Post-exertional malaise (PEM), the cardinal feature of ME/CFS, is profoundly debilitating and often unpredictable, significantly impacting the lives of those affected.
According to research, type (cognitive and/or physical) and severity of PEM can vary.
While the exact cause of PEM is unknown, it may be linked with:
- Changes in energy production and utilisation.
- Impaired recovery and signs of damage to muscles after exercise.
- The presence of immune cells in muscle tissue.
While researchers are making progress with studies relating to PEM, it is essential to recognise that they face many challenges, including, but not limited to:
- PEM can be triggered by different types of activity (i.e. not just physical activity),
- There is not yet a validated biomarker for PEM meaning that researchers predominantly rely on self-reported information,
- The variability and delayed onset of PEM,
- Detailed ethical considerations must be made to enable research into the PEM.
The following will discuss the above research difficulties in more detail, and provide ME Research UK resources relevant to research into PEM.
Research challenges
Different triggers
Researchers often investigate how physical activity impacts PEM, but it is also essential to consider that other forms of activity, or ‘stress’ on the body, may also lead to PEM, including:
- Cognitive activity like planning and decision making, computer work, or even some forms of crafting like knitting;
- Emotional activity such as that relating to a life event like moving house, losing a loved one, or even a miscommunication with a friend;
- Social activity like a guest visiting, having dinner with family or answering a phone call;
- Sensory ‘activity’ or stimulation like sitting next to a light that is too bright, being exposed to loud or ongoing noises, or being near someone with strong smelling perfume.
- Other ‘activity’ such as when the body is fighting off an infection, or during bodily functions like digesting food.
Studies—particularly those using cardiopulmonary exercise testing (CPET)—often examine how a physical exercise test influences PEM. However, it is extremely challenging for researchers to account for other factors that may also affect PEM, such as travel to the lab, room lighting, and interactions with research staff, all of which can vary in their impact from one participant to another.
It is also important to note that due to the severity of ME/CFS, and the low threshold for induction of PEM in those with severe and very severe forms of the disease, it is often not possible for those with severe forms of the disease to take part in studies, especially those which require them to attend a laboratory.
Lack of validated biomarker and reliance on subjective self-reported information.
As with ME/CFS overall, there is no validated biomarker for PEM. Rather, the symptom is often measured using self-reported questionnaires like the DePaul Symptom Questionnaire-PEM (DSQ-PEM). While these measures do provide insight into self-reported PEM, they are subjective, which means that the questions could be interpreted differently by different participants. While some studies do take biological samples, such as muscle biopsies, these are not specific to PEM.
Variability and delayed onset of the symptom.
PEM does not present uniformly in people with ME/CFS, varying both in its presentation and in the timing of onset after activity. For some individuals, symptoms may emerge within an hour, whereas for others, onset may be delayed by 48 hours or more. There are also variations in how long PEM lasts between people, and within the same person.
Ethical considerations for research into the complex symptom.
When researchers design a study using human participants, they are guided by ethical principles set out in the Declaration of Helsinki which, although complex, establish that the health, well-being, and rights of research participants must always take precedence over the interests of science and society, requiring rigorous risk-benefit assessments, independent ethical oversight, and free, informed consent.
To objectively measure PEM, researchers must induce the very symptom they are studying using methods such as CPET. Although no permanent damage has been definitively linked to this short-term experimental stress, participants have reported the need for extended recovery periods, and it is essential to recognise that the profound discomfort of a severe crash requires strict ethical justification.
ME/CFS research involving CPET is typically subject to ethics approval from institutional review boards or ethics committees. This approval ensures that research protocols adhere to ethical principles, protect participants’ rights and well-being, and minimise risks. Despite this, as members of ethical review boards are not always aware of the complexities of PEM, it is essential for researchers to be fully aware of all potential issues, and where appropriate, work with people with ME/CFS to ensure their studies minimise potential harm, and also that study documentation contains all relevant information to enable prospective participants to make fully informed decisions about whether or not they consent to take part.
Resources
1. ME Research UK articles relating to PEM:
- The experience of post-exertional malaise – part 1
- The experience of post-exertional malaise – part 2
- Subtypes of post-exertional malaise
- The assessment of post-exertional malaise
- Predicting the severity of post-exertional malaise
- Blood lactate monitoring – a tool to support the management of post exertional malaise?
- Unravelling the nature of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: The role of elastase, complement C4a and interleukin-1β
- Epigenetic changes in pain and post-exertional malaise
- Assistant Professor Rob Wüst on skeletal muscle alteration in ME/CFS and Long COVID.
- Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing
2. Completed research funded by ME Research UK relating to muscle function and metabolism
3. Ongoing research funded by ME Research UK investigating muscle microclots and microvascular pathology in ME/CFS – Dr Rob Wüst
