MEpedia - User contributions [en]

Bile salt

2019-04-08T14:08:46Z

77.111.245.85:x

{{Cleanup|date=March 2019|reason=Needs organizing/headings and properly cited. Image needs sourcing and license. Hypothesis and opinion without citations are on Discussion tab}}

'''Bile salts''' are found naturally in bile which is created and secreted by the liver. Bile acids are created from [[cholesterol]] (a type of fat), bile (digestion fluid), and proteins also found in the liver. The purpose of bile salts is to help breakdown and transport lipid compounds out of the intestinal lumen and into the intestinal cells.<ref>{{Cite journal|last=Cowen|first=A. E.|last2=Campbell|first2=C. B.|date=Dec 1977|title=Bile salt metabolism. I. The physiology of bile salts|url=https://www.ncbi.nlm.nih.gov/pubmed/274936|journal=Australian and New Zealand Journal of Medicine|volume=7|issue=6|pages=579–586|issn=0004-8291|pmid=274936}}</ref> Some examples of molecules that need bile salts for absorption include cholestrol and fat soluble vitamins.

Bile salts are recycled by the body. In fact, only approximately 5% of the bile salts that are used are excreted.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html|title=Secretion of Bile and the Role of Bile Acids In Digestion|website=www.vivo.colostate.edu|access-date=2019-03-22}}</ref> This metabolism of bile salts is called [https://www.sciencedirect.com/topics/medicine-and-dentistry/enterohepatic-circulation enterohepatic circulation].

=== Bile Salt Supplementation ===
Supplementing biles salts [https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery has been suggested] for those with biliary sludge (build up of bile) but not for individuals who have had their gallbladder removed. Experts at Harvard Health claim that there is no reason to supplement bile salts as long as you have a healthy functioning liver.<ref>{{Cite web|url=https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

There may be reasons to consider supplementing with bile salts if you have high cholestrol or have problems absorbing fat soluble vitamins (A,D,E,K). Note that unnecessary supplementation of bile salts has been known to cause diarrhea-- also known as bile acid malabsorption (BAM). BAM is considered to be a major cause of urgency and loose stool in ~1/3 of those with [[irritable bowel syndrome]] (IBS).<ref>{{Cite web|url=https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/identifying-diarrhea-caused-by-bile-acid-malabsorption/mac-20430098|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

===Bile Salts and the Immune System===
Bile salts are capable of communicating with [[macrophages]] (a kind of white blood cell) and facilitating an immune response. Therefore it is possible that those with altered concentrations of bile acids may be at risk for a lack of response to infections.<ref>{{Cite web|url=https://www.nature.com/articles/s41598-017-18305-x|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Secondary infections as a complication to having the flu virus are caused by the lack of immune response, probably as a result of a virus infiltrating macrophages production and become a transmission method.

'''Calcium Ion Channel Impairment'''

Sufferers of chronic fatigue have a noted reduction of specific macrophages, reduced in number compared to a healthy person with no post-viral complications.

Recent discoveries suggest a calcium ion channel impairment, for which a test is being developed:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

Calcium Ion Channel impairment in chronic fatigue sufferers:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

Macrophages In Action

Note how macrophages are relatively stable and ‘absorb’ or digest E-coli. This is how the body succumbs to secondary infection, where an invading virus deactivates the macrophage. Not every macrophage is the same phenotype, and newer macrophages will have the necessary immune response against invading viral infections.

https://www.the-scientist.com/image-of-the-day/image-of-the-day-macrophages-in-action-65701
=== Other Resources ===
Dr. Berg with a good explanation of bile salts:

https://youtu.be/wKLiXJqVIY8

A link between polymorphonuclear leukocyteintracellular calcium, plasma insulin, and essentialhypertension

https://bit.ly/2TLu2MP

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

https://www.nature.com/articles/s41598-017-18305-x

”The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus [1], rabies virus [2], and dengue virus [3].”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774560/

The role of macrophages in influenza A virus infection

https://www.futuremedicine.com/doi/pdf/10.2217/fvl.14.65

<references />
[[Category:Biochemistry and cell biology]]

Bile salt

2019-04-08T14:07:53Z

77.111.245.85:/* Other Resources */ x

{{Cleanup|date=March 2019|reason=Needs organizing/headings and properly cited. Image needs sourcing and license. Hypothesis and opinion without citations are on Discussion tab}}

'''Bile salts''' are found naturally in bile which is created and secreted by the liver. Bile acids are created from [[cholesterol]] (a type of fat), bile (digestion fluid), and proteins also found in the liver. The purpose of bile salts is to help breakdown and transport lipid compounds out of the intestinal lumen and into the intestinal cells.<ref>{{Cite journal|last=Cowen|first=A. E.|last2=Campbell|first2=C. B.|date=Dec 1977|title=Bile salt metabolism. I. The physiology of bile salts|url=https://www.ncbi.nlm.nih.gov/pubmed/274936|journal=Australian and New Zealand Journal of Medicine|volume=7|issue=6|pages=579–586|issn=0004-8291|pmid=274936}}</ref> Some examples of molecules that need bile salts for absorption include cholestrol and fat soluble vitamins.

Bile salts are recycled by the body. In fact, only approximately 5% of the bile salts that are used are excreted.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html|title=Secretion of Bile and the Role of Bile Acids In Digestion|website=www.vivo.colostate.edu|access-date=2019-03-22}}</ref> This metabolism of bile salts is called [https://www.sciencedirect.com/topics/medicine-and-dentistry/enterohepatic-circulation enterohepatic circulation].

=== Bile Salt Supplementation ===
Supplementing biles salts [https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery has been suggested] for those with biliary sludge (build up of bile) but not for individuals who have had their gallbladder removed. Experts at Harvard Health claim that there is no reason to supplement bile salts as long as you have a healthy functioning liver.<ref>{{Cite web|url=https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

There may be reasons to consider supplementing with bile salts if you have high cholestrol or have problems absorbing fat soluble vitamins (A,D,E,K). Note that unnecessary supplementation of bile salts has been known to cause diarrhea-- also known as bile acid malabsorption (BAM). BAM is considered to be a major cause of urgency and loose stool in ~1/3 of those with [[irritable bowel syndrome]] (IBS).<ref>{{Cite web|url=https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/identifying-diarrhea-caused-by-bile-acid-malabsorption/mac-20430098|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

===Bile Salts and the Immune System===
Bile salts are capable of communicating with [[macrophages]] (a kind of white blood cell) and facilitating an immune response. Therefore it is possible that those with altered concentrations of bile acids may be at risk for a lack of response to infections.<ref>{{Cite web|url=https://www.nature.com/articles/s41598-017-18305-x|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Secondary infections as a complication to having the flu virus are caused by the lack of immune response, probably as a result of a virus infiltrating macrophages production and become a transmission method.

'''Calcium Ion Channel Impairment'''

Sufferers of chronic fatigue have a noted reduction of specific macrophages, reduced in number compared to a healthy person with no post-viral complications.

Recent discoveries suggest a calcium ion channel impairment, for which a test is being developed:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

=== Other Resources ===
Dr. Berg with a good explanation of bile salts:

https://youtu.be/wKLiXJqVIY8

A link between polymorphonuclear leukocyteintracellular calcium, plasma insulin, and essentialhypertension

https://bit.ly/2TLu2MP

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

https://www.nature.com/articles/s41598-017-18305-x

”The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus [1], rabies virus [2], and dengue virus [3].”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774560/

The role of macrophages in influenza A virus infection

https://www.futuremedicine.com/doi/pdf/10.2217/fvl.14.65

<references />
[[Category:Biochemistry and cell biology]]

Talk:Bile salt

2019-04-08T13:57:19Z

77.111.245.85:/* Hypothesis and Opinion w/o Citations */

== Spam ==
This entire page was created to push a supplement and it's spam, imo. Also, the image does not show a source or license.

[[File:Bile Salt.png|thumb|Multiple bile salts surround a fat droplet so that it can be absorbed through the lumen. ]]--[[Special:Contributions/77.111.245.222|77.111.245.222]] 09:23, 5 April 2019 (EDT)
{{clear}}
==My thoughts ==
With editing, we should assume good faith. The potential treatments category covers any potential treatment as far as I can see, including those which are a particular brand (if there's only one brand of it), and being an encyclopedia treatments promoted for ME/CFS without any scientific basis are also covered, including any that might be a bit [[coffee enema | bizarre]] in my view, or that are known to not work. Having said that, I know nothing about bile salts, but I see references to [[electrolytes]], [[magnesium]], [[potassium]] and [[ion transportation]]/[[channelopathy]] which are already topics here. The article should cover the facts, with any evidence and/or criticism. It should not read as an attempt to market the product - there's no medical advice on MEpedia.

I don't see any remaining links to direct sales (not sure if they are gone).
I'm just a regular editor here so others who have been editing longer or decided on the MEpedia standards will have useful input. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 19:52, 5 April 2019 (EDT)

'''Image source'''
<br >
It seems to have come from [https://commons.wikimedia.org/wiki/File:Lipid_and_bile_salts.svg this image] on WikiMedia's Commons or another Wikipedia site so it's just a case of adding the copyright information, including the license, and the creator. Using [[Special:Upload]] for adding new files makes this easier [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 19:52, 5 April 2019 (EDT)

===Scientific sources ===

Some of these should be improved as per [[MEpedia:Science guidelines]], eg avoid websites with no author name on articles, ideally choose a book or journal. [[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 19:52, 5 April 2019 (EDT)

===Clean-up ===

The [[MEpedia:Article outlines]] show the typical format for pages, including headings and category names.
[[How to contribute]] links to more resources.

[[User:Notjusttired|notjusttired]] ([[User talk:Notjusttired|talk]]) 19:52, 5 April 2019 (EDT)

== Hypothesis and Opinion w/o Citations ==

'''The following has been moved off the page to the Discussion tab as this is hypothesis and opinion without citations.'''

Post-viral complications due to having had a virus, such as fatigue may be due to a reduction in bile acid production, which would require the addition of bile salts. A virus infiltrating macrophages, the mechanism of primary immune response, may also affect specific phenotypes and also therefore organs that produce the white blood cells.

A noted symptom of chronic fatigue such as constipation can be alleviated with Bile Salts, and is the correct supplement. Bile Salts are also needed to assist in the creation of Bile Acids, which may have been reduced during a viral infection and never restored.

The chronic fatigue sufferer may have developed excellent sleep hygiene, zero sugar intake, zero caffeine intake, taken a raft of pharmaceuticals, tried every supplement available and still have chronic fatigue. A lifetime of experiencing every virus that can contribute to the condition will also have availed themselves of macrophages for transportation.

Supplementation with Bile Salts may be problematic, requires the body to produce insulin in order to be effective. Taking Bile Salts with every meal may be counterproductive, inducing sleep after meals during the day. Recommended to take with a meal five hours before bed. Supplementation with Bile Salts may observe minor relapses of symptoms.

=== Side Effects ===
Bile Salts contain appreciable quantities of calcium phosphate and vitamin D3. Bile Salts may also contain Niacin.

Over-supplementation with Bile Salts can result in ‘skid-marks’

==== Calcium Phosphate ====
Calcium phosphate is produced by the body in quantity as a response to viral infections or mycoses. Calcium phosphate supplementation works very simply and effectively against the onset of a virus. Too much supplementation of calcium phosphate will result in fatigue.

A person suffering from a complication from having had a flu virus such as fatigue will observe significant addition to fatigue supplementing with calcium phosphate though sniffles and sneezes will be taken care of almost immediately. The body’s response to the onset of a virus by producing calcium phosphate in quantity continues long after the viral infection is dealt with.

The body produces calcium phosphate to assist the primary immune response by impeding viruses from using macrophages as a transmission method. A long term response to multiple viral infections over a lifetime is observable by small fractures that don’t heal, or perhaps a jaw bone that does not entirely close after a tooth is pulled.

Since Bile Salts contain calcium phosphate, supplementation after a period of 25-30 days will probably result in a very obvious resumption of post-viral complication such as fatigue. This would be a metabolic change and a sign to stop supplementation.

Once supplementation is stopped, it will take several days to normalize.

==== Vitamin D3 ====
Vitamin D3 can contribute to heart palpitations after lengthy supplementation. A sign that the body is excreting D3 would be reddish fluid(not blood) on toilet paper after excretion. This is a very minor result of supplementing with D3 and a sign of metabolic change.

A common complaint for sufferers of chronic fatigue is heart palpitations or post orthostatic tachycardia syndrome. POTS is presumed to be as a result of low blood volume. Obviously a person with chronic fatigue but not low blood volume can observe heart palpitations with Bile Salts, but should only be a minor relapse.

If supplementation with Bile Salts has gone on for 25 days or more and heart palpitations or a resumption of fatigue occurs these are signs of metabolic change, thus supplementation should be discontinued, and to wait out normalization.

=== Niacin ===
Bile Salts will contain appreciable amounts of vitamin B3 or Niacin. Niacin is the active ingredient in NADH. CBD oil may also contain B3. Supplementation with Bile Salts at length will contribute to insomnia. This is the same as NADH or CBD oil.

It will seem entirely counterproductive that a supplement that proposes to alleviate sleeplessness experienced in chronic fatigue may contribute to wakefulness.

Very definitive difficulty with sleep is a sign of metabolic change and a sign supplementation should be discontinued.

Unless the pharmaceutical industry comes up with a salt formulation that suppresses calcium phosphate, vitamin D, and B vitamins which are all essential vitamins and minerals, then there will probably no elegant, simple solution to chronic fatigue sufferers.--[[Special:Contributions/77.111.245.85|77.111.245.85]] 09:57, 8 April 2019 (EDT)

Bile salt

2019-04-08T13:56:35Z

77.111.245.85:cleanup info

{{Cleanup|date=March 2019|reason=Needs organizing/headings and properly cited. Image needs sourcing and license. Hypothesis and opinion without citations are on Discussion tab}}

'''Bile salts''' are found naturally in bile which is created and secreted by the liver. Bile acids are created from [[cholesterol]] (a type of fat), bile (digestion fluid), and proteins also found in the liver. The purpose of bile salts is to help breakdown and transport lipid compounds out of the intestinal lumen and into the intestinal cells.<ref>{{Cite journal|last=Cowen|first=A. E.|last2=Campbell|first2=C. B.|date=Dec 1977|title=Bile salt metabolism. I. The physiology of bile salts|url=https://www.ncbi.nlm.nih.gov/pubmed/274936|journal=Australian and New Zealand Journal of Medicine|volume=7|issue=6|pages=579–586|issn=0004-8291|pmid=274936}}</ref> Some examples of molecules that need bile salts for absorption include cholestrol and fat soluble vitamins.

Bile salts are recycled by the body. In fact, only approximately 5% of the bile salts that are used are excreted.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html|title=Secretion of Bile and the Role of Bile Acids In Digestion|website=www.vivo.colostate.edu|access-date=2019-03-22}}</ref> This metabolism of bile salts is called [https://www.sciencedirect.com/topics/medicine-and-dentistry/enterohepatic-circulation enterohepatic circulation].

=== Bile Salt Supplementation ===
Supplementing biles salts [https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery has been suggested] for those with biliary sludge (build up of bile) but not for individuals who have had their gallbladder removed. Experts at Harvard Health claim that there is no reason to supplement bile salts as long as you have a healthy functioning liver.<ref>{{Cite web|url=https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

There may be reasons to consider supplementing with bile salts if you have high cholestrol or have problems absorbing fat soluble vitamins (A,D,E,K). Note that unnecessary supplementation of bile salts has been known to cause diarrhea-- also known as bile acid malabsorption (BAM). BAM is considered to be a major cause of urgency and loose stool in ~1/3 of those with [[irritable bowel syndrome]] (IBS).<ref>{{Cite web|url=https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/identifying-diarrhea-caused-by-bile-acid-malabsorption/mac-20430098|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

===Bile Salts and the Immune System===
Bile salts are capable of communicating with [[macrophages]] (a kind of white blood cell) and facilitating an immune response. Therefore it is possible that those with altered concentrations of bile acids may be at risk for a lack of response to infections.<ref>{{Cite web|url=https://www.nature.com/articles/s41598-017-18305-x|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Secondary infections as a complication to having the flu virus are caused by the lack of immune response, probably as a result of a virus infiltrating macrophages production and become a transmission method.

'''Calcium Ion Channel Impairment'''

Sufferers of chronic fatigue have a noted reduction of specific macrophages, reduced in number compared to a healthy person with no post-viral complications.

Recent discoveries suggest a calcium ion channel impairment, for which a test is being developed:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

=== Other Resources ===
Dr. Berg with a good explanation of bile salts:

https://youtu.be/wKLiXJqVIY8

A link between polymorphonuclear leukocyteintracellular calcium, plasma insulin, and essentialhypertension

https://bit.ly/2TLu2MP

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

https://www.nature.com/articles/s41598-017-18305-x

”The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus [1], rabies virus [2], and dengue virus [3].”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774560/

The role of macrophages in influenza A virus infection

https://www.futuremedicine.com/doi/pdf/10.2217/fvl.14.65

<references />Calcium Ion Channel impairment in chronic fatigue sufferers:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

Macrophages In Action

Note how macrophages are relatively stable and ‘absorb’ or digest E-coli. This is how the body succumbs to secondary infection, where an invading virus deactivates the macrophage. Not every macrophage is the same phenotype, and newer macrophages will have the necessary immune response against invading viral infections.

https://www.the-scientist.com/image-of-the-day/image-of-the-day-macrophages-in-action-65701
[[Category:Biochemistry and cell biology]]

Bile salt

2019-04-08T13:55:24Z

77.111.245.85:there were citations for this information so it will go back onto page, for now

{{Cleanup|date=March 2019|reason=Needs organizing/headings and properly cited. Image needs sourcing and license}}

'''Bile salts''' are found naturally in bile which is created and secreted by the liver. Bile acids are created from [[cholesterol]] (a type of fat), bile (digestion fluid), and proteins also found in the liver. The purpose of bile salts is to help breakdown and transport lipid compounds out of the intestinal lumen and into the intestinal cells.<ref>{{Cite journal|last=Cowen|first=A. E.|last2=Campbell|first2=C. B.|date=Dec 1977|title=Bile salt metabolism. I. The physiology of bile salts|url=https://www.ncbi.nlm.nih.gov/pubmed/274936|journal=Australian and New Zealand Journal of Medicine|volume=7|issue=6|pages=579–586|issn=0004-8291|pmid=274936}}</ref> Some examples of molecules that need bile salts for absorption include cholestrol and fat soluble vitamins.

Bile salts are recycled by the body. In fact, only approximately 5% of the bile salts that are used are excreted.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html|title=Secretion of Bile and the Role of Bile Acids In Digestion|website=www.vivo.colostate.edu|access-date=2019-03-22}}</ref> This metabolism of bile salts is called [https://www.sciencedirect.com/topics/medicine-and-dentistry/enterohepatic-circulation enterohepatic circulation].

=== Bile Salt Supplementation ===
Supplementing biles salts [https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery has been suggested] for those with biliary sludge (build up of bile) but not for individuals who have had their gallbladder removed. Experts at Harvard Health claim that there is no reason to supplement bile salts as long as you have a healthy functioning liver.<ref>{{Cite web|url=https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

There may be reasons to consider supplementing with bile salts if you have high cholestrol or have problems absorbing fat soluble vitamins (A,D,E,K). Note that unnecessary supplementation of bile salts has been known to cause diarrhea-- also known as bile acid malabsorption (BAM). BAM is considered to be a major cause of urgency and loose stool in ~1/3 of those with [[irritable bowel syndrome]] (IBS).<ref>{{Cite web|url=https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/identifying-diarrhea-caused-by-bile-acid-malabsorption/mac-20430098|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

===Bile Salts and the Immune System===
Bile salts are capable of communicating with [[macrophages]] (a kind of white blood cell) and facilitating an immune response. Therefore it is possible that those with altered concentrations of bile acids may be at risk for a lack of response to infections.<ref>{{Cite web|url=https://www.nature.com/articles/s41598-017-18305-x|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Secondary infections as a complication to having the flu virus are caused by the lack of immune response, probably as a result of a virus infiltrating macrophages production and become a transmission method.

'''Calcium Ion Channel Impairment'''

Sufferers of chronic fatigue have a noted reduction of specific macrophages, reduced in number compared to a healthy person with no post-viral complications.

Recent discoveries suggest a calcium ion channel impairment, for which a test is being developed:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

=== Other Resources ===
Dr. Berg with a good explanation of bile salts:

https://youtu.be/wKLiXJqVIY8

A link between polymorphonuclear leukocyteintracellular calcium, plasma insulin, and essentialhypertension

https://bit.ly/2TLu2MP

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

https://www.nature.com/articles/s41598-017-18305-x

”The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus [1], rabies virus [2], and dengue virus [3].”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774560/

The role of macrophages in influenza A virus infection

https://www.futuremedicine.com/doi/pdf/10.2217/fvl.14.65

<references />Calcium Ion Channel impairment in chronic fatigue sufferers:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

Macrophages In Action

Note how macrophages are relatively stable and ‘absorb’ or digest E-coli. This is how the body succumbs to secondary infection, where an invading virus deactivates the macrophage. Not every macrophage is the same phenotype, and newer macrophages will have the necessary immune response against invading viral infections.

https://www.the-scientist.com/image-of-the-day/image-of-the-day-macrophages-in-action-65701
[[Category:Biochemistry and cell biology]]

Talk:Bile salt

2019-04-08T13:53:11Z

77.111.245.85:/* Hypothesis and Opinion w/o Citations */ new section

Bile salt

2019-04-08T13:50:59Z

77.111.245.85:Enough of hypothesizing and editorial without citations. Moving information to the Discussion tab.

{{Cleanup|date=March 2019|reason=Needs organizing/headings and properly cited. Image needs sourcing and license}}

'''Bile salts''' are found naturally in bile which is created and secreted by the liver. Bile acids are created from [[cholesterol]] (a type of fat), bile (digestion fluid), and proteins also found in the liver. The purpose of bile salts is to help breakdown and transport lipid compounds out of the intestinal lumen and into the intestinal cells.<ref>{{Cite journal|last=Cowen|first=A. E.|last2=Campbell|first2=C. B.|date=Dec 1977|title=Bile salt metabolism. I. The physiology of bile salts|url=https://www.ncbi.nlm.nih.gov/pubmed/274936|journal=Australian and New Zealand Journal of Medicine|volume=7|issue=6|pages=579–586|issn=0004-8291|pmid=274936}}</ref> Some examples of molecules that need bile salts for absorption include cholestrol and fat soluble vitamins.

Bile salts are recycled by the body. In fact, only approximately 5% of the bile salts that are used are excreted.<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html|title=Secretion of Bile and the Role of Bile Acids In Digestion|website=www.vivo.colostate.edu|access-date=2019-03-22}}</ref> This metabolism of bile salts is called [https://www.sciencedirect.com/topics/medicine-and-dentistry/enterohepatic-circulation enterohepatic circulation].

=== Bile Salt Supplementation ===
Supplementing biles salts [https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery has been suggested] for those with biliary sludge (build up of bile) but not for individuals who have had their gallbladder removed. Experts at Harvard Health claim that there is no reason to supplement bile salts as long as you have a healthy functioning liver.<ref>{{Cite web|url=https://www.health.harvard.edu/newsletter_article/do-i-need-to-take-bile-salts-after-gallbladder-surgery|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

There may be reasons to consider supplementing with bile salts if you have high cholestrol or have problems absorbing fat soluble vitamins (A,D,E,K). Note that unnecessary supplementation of bile salts has been known to cause diarrhea-- also known as bile acid malabsorption (BAM). BAM is considered to be a major cause of urgency and loose stool in ~1/3 of those with [[irritable bowel syndrome]] (IBS).<ref>{{Cite web|url=https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/identifying-diarrhea-caused-by-bile-acid-malabsorption/mac-20430098|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

=== Other Resources ===
Dr. Berg with a good explanation of bile salts:

https://youtu.be/wKLiXJqVIY8

A link between polymorphonuclear leukocyteintracellular calcium, plasma insulin, and essentialhypertension

https://bit.ly/2TLu2MP

Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

https://www.nature.com/articles/s41598-017-18305-x

”The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus [1], rabies virus [2], and dengue virus [3].”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774560/

The role of macrophages in influenza A virus infection

https://www.futuremedicine.com/doi/pdf/10.2217/fvl.14.65

<references />Calcium Ion Channel impairment in chronic fatigue sufferers:

https://www.iflscience.com/health-and-medicine/people-with-chronic-fatigue-have-a-defective-channel-in-immune-system-cells/

Macrophages In Action

Note how macrophages are relatively stable and ‘absorb’ or digest E-coli. This is how the body succumbs to secondary infection, where an invading virus deactivates the macrophage. Not every macrophage is the same phenotype, and newer macrophages will have the necessary immune response against invading viral infections.

https://www.the-scientist.com/image-of-the-day/image-of-the-day-macrophages-in-action-65701
[[Category:Biochemistry and cell biology]]

The Chronic Fatigue Syndrome Epidemic Cover-up: How a Little Newspaper Solved the Biggest Scientific and Political Mystery of Our Time

2019-02-24T01:27:19Z

77.111.245.85:cat

'''Creating The Chronic Fatigue Syndrome Epidemic Cover-up: How a Little Newspaper Solved the Biggest Scientific and Political Mystery of Our Time''' by Charles Ortleb.

{{Infobox book
| name = Creating The Chronic Fatigue Syndrome Epidemic Cover-up
| image = File:The Chronic Fatigue Syndrome Epidemic Cover-up.png
| caption = How a Little Newspaper Solved the Biggest Scientific and Political Mystery of Our Time
| author = Charles Ortleb
| illustrator =
| cover_artist =
| country = USA
| language = English
| subject = AIDS and Chronic Fatigue Syndrome
| genre = Diseases & Physical Ailments
| publisher = CreateSpace Independent Publishing Platform
| pub_date = 2018
| media_type = print and digital
| pages = 466 pages
| isbn = 978-1984115256
| website =
}}

==Synopsis==
In his bestselling book, The Black Swan, Nassim Nicholas Taleb wrote, "I see the risks of a very strange acute virus spreading throughout the planet." This book by Charles Ortleb warns that HHV-6, the virus that may be causing both Chronic Fatigue Syndrome and AIDS, is that virus.

This is a must-read book for anyone who wants to know the complicated history of the Chronic Fatigue Syndrome epidemic. Why have the CDC and NIH pretended that the communicable disease fraudulently called "Chronic Fatigue Syndrome" is a mystery for over three decades? By the end of this book of inconvenient truths the answer is crystal clear. The shocking news and bold analysis in this page-turner could lead to a revolution in the science and politics of Chronic Fatigue Syndrome, fibromyalgia, AIDS, autism, and many other illnesses. Scientists, doctors, nurses, patients, journalists, politicians, and historians must begin their journey to a full understanding of the Chronic Fatigue Syndrome epidemic with this book.

As the publisher and editor-in-chief of a small newspaper in New York, Charles Ortleb was the first journalist to devote a publication to uncovering the truth about Chronic Fatigue Syndrome. He assigned Neenyah Ostrom the duty of following every twist and turn of the Chronic Fatigue Syndrome story. No newspaper in the world did more to warn the world about the virus called HHV-6 which seems to be triggering Chronic Fatigue Syndrome and many other immunological disorders.

This provocative book will end the injustice of the silent treatment Neenyah Ostrom's reporting has been getting from the media and The Chronic Fatigue Syndrome community. Ostrom blew the lid off one of the biggest medical secrets of our time: the link between the Chronic Fatigue Syndrome epidemic and AIDS.

Ostrom interviewed most of the major researchers in the field, as well as countless patients and government scientists. She uncovered so many similarities between Chronic Fatigue Syndrome and AIDS that she came to the conclusion that they are part of the same epidemic, and she argued that until their connection is admitted by top government researchers, there is little hope of making real progress in the fight against Chronic Fatigue Syndrome.

Charles Ortleb's book captures all the challenges and excitement of running a small newspaper that was publishing a brilliant journalist who essentially was the Woodward and Bernstein of the Chronic Fatigue Syndrome epidemic. In Rolling Stone, David Black said Ortleb's newspaper deserved a Pulitzer Prize. Randy Shilts praised Ortleb's newspaper in And the Band Played On.

This book was originally published with the title "Truth to Power" in 2016. Hillary Johnson, the author of Osler's Web, called it "A rollicking, fascinating and important memoir."

==Online presence==
*[https://www.amazon.com/Chronic-Fatigue-Syndrome-Epidemic-Cover-up-ebook/dp/B0796CT24Q Amazon]

==Learn more==

==See also==

==References==
<references>

</references>
[[Category:History]]

[[Category:Books]]
[[Category:English books]]
[[Category:Health care and politics books]]‎
[[Category:History books‎ ]]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: History, Diagnostic Criteria, and Prevalence

2019-02-24T01:26:13Z

77.111.245.85:cat

{{Infobox book
| name = Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: History, Diagnostic Criteria and Prevalence
| image = File:Mecfs history diagnostic criteria prevalence.jpg
| caption =
| author = [[Mary Gloria Njoku|Mary Gloria C. Njoku]]
| illustrator =
| cover_artist =
| country = United States
| language = English
| subject = Epidemiology, history of medicine
| genre = Medical
| publisher = Booktango
| pub_date = 2016
| media_type = digital
| pages = 76
| isbn = 978-1-46897-326-6
| website =
}}
'''Myalgic, Encephalomyelitis/Chronic Fatigue Syndrome: History, Diagnostic Criteria and Prevalence''', by [[Mary Gloria Njoku|Mary Gloria C. Njoku]], with a foreword by [[Leonard Jason]], is an ebook published in 2016 that briefly covers several areas:<ref name="Njoku, 2016"/>
*an overview of the history from the 1800s to present;
*different [[definitions and diagnostic criteria]] such as [[Ramsay definition | Ramsey]] (1981), [[Holmes criteria | Holmes]] (1988), [[Oxford criteria | Oxford]] (1991), Australian definition (1990), [[ Fukuda criteria | Fukuda]] (1994), [[Canadian Consensus Criteria | Canadian Definition]] (2003), [[International Consensus Criteria | International Consensus Definition]] (2011), and the [[Institute of Medicine report |Institute of Medicine]], 2015;
*fatigue prevalence across varied continents (Africa, North America, South America, Australia/Oceania, and Europe); and
*[[pediatric]] [[epidemiology]].

==Synopsis==
This work is a comprehensive review of [[myalgic encephalomyelitis]] / [[chronic fatigue syndrome]] ([[ME/CFS]]) studies that were conducted with both community-based and hospital-based samples. A review of the prevalence of fatiguing illnesses in varied countries of the world shows evidence that the rates of [[fatigue]] and its syndromes vary across settings and countries, and that the methodology used impacts findings. Studies have also shown the presence of a severe and disabling form of fatigue that affects the ability of individuals to engage in normal occupational, educational, social and personal daily activities.

The history, definition and research findings in ME/CFS are presented to promote an understanding of the work that has been accomplished in this research area in varied continents of the world. It is hoped that some of the issues addressed in this work will help people to better understand ME/CFS and fatiguing illnesses reported in varied countries. Perhaps, the understanding that ME/CFS is a global condition might encourage both scientists and practitioners to work towards streamlining the definition and diagnostic criteria to strengthen work in this area and ultimately improve the treatment of persons with ME/CFS.

==Links==
*[https://www.amazon.com/Myalgic-Encephalomyelitis-Chronic-Fatigue-Syndrome-ebook/dp/B01LFM0S3U/ ME/CFS: History, Diagnostic Criteria and Prevalence - Amazon (US)]
*[https://www.amazon.co.uk/Myalgic-Encephalomyelitis-Chronic-Fatigue-Syndrome-ebook/dp/B01LFM0S3U/ ME/CFS: History, Diagnostic Criteria and Prevalence - Amazon (UK)]

==References==
<references>

<ref name="Njoku, 2016">{{citation
| author = [[Mary Gloria Njoku|Mary Gloria C. Njoku]]
| title = Myalgic, Encephalomyelitis/Chronic Fatigue Syndrome: History, Diagnostic Criteria and Prevalence
| type = ebook
| date = 2016
| ISBN = 978-1-4689-7326-6
}}</ref>

</references>
[[Category:History]]
[[Category:Books]][[Category:English books]][[Category:Medical books]]‎[[Category:History books ]]

Pregabalin

2018-12-27T00:42:33Z

77.111.245.85:/* Learn more */ move heading

[[File:Pregabalin Molecular Structure.png|300px|thumb|right|Pregabalin Molecular Structure]]
Pregabalin, marketed under the brand name [[Lyrica]] among others, is a medication used to treat epilepsy, neuropathic pain, [[fibromyalgia]], and generalized anxiety disorder.

==Side Effects==
This information contains side effect information about pregabalin, Lyrica's active ingredient. Some of the dosage forms listed on this page may not apply to the brand name Lyrica.

Always review a drug company's prescription drug's side effects and possible drug interactions with your doctor and pharmacist.

Pregnant women must always consult with their doctor and pharmacist when taking any prescription drug, over-the-counter drug, supplement, or herbal remedy for side effects, drug interactions, and possible miscarriage, injury, birth defect, addiction, or death to the embryo, fetus, or baby. Breastfeeding women should always talk to their doctor and pharmacist for information about breast milk being laced with the drug she has taken causing side effects, injury, addiction, or death, and drug interactions to the baby consuming her breast milk.

Check with your doctor and pharmacist before using any prescription or over-the-counter drug, supplement, or herbal remedy being administered to a child. Check with your doctor and pharmacist for children's side effects or drug interactions that may not be listed.

=== More commonly reported ones are: ===

<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Accidental injury
*bloating or swelling of the face, arms, hands, lower legs, or feet
*blurred vision
*burning, tingling, numbness or pain in the hands, arms, feet, or legs
*change in walking and balance
*clumsiness
*confusion
*dementia
*difficulty having a bowel movement
*difficulty with speaking
*double vision
*dry mouth
*false beliefs that cannot be changed by facts
*fever
*headache
*hoarseness
*increased appetite
*lack of coordination
*loss of memory
*lower back or side pain
*painful or difficult urination
*problems with memory
*rapid weight gain
*sensation of pins and needles
*shakiness
*sleepiness
*stabbing pain
*trembling, or other problems with muscle control or coordination
*unsteady walk
*unusual drowsiness
*unusual weight gain or loss<ref name=":0">{{Cite news|url=https://www.drugs.com/sfx/lyrica-side-effects.html|title=Lyrica Side Effects in Detail - Drugs.com|work=Drugs.com|access-date=2018-08-12|language=en-US}}</ref>
</div>

=== Less commonly reported ones are: ===

<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Anxiety
*bloated or feeling of fullness
*chest pain
*cold sweats
*cool, pale skin
*cough producing mucus
*decrease or change in vision
*depression
*excess air or gas in the stomach or intestines
*eye disorder
*false or unusual sense of well-being
*general feeling of discomfort or illness
*increased hunger
*loss of appetite
*loss of bladder control
*loss of consciousness
*loss of strength or energy
*muscle aches, twitching or jerking, or weakness
*nausea
*nervousness
*nightmares
*noisy breathing
*pain
*passing gas
*rhythmic movement of the muscles
*runny nose
*seizures
*shivering
*slurred speech
*sweating
*trouble sleeping
*twitching
*uncontrolled eye movements
*vomiting<ref name=":0" />
</div>

=== Other less commonly reported ones are: ===
*Difficult or labored breathing
*tightness in the chest<ref name=":0" />

=== Rarely reported ones are: ===
<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Blistering, peeling, or loosening of the skin
*chills
*cough
*diarrhea
*difficulty with swallowing
*dizziness
*fast heartbeat
*hives, itching, skin rash
*joint or muscle pain
*puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
*red skin lesions, often with a purple center
*red, irritated eyes
*sore throat
*sores, ulcers, or white spots in the mouth or on the lips
*unusual tiredness or weakness<ref name=":0" />
</div>

== Generic legal battle ==
*Mar 2012, Pfizer blocked Israel-based Teva Pharmaceutical Industries and other manufacturers from selling generic versions of Lyrica.<ref>{{Cite web|url=http://www.gabionline.net/Generics/News/Pfizer-wins-against-generic-versions-of-pain-drug-Lyrica|title=Pfizer wins against generic versions of pain drug Lyrica / News / Generics / Home - GaBI Online - Generics and Biosimilars Initiative|last=http://www.zwebb.com|first=Zwebb,|website=www.gabionline.net|language=en-GB|access-date=2018-08-12}}</ref>

*Jul 2012, the U.S. [[Food and Drug Administration]] (FDA) approved a generic version of Lyrica. Pregabalin, the active ingredient, is the generic name.<ref>{{Cite web|url=https://www.sharecare.com/health/fibromyalgia-treatment-medications/there-generic-version-of-lyrica|title=Is there a generic version of Lyrica? {{!}} Medications to Treat Fibromyalgia|last=Wiegman|first=Stacy|date=|website=Sharecare|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref><ref>{{Cite news|url=http://www.drugtopics.com/top-news/fda-approves-generic-lyrica|title=FDA approves generic Lyrica|last=|first=|date=Jul 10, 2012|work=Drug Topics|access-date=|archive-url=|archive-date=|dead-url=}}</ref> Two weeks after being approved by the FDA, marketing was blocked.<ref>{{Cite web|url=https://www.healthcentral.com/article/court-blocks-sale-of-generic-lyrica-upholds-pfizer-patents|title=Court Blocks Sale of Generic Lyrica, Upholds Pfizer Patents - Non-opioid Pain Medication - Chronic Pain {{!}} HealthCentral|last=Richards|first=Karen Lee|date=Jul 25, 2012|website=www.healthcentral.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref>

*2014, Pfizer Inc., the maker of Lyrica, successfully blocked the marketing of Pregabalin generics until December of 2018 arguing that the generics should not be marketed and made available until their patent ran out.<ref>{{Cite news|url=https://www.bloomberg.com/news/articles/2014-02-06/pfizer-wins-ruling-to-block-generic-lyrica-until-2018|title=Pfizer Wins Ruling to Block Generic Lyrica Until 2018|last=Decker|first=Susan|date=Feb 6, 2014|work=Bloomberg Business|access-date=|archive-url=|archive-date=|dead-url=}}</ref> Warner-Lamber, (a subsidieary of Pfizer), "still holds a “second medical use” patent for the use of pregabalin in the treatment of peripheral and central neuropathic pain, which expires in July 2017. A second medical use patent is one that relates to a new medical use for a known compound."<ref>{{Cite journal|last=Wise|first=Jacqui|date=2015-03-30|title=Doctors are warned not to prescribe generic pregabalin for pain control|url=https://www.bmj.com/content/350/bmj.h1724|journal=BMJ|language=en|volume=350|pages=h1724|doi=10.1136/bmj.h1724|issn=1756-1833|pmid=25825288}}</ref><ref>{{Cite web|url=https://www.fiercepharma.com/legal/don-t-use-generic-lyrica-for-pain-pfizer-warns-u-k-providers-or-else|title=Don't use generic Lyrica for pain, Pfizer warns U.K. providers--or else {{!}} FiercePharma|last=Staton|first=Tracy|date=Jan 15, 2015|website=www.fiercepharma.com|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref>
* Nov 2018, Pfizer Receives Sis Months Pediatric Exclusivity For Lyrica® (Pregabalin)<ref name=":02">{{Cite web|url=https://investors.pfizer.com/investor-news/press-release-details/2018/Pfizer-Receives-Six-Months-Pediatric-Exclusivity-for-LYRICA-pregabalin/default.aspx|title=Pfizer Receives Six Months Pediatric Exclusivity for LYRICA® (pregabalin)|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=Nov 27, 2018|website=investors.pfizer.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-12-27}}</ref>
<blockquote>Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and Drug Administration (FDA) has granted pediatric exclusivity for LYRICA<sup>®</sup>. This grant extends the period of U.S. market exclusivity for LYRICA by an additional six months, to June 30, 2019.<ref name=":02" /></blockquote>

== See also ==
*[[Fibromyalgia]]
==Learn more==

== References ==

[[Category:Potential treatments]]
[[Category:Analgesics]]
[[Category:Anticonvulsants]]
<references />

Pregabalin

2018-12-27T00:39:55Z

77.111.245.85:/* Generic legal battle */ nov 2018

[[File:Pregabalin Molecular Structure.png|300px|thumb|right|Pregabalin Molecular Structure]]
Pregabalin, marketed under the brand name [[Lyrica]] among others, is a medication used to treat epilepsy, neuropathic pain, [[fibromyalgia]], and generalized anxiety disorder.

==Side Effects==
This information contains side effect information about pregabalin, Lyrica's active ingredient. Some of the dosage forms listed on this page may not apply to the brand name Lyrica.

Always review a drug company's prescription drug's side effects and possible drug interactions with your doctor and pharmacist.

Pregnant women must always consult with their doctor and pharmacist when taking any prescription drug, over-the-counter drug, supplement, or herbal remedy for side effects, drug interactions, and possible miscarriage, injury, birth defect, addiction, or death to the embryo, fetus, or baby. Breastfeeding women should always talk to their doctor and pharmacist for information about breast milk being laced with the drug she has taken causing side effects, injury, addiction, or death, and drug interactions to the baby consuming her breast milk.

Check with your doctor and pharmacist before using any prescription or over-the-counter drug, supplement, or herbal remedy being administered to a child. Check with your doctor and pharmacist for children's side effects or drug interactions that may not be listed.

=== More commonly reported ones are: ===

<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Accidental injury
*bloating or swelling of the face, arms, hands, lower legs, or feet
*blurred vision
*burning, tingling, numbness or pain in the hands, arms, feet, or legs
*change in walking and balance
*clumsiness
*confusion
*dementia
*difficulty having a bowel movement
*difficulty with speaking
*double vision
*dry mouth
*false beliefs that cannot be changed by facts
*fever
*headache
*hoarseness
*increased appetite
*lack of coordination
*loss of memory
*lower back or side pain
*painful or difficult urination
*problems with memory
*rapid weight gain
*sensation of pins and needles
*shakiness
*sleepiness
*stabbing pain
*trembling, or other problems with muscle control or coordination
*unsteady walk
*unusual drowsiness
*unusual weight gain or loss<ref name=":0">{{Cite news|url=https://www.drugs.com/sfx/lyrica-side-effects.html|title=Lyrica Side Effects in Detail - Drugs.com|work=Drugs.com|access-date=2018-08-12|language=en-US}}</ref>
</div>

=== Less commonly reported ones are: ===

<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Anxiety
*bloated or feeling of fullness
*chest pain
*cold sweats
*cool, pale skin
*cough producing mucus
*decrease or change in vision
*depression
*excess air or gas in the stomach or intestines
*eye disorder
*false or unusual sense of well-being
*general feeling of discomfort or illness
*increased hunger
*loss of appetite
*loss of bladder control
*loss of consciousness
*loss of strength or energy
*muscle aches, twitching or jerking, or weakness
*nausea
*nervousness
*nightmares
*noisy breathing
*pain
*passing gas
*rhythmic movement of the muscles
*runny nose
*seizures
*shivering
*slurred speech
*sweating
*trouble sleeping
*twitching
*uncontrolled eye movements
*vomiting<ref name=":0" />
</div>

=== Other less commonly reported ones are: ===
*Difficult or labored breathing
*tightness in the chest<ref name=":0" />

=== Rarely reported ones are: ===
<div style="column-count:2;-moz-column-count:2;-webkit-column-count:2">
*Blistering, peeling, or loosening of the skin
*chills
*cough
*diarrhea
*difficulty with swallowing
*dizziness
*fast heartbeat
*hives, itching, skin rash
*joint or muscle pain
*puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
*red skin lesions, often with a purple center
*red, irritated eyes
*sore throat
*sores, ulcers, or white spots in the mouth or on the lips
*unusual tiredness or weakness<ref name=":0" />
</div>

== Generic legal battle ==
*Mar 2012, Pfizer blocked Israel-based Teva Pharmaceutical Industries and other manufacturers from selling generic versions of Lyrica.<ref>{{Cite web|url=http://www.gabionline.net/Generics/News/Pfizer-wins-against-generic-versions-of-pain-drug-Lyrica|title=Pfizer wins against generic versions of pain drug Lyrica / News / Generics / Home - GaBI Online - Generics and Biosimilars Initiative|last=http://www.zwebb.com|first=Zwebb,|website=www.gabionline.net|language=en-GB|access-date=2018-08-12}}</ref>

*Jul 2012, the U.S. [[Food and Drug Administration]] (FDA) approved a generic version of Lyrica. Pregabalin, the active ingredient, is the generic name.<ref>{{Cite web|url=https://www.sharecare.com/health/fibromyalgia-treatment-medications/there-generic-version-of-lyrica|title=Is there a generic version of Lyrica? {{!}} Medications to Treat Fibromyalgia|last=Wiegman|first=Stacy|date=|website=Sharecare|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref><ref>{{Cite news|url=http://www.drugtopics.com/top-news/fda-approves-generic-lyrica|title=FDA approves generic Lyrica|last=|first=|date=Jul 10, 2012|work=Drug Topics|access-date=|archive-url=|archive-date=|dead-url=}}</ref> Two weeks after being approved by the FDA, marketing was blocked.<ref>{{Cite web|url=https://www.healthcentral.com/article/court-blocks-sale-of-generic-lyrica-upholds-pfizer-patents|title=Court Blocks Sale of Generic Lyrica, Upholds Pfizer Patents - Non-opioid Pain Medication - Chronic Pain {{!}} HealthCentral|last=Richards|first=Karen Lee|date=Jul 25, 2012|website=www.healthcentral.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref>

*2014, Pfizer Inc., the maker of Lyrica, successfully blocked the marketing of Pregabalin generics until December of 2018 arguing that the generics should not be marketed and made available until their patent ran out.<ref>{{Cite news|url=https://www.bloomberg.com/news/articles/2014-02-06/pfizer-wins-ruling-to-block-generic-lyrica-until-2018|title=Pfizer Wins Ruling to Block Generic Lyrica Until 2018|last=Decker|first=Susan|date=Feb 6, 2014|work=Bloomberg Business|access-date=|archive-url=|archive-date=|dead-url=}}</ref> Warner-Lamber, (a subsidieary of Pfizer), "still holds a “second medical use” patent for the use of pregabalin in the treatment of peripheral and central neuropathic pain, which expires in July 2017. A second medical use patent is one that relates to a new medical use for a known compound."<ref>{{Cite journal|last=Wise|first=Jacqui|date=2015-03-30|title=Doctors are warned not to prescribe generic pregabalin for pain control|url=https://www.bmj.com/content/350/bmj.h1724|journal=BMJ|language=en|volume=350|pages=h1724|doi=10.1136/bmj.h1724|issn=1756-1833|pmid=25825288}}</ref><ref>{{Cite web|url=https://www.fiercepharma.com/legal/don-t-use-generic-lyrica-for-pain-pfizer-warns-u-k-providers-or-else|title=Don't use generic Lyrica for pain, Pfizer warns U.K. providers--or else {{!}} FiercePharma|last=Staton|first=Tracy|date=Jan 15, 2015|website=www.fiercepharma.com|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-08-12}}</ref>
* Nov 2018, Pfizer Receives Sis Months Pediatric Exclusivity For Lyrica® (Pregabalin)<ref name=":02">{{Cite web|url=https://investors.pfizer.com/investor-news/press-release-details/2018/Pfizer-Receives-Six-Months-Pediatric-Exclusivity-for-LYRICA-pregabalin/default.aspx|title=Pfizer Receives Six Months Pediatric Exclusivity for LYRICA® (pregabalin)|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=Nov 27, 2018|website=investors.pfizer.com|language=en-US|archive-url=|archive-date=|dead-url=|access-date=2018-12-27}}</ref>
<blockquote>Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and Drug Administration (FDA) has granted pediatric exclusivity for LYRICA<sup>®</sup>. This grant extends the period of U.S. market exclusivity for LYRICA by an additional six months, to June 30, 2019.<ref name=":02" /></blockquote>

==Learn more==

== See also ==
*[[Fibromyalgia]]

== References ==

[[Category:Potential treatments]]
[[Category:Analgesics]]
[[Category:Anticonvulsants]]
<references />

Post-exertional malaise

2018-12-27T00:23:30Z

77.111.245.85:x

'''Post-exertional malaise (PEM)''' refers to a ''worsening'' of [[List of symptoms in ME CFS|ME/CFS symptoms]] after minimal ''physical'' or ''mental'' [[exertion]],<ref name=":14" /><ref name=":32" /> which can be delayed 24-72 hours or more.<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-10-16}}</ref><ref>{{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=":15" /><ref name=":28">{{Cite web|url=https://youtu.be/RC9TjgE_PlU?t=137|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|last=Kaufman|first=David|date=Oct 16, 2018|website=YouTube|publisher=Unrest Film|archive-url=|archive-date=|dead-url=|access-date=|quote=Part of the Unrest Continuing Education module.}}</ref><ref name=":30">{{Cite journal|last=|first=|date=2018|title=SAGE Journals: Your gateway to world-class journal research|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=Sage Pub|language=en|volume=|pages=4-5|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=":31">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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=":0">{{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>{{Cite web|url=https://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|website=www.medscape.com|access-date=2018-10-10}}</ref><ref>{{Cite web|url=https://ammes.org/2018/06/04/deconstructing-post-exertional-malaise-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-a-patient-centered-cross-sectional-survey/|title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey – American ME and CFS Society|website=ammes.org|language=en-US|access-date=2018-10-16}}</ref> While in most diseases patients experience symptom relief after [[exercise|exercise,]]<ref>{{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><ref>{{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>{{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 (Houndmills, Basingstoke, England)|volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref><ref>{{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>{{Cite journal|last=Dunn|first=A. L.|last2=Trivedi|first2=M. H.|last3=O'Neal|first3=H. A.|date=June 2001|title=Physical activity dose-response effects on outcomes of depression and anxiety|url=https://www.ncbi.nlm.nih.gov/pubmed/11427783|journal=Medicine and Science in Sports and Exercise|volume=33|issue=6 Suppl|pages=S587–597; discussion 609–610|issn=0195-9131|pmid=11427783}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Almond|first2=Freya|last3=De Becker|first3=Pascale|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> Because recovery is often prolonged,<ref name=":13">{{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|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> lasting days or sometimes weeks to months,<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> patients refer to these post-exertional setbacks as ‘crashes’.<ref>{{Cite news|url=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/|title=How to Best Recover From a Crash: the ME/CFS Community Reports|work=Health Rising|access-date=2018-10-10|language=en-US}}</ref><ref name=":28" /> Depending on the criteria a patient meets ([[Canadian Consensus Criteria]] (CCC) for ME/CFS, [[International Consensus Criteria]] (ICC) for [[myalgic encephalomyelitis]], or [[Systemic Exertion Intolerance Disease]] (SEID) for ME/CFS's minimum of symptoms) will define the symptoms that will worsen.

PEM can be caused by physical as well as mental exertion<ref name=":14" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name=":3" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name=":1" /> with [[brain fog|brain fog,]]<ref name=":13" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name=":3" /> In contrast to most forms of exercise intolerance, the onset of PEM is frequently delayed<ref name=":15" /> with many patients reporting the height of their symptom flare-up, two<ref name=":13" /> or several days after the initial trigger.

The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=October 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>{{Cite journal|date=2017-05-01|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> [[immune activation|immune activation,]]<ref>{{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|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=|author-link=Jo Nijs|author-link2=Andrea Nees|author-link3=Lorna Paul|author-link4=Margot De Kooning|author-link5=Kelly Ickmans|via=|author-link6=Mira Meeus|author-link7=Jessica Van Oosterwijck}}</ref> [[gene expression]]<ref name=":20">{{Cite journal|last=Light|first=Alan R.|last2=White|first2=Andrea T.|last3=Hughen|first3=Ronald W.|last4=Light|first4=Kathleen C.|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=":21">{{Cite journal|last=Light|first=A. R.|last2=Bateman|first2=L.|last3=Jo|first3=D.|last4=Hughen|first4=R. W.|last5=VanHaitsma|first5=T. A.|last6=White|first6=A. T.|last7=Light|first7=K. C.|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>{{Cite journal|last=Meyer|first=Jacob D.|last2=Light|first2=Alan R.|last3=Shukla|first3=Sanjay K.|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron J.|last7=Cook|first7=Dane B.|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>{{Cite journal|last=White|first=A. T.|last2=Light|first2=A. R.|last3=Hughen|first3=R. W.|last4=VanHaitsma|first4=T. A.|last5=Light|first5=K. C.|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=":22">{{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=":23">{{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=":24">{{Cite journal|last=Van Oosterwijck|first=J.|last2=Nijs|first2=J.|last3=Meeus|first3=M.|last4=Lefever|first4=I.|last5=Huybrechts|first5=L.|last6=Lambrecht|first6=L.|last7=Paul|first7=L.|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=|author-link=Jessica Van Oosterwijck|author-link2=Jo Nijs|author-link3=Mira Meeus|author-link4=|author-link5=|via=|author-link7=Lorna Paul}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name=":16" /><ref name=":28" /> 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>{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=http://dx.doi.org/10.2522/ptj.20110368|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref>{{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=":17" /><ref>{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=http://dx.doi.org/10.1300/j092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref><ref name=":18" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name=":0" />

A 2015 review of the literature by the [[National Academy of Medicine]] (NAM) concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”<ref name=":0" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name=":19">{{Cite journal|last=Jason|first=Leonard A.|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=":8">{{Cite journal|last=McManimen|first=Stephanie L.|last2=Sunnquist|first2=Madison L.|last3=Jason|first3=Leonard A.|date=2016-08-24|title=Deconstructing post-exertional malaise: An exploratory factor analysis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/|journal=Journal of health psychology|doi=10.1177/1359105316664139|issn=1359-1053|pmc=5325824|pmid=27557649}}</ref>

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 house-bound or completely bed-bound 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=":32">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|title=Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|date=2018-05-18|website=www.cdc.gov|language=en-us|access-date=2018-11-21}}</ref> Examples of PEM given by the CDC are: attending a child’s school event may leave a patient house-bound 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 bed-bound and unable to do anything for days; keeping up with work may lead to spending evenings and weekends recovering.<ref name=":32" />
== Patients' description ==

=== 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 can cause severe debility. As one patient described it: [[File:Cfs woman sketch.jpg|435x435px|thumb|right|Post-exertional malaise (PEM) is a ''worsening'' of symptoms after minimal ''physical'' or ''mental'' [[exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[brain fog|brain fog,]] [[cognitive dysfunction]], and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[Headache|headaches]] and [[Migraine|migraines]]; [[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 <u>onset of PEM can be delayed 24-72 hours</u> and depending on ME/CFS severity can last days, weeks, or even months ]]<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=":0" /></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.|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 level that if exceeded, will result in a 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>{{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>{{Cite journal|last=Goudsmit|first=Ellen M.|last2=Nijs|first2=Jo|last3=Jason|first3=Leonard A.|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.

== History ==

=== 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=":10">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>{{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|Holmes definition]] of [[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>{{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 post-exertional malaise was first used in 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.

'''Currently used to define ME/CFS'''

In 2003, the [[Canadian Consensus Criteria]] (CCC) post-exertional malaise became a mandatory symptom for the diagnosis of ME/CFS. The CCC were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a flu-like distress.<ref name=":1">{{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> PEM is not a mandatory symptom under the CCC criterion.

The 2015 report of the National Academy of Medicine (NAM) 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=":0" /> PEM is a mandatory symptom under the SEID criterion.

'''Currently used to define Myalgic encephalomyelitis'''

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''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 and prolonged recovery, and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a substantial reduction in functioning, as even simple activities of daily living can cause a relapse.<ref name=":2">{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> PENE is a mandatory symptom under the ICC criterion.

===Dismissed as disturbed effort perceptions or kinesiophobia ===
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>https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf</ref>, while others saw it as an artifact of disturbed effort perceptions<ref>{{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 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>{{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.|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 [http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf Tampa scale 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 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=|dead-url=|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=":3">{{Cite journal|last=Chu|first=Lily|last2=Valencia|first2=Ian J.|last3=Garvert|first3=Donn W.|last4=Montoya|first4=Jose G.|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/pubmed/29856774|journal=PloS One|volume=13|issue=6|pages=e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|author-link=Lily Chu|author-link2=Ian Valencia|author-link3=Donn Gavert|author-link4=Jose Montoya|author-link5=|via=}}</ref> 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>{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/|title=Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=www.virology.ws|language=en-US|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term ‘crash’ to describe their relapses.

== 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 ===
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. 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=":15">{{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 exertional trigger.<ref name=":3" /> 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=":5">{{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 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=":9">{{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 |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>{{Cite journal|last=Bazelmans|first=Ellen|last2=Bleijenberg|first2=Gijs|last3=Voeten|first3=Marinus J. M.|last4=van der Meer|first4=Jos W. M.|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=|author-link=Ellen Bazelmans|author-link2=Gijs Bleijenberg|author-link3=Marinus Voeten|author-link4=Jos van der Meer|author-link5=Hans Folgering|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>{{Cite journal|last=Lapp|first=C. W.|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 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=":3" /> </blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the 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-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: [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or cognitive fog."<ref name=":1" /> </blockquote>[[Mark VanNess|Van Ness]] et al. noted how 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=":9" /></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=":3" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple triggers. Research has shown that ME/CFS patients experience PEM after both physical and cognitive exertion. 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=":14">{{Cite journal|last=Arroll|first=Megan A.|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=":10" /> </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=":11" /> 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, J.D.|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=":3" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name=":11">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Los 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=":16">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|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.
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|[[Vemeulen]] et al. 2010.
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|[[Hodges]] et al. 2018.
|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. "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=":17">{{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=":18">{{Cite journal|last=Hodges|first=L. D.|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. 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>{{Cite journal|last=Snell|first=Christopher R.|last2=Stevens|first2=Staci R.|last3=Davenport|first3=Todd E.|last4=Van Ness|first4=J. Mark|date=Nov 2013|title=Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23813081|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=1538-6724|pmid=23813081}}</ref> 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=":11" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name=":7">{{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> For these reasons PEM is usually assessed using self-reporting questionnaires.
== 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 without the disease.<ref>{{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>{{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>{{Cite journal|last=Jason|first=Leonard A.|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 [https://www.me-pedia.org/wiki/Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank], Jason et al. 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>{{Cite journal|last=Jason|first=Leonard A.|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.|last8=Strand|first8=Elin Bolle|last9=Vernon|first9=Suzanne D.|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>{{Cite journal|last=Jason|first=Leonard A.|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 expressing thoughts, PEM was once again represented with the item “physically drained/sick after mild activity.”<ref>{{Cite journal|last=Jason|first=Leonard A.|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. 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]], [[TNFa]], [[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>{{Cite journal|last=Maes|first=Michael|last2=Twisk|first2=Frank N. M.|last3=Johnson|first3=Cort|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=":0" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name=":12">{{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>{{Cite journal|last=Jason|first=L. A.|last2=Ohanian|first2=D.|last3=Brown|first3=A.|last4=Sunnquist|first4=M.|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 MS. 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 MS-patients.<ref name=":7" />
=== Major Depressive disorder ===
In the 1996 study by Komaroff et al., only 19% of patients with major [[depression]] reported PEM.<ref name=":12" /> 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>{{Cite journal|last=Hawk|first=Caroline|last2=Jason|first2=Leonard A.|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. Accordig to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/8588010|title=The validity and reliability of the fatigue syndrome that follows glandular fever. - PubMed - NCBI|last=Wjite|first=PD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at [[MicroRNA]]<nowiki/>s (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>{{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>{{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|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>

== 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=":10" /> </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=":0" />

=== Gene expression ===
One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[Leucocyte|leukocytes]] 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=":20" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name=":21" /> 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>{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=VanHaitsma|first4=Timothy A.|last5=Light|first5=Kathleen C.|date=Jan 2012|title=Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/PSY.0b013e31824152ed|issn=0033-3174|pmc=3256093|pmid=22210239}}</ref></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>{{Cite journal|last=Meyer|first=Jacob|last2=R. Light|first2=Alan|last3=Shukla|first3=Sanjay|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron|last7=Cook|first7=Dane|date=2013-10-01|title=Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression|url=https://www.researchgate.net/publication/258165434_Post-exertion_malaise_in_chronic_fatigue_syndrome_Symptoms_and_gene_expression|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|pages=190–209|doi=10.1080/21641846.2013.838444}}</ref> 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 [[functional disability]].<ref>{{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 ===
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref>{{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|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}}</ref> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
In 2005 the French team Yammes 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=":25">{{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|last2=Jones|first2=James F.|last3=Vernon|first3=Suzanne D.|last4=Rajeevan|first4=Mangalathu S.|date=Jan 2009|title=Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19015737|journal=Molecular Medicine (Cambridge, Mass.)|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|issn=1528-3658|pmc=2583111|pmid=19015737}}</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"
|<small>Study</small>
|<small>Number of participants</small>
|<small>Exercise challenge</small>
|<small>Cytokines tested:</small>
|<small>Results:</small>
|-
|<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref>{{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>
|<small>10 ([[Holmes criteria]], all cases were post-infectious)</small>
|<small>Walking 1 mile per hour for 30 min</small>
|<small>[[IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF- β]]</small>
|<small>Negative results</small>
|-
|<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref>{{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 Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|<small>12 ([[Australian criteria]])</small>
|<small>30 min hand grip exercises</small>
|<small>[[Interferon|IFN-γ]], IFN-α, IL-1 β, TNF- α</small>
|<small>Negative results</small>
|-
|<small>[[La Manca]] et al. (1999)</small><ref>{{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>
|<small>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</small>
|<small>An exhaustive treadmill exercise test</small>
|<small>[[IL-2]], [[Interleukin 4|IL-4]], [[IL-10]], IFN-γ, TNF-α</small>
|<small>Negative results</small>
|-
|<small>[[Cannon]] et al. (1997)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, interleukin-1 receptor antagonist ([[IL-1Ra]]), and soluble interleukin-1 receptor type II ([[IL-lsRII]]).</small>
|<small>Negative results</small>
|-
|<small>[[Gupta]] et al. (1998)</small><ref>{{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>
|<small>5 (Holmes criteria)</small>
|<small>30 min hand grip exercises</small>
|<small>IL-6</small>
|<small>Negative results</small>
|-
|<small>Cannon et al. (1999)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, IL-6</small>
|<small>Negative results</small>
|-
|<small>[[Yammes]] et al. (2009)</small><ref name=":25" />
|<small>9 (Fukuda criteria) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small>
|<small>Cycling test until maximal work load</small>
|<small>IL-6, TNF-a</small>
|<small>Negative results</small>
|-
|<small>[[Robinson]] et al (2010)</small><ref>{{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>
|<small>6 (Fukuda criteria)</small>
|<small>Incremental exercise test to exhaustion</small>
|<small>IL-6, [[sIL-6R]] and [[sgp130]]</small>
|<small>Negative results</small>
|-
|<small>[[White]] et al. (2010)</small><ref name=":26">{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=Bateman|first4=Lucinda|last5=Martins|first5=Thomas B.|last6=Hill|first6=Harry R.|last7=Light|first7=Kathleen C.|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>
|<small>19 (Fukuda criteria)</small>
|<small>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."</small>
|<small>IL-1β, IL-2, [[IL-12]], TNFα, soluble [[CD40L]], [[IFNγ]], [[Interleukin 4|IL-4]], IL-10, [[IL-13]], IL-6 and [[Interleukin 8|IL-8]]</small>

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

<small> </small>
|-
|<small>Andrew Lloyd et al. (2018)</small><ref name=":27">{{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>
|<small>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”</small>
|<small>Symptom limited exercise on an ergocycle.</small>
|<small>Growth factors: [[FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGFα]], [[TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small>

<small> </small>

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

<small> </small>

<small>Interleukins: IL-1α, IL-1β, [[IL-1RA]], IL-2, IL-4, [[IL-5]], IL-6, [[Interleukin 7|IL-7]], IL-8, IL-10, [[IL12p40]], [[IL12p70]], [[IL-13]], [[IL-15]], [[IL-17]], [[IL-17F]], [[IL-18]] and [[LIF]]</small>

<small> </small>

<small>[[Chemokine|Chemokines]]: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[CCL5]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small>

<small> </small>

<small>[[Interferon|Interferons]]: [[INF-α]], [[INF-β]], [[INF-ϒ]]</small>

<small> </small>

<small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small>

<small> </small>

<small>Other factors: [[CD40L]], [[FASL]], [[Leptin]], [[PAI-1]], [[Resistin]], TNF-α, [[TNF-β]], [[TRAIL]]</small>
|<small>Positive results: ME/CFS had a distinct [[cytokine profile]] post-exercise.</small>
|}
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 cytokines 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]], IL-8, CCL4, TNF-β and [[ICAM-1]]). This suggests a distinct [[cytokine inflammatory signature]] in ME/CFS.<ref name=":27" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare SF, 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 patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in IL-8), whereas the high SF patients showed a pattern of increases in both cytokine types at 8 h and no decreases at any time."<ref name=":26" /></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>{{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>{{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>{{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>{{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>{{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. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref>{{Cite journal|last=Van Oosterwijck|first=J.|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.|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=|author-link=Jessica Van Oosterwijck|author-link2=|author-link3=|author-link4=|author-link5=|via=|author-link8=Jo Nijs}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. 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>{{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. 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>{{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>{{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 team. 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>{{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>{{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>{{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>{{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>{{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. 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>{{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=":0" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|<small>Study</small>
|<small>Number of ME/CFS subjects</small>
|<small>Neurocognitive tests</small>
|<small>Results</small>
|-
|<small>[[Marshall]] et al. (1997)</small><ref>{{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>
|<small>8</small>
|<small>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).</small>
|<small>Negative</small>
|-
|<small>[[Blackwood]] et al. (1998)</small><ref>{{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}}</ref>
|<small>10</small>
|<small>"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)”</small>
|<small>Positive</small>
|-
|<small>[[La Manca]] et al. (1998)</small><ref>{{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>
|<small>19</small>
|<small>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)</small>
|<small>Positive</small>
|-
|<small>[[Claypoole]] et al. (2001)</small><ref>{{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>
|<small>21</small>
|<small>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)</small>
|<small>Negative</small>
|-
|<small>[[Dane Cook|Cook]] et al. (2005)</small><ref>{{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>
|<small>20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia</small>
|<small>Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)</small>
|<small>Negative</small>
|-
|<small>[[Yoshiuchi]] et al. (2007)</small><ref>{{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>
|<small>9</small>
|<small>A one-back memory task</small>
|<small>Negative</small>
|-
|<small>Cook et al. (2017)</small><ref>{{Cite journal|date=2017-05-01|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>
|<small>15</small>
|<small>The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task</small>
|<small>Positive</small>
|}

=== 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=":22" /> 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=":23" /><ref name=":24" /> 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>{{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>{{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>{{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>{{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>{{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 {{!}} 27 April 2012|website=www.meassociation.org.uk|language=en-US|access-date=2018-10-10}}</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=":0" />

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 [[Keiji Fukida|Fukuda]] et al. (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=":19" /> 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. Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=King|first2=Caroline P.|last3=Richman|first3=Judith A.|last4=Taylor|first4=Renee R.|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>{{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 ===
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>{{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>{{Cite web|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.|last2=Evans|first2=Meredyth Anne|date=2010|language=en|access-date=2018-10-10|last3=Porter|first3=Nicole|last4=Brown|first4=Molly|last5=Brown|first5=Abigail A.|last6=Hunnell|first6=Jessica|last7=Anderson|first7=Valerie C.|last8=Lerch|first8=Athena|last9=Meirleir|first9=Kenny de}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref>{{Cite journal|last=Strand|first=Elin B.|last2=Lillestøl|first2=Kristine|last3=Jason|first3=Leonard A.|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 particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref>{{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 5 items from the DSQ to measure PEM.<ref name=":4">https://www.commondataelements.ninds.nih.gov/Doc/MECFS/PEM_Subgroup_Summary.pdf</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).

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>{{Cite journal|last=Jason|first=Leonard|last2=Jessen|first2=Tricia|last3=Porter|first3=Nicole|last4=Boulton|first4=Aaron|last5=Gloria-Njoku|first5=Mary|date=2009-07-16|title=Examining Types of Fatigue Among Individuals with ME/CFS|url=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>{{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> 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=":5" /></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>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf</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=":5" />, though questions have been raised about the neutrality of the wording used.<ref name=":6">{{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=":6" />

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings.<ref name=":7" /> 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=":7" />

=== The DePaul Post-Exertional Malaise Questionnaire (DPEMQ) ===
The DPEMQ is a [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] based on input from hundreds of patients.<ref name=":29">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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><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=":29" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 International Consensus Criteria (ICC)<ref>{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> offered the most precise and elaborated definition of the post-exertional relapses that characterize ME. To differentiate it with 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=":2" /> 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.
# Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
# Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
# Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
# 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 many of these characteristics are necessary to diagnose PENE.
=== 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-specific fatigue.”<ref name=":8" /> 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=":13" /></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=":8" />
=== 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=":4" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref>{{Cite journal|last=Jason|first=Leonard|last2=McManimen|first2=Stephanie|last3=Sunnquist|first3=Madison|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise|journal=Fatigue: Biomedicine, Health & Behavior|doi=10.1080/21641846.2018.1453265}}</ref> 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>
# 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.
# 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=":4" />

==Notable studies==
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref>{{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)]
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="MeyerJ2013" /> [[http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref name="JasonL2015bio" /> [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="ShuklaS2015" /> [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]

*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref>{{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)]

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms,<ref name="VanNess2010" />]]
* 2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name=":31" /><ref name=":30" /> [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)]

==Notable articles==
* Dec 30, 2015 [http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/ Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)]<ref name="MEBlogg2015" />

*Nov 4, 2016 [http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome]<ref>{{Cite web|url=http://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|last=Tucker|first=Miriam|date=|website=www.medscape.com|type=Login Required|archive-url=|archive-date=|dead-url=|access-date=2018-09-06}}</ref>

==Talks & interviews==
* 2012, [https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be Top 10 Things You Should Know About Post-Exertional Relapse]<ref>{{Cite web|url=https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be|title=Top 10 Things You Should Know About Post-Exertional Relapse|last=Snell|first=Christopher|last2=Van Ness|first2=Mark|date=Jul 25, 2012|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=|last3=Stevens|first3=Staci}}</ref>
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]<ref>{{Cite web|url=https://www.youtube.com/watch?v=zZ8aPYihkpQ|title=CFS gene expression after exercise (part 1)|last=|first=|date=May 26, 2013|website=YouTube|publisher=Jw N|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* 2015, [https://www.youtube.com/watch?v=F1PP21TmUPs 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman]<ref>{{Cite web|url=https://www.youtube.com/watch?v=F1PP21TmUPs|title=Gene-expression and exercise/Gen-expressie en inspanning – dr. Lucinda Bateman|last=Bateman|first=Lucinda|date=Nov 3, 2015|website=Youtube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*2015, [https://www.youtube.com/watch?v=vfmrPd4-rIE Post-Exertion Malaise: The Intersection of Biology and Behavior]<ref name="CookD20151119v" />

*2016, [https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be|title=Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence|last=|first=|date=Jul 17, 2015|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

==See also==

*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==

*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health]<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-08-17}}</ref> (PEM Definition Included)
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]<ref name="SpotilaJ2010" />
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]<ref name="SpotilaJ20120523" />
*[https://www.verywellhealth.com/what-is-post-exertional-malaise-716023 What is Post-Exertional Malaise]<ref name="AboutHealthPEM" />
*[https://www.youtube.com/watch?v=ckT9BbSH0Lo Post-Exertional Malaise - The ME/CFS Ghost]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ckT9BbSH0Lo|title=Post-Exertional Malaise - The ME/CFS Ghost|last=|first=|date=May 13, 2016|website=YouTube|publisher=The ME/CFS Ghost|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[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?]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/|title=The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained? - Health Rising|last=Johnson|first=Cort|date=2016-07-04|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== References ==
<references>
<ref name="AboutHealthPEM">{{Cite news|url=https://www.verywellhealth.com/what-is-post-exertional-malaise-716023|title=What is Post-Exertional Malaise? Learn About a Key ME/CFS Symptom|last=Dellwo|first=Adrienne|date=|work=Verywell Health|access-date=2018-08-17|archive-url=|archive-date=|dead-url=}}</ref>
<ref name="CookD20151119v">{{citation
| last1 = Cook | first1 = DB | authorlink1 = Dane Cook
| title = Deciphering Post Exertion Malaise: The Intersection of Biology and Behavior
| type = video
| journal = Solve ME/CFS
| date = 19 Nov 2015
| url = https://www.youtube.com/watch?v=vfmrPd4-rIE
}}</ref>
<ref name="JasonL2015bio">{{Citation
| last1 = Jason | first1 = LA | authorlink1 = Leonard Jason
| last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn
| last3 = Zinn | first3 = MA | authorlink3 = Mark Zinn
| display-authors =
| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers
| journal = Current Neuropharmacology | volume = 13(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>
<ref name="McManimen, 2016">{{Citation
| last1 = McManimen | first1 = SL | authorlink1 =
| 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 = | issue = | page =
| date = 2016
| pmid = 27557649
| doi = 10.1177/1359105316664139
}}
</ref>
<ref name="MEBlogg2015">{{citation
| author = ME Blogg
| title = Suggestion to replace PEM by PAR
| date = 30 Dec 2015
| url = http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/
}}</ref>
<ref name="MeyerJ2013">{{citation
| last1 = Meyer | first1 = JD | authorlink1 = Jacob Meyer
| last2 = Light | first2 = AR | authorlink2 = Alan Light
| last3 = Shukla | first3 = SK | authorlink3 = Sanjay Shukla
| last4 = Clevidence | first4 = D | authorlink4 = Derek Clevidence
| last5 = Yale | first5 = S | authorlink5 = Steven Yale
| last6 = Stegner | first6 = AJ | authorlink6 = Aaron Stegner
| last7 = Cook | first7 = DB | authorlink7 = Dane Cook
| display-authors =
| title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression
| journal = Fatigue: Biomedicine, Health & Behavior | volume = 1 | issue = 4 | page = 190-209
| date = 2 Oct 2013
| doi = 10.1080/21641846.2013.838444
| url = http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444
}}</ref>
<ref name="ShuklaS2015">{{Citation
| last1 = Shukla | first1 = SK | authorlink1 = Sanjay Shukla
| last2 = Cook | first2 = D | authorlink2 = Dane Cook
| last3 = Meyer | first3 = JD | authorlink3 = Jacob Meyer
| last4 = Vernon | first4 = SD | authorlink4 = Suzanne Vernon
| last5 = Lee | first5 = T | authorlink5 = Thao Lee
| last6 = Clevidence | first6 = D | authorlink6 = Derek Clevidence
| last7 = Robertson | first7 = CE | authorlink7 = Charles Robertson
| last8 = Schrodi | first8 = SJ | authorlink8 = Steven Schrodi
| last9 = Yale | first9 = S | authorlink9 = Steven Yale
| last10 = Frank | first10= DN | authorlink10= Daniel Frank
| display-authors = 3
| title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
| journal = Plos One | volume = 10(12) | page =
| date = 18 December 2015
| pmid =
| doi = 10.1371/journal.pone.0145453
| url = http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453
}}</ref>
<ref name="SpotilaJ2010">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise in Chronic Fatigue Syndrome
| journal = Solve ME/CFS
| date = 2010
| url = http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf
}}</ref>
<ref name="SpotilaJ20120523">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise: Cause and Effect
| journal = Solve ME/CFS
| date = 23 May 2012
| url = http://solvecfs.org/post-exertional-malaise-cause-and-effect/
}}</ref>
<ref name="VanNess2010">{{Citation
| last1 = VanNess | first1 = M | authorlink1 = Mark VanNess
| last2 = Stevens | first2 = S | authorlink2 = Staci Stevens
| last3 = Bateman | first3 = L | authorlink3 = Lucinda Bateman
| last4 = Stiles | first4 = TL | authorlink4 = TL Stiles
| last5 = Snell | first5 = CR | authorlink5 = Christopher Snell
| display-authors =
| title = Postexertional malaise in women with chronic fatigue syndrome
| journal = Journal of Women's Health | volume = | issue = | page =
| date = February 2010
| pmid = 20095909
| doi = 10.1089/jwh.2009.1507
}}
</ref>
</references>

[[Category:Signs and symptoms]]

Talk:List of symptoms in ME CFS

2018-12-27T00:19:26Z

77.111.245.85:/* Symptoms Do NOT Correlate With Criteria */ x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[Canadian Consensus Criteria]] (CCC) MEpedia page you will see that the symptoms under the criteria do not match the symptoms on this '''List of symptoms in ME/CFS''' MEpedia page. [[Orthostatic intolerance]] seems to be missing altogether on this list page as well as other symptoms AND there seem to be symptoms listed on this page not listed on the CCC page. (Perhaps these symptoms are on the referenced/cited clinical information/research on the CCC MEpedia page but, if they are they should be listed on the CCC MEpedia page.) I'm not saying they aren't symptoms, but the heading says Canadian Consensus Criteria so, it should be LISTED on the CCC page and if on the CCC page should be on this list page.

Additionally, the [[International Consensus Criteria]] (ICC) symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

[[Systemic Exertion Intolerance Disease]] (SEID) isn't even listed.

Each of these pages needs to be double checked as this is where the symptoms are being pulled from.

See all: "List of symptoms in ME CFS/Canadian/XXXXXXXXXXXXX" on the Category:Signs and symptoms page. https://www.me-pedia.org/wiki/Category:Signs_and_symptoms

List of symptoms in ME CFS

2018-12-27T00:01:16Z

77.111.245.85:intro info

{{Cleanup|date=December 2018|reason= Canadian Consensus Criteria page's symptoms listed does not correlate with symptoms on this page. See "Discussion" Tab}}
{{stub}}

{{mbox|text=This page draws symptoms from subpages only.}}

[[Myalgic encephalomyelitis]] (ME) is a multi-systemic illness, so symptoms are commonly grouped according to the bodily system involved, for example [[nervous system|neurological system]], [[immune]] or [[cardiovascular system|cardiovascular (circulatory) system]] symptoms. [[ME/CFS]] is the acronym used to describe a set of symptoms that both ME and [[chronic fatigue syndrome]] (CFS) have in common and usually the patients' ME or CFS had an onset due to a [[flu-like illness]] or [[mononucleosis]], or other infections such as [[Brucellosis]], [[Epstein-Barr virus]], and [[Meningitis]].

However, it is unclear if ME is equivalent to CFS, is a specific form of it, or something entirely different. In ME/CFS research, the terms are often used synonymously, though there is no clear evidence to support either equating them or separating them.

The '''list of symptoms in ME CFS''' can be extensive and most patients will not have every symptom possible.

The [[International Consensus Criteria]] (ICC) is for diagnosing ME which is the most [[Severe and very severe ME|severe to very severe diagnosis]]. The [[Canadian Consensus Criteria]] (CCC) defines ME/CFS symptoms which diagnoses mostly moderate to severe patients. A minimum list of symptoms can be found for [[Systemic Exertion Intolerance Disease]] (SEID), another ME/CFS definition and meeting this criteria only (not meeting ICC or CCC) will diagnose a patient that is usually mild to moderate in symptoms and their severity.

==Canadian consensus criteria symptom list==

=== Cognitive ===
{{:List of symptoms in ME CFS/Canadian/Cognitive}}<div style="clear: both"></div><hr />
=== Motor (movement) and balance ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Motor_and_balance}} <div style="clear: both"></div><hr />
=== Sleep disruption ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sleep}} <div style="clear: both"></div><hr />
=== Visual and auditory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Visual_and_auditory}} <div style="clear: both"></div><hr />
=== Neuropsychological ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuropsychological}} <div style="clear: both"></div><hr />
=== Immune system ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Immune_system}} <div style="clear: both"></div><hr />
=== Reproductive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Reproductive}} <div style="clear: both"></div><hr/>
=== Respiratory (breathing)===
{{:List_of_symptoms_in_ME_CFS/Canadian/Respiratory}} <div style="clear: both"></div><hr />
=== Urinary ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Urinary}} <div style="clear: both"></div><hr />
=== Circulatory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Circulatory}} <div style="clear: both"></div><hr />
=== Digestive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Digestive}} <div style="clear: both"></div><hr />
=== Neuroendocrine ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuroendocrine}} <div style="clear: both"></div><hr />
=== Musculoskeletal ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Musculoskeletal}} <div style="clear: both"></div><hr />
=== Neurological (nervous system) ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neurological}} <div style="clear: both"></div><hr />
===Sensory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sensory}} <div style="clear: both"></div><br />
{{:List_of_symptoms_in_ME_CFS/box-footer|}}<div style="clear: both"></div>

==International consensus criteria symptom list ==

=== Post-exertional Neuroimmune Exhaustion (PENE) ===

''Previously known as [[Post-exertional malaise]].''
{{:List_of_symptoms_in_ME_CFS/ICC/PENE}} <div style="clear: both"></div><hr />

=== Neurological ===
<dl class="mw-body-content"><dt>1. '''Neurocognitive Impairments'''</dt>
<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Neurocognitive}}
</dd><div style="clear: both"></div>
<dt>2. '''Pain'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Pain}} <div style="clear: both"></div>

<dt>3. '''Sleep disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Sleep}} <div style="clear: both"></div>

<dt>4. '''Neurosensory, Perceptual and Motor Disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Neurosensory_and_perceptual}} <div style="clear: both"></div>

<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Motor}}
</dd><div style="clear: both"></div>
<hr />
</dl>

=== Immune, Gastro-intestinal and Genitourinary ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Immune}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Gastro}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Urinary}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/MCS}} <div style="clear: both"></div><hr />

=== Energy Metabolism/Ion Transportation ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Cardiovascular}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Respiratory}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Metabolism}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Extreme_Temperature}} <div style="clear: both"></div><hr />

===Children's symptoms===
* {{:List_of_symptoms_in_ME_CFS/ICC/Pediatric}} <div style="clear: both"></div>
{{:List_of_symptoms_in_ME_CFS/ICC/box-footer|}}<div style="clear: both"></div><hr />

==See also==

* [[Common symptoms in ME/CFS|Common symptoms]]
* [[Rare and uncommon symptoms]]
* [[Canadian Consensus Criteria]]

* [[International Consensus Criteria]]

* [[Institute of Medicine report]]

==Learn more==

* [http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf International Consensus Primer for medical practitioners]<ref name="ICP2011primer" />

* [http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx IOM report] - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]

* [http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf Canadian Consensus Criteria]

==References==
<references>
<ref name="ICP2011primer">{{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>
</references>

List of symptoms in ME CFS

2018-12-26T23:48:48Z

77.111.245.85:x

{{Cleanup|date=December 2018|reason= Canadian Consensus Criteria page's symptoms listed does not correlate with symptoms on this page. See "Discussion" Tab}}
{{stub}}

{{mbox|text=This page draws symptoms from subpages only.}}

[[Myalgic encephalomyelitis]] (ME) is a multi-systemic illness, so symptoms are commonly grouped according to the bodily system involved, for example [[nervous system|neurological system]], [[immune]] or [[cardiovascular system|cardiovascular (circulatory) system]] symptoms. [[ME/CFS]] is the acronym used to describe a set of symptoms that both ME and [[chronic fatigue syndrome]] (CFS) have in common and usually the patients illness had an onset due to a [[flu-like illness]], [[mononucleosis]], or other infections and risk factors have [[:Category:Triggers and risk factors|triggered]] ME and ME/CFS.

However, it is unclear if ME is equivalent to CFS, is a specific form of it, or something entirely different. In ME/CFS research, the terms are often used synonymously, though there is no clear evidence to support either equating them or separating them.

The '''list of symptoms in ME CFS''' can be extensive and most patients will not have every symptom possible.

The [[International Consensus Criteria]] (ICC) is for diagnosing ME which is the most [[Severe and very severe ME|severe to very severe diagnosis]]. The [[Canadian Consensus Criteria]] (CCC) defines ME/CFS symptoms which diagnoses mostly moderate to severe patients. A minimum list of symptoms can be found for [[Systemic Exertion Intolerance Disease]] (SEID), another ME/CFS definition and meeting this criteria only (not meeting ICC or CCC) will diagnose a patient that is usually mild to moderate in symptoms and their severity.

==Canadian consensus criteria symptom list==

=== Cognitive ===
{{:List of symptoms in ME CFS/Canadian/Cognitive}}<div style="clear: both"></div><hr />
=== Motor (movement) and balance ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Motor_and_balance}} <div style="clear: both"></div><hr />
=== Sleep disruption ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sleep}} <div style="clear: both"></div><hr />
=== Visual and auditory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Visual_and_auditory}} <div style="clear: both"></div><hr />
=== Neuropsychological ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuropsychological}} <div style="clear: both"></div><hr />
=== Immune system ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Immune_system}} <div style="clear: both"></div><hr />
=== Reproductive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Reproductive}} <div style="clear: both"></div><hr/>
=== Respiratory (breathing)===
{{:List_of_symptoms_in_ME_CFS/Canadian/Respiratory}} <div style="clear: both"></div><hr />
=== Urinary ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Urinary}} <div style="clear: both"></div><hr />
=== Circulatory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Circulatory}} <div style="clear: both"></div><hr />
=== Digestive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Digestive}} <div style="clear: both"></div><hr />
=== Neuroendocrine ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuroendocrine}} <div style="clear: both"></div><hr />
=== Musculoskeletal ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Musculoskeletal}} <div style="clear: both"></div><hr />
=== Neurological (nervous system) ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neurological}} <div style="clear: both"></div><hr />
===Sensory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sensory}} <div style="clear: both"></div><br />
{{:List_of_symptoms_in_ME_CFS/box-footer|}}<div style="clear: both"></div>

==International consensus criteria symptom list ==

=== Post-exertional Neuroimmune Exhaustion (PENE) ===

''Previously known as [[Post-exertional malaise]].''
{{:List_of_symptoms_in_ME_CFS/ICC/PENE}} <div style="clear: both"></div><hr />

=== Neurological ===
<dl class="mw-body-content"><dt>1. '''Neurocognitive Impairments'''</dt>
<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Neurocognitive}}
</dd><div style="clear: both"></div>
<dt>2. '''Pain'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Pain}} <div style="clear: both"></div>

<dt>3. '''Sleep disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Sleep}} <div style="clear: both"></div>

<dt>4. '''Neurosensory, Perceptual and Motor Disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Neurosensory_and_perceptual}} <div style="clear: both"></div>

<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Motor}}
</dd><div style="clear: both"></div>
<hr />
</dl>

=== Immune, Gastro-intestinal and Genitourinary ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Immune}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Gastro}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Urinary}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/MCS}} <div style="clear: both"></div><hr />

=== Energy Metabolism/Ion Transportation ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Cardiovascular}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Respiratory}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Metabolism}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Extreme_Temperature}} <div style="clear: both"></div><hr />

===Children's symptoms===
* {{:List_of_symptoms_in_ME_CFS/ICC/Pediatric}} <div style="clear: both"></div>
{{:List_of_symptoms_in_ME_CFS/ICC/box-footer|}}<div style="clear: both"></div><hr />

==See also==

* [[Common symptoms in ME/CFS|Common symptoms]]
* [[Rare and uncommon symptoms]]
* [[Canadian Consensus Criteria]]

* [[International Consensus Criteria]]

* [[Institute of Medicine report]]

==Learn more==

* [http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf International Consensus Primer for medical practitioners]<ref name="ICP2011primer" />

* [http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx IOM report] - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]

* [http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf Canadian Consensus Criteria]

==References==
<references>
<ref name="ICP2011primer">{{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>
</references>

List of symptoms in ME CFS

2018-12-26T23:47:23Z

77.111.245.85:intro information

{{Cleanup|date=December 2018|reason= Canadian Consensus Criteria page's symptoms listed does not correlate with symptoms on this page. See "Discussion" Tab}}
{{stub}}

{{mbox|text=This page draws symptoms from subpages only.}}

[[Myalgic encephalomyelitis]] (ME) is a multi-systemic illness, so symptoms are commonly grouped according to the bodily system involved, for example [[nervous system|neurological system]], [[immune]] or [[cardiovascular system|cardiovascular (circulatory) system]] symptoms. [[ME/CFS]] is the acronym used to describe a set of symptoms that both ME and [[chronic fatigue syndrome]] (CFS) have in common and usually the patients illness had an onset due to a [[flu-like illness]], [[mononucleosis]], or other infections and risk factors have [[:Category:Triggers and risk factors|triggered]] ME and ME/CFS.

However, it is unclear if ME is equivalent to CFS, is a specific form of it, or something entirely different. In ME/CFS research, the terms are often used synonymously, though there is no clear evidence to support either equating them or separating them.

The '''list of symptoms in ME CFS''' can be extensive and most patients will not have every symptom possible.

The [[International Consensus Criteria]] (ICC) is for diagnosing ME which is the most [[Severe and very severe ME|severe to very severe diagnosis]]. The [[Canadian Consensus Criteria]] (CCC) covers ME/CFS symptoms which diagnoses mostly moderate to severe patients. A minimum list of symptoms is found for [[Systemic Exertion Intolerance Disease]] (SEID), another ME/CFS definition and meeting this criteria only (not meeting ICC or CCC) will diagnose a patient that is usually mild to moderate in symptoms and their severity.

==Canadian consensus criteria symptom list==

=== Cognitive ===
{{:List of symptoms in ME CFS/Canadian/Cognitive}}<div style="clear: both"></div><hr />
=== Motor (movement) and balance ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Motor_and_balance}} <div style="clear: both"></div><hr />
=== Sleep disruption ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sleep}} <div style="clear: both"></div><hr />
=== Visual and auditory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Visual_and_auditory}} <div style="clear: both"></div><hr />
=== Neuropsychological ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuropsychological}} <div style="clear: both"></div><hr />
=== Immune system ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Immune_system}} <div style="clear: both"></div><hr />
=== Reproductive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Reproductive}} <div style="clear: both"></div><hr/>
=== Respiratory (breathing)===
{{:List_of_symptoms_in_ME_CFS/Canadian/Respiratory}} <div style="clear: both"></div><hr />
=== Urinary ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Urinary}} <div style="clear: both"></div><hr />
=== Circulatory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Circulatory}} <div style="clear: both"></div><hr />
=== Digestive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Digestive}} <div style="clear: both"></div><hr />
=== Neuroendocrine ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuroendocrine}} <div style="clear: both"></div><hr />
=== Musculoskeletal ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Musculoskeletal}} <div style="clear: both"></div><hr />
=== Neurological (nervous system) ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neurological}} <div style="clear: both"></div><hr />
===Sensory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sensory}} <div style="clear: both"></div><br />
{{:List_of_symptoms_in_ME_CFS/box-footer|}}<div style="clear: both"></div>

==International consensus criteria symptom list ==

=== Post-exertional Neuroimmune Exhaustion (PENE) ===

''Previously known as [[Post-exertional malaise]].''
{{:List_of_symptoms_in_ME_CFS/ICC/PENE}} <div style="clear: both"></div><hr />

=== Neurological ===
<dl class="mw-body-content"><dt>1. '''Neurocognitive Impairments'''</dt>
<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Neurocognitive}}
</dd><div style="clear: both"></div>
<dt>2. '''Pain'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Pain}} <div style="clear: both"></div>

<dt>3. '''Sleep disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Sleep}} <div style="clear: both"></div>

<dt>4. '''Neurosensory, Perceptual and Motor Disturbances'''</dt>
<dd style="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Neurosensory_and_perceptual}} <div style="clear: both"></div>

<dd style="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Motor}}
</dd><div style="clear: both"></div>
<hr />
</dl>

=== Immune, Gastro-intestinal and Genitourinary ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Immune}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Gastro}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Urinary}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/MCS}} <div style="clear: both"></div><hr />

=== Energy Metabolism/Ion Transportation ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Cardiovascular}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Respiratory}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Metabolism}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Extreme_Temperature}} <div style="clear: both"></div><hr />

===Children's symptoms===
* {{:List_of_symptoms_in_ME_CFS/ICC/Pediatric}} <div style="clear: both"></div>
{{:List_of_symptoms_in_ME_CFS/ICC/box-footer|}}<div style="clear: both"></div><hr />

==See also==

* [[Common symptoms in ME/CFS|Common symptoms]]
* [[Rare and uncommon symptoms]]
* [[Canadian Consensus Criteria]]

* [[International Consensus Criteria]]

* [[Institute of Medicine report]]

==Learn more==

* [http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf International Consensus Primer for medical practitioners]<ref name="ICP2011primer" />

* [http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx IOM report] - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]

* [http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf Canadian Consensus Criteria]

==References==
<references>
<ref name="ICP2011primer">{{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>
</references>

Talk:List of symptoms in ME CFS

2018-12-26T23:19:31Z

77.111.245.85:x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[Canadian Consensus Criteria]] (CCC) page you will see that the symptoms under the criteria do not match the symptoms on this '''List of symptoms in ME/CFS''' page. [[Orthostatic intolerance]] seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed on the CCC page. (Perhaps these symptoms are on the longer information on the CCC criteria but, if they are they should be listed on that page.) I'm not saying they aren't symptoms, but the heading says Canadian Consensus Criteria so, it should be LISTED on the CCC page and if on the CCC page should be on this list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the [[International Consensus Criteria]] (ICC) symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

[[Systemic Exertion Intolerance Disease]] (SEID) isn't even listed.

Each of these pages needs to be double checked as this is where the symptoms are being pulled from.

See all: "List of symptoms in ME CFS/Canadian/XXXXXXXXXXXXX" on the Category:Signs and symptoms page. https://www.me-pedia.org/wiki/Category:Signs_and_symptoms

Talk:List of symptoms in ME CFS

2018-12-26T23:19:08Z

77.111.245.85:x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[Canadian Consensus Criteria]] (CCC) page you will see that the symptoms under the criteria do not match the symptoms on this '''List of symptoms in ME/CFS''' page. [[Orthostatic intolerance]] seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed on the CCC page. (Perhaps these symptoms are on the longer information on the CCC criteria but, if they are they should be listed on that page.) I'm not saying they aren't symptoms, but the heading says Canadian Consensus Criteria so, it should be LISTED on the CCC page and if on the CCC page should be on this list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the [[International Consensus Criteria]] (ICC) symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

[[Systemic Exertion Intolerance Disease]] (SEID) isn't even listed.

Each of these pages needs to be double checked as this is where the symptoms are being pulled from.

See all: List of symptoms in ME CFS/Canadian/XXXXXXXXXXXXX on the Category:Signs and symptoms page. https://www.me-pedia.org/wiki/Category:Signs_and_symptoms

Talk:List of symptoms in ME CFS

2018-12-26T23:18:06Z

77.111.245.85:x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[Canadian Consensus Criteria]] (CCC) page you will see that the symptoms under the criteria do not match the symptoms on this '''List of symptoms in ME/CFS''' page. [[Orthostatic intolerance]] seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed on the CCC page. (Perhaps these symptoms are on the longer information on the CCC criteria but, if they are they should be listed on that page.) I'm not saying they aren't symptoms, but the heading says Canadian Consensus Criteria so, it should be LISTED on the CCC page and if on the CCC page should be on this list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the [[International Consensus Criteria]] (ICC) symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

[[Systemic Exertion Intolerance Disease]] (SEID) isn't even listed.

Each of these pages needs to be double checked as this is where the symptoms are being pulled from.

See all: List of symptoms in ME CFS/Canadian/XXXXXXXXXXXXX on the [[Category:Signs and symptoms]] page.

Talk:List of symptoms in ME CFS

2018-12-26T23:17:26Z

77.111.245.85:x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[Canadian Consensus Criteria]] (CCC) page you will see that the symptoms under the criteria do not match the symptoms on this '''List of symptoms in ME/CFS''' page. [[Orthostatic intolerance]] seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed on the CCC page. (Perhaps these symptoms are on the longer information on the CCC criteria but, if they are they should be listed on that page.) I'm not saying they aren't symptoms, but the heading says Canadian Consensus Criteria so, it should be LISTED on the CCC page and if on the CCC page should be on this list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the [[International Consensus Criteria]] (ICC) symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

[[Systemic Exertion Intolerance Disease]] (SEID) isn't even listed.

Each of these pages needs to be double checked as this is where the symptoms are being pulled from.

See all: List of symptoms in ME CFS/Canadian/XXXXXXXXXXXXX on the Signs and Symptoms category page.

Post-exertional malaise

2018-12-26T23:10:16Z

77.111.245.85:criteria and symptoms

'''Post-exertional malaise (PEM)''' refers to a ''worsening'' of [[List of symptoms in ME CFS|ME/CFS symptoms]] after minimal ''physical'' or ''mental'' [[exertion]],<ref name=":14" /><ref name=":32" /> which can be delayed 24-72 hours or more.<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-10-16}}</ref><ref>{{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=":15" /><ref name=":28">{{Cite web|url=https://youtu.be/RC9TjgE_PlU?t=137|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|last=Kaufman|first=David|date=Oct 16, 2018|website=YouTube|publisher=Unrest Film|archive-url=|archive-date=|dead-url=|access-date=|quote=Part of the Unrest Continuing Education module.}}</ref><ref name=":30">{{Cite journal|last=|first=|date=2018|title=SAGE Journals: Your gateway to world-class journal research|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=Sage Pub|language=en|volume=|pages=4-5|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=":31">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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=":0">{{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>{{Cite web|url=https://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|website=www.medscape.com|access-date=2018-10-10}}</ref><ref>{{Cite web|url=https://ammes.org/2018/06/04/deconstructing-post-exertional-malaise-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-a-patient-centered-cross-sectional-survey/|title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey – American ME and CFS Society|website=ammes.org|language=en-US|access-date=2018-10-16}}</ref> While in most diseases patients experience symptom relief after [[exercise|exercise,]]<ref>{{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><ref>{{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>{{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 (Houndmills, Basingstoke, England)|volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref><ref>{{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>{{Cite journal|last=Dunn|first=A. L.|last2=Trivedi|first2=M. H.|last3=O'Neal|first3=H. A.|date=June 2001|title=Physical activity dose-response effects on outcomes of depression and anxiety|url=https://www.ncbi.nlm.nih.gov/pubmed/11427783|journal=Medicine and Science in Sports and Exercise|volume=33|issue=6 Suppl|pages=S587–597; discussion 609–610|issn=0195-9131|pmid=11427783}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Almond|first2=Freya|last3=De Becker|first3=Pascale|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> Because recovery is often prolonged,<ref name=":13">{{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|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> lasting days or sometimes weeks to months,<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> patients refer to these post-exertional setbacks as ‘crashes’.<ref>{{Cite news|url=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/|title=How to Best Recover From a Crash: the ME/CFS Community Reports|work=Health Rising|access-date=2018-10-10|language=en-US}}</ref><ref name=":28" /> Depending on the criteria a patient meets ([[Canadian Consensus Criteria]] (CCC) for ME/CFS, [[International Consensus Criteria]] (ICC) for [[myalgic encephalomyelitis]], or [[Systemic Exertion Intolerance Disease]] (SEID) for ME/CFS's minimal symptoms) will dictate the symptoms that will worsen.

PEM can be caused by physical as well as mental exertion<ref name=":14" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name=":3" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name=":1" /> with [[brain fog|brain fog,]]<ref name=":13" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name=":3" /> In contrast to most forms of exercise intolerance, the onset of PEM is frequently delayed<ref name=":15" /> with many patients reporting the height of their symptom flare-up, two<ref name=":13" /> or several days after the initial trigger.

The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=October 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>{{Cite journal|date=2017-05-01|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> [[immune activation|immune activation,]]<ref>{{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|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=|author-link=Jo Nijs|author-link2=Andrea Nees|author-link3=Lorna Paul|author-link4=Margot De Kooning|author-link5=Kelly Ickmans|via=|author-link6=Mira Meeus|author-link7=Jessica Van Oosterwijck}}</ref> [[gene expression]]<ref name=":20">{{Cite journal|last=Light|first=Alan R.|last2=White|first2=Andrea T.|last3=Hughen|first3=Ronald W.|last4=Light|first4=Kathleen C.|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=":21">{{Cite journal|last=Light|first=A. R.|last2=Bateman|first2=L.|last3=Jo|first3=D.|last4=Hughen|first4=R. W.|last5=VanHaitsma|first5=T. A.|last6=White|first6=A. T.|last7=Light|first7=K. C.|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>{{Cite journal|last=Meyer|first=Jacob D.|last2=Light|first2=Alan R.|last3=Shukla|first3=Sanjay K.|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron J.|last7=Cook|first7=Dane B.|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>{{Cite journal|last=White|first=A. T.|last2=Light|first2=A. R.|last3=Hughen|first3=R. W.|last4=VanHaitsma|first4=T. A.|last5=Light|first5=K. C.|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=":22">{{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=":23">{{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=":24">{{Cite journal|last=Van Oosterwijck|first=J.|last2=Nijs|first2=J.|last3=Meeus|first3=M.|last4=Lefever|first4=I.|last5=Huybrechts|first5=L.|last6=Lambrecht|first6=L.|last7=Paul|first7=L.|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=|author-link=Jessica Van Oosterwijck|author-link2=Jo Nijs|author-link3=Mira Meeus|author-link4=|author-link5=|via=|author-link7=Lorna Paul}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name=":16" /><ref name=":28" /> 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>{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=http://dx.doi.org/10.2522/ptj.20110368|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref>{{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=":17" /><ref>{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=http://dx.doi.org/10.1300/j092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref><ref name=":18" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name=":0" />

A 2015 review of the literature by the [[National Academy of Medicine]] (NAM) concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”<ref name=":0" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name=":19">{{Cite journal|last=Jason|first=Leonard A.|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=":8">{{Cite journal|last=McManimen|first=Stephanie L.|last2=Sunnquist|first2=Madison L.|last3=Jason|first3=Leonard A.|date=2016-08-24|title=Deconstructing post-exertional malaise: An exploratory factor analysis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/|journal=Journal of health psychology|doi=10.1177/1359105316664139|issn=1359-1053|pmc=5325824|pmid=27557649}}</ref>

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 house-bound or completely bed-bound 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=":32">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|title=Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|date=2018-05-18|website=www.cdc.gov|language=en-us|access-date=2018-11-21}}</ref> Examples of PEM given by the CDC are: attending a child’s school event may leave a patient house-bound 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 bed-bound and unable to do anything for days; keeping up with work may lead to spending evenings and weekends recovering.<ref name=":32" />
== Patients' description ==

=== 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 can cause severe debility. As one patient described it: [[File:Cfs woman sketch.jpg|435x435px|thumb|right|Post-exertional malaise (PEM) is a ''worsening'' of symptoms after minimal ''physical'' or ''mental'' [[exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[brain fog|brain fog,]] [[cognitive dysfunction]], and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[Headache|headaches]] and [[Migraine|migraines]]; [[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 <u>onset of PEM can be delayed 24-72 hours</u> and depending on ME/CFS severity can last days, weeks, or even months ]]<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=":0" /></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.|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 level that if exceeded, will result in a 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>{{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>{{Cite journal|last=Goudsmit|first=Ellen M.|last2=Nijs|first2=Jo|last3=Jason|first3=Leonard A.|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.

== History ==

=== 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=":10">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>{{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|Holmes definition]] of [[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>{{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 post-exertional malaise was first used in 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.

'''Currently used to define ME/CFS'''

In 2003, the [[Canadian Consensus Criteria]] (CCC) post-exertional malaise became a mandatory symptom for the diagnosis of ME/CFS. The CCC were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a flu-like distress.<ref name=":1">{{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> PEM is not a mandatory symptom under the CCC criterion.

The 2015 report of the National Academy of Medicine (NAM) 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=":0" /> PEM is a mandatory symptom under the SEID criterion.

'''Currently used to define Myalgic encephalomyelitis'''

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''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 and prolonged recovery, and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a substantial reduction in functioning, as even simple activities of daily living can cause a relapse.<ref name=":2">{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> PENE is a mandatory symptom under the ICC criterion.

===Dismissed as disturbed effort perceptions or kinesiophobia ===
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>https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf</ref>, while others saw it as an artifact of disturbed effort perceptions<ref>{{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 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>{{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.|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 [http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf Tampa scale 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 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=|dead-url=|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=":3">{{Cite journal|last=Chu|first=Lily|last2=Valencia|first2=Ian J.|last3=Garvert|first3=Donn W.|last4=Montoya|first4=Jose G.|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/pubmed/29856774|journal=PloS One|volume=13|issue=6|pages=e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|author-link=Lily Chu|author-link2=Ian Valencia|author-link3=Donn Gavert|author-link4=Jose Montoya|author-link5=|via=}}</ref> 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>{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/|title=Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=www.virology.ws|language=en-US|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term ‘crash’ to describe their relapses.

== 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 ===
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. 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=":15">{{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 exertional trigger.<ref name=":3" /> 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=":5">{{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 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=":9">{{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 |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>{{Cite journal|last=Bazelmans|first=Ellen|last2=Bleijenberg|first2=Gijs|last3=Voeten|first3=Marinus J. M.|last4=van der Meer|first4=Jos W. M.|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=|author-link=Ellen Bazelmans|author-link2=Gijs Bleijenberg|author-link3=Marinus Voeten|author-link4=Jos van der Meer|author-link5=Hans Folgering|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>{{Cite journal|last=Lapp|first=C. W.|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 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=":3" /> </blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the 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-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: [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or cognitive fog."<ref name=":1" /> </blockquote>[[Mark VanNess|Van Ness]] et al. noted how 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=":9" /></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=":3" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple triggers. Research has shown that ME/CFS patients experience PEM after both physical and cognitive exertion. 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=":14">{{Cite journal|last=Arroll|first=Megan A.|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=":10" /> </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=":11" /> 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, J.D.|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=":3" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name=":11">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Los 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=":16">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|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.
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|[[Vemeulen]] et al. 2010.
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|[[Hodges]] et al. 2018.
|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. "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=":17">{{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=":18">{{Cite journal|last=Hodges|first=L. D.|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. 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>{{Cite journal|last=Snell|first=Christopher R.|last2=Stevens|first2=Staci R.|last3=Davenport|first3=Todd E.|last4=Van Ness|first4=J. Mark|date=Nov 2013|title=Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23813081|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=1538-6724|pmid=23813081}}</ref> 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=":11" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name=":7">{{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> For these reasons PEM is usually assessed using self-reporting questionnaires.
== 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 without the disease.<ref>{{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>{{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>{{Cite journal|last=Jason|first=Leonard A.|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 [https://www.me-pedia.org/wiki/Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank], Jason et al. 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>{{Cite journal|last=Jason|first=Leonard A.|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.|last8=Strand|first8=Elin Bolle|last9=Vernon|first9=Suzanne D.|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>{{Cite journal|last=Jason|first=Leonard A.|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 expressing thoughts, PEM was once again represented with the item “physically drained/sick after mild activity.”<ref>{{Cite journal|last=Jason|first=Leonard A.|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. 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]], [[TNFa]], [[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>{{Cite journal|last=Maes|first=Michael|last2=Twisk|first2=Frank N. M.|last3=Johnson|first3=Cort|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=":0" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name=":12">{{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>{{Cite journal|last=Jason|first=L. A.|last2=Ohanian|first2=D.|last3=Brown|first3=A.|last4=Sunnquist|first4=M.|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 MS. 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 MS-patients.<ref name=":7" />
=== Major Depressive disorder ===
In the 1996 study by Komaroff et al., only 19% of patients with major [[depression]] reported PEM.<ref name=":12" /> 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>{{Cite journal|last=Hawk|first=Caroline|last2=Jason|first2=Leonard A.|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. Accordig to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/8588010|title=The validity and reliability of the fatigue syndrome that follows glandular fever. - PubMed - NCBI|last=Wjite|first=PD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at [[MicroRNA]]<nowiki/>s (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>{{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>{{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|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>

== 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=":10" /> </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=":0" />

=== Gene expression ===
One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[Leucocyte|leukocytes]] 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=":20" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name=":21" /> 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>{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=VanHaitsma|first4=Timothy A.|last5=Light|first5=Kathleen C.|date=Jan 2012|title=Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/PSY.0b013e31824152ed|issn=0033-3174|pmc=3256093|pmid=22210239}}</ref></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>{{Cite journal|last=Meyer|first=Jacob|last2=R. Light|first2=Alan|last3=Shukla|first3=Sanjay|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron|last7=Cook|first7=Dane|date=2013-10-01|title=Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression|url=https://www.researchgate.net/publication/258165434_Post-exertion_malaise_in_chronic_fatigue_syndrome_Symptoms_and_gene_expression|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|pages=190–209|doi=10.1080/21641846.2013.838444}}</ref> 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 [[functional disability]].<ref>{{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 ===
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref>{{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|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}}</ref> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
In 2005 the French team Yammes 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=":25">{{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|last2=Jones|first2=James F.|last3=Vernon|first3=Suzanne D.|last4=Rajeevan|first4=Mangalathu S.|date=Jan 2009|title=Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19015737|journal=Molecular Medicine (Cambridge, Mass.)|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|issn=1528-3658|pmc=2583111|pmid=19015737}}</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"
|<small>Study</small>
|<small>Number of participants</small>
|<small>Exercise challenge</small>
|<small>Cytokines tested:</small>
|<small>Results:</small>
|-
|<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref>{{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>
|<small>10 ([[Holmes criteria]], all cases were post-infectious)</small>
|<small>Walking 1 mile per hour for 30 min</small>
|<small>[[IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF- β]]</small>
|<small>Negative results</small>
|-
|<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref>{{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 Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|<small>12 ([[Australian criteria]])</small>
|<small>30 min hand grip exercises</small>
|<small>[[Interferon|IFN-γ]], IFN-α, IL-1 β, TNF- α</small>
|<small>Negative results</small>
|-
|<small>[[La Manca]] et al. (1999)</small><ref>{{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>
|<small>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</small>
|<small>An exhaustive treadmill exercise test</small>
|<small>[[IL-2]], [[Interleukin 4|IL-4]], [[IL-10]], IFN-γ, TNF-α</small>
|<small>Negative results</small>
|-
|<small>[[Cannon]] et al. (1997)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, interleukin-1 receptor antagonist ([[IL-1Ra]]), and soluble interleukin-1 receptor type II ([[IL-lsRII]]).</small>
|<small>Negative results</small>
|-
|<small>[[Gupta]] et al. (1998)</small><ref>{{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>
|<small>5 (Holmes criteria)</small>
|<small>30 min hand grip exercises</small>
|<small>IL-6</small>
|<small>Negative results</small>
|-
|<small>Cannon et al. (1999)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, IL-6</small>
|<small>Negative results</small>
|-
|<small>[[Yammes]] et al. (2009)</small><ref name=":25" />
|<small>9 (Fukuda criteria) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small>
|<small>Cycling test until maximal work load</small>
|<small>IL-6, TNF-a</small>
|<small>Negative results</small>
|-
|<small>[[Robinson]] et al (2010)</small><ref>{{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>
|<small>6 (Fukuda criteria)</small>
|<small>Incremental exercise test to exhaustion</small>
|<small>IL-6, [[sIL-6R]] and [[sgp130]]</small>
|<small>Negative results</small>
|-
|<small>[[White]] et al. (2010)</small><ref name=":26">{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=Bateman|first4=Lucinda|last5=Martins|first5=Thomas B.|last6=Hill|first6=Harry R.|last7=Light|first7=Kathleen C.|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>
|<small>19 (Fukuda criteria)</small>
|<small>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."</small>
|<small>IL-1β, IL-2, [[IL-12]], TNFα, soluble [[CD40L]], [[IFNγ]], [[Interleukin 4|IL-4]], IL-10, [[IL-13]], IL-6 and [[Interleukin 8|IL-8]]</small>

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

<small> </small>
|-
|<small>Andrew Lloyd et al. (2018)</small><ref name=":27">{{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>
|<small>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”</small>
|<small>Symptom limited exercise on an ergocycle.</small>
|<small>Growth factors: [[FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGFα]], [[TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small>

<small> </small>

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

<small> </small>

<small>Interleukins: IL-1α, IL-1β, [[IL-1RA]], IL-2, IL-4, [[IL-5]], IL-6, [[Interleukin 7|IL-7]], IL-8, IL-10, [[IL12p40]], [[IL12p70]], [[IL-13]], [[IL-15]], [[IL-17]], [[IL-17F]], [[IL-18]] and [[LIF]]</small>

<small> </small>

<small>[[Chemokine|Chemokines]]: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[CCL5]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small>

<small> </small>

<small>[[Interferon|Interferons]]: [[INF-α]], [[INF-β]], [[INF-ϒ]]</small>

<small> </small>

<small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small>

<small> </small>

<small>Other factors: [[CD40L]], [[FASL]], [[Leptin]], [[PAI-1]], [[Resistin]], TNF-α, [[TNF-β]], [[TRAIL]]</small>
|<small>Positive results: ME/CFS had a distinct [[cytokine profile]] post-exercise.</small>
|}
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 cytokines 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]], IL-8, CCL4, TNF-β and [[ICAM-1]]). This suggests a distinct [[cytokine inflammatory signature]] in ME/CFS.<ref name=":27" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare SF, 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 patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in IL-8), whereas the high SF patients showed a pattern of increases in both cytokine types at 8 h and no decreases at any time."<ref name=":26" /></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>{{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>{{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>{{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>{{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>{{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. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref>{{Cite journal|last=Van Oosterwijck|first=J.|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.|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=|author-link=Jessica Van Oosterwijck|author-link2=|author-link3=|author-link4=|author-link5=|via=|author-link8=Jo Nijs}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. 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>{{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. 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>{{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>{{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 team. 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>{{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>{{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>{{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>{{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>{{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. 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>{{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=":0" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|<small>Study</small>
|<small>Number of ME/CFS subjects</small>
|<small>Neurocognitive tests</small>
|<small>Results</small>
|-
|<small>[[Marshall]] et al. (1997)</small><ref>{{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>
|<small>8</small>
|<small>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).</small>
|<small>Negative</small>
|-
|<small>[[Blackwood]] et al. (1998)</small><ref>{{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}}</ref>
|<small>10</small>
|<small>"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)”</small>
|<small>Positive</small>
|-
|<small>[[La Manca]] et al. (1998)</small><ref>{{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>
|<small>19</small>
|<small>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)</small>
|<small>Positive</small>
|-
|<small>[[Claypoole]] et al. (2001)</small><ref>{{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>
|<small>21</small>
|<small>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)</small>
|<small>Negative</small>
|-
|<small>[[Dane Cook|Cook]] et al. (2005)</small><ref>{{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>
|<small>20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia</small>
|<small>Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)</small>
|<small>Negative</small>
|-
|<small>[[Yoshiuchi]] et al. (2007)</small><ref>{{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>
|<small>9</small>
|<small>A one-back memory task</small>
|<small>Negative</small>
|-
|<small>Cook et al. (2017)</small><ref>{{Cite journal|date=2017-05-01|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>
|<small>15</small>
|<small>The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task</small>
|<small>Positive</small>
|}

=== 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=":22" /> 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=":23" /><ref name=":24" /> 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>{{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>{{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>{{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>{{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>{{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 {{!}} 27 April 2012|website=www.meassociation.org.uk|language=en-US|access-date=2018-10-10}}</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=":0" />

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 [[Keiji Fukida|Fukuda]] et al. (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=":19" /> 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. Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=King|first2=Caroline P.|last3=Richman|first3=Judith A.|last4=Taylor|first4=Renee R.|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>{{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 ===
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>{{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>{{Cite web|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.|last2=Evans|first2=Meredyth Anne|date=2010|language=en|access-date=2018-10-10|last3=Porter|first3=Nicole|last4=Brown|first4=Molly|last5=Brown|first5=Abigail A.|last6=Hunnell|first6=Jessica|last7=Anderson|first7=Valerie C.|last8=Lerch|first8=Athena|last9=Meirleir|first9=Kenny de}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref>{{Cite journal|last=Strand|first=Elin B.|last2=Lillestøl|first2=Kristine|last3=Jason|first3=Leonard A.|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 particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref>{{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 5 items from the DSQ to measure PEM.<ref name=":4">https://www.commondataelements.ninds.nih.gov/Doc/MECFS/PEM_Subgroup_Summary.pdf</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).

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>{{Cite journal|last=Jason|first=Leonard|last2=Jessen|first2=Tricia|last3=Porter|first3=Nicole|last4=Boulton|first4=Aaron|last5=Gloria-Njoku|first5=Mary|date=2009-07-16|title=Examining Types of Fatigue Among Individuals with ME/CFS|url=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>{{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> 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=":5" /></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>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf</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=":5" />, though questions have been raised about the neutrality of the wording used.<ref name=":6">{{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=":6" />

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings.<ref name=":7" /> 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=":7" />

=== The DePaul Post-Exertional Malaise Questionnaire (DPEMQ) ===
The DPEMQ is a [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] based on input from hundreds of patients.<ref name=":29">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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><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=":29" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 International Consensus Criteria (ICC)<ref>{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> offered the most precise and elaborated definition of the post-exertional relapses that characterize ME. To differentiate it with 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=":2" /> 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.
# Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
# Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
# Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
# 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 many of these characteristics are necessary to diagnose PENE.
=== 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-specific fatigue.”<ref name=":8" /> 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=":13" /></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=":8" />
=== 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=":4" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref>{{Cite journal|last=Jason|first=Leonard|last2=McManimen|first2=Stephanie|last3=Sunnquist|first3=Madison|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise|journal=Fatigue: Biomedicine, Health & Behavior|doi=10.1080/21641846.2018.1453265}}</ref> 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>
# 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.
# 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=":4" />

==Notable studies==
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref>{{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)]
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="MeyerJ2013" /> [[http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref name="JasonL2015bio" /> [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="ShuklaS2015" /> [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]

*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref>{{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)]

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms,<ref name="VanNess2010" />]]
* 2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name=":31" /><ref name=":30" /> [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)]

==Notable articles==
* Dec 30, 2015 [http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/ Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)]<ref name="MEBlogg2015" />

*Nov 4, 2016 [http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome]<ref>{{Cite web|url=http://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|last=Tucker|first=Miriam|date=|website=www.medscape.com|type=Login Required|archive-url=|archive-date=|dead-url=|access-date=2018-09-06}}</ref>

==Talks & interviews==
* 2012, [https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be Top 10 Things You Should Know About Post-Exertional Relapse]<ref>{{Cite web|url=https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be|title=Top 10 Things You Should Know About Post-Exertional Relapse|last=Snell|first=Christopher|last2=Van Ness|first2=Mark|date=Jul 25, 2012|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=|last3=Stevens|first3=Staci}}</ref>
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]<ref>{{Cite web|url=https://www.youtube.com/watch?v=zZ8aPYihkpQ|title=CFS gene expression after exercise (part 1)|last=|first=|date=May 26, 2013|website=YouTube|publisher=Jw N|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* 2015, [https://www.youtube.com/watch?v=F1PP21TmUPs 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman]<ref>{{Cite web|url=https://www.youtube.com/watch?v=F1PP21TmUPs|title=Gene-expression and exercise/Gen-expressie en inspanning – dr. Lucinda Bateman|last=Bateman|first=Lucinda|date=Nov 3, 2015|website=Youtube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*2015, [https://www.youtube.com/watch?v=vfmrPd4-rIE Post-Exertion Malaise: The Intersection of Biology and Behavior]<ref name="CookD20151119v" />

*2016, [https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be|title=Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence|last=|first=|date=Jul 17, 2015|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

==See also==

*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==

*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health]<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-08-17}}</ref> (PEM Definition Included)
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]<ref name="SpotilaJ2010" />
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]<ref name="SpotilaJ20120523" />
*[https://www.verywellhealth.com/what-is-post-exertional-malaise-716023 What is Post-Exertional Malaise]<ref name="AboutHealthPEM" />
*[https://www.youtube.com/watch?v=ckT9BbSH0Lo Post-Exertional Malaise - The ME/CFS Ghost]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ckT9BbSH0Lo|title=Post-Exertional Malaise - The ME/CFS Ghost|last=|first=|date=May 13, 2016|website=YouTube|publisher=The ME/CFS Ghost|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[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?]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/|title=The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained? - Health Rising|last=Johnson|first=Cort|date=2016-07-04|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== References ==
<references>
<ref name="AboutHealthPEM">{{Cite news|url=https://www.verywellhealth.com/what-is-post-exertional-malaise-716023|title=What is Post-Exertional Malaise? Learn About a Key ME/CFS Symptom|last=Dellwo|first=Adrienne|date=|work=Verywell Health|access-date=2018-08-17|archive-url=|archive-date=|dead-url=}}</ref>
<ref name="CookD20151119v">{{citation
| last1 = Cook | first1 = DB | authorlink1 = Dane Cook
| title = Deciphering Post Exertion Malaise: The Intersection of Biology and Behavior
| type = video
| journal = Solve ME/CFS
| date = 19 Nov 2015
| url = https://www.youtube.com/watch?v=vfmrPd4-rIE
}}</ref>
<ref name="JasonL2015bio">{{Citation
| last1 = Jason | first1 = LA | authorlink1 = Leonard Jason
| last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn
| last3 = Zinn | first3 = MA | authorlink3 = Mark Zinn
| display-authors =
| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers
| journal = Current Neuropharmacology | volume = 13(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>
<ref name="McManimen, 2016">{{Citation
| last1 = McManimen | first1 = SL | authorlink1 =
| 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 = | issue = | page =
| date = 2016
| pmid = 27557649
| doi = 10.1177/1359105316664139
}}
</ref>
<ref name="MEBlogg2015">{{citation
| author = ME Blogg
| title = Suggestion to replace PEM by PAR
| date = 30 Dec 2015
| url = http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/
}}</ref>
<ref name="MeyerJ2013">{{citation
| last1 = Meyer | first1 = JD | authorlink1 = Jacob Meyer
| last2 = Light | first2 = AR | authorlink2 = Alan Light
| last3 = Shukla | first3 = SK | authorlink3 = Sanjay Shukla
| last4 = Clevidence | first4 = D | authorlink4 = Derek Clevidence
| last5 = Yale | first5 = S | authorlink5 = Steven Yale
| last6 = Stegner | first6 = AJ | authorlink6 = Aaron Stegner
| last7 = Cook | first7 = DB | authorlink7 = Dane Cook
| display-authors =
| title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression
| journal = Fatigue: Biomedicine, Health & Behavior | volume = 1 | issue = 4 | page = 190-209
| date = 2 Oct 2013
| doi = 10.1080/21641846.2013.838444
| url = http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444
}}</ref>
<ref name="ShuklaS2015">{{Citation
| last1 = Shukla | first1 = SK | authorlink1 = Sanjay Shukla
| last2 = Cook | first2 = D | authorlink2 = Dane Cook
| last3 = Meyer | first3 = JD | authorlink3 = Jacob Meyer
| last4 = Vernon | first4 = SD | authorlink4 = Suzanne Vernon
| last5 = Lee | first5 = T | authorlink5 = Thao Lee
| last6 = Clevidence | first6 = D | authorlink6 = Derek Clevidence
| last7 = Robertson | first7 = CE | authorlink7 = Charles Robertson
| last8 = Schrodi | first8 = SJ | authorlink8 = Steven Schrodi
| last9 = Yale | first9 = S | authorlink9 = Steven Yale
| last10 = Frank | first10= DN | authorlink10= Daniel Frank
| display-authors = 3
| title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
| journal = Plos One | volume = 10(12) | page =
| date = 18 December 2015
| pmid =
| doi = 10.1371/journal.pone.0145453
| url = http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453
}}</ref>
<ref name="SpotilaJ2010">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise in Chronic Fatigue Syndrome
| journal = Solve ME/CFS
| date = 2010
| url = http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf
}}</ref>
<ref name="SpotilaJ20120523">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise: Cause and Effect
| journal = Solve ME/CFS
| date = 23 May 2012
| url = http://solvecfs.org/post-exertional-malaise-cause-and-effect/
}}</ref>
<ref name="VanNess2010">{{Citation
| last1 = VanNess | first1 = M | authorlink1 = Mark VanNess
| last2 = Stevens | first2 = S | authorlink2 = Staci Stevens
| last3 = Bateman | first3 = L | authorlink3 = Lucinda Bateman
| last4 = Stiles | first4 = TL | authorlink4 = TL Stiles
| last5 = Snell | first5 = CR | authorlink5 = Christopher Snell
| display-authors =
| title = Postexertional malaise in women with chronic fatigue syndrome
| journal = Journal of Women's Health | volume = | issue = | page =
| date = February 2010
| pmid = 20095909
| doi = 10.1089/jwh.2009.1507
}}
</ref>
</references>

[[Category:Signs and symptoms]]

Talk:List of symptoms in ME CFS

2018-12-26T23:02:06Z

77.111.245.85:x

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[CCC]] page you will see that the symptoms under the criteria do not match the symptoms listed. Orthostatic intolerance seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed under the criteria.

I'm not saying they aren't symptoms, but you the heading says Canadian Consensus Criteria then it should be LISTED on the CCC page and if on the CCC page should be on the list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the [[ICC]] symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

Talk:List of symptoms in ME CFS

2018-12-26T23:01:47Z

77.111.245.85:Symptoms Do NOT Correlate With Criteria

== Symptoms Do NOT Correlate With Criteria ==

If one looks at the [[CCC]] page you will see that the symptoms under the criteria do not match the symptoms listed. Orthostatic intolerance seems to be missing altogether on this list page as well as others AND there seem to be symptoms listed on this page not listed under the criteria.

I'm not saying they aren't symptoms, but you the heading says Canadian Consensus Criteria then it should be LISTED on the CCC page and if on the CCC page should be on the list page.

As it stands, this page is pretty useless as I can't rely on it.

Additionally, the ICC symptoms are basically the criteria copy and pasted, which is fine but it is different from how the CCC symptoms are set up. I think the entire page needs to be reworked.

List of symptoms in ME CFS

2018-12-26T22:57:05Z

77.111.245.85:x

{{Cleanup|date=December 2018|reason= Canadian Consensus Criteria page's symptoms listed does not correlate with symptoms on this page. See "Discussion" Tab}}
{{stub}}

{{mbox|text=This page draws symptoms from subpages only.}}

[[Myalgic Encephalomyelitis]] is a multi-systemic illness, so symptoms are commonly grouped according to the bodily system involved, for example [[nervous system|neurological system]], [[immune]] or [[cardiovascular system|cardiovascular (circulatory) system]] symptoms.

==Canadian consensus criteria symptom list==

=== Cognitive ===
{{:List of symptoms in ME CFS/Canadian/Cognitive}}<div style="clear: both"></div><hr />
=== Motor (movement) and balance ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Motor_and_balance}} <div style="clear: both"></div><hr />
=== Sleep disruption ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sleep}} <div style="clear: both"></div><hr />
=== Visual and auditory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Visual_and_auditory}} <div style="clear: both"></div><hr />
=== Neuropsychological ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuropsychological}} <div style="clear: both"></div><hr />
=== Immune system ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Immune_system}} <div style="clear: both"></div><hr />
=== Reproductive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Reproductive}} <div style="clear: both"></div><hr/>
=== Respiratory (breathing)===
{{:List_of_symptoms_in_ME_CFS/Canadian/Respiratory}} <div style="clear: both"></div><hr />
=== Urinary ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Urinary}} <div style="clear: both"></div><hr />
=== Circulatory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Circulatory}} <div style="clear: both"></div><hr />
=== Digestive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Digestive}} <div style="clear: both"></div><hr />
=== Neuroendocrine ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuroendocrine}} <div style="clear: both"></div><hr />
=== Musculoskeletal ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Musculoskeletal}} <div style="clear: both"></div><hr />
=== Neurological (nervous system) ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neurological}} <div style="clear: both"></div><hr />
===Sensory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sensory}} <div style="clear: both"></div><br />
{{:List_of_symptoms_in_ME_CFS/box-footer|}}<div style="clear: both"></div>

==International consensus criteria symptom list ==

=== Post-exertional Neuroimmune Exhaustion (PENE) ===

''Previously known as [[Post-exertional malaise]].''
{{:List_of_symptoms_in_ME_CFS/ICC/PENE}} <div style="clear: both"></div><hr />

=== Neurological ===
<dl class="mw-body-content"><dt>1. '''Neurocognitive Impairments'''</dt>
<dd style ="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Neurocognitive}}</dd><div style="clear: both"></div>
<dt>2. '''Pain'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Pain}} <div style="clear: both"></div>
<dt>3. '''Sleep disturbances'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Sleep}} <div style="clear: both"></div>
<dt>4. '''Neurosensory, Perceptual and Motor Disturbances'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Neurosensory_and_perceptual}} <div style="clear: both"></div>
<dd style ="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Motor}}</dd><div style="clear: both"></div>
<hr />
</dl>

=== Immune, Gastro-intestinal and Genitourinary ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Immune}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Gastro}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Urinary}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/MCS}} <div style="clear: both"></div><hr />

=== Energy Metabolism/Ion Transportation ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Cardiovascular}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Respiratory}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Metabolism}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Extreme_Temperature}} <div style="clear: both"></div><hr />

===Children's symptoms===
* {{:List_of_symptoms_in_ME_CFS/ICC/Pediatric}} <div style="clear: both"></div>
{{:List_of_symptoms_in_ME_CFS/ICC/box-footer|}}<div style="clear: both"></div><hr />

==See also==

* [[Common symptoms in ME/CFS|Common symptoms]]
* [[Rare and uncommon symptoms]]
* [[Canadian Consensus Criteria]]

* [[International Consensus Criteria]]

* [[Institute of Medicine report]]

==Learn more==

* [http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf International Consensus Primer for medical practitioners]<ref name="ICP2011primer" />

* [http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx IOM report] - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]

* [http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf Canadian Consensus Criteria]

==References==
<references>
<ref name="ICP2011primer">{{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>
</references>

List of symptoms in ME CFS

2018-12-26T22:56:39Z

77.111.245.85:Symptoms Do NOT Correlate With Criteria

{{Cleanup|date=December 2018|reason= Canadian Consensus Criteria page's symptoms listed does not correlate with symptoms on this page. See "Discussion" Tab.}}
{{stub}}

{{mbox|text=This page draws symptoms from subpages only.}}

[[Myalgic Encephalomyelitis]] is a multi-systemic illness, so symptoms are commonly grouped according to the bodily system involved, for example [[nervous system|neurological system]], [[immune]] or [[cardiovascular system|cardiovascular (circulatory) system]] symptoms.

==Canadian consensus criteria symptom list==

=== Cognitive ===
{{:List of symptoms in ME CFS/Canadian/Cognitive}}<div style="clear: both"></div><hr />
=== Motor (movement) and balance ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Motor_and_balance}} <div style="clear: both"></div><hr />
=== Sleep disruption ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sleep}} <div style="clear: both"></div><hr />
=== Visual and auditory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Visual_and_auditory}} <div style="clear: both"></div><hr />
=== Neuropsychological ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuropsychological}} <div style="clear: both"></div><hr />
=== Immune system ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Immune_system}} <div style="clear: both"></div><hr />
=== Reproductive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Reproductive}} <div style="clear: both"></div><hr/>
=== Respiratory (breathing)===
{{:List_of_symptoms_in_ME_CFS/Canadian/Respiratory}} <div style="clear: both"></div><hr />
=== Urinary ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Urinary}} <div style="clear: both"></div><hr />
=== Circulatory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Circulatory}} <div style="clear: both"></div><hr />
=== Digestive ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Digestive}} <div style="clear: both"></div><hr />
=== Neuroendocrine ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neuroendocrine}} <div style="clear: both"></div><hr />
=== Musculoskeletal ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Musculoskeletal}} <div style="clear: both"></div><hr />
=== Neurological (nervous system) ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Neurological}} <div style="clear: both"></div><hr />
===Sensory ===
{{:List_of_symptoms_in_ME_CFS/Canadian/Sensory}} <div style="clear: both"></div><br />
{{:List_of_symptoms_in_ME_CFS/box-footer|}}<div style="clear: both"></div>

==International consensus criteria symptom list ==

=== Post-exertional Neuroimmune Exhaustion (PENE) ===

''Previously known as [[Post-exertional malaise]].''
{{:List_of_symptoms_in_ME_CFS/ICC/PENE}} <div style="clear: both"></div><hr />

=== Neurological ===
<dl class="mw-body-content"><dt>1. '''Neurocognitive Impairments'''</dt>
<dd style ="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Neurocognitive}}</dd><div style="clear: both"></div>
<dt>2. '''Pain'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Pain}} <div style="clear: both"></div>
<dt>3. '''Sleep disturbances'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Sleep}} <div style="clear: both"></div>
<dt>4. '''Neurosensory, Perceptual and Motor Disturbances'''</dt>
<dd style ="padding-left: 0em">{{:List_of_symptoms_in_ME_CFS/ICC/Neurological/Neurosensory_and_perceptual}} <div style="clear: both"></div>
<dd style ="padding-left: 0em">{{:List of symptoms in ME CFS/ICC/Neurological/Motor}}</dd><div style="clear: both"></div>
<hr />
</dl>

=== Immune, Gastro-intestinal and Genitourinary ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Immune}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Gastro}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/Urinary}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Immune_Gastro/MCS}} <div style="clear: both"></div><hr />

=== Energy Metabolism/Ion Transportation ===
1. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Cardiovascular}} <div style="clear: both"></div>
2. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Respiratory}} <div style="clear: both"></div>
3. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Metabolism}} <div style="clear: both"></div>
4. {{:List_of_symptoms_in_ME_CFS/ICC/Energy_Ion/Extreme_Temperature}} <div style="clear: both"></div><hr />

===Children's symptoms===
* {{:List_of_symptoms_in_ME_CFS/ICC/Pediatric}} <div style="clear: both"></div>
{{:List_of_symptoms_in_ME_CFS/ICC/box-footer|}}<div style="clear: both"></div><hr />

==See also==

* [[Common symptoms in ME/CFS|Common symptoms]]
* [[Rare and uncommon symptoms]]
* [[Canadian Consensus Criteria]]

* [[International Consensus Criteria]]

* [[Institute of Medicine report]]

==Learn more==

* [http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf International Consensus Primer for medical practitioners]<ref name="ICP2011primer" />

* [http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx IOM report] - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]

* [http://www.investinme.org/Documents/PDFdocuments/CanadianDefinitionME-CFS.pdf Canadian Consensus Criteria]

==References==
<references>
<ref name="ICP2011primer">{{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>
</references>

Talk:List of symptoms in ME CFS

2018-12-26T22:50:39Z

77.111.245.85:/* Symptoms Do NOT Correlate With Criteria */ new section

Post-exertional malaise

2018-12-26T22:46:17Z

77.111.245.85:internal link

'''Post-exertional malaise (PEM)''' refers to a ''worsening'' of [[Canadian Consensus Criteria|ME/CFS symptoms]] after minimal ''physical'' or ''mental'' [[exertion]],<ref name=":14" /><ref name=":32" /> which can be delayed 24-72 hours or more.<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-10-16}}</ref><ref>{{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=":15" /><ref name=":28">{{Cite web|url=https://youtu.be/RC9TjgE_PlU?t=137|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|last=Kaufman|first=David|date=Oct 16, 2018|website=YouTube|publisher=Unrest Film|archive-url=|archive-date=|dead-url=|access-date=|quote=Part of the Unrest Continuing Education module.}}</ref><ref name=":30">{{Cite journal|last=|first=|date=2018|title=SAGE Journals: Your gateway to world-class journal research|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=Sage Pub|language=en|volume=|pages=4-5|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=":31">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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=":0">{{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>{{Cite web|url=https://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|website=www.medscape.com|access-date=2018-10-10}}</ref><ref>{{Cite web|url=https://ammes.org/2018/06/04/deconstructing-post-exertional-malaise-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-a-patient-centered-cross-sectional-survey/|title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey – American ME and CFS Society|website=ammes.org|language=en-US|access-date=2018-10-16}}</ref> While in most diseases patients experience symptom relief after [[exercise|exercise,]]<ref>{{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><ref>{{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>{{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 (Houndmills, Basingstoke, England)|volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref><ref>{{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>{{Cite journal|last=Dunn|first=A. L.|last2=Trivedi|first2=M. H.|last3=O'Neal|first3=H. A.|date=June 2001|title=Physical activity dose-response effects on outcomes of depression and anxiety|url=https://www.ncbi.nlm.nih.gov/pubmed/11427783|journal=Medicine and Science in Sports and Exercise|volume=33|issue=6 Suppl|pages=S587–597; discussion 609–610|issn=0195-9131|pmid=11427783}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Almond|first2=Freya|last3=De Becker|first3=Pascale|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> Because recovery is often prolonged,<ref name=":13">{{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|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> lasting days or sometimes weeks to months,<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> patients refer to these post-exertional setbacks as ‘crashes’.<ref>{{Cite news|url=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/|title=How to Best Recover From a Crash: the ME/CFS Community Reports|work=Health Rising|access-date=2018-10-10|language=en-US}}</ref><ref name=":28" />

PEM can be caused by physical as well as mental exertion<ref name=":14" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name=":3" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name=":1" /> with [[brain fog|brain fog,]]<ref name=":13" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name=":3" /> In contrast to most forms of exercise intolerance, the onset of PEM is frequently delayed<ref name=":15" /> with many patients reporting the height of their symptom flare-up, two<ref name=":13" /> or several days after the initial trigger.

The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=October 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>{{Cite journal|date=2017-05-01|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> [[immune activation|immune activation,]]<ref>{{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|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=|author-link=Jo Nijs|author-link2=Andrea Nees|author-link3=Lorna Paul|author-link4=Margot De Kooning|author-link5=Kelly Ickmans|via=|author-link6=Mira Meeus|author-link7=Jessica Van Oosterwijck}}</ref> [[gene expression]]<ref name=":20">{{Cite journal|last=Light|first=Alan R.|last2=White|first2=Andrea T.|last3=Hughen|first3=Ronald W.|last4=Light|first4=Kathleen C.|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=":21">{{Cite journal|last=Light|first=A. R.|last2=Bateman|first2=L.|last3=Jo|first3=D.|last4=Hughen|first4=R. W.|last5=VanHaitsma|first5=T. A.|last6=White|first6=A. T.|last7=Light|first7=K. C.|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>{{Cite journal|last=Meyer|first=Jacob D.|last2=Light|first2=Alan R.|last3=Shukla|first3=Sanjay K.|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron J.|last7=Cook|first7=Dane B.|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>{{Cite journal|last=White|first=A. T.|last2=Light|first2=A. R.|last3=Hughen|first3=R. W.|last4=VanHaitsma|first4=T. A.|last5=Light|first5=K. C.|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=":22">{{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=":23">{{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=":24">{{Cite journal|last=Van Oosterwijck|first=J.|last2=Nijs|first2=J.|last3=Meeus|first3=M.|last4=Lefever|first4=I.|last5=Huybrechts|first5=L.|last6=Lambrecht|first6=L.|last7=Paul|first7=L.|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=|author-link=Jessica Van Oosterwijck|author-link2=Jo Nijs|author-link3=Mira Meeus|author-link4=|author-link5=|via=|author-link7=Lorna Paul}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name=":16" /><ref name=":28" /> 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>{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=http://dx.doi.org/10.2522/ptj.20110368|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref>{{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=":17" /><ref>{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=http://dx.doi.org/10.1300/j092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref><ref name=":18" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name=":0" />

A 2015 review of the literature by the [[National Academy of Medicine]] (NAM) concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”<ref name=":0" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name=":19">{{Cite journal|last=Jason|first=Leonard A.|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=":8">{{Cite journal|last=McManimen|first=Stephanie L.|last2=Sunnquist|first2=Madison L.|last3=Jason|first3=Leonard A.|date=2016-08-24|title=Deconstructing post-exertional malaise: An exploratory factor analysis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/|journal=Journal of health psychology|doi=10.1177/1359105316664139|issn=1359-1053|pmc=5325824|pmid=27557649}}</ref>

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 house-bound or completely bed-bound 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=":32">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|title=Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|date=2018-05-18|website=www.cdc.gov|language=en-us|access-date=2018-11-21}}</ref> Examples of PEM given by the CDC are: attending a child’s school event may leave a patient house-bound 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 bed-bound and unable to do anything for days; keeping up with work may lead to spending evenings and weekends recovering.<ref name=":32" />
== Patients' description ==

=== 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 can cause severe debility. As one patient described it: [[File:Cfs woman sketch.jpg|435x435px|thumb|right|Post-exertional malaise (PEM) is a ''worsening'' of symptoms after minimal ''physical'' or ''mental'' [[exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[brain fog|brain fog,]] [[cognitive dysfunction]], and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[Headache|headaches]] and [[Migraine|migraines]]; [[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 <u>onset of PEM can be delayed 24-72 hours</u> and depending on ME/CFS severity can last days, weeks, or even months ]]<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=":0" /></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.|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 level that if exceeded, will result in a 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>{{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>{{Cite journal|last=Goudsmit|first=Ellen M.|last2=Nijs|first2=Jo|last3=Jason|first3=Leonard A.|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.

== History ==

=== 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=":10">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>{{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|Holmes definition]] of [[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>{{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 post-exertional malaise was first used in 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.

'''Currently used to define ME/CFS'''

In 2003, the [[Canadian Consensus Criteria]] (CCC) post-exertional malaise became a mandatory symptom for the diagnosis of ME/CFS. The CCC were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a flu-like distress.<ref name=":1">{{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> PEM is not a mandatory symptom under the CCC criterion.

The 2015 report of the National Academy of Medicine (NAM) 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=":0" /> PEM is a mandatory symptom under the SEID criterion.

'''Currently used to define Myalgic encephalomyelitis'''

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''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 and prolonged recovery, and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a substantial reduction in functioning, as even simple activities of daily living can cause a relapse.<ref name=":2">{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> PENE is a mandatory symptom under the ICC criterion.

===Dismissed as disturbed effort perceptions or kinesiophobia ===
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>https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf</ref>, while others saw it as an artifact of disturbed effort perceptions<ref>{{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 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>{{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.|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 [http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf Tampa scale 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 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=|dead-url=|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=":3">{{Cite journal|last=Chu|first=Lily|last2=Valencia|first2=Ian J.|last3=Garvert|first3=Donn W.|last4=Montoya|first4=Jose G.|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/pubmed/29856774|journal=PloS One|volume=13|issue=6|pages=e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|author-link=Lily Chu|author-link2=Ian Valencia|author-link3=Donn Gavert|author-link4=Jose Montoya|author-link5=|via=}}</ref> 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>{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/|title=Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=www.virology.ws|language=en-US|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term ‘crash’ to describe their relapses.

== 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 ===
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. 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=":15">{{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 exertional trigger.<ref name=":3" /> 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=":5">{{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 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=":9">{{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 |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>{{Cite journal|last=Bazelmans|first=Ellen|last2=Bleijenberg|first2=Gijs|last3=Voeten|first3=Marinus J. M.|last4=van der Meer|first4=Jos W. M.|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=|author-link=Ellen Bazelmans|author-link2=Gijs Bleijenberg|author-link3=Marinus Voeten|author-link4=Jos van der Meer|author-link5=Hans Folgering|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>{{Cite journal|last=Lapp|first=C. W.|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 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=":3" /> </blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the 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-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: [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or cognitive fog."<ref name=":1" /> </blockquote>[[Mark VanNess|Van Ness]] et al. noted how 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=":9" /></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=":3" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple triggers. Research has shown that ME/CFS patients experience PEM after both physical and cognitive exertion. 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=":14">{{Cite journal|last=Arroll|first=Megan A.|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=":10" /> </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=":11" /> 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, J.D.|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=":3" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name=":11">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Los 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=":16">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|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.
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|[[Vemeulen]] et al. 2010.
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|[[Hodges]] et al. 2018.
|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. "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=":17">{{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=":18">{{Cite journal|last=Hodges|first=L. D.|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. 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>{{Cite journal|last=Snell|first=Christopher R.|last2=Stevens|first2=Staci R.|last3=Davenport|first3=Todd E.|last4=Van Ness|first4=J. Mark|date=Nov 2013|title=Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23813081|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=1538-6724|pmid=23813081}}</ref> 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=":11" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name=":7">{{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> For these reasons PEM is usually assessed using self-reporting questionnaires.
== 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 without the disease.<ref>{{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>{{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>{{Cite journal|last=Jason|first=Leonard A.|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 [https://www.me-pedia.org/wiki/Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank], Jason et al. 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>{{Cite journal|last=Jason|first=Leonard A.|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.|last8=Strand|first8=Elin Bolle|last9=Vernon|first9=Suzanne D.|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>{{Cite journal|last=Jason|first=Leonard A.|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 expressing thoughts, PEM was once again represented with the item “physically drained/sick after mild activity.”<ref>{{Cite journal|last=Jason|first=Leonard A.|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. 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]], [[TNFa]], [[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>{{Cite journal|last=Maes|first=Michael|last2=Twisk|first2=Frank N. M.|last3=Johnson|first3=Cort|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=":0" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name=":12">{{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>{{Cite journal|last=Jason|first=L. A.|last2=Ohanian|first2=D.|last3=Brown|first3=A.|last4=Sunnquist|first4=M.|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 MS. 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 MS-patients.<ref name=":7" />
=== Major Depressive disorder ===
In the 1996 study by Komaroff et al., only 19% of patients with major [[depression]] reported PEM.<ref name=":12" /> 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>{{Cite journal|last=Hawk|first=Caroline|last2=Jason|first2=Leonard A.|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. Accordig to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/8588010|title=The validity and reliability of the fatigue syndrome that follows glandular fever. - PubMed - NCBI|last=Wjite|first=PD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at [[MicroRNA]]<nowiki/>s (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>{{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>{{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|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>

== 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=":10" /> </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=":0" />

=== Gene expression ===
One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[Leucocyte|leukocytes]] 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=":20" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name=":21" /> 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>{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=VanHaitsma|first4=Timothy A.|last5=Light|first5=Kathleen C.|date=Jan 2012|title=Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/PSY.0b013e31824152ed|issn=0033-3174|pmc=3256093|pmid=22210239}}</ref></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>{{Cite journal|last=Meyer|first=Jacob|last2=R. Light|first2=Alan|last3=Shukla|first3=Sanjay|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron|last7=Cook|first7=Dane|date=2013-10-01|title=Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression|url=https://www.researchgate.net/publication/258165434_Post-exertion_malaise_in_chronic_fatigue_syndrome_Symptoms_and_gene_expression|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|pages=190–209|doi=10.1080/21641846.2013.838444}}</ref> 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 [[functional disability]].<ref>{{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 ===
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref>{{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|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}}</ref> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
In 2005 the French team Yammes 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=":25">{{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|last2=Jones|first2=James F.|last3=Vernon|first3=Suzanne D.|last4=Rajeevan|first4=Mangalathu S.|date=Jan 2009|title=Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19015737|journal=Molecular Medicine (Cambridge, Mass.)|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|issn=1528-3658|pmc=2583111|pmid=19015737}}</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"
|<small>Study</small>
|<small>Number of participants</small>
|<small>Exercise challenge</small>
|<small>Cytokines tested:</small>
|<small>Results:</small>
|-
|<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref>{{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>
|<small>10 ([[Holmes criteria]], all cases were post-infectious)</small>
|<small>Walking 1 mile per hour for 30 min</small>
|<small>[[IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF- β]]</small>
|<small>Negative results</small>
|-
|<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref>{{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 Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|<small>12 ([[Australian criteria]])</small>
|<small>30 min hand grip exercises</small>
|<small>[[Interferon|IFN-γ]], IFN-α, IL-1 β, TNF- α</small>
|<small>Negative results</small>
|-
|<small>[[La Manca]] et al. (1999)</small><ref>{{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>
|<small>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</small>
|<small>An exhaustive treadmill exercise test</small>
|<small>[[IL-2]], [[Interleukin 4|IL-4]], [[IL-10]], IFN-γ, TNF-α</small>
|<small>Negative results</small>
|-
|<small>[[Cannon]] et al. (1997)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, interleukin-1 receptor antagonist ([[IL-1Ra]]), and soluble interleukin-1 receptor type II ([[IL-lsRII]]).</small>
|<small>Negative results</small>
|-
|<small>[[Gupta]] et al. (1998)</small><ref>{{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>
|<small>5 (Holmes criteria)</small>
|<small>30 min hand grip exercises</small>
|<small>IL-6</small>
|<small>Negative results</small>
|-
|<small>Cannon et al. (1999)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, IL-6</small>
|<small>Negative results</small>
|-
|<small>[[Yammes]] et al. (2009)</small><ref name=":25" />
|<small>9 (Fukuda criteria) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small>
|<small>Cycling test until maximal work load</small>
|<small>IL-6, TNF-a</small>
|<small>Negative results</small>
|-
|<small>[[Robinson]] et al (2010)</small><ref>{{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>
|<small>6 (Fukuda criteria)</small>
|<small>Incremental exercise test to exhaustion</small>
|<small>IL-6, [[sIL-6R]] and [[sgp130]]</small>
|<small>Negative results</small>
|-
|<small>[[White]] et al. (2010)</small><ref name=":26">{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=Bateman|first4=Lucinda|last5=Martins|first5=Thomas B.|last6=Hill|first6=Harry R.|last7=Light|first7=Kathleen C.|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>
|<small>19 (Fukuda criteria)</small>
|<small>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."</small>
|<small>IL-1β, IL-2, [[IL-12]], TNFα, soluble [[CD40L]], [[IFNγ]], [[Interleukin 4|IL-4]], IL-10, [[IL-13]], IL-6 and [[Interleukin 8|IL-8]]</small>

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

<small> </small>
|-
|<small>Andrew Lloyd et al. (2018)</small><ref name=":27">{{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>
|<small>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”</small>
|<small>Symptom limited exercise on an ergocycle.</small>
|<small>Growth factors: [[FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGFα]], [[TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small>

<small> </small>

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

<small> </small>

<small>Interleukins: IL-1α, IL-1β, [[IL-1RA]], IL-2, IL-4, [[IL-5]], IL-6, [[Interleukin 7|IL-7]], IL-8, IL-10, [[IL12p40]], [[IL12p70]], [[IL-13]], [[IL-15]], [[IL-17]], [[IL-17F]], [[IL-18]] and [[LIF]]</small>

<small> </small>

<small>[[Chemokine|Chemokines]]: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[CCL5]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small>

<small> </small>

<small>[[Interferon|Interferons]]: [[INF-α]], [[INF-β]], [[INF-ϒ]]</small>

<small> </small>

<small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small>

<small> </small>

<small>Other factors: [[CD40L]], [[FASL]], [[Leptin]], [[PAI-1]], [[Resistin]], TNF-α, [[TNF-β]], [[TRAIL]]</small>
|<small>Positive results: ME/CFS had a distinct [[cytokine profile]] post-exercise.</small>
|}
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 cytokines 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]], IL-8, CCL4, TNF-β and [[ICAM-1]]). This suggests a distinct [[cytokine inflammatory signature]] in ME/CFS.<ref name=":27" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare SF, 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 patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in IL-8), whereas the high SF patients showed a pattern of increases in both cytokine types at 8 h and no decreases at any time."<ref name=":26" /></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>{{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>{{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>{{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>{{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>{{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. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref>{{Cite journal|last=Van Oosterwijck|first=J.|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.|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=|author-link=Jessica Van Oosterwijck|author-link2=|author-link3=|author-link4=|author-link5=|via=|author-link8=Jo Nijs}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. 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>{{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. 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>{{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>{{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 team. 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>{{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>{{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>{{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>{{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>{{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. 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>{{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=":0" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|<small>Study</small>
|<small>Number of ME/CFS subjects</small>
|<small>Neurocognitive tests</small>
|<small>Results</small>
|-
|<small>[[Marshall]] et al. (1997)</small><ref>{{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>
|<small>8</small>
|<small>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).</small>
|<small>Negative</small>
|-
|<small>[[Blackwood]] et al. (1998)</small><ref>{{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}}</ref>
|<small>10</small>
|<small>"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)”</small>
|<small>Positive</small>
|-
|<small>[[La Manca]] et al. (1998)</small><ref>{{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>
|<small>19</small>
|<small>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)</small>
|<small>Positive</small>
|-
|<small>[[Claypoole]] et al. (2001)</small><ref>{{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>
|<small>21</small>
|<small>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)</small>
|<small>Negative</small>
|-
|<small>[[Dane Cook|Cook]] et al. (2005)</small><ref>{{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>
|<small>20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia</small>
|<small>Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)</small>
|<small>Negative</small>
|-
|<small>[[Yoshiuchi]] et al. (2007)</small><ref>{{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>
|<small>9</small>
|<small>A one-back memory task</small>
|<small>Negative</small>
|-
|<small>Cook et al. (2017)</small><ref>{{Cite journal|date=2017-05-01|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>
|<small>15</small>
|<small>The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task</small>
|<small>Positive</small>
|}

=== 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=":22" /> 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=":23" /><ref name=":24" /> 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>{{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>{{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>{{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>{{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>{{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 {{!}} 27 April 2012|website=www.meassociation.org.uk|language=en-US|access-date=2018-10-10}}</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=":0" />

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 [[Keiji Fukida|Fukuda]] et al. (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=":19" /> 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. Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=King|first2=Caroline P.|last3=Richman|first3=Judith A.|last4=Taylor|first4=Renee R.|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>{{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 ===
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>{{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>{{Cite web|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.|last2=Evans|first2=Meredyth Anne|date=2010|language=en|access-date=2018-10-10|last3=Porter|first3=Nicole|last4=Brown|first4=Molly|last5=Brown|first5=Abigail A.|last6=Hunnell|first6=Jessica|last7=Anderson|first7=Valerie C.|last8=Lerch|first8=Athena|last9=Meirleir|first9=Kenny de}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref>{{Cite journal|last=Strand|first=Elin B.|last2=Lillestøl|first2=Kristine|last3=Jason|first3=Leonard A.|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 particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref>{{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 5 items from the DSQ to measure PEM.<ref name=":4">https://www.commondataelements.ninds.nih.gov/Doc/MECFS/PEM_Subgroup_Summary.pdf</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).

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>{{Cite journal|last=Jason|first=Leonard|last2=Jessen|first2=Tricia|last3=Porter|first3=Nicole|last4=Boulton|first4=Aaron|last5=Gloria-Njoku|first5=Mary|date=2009-07-16|title=Examining Types of Fatigue Among Individuals with ME/CFS|url=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>{{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> 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=":5" /></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>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf</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=":5" />, though questions have been raised about the neutrality of the wording used.<ref name=":6">{{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=":6" />

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings.<ref name=":7" /> 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=":7" />

=== The DePaul Post-Exertional Malaise Questionnaire (DPEMQ) ===
The DPEMQ is a [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] based on input from hundreds of patients.<ref name=":29">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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><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=":29" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 International Consensus Criteria (ICC)<ref>{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> offered the most precise and elaborated definition of the post-exertional relapses that characterize ME. To differentiate it with 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=":2" /> 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.
# Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
# Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
# Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
# 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 many of these characteristics are necessary to diagnose PENE.
=== 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-specific fatigue.”<ref name=":8" /> 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=":13" /></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=":8" />
=== 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=":4" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref>{{Cite journal|last=Jason|first=Leonard|last2=McManimen|first2=Stephanie|last3=Sunnquist|first3=Madison|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise|journal=Fatigue: Biomedicine, Health & Behavior|doi=10.1080/21641846.2018.1453265}}</ref> 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>
# 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.
# 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=":4" />

==Notable studies==
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref>{{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)]
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="MeyerJ2013" /> [[http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref name="JasonL2015bio" /> [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="ShuklaS2015" /> [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]

*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref>{{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)]

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms,<ref name="VanNess2010" />]]
* 2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name=":31" /><ref name=":30" /> [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)]

==Notable articles==
* Dec 30, 2015 [http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/ Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)]<ref name="MEBlogg2015" />

*Nov 4, 2016 [http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome]<ref>{{Cite web|url=http://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|last=Tucker|first=Miriam|date=|website=www.medscape.com|type=Login Required|archive-url=|archive-date=|dead-url=|access-date=2018-09-06}}</ref>

==Talks & interviews==
* 2012, [https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be Top 10 Things You Should Know About Post-Exertional Relapse]<ref>{{Cite web|url=https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be|title=Top 10 Things You Should Know About Post-Exertional Relapse|last=Snell|first=Christopher|last2=Van Ness|first2=Mark|date=Jul 25, 2012|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=|last3=Stevens|first3=Staci}}</ref>
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]<ref>{{Cite web|url=https://www.youtube.com/watch?v=zZ8aPYihkpQ|title=CFS gene expression after exercise (part 1)|last=|first=|date=May 26, 2013|website=YouTube|publisher=Jw N|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* 2015, [https://www.youtube.com/watch?v=F1PP21TmUPs 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman]<ref>{{Cite web|url=https://www.youtube.com/watch?v=F1PP21TmUPs|title=Gene-expression and exercise/Gen-expressie en inspanning – dr. Lucinda Bateman|last=Bateman|first=Lucinda|date=Nov 3, 2015|website=Youtube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*2015, [https://www.youtube.com/watch?v=vfmrPd4-rIE Post-Exertion Malaise: The Intersection of Biology and Behavior]<ref name="CookD20151119v" />

*2016, [https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be|title=Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence|last=|first=|date=Jul 17, 2015|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

==See also==

*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==

*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health]<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-08-17}}</ref> (PEM Definition Included)
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]<ref name="SpotilaJ2010" />
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]<ref name="SpotilaJ20120523" />
*[https://www.verywellhealth.com/what-is-post-exertional-malaise-716023 What is Post-Exertional Malaise]<ref name="AboutHealthPEM" />
*[https://www.youtube.com/watch?v=ckT9BbSH0Lo Post-Exertional Malaise - The ME/CFS Ghost]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ckT9BbSH0Lo|title=Post-Exertional Malaise - The ME/CFS Ghost|last=|first=|date=May 13, 2016|website=YouTube|publisher=The ME/CFS Ghost|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[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?]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/|title=The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained? - Health Rising|last=Johnson|first=Cort|date=2016-07-04|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== References ==
<references>
<ref name="AboutHealthPEM">{{Cite news|url=https://www.verywellhealth.com/what-is-post-exertional-malaise-716023|title=What is Post-Exertional Malaise? Learn About a Key ME/CFS Symptom|last=Dellwo|first=Adrienne|date=|work=Verywell Health|access-date=2018-08-17|archive-url=|archive-date=|dead-url=}}</ref>
<ref name="CookD20151119v">{{citation
| last1 = Cook | first1 = DB | authorlink1 = Dane Cook
| title = Deciphering Post Exertion Malaise: The Intersection of Biology and Behavior
| type = video
| journal = Solve ME/CFS
| date = 19 Nov 2015
| url = https://www.youtube.com/watch?v=vfmrPd4-rIE
}}</ref>
<ref name="JasonL2015bio">{{Citation
| last1 = Jason | first1 = LA | authorlink1 = Leonard Jason
| last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn
| last3 = Zinn | first3 = MA | authorlink3 = Mark Zinn
| display-authors =
| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers
| journal = Current Neuropharmacology | volume = 13(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>
<ref name="McManimen, 2016">{{Citation
| last1 = McManimen | first1 = SL | authorlink1 =
| 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 = | issue = | page =
| date = 2016
| pmid = 27557649
| doi = 10.1177/1359105316664139
}}
</ref>
<ref name="MEBlogg2015">{{citation
| author = ME Blogg
| title = Suggestion to replace PEM by PAR
| date = 30 Dec 2015
| url = http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/
}}</ref>
<ref name="MeyerJ2013">{{citation
| last1 = Meyer | first1 = JD | authorlink1 = Jacob Meyer
| last2 = Light | first2 = AR | authorlink2 = Alan Light
| last3 = Shukla | first3 = SK | authorlink3 = Sanjay Shukla
| last4 = Clevidence | first4 = D | authorlink4 = Derek Clevidence
| last5 = Yale | first5 = S | authorlink5 = Steven Yale
| last6 = Stegner | first6 = AJ | authorlink6 = Aaron Stegner
| last7 = Cook | first7 = DB | authorlink7 = Dane Cook
| display-authors =
| title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression
| journal = Fatigue: Biomedicine, Health & Behavior | volume = 1 | issue = 4 | page = 190-209
| date = 2 Oct 2013
| doi = 10.1080/21641846.2013.838444
| url = http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444
}}</ref>
<ref name="ShuklaS2015">{{Citation
| last1 = Shukla | first1 = SK | authorlink1 = Sanjay Shukla
| last2 = Cook | first2 = D | authorlink2 = Dane Cook
| last3 = Meyer | first3 = JD | authorlink3 = Jacob Meyer
| last4 = Vernon | first4 = SD | authorlink4 = Suzanne Vernon
| last5 = Lee | first5 = T | authorlink5 = Thao Lee
| last6 = Clevidence | first6 = D | authorlink6 = Derek Clevidence
| last7 = Robertson | first7 = CE | authorlink7 = Charles Robertson
| last8 = Schrodi | first8 = SJ | authorlink8 = Steven Schrodi
| last9 = Yale | first9 = S | authorlink9 = Steven Yale
| last10 = Frank | first10= DN | authorlink10= Daniel Frank
| display-authors = 3
| title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
| journal = Plos One | volume = 10(12) | page =
| date = 18 December 2015
| pmid =
| doi = 10.1371/journal.pone.0145453
| url = http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453
}}</ref>
<ref name="SpotilaJ2010">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise in Chronic Fatigue Syndrome
| journal = Solve ME/CFS
| date = 2010
| url = http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf
}}</ref>
<ref name="SpotilaJ20120523">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise: Cause and Effect
| journal = Solve ME/CFS
| date = 23 May 2012
| url = http://solvecfs.org/post-exertional-malaise-cause-and-effect/
}}</ref>
<ref name="VanNess2010">{{Citation
| last1 = VanNess | first1 = M | authorlink1 = Mark VanNess
| last2 = Stevens | first2 = S | authorlink2 = Staci Stevens
| last3 = Bateman | first3 = L | authorlink3 = Lucinda Bateman
| last4 = Stiles | first4 = TL | authorlink4 = TL Stiles
| last5 = Snell | first5 = CR | authorlink5 = Christopher Snell
| display-authors =
| title = Postexertional malaise in women with chronic fatigue syndrome
| journal = Journal of Women's Health | volume = | issue = | page =
| date = February 2010
| pmid = 20095909
| doi = 10.1089/jwh.2009.1507
}}
</ref>
</references>

[[Category:Signs and symptoms]]

Post-exertional malaise

2018-12-26T22:35:39Z

77.111.245.85:internal links

'''Post-exertional malaise (PEM)''' refers to a ''worsening'' of [[List of symptoms in ME CFS|ME/CFS symptoms]] after minimal ''physical'' or ''mental'' [[exertion]],<ref name=":14" /><ref name=":32" /> which can be delayed 24-72 hours or more.<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-10-16}}</ref><ref>{{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=":15" /><ref name=":28">{{Cite web|url=https://youtu.be/RC9TjgE_PlU?t=137|title=Diagnosis and Management of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|last=Kaufman|first=David|date=Oct 16, 2018|website=YouTube|publisher=Unrest Film|archive-url=|archive-date=|dead-url=|access-date=|quote=Part of the Unrest Continuing Education module.}}</ref><ref name=":30">{{Cite journal|last=|first=|date=2018|title=SAGE Journals: Your gateway to world-class journal research|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=Sage Pub|language=en|volume=|pages=4-5|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=":31">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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=":0">{{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>{{Cite web|url=https://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|website=www.medscape.com|access-date=2018-10-10}}</ref><ref>{{Cite web|url=https://ammes.org/2018/06/04/deconstructing-post-exertional-malaise-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-a-patient-centered-cross-sectional-survey/|title=Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey – American ME and CFS Society|website=ammes.org|language=en-US|access-date=2018-10-16}}</ref> While in most diseases patients experience symptom relief after [[exercise|exercise,]]<ref>{{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><ref>{{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>{{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 (Houndmills, Basingstoke, England)|volume=8|issue=2|pages=161–168|doi=10.1191/1352458502ms779oa|issn=1352-4585|pmid=11990874}}</ref><ref>{{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>{{Cite journal|last=Dunn|first=A. L.|last2=Trivedi|first2=M. H.|last3=O'Neal|first3=H. A.|date=June 2001|title=Physical activity dose-response effects on outcomes of depression and anxiety|url=https://www.ncbi.nlm.nih.gov/pubmed/11427783|journal=Medicine and Science in Sports and Exercise|volume=33|issue=6 Suppl|pages=S587–597; discussion 609–610|issn=0195-9131|pmid=11427783}}</ref> the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up.<ref>{{Cite journal|last=Nijs|first=Jo|last2=Almond|first2=Freya|last3=De Becker|first3=Pascale|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> Because recovery is often prolonged,<ref name=":13">{{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|volume=19|issue=2|pages=239–244|doi=10.1089/jwh.2009.1507|issn=1931-843X|pmid=20095909}}</ref> lasting days or sometimes weeks to months,<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> patients refer to these post-exertional setbacks as ‘crashes’.<ref>{{Cite news|url=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/|title=How to Best Recover From a Crash: the ME/CFS Community Reports|work=Health Rising|access-date=2018-10-10|language=en-US}}</ref><ref name=":28" />

PEM can be caused by physical as well as mental exertion<ref name=":14" /> and the symptom complex it invokes does not necessarily relate to the initial trigger.<ref name=":3" /> ME/CFS patients suffer from a post-exertional [[Flu-like symptoms|flu-like feeling,]]<ref name=":1" /> with [[brain fog|brain fog,]]<ref name=":13" /> [[photophobia]] and other symptoms not usually reported after exertion.<ref name=":3" /> In contrast to most forms of exercise intolerance, the onset of PEM is frequently delayed<ref name=":15" /> with many patients reporting the height of their symptom flare-up, two<ref name=":13" /> or several days after the initial trigger.

The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in [[Cognitive dysfunction|cognitive functioning,]]<ref>{{Cite journal|last=Blackwood|first=S.|last2=MacHale|first2=S.|last3=Power|first3=M.|last4=Goodwin|first4=G.|last5=Lawrie|first5=S.|date=October 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>{{Cite journal|date=2017-05-01|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> [[immune activation|immune activation,]]<ref>{{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|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=|author-link=Jo Nijs|author-link2=Andrea Nees|author-link3=Lorna Paul|author-link4=Margot De Kooning|author-link5=Kelly Ickmans|via=|author-link6=Mira Meeus|author-link7=Jessica Van Oosterwijck}}</ref> [[gene expression]]<ref name=":20">{{Cite journal|last=Light|first=Alan R.|last2=White|first2=Andrea T.|last3=Hughen|first3=Ronald W.|last4=Light|first4=Kathleen C.|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=":21">{{Cite journal|last=Light|first=A. R.|last2=Bateman|first2=L.|last3=Jo|first3=D.|last4=Hughen|first4=R. W.|last5=VanHaitsma|first5=T. A.|last6=White|first6=A. T.|last7=Light|first7=K. C.|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>{{Cite journal|last=Meyer|first=Jacob D.|last2=Light|first2=Alan R.|last3=Shukla|first3=Sanjay K.|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron J.|last7=Cook|first7=Dane B.|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>{{Cite journal|last=White|first=A. T.|last2=Light|first2=A. R.|last3=Hughen|first3=R. W.|last4=VanHaitsma|first4=T. A.|last5=Light|first5=K. C.|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=":22">{{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=":23">{{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=":24">{{Cite journal|last=Van Oosterwijck|first=J.|last2=Nijs|first2=J.|last3=Meeus|first3=M.|last4=Lefever|first4=I.|last5=Huybrechts|first5=L.|last6=Lambrecht|first6=L.|last7=Paul|first7=L.|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=|author-link=Jessica Van Oosterwijck|author-link2=Jo Nijs|author-link3=Mira Meeus|author-link4=|author-link5=|via=|author-link7=Lorna Paul}}</ref> in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a [[Two-day cardiopulmonary exercise test|2-day cardiopulmonary exercise test]] (CPET) procedure.<ref name=":16" /><ref name=":28" /> 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>{{Cite journal|last=Snell|first=C. R.|last2=Stevens|first2=S. R.|last3=Davenport|first3=T. E.|last4=Van Ness|first4=J. M.|date=2013-06-27|title=Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome|url=http://dx.doi.org/10.2522/ptj.20110368|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=0031-9023}}</ref><ref>{{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=":17" /><ref>{{Cite journal|last=Vanness|first=J. Mark|last2=Snell|first2=Christopher R.|last3=Stevens|first3=Staci R.|date=Jan 2007|title=Diminished Cardiopulmonary Capacity During Post-Exertional Malaise|url=http://dx.doi.org/10.1300/j092v14n02_07|journal=Journal of Chronic Fatigue Syndrome|volume=14|issue=2|pages=77–85|doi=10.1300/j092v14n02_07|issn=1057-3321}}</ref><ref name=":18" /> These objective measures track strongly with the presence, severity and duration of PEM.<ref name=":0" />

A 2015 review of the literature by the [[National Academy of Medicine]] (NAM) concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”<ref name=":0" /> Disagreement exists however on the precise nature of PEM and how it should be defined,<ref name=":19">{{Cite journal|last=Jason|first=Leonard A.|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=":8">{{Cite journal|last=McManimen|first=Stephanie L.|last2=Sunnquist|first2=Madison L.|last3=Jason|first3=Leonard A.|date=2016-08-24|title=Deconstructing post-exertional malaise: An exploratory factor analysis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/|journal=Journal of health psychology|doi=10.1177/1359105316664139|issn=1359-1053|pmc=5325824|pmid=27557649}}</ref>

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 house-bound or completely bed-bound 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=":32">{{Cite web|url=https://www.cdc.gov/me-cfs/symptoms-diagnosis/symptoms.html|title=Symptoms {{!}} Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) {{!}} CDC|date=2018-05-18|website=www.cdc.gov|language=en-us|access-date=2018-11-21}}</ref> Examples of PEM given by the CDC are: attending a child’s school event may leave a patient house-bound 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 bed-bound and unable to do anything for days; keeping up with work may lead to spending evenings and weekends recovering.<ref name=":32" />
== Patients' description ==

=== 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 can cause severe debility. As one patient described it: [[File:Cfs woman sketch.jpg|435x435px|thumb|right|Post-exertional malaise (PEM) is a ''worsening'' of symptoms after minimal ''physical'' or ''mental'' [[exertion]]. Worsening symptoms may include [[chronic fatigue]]; [[flu-like symptoms]]; [[brain fog|brain fog,]] [[cognitive dysfunction]], and [[word-finding problems]]; [[unrefreshing sleep|unrefreshing sleep;]] [[Headache|headaches]] and [[Migraine|migraines]]; [[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 <u>onset of PEM can be delayed 24-72 hours</u> and depending on ME/CFS severity can last days, weeks, or even months ]]<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=":0" /></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.|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 level that if exceeded, will result in a 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>{{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>{{Cite journal|last=Goudsmit|first=Ellen M.|last2=Nijs|first2=Jo|last3=Jason|first3=Leonard A.|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.

== History ==

=== 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=":10">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>{{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|Holmes definition]] of [[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>{{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 post-exertional malaise was first used in 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.

'''Currently used to define ME/CFS'''

In 2003, the [[Canadian Consensus Criteria]] (CCC) post-exertional malaise became a mandatory symptom for the diagnosis of ME/CFS. The CCC were the first criteria to stress that the onset of PEM could be delayed and to describe its debility as a flu-like distress.<ref name=":1">{{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> PEM is not a mandatory symptom under the CCC criterion.

The 2015 report of the National Academy of Medicine (NAM) 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=":0" /> PEM is a mandatory symptom under the SEID criterion.

'''Currently used to define Myalgic encephalomyelitis'''

In 2011, the [[International Consensus Criteria]] (ICC) introduced the new term '''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 and prolonged recovery, and uses acute [[flu-like symptoms]] to describe PENE. By definition PENE results in a substantial reduction in functioning, as even simple activities of daily living can cause a relapse.<ref name=":2">{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> PENE is a mandatory symptom under the ICC criterion.

===Dismissed as disturbed effort perceptions or kinesiophobia ===
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>https://www.cdc.gov/me-cfs/pdfs/symptom-inventory-questionnaire-508.pdf</ref>, while others saw it as an artifact of disturbed effort perceptions<ref>{{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 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>{{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.|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 [http://www.paininmotion.be/EN/sem-TSK-CFSEnglish.pdf Tampa scale 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 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=|dead-url=|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=":3">{{Cite journal|last=Chu|first=Lily|last2=Valencia|first2=Ian J.|last3=Garvert|first3=Donn W.|last4=Montoya|first4=Jose G.|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/pubmed/29856774|journal=PloS One|volume=13|issue=6|pages=e0197811|doi=10.1371/journal.pone.0197811|issn=1932-6203|pmc=5983853|pmid=29856774|quote=|author-link=Lily Chu|author-link2=Ian Valencia|author-link3=Donn Gavert|author-link4=Jose Montoya|author-link5=|via=}}</ref> 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>{{Cite web|url=http://www.virology.ws/2011/11/23/chronic-fatigue-syndrome-and-the-cdc-a-long-tangled-tale/|title=Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale|website=www.virology.ws|language=en-US|access-date=2018-10-10}}</ref> ME/CFS patients usually use the abbreviation PEM or the term ‘crash’ to describe their relapses.

== 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 ===
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. 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=":15">{{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 exertional trigger.<ref name=":3" /> 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=":5">{{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 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=":9">{{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 |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>{{Cite journal|last=Bazelmans|first=Ellen|last2=Bleijenberg|first2=Gijs|last3=Voeten|first3=Marinus J. M.|last4=van der Meer|first4=Jos W. M.|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=|author-link=Ellen Bazelmans|author-link2=Gijs Bleijenberg|author-link3=Marinus Voeten|author-link4=Jos van der Meer|author-link5=Hans Folgering|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>{{Cite journal|last=Lapp|first=C. W.|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 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=":3" /> </blockquote>

=== Type of symptoms ===
The second characteristic of PEM is the 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-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: [[sore throat]], lymph glandular tenderness and/or [[Swollen lymph nodes|swelling]], general malaise, increased pain or cognitive fog."<ref name=":1" /> </blockquote>[[Mark VanNess|Van Ness]] et al. noted how 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=":9" /></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=":3" /></blockquote>

=== Triggers ===
A third characteristic of PEM is that it can be elicited by multiple triggers. Research has shown that ME/CFS patients experience PEM after both physical and cognitive exertion. 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=":14">{{Cite journal|last=Arroll|first=Megan A.|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=":10" /> </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=":11" /> 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, J.D.|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=":3" /> </blockquote>In some instances, the specific trigger of PEM cannot be identified.<ref name=":11">NINDS/CDC Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post-Exertional Malaise Subgroup Draft Recommendations Public Review Comments Due January 31, 2018</ref>

=== Los 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=":16">{{Cite journal|last=Stevens|first=Staci|last2=Snell|first2=Chris|last3=Stevens|first3=Jared|last4=Keller|first4=Betsy|last5=VanNess|first5=J. Mark|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.
|6
| -22%
| -26%
|?
|?
|?
|?
|-
|[[Vemeulen]] et al. 2010.
|15
| -6.3%
| -7.0%
| -5.3%
| -7.0%
| -1.9%
| -8.8%
|-
|[[Christopher Snell|Snell]] et al. 2013.
|51
| -5%
| -10.8%
| -7.2%
| -55.2%
|?
|?
|-
|[[Betsy Keller|Keller]] et al. 2014.
|22
| -13.8%
| -15.8%
| -12.5%
| -21.3%
| -5.9%
| -12.6%
|-
|[[Hodges]] et al. 2018.
|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. "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=":17">{{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=":18">{{Cite journal|last=Hodges|first=L. D.|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. 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>{{Cite journal|last=Snell|first=Christopher R.|last2=Stevens|first2=Staci R.|last3=Davenport|first3=Todd E.|last4=Van Ness|first4=J. Mark|date=Nov 2013|title=Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23813081|journal=Physical Therapy|volume=93|issue=11|pages=1484–1492|doi=10.2522/ptj.20110368|issn=1538-6724|pmid=23813081}}</ref> 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=":11" /> CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars.<ref name=":7">{{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> For these reasons PEM is usually assessed using self-reporting questionnaires.
== 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 without the disease.<ref>{{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>{{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>{{Cite journal|last=Jason|first=Leonard A.|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 [https://www.me-pedia.org/wiki/Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank], Jason et al. 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>{{Cite journal|last=Jason|first=Leonard A.|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.|last8=Strand|first8=Elin Bolle|last9=Vernon|first9=Suzanne D.|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>{{Cite journal|last=Jason|first=Leonard A.|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 expressing thoughts, PEM was once again represented with the item “physically drained/sick after mild activity.”<ref>{{Cite journal|last=Jason|first=Leonard A.|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. 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]], [[TNFa]], [[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>{{Cite journal|last=Maes|first=Michael|last2=Twisk|first2=Frank N. M.|last3=Johnson|first3=Cort|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=":0" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name=":12">{{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>{{Cite journal|last=Jason|first=L. A.|last2=Ohanian|first2=D.|last3=Brown|first3=A.|last4=Sunnquist|first4=M.|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 MS. 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 MS-patients.<ref name=":7" />
=== Major Depressive disorder ===
In the 1996 study by Komaroff et al., only 19% of patients with major [[depression]] reported PEM.<ref name=":12" /> 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>{{Cite journal|last=Hawk|first=Caroline|last2=Jason|first2=Leonard A.|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. Accordig to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/8588010|title=The validity and reliability of the fatigue syndrome that follows glandular fever. - PubMed - NCBI|last=Wjite|first=PD|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-10-24}}</ref>

=== Gulf war illness ===
[[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at [[MicroRNA]]<nowiki/>s (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>{{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>{{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|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>

== 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=":10" /> </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=":0" />

=== Gene expression ===
One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[Leucocyte|leukocytes]] 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=":20" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name=":21" /> 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>{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=VanHaitsma|first4=Timothy A.|last5=Light|first5=Kathleen C.|date=Jan 2012|title=Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256093/|journal=Psychosomatic Medicine|volume=74|issue=1|pages=46–54|doi=10.1097/PSY.0b013e31824152ed|issn=0033-3174|pmc=3256093|pmid=22210239}}</ref></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>{{Cite journal|last=Meyer|first=Jacob|last2=R. Light|first2=Alan|last3=Shukla|first3=Sanjay|last4=Clevidence|first4=Derek|last5=Yale|first5=Steven|last6=Stegner|first6=Aaron|last7=Cook|first7=Dane|date=2013-10-01|title=Post-exertion malaise in chronic fatigue syndrome: Symptoms and gene expression|url=https://www.researchgate.net/publication/258165434_Post-exertion_malaise_in_chronic_fatigue_syndrome_Symptoms_and_gene_expression|journal=Fatigue: Biomedicine, Health & Behavior|volume=1|pages=190–209|doi=10.1080/21641846.2013.838444}}</ref> 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 [[functional disability]].<ref>{{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 ===
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref>{{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|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}}</ref> Most findings however still have to be replicated by other research groups, using larger samples.

==== Oxidative stress ====
In 2005 the French team Yammes 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=":25">{{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|last2=Jones|first2=James F.|last3=Vernon|first3=Suzanne D.|last4=Rajeevan|first4=Mangalathu S.|date=Jan 2009|title=Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19015737|journal=Molecular Medicine (Cambridge, Mass.)|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|issn=1528-3658|pmc=2583111|pmid=19015737}}</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"
|<small>Study</small>
|<small>Number of participants</small>
|<small>Exercise challenge</small>
|<small>Cytokines tested:</small>
|<small>Results:</small>
|-
|<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref>{{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>
|<small>10 ([[Holmes criteria]], all cases were post-infectious)</small>
|<small>Walking 1 mile per hour for 30 min</small>
|<small>[[IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF- β]]</small>
|<small>Negative results</small>
|-
|<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref>{{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 Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref>
|<small>12 ([[Australian criteria]])</small>
|<small>30 min hand grip exercises</small>
|<small>[[Interferon|IFN-γ]], IFN-α, IL-1 β, TNF- α</small>
|<small>Negative results</small>
|-
|<small>[[La Manca]] et al. (1999)</small><ref>{{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>
|<small>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</small>
|<small>An exhaustive treadmill exercise test</small>
|<small>[[IL-2]], [[Interleukin 4|IL-4]], [[IL-10]], IFN-γ, TNF-α</small>
|<small>Negative results</small>
|-
|<small>[[Cannon]] et al. (1997)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, interleukin-1 receptor antagonist ([[IL-1Ra]]), and soluble interleukin-1 receptor type II ([[IL-lsRII]]).</small>
|<small>Negative results</small>
|-
|<small>[[Gupta]] et al. (1998)</small><ref>{{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>
|<small>5 (Holmes criteria)</small>
|<small>30 min hand grip exercises</small>
|<small>IL-6</small>
|<small>Negative results</small>
|-
|<small>Cannon et al. (1999)</small><ref>{{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>
|<small>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”</small>
|<small>Stepping up and down on a platform for 15 min</small>
|<small>IL-1 β, IL-6</small>
|<small>Negative results</small>
|-
|<small>[[Yammes]] et al. (2009)</small><ref name=":25" />
|<small>9 (Fukuda criteria) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small>
|<small>Cycling test until maximal work load</small>
|<small>IL-6, TNF-a</small>
|<small>Negative results</small>
|-
|<small>[[Robinson]] et al (2010)</small><ref>{{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>
|<small>6 (Fukuda criteria)</small>
|<small>Incremental exercise test to exhaustion</small>
|<small>IL-6, [[sIL-6R]] and [[sgp130]]</small>
|<small>Negative results</small>
|-
|<small>[[White]] et al. (2010)</small><ref name=":26">{{Cite journal|last=White|first=Andrea T.|last2=Light|first2=Alan R.|last3=Hughen|first3=Ronald W.|last4=Bateman|first4=Lucinda|last5=Martins|first5=Thomas B.|last6=Hill|first6=Harry R.|last7=Light|first7=Kathleen C.|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>
|<small>19 (Fukuda criteria)</small>
|<small>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."</small>
|<small>IL-1β, IL-2, [[IL-12]], TNFα, soluble [[CD40L]], [[IFNγ]], [[Interleukin 4|IL-4]], IL-10, [[IL-13]], IL-6 and [[Interleukin 8|IL-8]]</small>

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

<small> </small>
|-
|<small>Andrew Lloyd et al. (2018)</small><ref name=":27">{{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>
|<small>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”</small>
|<small>Symptom limited exercise on an ergocycle.</small>
|<small>Growth factors: [[FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGFα]], [[TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small>

<small> </small>

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

<small> </small>

<small>Interleukins: IL-1α, IL-1β, [[IL-1RA]], IL-2, IL-4, [[IL-5]], IL-6, [[Interleukin 7|IL-7]], IL-8, IL-10, [[IL12p40]], [[IL12p70]], [[IL-13]], [[IL-15]], [[IL-17]], [[IL-17F]], [[IL-18]] and [[LIF]]</small>

<small> </small>

<small>[[Chemokine|Chemokines]]: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[CCL5]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small>

<small> </small>

<small>[[Interferon|Interferons]]: [[INF-α]], [[INF-β]], [[INF-ϒ]]</small>

<small> </small>

<small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small>

<small> </small>

<small>Other factors: [[CD40L]], [[FASL]], [[Leptin]], [[PAI-1]], [[Resistin]], TNF-α, [[TNF-β]], [[TRAIL]]</small>
|<small>Positive results: ME/CFS had a distinct [[cytokine profile]] post-exercise.</small>
|}
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 cytokines 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]], IL-8, CCL4, TNF-β and [[ICAM-1]]). This suggests a distinct [[cytokine inflammatory signature]] in ME/CFS.<ref name=":27" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare SF, 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 patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in IL-8), whereas the high SF patients showed a pattern of increases in both cytokine types at 8 h and no decreases at any time."<ref name=":26" /></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>{{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>{{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>{{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>{{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>{{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. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref>{{Cite journal|last=Van Oosterwijck|first=J.|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.|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=|author-link=Jessica Van Oosterwijck|author-link2=|author-link3=|author-link4=|author-link5=|via=|author-link8=Jo Nijs}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. 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>{{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. 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>{{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>{{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 team. 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>{{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>{{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>{{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>{{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>{{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. 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>{{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=":0" /> This difference may be due to heterogeneity of the patient sample and methods used.

{| class="wikitable"
|<small>Study</small>
|<small>Number of ME/CFS subjects</small>
|<small>Neurocognitive tests</small>
|<small>Results</small>
|-
|<small>[[Marshall]] et al. (1997)</small><ref>{{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>
|<small>8</small>
|<small>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).</small>
|<small>Negative</small>
|-
|<small>[[Blackwood]] et al. (1998)</small><ref>{{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}}</ref>
|<small>10</small>
|<small>"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)”</small>
|<small>Positive</small>
|-
|<small>[[La Manca]] et al. (1998)</small><ref>{{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>
|<small>19</small>
|<small>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)</small>
|<small>Positive</small>
|-
|<small>[[Claypoole]] et al. (2001)</small><ref>{{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>
|<small>21</small>
|<small>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)</small>
|<small>Negative</small>
|-
|<small>[[Dane Cook|Cook]] et al. (2005)</small><ref>{{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>
|<small>20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia</small>
|<small>Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)</small>
|<small>Negative</small>
|-
|<small>[[Yoshiuchi]] et al. (2007)</small><ref>{{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>
|<small>9</small>
|<small>A one-back memory task</small>
|<small>Negative</small>
|-
|<small>Cook et al. (2017)</small><ref>{{Cite journal|date=2017-05-01|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>
|<small>15</small>
|<small>The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task</small>
|<small>Positive</small>
|}

=== 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=":22" /> 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=":23" /><ref name=":24" /> 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>{{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>{{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>{{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>{{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>{{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 {{!}} 27 April 2012|website=www.meassociation.org.uk|language=en-US|access-date=2018-10-10}}</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=":0" />

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 [[Keiji Fukida|Fukuda]] et al. (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=":19" /> 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. Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref>{{Cite journal|last=Jason|first=Leonard A.|last2=King|first2=Caroline P.|last3=Richman|first3=Judith A.|last4=Taylor|first4=Renee R.|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>{{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 ===
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>{{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>{{Cite web|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.|last2=Evans|first2=Meredyth Anne|date=2010|language=en|access-date=2018-10-10|last3=Porter|first3=Nicole|last4=Brown|first4=Molly|last5=Brown|first5=Abigail A.|last6=Hunnell|first6=Jessica|last7=Anderson|first7=Valerie C.|last8=Lerch|first8=Athena|last9=Meirleir|first9=Kenny de}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref>{{Cite journal|last=Strand|first=Elin B.|last2=Lillestøl|first2=Kristine|last3=Jason|first3=Leonard A.|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 particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref>{{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 5 items from the DSQ to measure PEM.<ref name=":4">https://www.commondataelements.ninds.nih.gov/Doc/MECFS/PEM_Subgroup_Summary.pdf</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).

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>{{Cite journal|last=Jason|first=Leonard|last2=Jessen|first2=Tricia|last3=Porter|first3=Nicole|last4=Boulton|first4=Aaron|last5=Gloria-Njoku|first5=Mary|date=2009-07-16|title=Examining Types of Fatigue Among Individuals with ME/CFS|url=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>{{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> 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=":5" /></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>https://www.commondataelements.ninds.nih.gov/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf</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=":5" />, though questions have been raised about the neutrality of the wording used.<ref name=":6">{{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=":6" />

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings.<ref name=":7" /> 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=":7" />

=== The DePaul Post-Exertional Malaise Questionnaire (DPEMQ) ===
The DPEMQ is a [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] based on input from hundreds of patients.<ref name=":29">{{Cite journal|last=Jason|first=Leonard A|last2=Holtzman|first2=Carly S|last3=Sunnquist|first3=Madison|last4=Cotler|first4=Joseph|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><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=":29" /></blockquote>

=== PENE ===
Of all case definitions, the 2011 International Consensus Criteria (ICC)<ref>{{Cite journal|last=Carruthers|first=Bruce M.|author-link=Bruce Carruthers|last2=van de Sande|first2=Marjorie I.|author-link2=Marjorie van de Sande|last3=De Meirleir|first3=Kenny L.|author-link3=Kenny De Meirleir|last4=Klimas|first4=Nancy G.|author-link4=Nancy Klimas|last5=Broderick|first5=Gordon|author-link5=Gordon Broderick|last6=Mitchell|first6=Terry|author-link6=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|author-link9=Nigel Speight|last10=Vallings|first10=Rosamund|author-link10=Rosamund Vallings|last11=Bateman|first11=Lucinda|author-link11=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> offered the most precise and elaborated definition of the post-exertional relapses that characterize ME. To differentiate it with 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=":2" /> 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.
# Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
# Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
# Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.
# 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 many of these characteristics are necessary to diagnose PENE.
=== 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-specific fatigue.”<ref name=":8" /> 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=":13" /></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=":8" />
=== 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=":4" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref>{{Cite journal|last=Jason|first=Leonard|last2=McManimen|first2=Stephanie|last3=Sunnquist|first3=Madison|date=2018-03-21|title=Patient perceptions of post exertional malaise|url=https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise|journal=Fatigue: Biomedicine, Health & Behavior|doi=10.1080/21641846.2018.1453265}}</ref> 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>
# 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.
# 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=":4" />

==Notable studies==
* 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome<ref>{{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)]
* 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and [[gene expression]]<ref name="MeyerJ2013" /> [[http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444 (Abstract)]
* 2015, Myalgic Encephalomyelitis: Symptoms and [[Biomarker]]s<ref name="JasonL2015bio" /> [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="ShuklaS2015" /> [http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453 (Full Text)]
*2016, Deconstructing post-exertional malaise: An exploratory factor analysis<ref name="McManimen, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325824/ (Full Text)]

*2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests<ref>{{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)]

[[File:2010 VanNess Post exertional worsening of symptoms chart.png|right|frame|Post-exertional worsening of symptoms,<ref name="VanNess2010" />]]
* 2018, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome<ref name=":31" /><ref name=":30" /> [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)]

==Notable articles==
* Dec 30, 2015 [http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/ Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)]<ref name="MEBlogg2015" />

*Nov 4, 2016 [http://www.medscape.com/viewarticle/871482#vp_1 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome]<ref>{{Cite web|url=http://www.medscape.com/viewarticle/871482#vp_1|title=Postexertion 'Crash,' not Fatigue per se, Marks Syndrome|last=Tucker|first=Miriam|date=|website=www.medscape.com|type=Login Required|archive-url=|archive-date=|dead-url=|access-date=2018-09-06}}</ref>

==Talks & interviews==
* 2012, [https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be Top 10 Things You Should Know About Post-Exertional Relapse]<ref>{{Cite web|url=https://www.youtube.com/watch?v=B20H1u1LjCE&feature=youtu.be|title=Top 10 Things You Should Know About Post-Exertional Relapse|last=Snell|first=Christopher|last2=Van Ness|first2=Mark|date=Jul 25, 2012|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=|last3=Stevens|first3=Staci}}</ref>
* 2013, [https://www.youtube.com/watch?v=zZ8aPYihkpQ CFS gene expression after exercise (part 1)]<ref>{{Cite web|url=https://www.youtube.com/watch?v=zZ8aPYihkpQ|title=CFS gene expression after exercise (part 1)|last=|first=|date=May 26, 2013|website=YouTube|publisher=Jw N|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* 2015, [https://www.youtube.com/watch?v=F1PP21TmUPs 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman]<ref>{{Cite web|url=https://www.youtube.com/watch?v=F1PP21TmUPs|title=Gene-expression and exercise/Gen-expressie en inspanning – dr. Lucinda Bateman|last=Bateman|first=Lucinda|date=Nov 3, 2015|website=Youtube|publisher=Wetenschap voor Patienten - ME/cvs Vereniging|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*2015, [https://www.youtube.com/watch?v=vfmrPd4-rIE Post-Exertion Malaise: The Intersection of Biology and Behavior]<ref name="CookD20151119v" />

*2016, [https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ux93w7yGQ5g&feature=youtu.be|title=Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence|last=|first=|date=Jul 17, 2015|website=YouTube|publisher=SolveCFS|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

==See also==

*[[Exercise]]
*[[Exertion]]
*[[Flu-like symptoms]]
*[[Malaise]]
==Learn more==

*[http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html International CFS/ME Awareness Day - What Health]<ref>{{Cite web|url=http://www.whathealth.com/awareness/event/internationalcfsmeawarenessday.html|title=International CFS/ME Awareness Day - 12th May 2019|last=Hartley|first=Simon|website=www.whathealth.com|language=en|access-date=2018-08-17}}</ref> (PEM Definition Included)
*[http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf Post-Exertional Malaise in Chronic Fatigue Syndrome]<ref name="SpotilaJ2010" />
*[http://solvecfs.org/post-exertional-malaise-cause-and-effect/ Post-Exertional Malaise: Cause and Effect]<ref name="SpotilaJ20120523" />
*[https://www.verywellhealth.com/what-is-post-exertional-malaise-716023 What is Post-Exertional Malaise]<ref name="AboutHealthPEM" />
*[https://www.youtube.com/watch?v=ckT9BbSH0Lo Post-Exertional Malaise - The ME/CFS Ghost]<ref>{{Cite web|url=https://www.youtube.com/watch?v=ckT9BbSH0Lo|title=Post-Exertional Malaise - The ME/CFS Ghost|last=|first=|date=May 13, 2016|website=YouTube|publisher=The ME/CFS Ghost|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[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?]<ref>{{Cite news|url=http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/|title=The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained? - Health Rising|last=Johnson|first=Cort|date=2016-07-04|work=Health Rising|access-date=2018-08-17|archive-url=|archive-date=|dead-url=|language=en-US}}</ref>

== References ==
<references>
<ref name="AboutHealthPEM">{{Cite news|url=https://www.verywellhealth.com/what-is-post-exertional-malaise-716023|title=What is Post-Exertional Malaise? Learn About a Key ME/CFS Symptom|last=Dellwo|first=Adrienne|date=|work=Verywell Health|access-date=2018-08-17|archive-url=|archive-date=|dead-url=}}</ref>
<ref name="CookD20151119v">{{citation
| last1 = Cook | first1 = DB | authorlink1 = Dane Cook
| title = Deciphering Post Exertion Malaise: The Intersection of Biology and Behavior
| type = video
| journal = Solve ME/CFS
| date = 19 Nov 2015
| url = https://www.youtube.com/watch?v=vfmrPd4-rIE
}}</ref>
<ref name="JasonL2015bio">{{Citation
| last1 = Jason | first1 = LA | authorlink1 = Leonard Jason
| last2 = Zinn | first2 = ML | authorlink2 = Marcie Zinn
| last3 = Zinn | first3 = MA | authorlink3 = Mark Zinn
| display-authors =
| title = Myalgic Encephalomyelitis: Symptoms and Biomarkers
| journal = Current Neuropharmacology | volume = 13(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>
<ref name="McManimen, 2016">{{Citation
| last1 = McManimen | first1 = SL | authorlink1 =
| 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 = | issue = | page =
| date = 2016
| pmid = 27557649
| doi = 10.1177/1359105316664139
}}
</ref>
<ref name="MEBlogg2015">{{citation
| author = ME Blogg
| title = Suggestion to replace PEM by PAR
| date = 30 Dec 2015
| url = http://me-cfs.se/blogg/suggestion-to-replace-pem-by-par/
}}</ref>
<ref name="MeyerJ2013">{{citation
| last1 = Meyer | first1 = JD | authorlink1 = Jacob Meyer
| last2 = Light | first2 = AR | authorlink2 = Alan Light
| last3 = Shukla | first3 = SK | authorlink3 = Sanjay Shukla
| last4 = Clevidence | first4 = D | authorlink4 = Derek Clevidence
| last5 = Yale | first5 = S | authorlink5 = Steven Yale
| last6 = Stegner | first6 = AJ | authorlink6 = Aaron Stegner
| last7 = Cook | first7 = DB | authorlink7 = Dane Cook
| display-authors =
| title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression
| journal = Fatigue: Biomedicine, Health & Behavior | volume = 1 | issue = 4 | page = 190-209
| date = 2 Oct 2013
| doi = 10.1080/21641846.2013.838444
| url = http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444
}}</ref>
<ref name="ShuklaS2015">{{Citation
| last1 = Shukla | first1 = SK | authorlink1 = Sanjay Shukla
| last2 = Cook | first2 = D | authorlink2 = Dane Cook
| last3 = Meyer | first3 = JD | authorlink3 = Jacob Meyer
| last4 = Vernon | first4 = SD | authorlink4 = Suzanne Vernon
| last5 = Lee | first5 = T | authorlink5 = Thao Lee
| last6 = Clevidence | first6 = D | authorlink6 = Derek Clevidence
| last7 = Robertson | first7 = CE | authorlink7 = Charles Robertson
| last8 = Schrodi | first8 = SJ | authorlink8 = Steven Schrodi
| last9 = Yale | first9 = S | authorlink9 = Steven Yale
| last10 = Frank | first10= DN | authorlink10= Daniel Frank
| display-authors = 3
| title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
| journal = Plos One | volume = 10(12) | page =
| date = 18 December 2015
| pmid =
| doi = 10.1371/journal.pone.0145453
| url = http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0145453
}}</ref>
<ref name="SpotilaJ2010">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise in Chronic Fatigue Syndrome
| journal = Solve ME/CFS
| date = 2010
| url = http://solvecfs.org/wp-content/uploads/2013/10/pem-series.pdf
}}</ref>
<ref name="SpotilaJ20120523">{{citation
| last1 = Spotila | first1 = JM | authorlink1 = Jennie Spotila
| title = Post-Exertional Malaise: Cause and Effect
| journal = Solve ME/CFS
| date = 23 May 2012
| url = http://solvecfs.org/post-exertional-malaise-cause-and-effect/
}}</ref>
<ref name="VanNess2010">{{Citation
| last1 = VanNess | first1 = M | authorlink1 = Mark VanNess
| last2 = Stevens | first2 = S | authorlink2 = Staci Stevens
| last3 = Bateman | first3 = L | authorlink3 = Lucinda Bateman
| last4 = Stiles | first4 = TL | authorlink4 = TL Stiles
| last5 = Snell | first5 = CR | authorlink5 = Christopher Snell
| display-authors =
| title = Postexertional malaise in women with chronic fatigue syndrome
| journal = Journal of Women's Health | volume = | issue = | page =
| date = February 2010
| pmid = 20095909
| doi = 10.1089/jwh.2009.1507
}}
</ref>
</references>

[[Category:Signs and symptoms]]