SMCI Comment on the Institute of Medicine Report—Part 3 of 5

Post-Exertional Malaise (PEM)
By Suzanne D. Vernon, PhD, SMCI Scientific Director

This is the third of our five-part blog series to break down the Institute of Medicine (IOM) report titled, “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.” As covered in the second blog post of this series, the IOM committee proposed specific criteria that focused on the central symptoms to make a diagnosis of ME/CFS.

This blog focuses on the second of the IOM-recommended diagnostic criteria and what we know to be the cardinal symptom of ME/CFS: post-exertional malaise (PEM). PEM is defined 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.1 Patients have long known that PEM is a characteristic feature of their disease and individuals have described it as “crash,” “debility” and “hitting the wall.” The description by Dr. Larry Baldwin, a general surgeon and ME/CFS patient, is telling of the profound physiological effect of PEM:

“This pattern (of symptoms) is specific and vastly different from any post-exertional experience I had as an athlete, surgery resident or while practicing surgery. While training for marathons I was able to run through the ‘wall’ that many runners experience. Now I experience a similar wall after minimal exertion and have not been able to train through or push through this wall.”

Dr. Baldwin described his post-exertion symptoms as post-exertional debility because the consequences of too much physical or cognitive exertion are much more than malaise, which is a general feeling of discomfort and an inadequate term. As you can see in the chart below, Dr. Baldwin tracked the symptoms he experiences and how these increase in severity with increasing physical or cognitive workload.

Note that symptoms of fatigue, brain fog and sleep disturbance appear after minimal exertion. Other symptoms like gastrointestinal and neurological symptoms occur after higher levels of exertion. Nasal congestion and impaired thermoregulation symptoms occur but do not increase in severity. Tracking PEM symptom patterns can help patients understand what triggers PEM and what the individual physiological effects are. Importantly, this will help the individual convey their PEM experience to their doctor.

Caption: Dr. Larry Baldwin submitted this chart detailing his PEM symptom pattern to the IOM committee.
Caption: Dr. Larry Baldwin submitted this chart detailing his PEM symptom pattern to the IOM committee.

If the above is an example of the PEM experience for the individual, what does PEM look like in a research setting? Dr. Dane Cook, one of SMCI’s funded investigators, uses an exercise challenge in an attempt to obtain physiological assessment of PEM as well as standardized questionnaires that assess symptoms. Cook finds that the symptoms experienced by ME/CFS patients are quite variable.

The chart below, which shows how patients report on the symptoms and severity they are being asked about, displays results from 12 ME/CFS patients that went through an exercise challenge and then reported their symptoms 24 hours later. Patients 3, 6 and 11 had increased severity of many of the same symptoms. Patient 9 had increased chills. Interestingly, the symptoms for patients 4, 7, 8 and 10 decreased or diminished in severity following the exercise challenge as evidenced by negative values.

This illustrates that, even with a standardized exercise challenge in the controlled setting of a research laboratory, defining PEM is elusive. Further, standardized symptom assessments may not be adequate to capture the individual PEM experience, as evidenced by the symptoms that Dr. Baldwin experiences compared with those measured in research.

It is worth noting that the other IOM-recommended diagnostic criteria—functional impact of fatigue, unrefreshing sleep, orthostatic intolerance and cognitive impairment—can be objectively assessed in a clinical setting. But until we know how to objectively measure PEM, doctors will have to rely on eliciting information from the patient. The IOM recommended that clinicians use the following questions to diagnosis PEM:

  • What happens to you after you engage in normal physical or mental exertion?
  • How long does it take you to feel bad?
  • How long does it take to recover from physical or mental effort?
  • If you go beyond your limits, what are the consequences?
  • What types of activities do you avoid because of what will happen if you do them? (Consider asking patients to keep a diary for a week or two.)

These are actually very good questions that do not bias a patient toward a particular symptom, like fatigue or pain, but rather elicit the patient’s own, individual experience. Responses will give the doctor the information on exertion intolerance needed to make a diagnosis of ME/CFS and provide the symptom management and supportive care needed.

The need for research that objectively measures and defines PEM is even more paramount given the variability in the patients’ symptoms, experience and the complexity of PEM. Research on PEM has used the cardiopulmonary exercise test (CPET) to provoke and amplify the physiological disturbance that could be responsible for the post-exertion state. Individuals being challenged with one CPET test who have measures taken before and hours after the exercise challenge show changes in gene expression2, immune function3 and brain blood flow4. Administering two CPET tests—one 24 hours after the first—shows that ME/CFS patients cannot reproduce the physiological measurements from the first test indicating possible metabolic disturbances5. The source(s) of this metabolic disturbance has not yet been identified. Research that combines and correlates the CPET physiological results with the patients’ symptom experience will help zoom in on the possible causes of PEM, which could lead to objective diagnostic tests and treatment.

The next blog post in this IOM series will deal with the third IOM-recommended diagnostic criteria: unrefreshing sleep. To ensure you receive notification of each blog post as it is published, simply sign up for notifications in the grey and blue “Sign Up” box on the top right of this page.


1. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lemer AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, Van de Sande MI. Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols (Canadian case definition). Journal of Chronic Fatigue Syndrome. 2003 11(1):7-115.

2. White AT, Light AR, Hughen RW, Vanhaitsma TA, Light KC. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosomatic Medecine 2012 Jan;74(1):46-54.

3. Sorensen B, Jones JF, Vernon SD, Rajeevan MS. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Molecular Medicine 2009 Jan-Feb;15(1-2):34-42.

4. He J, Hollingsworth KG, Newton JL, Blamire AM. Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation. NeuroImage Clinical 2013 Jan 5;2:168-73.

5. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment. Journal of Translational Medicine & Epidemiology 2014 Apr 23;12:104.