Warning Signals of Post-Exertional Malaise in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: A retrospective analysis of 197 patients, by Alaa Ghali, Carole Lacout, Maria Ghali, Aline Gury, Estelle Delattre, Christian Lavigne and Geoffrey Urbanski in J. Clin. Med. 2021, 10(11), 2517; [doi.org/10.3390/jcm10112517] 7 June 2021 (This article belongs to the Section Clinical Neurology)

Research abstract:

Post-exertional malaise (PEM), the key feature of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), is characterized by baseline symptom exacerbation after exposure to a stressor, and some patients can experience new or non-typical symptoms.

We hypothesized that new or non-typical symptoms occurring long enough before onset of baseline symptom exacerbation could be warning signals predicting PEM.

Adult ME/CFS patients who attended the internal medicine department of Angers University Hospital (France) between October 2011 and December 2019 were included in a retrospective medical records review. Patients who experienced one or more new or non-typical symptoms before baseline symptom exacerbation were compared with the rest of the study population for PEM features, epidemiological characteristics, fatigue features, and comorbidities.

New or non-typical symptoms preceded baseline symptom exacerbation in 27/197 (13.7%) patients, and the most frequent ones were mood disorders (37%). When compared to the rest of the study population, only PEM intensity was significantly lower in these patients (p = 0.004), even after adjustment for sex and age at disease onset (p = 0.007).

New or non-typical symptoms preceding baseline symptom exacerbation in some ME/CFS patients could be warning signals for PEM. Their identification could help preventing PEM occurrences or reducing their intensity leading to improving disease prognosis.

Excerpt fr0m paper:

4. Discussions 

… Besides mood disorders, we observed other frequent prodromal new or non-typical symptoms, such as nausea, paresthesia, and headaches. Interestingly, despite their heterogeneity and large variability between patients, prodromal new or non-typical symptoms often remained the same for each patient, which reinforces their predictive power.

One can wonder whether medication intake in patients with comorbid reactional depression or fibromyalgia to relieve symptoms can hinder the emergence of prodromal new or non-typical symptoms. In the current study, there were no significant differences in medication intake between patients both diagnosed with comorbid reactional depression and/or fibromyalgia and exhibiting prodromal new or non-typical symptoms when compared to the rest of the study population (Supplementary Table S1). Therefore, medication intake in these patients did not appear to affect the emergence of warning signals.

One question, however, remains unanswered: why a proportion of patients experienced new or non-typical symptoms before onset of baseline symptom exacerbation while others did not. Overall, the features and pathophysiology of PEM are still not well understood. Nevertheless, there is a growing body of evidence that PEM affects a variety of physiological systems.

Studies that used maximal and submaximal exercise to elicit PEM showed altered cardiorespiratory responses [24], impaired pain regulation [25], impaired cognitive performance and affected brain function [26], altered gut microbiome and increased bacterial translocation [27], and immune involvement [28]. Mitochondrial dysfunction was also discussed as having a role in the nature of PEM [29], not only after exercise [30], but also in resting conditions [31]. Research addressing this issue must be conducted.

5. Conclusions
Taking warning symptoms into consideration could alert patients to the fact that they are going beyond their energy reserves and therefore have to reduce or stop their activity level in order to avert PEM occurrence. Consequently, it seems necessary to systematically look for prodromal new or non-typical symptoms, which are different from those usually experienced by ME/CFS patients.

To do this, self-report questionnaires intended to assess PEM among these patients should include specific questions designed to examine the presence of the prodromal phase, explore warning symptoms that might occur after exposure to a PEM stressor and before onset of baseline symptom exacerbation, and specify whether or not these symptoms are different from those habitually experienced by patients.

Similarly, and given that patients with ME/CFS usually show difficulties in predicting PEM occurrence, especially when the onset of baseline symptom exacerbation is delayed after the stressor, they must learn how to identify and recognize which warning signs, if any, may herald PEM onset, and be informed about how the impending threat of PEM could be avoided.

To achieve this, it is important to facilitate access for patients to therapeutic educational programs, and raise awareness among primary care physicians about ME/CFS, in particular PEM issues.