubmed links not being looked up, even ones that previously worked, and this appears to be related (they use the journal template). [[User:Kmdenmark]] [[User:Canele]] [[User:Pyrrhus]] What's happening is that Citoid, which generates the references, and/or the VisualEditor can't find the '''templateData''' so doesn't know what fields are in the template to fill out. This seems to have happened when the Citation, Cite web and other templates were accidentally then restored. I've copied the templateData from [[Template:Cite web/doc]] to [[Template:Cite web]] so the web one is working, but this isn't much of a solution since it means there's duplicate data there. Cite news still isn't working (Insert, Template, Cite news brings up no boxes to fill out). Looking elsewhere, a purge of the Citation json has been suggested (which basically means delete old versions) but I don't have access to do this. [[User:Kmdenmark]] You might see a purge option on [[MediaWiki:Citoid-template-type-map.json]] to click - if not try clicking once on this [https://me-pedia.org/w/api.php?action=purge&titles=MediaWiki:Citoid-template-type-map.json link to purge the page] - I get "file not found" when I try, probably because the page is protected or I don't have edit access - it might need unprotecting first. (Purge instructions suggested at bottom of [https://phabricator.wikimedia.org/T106938 this page)]. I don't know how or why but the citoid tool or visual editor or both don't seem to see the templateData and/or some other values that exist. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 08:20, July 6, 2019 (EDT)
::::”Purging” refers simply to refreshing the cache, not removing old versions. You don’t need any special permissions to purge the cache. Since the [[MediaWiki:Citoid-template-type-map.json]] page hasn’t recently been changed, I don’t think that purging the cache will have any effect.
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 13:54, July 6, 2019 (EDT)
:::::I think it's worth trying, although editing and saving without changing first is probably a good idea. Purging involves clearing old versions from the cache (temporary memory) in this case - but can also mean deleting old copies (I don't think mediawiki allows that). Normally to clear the cache online you just refresh the page, but I think it's the server cache that's the issue not our local cache. We are on web hosting do no physical server to restart. At the moment I'm trying to guess what might help since I don't know exactly where the problem is. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 15:23, July 6, 2019 (EDT)
:::Thank you both for the updates, it's very helpful to know at least it's not just me! Most of this punches well above my technical-skills weightclass so I'm afraid I don't have much to add, but if I'm reading [https://www.mediawiki.org/wiki/Citoid/Where_citoid_is_enabled this] correctly, it looks like Citoid is enabled on en-Wikipedia, and I can confirm the ref issue is not happening there. Just in case that helps! Thanks again. [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 16:45, July 6, 2019 (EDT)
::::Yeah, the “edit and save without changing” trick works for TemplateData, and may work on Template pages in general, but it might be less applicable in other scenarios. MediaWiki uses a number of different caches, but most of the time, people refer to the MediaWiki server’s Page Cache when they say “purging the cache”. To purge the server’s Page Cache for a specific page, simply append <nowiki>?action=purge</nowiki> to the end of the page’s URL. (See https://www.mediawiki.org/wiki/Manual:Purge ). Hope this helps!
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 19:08, July 6, 2019 (EDT)
::::You probably already know this, but there is a [https://phabricator.wikimedia.org/T52372 known bug] where TemplateData in the doc subpage doesn’t show up in the main Template page. I encountered this recently. Although there are workarounds, this problem seems to show up surprisingly often. I think it might be better practice for us to consider storing all TemplateData in the main Template pages, and remove all TemplateData from doc subpages. This way we won’t have to worry about this bug anymore...
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 21:20, July 6, 2019 (EDT)
::::Okay, the TemplateData for all CS1 templates (<nowiki>{{Cite x}}</nowiki>) and the CS2 template (<nowiki>{{Citation}}</nowiki>) has been moved from the /doc subpages to the main Template pages. This should clear up everything on our end. If problems continue, it's probably on the side of the Citoid server. (Unless our TemplateData is wrong!)
::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 22:49, July 6, 2019 (EDT)
:::::Thank you!! So after purging the cache on [[Glucocorticoid]] (just for instance), the Cite Web template does how populate in the Manual tab--however, automatic ref generating still isn't working even for sources we use all the time, like PubMed (I was trying to add https://www.ncbi.nlm.nih.gov/pubmed/10990237 without having to fill in every author manually). Just an update on where it stands, I know all this debugging is a ton of work. It's very greatly appreciated! Definitely affects how much content I am able to add, whether or not the refs can be largely automated or if all of it needs to be copied by hand. Thank you! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 23:14, July 6, 2019 (EDT)
::::::[[User:Notjusttired]] The news and web citations are now being generated, plus doi links and everything but pubmed works as far as I know. I tried the purge suggested by [[User:Pyrrhus]] on all relevant modules and templates plus a trivial edit to the Cite journal template and a purge. I didn't know about the templateData bug but the solution sounds better than having duplicate templatedata like before. But pubmed generation still isn't working. I don't know how Citoid links with Cite journal, or Zotero - it's Zotero that generates the references apparently. Can't think what else to try. [[User:Canele]] Either a non-pubmed link to the article, or a doi link will generate a reference as a workaround. There's no question that if is just here, I'm also sure it was caused by the accidental delete of templates that were restored very soon after. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 17:17, July 7, 2019 (EDT)
:::::::So it sounds like we fixed the problem that we had on our side. Now there's just the remaining problem on the side of the Citoid server. The Zotero software that runs on the Citoid server must continually be updated to keep pace with the website changes on journal websites, pubmed website, etc. Sometimes the Zotero software on the Citoid server might fall behind, and will fail to automatically produce a citation based on a URL. In this case, you just have to try different URL's until you find one that can successfully be converted into a citation. Hope this helps.
:::::::[[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 20:56, July 7, 2019 (EDT)
::::::::Yes thank you both, that helps a lot and I agree that's where we are--just tried en-Wikipedia and encountered the same PubMed-specific problem. In this case it's an old text so I don't have a great option for different links to it (and predictably PMID is also down when PubMed URL is down) but that should be a good workaround for most things until they update Citoid/Zotero. A million thanks! [[User:Canele|Canele]] ([[User talk:Canele|talk]]) 21:04, July 7, 2019 (EDT)
{{done}} Resolved as best as we could. [[User:Pyrrhus|Pyrrhus]] ([[User talk:Pyrrhus|talk]]) 20:27, July 12, 2019 (EDT)
:Citations from pubmed are fully working now - I haven't made any change since I last posted here. [[User:Canele]] [[User:JenB]] [[User:Pyrrhus]] if you find any examples of them not working please tag me and I will take a look. Canele's original [https://www.ncbi.nlm.nih.gov/pubmed/10990237 pmc ref] works for me on my user page. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 16:13, July 14, 2019 (EDT)
{{collapse bottom}}
{{done}} Now working.

===Auto-signing section headers===
Hi, starting a new section on a talk page automatically adds a signature to the header, with no possibility to remove it during the same edit. This is a very annoying feature. Can we get rid of it? [[User:Guido den Broeder|Guido den Broeder]] ([[User talk:Guido den Broeder|talk]]) 19:18, September 15, 2019 (EDT)

=== http to Secure https -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 17:58, October 21, 2020 (UTC) ===
{{Collapse top|Added to MEpedia suggested tasks}}
Hello,

There is a technical website issue that needs to be resolved. Currently, http and https are both being used in the URLs throughout the website.

This means that some users will land on non-secure pages (http w/out "s").

All pages need automatically redirect from http to https. This will keep everything secure, and improve SEO and organic search traffic.

I am not very familiar with the wiki platform, so I can't give specific details on where to make the changes. However, it looks like it's covered on here...

https://www.mediawiki.org/wiki/Manual:HTTPS

The above link goes over the dangers of having "http" URLs, and also talks about settings to auto-redirect everything to https (secure).

Thanks
:This is a great idea. I've added this to the [[MEpedia:Suggested_tasks#Developer_suggestions MEpedia suggested tasks], under Developer suggestions - feel free to edit or add it this page any time. ~[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 11:58, October 22, 2020 (UTC)
{{collapse bottom}}
=== Create and submit XML sitemap -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 18:22, October 21, 2020 (UTC) ===
{{collapse top |Added to MEpedia suggested tasks}}
A technical site improvement involving XML sitemap. This is a file that shows all the pages on a website. You then submit it to Google (Google Search Console) so Google can do a better job of displaying the website's pages/content in search results.

I don't believe me-pedia currently has an XML sitemap, because it would likely be found here - https://me-pedia.org/sitemap.xml

It looks like the instructions are here - https://www.mediawiki.org/wiki/Extension:AutoSitemap

After there's a sitemap file created, we will need to submit this file in Google Search Console. To do this, go here - https://search.google.com/search-console/welcome, in the URL Prefix section, add "https://me-pedia.org". Then verify using one of the methods provided. After that, you will see a Sitemaps section on the left. Here you will be able to add the URL where Google can find the XML sitemap.

After this, you'll want to create a second property in Google Search Console. This time, add the URL "http://me-pedia.org" (<<< w/out the "s"). Then do the same steps as above.

Let me know if there are any questions.
:This is a great find! I previously suggested adding a sitemap but this extension would be a better method - although we need to update the MediaWiki version first (this should happen later this year). I've added the to [[MEpedia:Suggested_tasks]].

Are you interested in joining the Slack channel, where we discuss things like developer agegroup suggestions? ~[[User:Notjusttired|Njt]] ([[User talk:Notjusttired|talk]]) 12:09, October 22, 2020 (UTC)
{{collapse bottom}}

== Duplicate Citations: Merge these together -- [[User:Fireballsky|Fireballsky]] ([[User talk:Fireballsky|talk]]) 21:38, November 21, 2020 (UTC) ==

There are a lot of instances where the Reference section will show the exact same citation (word for word) multiple times. I've even seen the same citation listed 5 or 6 times.

For instance, the Myalgic encephalomyelitis: International Consensus Criteria citation is listed (3) times in the Reference section of the Immune system page - [[https://me-pedia.org/wiki/Immune_system]]

Supposedly, there's a tool to fix these...

https://en.wikipedia.org/wiki/Wikipedia:Citing_sources#Duplicate_citations
https://en.wikipedia.org/wiki/Wikipedia:AutoWikiBrowser

== Can I just delete the consequential symptoms page? -- [[Special:Contributions/198.144.121.43|198.144.121.43]] 02:34, February 12, 2022 (UTC) ==

I do not have the health capacity to read the rules or search dark-ish references that could support the claim. I added to Talk but I fear the page will sit there for years potentially doing harm.

* [[Consequential Symptoms]] - I agree, I don't really know what that page is even talking about. [[User:Forestglip|Forestglip]] ([[User talk:Forestglip|talk]]) 23:16, May 19, 2024 (UTC)

** Given there are no references on that page, and that a quick google search reveals it may be slightly misleading, I would agree. The term “consequential symptoms” does exist in medicine for conditions which arise as a result of an underlying condition. However, I’ve never heard this being used in relation to worsening from PEM as this page suggests. Maybe, in the slim likelihood that someone would in the future like to invest some time into the page, we could send it back to “draft” state?

== Adding mobile-friendly skins -- [[Special:Contributions/104.193.135.218|104.193.135.218]] 22:34, May 19, 2024 (UTC) -- [[Special:Contributions/104.193.135.218|104.193.135.218]] 22:34, May 19, 2024 (UTC) ==

Someone on [https://s4me.info/threads/read-first-welcome-to-the-mepedia-subforum.5306/page-2#post-533134 S4ME] was commenting on the editor being buggy on mobile:

"Is there a recommended browser to use when editing mepedia on mobile? I’ve managed a couple edits, but atleast on my safari browser on my phone it’s very clonky and the ui has some obvious bugs. Am unable to use tablet or laptop due to severity."

Maybe consider installing a more [https://m.mediawiki.org/wiki/Manual:Mobiles,_tablets_and_responsive_design mobile-friendly skin]. This doesn't require changing the default, but it allows users to select a custom skin if they would like.

Post-exertional malaise

2024-05-20T12:40:58Z

Yannlk:patient is noy preferred term

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

'''Post-exertional malaise (PEM)''' refers to a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]] and/or the appearance of new symptoms after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /> and is often delayed 24-72 hours or more.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" />

While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> When in PEM, people with ME/CFS have a lower capacity for exertion and the baseline for tiggering more PEM is lower.<ref name="Stussman2020" />

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer.<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> PEM can lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref> Some people with ME refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Post-exertional malaise

2024-05-20T12:38:50Z

Yannlk:worked on the lead

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

'''Post-exertional malaise (PEM)''' refers to a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]] and/or the appearance of new symptoms after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /> and is often delayed 24-72 hours or more.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" />

While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref> When in PEM, people with ME/CFS have a lower capacity for exertion and the baseline for tiggering more PEM is lower.<ref name="Stussman2020" />

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer.<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> PEM can lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref> Some ME/CFS patients refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Post-exertional malaise

2024-05-20T12:23:53Z

Yannlk:added that pem can lead to permanent worsening

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

'''Post-exertional malaise (PEM)''' refers to a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]] and/or the appearance of new symptoms after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /> and is often delayed 24-72 hours or more.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" /> While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref>

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, months, or longer,<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> Some ME/CFS patients refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" /> In some cases, PEM may lead to a permanent worsening of the condition and increased disability.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206/chapter/recommendations#post-exertional-malaise|title=Recommendations {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-20}}</ref><ref>Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.</ref><ref>{{Cite journal|title=Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients|date=January 2024|url=https://www.mdpi.com/1648-9144/60/1/83|journal=Medicina|volume=60|issue=1|pages=83|last=Thoma|first=Manuel|last2=Froehlich|first2=Laura|last3=Hattesohl|first3=Daniel B. R.|last4=Quante|first4=Sonja|last5=Jason|first5=Leonard A.|last6=Scheibenbogen|first6=Carmen|language=en|doi=10.3390/medicina60010083|pmc=PMC10819994|pmid=38256344|issn=1648-9144}}</ref>

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Post-exertional malaise

2024-05-19T18:59:08Z

Yannlk:put emphasis on the fact crashes can last a while

[[File:Cfs woman sketch.jpg|435x435px|thumb|Post-exertional malaise (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|''physical'' or ''cognitive'' exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[cognitive dysfunction]], [[brain fog|brain fog]] and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[headache]]s and [[migraine]]s; [[chronic pain]]; [[Myalgia|muscle pain]] and [[muscle fatigability]]; [[orthostatic intolerance]], [[neurally mediated hypotension|neurally mediated hypotension]] or [[Postural orthostatic tachycardia syndrome|POTS]]; and more. The onset of PEM can be [[delayed onset of post-exertional symptoms|delayed for 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months.<ref name="Chu2018" />]]

'''Post-exertional malaise (PEM)''' refers to a [[post-exertional symptom exacerbation|''worsening'' of ME/CFS symptoms]] and/or the appearance of new symptoms after ''physical'' or ''cognitive'' [[exertion]] which was previously tolerated,<ref name="Arroll2014" /><ref name="CDC-symptoms" /> and is often delayed 24-72 hours or more.<ref name="Chu2018" /><ref name="Hodges2020t" /><ref name="Jason2018-supp">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome | pages = 4-5|url=http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf|journal=Journal of Health Psychology | date = 2018 | language=en|volume=|doi=10.1177/1359105318805819/suppl_file/appendix.__the_development_of_a_comprehensive_measure_of_post-exertional_malaise.8.20.2018.pdf|via=}}</ref><ref name="Jason2018">{{Cite journal | last= Jason | first = Leonard A | authorlink = Leonard Jason | last2 = Holtzman | first2 = Carly S | last3 = Sunnquist | first3 = Madison | author-link3 = Madison Sunnquist | last4 = Cotler | first4 = Joseph | authorlink4 = Joseph Cotler | date = 2018-10-24 | title = The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome|url=https://doi.org/10.1177/1359105318805819|journal=Journal of Health Psychology|language=en|pages=1359105318805819|doi=10.1177/1359105318805819|issn=1359-1053}}</ref> PEM is considered to be the '''hallmark symptom''' of [[ME/CFS]],<ref name="Chu2018" /><ref name="GuidelinesChange2021">{{Cite web|url=https://www.guidelinesinpractice.co.uk/neurology-/key-learning-points-revised-nice-guidance-on-me/cfs/456897.article | title = Key learning points: revised NICE guidance on ME/CFS | last = Strain | first=David | authorlink=David Strain | last2 = | first2 = | authorlink2 = | date = 2022-04-21 | website = Guidelines in Practice|language=en|archive-url=|archive-date=|url-status=|access-date=2022-06-13}}</ref> and interferes with the ability to lead a "normal" life.<ref name="CDC-symptoms" /><ref name="Jason2018" /><ref name="GuidelinesChange2021" /> While in most [[differential diagnosis|fatiguing diseases]] patients experience symptom relief after [[exercise]],<ref name="Robb1989">{{Cite journal | last = Robb-Nicholson | first = L. C. | last2 = Daltroy | first2 = L. | last3 = Eaton | first3 = H. | last4 = Gall | first4 = V. | last5 = Wright | first5 = E. | last6 = Hartley | first6 = L.H. | last7 = Schur | first7 = P.H. | last8 = Liang | first8 = M.H. | date = Dec 1989 | title = Effects of aerobic conditioning in lupus fatigue: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/2590802|journal=British Journal of Rheumatology|volume=28|issue=6 | pages = 500–505|issn=0263-7103|pmid=2590802}}</ref><ref name="Mostert2002">{{Cite journal | last = Mostert | first = S. | last2 = Kesselring | first2 = J. | date = Apr 2002 | title = Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/11990874|journal=Multiple Sclerosis |volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion may cause PEM.<ref name="CDE" /><ref name="Mayo">{{Cite news | url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-and-chronic-disease/art-20046049 | title = What you need to know about exercise and chronic disease|work=Mayo Clinic|access-date=2018-10-10|language=en}}</ref><ref name="Nijs2008">{{Cite journal | last = Nijs | first = Jo | authorlink = Jo Nijs | last2 = Almond | first2 = Freya | last3 = De Becker | first3 = Pascale | author-link3 = Pascale De Becker | last4 = Truijen | first4 = Steven | last5 = Paul | first5 = Lorna | date = May 2008 | title = Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/18441039|journal=Clinical Rehabilitation|volume=22|issue=5 | pages = 426–435|doi=10.1177/0269215507084410|issn=0269-2155|pmid=18441039}}</ref>

In ME/CFS [[Recovery period is prolonged, usually taking 24 hours or longer|recovery time from exertion is prolonged]],<ref name="VanNess2010" /> lasting days, weeks, or months,<ref name="FDA-2013">{{citation | date = September 2013|url=https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf | title = The Voice of the Patient. {{!}} Chronic Fatigue Syndrome and Myalgic Encephalomyelitis|publisher=Center for Drug Evaluation and Research (CDER) {{!}} U.S. Food and Drug Administration.}}</ref> Some ME/CFS patients refer to these post-exertional episodes as "[[crash]]es".<ref name="niceng206">{{Cite web|url=https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref><ref name="Unrest-film" />

===Characteristics ===
[[File:Post-exertional_Malaise_dimensions_ME_CFS.png|thumb|left|alt=Pie chart showing five dimensions. 1 Dead, heavy feeling after starting to exercise; 2 Next day soreness or fatigue after non-strenuous, everyday activities; 3 Mentally tired after the slightest effort; 4 Minimum exercise makes you physically tired; 5 Physically drained or sick after mild activity|Five dimensions of post-exertional malaise in ME/CFS. Post-exertional malaise (PEM) is not the same as [[post-exertional symptom exacerbation]]. 
Image: MEpedia. Data from: Jason (2018). [https://www.researchgate.net/publication/358281945_DePaul_Symptom_Questionnaire_-_Post-Exertional_Malaise_short_form_DSQ-PEM DePaul Symptom Questionnaire: Post-Exertional Malaise short form (DSQ-PEM)]<ref name="Cotler2018" />.]]

The distinctive characteristics of post-exertional malaise were found by scientific research including patient interviews and questionnaires, then confirmed and expanded on by biomedical research, especially using [[exercise]] tests.<ref name="Cotler2018" /><ref name="Vink2015">{{Cite journal | last = Vink | first = Mark | authorlink = Mark Vink | date = 2015-09-10 | title = The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.researchgate.net/publication/282133390_The_Aerobic_Energy_Production_and_the_Lactic_Acid_Excretion_are_both_Impeded_in_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome|journal=Journal of Neurology and Neurobiology ( ISSN 2379-7150 )|volume=1|doi=10.16966/2379-7150.112}}</ref><ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25= Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012| isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref>
{{See also|#DSQ-PEM|DePaul Symptom Questionnaire PEM subscale}}
Too much exertion causes ME/CFS patients abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref name="Blackwood1998">{{Cite journal | last = Blackwood | first = S. | last2 = MacHale | first2 = S. | last3 = Power | first3 = M. | last4 = Goodwin | first4 = G. | last5 = Lawrie | first5 = S. | date = Oct 1998 | title = Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2170292/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=65|issue=4 | pages = 541–546|issn=0022-3050|pmc=2170292|pmid=9771781|via=}}</ref><ref name="Cook2017" /> [[immune activation]],<ref name="Nijs2014">{{Cite journal | last = Nijs | first = Jo | last2 = Nees | first2 = Andrea | last3 = Paul | first3 = Lorna | last4 = De Kooning | first4 = Margot | last5 = Ickmans | first5 = Kelly | last6 = Meeus | first6 = Mira | last7 = Van Oosterwijck | first7 = Jessica | authorlink = Jo Nijs | author-link2 = Andrea Nees | author-link3 = Lorna Paul | author-link4 = Margot De Kooning | author-link5 = Kelly Ickmans|via= | authorlink6 = Mira Meeus | authorlink7 = Jessica Van Oosterwijck | date = 2014 | title=Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review | url = https://www.ncbi.nlm.nih.gov/pubmed/24974723|journal=Exercise Immunology Review|volume=20 | pages = 94–116|issn=1077-5552|pmid=24974723|issue=|quote=}}</ref> [[gene expression]]<ref name="Light2009">{{Cite journal | last = Light | first=Alan R. | author-link = Alan Light | last2 = White | first2 = Andrea T. | authorlink2 = Andrea White | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | authorlink4 = Kathleen Light | date = Oct 2009 | title = Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects|url=http://dx.doi.org/10.1016/j.jpain.2009.06.003|journal=The Journal of Pain|volume=10|issue=10|pages=1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1526-5900}}</ref><ref name="Light2011">{{Cite journal | last = Light | first=A.R. | authorlink = Alan Light | last2 = Bateman | first2 = L. | authorlink2 = Lucinda Bateman | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = VanHaitsma | first5 = T.A. |last6 = White | first6 = A.T. | authorlink6 = Andrea White | last7 = Light | first7 = K.C. | authorlink7 = Kathleen Light | date = 2011-07-13 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome|url=http://dx.doi.org/10.1111/j.1365-2796.2011.02405.x|journal=Journal of Internal Medicine|volume=271|issue=1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=0954-6820}}</ref><ref name="Meyer2013">{{Cite journal | last = Meyer | first=Jacob D. | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | authorlink7 = Dane Cook | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression|url=http://dx.doi.org/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |volume=1|issue=4|pages=190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846}}</ref><ref name="White2011">{{Cite journal | last = White | first = A. T. | author-link = Andrea White | last2 = Light | first2 = A.R. | authorlink2 = Alan Light | last3 = Hughen | first3 = R.W. | last4 = VanHaitsma | first4 = T.A. | last5 = Light | first5 = K.C. | authorlink5 = Kathleen Light | date = 2011-12-30 | title = Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls|url=http://dx.doi.org/10.1097/psy.0b013e31824152ed|journal=Psychosomatic Medicine|volume=74|issue=1 | pages = 46–54|doi=10.1097/psy.0b013e31824152ed|issn=0033-3174}}</ref> and endogenous pain inhibition<ref name="Whiteside2004">{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome|url=http://dx.doi.org/10.1016/j.pain.2004.02.029|journal=Pain|volume=109|issue=3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref><ref name="Meeus2010">{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study|url=http://dx.doi.org/10.2340/16501977-0595|journal=Journal of Rehabilitation Medicine|volume=42|issue=9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977}}</ref><ref name="VanOosterwijck2010">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Nijs | first2 = J. | authorlink2 = Jo Nijs | last3 = Meeus | first3 = M. | authorlink3 = Mira Meeua | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | authorlink7 = Lorna Paul | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study|url=http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x|journal=Journal of Internal Medicine|volume=268|issue=3|pages=265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote=}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls.
{{See also|List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis}}
Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name="Stevens2018" /><ref name="Unrest-film" /> On the second day [[Two-day cardiopulmonary exercise test|CPET]], ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases.<ref name="Snell2013">{{Cite journal | last = Snell | first = Christopher R. | authorlink1 = Christopher Snell | last2 = Stevens | first2 = Staci R | authorlink2 = Staci Stevens | last3 = Davenport | first3 = Todd E. | authorlink3 = Todd Davenport | last4 = VanNess | first4 = J. Mark | authorlink4 = Mark VanNess | date = 2013-06-27 | title = Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=https://academic.oup.com/ptj/article/93/11/1484/2735315|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref name="Vermeulen2010">{{Cite journal | last = Vermeulen | first = Ruud CW | last2 = Kurk | first2 = Ruud M | last3 = Visser | first3 = Frans C | last4 = Sluiter | first4 = Wim | last5 = Scholte | first5 = Hans R | date = 2010 | title=Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity|url=http://dx.doi.org/10.1186/1479-5876-8-93|journal=Journal of Translational Medicine|volume=8|issue=1 | pages = 93|doi=10.1186/1479-5876-8-93|issn=1479-5876}}</ref><ref name="Keller2014" /><ref name="VanNess2007">{{Cite journal | last1 = VanNess | first1 = J Mark | authorlink1 = Mark VanNess | last2 = Snell | first2 = Christopher R | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Staci R | authorlink3 = Staci Stevens | title = Diminished Cardiopulmonary Capacity During Post-Exertional Malaise| journal = Journal of Chronic Fatigue Syndrome | volume = 14 | issue = 2 | pages = 77-85 | date = 2007 | pmid = | url = https://www.researchgate.net/publication/249887130_Diminished_Cardiopulmonary_Capacity_During_Post-Exertional_Malaise | doi = 10.1300/J092v14n02_07}}</ref><ref name="Hodges2018" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name="IOM2015">{{Cite book |url=http://www.ncbi.nlm.nih.gov/books/NBK274235/ | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness | last = Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last2 = Board on the Health of Select Populations | last3 = Institute of Medicine | date = 2015 | publisher=National Academies Press (US)|isbn=9780309316897|series=The National Academies Collection: Reports funded by National Institutes of Health|location=Washington (DC)|pmid=25695122}}</ref><ref name="ICC" /> <ref name="Loy2013">{{Cite journal | last = Loy | first = Bryan D. | last2 = O'Connor | first2 = Patrick J. | last3 = Dishman | first3 = Rodney K. | date = Oct 2013 | title = The effect of a single bout of exercise on energy and fatigue states: a systematic review and meta-analysis|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.843266?journalCode=rftg20|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=1|issue=4|pages=223–242|doi=10.1080/21641846.2013.843266|issn=2164-1846}}</ref> [[Brian Vastag]] won a groundbreaking long term disability (LTD) claim using CPET to prove his PEM was a severe disabling symptom.<ref name="Vastag-Prudential">{{Citation|url=https://cases.justia.com/federal/district-courts/new-jersey/njdce/2:2015cv06197/323449/44/0.pdf?ts=1527932072 | last = US District Court District of New Jersey | title = Brian Vastag v. Prudential Insurance Company of America, Civ. No. 15-6197 (KSH) (CLW) (D.N.J. May. 31, 2018)}}</ref><ref name="Vastag-wins">{{Cite web|url=https://www.meaction.net/2018/06/04/victory-for-me-disability-claim-court-upholds-plaintiffs-lawsuit-after-being-denied-disability/ | title = Victory for ME Disability Claim - U.S. Court Upholds Plaintiff's Lawsuit After Being Denied Disability | last = Tillman | first=Adriane | author-link = | date = 2018-06-04 | website = #MEAction|language=en-US|archive-url=|archive-date=|url-status=|access-date=2019-02-02}}</ref>

A 2015 review of the literature by the [[National Academy of Medicine]] concluded there to be "sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions."<ref name="IOM2015" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name="Jason2015">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth | last3 = So | first3 = Suzanna | last4 = Scott | first4 = Jilian | last5 = Brown | first5 = Abigail | date = 2015 | title=Problems in Defining Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295644/|journal=Journal of prevention & intervention in the community|volume=43|issue=1|pages=20–31|doi=10.1080/10852352.2014.973239|issn=1085-2352|pmc=4295644|pmid=25584525}}</ref> with some diagnostic criteria emphasizing [[Paresis|muscle weakness]] and others a more a general form of [[fatigue]] and exhaustion.<ref name="McManimen2016" />

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms<ref name="VanNess2010" />]]
The [[Centers for Disease Control and Prevention]] (CDC) outline different types of exertion that may trigger PEM and how it impacts patients noting some may be housebound or completely bedbound during a crash. "People with ME/CFS may not be able to predict what will cause a crash or how long it will last."<ref name="CDC-symptoms">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html | title = Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>

==Causes ==
PEM can be caused by [[Exertion#Exertion in ME.2FCFS|mental/cognitive as well as physical exertion]]<ref name="Arroll2014" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name="Chu2018" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name="CCC" /> with [[brain fog|brain fog,]]<ref name="VanNess2010" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name="Chu2018" /> In contrast to most forms of exercise intolerance, the [[delayed onset of post-exertional symptoms|onset of PEM is frequently delayed]]<ref name="Yoshiuchi2007" /> with many patients reporting the height of their symptom flare-up, two<ref name="VanNess2010" /> or several days after the initial trigger.

==Examples==
Examples of PEM given by the CDC are:
*attending a child's school event may leave a patient housebound for a couple of days unable to do needed tasks, like laundry; grocery shopping may cause a crash that requires a nap in the car before driving home or a call for a ride home;
*a shower may leave a patient bedbound and unable to do anything for days;
*keeping up with work may lead to spending evenings and weekends recovering.<ref name="CDC-symptoms" />
== PEM described by Dr. David Kaufman ==
{{#ev:youtube|https://www.youtube.com/watch?v=RC9TjgE_PlU|400|right|'''PEM described by Dr. David Kaufman''' (2018) Kaufman/''Unrest'' Video begins @2:16 and PEM is described until @3:35|frame|start=136&rel=0&autoplay=0}}

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

(Video begins @2:16 and PEM is described until @3:35. View entire 11:47 for a full description of ME/CFS)

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module'''. US medical providers can [https://www.unrest.film/cme register to watch] [[Unrest]] online for free and receive Continuing Education credit.<ref name="Unrest-film">{{Cite web|url=https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = Kaufman | first=David | authorlink = David Kaufman|archive-url=|archive-date=|url-status=|publisher=Unrest Film}}</ref>

==Patients' description==
[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why [[ME/CFS|#ME/CFS]] research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.<ref>{{Cite web|url=https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We're only out and about at our best, and our (more frequent) worst often remains hidden. I'm convinced it's why #MEcfs research funding is so low - the problem isn't visible enough. I'm seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = twitter.com|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM2.JPG|300px|thumb|right|#twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.<ref>{{Cite web|url=https://twitter.com/kaisecam/status/1085886323276349440 | title = #twofacesofME #MEcfs - It's not always easy to predict when you'll take a turn for the worst. It's not even easy to tell how you'll feel when you crash. You just know that at some point in the future, it's going to happen.pic.twitter.com/nTJVG63jRm | last = Kaise 🥄 | first = Mx | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM3.JPG|300px|thumb|right|#TwoFacesofME Workday me v's weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.<ref>{{Cite web|url=https://twitter.com/RachelFrancis/status/1085940724774912000 | title = #TwoFacesofME Workday me vs weekend me. I'm so grateful that most of the time I can work, but losing out on family time on a weekend to recover is hard.pic.twitter.com/qZNiQaVHyD | last = Francis | first = Rachel | date = 2019-01-17 | website = twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair]] on a rare trip out. Second photo, the inevitable [[crash]]. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak etc., etc. #TwoFacesofME<ref>{{Cite web|url=https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak etc., etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = Twitter | date = 2019-01-17|access-date=2019-01-17|language=en | first=Henry | last = Köhler}}</ref>]]

[[File:PEM6.JPG|300px|thumb|right|What the [world] don't [see] two faces of M.E.<ref>{{Cite web|url=https://twitter.com/SharonTiday/status/1085122891220430848 | title = What the don't two faces of M.E.pic.twitter.com/DYZVhtyrG5 | last = CFDA Awareness# | first = | date = 2019-01-15 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM7.JPG|300px|thumb|right|Joining #pwME sharing #TwoFacesofME for #MEAwareness 1: a fall day when I got outside (but ended up in bed a week) 2: what no one sees (constant [[Chronic pain|pain]], post exertional malaise & [[Sleep dysfunction|sleep deprivation]]) Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)<ref>{{Cite web|url=https://twitter.com/ceibakoru/status/1085894325832040448 | title = Joining #pwME sharing #TwoFacesofME for #MEAwareness, 1: a fall day when I got outside (but ended up in bed a week), 2: what no one sees (constant pain, post exertional malaise & sleep deprivation). Bonus for comparison: snowboarding shortly after cancer treatment (but before ME)pic.twitter.com/EpsMLT8E11 | last = Ceiba 🌳Koru 🌀 | date = 2019-01-17 | website = Twitter|language=en|access-date=2019-01-17}}</ref>]]

=== An illness within an illness ===

PEM refers to a worsening of many ME/CFS symptoms as a result of physical or mental exertion. It consists of more than post-exertional fatigue and pain, and can cause severe debility.<ref name="Stussman2020" /> As one patient described it: <blockquote>"When I do any activity that goes beyond what I can do—I literally collapse—my body is in major pain, it hurts to lay in bed, it hurts to think, I can’t hardly talk—I can't find the words, I feel my insides are at war."<ref name="IOM2015" /></blockquote> Another patient emphasized that the feeling of PEM is very different from what one experiences as a healthy person: <blockquote>"PEM is like nothing else you will experience in healthy life; a combination of a hangover, the flu, finishing a 10k run, all at the same time at varying levels of severity."<ref>{{Cite news | url=https://twitter.com/Fatigo_MECFS/status/1050305665565102080 | title = Fatigo_MECFS on Twitter|work=Twitter|access-date=2018-10-11|language=en}}</ref></blockquote>Considering the serious but fluctuating debility PEM causes, ME/CFS expert Dr. [[Anthony Komaroff]] described it as "an illness within an illness".<ref>{{Cite news | url=https://phoenixrising.me/archives/11884 | title = Post-Exertional Malaise II: Perception and Reality By Jennifer M. Spotila, J.D. | last=Spotila | first=Jennifer | author-link = Jennifer Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref>

=== Energy conservation and pacing ===
Patients often report the feeling of a red line, an [[energy limit]] that if exceeded, will result in a [[crash]] or relapse. As one [[Norway|Norwegian] patient described: <blockquote>“....And suddenly it is just too much. The body turns itself off, as if it has gone on strike. You have pushed too much for too long, it repeats itself, and the body stops functioning.”<ref name="Lauren2011">{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>Energy conservation strategies such as [[pacing]] and the [[Energy Envelope Theory|envelope theory]] have been developed to minimize PEM while allowing patients to stay as active as possible.<ref name="Goudsmit2012">{{Cite journal | last = Goudsmit | first=Ellen M. | author-link = Elen Goudsmit | last2 = Nijs | first2 = Jo | authorlink2 = Jo Nijs | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Wallman | first4 = Karen E.| date = 2012 | title = Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document|url=https://www.ncbi.nlm.nih.gov/pubmed/22181560|journal=Disability and Rehabilitation|volume=34|issue=13|pages=1140–1147|doi=10.3109/09638288.2011.635746|issn=1464-5165|pmid=22181560}}</ref> These techniques advise patients to balance energy availability and expenditure and to recognize early signs of PEM so they can reduce activity levels before a relapse occurs.

== The distinctive characteristics of PEM ==
Four aspects differentiate the post-exertional malaise of ME/CFS patients from the exercise intolerance commonly reported in patients suffering from [[deconditioning]] or other conditions.

=== Timing ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertional Malaise: History, Characteristics, Evidence'' (2015) By Dr. Lily Chu/Solve CFS">https://www.youtube.com/watch?v=hxJPrkWHcBo</embedvideo>
First of all, there is the time lapse. While physical complaints are usually reported during or shortly after exercise, PEM often has a delayed onset, hours or sometimes even days after the original trigger. Yoshiuchi et al. (2007) for example wrote that: "after a briefer maximal exercise task, reports of worsening CFS symptoms were inconsistent or absent until 5 days after the challenge, a pattern not typically observed in real life."<ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> The authors noted that this delay could be used to distinguish ME/CFS from other fatiguing illness. Another study from Stanford University showed that in up to 37% of the 150 ME/CFS patients studied, PEM may not begin until a day or more after an [[Exertion|exertional]] trigger.<ref name="Chu2018" />

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about PEM and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her condition worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM "[[Canadian Consensus Criteria#Definition|option]]"]]

Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:<blockquote>"It's really counter-intuitive to feel bad after a delay of 24 hours after exertion. It may take quite some time before people even make that connection, if ever. I only noticed it about three years in, and I hesitated to mention to others because I thought it might make me sound nuts."<ref name="s4me">{{Cite news | url=https://www.s4me.info/threads/s4me-submission-to-the-public-review-on-common-data-elements-for-me-cfs-concerns-with-the-proposed-measure-of-post-exertional-malaise.2220/ | title = S4ME: Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise|work=Science for ME|access-date=2018-10-10|language=en-US}}</ref></blockquote>Another time-related characteristic of PEM is a [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery period]]. In a 2010 study 25 M/CFS patients and 23 matched controls were followed up for seven days after performing a maximal cardiopulmonary exercise test. After two days, all controls subjects were recovered while only one ME/CFS patient was. Most (60%) of the ME/CFS participants reported that it took more than five days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test.<ref name="VanNess2010">{{Cite journal | last = VanNess | first = J. Mark | authorlink = Mark VanNess | last2 = Stevens | first2 = Staci R. | authorlink2 = Staci Stevens | last3 = Bateman | first3 = Lucinda | authorlink3 = Lucinda Bateman | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | authorlink4 = Christopher Snell | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: <blockquote>"For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h."<ref name="Bazelmans2005">{{Cite journal | last = Bazelmans | first = Ellen | authorlink = Ellen Bazelmans | last2 = Bleijenberg | first2 = Gijs | author-link2 = Gijs Bleijenberg | last3 = Voeten | first3 = Marinus J.M. | last4 = van der Meer | first4 = Jos W.M. | author-link4 = Jos van der Meer | last5 = Folgering | first5 = Hans | date = Oct 2005 | title = Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16223622|journal=Journal of Psychosomatic Research|volume=59|issue=4|pages=201–208|doi=10.1016/j.jpsychores.2005.04.003|issn=0022-3999|pmid=16223622|quote=|via=}}</ref></blockquote>[[Charles Lapp|Lapp]] et al. followed 31 ME/CFS patients for 12 days after performing a maximal exercise test of 8-10 minutes. The average relapse lasted 8,82 days, although 22% of patients were still in relapse when the study ended at 12 days.<ref name="Lapp1997">{{Cite journal | last = Lapp | first = C.W. | authorlink = Charles Lapp | date = Jul 1997 | title = Exercise limits in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9236491|journal=The American Journal of Medicine|volume=103|issue=1 | pages = 83–84|issn=0002-9343|pmid=9236491}}</ref> In the Stanford study by [[Lily Chu|Chu]] et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: <blockquote>"In many medical conditions, exertion-exacerbated symptoms usually start during exertion or immediately after and usually resolve immediately or shortly after exertion stops. In contrast, PEM may not start until hours or even days after the trigger starts or has been removed, may peak after the first day, and may not stop until hours to months later. This characteristic of PEM often leads patients and clinicians to believe that symptom exacerbations are random rather than associated with a trigger; most people will not intuit that symptoms are caused by a trigger that occurred hours to days prior unless specifically asked by their clinicians to pay attention."<ref name="Chu2018" /></blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the [[List of symptoms in ME CFS|type of symptoms reported]]. The [[Canadian Consensus Criteria]], a 2003 clinical guideline formed by experts in the field, underlines that many PEM symptoms are [[Immune system|immune-related]]: <blockquote>"The [[malaise]] that follows exertion is difficult to describe but is often reported to be similar to the generalized [[pain]], discomfort and fatigue associated with the acute phase of [[influenza]]. Delayed malaise and fatigue may be associated with signs of immune activation such as a [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or [[Brain fog|cognitive fog]]."<ref name="CCC" /> </blockquote>[[Mark VanNess|VanNess]] et al. noted how [[Cognitive dysfunction|cognitive difficulties]] after exertion differentiate ME/CFS patients from healthy controls: <blockquote>"Another interesting difference between groups was the reported symptom of [[cognitive dysfunction]], for example, ''[[Brain fog|brain-fog]]'' or ''difficulty concentrating.'' Problems of this nature were not reported by any of the control subjects, whereas 12 patients (48%) experienced these problems: "Carrying on conversations was hard." "Can't think straight. "My mind was not clear."<ref name="VanNess2010" /></blockquote>This was elaborated by [[Lily Chu|Chu]] et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: <blockquote>"There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ [[Inflammation|inflammatory]]-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion. Conversely, symptoms typically associated with physical exertion in other conditions, like [[Dyspnea|shortness of breath]] or [[chest pain]] in chronic lung or [[heart]] disease, are rarely reported in ME/CFS. Furthermore, it is well-established that physical activity improves [[Mood swings|mood]], [[Sleep dysfunction|sleep]], and pain in both healthy people as well those with chronic illnesses like depression or anxiety yet our subjects report worsened sleep, mood, and pain with physical activity."<ref name="Chu2018" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple types of triggers. Research has shown that ME/CFS patients experience PEM after [[Exertion#Exertion in ME.2FCFS|cognitive effort, physical or emotions]].<ref name="Stussman2020" /> A 2014 study for example followed up on 32 ME/CFS patients after completing a battery of neurocognitive tests. As the authors concluded: "following a challenging cognitive demand, fatigue significantly increased two days after testing", which was "suggestive of post-exertional symptom exacerbation following mental effort."<ref name="Arroll2014">{{Cite journal | last = Arroll | first = Megan A. | author-link = Megan Arroll | last2 = Attree | first2 = Elizabeth A. | last3 = O'Leary | first3 = John M. | last4 = Dancey | first4 = Christine P. | date = 2014-04-03 | title = The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2014.892755|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=2|issue=2 | pages = 57–63|doi=10.1080/21641846.2014.892755|issn=2164-1846}}</ref> Commenting on the [https://www.me-pedia.org/wiki/1980-81_Ayrshire_outbreak outbreak in West Kilbride, Ayrshire], Ramsay remarked: <blockquote>"Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain."<ref name="Ramsay1988" /> </blockquote>Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds<ref>{{Cite web|url=http://anilvanderzee.com/dance-hermit-16-vs-sumo-baby-part-1/ | title = Dance hermit ’16 vs. Sumo Baby (part 1) {{!}} Anil van der Zee|website=anilvanderzee.com|language=en-GB|access-date=2018-10-13}}</ref>. While PEM was often thought of as symptom exacerbation after exercise, it is clear that for some ME/CFS patients even basic activities of daily living such as toileting, bathing, dressing, communicating, and reading can trigger relapses.<ref name="CDC-PEM-comments" /> As long time ME/CFS expert [[Jennie Spotila|Jennifer Spotila]] explained in a four-piece exploration of the phenomenon post-exertional malaise:<blockquote>"The use of the word ‘exertion’ may create the impression that PEM is triggered by strenuous or intense activity, but this is not the case […] Some patients need only attempt to make a simple meal or get dressed before PEM descends."<ref>{{Cite news | url=https://phoenixrising.me/archives/11883 | title = Unraveling Post-exertional Malaise By Jennifer M. Spotila|work=Phoenix Rising|access-date=2018-10-10|language=en-US}}</ref></blockquote>This was confirmed by Chu et al. <blockquote>"[…] our results provide formal evidence supporting patient narratives, clinician experiences, and current case definitions which assert that even tasks like walking, cooking, or reading can provoke PEM."<ref name="Chu2018" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name="CDC-PEM-comments">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Loss of functional capacity ===
A fourth distinctive element of PEM is often described as a loss of stamina and/or functional capacity. This refers to the results of the 2-day cardiopulmonary exercise test (CPET) procedure. A CPET is usually reproducible and normally has a test-retest difference of 7-12%<ref name="Stevens2018">{{Cite journal | last = Stevens | first = Staci | authorlink=Staci Stevens | last2 = Snell | first2 = Chris | authorlink2 = Christopher Snell | last3 = Stevens | first3 = Jared | last4 = Keller | first4 = Betsy | last5 = VanNess | first5 = J. Mark | authorlink5 = Mark VanNess | date = 2018 | title=Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full|journal=Frontiers in Pediatrics|language=English|volume=6|doi=10.3389/fped.2018.00242|issn=2296-2360}}</ref>. ME/CFS patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. These results have been replicated by several research teams, though there is inconsistency on which measure (VO2 or maximal workload, at peak or ventilatory threshold), the decline in functional capacity is best represented.

{| class="wikitable"
! colspan="8" |Physiological changes between first and second exercise test during 2-day CPET procedure in patients with ME/CFS
|-
|
|Number of ME/CFS patients
|VO2 peak
|VO2 at VT
|Workload peak
|Workload at VT
|HR peak
|O2pulse at VT
|-
|[[Mark VanNess|VanNess]] et al. 2007.<ref name="VanNess2007" />
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|Vermeulen et al. 2010.<ref name="Vermeulen2010" />
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.<ref name="Snell2013" />
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.<ref name="Keller2014" />
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|Hodges et al. 2018.<ref name="Hodges2018" />
|10
| +5.3%
| +6.1%
| -6.7%
| -11.4%
| -0.6%
|?
|}
The drop in functional capacity on the second CPET is usually not seen in other diseases. According to [[Betsy Keller|Keller]] et al. (2014) "ME/CFS patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".<ref name="Keller2014">{{Cite journal | last = Keller | first=Betsy A. | last2 = Pryor | first2 = John Luke | last3 = Giloteaux | first3 = Ludovic | date = 2014-04-23 | title = Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment|url=https://www.ncbi.nlm.nih.gov/pubmed/24755065|journal=Journal of Translational Medicine|volume=12|pages=104|doi=10.1186/1479-5876-12-104|issn=1479-5876|pmc=4004422|pmid=24755065}}</ref> A preliminary study from [[New Zealand]] suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME/CFS.<ref name="Hodges2018">{{Cite journal | last = Hodges | first = L. D. | authorlink = Lynette Hodges | last2 = Nielsen | first2 = T. | last3 = Baken | first3 = D. | date = Jul 2018 | title = Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study|url=https://www.ncbi.nlm.nih.gov/pubmed/28782878|journal=Clinical Physiology and Functional Imaging|volume=38|issue=4 | pages = 639–644|doi=10.1111/cpf.12460|issn=1475-097X|pmid=28782878}}</ref>

Questions have however been raised about the clinical use of the 2-day CPET procedure. [[Christopher Snell|Snell]] et al. (2013) suggested it might be unethical to use this method since many ME/CFS patients might suffer a serious relapse as a result of exercise performance.<ref name="Snell2013" /> Others have noted that the CPET- procedure is not practical either. It cannot be used in patients with severe ME/CFS (thus excluding these patients from study) and because of cost and expertise, may not be available to most clinicians.<ref name="CDC-PEM-comments" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name="Cotler2018" /> For these reasons PEM is usually assessed using self-reporting questionnaires.
==PEM in children ==
It is important to understand that in [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|children with ME/CFS]] may not describe having PEM. They can experience a "crash" or relapse from exertion, perhaps from just taking the school bus, having to spend prolonged periods in bed.<ref name="Bell2016">{{Cite web | last = Bell | first = David S | authorlink = David Bell |url=https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children | date = 2016-06-25 | website = [[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US}}</ref>

== Differentiation ==
Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases.

=== Healthy controls and idiopathic chronic fatigue ===
PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas.

The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref>

[[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref>

=== Multiple sclerosis ===
According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" />

=== Major Depressive disorder ===
In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote>
A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />

== Objective findings after exertion: ==
In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" />
A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" />

=== Gene expression ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo>

One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref>

=== Immune activation ===
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo>
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo>
In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref>

==== Complement C4a ====
In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref>
==== Cytokines ====
The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below).

{| class="wikitable"
|Study
|Number of participants
|Exercise challenge
|Cytokines tested:
|Results:
|-
|[[Daniel Peterson|Peterson]] et al. (1994)<ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>
|10 ([[Holmes criteria]], all cases were post-infectious)
|Walking 1 mile per hour for 30 min
|[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]
|Negative results
|-
|[[Andrew Lloyd|Lloyd]] et al. (1994)<ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|12 ([[Australian criteria]])
|30 min hand grip exercises
|[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|La Manca et al. (1999)<ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref>
|20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included
|An exhaustive treadmill exercise test
|[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]
|Negative results
|-
|Cannon et al. (1997)<ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref>
|8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).
|Negative results
|-
|Gupta et al. (1998)<ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref>
|5 (Holmes criteria)
|30 min hand grip exercises
|[[Interleukin 6|IL-6]]
|Negative results
|-
|Cannon et al. (1999)<ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref>
|10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”
|Stepping up and down on a platform for 15 min
|[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]
|Negative results
|-
|Jammes et al. (2009)<ref name="Jammes2009" />
|9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.
|Cycling test until maximal work load
|[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]
|Negative results
|-
|Robinson et al (2010)<ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref>
|6 (Fukuda criteria)
|Incremental exercise test to exhaustion
|[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]
|Negative results
|-
|Andrea White et al. (2010)<ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref>
|19 (Fukuda criteria)
|The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."
|[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]

 
|Positive results for a subgroup (11/19) of patients with high PEM

 
|-
|Andrew Lloyd et al. (2018)<ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref>
|24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"
|Symptom limited exercise on an ergocycle.
|Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]

 

[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]

 

Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]

 

[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])

 

[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]

 

[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]

 

Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]
|Positive results: ME/CFS had a distinct cytokine profile post-exercise.
|}
Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>

=== Autonomic response ===
Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear.

A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref>

=== Sleep ===
A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref>
=== Cognitive performance ===
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|Study
|Number of ME/CFS subjects
|Neurocognitive tests
|Results
|-
|[[Sonya Marshall]] et al. (1997)<ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref>
|8
|Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).
|Negative
|-
|Blackwood et al. (1998)<ref name="Blackwood1998" />
|10
|"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”
|Positive
|-
|La Manca et al. (1998)<ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref>
|19
|The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)
|Positive
|-
|Claypoole et al. (2001)<ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref>
|21
|The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)
|Negative
|-
|[[Dane Cook|Cook]] et al. (2005)<ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref>
|20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia
|Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)
|Negative
|-
|Yoshiuchi et al. (2007)<ref name="Yoshiuchi2007" />
|9
|A one-back memory task
|Negative
|-
|Cook et al. (2017)<ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref>
|15
|The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task
|Positive
|}

=== Pain modulation ===
Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref>

=== Other ===

==== The gut microbiome ====
Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref>

==== Catecholaminergic hyporeactivity ====
Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref>

==== Nitric oxide metabolites ====
A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>

== Problems in defining PEM ==

=== Asking the right questions ===
[[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" />

Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives.

Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref>

These observations point to the need of a more precise definition of PEM and several attempts to this end have been made.

=== More than just fatigue and pain ===
Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes:
# Exhausted or tired.
# Heaviness in the limbs or whole-body.
# Fogginess in the head.
# Weakness in the muscles.
# Drained of energy.
===The DePaul Symptom Questionnaire (DSQ) subscale ===
The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders.

The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref>
# Dead, heavy feeling after starting to exercise.
# Next day soreness after non-strenuous, everyday activities.
# Mentally tired after the slightest effort.
# Minimum exercise makes physically tired.
# Physically drained or sick after mild activity.
To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" />

Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" />

Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions:
# Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
# Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
# If you feel worse after activities, how long does this last?
# If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended?
# If you do not exercise, is it because exercise makes your symptoms worse?
An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" />

=== The DePaul Post-Exertional Malaise Questionnaire ===
The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics:
# [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
# [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms.
# [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]].
# [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer.
# [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level.
The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present.

=== Muscle weakness ===
A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" />

=== Common data elements PEM working group ===
The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote>
# [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms.
# [[lack of stamina|Loss of stamina]] and/or functional capacity.
# An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
# A prolonged, unpredictable recovery period that may last days, weeks, or even months.
# Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />

== Symptom recognition ==

=== Case definitions ===
Early descriptions of symptom exacerbation in [[Myalgic encephalomyelitis|ME]] focused on post-exertional muscle weakness. Renowned ME-expert [[Melvin Ramsay]] for example wrote: <blockquote>"[[Muscle fatigability]] whereby, even after a minor degree of physical effort, three, four or five days or longer elapse before full [[muscle]] power is restored is unique and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME."<ref name="Ramsay1988">Ramsay M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease. Gower Medical Publishing. Second edition.</ref> </blockquote>In a 1985 study [[Peter Behan|Behan]] et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".<ref name="Behan1985">{{Cite journal | last = Behan | first=P. O. | last2 = Behan | first2 = W.M. | last3 = Bell | first3 = E.J. | date = May 1985 | title = The postviral fatigue syndrome - an analysis of the findings in 50 cases|url=https://www.ncbi.nlm.nih.gov/pubmed/2993423|journal=The Journal of Infection|volume=10|issue=3|pages=211–222|issn=0163-4453|pmid=2993423}}</ref>

====Formerly used to define Chronic fatigue syndrome====

In the 1988 [[Holmes criteria]] for [[Chronic fatigue syndrome|CFS]], unexplained generalized [[muscle weakness]] was one of the 11 minor symptoms, yet it was fatigue that set the tone. Another minor symptom referred to "prolonged (24 hours or greater) generalized fatigue after levels of [[exercise]] that would have been easily tolerated in the patient's premorbid state".<ref name="Holmes1988">{{Cite journal | last = Holmes | first = G. P. | last2 = Kaplan | first2 = J.E. | last3 = Gantz | first3 = N.M. | last4 = Komaroff | first4 = A.L. | last5 = Schonberger | first5 = L.B. | last6 = Straus | first6 = S.E. | last7 = Jones | first7 = J.F. |last8 = Dubois | first8 = R.E. | last9 = Cunningham-Rundles | first9 = C. | date = Mar 1988 | title = Chronic fatigue syndrome: a working case definition|url=https://www.ncbi.nlm.nih.gov/pubmed/2829679|journal=Annals of Internal Medicine|volume=108|issue=3|pages=387–389|issn=0003-4819|pmid=2829679}}</ref> PEM is not a mandatory symptom under the Holmes definition.

The wording "postexertional malaise" was used in the article Symptoms and signs of chronic fatigue syndrome by Anthony Komaroff and Dedra Buchwald, from 1991.<ref>{{Cite journal|title=Symptoms and Signs of Chronic Fatigue Syndrome|date=1991-01-01|url=http://academic.oup.com/cid/article/13/Supplement_1/S8/423106/Symptoms-and-Signs-of-Chronic-Fatigue-Syndrome|journal=Clinical Infectious Diseases|volume=13|issue=Supplement_1|pages=S8–S11|last=Komaroff|first=Anthony L.|last2=Buchwald|first2=Dedra|language=en|doi=10.1093/clinids/13.Supplement_1.S8|issn=1537-6591}}</ref>

The wording "postexertional malaise" was used as one of the 8 minor symptoms in the 1994 [[Fukuda criteria]], but without further clarification of the term, except that it lasts more than 24 hours. PEM is not a mandatory symptom under the Fukuda criterion.

====Retired criteria for Chronic fatigue syndrome====

The [[Oxford criteria]] has been retired from use after a number of [[Oxford_criteria#Criticisms|scientific critcisms]] were raised, including that it does not list PEM as a requirement or even a symptom.<ref name="P2PPreview2015">{{Cite journal | last = Haney | first = Elizabeth | last2 = Smith | first2 = M.E. Beth | last3 = McDonagh | first3 = Marian | last4 = Pappas | first4 = Miranda | last5 = Daeges | first5 = Monica | last6 = Wasson | first6 = Ngoc | last7 = Nelson | first7 = Heidi D. | date = Jun 16, 2015 | title = Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | url = http://annals.org/article.aspx?doi=10.7326/M15-0443|journal=Annals of Internal Medicine|language=en|volume=162|issue=12 | pages = 834|doi=10.7326/m15-0443|issn=0003-4819|via=}}</ref> Patients with the symptom of [[fatigue]], which many illnesses and diseases have, are incorrectly given the CFS diagnosis in research studies when the [[Oxford criteria]] is used.
<blockquote>The [[United States]] [[National Institutes of Health]] (NIH) has issued a draft report that highlights the dire need for scientific research that will help find a cure for the millions of people suffering from [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) worldwide. The report also highlights the fact that the decades-old UK Royal Society of Medicine’s Oxford criteria for ME/CFS are severely “flawed,” and that continuing to use these criteria may “cause harm.” Further, the NIH report says that the Royal Society definition should “be retired” and replaced with a single case definition agreed to by the ME/CFS community.<ref name="Oxfordscrapped">{{Cite web|url=http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ | title = US NIH Report Calls for UK Definition of ME/CFS to be Scrapped | last = Swift | first=Penny | date = 2015-01-16 | website = The Argus Report|language=en-US|access-date=2019-02-28}}</ref></blockquote>
{{See also|Oxford criteria}}

====Currently used as the hallmark symptom defining ME/CFS====
Post-exertional malaise was recognized as a symptom of [[chronic fatigue syndrome]] in the 1994 [[Fukuda criteria]], but did not fully describe it, and only identified it as an optional symptom.<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref>

The 2003 [[Canadian Consensus Criteria]] (CCC) for ME/CFS used PEM as the key compulsory symptom for diagnosis. The CCC's were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a [[flu-like symptoms|flu-like distress]].<ref name="CCC">{{Cite journal | last = Carruthers | first = Bruce M. | last2 = Jain | first2 = Anil Kumar | last3 = De Meirleir | first3 = Kenny L. | last4 = Peterson | first4 = Daniel L. | last5 = Klimas | first5 = Nancy G. | last6 = Lerner | first6 = A. Martin | last7 = Bested | first7 = Alison C. | last8 = Flor-Henry | first8 = Pierre | last9 = Joshi | first9 = Pradip | date = Jan 2003 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_02|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=11|issue=1 | pages = 7–115|doi=10.1300/j092v11n01_02|issn=1057-3321}}</ref> [[Canadian Consensus Criteria#Definition|PEM and/or post-exertional fatigue]] is a mandatory symptom under the CCC criterion.<ref name="CCC-overview">{{Cite web|url=http://www.investinme.org/Documents/PDFdocuments/Canadian_ME_Overview_A4.pdf | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview fo the Canadian Consensus Document | last = Carruthers | first = Bruce | authorlink=Bruce Carruthers | last2 = van de Sande | first2 = Marjorie | authorlink2 = Marjorie van de Sande | date = |website=Invest in ME Research | pages = 4|type=|archive-url=|archive-date=|url-status=|access-date=|quote=Physical or mental exertion often causes debilitating malaise and/or fatigue, generalized pain, deterioration of cognitive functions, and worsening of other symptoms that may occur immediately after activity or be delayed. Patients experience rapid muscle fatigue and lack endurance.}}</ref> The [[International Consensus Criteria]] for [[myalgic encephalomyelitis |ME]] replaced post-exertional malaise with a similar symptom of [[post-exertional neuroimmune exhaustion]], though this criteria is rarely used in clinical practice.<ref name="ICC" />

The [[National Academy of Medicine]] 2015 report describes PEM more generally as "an exacerbation of some or all of an individual's ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability." The report confirmed PEM as the hallmark symptom of ME/CFS and advised to rename the disease accordingly to [[Systemic Exertion Intolerance Disease]] (SEID).<ref name="IOM2015" /> PEM is a mandatory symptom under the SEID criterion, which was adopted by the [[Centers for Disease Control|CDC]] and is used as the current ME/CFS criteria.<ref name="CDC-symptoms" />

The UK uses the [[NICE ME/CFS diagnostic criteria 2021|NHS diagnostic criteria]], which were changed in 2021 to use post-exertional malaise as the hallmark symptom a required (compulsory) symptom that is needed for ME/CFS to be diagnosed.<ref name="CDC-symptoms" /><ref name="GuidelinesChange2021" />

====Currently used to define Myalgic encephalomyelitis====

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''[[post-exertional neuroimmune exhaustion|Post-Exertional Neuro-immune Exhaustion]] (PENE)''' to refer to the characteristic exercise and exertion intolerance of [[myalgic encephalomyelitis]] (ME) patients. It notes a [[delayed onset of post-exertional symptoms|delayed onset]] and [[Recovery period is prolonged, usually taking 24 hours or longer|prolonged recovery]], and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a [[Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities|substantial reduction in functioning]], as even simple activities of daily living can cause a relapse.<ref name="ICC">{{Cite journal | last = Carruthers | first = Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | author-link8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | authorlink12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14=Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23=Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24=Modra Murovska | last25 = Pall | first25 = Martin | author-link25=Martin Pall | last26 = Stevens | first26 = Staci | authorlink26 = Staci Stevens | date = 2011-08-22 | title = Myalgic encephalomyelitis: International Consensus Criteria|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref> PENE is a mandatory symptom under the ICC criterion.

====Long COVID ====
Post-exertional malaise is a potential symptom of [[Long COVID]] in the [[World Health Organization Long COVID diagnostic criteria|World Health Organization]]'s definition.<ref name="WHO-longcovid-criteria">{{citation | title = A clinical case definition of post COVID-19 condition by a Delphi consensus
| date = Oct 6, 2021 |publisher=[[World Health Organization]] | others = World Health Organization (WHO) clinical case definition working group on post COVID-19 condition | first1 = Joan B. | last1 = Soriano | first2 = Maya | last2 = Allan | first3 = Carine | last3 = Alsokhn | first4 = Nisreen A. | last4 = Alwan | authorlink4 = Nisreen Alwan | first5 = Lisa | last5 = Askie | first6 = Hannah E. | last6 = Davis | authorlink6 = Hannah Davis | first7 = Janet V. | last7 = Diaz | first8 = Tarun | last8 = Dua | first9 = Wouter | last9 = de Groote | first10 = Robert | last10 = Jakob | first11 = Marta | last11 = Lado | first12 = John | last12 = Marshall | first13 = Srin | last13 = Murthy | first14 = Jacobus | last14 = Preller | first15 = Pryanka | last15 = Relan | first16 = Nicoline | last16 = Schiess | first17 = Archana | last17 = Seahwag | ref = WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1 | url = https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1}}</ref>

===Psychological paradigm ===
====Dismissed as disturbed effort perceptions or kinesiophobia ====
[[File:Brian vastag.png|thumb|right|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]
The existence of PEM as a distinctive and complex symptom of ME/CFS has been dismissed in early research into the disease. Some interpreted it as just fatigue after exercise<ref name="CDC-questionnaire">{{Cite web|url = https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf | title = Symptoms Inventory Questionnaire {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-05-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-11-21}}</ref>, while others saw it as an artifact of disturbed effort perceptions<ref name="Laurie1997">{{Cite journal | last = Lawrie | first = S. M. | last2 = Machale | first2 = S.M. | last3 = Power | first3 = M.J. | last4 = Goodwin | first4 = G.M. | date=Sep 1997 | title = Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?|url=https://www.cambridge.org/core/journals/psychological-medicine/article/editorial-is-the-chronic-fatigue-syndrome-best-understood-as-a-primary-disturbance-of-the-sense-of-effort/434A5EB2C5B4F971A4A36C1DC3400A7E|journal=Psychological Medicine|language=en|volume=27|issue=5 | pages = 995–999|issn=1469-8978}}</ref><ref>{{Cite journal | last = Rosen | first = S D | last2 = King | first2 = J C | last3 = Wilkinson | first3 = J B | last4 = Nixon | first4 = P G | date = Dec 1990 | title = Is chronic fatigue syndrome synonymous with effort syndrome?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1292947/|journal=Journal of the Royal Society of Medicine|volume=83|issue=12 | pages = 761–764|issn=0141-0768|pmc=1292947|pmid=2125315}}</ref><ref>{{Cite journal | last = Wallman | first = Karen E. | last2 = Sacco | first2 = Paul | date = Jan 2007 | title = Sense of effort during a fatiguing exercise protocol in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/17365951|journal=Research in Sports Medicine|volume=15|issue=1 | pages = 47–59|doi=10.1080/15438620601184331|issn=1543-8627|pmid=17365951}}</ref> or an [[Illness beliefs|irrational fear of movement]]<ref>{{Cite journal | last = Silver | first=A. | last2 = Haeney | first2 = M. | last3 = Vijayadurai | first3 = P. | last4 = Wilks | first4 = D. | last5 = Pattrick | first5 = M. | last6 = Main | first6 = C.J. | date = Jun 2002 | title = The role of fear of physical movement and activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12069873|journal=Journal of Psychosomatic Research|volume=52|issue=6 | pages = 485–493|issn=0022-3999|pmid=12069873}}</ref><ref name="Fischler1997">{{Cite journal | last = Fischler | first=B. | last2 = Dendale | first2 = P. | last3 = Michiels | first3 = V. | last4 = Cluydts | first4 = R. | last5 = Kaufman | first5 = L. | last6 = De Meirleir | first6 = K. | authorlink6 = Kenny De Meirleir | date = Apr 1997 | title = Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology|url=https://www.ncbi.nlm.nih.gov/pubmed/9160276|journal=Journal of Psychosomatic Research|volume=42|issue=4|pages=369–378|issn=0022-3999|pmid=9160276}}</ref>. One example of this is the [[Tampa scale for kinesiophobia]], adapted for [[chronic fatigue syndrome]]. Some of the questions in this scale ask about the experience of PEM such as: "If I were to try to overcome it, my symptoms would increase" or "my symptoms let me know when to stop exercising so that I do not harm myself". Yet these symptoms are classified as an indicator of [[illness beliefs|irrational fear of movement and exercise]], instead of PEM.<ref>{{Cite web|url=http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf | title = Tampa Scale Kinesiophobia - Version Chronic Fatigue Syndrome | last = Nijs | first = J | last2 = De Meirleir | first2 = K | date = 2004 | website = painmotion.be|publisher=Archives of Physical Medicine and Rehabilitation|archive-url=|archive-date=|url-status=|access-date= | last3 = Duquet | first3 = W}}</ref>

== Critique of the term ==
The name post-exertional malaise was introduced by the 1994 Fukuda criteria and had no prior medical meaning attached to it.<ref name="Chu2018" /> While in the scientific literature, the term has become the standard to describe the relapses ME/CFS patients suffer after exertion, patients argue that it trivializes their experience. The term malaise after all refers to "a general feeling of discomfort, illness, or unease whose exact cause is difficult to identify"<ref>{{Cite web|url=https://en.oxforddictionaries.com/definition/malaise | title = Definition of malaise in English by Oxford Dictionaries|website=Oxford Dictionaries {{!}} English|access-date=2018-10-13}}</ref>. Doctor of [http://sph.berkeley.edu/ Public Health at Berkely], [[David Tuller]], calls post-exertional malaise a "complete misnomer" arguing what ME/CFS patients experience "is much closer to a serious crash or relapse than a Victorian fainting spell."<ref name="Tuller20111123">{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/ | last = Tuller | first = David | authorlink = David Tuller | title = Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=[[Virology blog]]|language=en-US | date = 2011-11-23|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term "[[crash]]" to describe their relapses.

==Notable studies==
*2021, Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Bond2021">{{Cite journal | title = Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2021 | url=https://www.mdpi.com/1660-4601/18/5/2366/htm|journal=International Journal of Environmental Research and Public Health|volume=18|issue=5|pages=2366 | last = Bond | first=Joshua | authorlink = Joshua Bond | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Hodges | first3 = Lynette | author-link3 = Lynette Hodges|language=en|doi=10.3390/ijerph18052366|pmc=PMC7957494|pmid=33671082|access-date=|issn=1660-4601|quote=|via=}}</ref> - [https://doi.org/10.3390/ijerph18052366 (Full text)]
*2020, The physiological time line of post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Hodges2020t">{{Cite journal | title = The physiological time line of post‐exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = May 2020|url=https://onlinelibrary.wiley.com/doi/10.1002/tsm2.133|journal=Translational Sports Medicine|volume=3|issue=3|pages=243–249 | last = Hodges | first = Lynette | authorlink = Lynette Hodges | last2 = Nielsen | first2 = Tessa | authorlink2 = Tessa Nielsen | last3 = Cochrane | first3 = Darryl | author-link3 = Darryl Cochrane | last4 = Baken | first4 = Donald | author-link4 = Donald Baken|language=en|doi=10.1002/tsm2.133|pmc=|pmid=|access-date=|issn=2573-8488|quote=|via=}}</ref> - [https://doi.org/10.1002/tsm2.133 (Full text)]
*2020, Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Stussman2020">{{Cite journal | last = Stussman | first=Barbara | author-link = | last2 = Williams | first2 = Ashley | authorlink2 = | last3 = Snow | first3 = Joseph | authorlink3 = Joseph Snow | last4 = Gavin | first4 = Angelique | author-link4 = | last5 = Scott | first5 = Remle | authorlink5 = | last6 = Nath | first6 = Avindra | authorlink6 = Avindra Nath | last7 = Walitt | first7 = Brian | authorlink7 = Brian Walitt | date = 2020 | title=Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full|journal=Frontiers in Neurology|language=English|volume=11|issue=|pages=|doi=10.3389/fneur.2020.01025|issn=1664-2295|pmc=|pmid=|access-date=|quote=|via=}}</ref> [https://www.frontiersin.org/articles/10.3389/fneur.2020.01025/full (Full text)]
*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref name="Mateo2018">{{Cite journal | last = Mateo | first = Lariel J. | date = 2018 | title=Comparing Post-Exertional Symptoms Following Serial Exercise Tests|url=https://scholarlycommons.pacific.edu/purcc/2018/events/87/|journal=PURCC|language=en|volume=|pages=|via=Scholarly Commons}}</ref> - [https://scholarlycommons.pacific.edu/purcc/2018/events/87/ (Abstract)]
*2018, Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey<ref name="Chu2018">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = Donn Gavert | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | date = 2018 | title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853|journal=PloS One|volume=13|issue=6| pages = e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983853 (Full text)]
*2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name="Jason2018" /><ref name="Jason2018-supp" /> - [http://journals.sagepub.com/doi/abs/10.1177/1359105318805819?journalCode=hpqa& (Abstract)] [http://journals.sagepub.com/doi/suppl/10.1177/1359105318805819/suppl_file/Appendix.__The_Development_of_a_Comprehensive_Measure_of_Post-Exertional_Malaise.8.20.2018.pdf (Questionnaire)]
*2017, Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise<ref name="Linderheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | authorlink9 = Alan Light | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise|url=https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref> - [https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166 (Full text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen2016">{{Cite journal | last = McManimen | first = SL | authorlink = Stephanie McManimen | last2 = Sunnquist | first2 = ML | authorlink2 = Madison Sunnquist | last3 = Jason | first3 = LA | authorlink3 = Leonard Jason | title = Deconstructing post-exertional malaise: An exploratory factor analysis.| journal = Journal of Health Psychology | volume = 24 | issue = 2 | pages = 188–198| date = 2016 | pmid = 27557649 | pmc =PMC5325824 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ | doi = 10.1177/1359105316664139}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]
* 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers<ref name="JasonL2015bio">{{Cite journal | last1 = Jason | first1 = LA | authorlink1 = Leonard Jason | last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn | last3 = Zinn | first3 = | authorlink3 = Mark Zinn| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers | journal = Current Neuropharmacology | volume = 13 | issue = 5 | page = 701-734 | date = September 2015 | doi =10.2174/1570159X13666150928105725 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/#!po=2.51799 (Full Text)]
*2015, Changes in Gut and Plasma [[Microbiome]] following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Shukla2015" /> - [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2015, Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains<ref name="Jason2015qu">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | author-link2 = Madison Sunnquist | last3 = Brown | first3 = Abigail | author-link3 = Abigail Brown | last4 = Furst | first4 = Jacob | authorlink4 = | last5 = Cid | first5 = Marjoe | authorlink5 = | last6 = Farietta | first6 = Jillianna | authorlink6 = | last7 = Kot | first7 = Bobby | last8 = Bloomer | first8 = Craig | last9 = Nicholson | first9 = Laura | date = September 2015 | title = Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/|journal=Journal of neurology and neurobiology|volume=1|issue=4|pages=|doi=|issn=2379-7150|pmc=4830389|pmid=27088131|access-date=|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830389/ (Full text)] - assessed different types of post-exertional malaise
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="Meyer2013" /> - [http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2010, Postexertional Malaise in Women with Chronic Fatigue Syndrome<ref name="VanNess2010" /> - [https://www.liebertpub.com/doi/10.1089/jwh.2009.1507 (Abstract)]
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref name="Paul1999">{{Cite journal | last = Paul | first = L. | last2 = Wood | first2 = L. | last3 = Behan | first3 = W.M. | last4 = Maclaren | first4 = W.M. | date = 1999 | title = Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10209352|journal=European Journal of Neurology|volume=6|issue=1 | pages = 63–69|issn=1351-5101|pmid=10209352|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pubmed/10209352 (Abstract)]
* 1994, The chronic fatigue syndrome: a comprehensive approach to its definition and study<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | author-link = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959|issn=0003-4819|pmid=7978722|via=|publisher=American College of Physicians}}</ref> - [https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf (Full text)]

==Talks and interviews==
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]
*2012, [https://www.youtube.com/watch?v=B20H1u1LjCE Top 10 Things You Should Know About Post-Exertional Relapse] - University of the Pacific/Solve CFS - 2010 study, PEM in Women with CFS is discussed

==See also==
*[[Delayed onset muscle soreness]]
*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==
*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health] (PEM Definition Included)
*[http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome] - Medscape
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]
*[https://www.healthrising.org/the-community-reports-best-practices-on-managing-thriving-with-or-just-surviving-chronic-fatigue-syndrome-mecfs/how-to-best-recover-from-a-crash-the-mecfs-community-reports/ How to Best Recover From a Crash: the ME/CFS Community Reports] - Health Rising
*[http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/ The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?]

== References ==
{{Reflist}}

[[Category:Signs and symptoms]]
[[Category:Neurological signs and symptoms]]
[[Category:Post-exertional neuroimmune signs and symptoms]]
[[Category:Long COVID signs and symptoms]]

Primer for journalists

2024-05-19T18:44:21Z

Yannlk:updated a couple of things that were written before me/cfs became standard

{{mbox|text= Editors: Edits to this Primer may require the same edits to the other [[:Category:Primers|Primers]].}}
[[myalgic encephalomyelitis|Myalgic encephalomyelitis]] (ME), sometimes referred to as [[chronic fatigue syndrome]] (CFS), and not to be confused with [[chronic fatigue]] (CF) is widely misunderstood. In this '''Primer for journalists''', we provide evidence-based statements (with links to further reading & sources) to support journalists writing about the disease. '''Chronic Fatigue Syndrome''' must never be shortened to ''Chronic Fatigue'' in the body of an article or its headline. This has caused much confusion for readers who do not understand ME/CFS is a debilitating lifelong illness and it is not the same as [[chronic fatigue]] (CF); CF is a symptom of many different illnesses. Although the [[Fukuda criteria|Fukuda]]<ref name="fukuda1994">{{Cite journal | last = Fukuda | first = K. | authorlink = Keiji Fukuda | last2 = Straus | first2 = S.E. | authorlink2 = Stephen Straus | last3 = Hickie | first3 = I. | authorlink3 = Ian Hickie | last4 = Sharpe | first4 = M.C. | authorlink4 = Michael Sharpe | last5 = Dobbins | first5 = J.G. | authorlink5 = James Dobbins | last6 = Komaroff | first6 = A. | authorlink6 = Anthony Komaroff | date = 1994-12-15 | title = The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group | url = https://www.researchgate.net/profile/Michael_Sharpe2/publication/247808895_The_Chronic_Fatigue_Syndrome_A_Comprehensive_Approach_to_Its_Definition_and_Study/links/0c96053201643bfc4b000000/The-Chronic-Fatigue-Syndrome-A-Comprehensive-Approach-to-Its-Definition-and-Study.pdf|journal=Annals of Internal Medicine|volume=121|issue=12 | pages = 953–959 |issn=0003-4819|pmid=7978722|via=|doi=10.7326/0003-4819-121-12-199412150-00009|publisher=American College of Physicians}}</ref> and the [[Oxford criteria|Oxford Criteria]]<ref name="PMC1293107">{{Cite journal | title = A report--chronic fatigue syndrome: guidelines for research. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/|journal=Journal of the Royal Society of Medicine | date = Feb 1991|issn=0141-0768|pmc=1293107|pmid=1999813 | pages = 118–121 |volume=84|issue=2 | first = MC | last = Sharpe | first2 = LC | last2 = Archard | first3 = JE | last3 = Banatvala | first4 = LK | last4 = Borysiewicz | first5 = AW | last5 = Clare | first6 = A | last6 = David | first7 = RH | last7 = Edwards | first8 = KE | last8 = Hawton | first9 = HP | last9 = Lambert}}</ref> were previously used for diagnosing ME/CFS, they are now regarded as overly broad, there being criticism that patients were being [[misdiagnosis of myalgic encephalomyelitis and chronic fatigue syndrome|misdiagnosed]] in both clinical and research settings as having ME/CFS when in fact they were suffering from the symptom CF or another fatiguing diagnosis.<ref name="Vink2019">{{Cite journal | last = Vink | last2 = Vink-Niese | date = 2019-09-20 | title = Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies | url = https://www.mdpi.com/2075-4418/9/4/124|journal=Diagnostics|language=en|volume=9|issue=4|page=124|doi=10.3390/diagnostics9040124|issn=2075-4418 | first = Mark | first2 = Alexandra|pmc=|pmid=|quote= | author-link = Mark Vink | authorlink2 = Alexandra Vink-Niese|access-date=|via=}}</ref><ref name="Carruthers, 2003" /><ref name="ICC2011primer" /></div><ref>{{Cite web | title = What Does a True ME Definition Look Like? | url = https://www.meadvocacy.org/what_does_a_true_me_definition_look_like|website=MEadvocacy.org|access-date=2019-01-25 | first = | last = }}</ref><ref name="fukuda1994"/><ref>[http://theargusreport.com/us-nih-report-calls-uk-definition-mecfs-scrapped/ US NIH Report Calls for UK Definition of ME/CFS to be Scrapped - The Argus Report By: Penny Swift]</ref><ref>{{Cite web | url = http://occupyme.net/2016/08/16/ahrq-evidence-review-changes-its-conclusions/|website=occupyme.net|access-date=2019-01-25 | title = AHRQ Evidence Review Changes Its Conclusions | date = Aug 16, 2016 | last = Spotila | first=Jennie | authorlink=Jennie Spotila | last2 = Dimmock | first2 = Mary | authorlink2 = Mary Dimmock|archive-url=|archive-date=}}</ref>

In the past, there have been media reports of athletes diagnosed with ME or CFS who have recovered in a relatively short period of time after rest, supplementation, and diet changes;<ref name="Inews2018">{{Cite news |url = https://inews.co.uk/news/health/marathon-runner-quit-work-me-cfs-diet-change/ | title = Marathon runner forced to quit work after developing ME claims diet change gave him his life back | first = Claudia | last = Tanner|publisher =iNews | date = 2018}}</ref><ref name="Times2017">{{Cite news | url = https://www.thetimes.co.uk/article/muslim-fighter-with-me-who-left-an-arranged-marriage-to-win-world-title-svxhhzt57 | title = Muslim fighter with ME who left an arranged marriage to win world | last = Broadbent | first = Rick | date = 2017-12-02|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref><ref name="ABC2018">{{Cite news |url = http://www.abc.net.au/7.30/committee-reviews-potentially-harmful-and-old/10010408 |at=6mins 18s| title = Committee reviews 'potentially harmful and old fashioned' chronic fatigue treatments|publisher =ABC News | first =Andy|last = Park | first2 = Clare | last2 = O'Halloran}}</ref><ref name="London2019">{{Cite news | url = https://www.thetimes.co.uk/article/nathan-douglas-london-2012-was-the-darkest-period-of-my-life-vxt5gftcx | title = Nathan Douglas: London 2012 was the darkest period of my life | last = Broadbent | first = Rick | date = 2019-02-27|work=The Times|access-date=2019-02-28|archive-url=|archive-date=|language=en|issn=0140-0460|quote=}}</ref> these athletes may have had [[overtraining syndrome]] (which has the symptom of [[chronic fatigue]]) and not ME or CFS,<ref name="spence"/> while people with adrenal failure, [[idiopathic chronic fatigue]] or other fatiguing illnesses may be erroneously diagnosed with CFS.<ref name="recovery"/><ref name="Anoop2012"/><ref name="ICC" /> ME and CFS in professional athletes is normally a career-ending diagnosis.<ref name="Squash" /><ref name="Annadale"/><ref name="Shattered"/><ref name="Olympian"/><ref name="FIFA"/><ref name="olaf"/><ref name="LA"/>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''What is ME/CFS'' By Open Medicine Foundation - OMF. Linda Tannenbaum, Founder & CEO/President, talks about ME/CFS and how OMF is leading research and delivering hope (2018)">https://www.youtube.com/watch?v=pqDubEeIBtA</embedvideo>

The core [[List of symptoms in ME CFS|ME/CFS symptoms]] are: [[post-exertional malaise]] (PEM); [[chronic fatigue]] (CF); [[unrefreshing sleep]]/[[Sleep dysfunction|sleep problems]]; and [[Cognitive dysfunction|cognitive impairment]]/[[brain fog]] and/or [[orthostatic intolerance]] (OI).<ref name="symptoms"/><ref name="clinicians">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness {{!}} Clinicians Guide | last = | first = | date = 2015 | publisher=Nation Academies Press|archive-url=|archive-date=|access-date= | authorlink = }}</ref>{{Rp|9-10}} A patient can have many more symptoms<ref name="what-is">{{Cite web | url = https://www.omf.ngo/what-is-mecfs/ | title = What is ME/CFS? | last = | first = | date = |archive-url=|archive-date=|access-date= | authorlink = |website=[[Open Medicine Foundation]]}}</ref> and meet different criteria. [[Systemic Exertion Intolerance Disease]] (SEID), an ME/CFS criterion, allows for a patient to be [[Systemic Exertion Intolerance Disease#Diagnostic criteria|diagnosed with the minimum core symptoms]]<ref name="DiagnosticAlgorithm">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg | title = Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - Diagnostic Algorithm | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190528223706/https://www.nap.edu/resource/19012/MECFS_DiagnosticAlgorithm.jpg|archive-date=2019-05-28|access-date=}}</ref> and the patient may have other symptoms.<ref name="clinicians"/<ref name="IOM2015">{{Cite web | url = https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf | title = Beyond Myalgid Encephalomyelitis/Chronic Fatigue Syndrome - Redefining an Illness - Clinician's Guide | date = 2015 | access-date=|website=nap.edu | last = | first = | authorlink = |archive-url=|archive-date= | page = 9}}</ref> The [[Canadian Consensus Criteria]] (CCC) requires the core symptoms and [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]], [[Neuroendocrine system|neuroendocrine]], [[immune system]], and [[myalgia]] symptoms to meet [[Canadian Consensus Criteria#Definition|its ME/CFS diagnostic criteria]].<ref name="Carruthers, 2003">{{Cite journal | last1 = Carruthers | first1 = Bruce M. | authorlink1 = Bruce Carruthers | last2 = Jain | first2 = Anil Kumar | authorlink2 = Anil Kumar Jain | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Peterson | first4 = Daniel L. | authorlink4 = Daniel Peterson | last5 = Klimas | first5 = Nancy G. | authorlink5 = Nancy Klimas | last6 = Lerner | first6 = A. Martin | authorlink6 = Martin Lerner | last7 = Bested | first7 = Alison C. | authorlink7 = Alison Bested | last8 = Flor-Henry | first8 = Pierre | authorlink8 = Pierre Flor-Henry | last9 =Joshi | first9 = Pradip | authorlink9 = Pradip Joshi | last10 = Powles | first10 = AC Peter | authorlink10 = A C Peter Powles | last11 = Sherkey | first11 = Jeffrey A. | authorlink11 = Jeffrey Sherkey | last12 = van de Sande | first12 = Marjorie I. | authorlink12 = Marjorie van de Sande | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols | journal = Journal of Chronic Fatigue Syndrome | volume = 11 | issue = 2 | pages = 7-115 | date = 2003 | pmid = | doi = 10.1300/J092v11n01_02
| url = http://phoenixrising.me/wp-content/uploads/Canadian-definition.pdf }}</ref> The [[International Consensus Criteria]] (ICC) is used to diagnose [[myalgic encephalomyelitis]] (ME) which requires the core symptoms and neurological, immune/[[Gastrointestinal system|gastrointestinal]]/genitourinary impairment, and [[portal:Energy metabolism|energy metabolism]]/[[Ion transportation|ion transport]] impairment [[International Consensus Criteria#Criteria|symptoms for a diagnosis]].<ref name="ICC">{{Cite journal | last = Carruthers | first=Bruce M. | author-link = Bruce Carruthers | last2 = van de Sande | first2 = Marjorie I. | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = Kenny L. | authorlink3 = Kenny De Meirleir | last4 = Klimas | first4 = Nancy G. | author-link4 = Nancy Klimas | last5 = Broderick | first5 = Gordon | author-link5 = Gordon Broderick | last6 = Mitchell | first6 = Terry | authorlink6 = Terry Mitchell | last7 = Staines | first7 = Donald | author-link7 = Donald Staines | last8 = Powles | first8 = A.C. Peter | authorlink8 = A C Peter Powles | last9 = Speight | first9 = Nigel | authorlink9 = Nigel Speight | last10 = Vallings | first10 = Rosamund | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = Lucinda | authorlink11 = Lucinda Bateman | last12 = Baumgarten-Austrheim | first12 = Barbara | author-link12 = Barbara Baumgarten-Austrheim | last13 = Bell | first13 = David | author-link13 = David Bell | last14 = Carlo-Stella | first14 = Nicoletta | author-link14 = Nicoletta Carlo-Stella | last15 = Chia | first15 = John | author-link15 = John Chia | last16 = Darragh | first16 = Austin | author-link16 = Austin Darragh | last17 = Jo | first17 = Daehyun | author-link17 = Daehyun Jo | last18 = Lewis | first18 = Donald | author-link18 = Donald Lewis | last19 = Light | first19 = Alan | author-link19 = Alan Light | last20 = Marshall-Gradisnik | first20 = Sonya | author-link20 = Sonya Marshall-Gradisnik | last21 = Mena | first21 = Ismael | author-link21 = Ismael Mena | last22 = Mikovits | first22 = Judy | author-link22 = Judy Mikovits | last23 = Miwa | first23 = Kunihisa | author-link23 = Kunihisa Miwa | last24 = Murovska | first24 = Modra | author-link24 = Modra Murovska | last25 = Pall | first25 = Martin | author-link25 = Martin Pall | last26 = Stevens | first26 = Staci | author-link26 = Staci Stevens | date = 2011-08-22 | title=Myalgic encephalomyelitis: International Consensus Criteria | url = https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2011.02428.x|journal=Journal of Internal Medicine|language=en|volume=270|issue=4|pages=327–338|doi=10.1111/j.1365-2796.2011.02428.x|issn=0954-6820|pmc=3427890|pmid=21777306|via=}}</ref>

The acronym ME/CFS is widely used in research, by clinicians, patient organizations, and patients.

"The most common overlapping condition with ME/CFS is [[fibromyalgia]]."<ref name="ICC2011primer">{{citation | last1 = Carruthers | first1 = BM | authorlink1 = Bruce Carruthers | last2 = van de Sande | first2 = MI | authorlink2 = Marjorie van de Sande | last3 = De Meirleir | first3 = KL | authorlink3 = Kenny de Meirleir | last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas | last5 = Broderick | first5 = G | authorlink5 = Gordon Broderick | last6 = Mitchell | first6 = T | authorlink6 = Terry Mitchell | last7 = Staines | first7 = D | authorlink7 = Donald Staines | last8 = Powles | first8 = ACP | authorlink8 = A C Peter Powles | last9 = Speight | first9 = N | authorlink9 = Nigel Speight | last10 = Vallings | first10 = R | authorlink10 = Rosamund Vallings | last11 = Bateman | first11 = L | authorlink11 = Lucinda Bateman | last12 = Bell | first12 = DS | authorlink12 = David Bell | last13 = Carlo-Stella | first13 = N | authorlink13 = Nicoletta Carlo-Stella | last14 = Chia | first14 = J | authorlink14 = John Chia | last15 = Darragh | first15 = A | authorlink15 = Austin Darragh | last16 = Gerken | first16 = A | authorlink16 = Anne Gerken | last17 = Jo | first17 = D | authorlink17 = Daehyun Jo | last18 = Lewis | first18 = DP | authorlink18 = Donald Lewis | last19 = Light | first19 = AR | authorlink19 = Alan Light | last20 = Light | first20 = KC | authorlink20 = Kathleen Light | last21 = Marshall-Gradisnik | first21 = S | authorlink21 = Sonya Marshall-Gradisnik | last22 = McLaren-Howard | first22 = J | authorlink22 = John McLaren-Howard | last23 = Mena | first23 = I | authorlink23 = Ismael Mena | last24 = Miwa | first24 = K | authorlink24 = Kunihisa Miwa | last25 = Murovska | first25 = M | authorlink25 = Modra Murovska | last26 = Stevens | first26 = SR | authorlink26 = Staci Stevens | title = Myalgic encephalomyelitis: Adult & Paediatric: International Consensus Primer for Medical Practitioners | date = 2012 | isbn = 978-0-9739335-3-6 | url = http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf}}</ref><ref name="Primer2014"/><ref name="Jason2001">{{Cite journal | last= Jason | first = Leonard | last2 = Taylor | first2 = R.R. | last3 = Kennedy | first3 = C.L. | last4 = Song | first4 = S | last5 = Johnson | first5 = D | last6 = Torres | first6 = S.R. | date = 2001-01-01 | title = Chronic fatigue syndrome: Comorbidity with fibromyalgia and psychiatric illness | url = https://www.researchgate.net/publication/285787383_Chronic_fatigue_syndrome_Comorbidity_with_fibromyalgia_and_psychiatric_illness|journal=Medicine and Psychiatry|volume=4 | pages = 29–34}}</ref> While some have posited ME/CFS and fibromyalgia are variants of the same illness, [[Benjamin Natelson]], MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiologic processes leading to different treatments.<ref>{{Cite journal | last = Natelson | first = Benjamin H. | date = 2019-02-19 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: Definitions, Similarities, and Differences | url = https://www.clinicaltherapeutics.com/article/S0149-2918(19)30003-7/abstract|journal=Clinical Therapeutics|language=English|volume=41|issue=4 | page = 612|doi=10.1016/j.clinthera.2018.12.016|issn=0149-2918|pmid=30795933}}</ref>

While ME/CFS is recognised as a physical disease by researchers, a [[Psychologization|psychiatric approach]] was taken with ME/CFS in the past, and some clinicians are still using this practice. At this time there are no approved drug treatments. In the past, [[Graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT) were used for ME/CFS. They are now discouraged or banned by major health guidelines as they were based on a psychological view of the illness and have lead to patient harm.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/ng206|title=Overview {{!}} Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management {{!}} Guidance {{!}} NICE|date=2021-10-29|website=www.nice.org.uk|access-date=2024-05-19}}</ref><ref name="etiology" />The [[Centers for Disease Control and Prevention]] (CDC) website states "ME/CFS is a '''biological illness''', not a psychologic disorder" and impacts multiple body systems.<ref name="etiology">{{Cite web | title = Etiology and Pathophysiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/etiology-pathophysiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08| access-date = 2019-01-22 |language=en-us}}</ref> The CDC recognizes the hallmark symptom of PEM which is a worsening of symptoms after physical, mental or emotional exertion<ref name="symptoms">{{Cite web | title = Symptoms of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-22|language=en-us}}</ref> and says [[ME/CFS]] is a "disabling and complex disease."<ref name="whatis">{{Cite web | url = https://www.cdc.gov/me-cfs/about/index.html | title = What is ME/CFS? {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2019-01-18 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-04-12}}</ref>

[[File:SEID algorithm.JPG|400px|thumb|right|Diagnostic Algorithm for [[Systemic Exertion Intolerance Disease|SEID]]'s minimum [[List of symptoms in ME CFS#Systemic Exertion Intolerance Disease (SEID) symptom list|ME/CFS core symptoms]]]]

==What do we know?==
ME is a debilitating illness that has been recognized as a neurological disease by the [[World Health Organization]] (WHO) since 1969.<ref name="icd10">{{Cite book | url = https://apps.who.int/iris/bitstream/handle/10665/70934/ICD_10_1969_eng_v2a.pdf?sequence=3&isAllowed=y | title = International Classification of Diseases | last = World Health Organization | first = |publisher=WHO| year = 1969|isbn=|editor-link=|edition=Eighth revision|volume=2|location=Geneva|pages=173|chapter=|quote=Encephalomyelitis (chronic), (myalgic, benign) 323|editor-last2=|editor-link2=}}</ref>

It is a systemic [[Neuro-immune disease|neuroimmune]] disease characterized by [[post-exertional malaise]] (PEM) (a severe worsening of symptoms after even minimal [[exertion]]). It causes dysregulation of both the [[immune system]] and the [[nervous system]]. The effects of ME are devastating enough to leave [[Severe and very severe ME|25% of patients housebound or bedbound]]. For moderate to severe patients, the disability of living with ME is like living with late-stage cancer, advanced stage AIDS, or congestive heart failure for decades.

[[ME/CFS]] costs the US economy up to $24 billion per year in direct medical costs, and lost production.<ref name="IOM2015MECFS" /> Despite this, funding for research is not commensurate with the level of disease burden. In the 2015 financial year, the [[National Institutes of Health]] (NIH) provided only $5 million in research funding for ME/CFS, which is less funding than hayfever. This is in stark contrast to funding levels for other similarly disabling illnesses, like [[multiple sclerosis]] ($105 million) and HIV/AIDS ($3 billion).{{Citation needed|reason=Reference needed for NIH funding levels | date = 4 November 2019}} The [[Institute of Medicine]], a special advisory committee of the [[U.S. Department of Health and Human Services]] (HHS) (ref: [[Chronic Fatigue Syndrome Advisory Committee|CFSAC]] recommendations) and [[NIH]] expert advisory panel agree that it is imperative to increase research funding into ME/CFS.<ref name="NIHP2PFIN" />

== Disease onset and course of illness==
[[Onset of ME/CFS|ME/CFS can begin]] from many acute/sudden<ref name="Chu2019">{{Cite journal | last = Chu | first = Lily | authorlink = Lily Chu | last2 = Valencia | first2 = Ian J. | authorlink2 = Ian Valencia | last3 = Garvert | first3 = Donn W. | authorlink3 = | last4 = Montoya | first4 = Jose G. | authorlink4 = Jose Montoya | authorlink5 = | date = Jan 14, 2019 | title = Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome | url = https://www.frontiersin.org/articles/10.3389/fped.2019.00012/abstract|journal=Frontiers in Pediatrics|volume=|issue=|pages=|doi=10.3389/fped.2019.00012|quote=|via=}}</ref> events: usually [[Viral onset hypothesis|viral]] or [[Bacterial disease onset|bacterial]] infections, but also [[trauma]], surgery or childbirth, [[anaphylaxis|allergic reaction]], and [[stress]].<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=[[Centers for Disease Control and Prevention]] | page = 6|archive-url=|archive-date=|access-date=}}</ref> There is also a gradual onset in some people,<ref name="Chu2019" /><ref name="clinical">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/index.html | title = Presentation and Clinical Course of ME/CFS {{!}} Information for Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS | date = 2018-12-12 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-02-07}}</ref> that is not attributed to any one event. Occasionally, ME/CFS has been triggered by [[Environmentally acquired illness|environmental toxins]] or the receipt of an [[Vaccine|immunizing injection]].<ref>[https://www.masscfids.org/images/pdf/Primer_2014.pdf Chronic Fatigue Syndrome Myalgic Encephalomyelitis - Primer for Clinical Practitioners - 2014 Edition - Massachusettes CFIDS/FM Assoc]</ref> Some say that the disease [[Myalgic encephalomyelitis|ME]] always has an acute/sudden [[Infection|infectious]] onset.<ref name="Evans2018">{{Cite journal | last = Evans | first = Meredyth | authorlink = Meredyth Evans | authorlink2 = Leonard Jason | date = 2018 | title = Onset patterns of chronic fatigue syndrome and myalgic encephalomyelitis | url = https://www.openaccessjournals.com/articles/Onset%20patterns%20of%20chronic%20fatigue%20syndrome%20and%20myalgic%20encephalomyelitis.pdf|journal=Research on Chronic Diseases|volume=|issue=|pages=2|quote=|via= | last2 = Jason | first2 = Leonard}}</ref>

The disease [[ME/CFS]] is often diagnosed when a person does not recover from a [[flu-like illness]], [[mononucleosis]] or another [[HHV|herpesvirus]], [[Q fever]], an unidentified [[virus]], or [[:Category:Infectious agents|other infection]], and meets one or more [[Definitions of myalgic encephalomyelitis and chronic fatigue syndrome|diagnostic criteria for either ME, CFS, or ME/CFS]].<ref name="IOM2015"/>{{Rp|157-158}}<ref>[http://www.cortjohnson.org/blog/2014/01/09/lipkin-study-vagus-nerve-hhv-6-loomis-hhv-6-foundation/ The Lipkin Study, The Vagus Nerve Infection Hypothesis and HHV-6: Kristin Loomis of the HHV-6 Foundation Talks – Pt. I - Health Rising - By: Cort Johnson - June 2014]</ref> Patients experience [[List of symptoms in ME CFS|numerous symptoms]] and disease severity which fluctuate from day to day, week to week, month to month, year to year, and even decade to decade. Furthermore, symptoms and disease severity vary among patients.<ref name="Primer2014"/><ref name="WebMD">[http://www.webmd.com/chronic-fatigue-syndrome/chronic-fatigue-syndrome-symptoms Chronic Fatigue Syndrome - Symptoms - Web MD]</ref>

The CDC recognizes that there can be different causes and it is possible that two or more things could cause the illness. Areas of research include infections, [[immune system]] changes, physical or psychological [[stress]] affecting body chemistry, changes in [[Metabolic|energy production]], and a possible [[Genetics of chronic fatigue syndrome|genetic link]].<ref name="causes">{{Cite web | title = Possible Causes {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/about/possible-causes.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-27|language=en-us}}</ref><ref name="etiology" /> The CDC notes there are abnormalities with the immune system, [[Metabolic|cellular metabolism]], neuroendocrine disturbances, and [[blood pressure]] or heart rate regulation.<ref name="etiology" />
===Not a mental health disorder===
In the past, CFS was believed to be a mental health disorder. This is why the CDC now states: "ME/CFS is a biological illness, not a psychologic disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have multiple pathophysiological changes that affect multiple systems."<ref name="etiology" />

===No clear evidence that ME/CFS is contagious===
[[:Category:Infectious agents|Infectious episodes]] have led to [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreaks]] over the years and 72% of ME/CFS patients report an [[Onset of ME/CFS|onset]] of a viral or bacterial infection.<ref>{{Cite web | url = https://www.cdc.gov/grand-rounds/pp/2016/20160216-presentation-chronic-fatigue-H.pdf | title = CDC Public Health Grand Rounds - Chronic Fatigue Syndrome - Advancing Research and Clinical Education | last = | first = | author-link =| date = |website=cdc.gov | page = 6|archive-url=|archive-date=|access-date=}}</ref> Nowadays, the vast majority of ME/CFS cases are sporadic rather than epidemic - although some outbreaks have been caused by known viruses such as the [[2003 Hong Kong outbreak|SARS pandemic]] and [[2019 Coronavirus pandemic outbreak|COVID-19]] - there is no clear evidence that sporadic ME/CFS cases are contagious.<ref name="pediatricprimer">{{Cite journal | last = Rowe | first = Katherine S. | last2 = Vallings | first2 = Rosamund | last3 = Stewart | first3 = Julian M. | last4 = Speight | first4 = Nigel | last5 = Schwartz | first5 = Malcolm S. | last6 = Medow | first6 = Marvin S. | last7 = Gurwitt | first7 = Alan | last8 = Friedman | first8 = Kenneth J. | last9 = Underhill | first9 = Rosemary A. | date = 2017 | title = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref>

Families, partners, and friends do not report contracting ME/CFS from someone with the disease nor do patients report passing it on to others.<ref>{{Cite web | url = http://forums.prohealth.com/forums/index.php?threads/is-cfs-contagious.189664/ | title = Is CFS contagious? |website = ProHealth Forums|access-date=2019-02-13}}</ref> However, [[Rosemary Underhill|Underhill]] and O'Gorman (2006) researched 219 patients with ME/CFS, and concluded that close household contact and genetics were both risk factors for CFS, finding 3.2% of spouses/partners of those with CFS also had the illness.<ref name="UnderhillInfectious">{{Cite journal | last = Underhill | first = Rosemary A. | last2 = O'Gorman | first2 = Ruth | date = 2006-01-01 | title = Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families of CFS Patients | url = https://doi.org/10.1300/J092v13n01_02|journal=Journal of Chronic Fatigue Syndrome|volume=13|issue=1|pages=3–13|doi=10.1300/J092v13n01_02|issn=1057-3321}}</ref> This was a higher prevalence than all genetic relatives except children of patients. Because ME/CFS can run in families, a [[Genetics of chronic fatigue syndrome|genetic link]] is a line of research recommended by the CDC.<ref name="causes" /> 

[[Michael Sikora]] and collaborators at the [[Open Medicine Foundation]] hope that their research on the role of [[T cell]]s and immune-related [[Genetics of chronic fatigue syndrome|genes]] will help address "whether ME/CFS is an autoimmune or infectious disease, or simply an activation of the immune system".<ref name="omf-funded">{{Cite web | url = https://www.omf.ngo/2018/06/04/omf-funded-research/ | title = OMF funded research | date = Jun 4, 2018 | website = [[Open Medicine Foundation]]}}</ref>

====Blood donation and organ transplant====
A [[Blood donation|tissue and blood donation]] ban is in force for ME/CFS in the [[United Kingdom]] (even if recovered),<ref name="BloodUK">{{Cite web | url = https://my.blood.co.uk/KnowledgeBase | title = Knowledgebase|website=My Donor Record - Health, Eligibility & Travel | last = | first = | authorlink = |archive-url=|archive-date=|url-status=|access-date=2021-10-08}}</ref> [[Australia]],<ref name="donate">{{Cite web|url = https://www.donateblood.com.au/faq/chronic-fatigue-syndrome |title=Chronic fatigue syndrome – I have/had chronic fatigue syndrome. Can I donate?|access-date=2022-05-25|website = Australian Red Cross}}</ref> [[New Zealand]],<ref name="NZBlood">{{Cite web |url = https://www.nzblood.co.nz/become-a-donor/am-i-eligible/detailed-eligibility-criteria/ | title = Detailed Eligibility Criteria|access-date=2022-05-25 | date = |website=NZ Blood|quote=}}</ref> most of [[Canada]],<ref name="Wilson2014">{{Cite journal | title = The Use of Preliminary Scientific Evidence in Public Health: A Case Study of XMRV | date = 2014-04-08 | url = https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001623|journal=PLOS Medicine|volume=11|issue=4| pages = e1001623 | last = Wilson | first = Kumanan | last2 = Atkinson | first2 = Katherine | last3 = Keelan | first3 = Jennifer|language=en|doi=10.1371/journal.pmed.1001623|pmc=PMC3979645|pmid=24714396|issn=1549-1676}}</ref> and for a time also in the [[United States]],<ref name="post">{{Cite web | url = http://voices.washingtonpost.com/checkup/2010/12/red_cross_bars_chronic_fatique.html | title = Red Cross bars chronic fatigue patients from donating blood | last = Stein | first = Rob | authorlink = | date = Dec 3, 2010 | website = Washington Post|archive-url=|archive-date=|access-date=2022-05-25}}</ref> initially due to the research on [[Xenotropic murine leukemia virus-related virus|XMRV]] as being the likely infectious trigger of CFS<ref>{{Cite web | url = https://www.meassociation.org.uk/2010/04/xmrv-testing-in-the-uk/ | title = XMRV testing in the UK | last = | first = | author-link =| date = 2010 | website = [[ME Association]]|language=en-US|archive-url=|archive-date=|access-date=2019-02-13}}</ref> and showing that patients carried the virus.<ref name="post" /> Two papers on XMRV were retracted as the result was caused by laboratory contamination,<ref name="Redaction2012">{{Cite journal | date = Dec 2012 | title = Redaction, retraction and reaction | url = https://www.nature.com/articles/nrmicro2928|journal=Nature Reviews Microbiology|language=en|volume=10|issue=12 | pages = 799|doi=10.1038/nrmicro2928|issn=1740-1534}}</ref><ref name="transfusion">{{Cite web | url = https://transfusionnews.com/2012/10/05/multicenter-study-finds-no-correlation-between-chronic-fatigue-syndrome-and-xmrv/ | title = Multicenter Study Finds No Correlation between Chronic Fatigue Syndrome and XMRV|website=transfusionnews.com|access-date=2019-02-13}}</ref> but many blood donation bans remain.<ref name="Wilson2014"/>

The US American Red Cross no longer has statements barring transfusions or transplants for CFS,<ref name="redcross">{{Cite web | url = https://www.redcrossblood.org/faq.html#eligibility-health|access-date=2019-02-13 | title = Frequently Asked Questions | date = | last = | first = | authorlink = |archive-url=|archive-date=|website=American Red Cross|quote=Your search for "Chronic fatigue syndrome" returned no results.}}</ref> but patients are expected to be in "good health" which would exclude most.<ref name="redcross"/> The American Association of Blood Banks advises to either accept or defer ME/CFS donors based on "clinical judgment of the donor's health status".<ref name="AABBOct2012">{{Cite web | last = American Association of Blood Banks | url = https://www.aabb.org/docs/default-source/default-document-library/regulatory/eid/xmrvfactsheet.pdf?sfvrsn=cd162fa3_2 | date = October 2012 | title = Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and other Polytropic Murine Leukemia Viruses (pMLV)|pages = 3 |quote=An updated AABB Association Bulletin #12-05 (November 2012) states that individual collectors of blood and cellular therapy products should accept or defer donors with a history of CFS based on their clinical judgment of the donor's health status.|access-date=2022-05-25}}</ref> Patient charities discourage ME/CFS patients from donating blood,<ref name="MassBlood2015">{{Cite web | url = https://www.massmecfs.org/research/recent-research/19-xmrv/237-aabbs-recommendation-on-cfidsme-and-blood-donation | title = AABB's recommendation on ME/CFS and blood donation | date = Nov 25, 2015 |website=[[Massachusetts ME/CFS & FM Association]]|access-date=2022-05-25}}</ref>

== Mini-Docs ==
<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Jen Brea/TED (2016)">https://www.youtube.com/watch?v=Fb3yp4uJhq0</embedvideo>
[[What happens when you have a disease doctors can't diagnose - TED Talk (2016)|''What happens when you have a disease doctors can't diagnose'']] By [[Jennifer Brea|Jen Brea]]/TED

Five years ago, TED Fellow Jen Brea became progressively ill with myalgic encephalomyelitis, commonly known as chronic fatigue syndrome, a debilitating illness that severely impairs normal activities and on bad days makes even the rustling of bed sheets unbearable. In this poignant talk, Brea describes the obstacles she's encountered in seeking treatment for her illness, whose root causes and physical effects we don't fully understand, as well as her mission to document through film the lives of patients that medicine struggles to treat.<ref>{{Cite web | url = https://www.youtube.com/watch?v=Fb3yp4uJhq0 | title = What happens when you have a disease doctors can't diagnose | date = Jan 17, 2017|access-date=|website=YouTube | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=|publisher=TED}}</ref><ref>{{Cite web | url = https://www.ted.com/talks/jen_brea_what_happens_when_you_have_a_disease_doctors_can_t_diagnose | title = What happens when you have a disease doctors can't diagnose | date = Jun 2016|access-date=|website=TED | last = Brea | first=Jennifer | authorlink=Jennifer Brea|archive-url=|archive-date=}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Veronica Weber/Palo Alto Online (2015)">https://www.youtube.com/watch?v=9_HwOUiImvw</embedvideo>

[[Invisible Illness - Stories of Chronic Fatigue Syndrome|''Invisible Illness - Stories of Chronic Fatigue Syndrome'']] By Veronica Weber/Palo Alto Online

This mini documentary reveals 3 stories of people who have been impacted by [[Chronic Fatigue Syndrome]] - a little known disease that affects roughly 836,000-2.5 million people in the U.S. and receives little research funding. They share emotions of treating loved ones with the disease, their frustrations of being ignored by members of society and the healthcare industry and express hopes of treatment and research. Video by Veronica Weber/Palo Alto Online<ref>{{Cite web | url = https://www.youtube.com/watch?v=9_HwOUiImvw | title = Invisible Illness - Stories of Chronic Fatigue Syndrome | date = Jul 10, 2015 |access-date=|website=YouTube | last = Weber | first = Veronica | authorlink=|archive-url=|archive-date=|publisher=Palo Alto Online}}</ref>

<embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="By Dr. David Kaufman/Unrest (2018)">https://www.youtube.com/watch?v=RC9TjgE_PlU</embedvideo>

''Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome'' By Dr. [[David Kaufman]]/[[Unrest|''Unrest'']]

This video on the diagnosis and management of myalgic encephalomyelitis and chronic fatigue syndrome is '''part of the Unrest Continuing Education module''', made available through the American Medical Women’s Association and Indiana University School of Medicine, and in partnership with #MEAction. US medical providers can visit: https://www.unrest.film/cme to register to watch [[Unrest]] online for free and receive Continuing Education credit.<ref>{{Cite web | url = https://www.youtube.com/watch?v=RC9TjgE_PlU | title = Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome | date = Oct 16, 2018|access-date=|website=YouTube | last = | first = | authorlink = David Kaufman|archive-url=|archive-date=|publisher=Unrest Film}}</ref>

==Epidemiology ==
In the [[United States]], 836,000 - 2.5 million people suffer from ME/CFS. "The total economic costs of ME/CFS are estimated at $17 to $24 billion annually."<ref name="clinicians" /> Some CFS patients can work with [https://www.dol.gov/general/topic/disability/jobaccommodations job accommodations] but 1/3 to 1/2 become unemployed and [[Disability|many rely on SSDI/SSI]].<ref>[https://www.masscfids.org/job-accommodations Job Accommodations - MASS CFIDS]</ref>
*[[Epidemiology of myalgic encephalomyelitis and chronic fatigue syndrome|Epidemiology]]
:All races and cultures are afflicted with ME/CFS.<ref>[http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-91 Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care - July 2011]</ref><ref name="epidemiology">{{Cite web | title = Epidemiology {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/epidemiology.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-29|language=en-us}}</ref> Children and adolescents are also diagnosed.<ref>{{Cite web | title = ME/CFS in Children {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/me-cfs-children/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-01-29|language=en-us}}</ref><ref>{{Cite web | title = Pediatric ME/CFS Home Page | url = https://www.massmecfs.org/pediatric-me-cfs-home-page|website=massmecfs.org|access-date=2019-01-29}}</ref>
*[[Female predominant diseases]]
:Like many [[Autoimmune disease|autoimmune]] and [[Neuro-immune disease|neuro-immune]] diseases where mostly women are afflicted,<ref>[http://www.rightdiagnosis.com/artic/fact_sheet_autoimmune_disease_in_women_nwhic.htm Fact Sheet Autoimmune Disease in Women: NWHIC - Right Diagnosis - Aug 2015]</ref> the ME/CFS female/male patient ratio per Capelli et al. is 6:1<ref>{{Cite journal | title = Chronic fatigue syndrome/myalgic encephalomyelitis: an update | url = https://www.ncbi.nlm.nih.gov/pubmed/21244747|journal=International Journal of Immunopathology and Pharmacology | date = Oct 2010|issn=0394-6320|pmid=21244747 | pages = 981–989|volume=23|issue=4|doi=10.1177/039463201002300402 | first = E. | last=Capelli | first2 = R. | last2 = Zola | first3 = L. | last3 = Lorusso | first4 = L. | last4 = Venturini | first5 = F. | last5 = Sardi | first6 = G. | last6 = Ricevuti}}</ref> while the CDC states 4:1.<ref name="epidemiology"/>
*[[Pediatric myalgic encephalomyelitis and chronic fatigue syndrome|Pediatric]]
:Pediatric ME/CFS is defined by the CDC<ref>{{Cite web | url = https://www.cdc.gov/me-cfs/me-cfs-children/factsheet-healthcare-professional.html | title = Pediatric ME/CFS: Fact Sheet for Healthcare Professionals {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2017-10-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-10-13}}</ref> and the [[National Academy of Medicine]] (NAM)<ref name="IOM2015"/>{{Rp|181}} although it is usually diagnosed in adults.<ref name="whatis"/> "Children below the age of 8 or 9 do not have the symptom pattern of adolescents past puberty. If the onset of the disease occurs during adolescence, the most common time of onset, the pattern is similar to that of adults."<ref>{{Cite web | url = https://www.omf.ngo/2016/06/25/mecfs-in-children-by-dr-david-s-bell-2/ | title = ME/CFS in Children - by David S. Bell, MD | date = 2016-06-25|publisher=[[Open Medicine Foundation]]|access-date=2018-08-11|language=en-US | last = Bell | first = David | authorlink = David Bell}}</ref> The prognosis in adolescents is considered to be better than in adults.<ref name="prognosis">{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/presentation-clinical-course/prognosis.html | title = Prognosis {{!}} Presentation and Clinical Course {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | date = 2018-11-08 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2019-01-31}}</ref><ref>{{Cite journal | last = Rowe | first = Peter C. | last2 = Underhill | first2 = Rosemary A. | last3 = Friedman | first3 = Kenneth J. | last4 = Gurwitt | first4 = Alan | last5 = Medow | first5 = Marvin S. | last6 = Schwartz | first6 = Malcolm S. | last7 = Speight | first7 = Nigel | last8 = Stewart | first8 = Julian M. | last9 = Vallings | first9 = Rosamund | date = 2017 | title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer |url = https://www.frontiersin.org/articles/10.3389/fped.2017.00121/full|journal=Frontiers in Pediatrics|language=English|volume=5|doi=10.3389/fped.2017.00121|issn=2296-2360}}</ref> Children are diagnosed with ME/CFS at three months of illness under SEID and CCC and ME is diagnosed immediately under ICC.<ref>{{Cite web | url = https://www.masscfids.org/pediatric-me-cfs-links | title = Pediatric ME/CFS links|website=[[Massachusetts ME/CFS & FM Association]]|language=en-GB|access-date=2018-08-11}}</ref><ref name="clinicians" /><ref name="Carruthers, 2003" /><ref name="ICC" />
*[[Prevalence of myalgic encephalomyelitis and chronic fatigue syndrome|Prevalence]]
:"Worldwide, there may be as many as 17 – 24 million people with ME/CFS."<ref>{{Cite web | url = https://ammes.org/how-many-people-have-mecfs/ | title = How Many People Have ME/CFS?|website = [[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|access-date=2019-01-31}}</ref> 25% of ME/CFS patients are [[Severe and very severe ME|housebound or bedbound]] at some point in their illness.<ref name="keyfacts">{{Cite web | url = https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf | title = Myalgic Encelphalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Key Facts | last = | first = | author-link =| date = 2015 | website = nap.edu|archive-url=https://web.archive.org/web/20190327085836/https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf|archive-date=2019-03-27|url-status=dead|access-date=}}</ref><ref name="IOM2015"/>{{Rp|32}} 90% of patients are undiagnosed.<ref name="whatis"/>
*[[Prognosis for myalgic encephalomyelitis and chronic fatigue syndrome|Prognosis]]
:The prognosis for a patient diagnosed with ME/CFS is considered to be poor with only a minority (a median estimate of 5%) returning to pre-morbid levels of functioning.<ref name="Cairns2005">{{Cite journal | last = Cairns | first = R. | author-link = | last2 = Hotopf | first2 = M. | authorlink2 = Matthew Hotopf | date = Jan 2005 | title = A systematic review describing the prognosis of chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/15699087|journal=Occupational Medicine (Oxford, England)|volume=55|issue=1|pages=20–31|doi=10.1093/occmed/kqi013|issn=0962-7480|pmid=15699087|quote=|via=}}</ref> The majority of patients remains significantly impaired. A substantial improvement however is noted in an estimated 40% of patients.<ref name="Cairns2005" /><ref name="Joyce1997">{{Cite journal | last= Joyce | first = J. | last2 = Hotopf | first2 = M. | last3 = Wessely | first3 = S. | date = Mar 1997 | title = The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review | url = https://www.ncbi.nlm.nih.gov/pubmed/9093600|journal=QJM: monthly journal of the Association of Physicians|volume=90|issue=3|pages=223–233|issn=1460-2725|pmid=9093600}}</ref>

==ME vs CFS vs CF==

The name myalgic encephalomyelitis (ME) was coined following an [[Epidemic myalgic encephalomyelitis|outbreak]] of an illness at the [[1955 Royal Free Hospital outbreak|Royal Free Hospital]] in the UK, in 1955. The name chronic fatigue syndrome (CFS) was coined by the [[Centers for Disease Control and Prevention]] (CDC) following an [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|outbreak]] of a [[flu-like illness]] at [[1984 Incline Village chronic fatigue syndrome outbreak|Incline Village]], at Lake Tahoe, in the 1980s. There is disagreement as to whether ME and CFS are the same disease, entirely separate illnesses, or whether ME constitutes a more severe subset of CFS. Adding to the confusion, the diagnostic name given to patients is more often dependent on the country in which they live, than differing characteristics of their illness, as some countries use CFS (eg: US, [[Australia]]), and other countries (particularly in Europe) use ME. At this point in time, there is no clear biological evidence to resolve whether the illnesses are the same or different, and there is unlikely to be a resolution until firm [[diagnostic biomarker|biomarkers]] have been identified. As such, many patients and researchers use the term ME/CFS.<ref name="Klimas20140621video" /> See: [[Definitions of ME and CFS]].

The name Chronic Fatigue Syndrome is itself controversial, as many consider it [[stigma and discrimination|stigmatizing]]. In February 2016, Dr [[Anthony Komaroff]], who was part of the CDC group of clinicians who coined the name Chronic Fatigue Syndrome, said of it:
<blockquote>"I think that was a big mistake because the name, in my opinion, and the opinion of a lot of people, it both trivializes and stigmatizes the illness. It makes it seem unimportant, maybe not even real"<ref name="Komaroff20160217video" /></blockquote>

It is important to distinguish between ME/CFS and chronic fatigue (CF), which is a symptom of many different medical conditions (e.g.: anemia, [[hepatitis]], [[multiple sclerosis]], [[Thyroid disease|hypothyroidism]], [[depression]], ME/CFS). "Chronic fatigue" is not an illness in its own right and it is incorrect and misleading to refer to ME/CFS as "chronic fatigue". While [[fatigue]] is a component of ME/CFS, many consider [[post-exertional malaise]] (PEM) to be the cardinal feature of ME/CFS.<ref name="Carruthers, 2003" /><ref name="IOM2015MECFS" />

==Evidence of a disease==

=== Symptoms ===
[[List of symptoms in ME CFS|Symptom presentation varies enormously]] between individuals. Symptom presentation also varies within individuals, as individuals often report that symptoms change over time (increasing or decreasing) and new symptoms may appear while others disappear.<ref>{{Cite web | title = Symptoms and Diagnosis of ME/CFS {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/symptoms-diagnosis/index.html|website=[[Centers for Disease Control and Prevention]] | date = 2019-01-18|access-date=2019-02-01|language=en-us}}</ref> There are many symptoms which people with ME/CFS experience, though those listed below are the core symptoms found in all patients.

[[File:Cfs woman sketch.jpg|435x435px|thumb|[[Post-exertional malaise]] (PEM) is a [[List of symptoms in ME CFS|''worsening'' of ME/CFS symptoms]] after minimal [[Exertion#Exertion in ME.2FCFS|physical, mental or emotional exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]], [[brain fog]]/[[cognitive dysfunction]], and [[word-finding problems]], [[unrefreshing sleep]], [[headache]]s and [[migraine]]s, [[chronic pain]], [[Myalgia|muscle pain]] and [[muscle fatigability]], [[orthostatic intolerance]], [[neurally mediated hypotension]], or [[Postural orthostatic tachycardia syndrome|POTS]] and more. The [[Delayed onset of post-exertional symptoms|onset of PEM can be delayed 24-72 hours]] and depending on ME/CFS severity can last days, weeks, or even months]]

[[File:Rosa SEID.JPG|400px|thumb|left|Rosa age 25 in 1986 and mildly ill with [[Systemic Exertion Intolerance Disease#Diagnostic criteria|ME/CFS's core symptoms]]. In 2015 the [[SEID]] criteria were released. Rosa read about [[Post-exertional malaise|PEM]] and how it is delayed and makes [[List of symptoms in ME CFS|ME/CFS symptoms]] like [[Chronic fatigue|CF]], [[Orthostatic intolerance|OI]], and [[Cognitive dysfunction|cognition]] worse. Her life since [[Pediatric myalgic encephalomyelitis/chronic fatigue syndrome|age 17]] fell into place as she never connected her worsening symptoms with increased [[Exertion#Exertion in ME.2FCFS|physical or mental activity]] 24-72 hours prior. She believes not understanding PEM made her illness worsen over the years and is now disabled meeting the [[Canadian Consensus Criteria|CCC]] with PEM.]]

[[File:Brian vastag.png|thumb|left|[[Brian Vastag]] is an American and award-winning journalist and an ME/CFS patient that won a disability case against Prudential, proving that PEM is a severe symptom that keeps him from gainful employment]]

[[File:PEM1.JPG|300px|thumb|right|I think [https://twitter.com/hashtag/twofacesofme?f=tweets&vertical=default&src=hash #TwoFacesofME] is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #[[ME/CFS|MEcfs]] research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.<ref>{{Cite web | url = https://twitter.com/JackCroxall/status/1085900441328803840 | title = I think #TwoFacesofME is a really important hashtag. We’re only out and about at our best, and our (more frequent) worst often remains hidden. I’m convinced it’s why #MEcfs research funding is so low - the problem isn’t visible enough. I’m seriously ill in both these photos.pic.twitter.com/hNjK5140kv | last = Croxall | first = Jack | date = 2019-01-17 | website = @JackCroxall|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM4.JPG|300px|thumb|right|First photo, me in my [[Severe and very severe ME|wheelchair on a rare trip out]]. Second photo, the inevitable crash. Eye half closed, [[Speech difficulties|slurred speech]], [[Dizziness|dizzy]], weak, etc. #TwoFacesofME<ref>{{Cite web | url = https://twitter.com/hopeforMEyet/status/1085909800766980096 | title = First photo, me in my wheelchair on a rare trip out. Second photo, the inevitable crash. Eye half closed, slurred speech, dizzy, weak, etc. #TwoFacesofMEpic.twitter.com/P2OPnnpQvF | last = Karen | date = 2019-01-17 | website = @hopeforMEyet|language=en|access-date=2019-01-17}}</ref>]]

[[File:PEM5.JPG|300px|thumb|right|#TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not [[Severe and very severe ME|severely ill]], and my life is ok, even [so] I wish that one day science will help me & all the #MeCfs sufferers around the globe.<ref>{{Cite web | title = #TwoFacesofME First photo from the morning, the other one from the afternoon ( when I failed to nap 30-60 minutes). I am Not severely ill, and my life is ok, even do I wish that one day science will help me & all the #MeCfs sufferers around the globe.pic.twitter.com/wmhfHcfP0p | url = https://twitter.com/Authorportrait/status/1085815918846832640 | website = @Authorportrait | date = 2019-01-17|access-date=2019-01-17|language=en | first = Henry | last = Köhler}}</ref>]]

*[[Post-exertional malaise]] (PEM) is the hallmark symptom of ME/CFS. After physical, mental or emotional [[exertion]] (which for some patients can be a shower or making out a to-do list, others grocery shopping, socializing or reading a news article, while some just walking to the mailbox, getting to the doctor or mentally following a T.V. program)<ref name="what-is" /><ref name="symptoms"/><ref name="Cairns2005" /> there is a payback of significant '''worsening''' [[List of symptoms in ME CFS|ME/CFS symptoms]] which can be [[Delayed onset of post-exertional symptoms|delayed for 24-72 hours or more]]<ref name="symptoms"/><ref name="Lindheimer2017">{{Cite journal | last = Lindheimer | first=Jacob B. | last2 = Meyer | first2 = Jacob D. | last3 = Stegner | first3 = Aaron J. | last4 = Dougherty | first4 = Ryan J. | last5 = Van Riper | first5 = Stephanie M. | last6 = Shields | first6 = Morgan | last7 = Reisner | first7 = Amanda | last8 = Shukla | first8 = Sanjay K. | last9 = Light | first9 = Alan R. | date = 2017-04-03 | title = Symptom variability following acute exercise in myalgic encephalomyelitis/chronic fatigue syndrome: a perspective on measuring post-exertion malaise | url = https://www.tandfonline.com/doi/full/10.1080/21641846.2017.1321166|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=5|issue=2 | pages = 69–88|doi=10.1080/21641846.2017.1321166|issn=2164-1846}}</ref><ref name="Yoshiuchi2007">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Cook | first2 = Dane B. | last3 = Ohashi | first3 = Kyoko | last4 = Kumano | first4 = Hiroaki | last5 = Kuboki | first5 = Tomifusa | last6 = Yamamoto | first6 = Yoshiharu | last7 = Natelson | first7 = Benjamin H. | date = 2007-12-05 | title = A real-time assessment of the effect of exercise in chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/17655887|journal=Physiology & Behavior|volume=92|issue=5 | pages = 963–968|doi=10.1016/j.physbeh.2007.07.001|issn=0031-9384|pmc=2170105|pmid=17655887}}</ref> and can last 24 hours and even days, weeks, or months.<ref name="VanNess2010">{{Cite journal | last = VanNess | first=J. Mark | last2 = Stevens | first2 = Staci R. | last3 = Bateman | first3 = Lucinda | last4 = Stiles | first4 = Travis L. | last5 = Snell | first5 = Christopher R. | date = Feb 2010 | title = Postexertional malaise in women with chronic fatigue syndrome | url = https://www.ncbi.nlm.nih.gov/pubmed/20095909|journal=Journal of Women's Health (2002)|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref><ref>[https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm368806.pdf The Voice of the Patient.] A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative. September 2013</ref> The patient will experience even greater fatigue as well as exasperate the [[flu-like symptoms]] and body [[pain]]. Every patient experiences different symptoms and symptom severity from different activities and exertion output according to how sick he or she is with the disease.<ref name="prognosis" /><ref name="what-is" /><ref name="Cairns2005" /> Regarding PEM the [[CFIDS Association of America]] states:
<blockquote>This is a term which describes a symptom in which exercise or exertion can bring on [[malaise]] (illness). In the case of people with ME/CFS, malaise often occurs during a period some 24-72 hours after exertion. For example, in some cases, a short walk can worsen ME/CFS symptoms two days later. This lack of understanding about the delayed onset of symptoms has, in the past, made it harder to test for ME/CFS. Follow up tests, taken less than 24 hours after an initial exercise test, may show that the patient can still perform activities at the same level (before post exertional malaise has a chance to take hold).<ref>[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html What Health - International CFS/ME Awareness Day 2017 - CFIDS Association of America]</ref></blockquote>
*[[chronic fatigue]]
*[[cognitive dysfunction]]

*[[orthostatic intolerance]] (OI) such as [[postural orthostatic tachycardia syndrome]] (POTS) or [[neurally mediated hypotension]] (NMH)
*[[unrefreshing sleep]]/[[sleep dysfunction|sleep disturbance]] <ref name="DiagnosticAlgorithm" /><ref name="clinicians" />
==== Other possible symptoms ====
*[[chronic pain]]
*[[immune system]]
*[[:Category:Neurological signs and symptoms|neurological signs and symptoms]] See also: [[neuroinflammation]].
*[[List of symptoms in ME CFS|List of symptoms in ME/CFS]]

=== Comorbids ===
*[[fibromyalgia]] (FMS)
*[[irritable bowel syndrome]] (IBS)
*[[multiple chemical sensitivity]] (MCS)
*[[temporomandibular joint disorder]] (TMJ) <ref>[http://solvecfs.org/what-is-mecfs/ What is ME/CFS? - Solve ME/CFS Initiative]</ref>

=== Government guides on symptoms ===
'''US Government guides on symptoms'''
*[https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf Clinicians Guide] via The [[Institute of Medicine report]] (IOM)
*[https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html CDC - ME/CFS Symptoms]

'''Canada guides on symptoms'''
*[http://linkis.com/org/tUheh Alberta Clinicians Guide]

===Biological abnormalities===
Because there is currently no biomedical test for ME/CFS, many have incorrectly assumed that there are no medical abnormalities found in people with the illness. As a result, ME/CFS symptoms are often considered to be [[Medically unexplained physical symptoms|medically unexplained]], and therefore [[Psychologization|psychological]] in origin. While it is true that the illness is poorly understood, many biological abnormalities have been found in a range of different body systems, particularly in the [[central nervous system]], [[autonomic nervous system]], [[immune system]], and [[Metabolic|energy metabolism]].<ref name="IOM2015MECFS" /> Unfortunately, none have yet proved to be specific enough to ME/CFS as to be useful as a [[Diagnostic biomarker|biomarker]] of the disease, and many were identified in small studies, which need replication. Whilst there have been [[List of abnormal findings in chronic fatigue syndrome and myalgic encephalomyelitis|many abnormalities identified]] found to be associated with the disease, it cannot yet be determined whether these are a cause or consequence.
* [[Gastrointestinal system]]
* [[Natural killer cell]]

==== Notable studies ====
* [[Cytokine#Notable_studies|Cytokine ("Notable studies")]]
*Immune findings by [[Mady Hornig]] & [[Ian Lipkin]]<ref name="Hornig20150201immune" />
*[[List of enterovirus infection studies]]

*2014, [[Neuroinflammation]] Japanese Neuroinflammation study<ref name="NakatomiY2014" />
*2015, Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology<ref name="stanfordleptin">{{Cite journal | last1 = Stringer | first1 = EA | last2 = Baker | first2 = KS | last3 = Carrol | first3 = IR | last4 = Montoya | first4 = JG | authorlink4 = Jose Montoya | last5 = Chu | first5 = L | authorlink5 = Lily Chu | last6 = Maeker | first6 = HT | last7 = Younger | first7 = JW | authorlink7 = Jarred Younger| title = Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology | journal = J Transl Med.| date = Apr 9, 2013 | pmid = 23570606 | pmc = 3637529 | doi = 10.1186/1479-5876-11-93| url = http://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 }}</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 (Full text)]
::Younger's Leptin study
*2014, Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome<ref name="Zeineh2014">{{Cite journal | last = Zeineh | first = Michael M. | author-link = Michael Zeineh | last2 = Kang | first2 = James | last3 = Atlas | first3 = Scott W. | last4 = Raman | first4 = Mira M. | last5 = Reiss | first5 = Allan L. | last6 = Norris | first6 = Jane L. | last7 = Valencia | first7 = Ian | last8 = Montoya | first8 = Jose G. | date = 2014-10-29 | title = Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome | url = https://pubs.rsna.org/doi/10.1148/radiol.14141079|journal=Radiology|volume=274|issue=2 | pages = 517–526|doi=10.1148/radiol.14141079|issn=0033-8419}}</ref>
<blockquote>Bilateral [[white matter]] atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a [[Diagnostic biomarker|biomarker]] for CFS.</blockquote>
:*2014, [[Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder - New York Times: Well (2014)|Brains of People With Chronic Fatigue Syndrome Offer Clues About Disorder By David Tuller - New York Times: Well]]
[[File:ME-CFS Brain Images.jpg|500px|thumb|center|Top scans: Healthy control patient; Bottom scans: chronic fatigue syndrome (CFS) patient. Image By: [[Michael Zeineh]]]]
*2016, [[Metabolic features of chronic fatigue syndrome]]

*2019, [[Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy (2019) Mueller, et al|Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy]]<ref name="Mueller2019">{{Cite journal | url = https://link.springer.com/epdf/10.1007/s11682-018-0029-4 | title = Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy | last = Mueller | first = Christina | authorlink= | last2 = Lin | first2 = Joanne | authorlink2 = | date = 2019 | journal=Brain Imaging and Behavior|volume=14|issue= | pages = 562–572|doi=10.1007/s11682-018-0029-4|archive-url=|archive-date=|access-date=2019-01-17 | last3 = Sheriff | first3 =Sulaiman | authorlink3 = | last4 = Maudsley | first4 = Andrew | authorlink4 = | last5 = Younger | first5 = Jarred | authorlink5 = Jarred Younger}}</ref>
**2018, [https://www.youtube.com/watch?v=rxdzaWD5wfU ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study]<ref>{{Cite web | url = https://www.youtube.com/watch?v=rxdzaWD5wfU | title = ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study | date = Dec 14, 2018|access-date=|website=YouTube | last = Younger | first=Jarred | authorlink=Jarred Younger|archive-url=|archive-date=|publisher=SolveCFS}}</ref> (TALK)

===Causes & triggers===

*Outbreaks - see [[List of myalgic encephalomyelitis and chronic fatigue syndrome outbreaks|List of outbreaks]]
*Possible infectious triggers: [[Enterovirus]]es, [[Epstein-Barr virus]]<ref name="Hickie2006" />, [[Q fever]]<ref name="Hickie2006" />, [[Ross River virus]]<ref name="Hickie2006" />, [[mononucleosis]]<ref name="Jason, Katz, 2017" />, ([[Ebola virus disease|Ebola]]?)<ref name="Hickie2006" />
*Non-viral triggers - [[trauma]], chemical

== Tests ==
* [[Natural killer cell]] (NKC) Blood Test
* Sleep study for [[sleep apnea]], [[Restless legs syndrome|restless leg syndrome]], and other sleep disturbances.
* [[Tilt table test]] for [[Orthostatic intolerance|OI]] or [[Postural orthostatic tachycardia syndrome|POTS]].

==Treatments==
There are currently no [[U.S. Food and Drug Administration|Food and Drug Administration]] (FDA) approved treatments for ME/CFS. Treatments consist mostly of symptom management, rather than treatment of the underlying cause of the disease, which is not yet understood.<ref name="Primer2014" /> There are many [[:Category:Potential_treatments|potential treatments]], though their evidence-base is limited, as most research into treatments has gone into psychological approaches to treatment.

=== Drugs ===
[[File:Ampligen.jpg|200px|thumb|right|Ampligen]]
Two treatments that have garnered much attention are [[Ampligen]], produced by [[AIM ImmunoTech]] (formerly Hemispherx Biopharma), and [[Rituximab]]. Many people have reported improvements from Ampligen, and a few recovered but relapsed when they stopped taking it.<ref name="TownCFS">{{Cite web | url = https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue | title = A Town for People with Chronic Fatigue Syndrome|website=New Yorker | date = Sep 3, 2019 | first = Mike | last = Mariani|access-date=2022-04-13}}</ref>

Attempts to obtain FDA approval for Ampligen in the US have failed, but it is available to some people on [[compassionate use]].<ref name="experimental">{{Cite web | url = https://ammes.org/experimental-treatments/ | title = Experimental treatments | last = | first = | date = |website=[[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|archive-url=|archive-date=|access-date=2021-03-18}}</ref> [[Argentina]] approved the use of Ampligen for [[Severe and very severe ME|severe ME/CFS]] in 2016.<ref>{{Cite news | url = http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html | title = Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic | last = Hemispherx Biopharma, Inc. | date = Aug 23, 2016|work=GlobeNewswire News Room|access-date=2018-08-13|archive-url=|archive-date=|language=en-US}}</ref><ref>{{Cite news | url = http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf | title = Hemispherx Biopharma, Inc. Executive Informational Overview | last = | first = | date = Nov 27, 2016|work=Crystal Research Associates|access-date=|archive-url=|archive-date=|format=PDF}}</ref> Also in 2016, it was made available on a limited basis in Europe.<ref>{{Cite web | url = https://www.bizjournals.com/philadelphia/news/2016/07/25/hemispherx-ships-ampligen-for-european-chronic.html | title = Hemispherx ships Ampligen for European chronic fatigue syndrome program | last = George | first = John | date = Jul 25, 2016 | website = bizjournals.com|archive-url=|archive-date=|access-date=2018-08-13}}</ref> In July 2018, AIM ImmunoTech announced the expansion of its US [[compassionate use]] program, '''AMP-511''', to new ME/CFS patients for the first time in over a year.<ref>[http://www.4-traders.com/HEMISPHERX-BIOPHARMA-INC-31148494/news/Hemispherx-BioPharma-Opens-FDA-Approved-Reimbursement-Based-Expanded-Access-Treatment-Program-for-26862569/ Hemispherx BioPharma : Opens FDA-Approved Reimbursement Based Expanded Access Treatment Program for ME/CFS to New Enrollees - 4 Traders]</ref><ref>{{Cite web | url = https://finance.yahoo.com/news/hemispherx-biopharma-inc-announces-advancement-133000883.html | title = Hemispherx Biopharma Inc. Announces Advancement in Expanded Access Program for Ampligen in the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last = | first = | author-link =| date = Jan 2, 2019|website=finance.yahoo.com|publisher=GlobeNewswire|language=en-US|archive-url=|archive-date=|access-date=2019-02-10}}</ref>

[[Rituximab]], a lymphoma drug, had shown promising results in initial trials in Norway,<ref>{{Cite journal | last = Fluge | first = Øystein | authorlink = Øystein Fluge | last2 = Risa | first2 = Kristin | authorlink2 = | last3 = Lunde | first3 = Sigrid | author-link3 = | last4 = Alme | first4 = Kine | authorlink4 = | last5 = Rekeland | first5 = Ingrid Gurvin | authorlink5 = | last6 = Sapkota | first6 = Dipak | authorlink6 = | last7 = Kristoffersen | first7 = Einar Kleboe | last8 = Sørland | first8 = Kari | last9 = Bruland | first9 = Ove | date = 2015-07-01 | editor-last = van der Feltz-Cornelis|editor-first = Christina | title = B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment | url = http://dx.plos.org/10.1371/journal.pone.0129898|journal=PLOS ONE|language=en|volume=10|issue=7| pages = e0129898|doi=10.1371/journal.pone.0129898|issn=1932-6203|pmc=4488509|pmid=26132314|access-date=|quote=|via=}}</ref> and there were groups crowdsourcing funding for further trials in other countries. In 2017, Drs. [[Øystein Fluge]] and [[Olav Mella]] announced that their Rituximab trial had failed. They stated that they would focus their efforts on attempting to identify a subgroup of ME/CFS patients with an immune profile that would be responsive to Rituximab.<ref>{{Cite web | url = https://www.simmaronresearch.com/blog/2017/11/norwegian-rituximab-chronic-fatigue-syndrome-mecfs-trial-fails | title = Norwegian Rituximab Chronic Fatigue Syndrome (ME/CFS) Trial Fails|website=Simmaron Research|language=en-US|access-date=2021-11-21}}</ref> A phase III trial published in 2019 showed Rituximab does not improve ME/CFS.<ref name="phase3-2019">{{Cite journal | last = Fluge | first = Øystein | last2 = Rekeland | first2 = Ingrid G. | last3 = Lien | first3 = Katarina | last4 = Thürmer | first4 = Hanne | last5 = Borchgrevink | first5 = Petter C. | last6 = Schäfer | first6 = Christoph | last7 = Sørland | first7 = Kari | last8 = Aßmus | first8 = Jörg | last9 = Ktoridou-Valen | first9 = Irini | date = 2019-04-02 | title = B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial | url = https://www.ncbi.nlm.nih.gov/pubmed/30934066|journal=Annals of Internal Medicine|doi=10.7326/M18-1451|issn=1539-3704|pmid=30934066}}</ref> 

[[Jarred Younger]] announced in March 2016 that he will be undertaking a trial of [[low dose naltrexone]] (LDN) in ME/CFS.<ref name="younger-research">{{Cite web | last = Younger | first=Jarred | authorlink = Jarred Younger | title = Research. Neuroinflammation Pain and Fatigue Laboratory|access-date= Nov 21, 2021 | url = https://sites.uab.edu/younger/research/}}</ref>

=== Treating other conditions ===
Different forms of [[Orthostatic intolerance|OI]] are treated with beta-blockers (Metopropol), [[Fludrocortisone]] (Florinef), and [[Mestinon|Pyridostigmine]].<ref name="Carruthers, 2003" /> When treating other diseases, illnesses, and conditions, and ME/CFS comorbidities or overlapping conditions such as sleep difficulties, cognitive problems, pain, and other symptoms it is important to remember that patients are [[Medicine sensitivities|sensitive to medications]].<ref name="monitor">{{Cite web | title = Monitoring the Use of All Medicines and Supplements {{!}} Clinical Care of Patients {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/monitoring-medication.html|website=[[Centers for Disease Control and Prevention]] | date = 2018-11-08|access-date=2019-01-27|language=en-us}}</ref> The CDC advice to health care practitioners is to be aware that because all drugs can cause side effects, ME/CFS patient symptoms can worsen. "This is particularly true of any medication that acts on the [[central nervous system]], such as sedating medications: therapeutic benefits can often be achieved at lower-than-standard doses. Patients with ME/CFS might tolerate or need only a fraction of the usual recommended doses for medications. After initial management with lower dosing, one or more gradual increases may be considered as necessary and as tolerated by the patient."<ref name="prognosis" /> For instance, tricyclic drugs can improve mood and help with sleep and pain. However, in some in can worsen OI.<ref name="prognosis" />
===Exercise as treatment===
[[File:J Brea TED.JPG|200px|thumb|right|[[Jen Brea|Jennifer Brea]] is an [[United States|American]] who was studying at Harvard; while on a trip to [[Kenya]] she became very ill with what would eventually be diagnosed as [[ME/CFS]]. Brea began experiencing [[Nervous system|neurological]] problems. Her neurologist diagnosed her with "conversion disorder" ([[hysteria]]). When walking home from his office, she collapsed. [[Severe and very severe ME|Jen then needed to use a wheelchair]] keeping her legs up due to [[Postural orthostatic tachycardia syndrome|POTS]] as her blood pooled into her legs]].
Previously, two common treatment recommendations for ME/CFS were [[graded exercise therapy]] (GET) and [[cognitive behavioral therapy]] (CBT). These treatments are based on disproven the hypothesis that the disease might have begun with a viral infection but has been perpetuated by [[deconditioning]] from lack of activity, and [[illness beliefs|fear and avoidance]] of activity. GET and CBT are aimed at addressing these hypothesized causes by challenging the proposed unhelpful thoughts that result in avoidance of activity and reconditioning through a gradual increase in exercise. These treatments are controversial and are at odds with much of the research literature, which suggests that exercise is harmful to people with ME/CFS. A large patient survey of treatment responses found that 74% of people who had tried GET, reported that their symptoms subsequently worsened,<ref name="MEASSUK20150529survey" /> which is consistent with other patient surveys and many research findings.<ref name="Phoenix20160222Norway2012" /><ref name="OxfordBrookesSurvey">{{Cite web|url = https://www.meassociation.org.uk/wp-content/uploads/NICE-Patient-Survey-Outcomes-CBT-and-GET-Final-Consolidated-Report-03.04.19.pdf| title = Evaluation of a survey exploring the experiences of adults and children with ME/CFS who have participated in CBT and GET interventional programmes. FINAL REPORT | last = Oxford Clinical Allied Technology and Trials Services Unit (OxCATTS)|location=Oxford Brookes University | date = Feb 27, 2019}}</ref>

The [[PACE trial]], published in 2011, is the largest GET trial ever conducted. It has received much publicity as a result of its recovery rate claims, though it has come under strong criticism from within both the scientific and patient community for significant flaws in its design, and for overstating (and in some cases misrepresenting) outcomes in both the initial trial, and follow-up studies.<ref>{{Cite journal | last = Coyne | first = James Charles | last2 = Laws | first2 = Keith R | date = 2016 | title=Results of the PACE follow-up study are uninterpretable | url = http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00551-9/fulltext|journal=The Lancet Psychiatry|language=English|volume=3|issue=2| pages = e6–e7|doi=10.1016/S2215-0366(15)00551-9|issn=2215-0366|via=}}</ref> From 2015 to present day, the study was the subject of a series of investigative pieces that were highly critical of the trial by journalist Dr. [[David Tuller]]<ref name="viroblogMECFS" />, science writer [[Julie Rehmeyer]], patient advocate [[Tom Kindlon]], Dr. [[Keith Geraghty]]<ref name="Geraghty, 2017">{{Cite journal | last1 = Geraghty | first1 = Keith | authorlink1 = Keith Geraghty| title = Further Commentary on the PACE Trial: Biased Methods and Unreliable Outcomes| journal = Journal of Health Psychology | volume = | issue = | page = | date = May 2017 | doi = 10.1177/1359105317714486}}</ref>, psychologist [[Carolyn Wilshire]]<ref name="Wilshire C, et al, 2017">{{Cite journal | last1 = Wilshire | first1 = C | authorlink1 = Carolyn Wilshire | last2 = Kindlon | first2 = T | authorlink2 = Tom Kindlon | last3 = McGrath | first3 = S | authorlink3 = Simon McGrath | title = PACE trial claims of recovery are not justified by the data: a rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White | journal = Fatigue: Biomedicine, Health & Behavior | volume = 5 | issue = 1 | page = 62-67 | date = 2017 | doi = 10.1080/21641846.2017.1259724}}</ref> and others. A petition signed by almost 12,000 ME/CFS patients and allies,<ref name="MEACTIONpacepetition" /> and an open letter signed by 42 ME/CFS experts from around the world,<ref name="openletrLANCET2">{{Cite web | last1 = Davis | first1 = Ronald W | authorlink1 = Ronald Davis | last2 = Edwards | first2 = Jonathan C W | authorlink2 = Jonathan Edwards | last3 = Jason | first3 = Leonard A | authorlink3 = Leonard Jason | last4 = Levin | first4 = Bruce | authorlink4 = Bruce Levin | last5 = Racaniello | first5 = Vincent R | authorlink5 = Vincent Racaniello | last6 = Reingold | first6 = Arthur L | authorlink6 = Arthur Reingold | last7 = Ablashi | first7 = Dharam V | authorlink7 = Dharam Ablashi | last8 = Baraniuk | first8 = James N | authorlink8 = James Baraniuk | last9 = Barcellos | first9 = Lisa F | authorlink9 = Lisa Barcellos | last10 = Bateman | first10 = Lucinda | authorlink10 = Lucinda Bateman | last11 = Bell | first11 = David S | authorlink11 = David Bell | last12 = Bested | first12 = Alison C | authorlink12= Alison Bested | last13 = Broderick | first13 = Gordon | authorlink13 = Gordon Broderick | last14 = Chia | first14 = John | authorlink14 = John Chia | last15 = Chu | first15 = Lily | authorlink15 = Lily Chu | last16 = Enlander | first16 = Derek | authorlink16 = Derek Enlander | last17 = Fletcher | first17 = Mary Ann | authorlink17 = Mary Ann Fletcher | last18 = Friedman | first18 = Kenneth | authorlink18 = Kenneth Friedman | last19 = Kaufman | first19 = David L | authorlink19 = David Kaufman | last20 = Klimas | first20 = Nancy | authorlink20 = Nancy Klimas | last21 = Lapp | first21 = Charles W | authorlink21 = Charles Lapp | last22 = Levine | first22 = Susan | authorlink22 = Susan Levine | last23 = Light | first23 = Alan R | authorlink23 = Alan Light | last24 = Marshall-Gradisnik | first24 = Sonya | authorlink24 = Sonya Marshall-Gradisnik | last25 = Medveczky | first25 = Peter G | authorlink25= Peter Medveczky | last26 = Nahle | first26 = Zaher | authorlink26 = Zaher Nahle | last27 = Oleske | first27 = James M | authorlink27= James Oleske | last28 = Podell | first28 = Richard N | authorlink28= Richard Podell | last29 = Shepherd | first29 = Charles | authorlink29= Charles Shepherd | last30 = Snell | first30 = Christopher R | authorlink30 = Christopher Snell | last31 = Speight | first31 = Nigel | authorlink31= Nigel Speight | last32 = Staines | first32 = Donald | authorlink32= Donald Staines | last33 = Stark | first33 = Philip B | authorlink33= Philip Stark | last34 = Stein | first34 = Eleanor | authorlink34= Eleanor Stein | last35 = Swartzberg | first35 = John | authorlink35= John Swartzberg | last36 = Tompkins | first36 = Ronald G | authorlink36= Ronald Tompkins | last37 = Underhill | first37 = Rosemary | authorlink37= Rosemary Underhill | last38 = Vallings | first38 = Rosamund | authorlink38= Rosamund Vallings | last39 = VanElzakker | first39 = Michael | authorlink39= Michael VanElzakker | last40 = Weir | first40 = William | authorlink40= William Weir | last41 = Zinn | first41 = Marcie L | authorlink41= Marcie Zinn | last42 = Zinn | first42 = Mark A | authorlink42= Mark Zinn | title = An open letter to the Lancet - again | date = Feb 10, 2016
| website = Virology Blog| url = http://www.virology.ws/2016/02/10/another-request-for-data-from-the-pace-trial/ }}</ref> were sent to The Lancet, both calling for the data to be reanalysed. Twenty-four ME/CFS organizations from 14 different countries have written to Queen Mary University London requesting that the trial data be released for reanalysis.<ref name="MEACTION20160313openletr" /> To date, the authors of the trial and editor of The Lancet have refused such requests. Despite such criticism, the PACE trial continues to influence both government and the medical profession's approach to the treatment of ME/CFS in many countries.

One of the reasons that exercise may be harmful to people with ME/CFS, is the presence of [[post-exertional malaise]] (PEM), which is an exacerbation of symptoms following physical, mental or even emotional [[exertion]]. Studies have revealed immunological, muscular, [[Nervous system|neurological]], [[Autonomic nervous system|autonomic]] and [[Cardiovascular system|cardiovascular]] abnormalities in response to exercise in people with ME/CFS. As these results are not also found in healthy sedentary controls, the adverse effects of exercise cannot be said to be due to deconditioning.<ref name="TwiskF2015">{{Cite journal | last1 = Twisk | first1 = Frank NM | authorlink1 = Frank Twisk | last2 = Geraghty | first2 = Keith J | authorlink2 = Keith Geraghty | title = Deviant Cellular and Physiological Responses to Exercise in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome| journal = Jacobs Journal of Physiology | volume = 1 | issue =2 | pages = 007 | date = Jul 11, 2015 | url = http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf}}</ref>{{citation needed|reason=VanNess2010 / Workwell Foundation studies need to be cited here.}}{{citation needed|reason=The Lights epigenetic changes post-exercise study needs to be cited here.}}

People with ME/CFS should approach [[exercise]] with caution, as there is much evidence of potential for harm.<ref name="OxfordBrookesSurvey"/><ref name="ICC2011primer"/>

[[Anaerobic threshold]], use of heart rate monitors for activity and [[pacing]]. Analeptic, not aerobic. [[Energy Envelope Theory|Energy envelope]]/pacing - people do better if stay within their envelope, than push to increase activity

====Graded exercise therapy & Cognitive behavioral therapy ====
[[File:Emma Shorter.JPG|400px|thumb|right|[[Emma Shorter]], is a citizen of [[Scotland]]. Here, she gives testimony before Parliament's Petitions Committee on [[graded exercise therapy|GET]] and how it put her in a wheelchair]].
GET and CBT have been recently abandoned in the [[United Kingdom|UK]], [[Ireland]] and many parts of Europe by ME Clinics.<ref name="niceng206">{{Cite web | url = https://www.nice.org.uk/guidance/ng206 | title = Myalgic Encephalomyelitis (or Encephalopathy)/Chronic Fatigue Syndrome:diagnosis and management. NICE guideline. | last=NICE Guideline Development Group | first = | authorlink = |publisher=[[National Institute for Health and Care Excellence]] | date = 2021-10-29}}</ref> They are highly controversial and not recommended by patients, most patient advocates, and research organizations nor by many doctors or researchers outside of the UK. Based on the flawed [[PACE trial]] which used the flawed [[Oxford criteria]] to diagnose and recruit patients, GET and CBT found its way into treating people with ME/CFS.

[[Exercise]], especially GET, can harm an ME/CFS patient further.<ref name="OxfordBrookesSurvey"/>

*[[Jennifer Brea]] walked home from her Neurologist's office and became [[severe and very severe ME|wheelchair-bound]].
*This is an experience of serious harm due to GET shared [https://twitter.com/TomKindlon/status/846425974052966400 by K. Miles, via Tom Kindlon on Twitter].
*[[Emma Shorter]] was able to walk a few minutes a day until GET put her in a wheelchair.
*[[Maik Speedy|Dr Maik Speedy]] was also seriously injured by GET and has been bedbound since.
*British MP [[Brynmor John]] collapsed outside the House of Commons gym in 1998 and [[Causes of death|died]], as a result of following his doctor's advice to exercise back to health.

==== Claims of recovery and cures ====
Charlatans claim they can cure CFS (per the CDC "there is no cure"<ref name="treatments">{{Cite web | url = https://www.cdc.gov/me-cfs/treatment/index.html | title = Treatment {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | last = | first = | date = 2018-07-03 | website = [[Centers for Disease Control and Prevention]]|language=en-us|archive-url=|archive-date=|access-date=2021-11-22}}</ref>) when in reality they may be able to treat [[chronic fatigue]] (CF). ME/CFS patients experience an ongoing improper immune response and other abnormalities for at least 6 months straight with a reduction in activity with a specific symptom set for at least 50% of the time.<ref name="etiology" /><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html | title = IOM 2015 Diagnostic Criteria {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-10 | website = [[Centers for Disease Control and Prevention]]|language=en-us|access-date=2018-09-07}}</ref><ref>{{Cite web | url = https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/approach-to-diagnosis.html | title = Proposed Approach to ME/CFS Diagnosis in Children and Adults {{!}} Diagnosis {{!}} Healthcare Providers {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2018-07-12 | website = [[Centers for Disease Control and Prevention]] |language=en-us|access-date=2018-09-07}}</ref>

Additionally, there have been media reports of some athletes―usually amateur athletes,―diagnosed with CFS that recovered after a relatively short period of time with rest, supplementation, and diet changes,<ref name="Inews2018" /><ref name="Times2017" /><ref name="ABC2018" /><ref name="London2019" /> but they may have had [[overtraining syndrome]],<ref name="spence">{{Cite web | last = Spence | first = Vance | authorlink = Vance Spence|website=Irish M.E. Association| title = Snippets {{!}} A presentation by MERGE Chairman Dr Vance Spence on 12 November 2005 at the Oak Tree Court Conference Centre, Coventry, at the invitation of the Warwickshire Network for ME|url = https://www.imet.ie/imet_website/snippets/7th_december_2005_snippets.html|quote=(Mommersteeg et al, 2005) shows that the "burnout" experienced by athletes differs from CFS, and is certainly not ME as described in earlier literature. This is just one example of many media stories - thrown out into the public arena - which have an uncertain meaning in the context of ME/CFS}}</ref> while some people with adrenal failure, [[idiopathic chronic fatigue]] or another fatiguing illness may be erroneously diagnosed with CFS<ref name="ICC"/><ref name="recovery">{{Cite web | url = https://www.researchgate.net/profile/Diane_Cox2/publication/257764167_Severe_Chronic_Fatigue_Syndrome_CFSME_Recovery_is_possible/links/00b49525d3a11018ad000000/Severe-Chronic-Fatigue-Syndrome-CFS-ME-Recovery-is-possible.pdf | title = Severe Chronic Fatigue Syndrome: Recovery is Possible | last = Burley | first = Lucy | authorlink=Lucy Burley | last2 = Cox | first2 = Diane | authorlink2 = Diane Cox | date = Aug 1, 2007|pages=339-344|language=en|doi=10.1177/030802260707000803|archive-url=|archive-date=|url-status=|access-date=2019-02-11 | last3 = Findley | first3 = Leslie|journal=British Journal of Occupational Therapy|volume=70|issue=8 | authorlink3 = Leslie Findley}}</ref><ref name="Anoop2012">{{Cite journal | last = Devasahayam | first = Anoop | author-link = | last2 = Lawn | first2 = Tara | authorlink2 = | last3 = Murphy | first3 = Maurice | authorlink3 = | last4 = White | first4 = Peter D | authorlink4 = Peter White | date = Jan 2012 | title = Alternative Diagnoses to Chronic Fatigue Syndrome in Referrals to a Specialist Service: Service Evaluation Survey | url = https://journals.sagepub.com/doi/epub/10.1258/shorts.2011.011127|journal=JRSM Short Reports|volume=3|issue=1|pages=1–5|doi=10.1258/shorts.2011.011127|issn=2042-5333|pmc=PMC3269106|pmid=22299071|access-date=|quote=Half of all the referred patients to a specialist CFS clinic had alternative medical and psychiatric diagnoses.|via=}}</ref> ME and CFS in professional athletes normally results in very premature retirement.<ref name="Squash">{{Cite news | title = Illness robbed Marshall of crowning glory | first = Sam | last = Murley | date = Apr 10, 2019 | url = https://www.royalgazette.com/sport/article/20190410/illness-robbed-marshall-of-crowning-glory/|publisher =Royal Gazette}}</ref><ref name="Annadale">{{Cite web| title = Annadale Striders Interview - Derek Graham | url = http://annadalestriders.co.uk/derek-graham-interview/|website=Annadale Striders}}</ref><ref name="Shattered">{{Cite book |url = https://books.google.co.uk/books/about/Shattered.html?id=mkbxPAAACAAJ&redir_esc=y | title = Shattered: A Champion's Fight Against a Mystery Illness | first=Peter | last= Marshall | first2 = Nick | last2 = Kehoe | date = 2001|publisher =Mainstream}}</ref><ref name="Olympian">{{Cite news | date = May 4, 2012| title = Linley Frame: Olympian and Chronic Fatigue Syndrome sufferer|url = https://www.abc.net.au/local/audio/2012/05/04/3495770.htm|website =Australian Broadcasting Corporation}}</ref><ref name="FIFA">{{Cite web|url = http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-url=https://web.archive.org/web/20150610042710/http://www.fifa.com/womensworldcup/classic-players/player=michelle-akers-usa-1329785.html|archive-date = 2015-06-10| title = Michelle Akers USA|website=FIFA}}</ref><ref name="olaf">{{Cite news | url = https://www.welt.de/sport/gallery118782921/Benefizspiel-fuer-den-schwer-kranken-Olaf-Bodden.html | title = Benefizspiel für den schwer kranken Olaf Bodden | last = | first = | date = 2021 | website = Die Welt|archive-url=|archive-date=|url-status=|access-date=2021-11-17}}</ref><ref name="LA">{{Cite news | title = Garton enjoying life after United in LA | first = Andy | last = Mitten | date = Jul 24, 2014 | url = https://www.manchestereveningnews.co.uk/sport/football/football-news/andy-mitten-billy-garton-enjoying-7508558.amp|website =Manchester Evening News}}</ref>

==Severely ill patients==
Considerable variation exists in the severity of the disease. The [[International Consensus Criteria]] lists the following severity levels (it should be noted that even "mild" ME/CFS consists of significant debility):

*Mild = 50% reduction in pre-illness activity levels
*Moderate = mostly housebound
*Severe = mostly bedridden
*Very Severe = totally bedridden, and needing help with basic functions.

At least [[Severe and very severe ME|25% of people with ME/CFS are bedbound or housebound]], often for years or even decades, so are largely an invisible population.<ref name="IOM2015MECFS" /><ref name="DerekPrisk2009" /><ref>[http://iacfsme.org/PDFS/2017JanNewsletter/8-Japan-2014-Patient-Survey.aspx ME/CFS Patient Survey Report: Ministry of Health Survey Reveals Harsh Reality of ME/CFS Patients in Japan - IACFSME - By Mieko Shinohara]</ref> So invisible in fact, that they have rarely been included as part of research because their level of debility precludes them from traveling to laboratories for required testing. The [[Open Medicine Foundation]]'s [[ME/CFS Severely Ill, Big Data Study]] will be the first in-depth study of people with a severe form of ME/CFS. This study has so far produced the groundbreaking paper [[Metabolic features of chronic fatigue syndrome]].
It is estimated that 25% of ME/CFS patients are severely ill and are housebound or bedbound.

Notable patients with severe or very severe ME/CFS include [[Whitney Dafoe]], [[Karina Hansen]], [[Lynn Gilderdale]], [[Laura Hillenbrand]], [[Tom Kindlon]], [[Vanessa Li]], [[Doctor Speedy]], [[Naomi Whittingham]], [[Jamison Hill]] and [[Jessica Taylor-Bearman]].

Though uncommon, there have been [[causes of death|instances of deaths]] which have been attributed to the disease (see [[Sophia Mirza]], [[Merryn Crofts]]). National Statistics report an average of 10 - 12 deaths per year in England and Wales [[Causes of death|partly or fully caused by ME/CFS]], with almost all patients dying being of working age.
<ref name="ONS2018">{{Cite web | url = https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/adhocs/008461mentionsofpostviralfatiguesyndromebenignmyalgicencephalomyelitisdeathsregisteredinenglandandwales2001to2016 | title = Mentions of postviral fatigue syndrome (benign myalgic encephalomyelitis), deaths registered in England and Wales, 2001 to 2016 | website = Office for National Statistics|access-date=2019-03-06}}</ref>

==Patients and psychiatry/psychology==

*Objections and scope
*Mind-body dualism
*[[Psychologization]]
*[[Cognitive behavioral therapy]]
*The [[PACE trial]]. See [http://www.meaction.net/wp-content/uploads/2015/05/MEAction%E2%80%93patient-view-of-the-PACE-Trial-Controversy.pdf Patient view of the PACE Trial controversy]
*[[Ethical issues]]
*[[Patient mental health]]

===Stigmatization===

*Pretty young women slumped on desk
*[[Yuppie Flu]]
*Accusations of laziness/lethargy
*Epidemiological evidence - age, gender, demographic, racial/cultural
*[[Stigma and discrimination]]

===Accusations of harassment===

*No arrests or convictions<ref>{{Cite web | url = http://www.virology.ws/2016/02/01/trial-by-error-continued-a-few-words-about-harassment/ | title = Trial By Error, Continued: A Few Words About “Harassment” | last = Tuller | first = David | authorlink = David Tuller | date = Feb 1, 2016 | website = [[Virology blog]]|archive-url=|archive-date=|access-date=2019-01-21}}</ref>
* Potential harassment and "wild speculations" about threats to researchers were unsuccessful arguments used in [[Queen Mary University of London]]'s failed attempt to deny access to the [[PACE trial]] data at the 2015 tribunal. The tribunal judgement stated that the only evidence of harassment provided was a single heckler in a single seminar.<ref name="FirstTierTribunal2015">{{Cite news | title = First-tier tribunal: Information Rights Appeal EA/2015/0269. | url = https://informationrights.decisions.tribunals.gov.uk//DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF | page = 40 | last = Kennedy | first = Brian | last2 = Stephenson | first2 = Darryl | last3 = Watson | first3 = Nigel|quote=The evidence of <nowiki>[expert witness]</nowiki> Professor Anderson that third parties could not identify participants from the information alone and that, when pressed, he said that the chance of an "activist" being able to discover information that would lead to individual identification was remote, it was clear that his assessment of activist behaviour was, in our view, grossly exaggerated and the only actual evidence was that an individual at a seminar had heckled Professor Chalder. The identity of those questioning the research, who had signed an open letter or supported it, was impressive.}}</ref>

*Mistreatment of patients, including forced harmful treatment of children, is not mentioned. E.g., the story of "B", aged 8,<ref name="StoryofB">{{cite web | title = The Story of B - Children with ME. Appropriate ME Treatment Parliament debate | date = Jan 24, 2018 | url = https://www.youtube.com/watch?v=5HzZ4U6yU6o&autoplay=0}}</ref> and [[Ean Proctor]] and others "The Mental Health Movement: Persecution of Patients?"<ref>[http://www.theoneclickgroup.co.uk/documents/ME-CFS_docs/The%20Mental%20Health%20Movement%20-%20Persecution%20of%20Patients.pdf The Mental Health Movement: Persecution of Patients?]</ref>

* A pattern of [[intimidation and bullying of PACE trial critics]] has included targeting scientists' employers, professional bodies, politicians including the [[Countess of Mar]], and smear tactics in the national press.

== Working with government to move forward ==

Advocates met with senate staffers the week of March 16, 2016, and discussed research and drug development by the [[NIH]], the [[Centers for Disease Control and Prevention|CDC]] reinstating and increasing funding and education based on [[IOM]] recommendations and the [[HHS]] funding to develop Centers of Excellence.<ref>[http://www.meaction.net/2016/03/16/meaction-meets-with-senate-staffers/ #MEAction meets with Senate staffers]</ref> [[The MEAction Network]] reports on this ongoing process.

====CDC Website updates====
*Jul 3, 2017, the CDC's Chronic Fatigue Syndrome page has been changed to [[ME/CFS|Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]] (ME/CFS) and GET and CBT recommendations have been removed.<ref>{{Cite web|url = http://www.virology.ws/2017/07/10/trial-by-error-the-cdc-drops-cbtget/ | title = Trial By Error: The CDC Drops CBT/GET - Virology Blog | last = Tuller | first = David | authorlink = David Tuller | date = Jul 10, 2017 | website = [[Virology blog]]}}</ref><ref>[https://www.cdc.gov/me-cfs/index.html Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - CDC.gov]</ref>

*Jul 12, 2018, the "Information for Healthcare Providers" tab and its sub-tabs were updated.<ref>[https://www.cdc.gov/me-cfs/healthcare-providers/index.html Information for Healthcare Providers - ME/CFS - CDC]</ref><ref>[https://www.cdc.gov/media/releases/2018/a0712-new-website-me-cfs.html New ME/CFS Web Content for Healthcare Providers - CDC - Jul 12, 2018]</ref>

* Feb 25, 2019, Dr. [[Elizabeth Unger]], Chief of CDC's Chronic Viral Disease Branch (CVDB), that houses the ME/CFS program, in collaboration between ''Medscape'' and the CDC put out brief video and commentary page with links to the CDC's July 12th, 2018 updates for medical professionals: ''[https://www.medscape.com/viewarticle/908622?src=rss Chronic Fatigue Syndrome: It's Real, and We Can Do Better].''<ref>{{Cite web | title = Chronic Fatigue Syndrome: It's Real, and We Can Do Better |url = https://www.medscape.com/viewarticle/908622?src=rss| website = Medscape |access-date=2019-02-25 | date = Feb 25, 2019 | last = Unger | first=Elizabeth | authorlink = Elizabeth Unger | last2 = Medscape | first2 = | authorlink2 = |archive-url=|archive-date=}}</ref>
'''MEAction input'''
*Jul 29, 2018, [https://www.meaction.net/2018/07/29/cdc-revises-its-information-on-me/ CDC Revises its Information on ME] #[[MEAction]] report on the CDC July 2017 and July 2018 website updates. Recommendations for the CDC's ME/CFS page have been created from patient feedback on the updates as well as asking for further patient input.

==Expert opinions==

===Quotes from ME/CFS experts and patients===
*[[Individual quotes]]
*[http://thoughtsaboutme.com/quotes/ Thoughts About ME - List of Quotes]

===Doctors===
'''UK'''
*[[Jonathan Edwards]]
*[[Charles Shepherd]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">

*[[Lucinda Bateman]]
*[[Lily Chu]]
*[[David Kaufman]]
*[[Nancy Klimas]]
*[[Anthony Komaroff]]
*[[Susan Levine]]
*[[Jose Montoya]]
*[[Benjamin Natelson]]
*[[Daniel Peterson]]
*[[Alan Pocinki]]
*[[Peter Rowe]]
*[[Ronald Tompkins]]
*[[David Tuller]]

</div>

===Researchers===
'''Australia'''
*[[Neil McGregor]]

'''UK'''
*[[Keith Geraghty]]

'''US'''
<div style="column-count:4;-moz-column-count:4;-webkit-column-count:4">
*[[Ron Davis]]
*[[Gunnar Gottschalk]]
*[[Maureen Hanson]]
*[[Mady Hornig]]
*[[Leonard Jason]]
*[[Betsy Keller]]
*[[Ian Lipkin]]
*[[Staci Stevens]]
*[[Suzanne Vernon]]
*[[Jarred Younger]]

</div>

===Patients===
====Australia====

===== Canada =====
*[[Scott Simpson]]

====Scotland====
*[[Emma Shorter]]

====US====
<div style="column-count:2;">
*[[Jennifer Brea]]
*[[Carol Head]]
*[[Ryan Prior]]
*[[Julie Rehmeyer]]
*[[Jaime Seltzer]]
</div>

====UK====
*[[Adam Lowe]]
*[[Graham McPhee]]
*[[Jessica Taylor-Bearman]]

====Ireland====
*[[Tom Kindlon]]

===Patient groups & charities===

'''[[:Category:Patient groups|Patient groups]]'''
<div style="column-count:3">
*[[:Category:American patient groups|American patient groups]]
*[[:Category:Australian patient groups|Australian patient groups]]
*[[:Category:Belgian patient groups|Belgian patient groups]]
*[[:Category:British patient groups|British patient groups]]
*[[:Category:Canadian patient groups|Canadian patient groups]]
*[[:Category:Dutch patient groups|Dutch patient groups]]
*[[:Category:Irish patient groups|Irish patient groups]]
*[[:Category:Italian patient groups|Italian patient groups]]
*[[:Category:New Zealand patient groups|New Zealand patient groups]]
*[[:Category:Norwegian patient groups|Norwegian patient groups]]
*[[:Category:Scottish patient groups|Scottish patient groups]]
*[[:Category:Swedish patient groups|Swedish patient groups]]
</div>

==Photos==
*[https://phoenixrising.me/stock-photography Stock photographs suitable for ME/CFS articles] - curated by [[Phoenix Rising]]
*[https://forums.phoenixrising.me/threads/the-real-me-a-stock-photography-resource-for-the-media.43734/ Advice on photograph choice]

==History==
*[[Osler's Web|''Osler's Web'']] is a book by [[Hillary Johnson]] on the early history of CFS.
*[[Thirty Years of Disdain|''Thirty Years of Disdain'']] by [[Mary Dimmock]] and Matthew Lazell-Fairman picks up on the ME/CFS history where Osler's Web leaves off.

=== Deaths of ME/CFS patients ===
*[[Causes of death]]
*[[Suicide]]

'''Death certificates with ME or CFS'''
*[[Merryn Crofts]]' death is attributed to ME.
*[[Sophia Mirza]]'s death is attributed to CFS.

In the UK, United States, and Australia there are further reports of loved ones who have died due to ME/CFS.<ref>[https://www.newscientist.com/letter/mg19125620-600-not-sadly-the-first/ Sadly, not the first (Comment Section)]</ref> See Editor's Note<ref>[https://www.newscientist.com/article/dn9342-first-official-uk-death-from-chronic-fatigue-syndrome/ First official UK death from chronic fatigue syndrome - New Scientist]</ref>

==Other tips and articles for journalists==
*2021, [https://www.theopennotebook.com/2021/01/26/how-to-report-with-accuracy-and-sensitivity-on-contested-illnesses/ How to Report with Accuracy and Sensitivity on Contested Illnesses] - by ME/CFS patient and science writer Julie Rehmeyer, Open Notebook
*Always interview a patient
*Interview more than one researcher (not just from the psychological etiology view)
*Avoid using derogatory, outdated & incorrect term "[[Yuppie Flu]]"
*Never shorten the disease name [[chronic fatigue syndrome]] (CFS) to the symptom [[chronic fatigue]] (CF). [[Chronic fatigue syndrome|CFS]], [[myalgic encephalomyelitis|ME]] or [[ME/CFS]] can be used to save print space.
*Use photographic imagery that represents the reality for patients - serious illness & disability - not well-groomed & slightly tired office workers at their computer or students with a pile of books sleeping at their desk. [[Solve ME/CFS Initiative]]'s [https://www.youtube.com/watch?v=cF2OuYFDriY Times Square Public Awareness Ad] shows the reality of the disease ME/CFS. Using photos of patients whether chronically ill yet functioning or a severely ill patient or stock photos that reflect life with this disease is necessary.
{{See also|Long_COVID#Articles_for_journalists_covering_Long_COVID|Articles for journalists covering Long COVID}}

==Learn more==
'''Key facts'''
*[https://www.nap.edu/resource/19012/MECFS_KeyFacts.pdf Key Facts] - Institute of Medicine (2015)

'''Research'''
*[[Institute of Medicine report]] (2015) The CDC based its updated [https://www.cdc.gov/me-cfs/index.html ME/CFS page] on information in this report.
*[[Notable studies]]

'''Films'''
*''[[Forgotten Plague]]'' is a US documentary about [[Ryan Prior]], an afflicted journalist who investigates the disease and its history and why the CDC has left millions sidelined from life; available for [http://www.forgottenplague.com/ streaming and DVD purchase]. (2015)
[[File:Forgotten Plague.jpeg|200px|thumb|center]]
*''[[Unrest]]'' is a US documentary film that aired on PBS's ''Independent Lens'' in 2018 and is available for [https://www.unrest.film/watch/#digital streaming] and [https://www.unrest.film/store/ DVD purchase]. [[Jennifer Brea]], a person with [[myalgic encephalomyelitis|ME]], directs. (2017)
[[File:Unrest.jpg|400px|thumb|center]]

'''ME/CFS organization and researchers material'''
*[https://www.youtube.com/watch?v=hRdn4A2SGic Beyond the Data – Chronic Fatigue Syndrome: Advancing Research and Clinical Education] (The CDC's Dr. [[John Iskander]] interviews Dr. [[Anthony Komaroff]]. Video, 2016)
*[https://drive.google.com/file/d/1h_ZwdR4567k-mSoWahnC_id0F_fAA3Fb/view Caring for People with Myalgic Encephalomyelitis] (2018) Guide for Caretakers
*[http://youtu.be/c2vIQ92wU9Y ME/CFS Diagnosis and Name with Dr Nancy Klimas (video)]
*[http://www.openmedicinefoundation.org/what-is-mecfs/ What is ME/CFS?] By the [[Open Medicine Foundation]]

'''[[Patient mental health]]'''

:Patients that had been deemed as suffering from mental health and not a biological illness:
:*[[Karina Hansen]] is a young [[Denmark|Danish]] woman taken from her family for 3 1/2 years due to [[Per Fink]]'s insistence her ME was due to mental health issues.
:*[[Sophia Mirza]] was taken forcibly from her home to a mental hospital only to be returned shortly after; she then died of ME.
:*[[Ean Proctor]] was taken from his parents as a young boy and he was told his "parents were letting him die." He had become [[paralysis|paralyzed]] and mute and was let go in the deep end of a pool to make him swim and another time put him on a scary theme park ride to scare him into moving.

'''More mental health information'''
*ME/CFS is not [[depression]]. It causes a lack of energy, not a lack of desire.<ref name="Griffith, 2008">{{Cite journal | last1 = Griffith | first1 = J.P. | authorlink1 = | last2 = Zarrouf | first2 = F.A. | authorlink2 = | title = A Systematic Review of Chronic Fatigue Syndrome: Don’t Assume It’s Depression| url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292451/| pmc =2292451| journal = Primary Care Companion to The Journal of Clinical Psychiatry | volume = 10 | issue = 2 | page = 120–128| date = 2008 | pmid = 18458765 | doi = 10.4088/pcc.v10n0206 }}</ref><ref name="Hawk, 2006">{{Cite journal | last1 = Hawk | first1 = C | authorlink1 = | last2 = Jason | first2 = L | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = S | authorlink3 = Susan Torres-Harding| title = Differential diagnosis of chronic fatigue syndrome and major depressive disorder | journal = International Journal of Behavioral Medicine | volume = 13 | issue = 3 | page = 244-51 | date = 2006 | pmid = 17078775 | doi = 10.1207/s15327558ijbm1303_8
| url = http://www.healthrising.org/wp-content/uploads/2014/04/Hawk.-Jason.-Differential-Diagnosis-of-Chronic-Fatigue-Syndrome-and-Major-Depressive-Disorder.pdf }}</ref><ref name="myhill">{{Cite web|url = http://drmyhill.co.uk/wiki/CFS_or_depression_-_what_are_the_differences| title = CFS or depression - what are the differences | last = Myhill | first = Sarah | authorlink = Sarah Myhill | website = DrMyhill|access-date = 2021-03-22}}</ref>

==See also==
*[[Primer for the public#Disease_names_and_acronyms_around_the_world|Primer for the public (''Disease names and acronyms around the world'' section)]]

==References==
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[[Category:Primers]]