Dissecting the nature of post-exertional malaise, Hartle et al, 2021

Background
Post-exertional malaise (PEM) is a defining characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the patients’ perspective.

Methods
A PEM questionnaire administered to 150 ME/CFS patients. It included open-ended questions about triggers, experiences, recovery, and prevention. Responses were re-coded into concise, representative topics. Chi-Square tests of independence were then used to test for differences and relationships between duration of ME/CFS illness (<4 years and >10 years), PEM onset and duration, and gender with PEM trigger, experience, recovery, and prevention.

Results
Physical exertion was the most common trigger of PEM. The onset of PEM occurred within minutes after physical exertion compared to within hours after cognitive exertion (<0.05). ME/CFS patients sick for <4 years reported stress as a trigger significantly more often than those sick for >10 years (<0.001). ME/CFS patients sick for <4 years experienced more orthostatic symptoms during PEM than those sick for >10 years. ME/CFS patients sick for >10 years reported using medications to recover from PEM significantly more that those sick for <4 years (<0.01). Pacing and avoiding specific triggers were common approaches to prevent PEM.

Conclusions
There are differences in PEM triggers, experiences and recovery based on duration of illness. Asking about PEM is important for diagnosis and to understand how to manage PEM. Given that PEM occurs more quickly after physical versus cognitive exertion, these results should instigate research on the relationship of upright posture, hypoperfusion and PEM.

Full text: https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1905415

 

Looks like most people report onset of PEM shortly after exertion



@Trish

 

The questionnaire (copied from the paper).

PEM Questionnaire: The PEM Questionnaire was designed by the Bateman Horne Center so ME/CFS patients could describe PEM in their own words. It was an online survey administered to ME/CFS patients one time during the first year of the study. The PEM Questionnaire included the following six questions, and the type of response is in parentheses:

1. What kind of exertion triggers your PEM? (open-ended text response)
   
   
2. Does PEM happen … (single choice),
   
   1. minutes after exertion
      
      
   2. hours after exertion
      
      
   3. a day or more after exertion
      
      
   4. not at all
      
   
   
3. Please describe what happens to you when PEM occurs (open-ended text response)
   
   
4. How long does it take you to recover from PEM? (single choice)
   
   1. at least a day
      
      
   2. several days
      
      
   3. at least a week
      
      
   4. several weeks
      
      
   5. a month or more
      
   
   
   
5. What do you do to recover from PEM? (open-ended text response)
   
   
6. What do you do to prevent PEM from occurring? (open-ended text response)
   

 

I also find Q2 problematic - use of a single choice option for such a thing is in my experience totally barking.

Also only in my experience but cognitive exertion can produce serious PEM in minutes, physical exertion mostly takes much longer, and rarely produces the same degree of PEM if attention is paid.

I suspect because it's possible to simply stop doing things when a certain level of warning signals is received, but it is not possible to stop thinking, especially given the much, much faster onset.

Q4 is also problematic as it assumes that 'recover' is a thing, a fixed level, when it's not - and it's also variable, possibly depending on the type of trigger, but possibly not, and possibly on the degree of PEM, but possibly not.

 

I know things were very different when I was first diagnosed & there's a lot.more information available now but when I was sick for less than 5 years I still hadn't gotten my head around PEM.

This isn't to discount the experience of the more newly ill but I would suggest that it is possible for patients, either the more newly ill or those who interact less with other patients, to miss some signs of PEM.

 

I recognize a kind of reaction to physical exertion that has a short delay, perhaps 20-40 minutes. This is not PEM but I think a combination of muscle fatigueability and the cumulative effects of orthostatic intolerance. Orthostatic intolerance doesn't necessarily begin immediately (unless it's severe). Rather it sets in gradually as the body becomes more and more tired and stressed from being exposed to upright position.

PEM is almost always delayed until the next day, rarer and much more unpleasant.

I find some exposure to daily orthostatic stress tolerable as long as it isn't too much.

 

Only 150 people completing the questionnaire seems a bit light and the criteria for recruitment a bit loose?

also the use of open ended questions is good for exploration but to then group and recode comments and apply statistics...not so much ...this is mixing methods in my book and introduces a level of interpretation (and bias/error) that is on top of all the other problems you have with self reported questionnaires from participants that have already been biased by the attendance at the same center. This “grouping” invalidates it for me as no more than a woolly focus group. They need to ask specific questions on their new groupings and apply the stats to that piece of work not do it on the qualitative stuff.

I agree the results look odd ...I could see if people aren’t managing things well in the early years, it would be difficult to differentiate what are the specific triggering events. That was me for around a year where I was constantly crashing and pushing through.

I guess the small sample size (75) means they have lumped people into the groups and can’t analyse numbers that are say 1 or 2 years in vs the rest? Perhaps there is variance within the under 4 year group? But you would think that the over 10 years (what happened to the 4-10 group wonder ?) would have learned that by now.

I suspect this is a mix of bad design and a bit of interpretation/selection bias? But perhaps we are all weird and just have our own biased little group of 24-48 hr delayers?

 

How much I've gone over my limit determines how much TIME it requires to feel back to my baseline. I can rest, sleep etc as much as I want, but that makes no difference on the duration of PEM.

 

Yes, indeed. For me, a good part of PEM is immune-type symptoms (after the sleeplessness, the second symptom is always my throat swelling up so much that my neck disappears), and it's not possible to provoke that within minutes.

So soon after exertion, it's just fatiguability, the effects of OI, and general tiredness.

 

100% agree with this and can very readily differentiate the same day onset of POTS OI related fatigue vs the delayed (next day) onset of PEM.

At the risk of making uninformed assumptions about what's happening, the same day symptoms are like a crash after excessive adrenaline: exhausted, headache and sleepy. They usually dissipate with short rest/nap. The delayed symptoms come the next day and are general malaise, cognitive difficulty and symptoms more fitting of immune "stuff", whatever that means.

Where it gets a bit complicated is a PEM state seems to worsen my autonomic function, so it becomes quicker and easier to trigger the OI related symptoms again.

 

For me the distinction between fatiguability and PEM is of central importance and can be widely missed by researchers. My definitions are something like:

Subjectively the results of fatiguability are directly related to the triggering activity and are more or less immediately following on from it, though this is potentially confused by orthostatic intolerance which perhaps triggers broader symptoms like headache, dizziness and nausea. The increased fatiguability is common to diverse medical conditions and is not necessarily qualitatively different to over exertion in healthy people. Though again this is confused by issues around orthostatic intolerance. Recovery from the consequences of fatiguability begins immediately on starting to rest. Increased susceptibility to fatiguability may relate to physical, emotional or cognitive exertion or to sensory stimuli.

In contrast post exertional malaise is subjectively a change of state that on occasion may for some even feel as if it can switch on and switch off. The subjective experience is not necessarily directly related to the triggering activity or sensation, it involves more general symptoms such sore throat or swollen glands or impaired memory and confusion. It has some similarities to a retriggering of the initial illness state, and can be delayed by hours or days after the triggering exertion. But also though the passage of time is necessary to return to the previous base line, such recovery does not necessarily begin with the onset of rest. If I am experiencing PEM it can continue to worsen for several days despite total rest, only later ultimately dissipating with time and rest or alternatively climaxing in a migraine, vomiting and explosive diarrhoea after which sleep becomes possible and then recovery.

PEM has a confusing knock on of increasing susceptibility to fatiguability and reducing the threshold for triggering PEM. This means it is possible to end up in a continuous state of PEM, which is retriggering itself from minimal activity such as eating or toileting.

Making sense of the variability in my ME has taken me decades and at times is still problematic. It was only once I had understood my acquired food intolerances, I believe associated with the ME, the concept of orthostatic intolerance, which can be a more limiting factor on activity than exertion, hypersensitivity to sensory stimuli and the distinction between increased fatiguability and PEM that I feel I am beganing to grasp the variability of my symptoms, which is complicated by these issues interacting with each other.

However even now still much of my understanding is post hoc description rather than predictive of future symptoms.

 

Excellent post @Peter Trewhitt.

After a couple of decades of experience pacing, and in recent years a great deal more awareness, adaptation and medication for OI, it still surprised me how much lockdown boosted my cognitive energy & symptom stability. I thought I had OI figured out and that my limited, pre-lockdown daily activities were fairly balanced but they were seemingly still taking their toll. I suspect reduced exertion & stimuli played a part too.

I had 20 years of not knowing knowing anything about OI, then a further 4 years thinking I had it controlled but still hadn't grasped the full impact it had. The myth that "you'd know it if you had it" is such a gross oversimplification in my experience.

 

I'm not sure if this would be a helpful in terms of an analogy that might convey the nature of PEM to healthy people, but...

There is a non-infectious condition that produces a "flu-like" immune response that many people are familiar with. That condition is sunburn.

A serious sunburn does provoke a noticeable immune response, probably because of all the cell injury and cell death going on.

It's been quite a long time since I've had a sunburn (not since before ME), but I had one a long time ago which was quite serious. Naturally, it was painful, but it also produced this weird, flu-like sick feeling which was not unlike PEM [that is, not unlike the type of PEM that appears the day after exertion with ME].


[ETA: By a "quite serious" sunburn I mean one that develops some degree of blistering over a significant area.]

 

So all patient participants were patients from the Bateman Horne Centre. Looking on their website, this is what they say about PEM (my bolding),

Post Exertional Malaise (PEM)

PEM is the worsening of a patients’ symptoms and function after exposure to physical, cognitive, emotional, or orthostatic stressors that were normally tolerated before disease onset.

PEM is an exacerbation or relapse of symptoms that occurs as a consequence of exertional activity. Exceeding cellular energy capacity results in a “pay back of symptoms” or a “crash” which can occur up to 24-48 hours after peak exertion.

Subjective reports of PEM and prolonged recovery are supported by objective evidence in the scientific literature, including failure to normally reproduce exercise test results (2-day cardiopulmonary exercise test) and impaired cognitive function after exertion.

True PEM appears to be pathognomonic to ME/CFS, and is a distinugishing factor when making a differential diagnosis.

https://batemanhornecenter.org/education/me-cfs/


This could then, in my opinion, explain why so many said that onset was, effectively, immediate.

 

Almost certainly, they have conditioned the recipients of the questionnaires before they asked the questions and then muddled the results together to get their findings. I suspect there is quite a variance within the responses in the description of PEM and they have contrived some of the groupings, but without seeing the free responses it’s difficult to tell. Almost certainly these were grouped according to what they believe the groupings should be (I.e. their interpretation of what PEM is as the experts)

it’s why you can’t really run a chi square test on something you have already artificially grouped, since you are not looking at a mass of data to make sense of it ...you have already in a way decided the outcome before you ran the test.

 

Lots of confusing data here.

A surprisingly large number - given that virtually everybody met PEM-obligatory criteria - don't report PEM after physical exertion:

The figure of 58.2% seems to conflict with Table 3 which shows medium level activity as a trigger for 71.5% but high level physical activity for only 31.8%. Presumably this is due to more patients being able to completely avoid high level physical activity and therefore not reporting it as a PEM trigger.

That directly contradicts my experience. I suspect two confounding factors here. One, mixing up fatiguability and PEM. Two, OI. The latter is recognised by the authors:

It would be good to find a way to disentangle this. Theoretically possible with an interventional study that tries to induce PEM through cognitive or physical exertion while in a horizontal position (and controlling for other factors like social effort, travel, environment, etc). There's just that pesky issue of ethics.

That's an interesting point to look at but there weren't huge differences between the groups and the ones there were may well have been secondary to the more recently ill still adjusting to their situation. They were younger, too, so had less life experience to fall back on. For example they reported stress as a PEM trigger more often, and they reported more types of PEM triggers full stop. The long-term ill probably just had more experience in avoiding triggers and dealing with the fallout of being ill. Still surprised by this though:

Only four????!

Was pleased to see rare recognition that PEM doesn't only involve subjective symptoms but also objective signs (my heart rate monitor couldn't agree more):

 

How interesting – my experience is similar, but not quite the same.

I have red hair and skin that can't tan at all, so severe sunburn was frequent in the days before the effective sunscreens that came onstream in the 1980s.

They do still happen, of course. I burnt my wheelchair controller hand yesterday, because even after 62 years, I still forget that I can get significant sunburn in middle England, in March.

But it isn't sunburn that causes the 'flu-like symptoms; I've never experienced that, even at the times I was hospitalised with sunburns as a kid. It only began after ME onset, and seems to be either UV exposure, overheating, or both, combined with physical effort such as tidying the garden.

The symptoms happen at the time rather than the following day, and speed of onset depends on the temperature. At around 18 C / 65 F I can probably do half an hour's pottering around in the sun before I start feeling ill, but that's pretty much my tolerance limit. I don't even bother setting foot out of the door if it's more than 25 C / 77F, let alone attempt anything that involves effort!

 

Experience

Fatigue 84.0 (63/75) 84.2 (64/76) 84.1 (127/151)
Pain/musculoskeletal 73.3 (55/75) 68.4 (52/76) 70.9 (107/151)
Orthostatic intolerance 62.7 (47/75) 47.4 (36/76) 55.0 (83/151)
Neurologic 54.7(41/75) 53.9 (41/76) 54.3 (82/151)
Infection/immune 33.3 (25/75) 32.9(25/76) 33.1 (50/151)
GI 30.7 (23/75) 34.2 (26/76) 32.5 (49/151)
Respiratory 21.3 (16/75) 17.1 (13/76) 19.2 (29/151)
Temp dysregulation 18.7 (14/75) 18.4 (14/76) 18.5 (28/151)
Sleepy 13.3 (10/75) 18.4 (14/76) 15.9 (24/151)
Behavioral 6.7 (5/75) 18.4 (14/76) 12.6 (19/151)
Polydipsia 2.7 (2/75) 3.9 (3/76) 3.3 (5/151)
Polyuria 2.7 (2/75) 0.0 (0/76) 1.3 (2/151)

I'm surprised that headache/migraine, head pain doesn't seem to feature anywhere unless it's included under Neurologic; I can't find a description of what exactly is classed as neurologic (I'm guessing brainfog, memory problems, but there are several others).

A lot of pwME describe it as having the worst hangover/flu; they seem to cover the 'flu-like symptoms' but not the 'hangover'.

 

Cognitive impairment is what I experience, it feels like an energy deficit where I can't process information or even talk for very long. I don't have memory problems or feel 'foggy'. During the early years I used to get swollen glands under my jaw and felt flu-like during PEM, but that is no longer the case. I've never had pain.