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Post-exertional malaise
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== Differentiation == Several studies have shown that PEM is the symptom of ME/CFS that best differentiates it from other diseases. === Healthy controls and idiopathic chronic fatigue === PEM was one of the symptoms in the CDC symptom inventory list that differentiated subjects with ME/CFS from those with [[idiopathic chronic fatigue|long term chronic fatigue]] without ME/CFS.<ref name="Wagner2005">{{Cite journal | last = Wagner | first=Dieter | last2 = Nisenbaum | first2 = Rosane | last3 = Heim | first3 = Christine | last4 = Jones | first4 = James F. | last5 = Unger | first5 = Elizabeth R. | last6 = Reeves | first6 = William C. | date = 2005-07-22 | title = Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16042777|journal=Population Health Metrics|volume=3 | pages = 8|doi=10.1186/1478-7954-3-8|issn=1478-7954|pmc=1183246|pmid=16042777}}</ref> It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue.<ref name="Vollmer2006">{{Cite journal | last = Vollmer-Conna | first=Uté | last2 = Aslakson | first2 = Eric | last3 = White | first3 = Peter D | date = Apr 2006 | title = An empirical delineation of the heterogeneity of chronic unexplained fatigue in women|url=https://www.futuremedicine.com/doi/abs/10.2217/14622416.7.3.355|journal=Pharmacogenomics|language=en|volume=7|issue=3|pages=355–364|doi=10.2217/14622416.7.3.355|issn=1462-2416}}</ref> Data for this study came from the epidemiological study in Wichita, Kansas. The other major epidemiological study, carried out in Chicago, also identified PEM as the hallmark symptom of ME/CFS. In a 10 year follow-up study on the 32 patients originally identified as having ME/CFS, all of the contacted patients reported post-exertional malaise at some point in time. This symptom was able to differentiate ME/CFS patients with those with [[idiopathic chronic fatigue]], those with exclusionary illnesses and healthy controls. According to the author: <blockquote>"Among all the variables in this study, only for post-exertional malaise did the CFS group significantly differ from the other three conditions. This reaffirms the importance of this being a cardinal and critical symptom for CFS."<ref name="Jason2011history">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | date = Feb 2011 | title = Natural History of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171164/|journal=Rehabilitation psychology|volume=56|issue=1|pages=32–42|doi=10.1037/a0022595|issn=0090-5550|pmc=3171164|pmid=21401284}}</ref> </blockquote>Using a large sample of ME/CFS patients from Newcastle, [[Norway]] and the [[Solve_ME/CFS_Initiative#Biobank Solve ME/CFS Biobank]], Jason et al. (2014) conducted an analysis of different case definitions and symptoms. The domain of post-exertional malaise was found to be most adequate at differentiating ME/CFS patients from controls. As the authors noted: <blockquote>Using the latent variables from the empiric criteria, only one factor (PEM) was needed to reach a sensitivity of 90.8%, specificity of 92.5% and accuracy of 91.6%, and this was the only data mining where all percentages were over 90%. […] the fact that PEM came out in all analyses supports the importance of this domain in the case definition.<ref name="Jason2014criteria">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Reed | first5 = Jordan | last6 = Furst | first6 = Jacob | last7 = Newton | first7 = Julia L. | authorlink7 = Julia Newton | last8 = Strand | first8 = Elin Bolle | authorlink8 = Elin Strand | last9 = Vernon | first9 = Suzanne D. | authorlink9 = Suzanne Vernon | date = 2014-04-01 | title = Comparing and Contrasting Consensus versus Empirical Domains|url=https://www.ncbi.nlm.nih.gov/pubmed/26977374|journal = Fatigue: Biomedicine, Health & Behavior |volume=3|issue=2 | pages = 63–74|doi=10.1080/21641846.2015.1017344|issn=2164-1846|pmc=4788637|pmid=26977374}}</ref> </blockquote>A 2014 examination, using 236 patients and 86 controls, showed that three symptoms accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise.<ref name="Jason2014">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Sunnquist | first2 = Madison | last3 = Brown | first3 = Abigail | last4 = Evans | first4 = Meredyth | last5 = Vernon | first5 = Suzanne D. | last6 = Furst | first6 = Jacob | last7 = Simonis | first7 = Valerie | date = 2014-01-01 | title = Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis|url=https://www.ncbi.nlm.nih.gov/pubmed/24511456|journal = Fatigue: Biomedicine, Health & Behavior |volume=2|issue=1 | pages = 40–56|doi=10.1080/21641846.2013.862993|issn=2164-1846|pmc=3912876|pmid=24511456}}</ref> Another data mining study by the same research group, suggested the selection of four symptoms: next to extreme tiredness, unrefreshing sleep and [[Word-finding problems|difficulty finding the right word to say]] or [[Aphasia|expressing thoughts]], PEM was once again represented with the item “physically drained/sick after mild activity.”<ref name="Jason2015case">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Kot | first2 = Bobby | last3 = Sunnquist | first3 = Madison | last4 = Brown | first4 = Abigail | last5 = Evans | first5 = Meredyth | last6 = Jantke | first6 = Rachel | last7 = Williams | first7 = Yolonda | last8 = Furst | first8 = Jacob | last9 = Vernon | first9 = Suzanne D. | date = 2015 | title=Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition|url=https://www.ncbi.nlm.nih.gov/pubmed/26029488|journal=Health Psychology and Behavioral Medicine|volume=3|issue=1 | pages = 82–93|doi=10.1080/21642850.2015.1014489|issn=2164-2850|pmc=4443921|pmid=26029488}}</ref> [[Michael Maes|Maes]] et al. (2012) divided ME/CFS patients into two groups: those with or without PEM lasting for more than 24 hours. Analysis showed this to be a meaningful division as the former group (45% of the sample) not only had higher symptom scores on concentration difficulties and a subjective experience of infection, but also higher markers of immune-activation such as [[Interleukin 1|IL-1]], [[TNFα]], [[lysozyme]] and [[neopterin]], than the CFS group without PEM. According to the authors their findings, "underscore the relevance of post-exertional malaise to identify a subgroup of CFS patients that should be diagnosed as ME".<ref name="Maes2012">{{Cite journal | last = Maes | first = Michael | authorlink = Michael Maes | last2 = Twisk | first2 = Frank N.M. | author-link2 = Frank Twisk | last3 = Johnson | first3 = Cort | authorlink3 = Cort Johnson | date = 2012-12-30 | title = Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data|url=https://www.ncbi.nlm.nih.gov/pubmed/22521895|journal=Psychiatry Research|volume=200|issue=2-3 | pages = 754–760|doi=10.1016/j.psychres.2012.03.031|issn=1872-7123|pmid=22521895}}</ref> === Multiple sclerosis === According to a 2015 report by the National Academy of Medicine, the prevalence of PEM among ME/CFS patients varies from 69 to 100%, which is much higher than in other disease groups.<ref name="IOM2015" /> In a 1996 study by Komaroff et al. 13 of 25 MS-patients (52%) reported PEM<ref name="Komaroff1996">{{Cite journal | last = Komaroff | first = A. L. | last2 = Fagioli | first2 = L.R. | last3 = Geiger | first3 = A.M. | last4 = Doolittle | first4 = T.H. | last5 = Lee | first5 = J. | last6 = Kornish | first6 = R.J. | last7 = Gleit | first7 = M.A. |last8 = Guerriero | first8 = R.T. | date = Jan 1996 | title = An examination of the working case definition of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8579088|journal=The American Journal of Medicine|volume=100|issue=1 | pages = 56–64|issn=0002-9343|pmid=8579088}}</ref>, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients.<ref name="Jason2017">{{Cite journal | last= Jason | first = L.A. | authorlink = Leonard Jason | last2 = Ohanian | first2 = D. | last3 = Brown | first3 = A. | last4 = Sunnquist | first4 = M. | authorlink4 = Madison Sunnquist | last5 = McManimen | first5 = S. | last6 = Klebek | first6 = L. | last7 = Fox | first7 = P. | last8 = Sorenson | first8 = M. | date = 2017 | title=Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29430570|journal=Insights in Biomedicine|volume=2|issue=2|doi=10.21767/2572-5610.10027|issn=2572-5610|pmc=5800741|pmid=29430570}}</ref> Both studies used a broad definition of PEM which focused on fatigue after exercise. Preliminary research suggests that adding more specific questions, for example about the prolonged recovery and various type of triggers, PEM might be able to differentiate ME/CFS from [[multiple sclerosis]]. A 2018 study for example showed that ME/CFS patients reported to experience PEM more often through mental exertion and to recover more slowly from PEM compared to multiple sclerosis patients.<ref name="Cotler2018" /> === Major Depressive disorder === In the 1996 study by Komaroff et al. (2006) only 19% of patients with major [[depression]] reported PEM.<ref name="Komaroff1996" /> A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder.<ref name="Hawk2006">{{Cite journal | last = Hawk | first = Caroline | last2 = Jason | first2 = Leonard A. | authorlink2 = Leonard Jason | last3 = Torres-Harding | first3 = Susan | date = 2006 | title=Differential diagnosis of chronic fatigue syndrome and major depressive disorder |url = https://www.ncbi.nlm.nih.gov/pubmed/17078775|journal=International Journal of Behavioral Medicine|volume=13|issue=3|pages=244–251|doi=10.1207/s15327558ijbm1303_8|issn=1070-5503|pmid=17078775}}</ref> In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms. White et al. studied patients with persistent symptoms of fatigue and poor concentration after glandular fever. According to the authors "the complaint of post-exertional physical fatigue may help to differentiate post-viral fatigue states from psychiatric disorders."<ref name="White2018">{{Cite journal | url=https://www.ncbi.nlm.nih.gov/pubmed/8588010 | title = The validity and reliability of the fatigue syndrome that follows glandular fever | date = 1995 | volume =25|issue =5|pages =917-24|doi=10.1017/s0033291700037405 | last = White | first = PD | authorlink = Peter White |journal=Journal of Psychological Medicine |access-date=2018-10-24}}</ref> === Gulf war illness === [[James Baraniuk|Baraniuk]] and Shivapurkar (2017) looked at MicroRNAs (miRNA) in the [[cerebrospinal fluid]] of ME/CFS patients, healthy controls and patients with [[Gulf War Illness]] before and after an exercise challenge (a submaximal bicycle exercise). While there were no differences in miRNA between the groups at baseline, a distinct signature appeared after exercise. According to the authors, "exercise caused distinct patterns of miRNA changes in CFS and […] [[Gulf War Illness|GWI]] indicating significant pathophysiological differences between conditions."<ref name="Baraniuk2017">{{Cite journal | last = Baraniuk | first = James N. | last2 = Shivapurkar | first2 = Narayan | date = 2017-11-10 | title = Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects|url=https://www.nature.com/articles/s41598-017-15383-9|journal=Scientific Reports|language=en|volume=7|issue=1|doi=10.1038/s41598-017-15383-9|issn=2045-2322}}</ref> A 2013 study under the guidance of [[Nancy Klimas]] compared the immune signature in 30 Gulf war patients, 22 ME/CFS patients and 30 controls, after an graded exercise test. Results indicated the importance of physical exercise for differentiating these different groups: <blockquote>"Common to both GWI and CFS illness signatures were the direct or indirect contributions of IL-10 and IL-23 expression though these occurred at very different times. While levels measured at rest supported an illness signature in GWI, their impact in CFS was only observable during and after exercise, again emphasizing the importance of a challenge and response timeline in distinguishing these illnesses."<ref name="Smylie2013">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | authorlink9 = Nancy Klimas | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23800166|journal=BMC immunology|volume=14|pages=29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc=3698072|pmid=23800166}}</ref></blockquote> A study by Washington et al. (2020) found different brain activation patterns after exercise in patients with Gulf War Illness compared to ME/CFS, including the opposite response in some areas, despite both illnesses causing post-exertional malaise.<ref name="Washington2020">{{Cite journal | last = Washington | first = Stuart D. | authorlink = | last2 = Rayhan | first2 = Rakib U. | authorlink2 = Rakib Rayhan | last3 = Garner | first3 = Richard | author-link3 = | last4 = Provenzano | first4 = Destie | author-link4 = | last5 = Zajur | first5 = Kristina | authorlink5 = | last6 = Addiego | first6 = Florencia Martinez | authorlink6 = | last7 = VanMeter | first7 = John W. | last8 = Baraniuk | first8 = James N. | authorlink8 = James Baraniuk | date = 2020-07-01 | title = Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074|journal=Brain Communications|language=en|volume=2|issue=2|pages=|doi=10.1093/braincomms/fcaa070|pmc=|pmid=|access-date=|quote=|via=}}</ref> The same study found that brain activation patterns did not change after exercise in healthy controls.<ref name="Washington2020" />
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