Post-exertional malaise

Post-exertional malaise (PEM) refers to severe symptom exacerbation after minimal exertion and is considered to be the hallmark symptom of ME/CFS. While in most diseases patients experience symptom relief after exercise   , the opposite is true for ME/CFS patients for whom even minimal exertion can cause a symptom flare-up. Because recovery is often prolonged, lasting days or sometimes weeks to months, post-exertional setbacks as these are referred to as ‘crashes’ by patients.

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

The distinctive characteristics of post-exertional malaise are confirmed by scientific research. Exertion induces abnormalities in cognitive functioning, immune activation , gene expression   and endogenous pain inhibition   in ME/CFS patients that were not seen before exertion or in healthy controls. Most importantly PEM can be demonstrated by a 2-day cardiopulmonary exercise (CPET) test procedure. On the second day CPET, ME/CFS patients display a significant drop in VO2 max and maximal workload, that is not seen in healthy controls or other diseases. These objective measures track strongly with the presence, severity and duration of PEM.

A 2015 review of the literature by the National Academy of Medicine concluded there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.” Disagreement exists however on the precise nature of PEM and how it should be defined, with some diagnostic criteria emphasizing muscle weakness and others a more a general form of fatigue and exhaustion.

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: "“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.”" Another patient emphazised that the feeling of PEM is very different from what one experiences as a healthy person: "'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.'"Considering the serious but fluctuating debility PEM causes, ME/CFS expert Anthony Komaroff described it as “an illness within an illness”.

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 Norwegian patient described: "“....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.”"Energy conservation strategies such as pacing and the envelope theory have been developed to minimize PEM while allowing patients to stay as active as possible. 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.

Case definitions
Early descriptions of symptom exacerbation in ME focused on post-exertional muscle weakness. Renowned ME-expert Melvin Ramsay for example wrote: "'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.'"In a 1985 study Behan et al. noted that all of their patients “had the same primary symptom that of gross fatigue made worse by exercise".

In the 1988 Holmes definition of 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”.

The wording post-exertional malaise was first used in one of the 8 minor symptoms in the Fukuda criteria, but without further clarification of the term, except that it lasts more than 24 hours.

In 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.

The International Consensus Criteria (ICC) introduced the new term Post-Exertional Neuro-immune Exhaustion (PENE) to refer to the characteristic exercise intolerance of 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.

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).

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, while others saw it as an artifact of disturbed effort perceptions  or an irrational fear of movement. One example of this is the 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.

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. 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”. Doctor of 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.” 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.” 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. Patients may not be familiar with this characteristic of their relapses, since it is very counter-intuitive. As one patient noted:"'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.'"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 7 days after performing a maximal cardiopulmonary exercise test. After 2 days, all controls subjects were recovered while only 1 ME/CFS patients was. Most (60%) of the ME/CFS participants reported that tit took more than 5 days to fully recover from the test and many reported feeling at their worst 24 to 48 hours after the test. Other studies have found the same prolonged recovery period in ME/CFS patients after exertion. A Dutch study for example noted: "'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.'"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. In the Stanford study by Chu et al. 87% of respondents indicated that they endure PEM for 24 hours or more. The authors concluded: "'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.'"

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: "'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 swelling, general malaise, increased pain or cognitive fog.'"Van Ness et al. noted how cognitive difficulties after exertion differentiate ME/CFS patients from healthy controls: "'Another interesting difference between groups was the reported symptom of cognitive dysfunction, for example, ‘‘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.”"This was elaborated by Chu et al., the research team who conducted the first in-depth investigation on how ME/CFS patients describe their PEM: "'There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ 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 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, 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.'"

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.”  Commenting on the outbreak in West Kilbride, Ayrshire, Ramsay remarked: "“Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain.”"Some other precipitants of PEM that have been reported include positional changes and exposure to excessive light or sounds. 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. As long time ME/CFS expert Jennifer Spotila explained in a four-piece exploration of the phenomenon post-exertional malaise:"“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.”"This was confirmed by Chu et al. "'[…] 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.'"In some instances, the specific trigger of PEM cannot be identified.

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%. 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.

The drop in functional capacity on the second CPET is usually not seen in other diseases. According to 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". 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.

Questions have however been raised about the clinical use of the 2-day CPET procedure. 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. 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. CPET for ME/CFS is usually not covered by insurance and can cost hundreds of dollars. 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 Centers for Disease Control (CDC) symptom inventory list that differentiated subjects with ME/CFS from those without the disease. It was also the highest loading factor among a data set of 38 measurements used for a principal component analysis of unexplained chronic fatigue. 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: "'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.'"Using a large sample of ME/CFS patients from Newcastle, Norway and the 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: "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."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. Another data mining study by the same research group, suggested the selection of four symptoms:  next to extreme tiredness, unrefreshing sleep and difficulty finding the right word to say or expressing thoughts, PEM was once again represented with the item “physically drained/sick after mild activity.”

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 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".

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. In a 1996 study by Komaroff et al. 13 of  25 MS-patients (52%) reported PEM, a figure similar to what Jason et al. found with the DSQ PEM subscale in a cohort of 106 MS-patients. 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.

Major Depressive disorder
In the 1996 study by Komaroff et al., only 19% of patients with major depression reported PEM. A similar figure was found by Hawk et al., who found PEM in 3 patients in their sample of 15 with major depressive disorder. In contrast all of the 15 studied ME/CFS patients reported PEM, making it the largest discriminant function for all investigated symptoms.

Gulf war illness
Baraniuk and Shivapurkar (2017) looked at MicroRNA 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 […] GWI indicating significant pathophysiological differences between conditions." 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: "'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.'"

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: "'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.'"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.

Gene expression
One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the leukocytes of ME/CFS patients showed an increase in expression of 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. The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients. 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:"'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.'"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. An 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.

Immune activation
There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients. 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. A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of heat shock proteins HSP 27 and HSP 70 after exercise. 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: "“…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.”"A Canadian research team had already reported a marked decline of HSP 27 during the post-exercise period of 6 ME/CFS patients in 2002.

Complement C4a
In 2003 Sorensen et al. found that the 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. 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. 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.

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).

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. 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:"'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.'"

Autonomic response
Several research teams have noted post-exertional abnormalities in the 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: "“...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.”"A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients. In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. "“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”"The Belgium team Van Oosterwijck et al. reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise. 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 6 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. 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. 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. 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. 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.

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. 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. 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. 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.

Cognitive performance
While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below). This difference may be due to heterogeneity of the patient sample and methods used.

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. 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. 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.

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.

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.

Nitric oxide metabolites
A 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.

Asking the right questions
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. 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.”

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 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. 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. 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.

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 symptom inventory for example, only asks about fatigue after exertion, while PEM entails much more than that. An Australian group at the University of New South Wales tried to better define PEM, using 19 ME/CFS patients after exposure to different stressors. 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:
 * 1) Exhausted or tired.
 * 2) Heaviness in the limbs or whole-body.
 * 3) Fogginess in the head.
 * 4) Weakness in the muscles.
 * 5) 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. In a Norwegian comparison with physician assessments, The DSQ scored a sensitivity of 92% and a specificity of 75%. 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. In early 2018 the Common Data Elements working group on PEM formed by NINDS and the CDC, recommended the use of 5 items from the DSQ to measure PEM. 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).
 * 1) Dead, heavy feeling after starting to exercise.
 * 2) Next day soreness after non-strenuous, everyday activities.
 * 3) Mentally tired after the slightest effort.
 * 4) Minimum exercise makes physically tired.
 * 5) Physically drained or sick after mild activity.

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) 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:"'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.'"The NINDS/CDC common data elements PEM subgroup also noted about the DSQ: "'...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."In an online poll to which 783 people responded, 68% answered that the DSQ PEM did not reflect their experience of post-exertional malaise, though questions have been raised about the neutrality of the wording used. 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.

Furthermore, the authors have recently revised the DSQ PEM subscale to include new items, some based on Ramsay’s writings. 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: An analysis showed that these questions (the duration of PEM in particular) helped to differentiate ME/CFS patients from controls with MS or post-polio syndrome.
 * 1) Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?
 * 2) Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?
 * 3) If you feel worse after activities, how long does this last?
 * 4) 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?
 * 5) If you do not exercise, is it because exercise makes your symptoms worse?

PENE
Of all case definitions the International Consensus Criteria (ICC, Carruthers et al., 2011) 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” and has the following characteristics: The definition fails however to make clear how many of these characteristics are necessary to diagnose PENE.
 * 1) 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.
 * 2) Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
 * 3) Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
 * 4) Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.
 * 5) Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.

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.” 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: "'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.'"A Norwegian in depth-report of ME/CFS-patients relationship to exercise also highlighted muscle weakness: "'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.'"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.

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 "'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.'"A 2018 analysis showed that patients' preferences to describe PEM are generally not well-represented within present case definition criteria or descriptions. 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: "'PEM is defined as an abnormal response to minimal amounts of physical or cognitive exertion that is characterized by:"
 * 1) 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, muscle pain, joint pain, 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.
 * 2) Loss of stamina and/or functional capacity.
 * 3) An onset that can be immediate or delayed after the exertional stimulus by hours, days or even longer.
 * 4) A prolonged, unpredictable recovery period that may last days, weeks, or even months.
 * 5) 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."

Notable studies

 * 1999, Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome (Abstract)
 * 2013, Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression [(Abstract)
 * 2015, Myalgic Encephalomyelitis: Symptoms and Biomarkers (Full Text)
 * 2015, Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (Full Text)
 * 2016, Deconstructing post-exertional malaise: An exploratory factor analysis (Full Text)


 * 2018, Comparing Post-Exertional Symptoms Following Serial Exercise Tests (Abstract)



Notable articles

 * Dec 30, 2015 Suggestion to replace PEM (Post Exertional Malaise) with PAR (Post Activity Relapse)


 * Nov 4, 2016 Postexertion 'Crash,' not Fatigue per se, Marks Syndrome

Talks & interviews

 * 2012, Top 10 Things You Should Know About Post-Exertional Relapse
 * 2013, CFS gene expression after exercise (part 1)
 * 2015, 72. Gene-expression and exercise / Gen-expressie en inspanning – dr. Lucinda Bateman
 * 2015, Post-Exertion Malaise: The Intersection of Biology and Behavior


 * 2016, Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence

Learn more

 * International CFS/ME Awareness Day - What Health (PEM Definition Included)
 * Post-Exertional Malaise in Chronic Fatigue Syndrome
 * Post-Exertional Malaise: Cause and Effect
 * What is Post-Exertional Malaise
 * Post-Exertional Malaise - The ME/CFS Ghost
 * The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?