Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey

Considerable controversy has existed with efforts to assess post-exertional malaise (PEM), which is one of the defining features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). While a number of self-report questionnaires have been developed to assess this symptom, none have been comprehensive, and a recent federal government report has recommended the development of a new PEM measure. The current study involved a community-based participatory research process in an effort to develop a comprehensive PEM instrument, with critical patient input shaping the item selection and overall design of the tool. A survey was ultimately developed and was subsequently completed by 1534 members of the patient community. The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM instrument. This study indicates that there are unique benefits that can be derived from patients collaborating with researchers in the measurement of key symptoms defining ME and CFS.


Introduction
Among patients with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), post-exertional malaise (PEM) has long been considered a hallmark symptom [1]. However, in a field which includes more than twenty case definitions for ME and CFS, there has not been agreement regarding defining PEM [2]. For example, discrepancies occur with two of the most frequently used ME and CFS case definitions, the Fukuda [3] and Canadian Consensus Criteria (CCC; [4]). The Fukuda et al. criteria do not define the term beyond requiring that it last for more than 24 h nor does it make PEM a requirement for diagnosis. In contrast, the CCC case definition requires the presence of PEM for diagnosis and goes further to describe the symptomatic experience as similar to flu-like distress, with a potential delayed onset [4].
Several activity and self-report measurements that assess the extent of activity and how such activity might result in exacerbation of symptoms have been proposed to measure PEM. These include actigraphy, exercise challenges, time logs, and self-reports [5]. For example, following an exercise task, Mateo et al. [6] reported a broad spectrum of PEM-related symptoms including fatigue, muscle/joint pain, cognitive dysfunction, decrease in function, headaches, sleep disturbances, pain, weakness, cardiopulmonary symptoms, lightheadedness, and flu-like symptoms. Others have found posted on Facebook, Twitter, and LinkedIn social media pages and were widely shared with patient groups internationally. Hundreds of emails were received during the next three months, and Jason and Holtzman posted nine revisions of the survey for patients to provide comments. The comments and items received helped shape each new revision of the questionnaire. For example, when one participant commented "I also experience different types of PEM. I have the immediate PEM, where I do too much . . . But if I stop [exerting myself], these [PEM symptoms] go away fairly quickly . . . But if I am not able to stop during this immediate PEM stage and have to push on while experiencing these symptoms, then I get the "Post-PEM" usually two or more days later," we used this input to introduce survey items that asked about both the immediate and delayed onset of PEM and its relationship to potential triggers.
After several months, when we were receiving few additional patient comments regarding our survey that we had been posting, we decided to collect data using this survey with the next phase of this project. Institutional Review Board (IRB) approval was obtained for collecting data based on the survey that had been developed using input from the patient community. Participants provided informed consent. Participants were required to be over the age of 18 years old, able to read and write in English, and have a current self-reported diagnosis of ME and/or CFS. Participants completed the questionnaire online using Research Electronic Data Capture (REDCap), a secure online survey tool [18]. Respondents were instructed to save their answers and return to complete the survey at a later time if they were not able to finish the survey in one sitting due to their illness.

Materials
The first part of the survey assessed demographic characteristics, as well as information about illness/diagnosis status (see Table 1). Following this background assessment, the respondents were asked about the onset of their PEM symptoms (see Table 2), and then asked questions relating to factors that trigger PEM (Table 3). This included examples of triggers beyond physical or cognitive exertion, such as "basic activities of daily living", "positional changes", and "emotional events". The survey also asked specific questions about the relationship between triggers of PEM and other factors, such as participants' individual energy limits or the extent to which they may exert themselves.
Next, the participants were asked to evaluate a list of symptoms that are exacerbated following physical and/or cognitive exertion ( Table 4). The symptoms included items which have been assessed through other operationalized measures (e.g., "physical fatigue", "unrefreshing sleep", and "flu-like symptoms"), as well as items suggested by patients (e.g., "physical fatigue while mentally wired", "brain twangs" and "burning sensation all over your skin"). Each item was rated for frequency for the past six months on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, 4 = all of the time. Symptoms of 2 or higher were considered to be the threshold for PEM, based on past studies [19]. For each symptom, frequency values were multiplied by 25 to convert to 100-point scales, with higher values indicating more frequent symptoms. Table 5 shows item responses of participant experiences of PEM by asking the question "If you go beyond your energy limits by engaging in pre-illness tolerated exercise or activities of daily living, do you experience any of the following?" Several common phrases used to describe PEM were then listed, including "a severity and duration of symptoms that are out of proportion to the initial trigger" and "global worsening of multi-systemic symptoms (an example of this might be aches all over your body plus cognitive problems plus light and/or sound sensitivity)".
Following the PEM symptom list, the survey included an assessment of duration of PEM and length of recovery time, as well as information about illness course and functioning (Table 6). To better understand the relationship between PEM and exertion, participants were asked if the severity and duration of PEM was out-of-proportion to the type, intensity, frequency, and duration of exertion. Participants were then asked whether they had ever experienced an "adrenaline surge" after going beyond their energy limit, and how long the surge lasts before the onset of PEM. Next, patients were assessed on their illness course and functional status by asking how long ago they began feeling sick with ME or CFS, if the illness has been present for at least 50% of the time, and how they would describe their illness and functioning. Participants were also asked if they are managing their PEM symptoms by pacing or "staying within their energy envelope," one of the few patient recommended treatments for ME and CFS [20].
The survey also requested information about past tests the participant may have completed, such as a cardiopulmonary or tilt table test. Lastly, the survey assessed if the participants felt that this patient-driven survey accurately depicts their PEM experience.

Results
The international online convenience sample included 1,534 adults identifying as having ME and/or CFS who completed the questionnaire (347 additional respondents had incomplete surveys and were not included in this analysis). Respondents were from over 35 countries. As indicated in Table 1, 41.1% of participants reported currently living in the United States. The sample consisted of mostly females (84.6%). The majority of participants were white/Caucasian (97.5%), and 2% identified as being of Latino or Hispanic origin. Just over half of the participants were married or living with a partner (56.6%), 39.3% had a standard college degree, and 45.7% were receiving disability payments. Table 1 indicates that 50.7% of participants had a diagnosis of CFS, 22.0% had a diagnosis of ME, and 27.2% had a diagnosis of both ME and CFS. For our entire sample, 94.4% reported being diagnosed by a medical doctor. Descriptive statistics of PEM onset are reported in Table 2. Over half of participants had experienced onset of symptom exacerbation immediately after exertion (72.3%), while 91.4% had experienced delayed onset after exertion. To determine the length of the delay between exertion and the onset of PEM, participants selected periods for when the onset of PEM might occur when onset is delayed. A delay of between 1-2 days after exertion was experienced by 53.1% of the participants.  Note: * For this item, participants could select more than one answer. There is also an option for participants to describe what activities and which symptoms affect immediate and/or delayed onset. Table 3 describes PEM triggers, with 78.2% endorsing "basic activities of daily living", 64.5% endorsing "positional changes", and 93.2% endorsing "emotional stress (good or bad)". Additionally, 84.9% said there were some instances in which the specific precipitants could not be identified. The highest endorsed non-exertion triggers reported by participants were as follows: emotional events (88.3%), noise (85.5%), and sensory overload (83.6%).  Table 4 reports the proportion of participants who endorsed the worsening of symptoms due to physical or cognitive exertion. The most commonly endorsed symptoms were as follows: reduced stamina and/or functional capacity (99.4%), physical fatigue (98.9%), cognitive exhaustion (97.4%), problems thinking (97.4%), unrefreshing sleep (95.0%), muscle pain (87.9%), insomnia (87.3%), muscle weakness/instability (87.3%), temperature dysregulation (86.9%), and flu-like symptoms (86.6%). The symptoms endorsed by less than half of the sample included the following: loss of appetite (49.0%), migraines (46.2%), cardiac pain and/or arrhythmia (41.2%), brain twangs (29.9%), burning sensation all over your skin (29.7%), paralysis/inability to move (29.4%), pre-menstrual symptoms (21.1%), and decreased heart rate (15.1%). Note: % endorsed "yes" means they responded yes to experiencing symptom at any level. % endorsed at "2" threshold means that they experience the symptom at least half the time. Means reflect frequency only (0-100 scale).
In order to gauge participant's general experiences of PEM, participants were asked if they experienced any of the common phrases used to describe PEM (listed in Table 5) after exertion. All of the phrases were endorsed by over 90% of the sample. Table 5. If you go beyond your energy limits by engaging in pre-illness tolerated exercise or activities of daily living, do you experience any of the following? (N = 1534).

Items % (n)
An onset that is immediate or delayed by hours or days 98. The findings reported in Table 6 indicate that over half the participants (58.0%) said PEM lasts on average 3-6 days, with 1-2 days (38.9%), 1 week-1 month (46.7%), and 1-6 months (30.3%) also being frequently reported. Additionally, 67.1% of the sample had experienced a "crash" that never resolved. Over half of the sample (57.2%) said they had experienced an adrenaline surge during or after going beyond their energy limits, and the most commonly reported length of time was "a few hours" (35.8%). Further information about the natural history of participants' ME/CFS illness are also provided in Table 6. The majority of subjects have been sick for over 10 years, with 97.1% reporting their illness being present for more than 50% of the time. Additionally, nearly half of participants described the course of their illness as fluctuating, experiencing good periods and bad periods. Lastly, nearly half of participants classified their status as being able to do light house work, but not being able to work part-time. Table 6 also contains information on how participants were currently managing their PEM symptoms. Only 6% of patients with ME or CFS felt that pacing completely allowed them to avoid PEM, while the majority reported pacing only being effective some of the time and only at a moderate/mild level. Participants also identified the pacing method they used (e.g., 87.1% indicated it was based on their bodies' reactions whereas 10.7% indicated it was with a heart rate monitor, and 17.3% indicated both).
Patients were also asked about tests to assess their cardiovascular health difficulties and orthostatic intolerance, which are common symptoms of ME and CFS and are often made worse after exertion. Almost a quarter (24.5%) indicated they had undergone a cardiopulmonary test and 29.7% indicated they had taken part in a stand lean/tilt table test. Of those patients, 9.3% had normal cardiopulmonary results, whereas 14.9% had abnormal results. Only 4.8% of the sample had completed an exercise test on back-to-back days.
At the end of the questionnaire, participants were asked if they felt this survey accurately captured their experiences of PEM, and 29.8% felt the survey was very accurate, 57.7% reported it was accurate, 10.7% were neutral, 1.2% thought it was not accurate, and 0.1% said it was not at all accurate.   How long ago did your problem with ME/CFS begin?
6-11 months ago 0.6 (9) 1-2 years ago 2.9 (45) 3-5 years ago 12.  Note: * For these items, participants could select more than one answer. There is also an option for participants to describe pacing techniques not listed.

Discussion
The objective of this study was to use community-based participatory research in an effort to develop a comprehensive way to assess PEM. Based on the comments and items suggested from patients, the following specific aspects of PEM were found to be the most critical domains: the timing of PEM onset, triggers of PEM, symptoms that are exacerbated following exertion or exposure to triggers, phrases used to describe consequences of PEM, duration of PEM, relationship between exertion and length of recovery, and the importance of considering personal characteristics (e.g., how long the patient has had ME/CFS, the course of their illness, their level of functioning, and coping methods used). The patient perspective provided the authors with the critical information to develop this survey of PEM. Of the patients who took part, 87.5% felt that the resulting survey was either very accurate or accurate.
Onset of symptom exacerbation after exertion was found to vary between patients. As shown in Table 2, the majority of patients experienced both immediate and delayed onset of PEM, and the extent of the delay of symptoms varied considerably. In addition to the unpredictability of PEM onset, several factors affect the duration of PEM before recovery, including the type, intensity, frequency, and duration of the exertion (see Table 6). These findings are consistent with patients' reporting of prolonged recovery from PEM symptoms. In one study in which patients and healthy controls participated in a fatiguing exercise test, the patient group's recovery was prolonged [21]. In addition, VanNess et al. [13] found patients with CFS, in comparison to healthy controls, take considerably longer to recover after completing a maximal cardiopulmonary exercise test the next day and a week later. Our findings are also consistent with a study by Chu et al. [11] who found that when comparing PEM symptom onset between those with ME or CFS to healthy controls, 87-95% of controls had recovered within 24 h after completing an exercise test. Among those with ME and CFS, PEM symptoms peaked at 24 to 48 h later, and 45-60% still experienced symptoms up to 5 days later.
Our survey also assessed specific triggers that bring on symptom exacerbation. The effects of physical and cognitive exertion on PEM have been well-established [13,[21][22][23] and these findings are consistent with the current study. For example, only 37% of subjects reported being able to exercise "a little" without PEM-related symptoms, as long as they stay within "certain limits" (see Table 3). Furthermore, basic activities of daily living (e.g., getting dressed, cooking a meal, bathing), positional changes (e.g., going from lying down to standing up), and emotional stress lead to exacerbation in 78.2%, 64.5%, and 93.2% of patients, respectively.
Another issue explored involved whether there are precipitants of PEM beyond physical or cognitive exertion. The highest reported triggers in addition to physical/cognitive exertion were emotional events (88.3%), noise (85.3%), and sensory (83.6%) and visual overload (79.7%). This is consistent with past literature reporting these types of stimuli as exacerbating symptoms [24]. It has also been hypothesized that exposure to mold could trigger illness onset and PEM symptomology [25]. In our sample, 39.4% reported mold triggering their PEM. This is consistent with findings by Brewer, Thrasher, Straus, Madison, and Hooper [26], where 30% of patients with ME and CFS were reported to have multiple mycotoxins present in their bodies.
Partly as a function of this survey and the interactions with the patient community, there have been several additional developments in the assessment of PEM. First, Cotler et al. [27] found that use of the 5 recommended PEM DSQ items was an excellent screen in identifying PEM in patients with ME and CFS. In addition, as a second step in the process of assessing PEM, 5 additional DSQ items (including the assessment of duration of symptoms) were successfully used to differentiate PEM from other chronic illnesses. In addition, the findings from the patient survey reported on in this article were revised in order to construct a briefer, more concise measure of PEM, which was significantly related to physical functioning [28].
There are several limitations to this study. First, we did not obtain confirmation of ME or CFS diagnoses by independent medical personnel. In addition, we do not know what case definitions, if any, were used in their diagnoses. In addition, consistent with other ME and CFS studies, the sample was not demographically diverse. However, having a sample from several geographic regions did increase the generalizability of findings. Another limitation of the study was the length of the questionnaire. Though participants were presented with the option of pausing, it is reasonable that some may have still found it difficult to complete.
The open, participatory nature of this study provided a unique way of both designing the survey and gathering comprehensive information from the ME and CFS community regarding PEM. There are unique benefits that can accrue to the research and patient community by actively collaborating on instrument development as well as other policy issues, such as the selection of a name for the illness as well as the case definition [29]. By collaborating with the ME and CFS community, we have provided a model of community-based participatory research, which has multiple advantages to both the patient and research communities [30]. We close with this quote regarding what needs to occur to further this type of collaborative research in the ME and CFS areas: "An alternative vision is still possible if those in power are willing to bring all interested parties to the table, including international representatives, historians on the science of illness criteria, and social scientists adept at developing consensus. In a collaborative, open, interactive, and inclusive process, issues may be explored, committees may be charged with making recommendations, and key gatekeepers may work collaboratively and transparently to build a consensus for change. Involve all parties-patients, scientists, clinicians, and government officials-in the decision-making process [31]."