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Post-exertional malaise
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== Problems in defining PEM == === Asking the right questions === [[Leonard Jason|Jason]] et al. (1999) reported that in a group of ME/CFS patients, the percentage endorsing PEM ranged from 40,6 to 93,8% depending on how the question assessed this symptom.<ref name="Jasonblog2012">{{Cite web|url=https://www.meassociation.org.uk/2012/04/to-pem-or-not-to-pem-that-is-the-question-for-case-definition-research-1st-website-27-april-2012/ | title = To PEM or not to PEM? That is the question for case definition {{!}} Research 1st website | date = 27 April 2012 | website = Research first blog|language=en-US|access-date=2018-10-10 | last= Jason | first = Leonard | authorlink = Leonard Jason | last2 =Evans | first2 =Meredyth | authorlink2 = Meredyth Evans}}</ref> The report of the National Academy of Medicine noted that “the prevalence of PEM among ME/CFS patients as diagnosed by existing criteria varies from 69 to 100 percent.”<ref name="IOM2015" /> Some patients try to reduce post-exertional relapses by [[pacing]] themselves and reducing exertion that exceeds their energy limits. Questionnaires assessing PEM by frequency instead of propensity, might erroneously label these patients as not having PEM. In a 2015 study, Jason et al. measured ME/CFS patients’ responses to the PEM-criterion in the [[Fukuda criteria|Fukuda (1994)]] definition: ‘Do you feel generally worse than usual or fatigued for 24 hours or more after you have exercised?’ Although the majority (75%) endorsed this item, a notable percentage (25%) did not. Yet when the question was framed differently, leaving out the 24 hours’ time period and substituting exercise with normal daily activity, these participants also agreed they experienced high levels of fatigue after normal daily activity.<ref name="Jason2015" /> This clearly shows that patients who have already modified their activities to avoid or reduce PEM may potentially show up as false negatives. Another issue is the definition of PEM in the Fukuda criteria. While the wording used here is vague, the time criterion is rather strict requiring PEM to last more than 24 hours.<ref name="fukuda1994" /> Some patients do not endorse this item because they only have post-exertional malaise for less than 24 hours.<ref name="Jason1999">{{Cite journal | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = King | first2 = Caroline P. | last3 = Richman | first3 = Judith A. | last4 = Taylor | first4 = Renee R. | authorlink4 = Reneé Taylor | last5 = Torres | first5 = Susan R. | last6 = Song | first6 = Sharon | date = Jan 1999 | title = U.S. Case Definition of Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v05n03_02?journalCode=icfs20|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=5|issue=3-4|pages=3–33|doi=10.1300/j092v05n03_02|issn=1057-3321}}</ref> A 2018 study concluded that setting the criterion at 24 hours would exclude almost 30% of ME/CFS patients. It advises that this definition might be useful in research settings but that in a clinical context, a 14-23 hour time period might be more appropriate.<ref name="Cotler2018">{{Cite journal | last = Cotler | first=Joseph | last2 = Holtzman | first2 = Carly | last3 = Dudun | first3 = Catherine | last4 = Jason | first4 = Leonard A. | date = 2018-09-11 | title = A Brief Questionnaire to Assess Post-Exertional Malaise|url=https://www.ncbi.nlm.nih.gov/pubmed/30208578|journal=Diagnostics (Basel, Switzerland)|volume=8|issue=3|doi=10.3390/diagnostics8030066|issn=2075-4418|pmid=30208578}}</ref> These observations point to the need of a more precise definition of PEM and several attempts to this end have been made. === More than just fatigue and pain === Few instruments have assessed PEM adequately. The [[CDC 2005 Symptom Inventory for CFS|CDC symptom inventory]] for example, only asks about fatigue after exertion, while PEM entails much more than that. An [[Australia|Australian]] group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors.<ref name="Keech2015">{{Cite journal | last = Keech | first = Andrew | last2 = Sandler | first2 = Carolina X. | last3 = Vollmer-Conna | first3 = Ute | last4 = Cvejic | first4 = Erin | last5 = Lloyd | first5 = Andrew R. | last6 = Barry | first6 = Benjamin K. | date = Dec 2015 | title = Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/26359713|journal=Journal of Psychosomatic Research|volume=79|issue=6 | pages = 537–549|doi=10.1016/j.jpsychores.2015.08.008|issn=1879-1360|pmid=26359713}}</ref> Participants indicated that the term fatigue did not adequately describe the sensation they experienced on a daily basis. A word frequency analysis of descriptors nominated by these patients indicated 5 themes: # Exhausted or tired. # Heaviness in the limbs or whole-body. # Fogginess in the head. # Weakness in the muscles. # Drained of energy. ===<span id="DSQ-PEM">The DePaul Symptom Questionnaire (DSQ) subscale</span> === The instrument most commonly used to assess PEM is a subscale from the [[DePaul Symptom Questionnaire]] (DSQ). The DSQ is a 54-item questionnaire was developed in 2010 to operationalize the Canadian Consensus Criteria, providing concrete directives to assess ME/CFS-symptoms with their frequency and severity.<ref name="CCC-REVISED">{{Cite journal|url=https://www.semanticscholar.org/paper/The-Development-of-a-Revised-Canadian-Myalgic-Case-Jason-Evans/b2a2564f55daa57721d24502df6bd6c161238ff0 | title = The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition | last= Jason | first = Leonard A. | author-link = Leonard Jason | last2 = Evans | first2 = Meredyth Anne | authorlink2 = Meredyth Evans | date = 2010 | language=en | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Brown | first4 = Molly | authorlink4 = Molly Brown | last5 = Brown | first5 = Abigail A. | authorlink5 = Abigail Brown | last6 = Hunnell | first6 = Jessica | last7 = Anderson | first7 = Valerie C. | last8 = Lerch | first8 = Athena | last9 = Meirleir | first9 = Kenny de | authorlink9 = Kenny De Meirleir|journal=Am J Biochem and Biotech|volume=6|issue=2|pages=120-135}}</ref> In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%.<ref name="Strand2016">{{Cite journal | last = Strand | first=Elin B. | author-link = Elin Strand | last2 = Lillestøl | first2 = Kristine | last3 = Jason | first3 = Leonard A. | authorlink3 = Leonard Jason | last4 = Tveito | first4 = Kari | last5 = Diep | first5 = Lien My | last6 = Valla | first6 = Simen Strand | last7 = Sunnquist | first7 = Madison | last8 = Helland | first8 = Ingrid B. | last9 = Herder | first9 = Ingrid | date = 2016-01-02 | title = Comparing the DePaul Symptom Questionnaire with physician assessments: a preliminary study|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1126026|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=4|issue=1 | pages = 52–62|doi=10.1080/21641846.2015.1126026|issn=2164-1846}}</ref> This indicated that the DSQ is a useful tool in detecting and screening symptoms, but that a follow-up medical examination is necessarily to confirm the diagnosis and identify possible exclusionary medical and psychiatric disorders. The post-exertional malaise subscale on the DSQ (DSQ-PEM) particularly demonstrated excellent clinical utility as it was able to differentiate between ME/CFS patients and controls.<ref name="Murdock2017">{{Cite journal | last = Murdock | first = Kyle W. | last2 = Wang | first2 = Xin Shelley | last3 = Shi | first3 = Qiuling | last4 = Cleeland | first4 = Charles S. | last5 = Fagundes | first5 = Christopher P. | last6 = Vernon | first6 = Suzanne D. | date = Apr 2017 | title = The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis/chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/27600520|journal=Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation|volume=26|issue=4 | pages = 913–921|doi=10.1007/s11136-016-1406-3|issn=1573-2649|pmc=5336422|pmid=27600520}}</ref> In early 2018 the Common Data Elements working group on PEM formed by [[National Institute of Neurological Disorders and Stroke|NINDS]] and the CDC, recommended the use of five items from the DSQ to measure PEM.<ref name="CDE">{{Cite web | title = Post-exertional Malaise Subgroup Statement of Purview | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup|website =[[National Institutes of Health]]|access-date=2021-02-21|url=https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/PEM_Subgroup_Summary.pdf | date = | first = | authorlink = |archive-url=|archive-date=|url-status=}}</ref> # Dead, heavy feeling after starting to exercise. # Next day soreness after non-strenuous, everyday activities. # Mentally tired after the slightest effort. # Minimum exercise makes physically tired. # Physically drained or sick after mild activity. To meet criteria for post-exertional malaise, one of these items need to be endorsed at sufficient frequency and severity (2 or greater on a scale of 0-4).<ref name="Cotler2018" /> Although the DSQ has good test-retest reliability and is regarded as a useful tool in making the diagnosis of ME/CFS, its ability to capture PEM accurately has been questioned. Originally these five items formed one of the five subdomains of the ME/CFS Fatigue Types Questionnaire (MFTQ)<ref name="Jason2009">{{Cite journal | last= Jason | first = Leonard | authorlink1=Leonard Jason | last2 = Jessen | first2 = Tricia | last3 = Porter | first3 = Nicole | authorlink3 = Nicole Porter | last4 = Boulton | first4 = Aaron | last5 = Gloria-Njoku | authorlink5 = Mary Gloria Njoku | first5 = Mary | date = 2009-07-16 | title = Examining Types of Fatigue Among Individuals with ME/CFS|url=http://dsq-sds.org/article/view/938|journal=Disability Studies Quarterly|language=en|volume=29|issue=3|doi=10.18061/dsq.v29i3.938|issn=2159-8371}}</ref><ref name="Jason2018perceptions" /> and critics argue that these items are focused too much on fatigue/tiredness to be an adequate measure of PEM. A document formulated by the Science for ME PEM working group to address these issues, explained:<blockquote>"The DSQ PEM items focus largely on feeling fatigue or tiredness, and, apart from one item, do not mention that post-exertional symptoms may be delayed. There is no mention of prolonged recovery or the loss of functional capacity."<ref name="s4me" /></blockquote>The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: <blockquote>"...the instrument does not assess the full range of symptoms that could be exacerbated by PEM and only one item addresses the sometimes delayed onset/ prolonged duration of PEM.<ref name="CDE-PEMAssessment">{{Cite web |url = https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/F2771_Guidance_for_Core_PEM_Assessment.pdf| title = Guidance for Core PEM Assessment|access-date = 2021-02-21 | last = NINDS CDE Project Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Post Exertional Malaise Subgroup}}</ref> </blockquote>In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise<ref name="s4me" />, though questions have been raised about the neutrality of the wording used.<ref name="Jason2018perceptions">{{Cite journal | last= Jason | first = L. A. | last2 = McManimen | first2 = S.L. | last3 = Sunnquist | first3 = M. | last4 = Holtzman | first4 = C.S. | date = 2018-03-21 | title = Patient perceptions of post exertional malaise|url=https://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1453265|journal = Fatigue: Biomedicine, Health & Behavior |language=en|volume=6|issue=2 | pages = 92–105|doi=10.1080/21641846.2018.1453265|issn=2164-1846}}</ref> In response Jason et al. noted that the DSQ PEM items were developed and selected to screen for the presence of PEM, rather than to comprehensively measure all aspects and variations of PEM. A 2018 analysis, using a large patient sample (n = 704), showed that screening items from the DSQ PEM subscale, were able to identify 97% of patients, which was higher than any other item to describe PEM.<ref name="Jason2018perceptions" /> Furthermore, the authors later revised the DSQ PEM subscale to include new items, some based on [[Melvin Ramsay]]'s writings.<ref name="Cotler2018" /> An extra 5 questions can be used after the initial screening with the DSQ PEM subscale, to better differentiate ME/CFS from other, comparable conditions: # Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort? # Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort? # If you feel worse after activities, how long does this last? # If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended? # If you do not exercise, is it because exercise makes your symptoms worse? An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with [[Multiple sclerosis|MS]] or [[post-polio syndrome]].<ref name="Cotler2018" /> === The DePaul Post-Exertional Malaise Questionnaire === The [[DePaul Post-Exertional Malaise Questionnaire]] (DPEMQ) is a questionnaire based on input from hundreds of patients.<ref name="Jason2018" /><blockquote>Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.<ref name="Jason2018" /></blockquote> === PENE === Of all case definitions, the 2011 [[International Consensus Criteria]] (ICC)<ref name="ICC" /> offered the most precise and elaborated definition of the post-exertional symptoms that characterize ME. To differentiate it from post-exertional malaise, the term used in the [[Fukuda criteria]], the authors introduced a new name: '''Post-Exertional Neuroimmune Exhaustion''' (PENE). PENE is described as “a [[pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions]]”<ref name="ICC" /> and has the following characteristics: # [[Marked, rapid physical and/or cognitive fatigability in response to exertion]], which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse. # [[Post-exertional symptom exacerbation]]: e.g. acute [[flu-like symptoms]], [[pain]] and worsening of other symptoms. # [[Post-exertional exhaustion: immediate or delayed|Post-exertional exhaustion]] may occur immediately after activity or be [[delayed onset of post-exertional symptoms|delayed by hours or days]]. # [[Recovery period is prolonged, usually taking 24 hours or longer]]. A relapse can last days, weeks or longer. # [[lack of stamina|Low threshold of physical and mental fatigability]] (lack of stamina) results in a substantial reduction in pre-illness activity level. The definition fails however to make clear how frequent these symptoms must occur to diagnose PENE, but all must be present. === Muscle weakness === A more prominent criticism of PENE came from a 2016 factor analysis of PEM, using a large sample of 704 participants. Results suggested that “PEM is composed of two empirically different experiences, one for generalized [[fatigue]] and one for [[muscle fatigability|muscle-specific fatigue]].”<ref name="McManimen2016" /> The latter refers to the description of ME by Ramsay, where post-exertional muscle weakness was highlighted. This element of PEM was confirmed in a study by the [[Workwell Foundation]] where the symptoms of 25 ME/CFS patients and 23 age-matched controls were followed up. As the report noted: <blockquote>"The two groups also differed with respect to the experience of physical weakness or instability immediately after testing. This was reported by 16 patients (64%) as opposed to 5 controls (22%). Weakness persisted into the next day in 10 patients (40%) but in only 1 control (4%). However, distinct differences can be observed in the severity of the weakness between groups when analyzing their reports. The sole report of weakness from a control stated: '[I had] tired legs when going up stairs—fine overall.' In contrast, statements from CFS patients included: 'Unable to walk without assistance.' '[I experienced] falling from muscle weakness.'<ref name="VanNess2010" /></blockquote>A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: <blockquote>"Some related how they would struggle to get home after exercise – one had to stop her car on her way from the fitness centre. Another was walking in the woods and suddenly felt it would be impossible to make his way back home. They described feeling that something completely wrong had happened to their bodies, without understanding what was going on. Thought processes did not work as usual, motor abilities were reduced, or the legs would not move them as they would usually expect. Some participants described a paralyzed feeling subsequent to activity, where a lot of energy would be needed to be able to move."<ref>{{Cite journal | last = Larun | first = Lillebeth | last2 = Malterud | first2 = Kirsti | date = May 2011 | title = Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20580520|journal=Patient Education and Counseling|volume=83|issue=2|pages=222–226|doi=10.1016/j.pec.2010.05.027|issn=1873-5134|pmid=20580520}}</ref></blockquote>While many descriptions of PEM like the DSQ subscale assess this element indirectly by asking patients about a dead heavy feeling after exercise or next day soreness, it is fully lacking in the ICC definition of PENE.<ref name="McManimen2016" /> === Common data elements PEM working group === The NINDS/CDC Common Data Elements (CDE) PEM working group emphasized the need of a better definition of PEM. Its draft recommendations highlighted that <blockquote>"The definition of PEM is based primarily on clinician experience, patient reports and a few formal studies. There is a dearth of studies asking participants about their experiences of PEM in an openended manner, which is needed."<ref name="CDE" /> </blockquote>A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions.<ref name="Jason2018perceptions" /> Although the CDE working group acknowledged the need to device a better instrument to assess PEM, it currently promotes the use of the DSQ PEM subscale as a screening tool, after which a clinician's assessment is advised to diagnose PEM. The CDE PEM working group also provided a description of PEM, based on the 2015 literature review by the National Academy of Medicine: <blockquote>"PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:</blockquote> # [[post-exertional symptom exacerbation|Exacerbation of some or all of an individual study participant's ME/CFS symptoms]]. Symptoms exacerbated can include physical fatigue, cognitive fatigue, problems thinking (e.g. slowed information processing speed, memory, concentration), [[unrefreshing sleep]], [[Myalgia|muscle pain]], [[Arthralgia|joint pain]], [[Headache|headaches]], weakness/instability, light-headedness, flu-like symptoms, sore throat, [[nausea]], and other symptoms. Study participants can experience new or non-typical symptoms as well as exacerbation of their more typical symptoms. # [[lack of stamina|Loss of stamina]] and/or functional capacity. # An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer. # A prolonged, unpredictable recovery period that may last days, weeks, or even months. # Severity and duration of symptoms that is often out-of-proportion to the type, intensity, frequency, and/or duration of the exertion. For some study participants, even basic activities of daily living like toileting, bathing, dressing, communicating, and reading can trigger PEM."<ref name="CDE" />
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