Deciphering Post Exertional “Malaise” 


PEM? – Cook asserts it’s compulsory in ME/CFS: no PEM – no ME/CFS….

In the last blog we found that the “fatigue” in chronic fatigue syndrome and multiple sclerosis (MS) were very differentWhile exercise knocked the ME/CFS patients into a new sphere of suffering, it had only temporary and  moderate effects on the MS patients. Upregulated genes clearly linked with the exertion problems in ME/CFS that were unchanged in MS. These are two very different disorders –  when it comes to exercise.

Now, taking advantage of Dane Cook’s recent Solve ME/CFS Initiative  (SMCI) webinar, we take a look at two more studies that further underscore the perhaps unique post-exertional malaise problems found in ME/CFS.

A “Defining, Compulsory and Cardinal Feature”

Cook called post-exertional malaise a “defining, compulsory and cardinal feature” of chronic fatigue syndrome.   (Dr. Unger would disagree, but most ME/CFS experts and doctors would agree.) Cook noted that PEM is a horrible term that in no way reflects the extent of the debility it causes in ME/CFS.

A Short Digression – the Malaise of It All

The word malaise is clearly the issue here.  According to Wikipedia malaise, a French word in use since the 12th century, refers to “a feeling of general discomfort or uneasiness, of being “out of sorts” … [that is] often the first indication of an infection or other disease”. Medline says it refers to “a generalized feeling of discomfort, illness, or lack of well-being”.

Cook is right: PEM is another powder-puff term that somehow has gotten latched onto, whoops, another powder-puff term, “chronic fatigue syndrome”.


“Malaise” – another medical term that fails to do justice

Somebody came up with the term “post-exertional malaise” – but who and when? And is it exclusive to ME/CFS? A PubMed search indicates it first shows up in a medical abstract in a review paper on chronic fatigue syndrome in 1993 by none other than, whoops again, Dr. Anthony Komaroff, who has regretted his part in bringing the name chronic fatigue syndrome into existence for twenty years or so. Did he also help bring PEM into existence? He appears to be off the hook on this one.

Ramsey does not appear to have used it in his ME definition, but PEM was listed as a minor criterion in the 1988 Holmes Definition of CFS. It has become one of eight key symptoms in the Fukuda criteria, was not mentioned in the Oxford criteria, was retained in the Empirical Criteria, and was made a cardinal symptom for the first time in the Canadian Consensus Criteria. In the International Consensus Criteria PEM was transformed into PENNE.

After 1993, the next research reference to PEM in PubMed is fifteen years later in 2008. The Workwell exercise studies probably  brought PEM to the fore, and since then it’s been referred to fairly frequently.  All of the 25 references to PEM in PubMed involve chronic fatigue syndrome. It is apparently a term developed for and exclusively used to refer to ME/CFS.

Onward with the Webinar

What is PEM? Depending on how you look at it it can mean many things. These studies will add another dimension.

What is PEM? Depending on how you look at it it can mean many things. These studies will add another dimension.

But what is PEM? Depending on how you’re looking at it, PEM could refer to the increased pain and fatigue people with ME/CFS experience after exercise, reduced aerobic energy production during exercise, an earlier entry into anaerobic energy production,  reduced cognitive results on tests, impaired pain regulation, increased activation of the complement system, increased oxidative stress, and finally changes in gene expression – the topic Cook addressed next.

[It’s no surprise the SolveME/CFS Initiative (SMCI) funded Cook’s exercise/gene expression and cognition study. The SMCI, then the CFIDS Association of America, provided seed money for the pilot studies that helped get both the two-day exercise test studies and the Lights’ gene expression work started. Exercise studies now permeate ME/CFS research and the Lights have received several big NIH grants to continue their work. That’s a lot of bang for your buck and it demonstrates how powerful the pilot study approach can be.]

PEM Study #1: Replicating and extending the Lights’ work 

ME/CFS patients and controls performed maximal exercise test to exhaustion (legs won’t go any more) and had blood collected before and after exercise.  This was a little different from the first Light study where the participants engaged in moderate exercise for a longer period of time. This study, which was published in 2013, found  startling changes in several receptors. These included an adrenergic (sympathetic nervous system) receptor and the NR3C1 receptor that binds with cortisol. A receptor that regulates ATP production (P2X) tanked at 48 hours and then basically disappeared at 72 hours in the ME/CFS patients. The opposite pattern prevailed in the healthy controls.

Cortisol – Again!

“There is a lot of information about cortisol and ME/CFS, but very few answers to its biological significance.” – Dane Cook

The research community glommed onto cortisol early on in ME/CFS and has never let go. Low cortisol makes sense given the problems with energy regulation and immune functioning found in this disorder.

Dane Cook on Deciphering Post Exertional Malaise

Easily the single most studied biological factor in this disorder, it appears, after decades of inconsistent results, that a consensus is finally being reached that salivary wakening cortisol is mildly low in ME/CFS, but other aspects of it may be normal (at least in a significant percentage of patients).


Cortisol just keeps popping up

Brodericks homeostatic model of ME/CFS suggests women with ME/CFS inhabit an altered homeostatic state characterized by hypocortisolism, high estradiol, and a shift towards Th2 activation. Abnormalities in cortisol genes have been found in ME/CFS.

Nobody believes cortisol is “it” in chronic fatigue syndrome, but reduced cortisol does appear to be associated with increased  fatigue and pain. Some studies suggest reduced cortisol is a secondary factor that occurs later in the illness than other components of ME/CFS. Salivary cortisol levels were not different early in the disorder between adolescents who came down with ME/CFS after infectious mononucleosis and those who did not. Just to confuse the issue more, CBT has normalized mildly lower cortisol levels in several studies.

The NRC31 receptor

NRC31 is the receptor to which cortisol and other glucocorticoids (steroid hormones such as hydrocortisone, prednisone, and prednisolone) bind.  This receptor is found in the cytoplasm of the cell. After cortisol flows through the cell wall and attaches to it, it’s transported into the nucleus where it affects a variety of genes.

Found in almost every cell in our bodies, NRC31 turns on or off genes involved in metabolism and immune functioning. Glucocorticoids turn the immune system down by upregulating anti-inflammatory and downregulating pro-inflammatory cytokine levels.  According to Wikipedia, NRC31 also appears to play a major role in regulating the effects of stress on the brain. Cortisol also spares glucose in response to exercise.

This was the first time gene expression of the cortisol receptor had been studied in response to exercise.   The increased levels of inflammation expected with an upregulation of this receptor are what we would expect to find in ME/CFS.

The significant increases in this receptor seen after exercise in the ME/CFS patients could reflect an attempt to make more glucose available for energy or, perhaps more likely, reflect an attempt to reduce inflammation induced by the exercise.

Sympathetic Nervous System

Increased levels of the AD2 receptor are consistent with the sympathetic nervous system upregulation in both chronic fatigue syndrome and fibromyalgia.  The one-two combination of  the upregulated sympathetic nervous system and cortisol/inflammatory receptors was intriguing given Dr. Klimas’s gene expression findings (unpublished) suggesting that the sympathetic nervous system  kicks off an immune cascade that causes the symptoms associated with PEM.  [The Solve ME/CFS study did not measure gene expression during exercise.]

It is important that the changes in gene expression seen were correlated with the symptom flares experienced by the ME/CFS patients; increases in the cortisol receptor, for instance, mirrored increases in the fatigue reported by the people with ME/CFS.

Take away Points

Cook documents some gene expression changes found during exercise in the first Light study and adds the ubiquitous cortisolreceptor to  the mix.

PEM Study II –  the Uber Post-Exertional Malaise Study

“It’s clear to me that post-exertional malaise affects both  the immune system and the brain.”

The Cook/Light/Broderick Solve ME/CFS study underway Cook talked about next is the kind of complicated multi-system study Solve ME/CFS loves to fund. No other studies have tried to tie PEM to so many aspects of ME/CFS.


Exercise is the constant. It’s hard on the ME/CFS patients, but Cook noted that nothing reveals the biological abnormalities in the disease better.

First they collected blood and had the ME/CFS and healthy controls do mentally fatiguing cognitive tasks while examining their brain functioning using a fMRI. Then they hit them with exercise (“moderate” exercise for thirty minutes) and then examined their gene expression, lactate levels, symptoms, cognitive functioning and brain activity 24 hours later using  fMRI, all the while measuring their symptoms.

This is an important study. If Cook et al. can show that even moderate exercise hammers ME/CFS patients’ ability to think and messes up the way their brain functions at the same time, he’ll have built a powerful case for how destructive PEM is.

Many Pathways

PEM may be unique to ME/CFS, but that doesn’t mean it doesn’t require further refinement. Cook’s closer look at PEM revealed that it inhabits a complex world into itself.  An analysis of the symptoms elicited by the exercise revealed a remarkably heterogeneous group. Memory and concentrations were highlighted in some people while headaches were the biggest component in others. One unfortunate person suffered from headaches, chills, and muscle pains.  Muscle pains were almost the sole issue for one person, while another person’s joint pains improved markedly. While most people got worse, a few people actually got a bit better – one person’s  joint pain  improved  markedly. Exercise clearly has very different effects in different people with ME/CFS.

The whole issue of symptom expression is complicated by the fact that many peoples’ symptoms, even at baseline, are already near the top of the charts. Even though they feel much worse after exercise, according to the charts they can’t get much worse! This “ceiling effect” complicates assessing symptom changes after exercise.


If you feel that you’re, well, stupider after exercise, you’re right.  If you feel you get stupider the more you exert your brain, you may be right as well.  Your brain should get better after exercise and after engaging in difficult cognitive tests, but the ME/CFS  patients’ brains behaved diametrically opposite to the healthy brains in the all the cognitive tests.

Practice Does Not Make Perfect – in ME/CFS


As the ME/CFS patients brains got more fatigued they did worse and worse on the cognitive tests.. and then came the exercise session

The cognitive tests were given three times at baseline and three times 24 hours after exercise. At baseline, while the controls got better and better on the cognitive test each time they took it, the people with Chronic Fatigue Syndrome  – demonstrating that practice does not make perfect in ME/CFS – actually got worse and worse. The difficult cognitive tests appeared to be producing their own kind of post-exertional malaise or relapse. Every time the ME/CFS patients took them, their brains took a hit.

While exercise appears to have stimulated the healthy controls brains – they continued to get better and better at the tests – ME/CFS patients continued to tank on the tests. By the last test they were making almost twice as many errors as in the first test done at baseline.

Brain Drain

That’s pretty good evidence that exercise is messing up cognition in ME/CFS, but would Cook be able to show it was messing up ME/CFS patients’ brains as well?

He would.

Functional MRIs taken during the cognitive testing showed reduced activity in a part of the brain devoted to sustained attention – the parietal cortex – as well as increased activity in three areas of the brain involved in executive functioning: the anterior cingulate, the hippocampus, and the frontal cortex.

It appears that the ME/CFS patients’ inability to maintain sustained focus on a task (parietal cortex) put more pressure on other parts of the brain (frontal cortex, anterior cingulate, hippocampus) involved in executive functioning… and that was just at baseline.

brain drain

As exercise sapped the sustained attention area of the brain the errors on the cognitive test mounted

Twenty-four hours after exercise – plenty of time one might think for the brain to recover – the situation was much worse for the ME/CFS patients.  Those splotches of color in the fMRI indicating differences in brain functioning in the ME/CFS patients were now much larger. (One can only imagine what they would look like after two exercise tests.)  Cook explained that they indicate how much harder a person with ME/CFS has to work to accomplish the same task as a healthy person.

Put the exercise and cognitive tests and the fMRI all together and you have a brain that was already having problems sustaining attention on a task before exercise getting worsening cognitively and functionally after exercise.

People with ME/CFS say it’s hard, really hard, to think, particularly after exercise, and this study helps explain why. Sustained attention was already poor at baseline, but it takes an even bigger hit after exercise. Other areas of the brain work extra hard to compensate – making cognition more effortful – but the effort largely fails and the errors mount and mount. By the end of the test the ME/CFS patients were making about double the errors of the healthy controls. Plus their symptoms – whether it’s headaches and chills in one patient or muscle pain and trouble concentrating – are sky high.

Gene expression was apparently also part of the this study but the results were not announced. [We also await the results of the big Enlander exercise test underway.]

Take Away Points

A reduced ability to think after exercise is documented and tied to changes in brain  functions. Reductions in the ability of ME/CFS patients ability to sustain attention stand out, as does the need to engage more regions of  the brain than usual to do mental exercises. People with ME/CFS also get worse, not better over time, when they engage in mentally fatiguing exercises.

Healthy people react in the opposite manner at all points;  in contrast to the people with ME/CFS   they do better over time and after exercise at mental tests.

Cook essentially documents and expands on the debilitating effects of exercise on ME/CFS.


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