Post-Exertional Malaise - a discussion including defining and measuring PEM

[chillier]

True, that refutes "effort preference" things, but that possibly might not be enough to convince BPS fans as they might still claim the findings to be psychological if things like "anxiety" impact VO2max, which it could according to some studies?

I think the problem at hand is that unless the 2-day CPET procedure (with add-ons like muscle biopsy's, blood samples etc) can actually find something really biologically meaningful, the psychologists could always try to claim that is proves their beliefs about ME/CFS.

My understanding is the biggest parameter change is not VO2max, but a reduction in Ventilatory Threshold: The elbow where VCO2 begins to rapidly increase relative to VO2 due to a transition to anaerobic respiration. This - like RER - would be objective. I don't know about how anxiety might affect that, but your point about fibre type sounds like it could be relevant with respect to that.

 

[Kitty]

If we separate post-exertional malaise from post-exertional effects (measurable changes after exertion), I dare say it'll have the support of folk whose PEEs include urinary output going from the pretty-ordinary to the frankly-bloody-ridiculous.

 

[Sean]

No matter how robust and definitive any biological findings might be there will always be some in the psychosomatic school who simply cannot accept them and will reject them to the end of their days.

Which is ironic considering one of their main arguments is how we are in denial about it being psychosomatic.

 

[SNT Gatchaman]

The second CPET shows reduced physiological performance as a cardinal marker of exercise intolerance.

Does cardinal mean the best available, or definitive, or always the case, or what?

Here I meant in the "best currently available" sense, not definitive. For "always the case" I note in Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment (2014, JTM) fig 4 that "Subjects’ whose VO2 @VT did not decrease during Test 2 showed a decrease in VO2 peak." So the ventilatory threshold measure alone isn't AUC 1.0.

Does marker mean correlate or something in a causal relation? Generally marker means correlate, and that is the issue.

Yes I mean correlate, as in "this is what exercise intolerance looks like as best as we can show non-invasively" - you exercise and then you can't exercise as well. The patient says so subjectively and 2CPET data seems to support that objectively.

Causality of course awaited with intense interest. I think invasive CPET and muscle biopsies will help with this, but I'd really like to come back to some of the older eg MR spectroscopy findings and bring them up date too. I'm particularly interested to see if a commercial wearable muscle oxygen sensor could complement these studies. It's non-invasive and could be potentially used with severe patients if they don't have touch hypersensitivity or skin allergies. Very early days in looking at this but for an informal pilot n=3, I as a moderate person look really abnormal, a milder pwME looks mildly abnormal and HC looks completely normal. My suspicion is that a severe person will look really really abnormal, but all this needs to be formally trialled, including sedentary HCs. I don't think it's been looked at in ME yet. May be spurious, may be LC-specific. Even if it were to pan out, it may not have anything to do with PEM as you say.

 

[Jonathan Edwards]

Yes I mean correlate, as in "this is what exercise intolerance looks like as best as we can show non-invasively" - you exercise and then you can't exercise as well. The patient says so subjectively and 2CPET data seems to support that objectively.

And that is what I would disagree with and warn may be a slippery road to go down.

You are suggesting not so much correlation as identity. The same thing.

Exertion (rather than exercise, as members have often reminded me) intolerance is not being able to tolerate exertion because of feeling ill whether at the time or later. It is something I have first hand experience of.

PEM may not be an ideal term but indicates symptoms occurring later and for longer than seen in most other conditions where you feel unwell with exertion. If you have flu or respiratory or cardiac failure or arthritis and you try to climb four flight of stairs you are likely to feel terrible immediately afterwards in various ways. The point of the term PEM and the reason for highlighting it is that it seems to mark some aspect of ME/CFS that indicates a longer term physiologic response.

But the 2nd day CPET does not measure either exertion intolerance or PEM. In effect it measures a form of 24hr fatiguability. That might be mediated by some of the same pathways as the others but might be mediated quite differently.


The danger I see in claiming that the 2 day CPET data measure PEM is that it would be all too easy to say "What are they complaining about? Half the patients who claim to have PEM have fairly normal results - the difference is just a statistical one. And what's the big deal about a 20% reduction in ability to do maximal exertion on a bike on day 2? Why does it stop people going to work if they don't even need to ride a bike at work? The effect cannot be cumulative or relevant to everyday exertion or they would be immobile after three weeks or normal activity. It must be a quirk of doing much more than you are used to or need to."

I am not saying that the 2 day PET might not reveal some biological process that gives a clue to PEM. But even fairly good correlation is no way identity. Moreover, it is a very awkward and artificial way to document the real everyday problems of PWME. If someone had significant PEM after a CPET I would expect them to say "sorry, there is no way I can get on that bike tomorrow". In fact they would never have volunteered for day 1.

 

[Hutan]

If someone had significant PEM after a CPET I would expect them to say "sorry, there is no way I can get on that bike tomorrow". In fact they would never have volunteered for day 1.

It took me a while to get what I think Jonathan saying, as lots of people risk painful outcomes in order to achieve something worthwhile. And I had significant PEM after the first PEM and I happily turned up for the second CPET (although at that time I didn't have PEM).

I think you are saying that if someone actually has PEM at the time that the second CPET is scheduled for, they would say they couldn't do the test? And, I think that is probably right. Possibly some people might be so motivated that they would somehow get themselves ready, drag themselves to the clinic and onto the bike, but if people experience PEM like I do, I reckon it would be a small percentage.

So, it seems likely that most, or at least a lot, of people doing the second CPET wouldn't actually be in a state of PEM, as I would define it.

As Jonathan says, people who think that 8 minutes of cycling is likely to put them into prolonged PEM probably don't sign up for a 2xCPET, because they know they won't be able to do the second test.

One thing to think about is whether there might be some sort of adrenalin type effect, allowing people to not fall into PEM for a bit. Possibly I have been able to keep going sometimes when I really have to - the PEM seems to be delayed. I'm not sure, it's so hard to tell.

 

[Trish]

I think it's possible that for many pwME who do a 2 day CPET they are heading into PEM by the time they do the second CPET, which, if they were able to rest might not be full blown PEM, but the cumulative effect of the two exercise challenges only 1 day apart then sends them into full PEM lasting days or weeks. The Hanson study found the healthy sedentary controls recovery after the second took only a day or two, whereas the average recovery time to preCPET level was about 2 weeks.
Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 2023, Moore, Hanson et al

 

[Ravn]

Trying to get my head around to what degree the discussion about PEM and CPET is about semantics or differences in substance.

I think what's happening is people are discussing PEM at two different levels but don't always identify clearly which one they're referring to, and sometimes the two levels get mixed up. The two levels being

1) an underlying PEM mechanism: some unknown molecular/cellular/neurological/whatever mechanism which in itself isn't directly perceptible by us but which via unknown pathways eventually manifests as

2) PEM signs & symptoms: the very peculiar constellation of signs & symptoms we experience; some of them are subjective (e.g. sore throat, heavy legs), some of them can be measured (e.g. increased resting HR, reduced ventilatory threshold at day2 CPET)

So PEM mechanism vs PEM signs & symptoms.

To my mind this means the 2day CPET measures one element out of the many PEM signs & symptoms PEM manifests as. It's unclear how that relates to the underlying mechanism.

Confusion potential: I strongly suspect the PEM mechanism silently kicks in before signs & symptoms manifest and also lasts longer than the overt signs & symptoms.

On the first point, if we accept exertion is the trigger for PEM then logically the underlying PEM mechanism has to start at the time of exertion even if it takes time to build up or run through a cascade of downstream processes before signs & symptoms become obvious.

On the second point, in my experience individual PEM signs & symptoms have different timelines. For example a sore throat and unquenchable thirst are only prominent on the first couple of days of the PEM experience while the heavy legs persist much longer. The longest lasting feature though is the reduced PEM threshold which persists for several days after all the other signs & symptoms have returned to their usual levels. So based on signs & symptoms experienced I feel as though I have recovered to my usual but there's actually still something going on beneath the surface that only shows its ugly face if I try to do too much too soon, i.e. the underlying PEM mechanism is still active. I'm speculating that this somehow links in with the VT reduction on the day2 CPET and may also explain @Hutan's CPET experience (PEM signs & symptoms after day 1 had settled but day 2 CPET performance was still lower).

 

[Ravn]

Re Workwell, I've never been able to get a clear picture of their view of PEM. They've done presentations that made me think they view PEM the same as I do. But some of the language used in their written resources makes me doubt it. At the very least it's confusing, on two points in particular.

One, they describe symptoms immediately after exercise as different from symptoms the next day. That much I agree with. But then they name those symptom 'early PEM', a claim I don't think can be supported at this stage. Yes, the underlying PEM mechanism is very likely already busily at work under the bonnet but I would argue that at this early stage it's asymptomatic and that any symptoms experienced at that early stage are due to fatiguability or even, dare I say it, deconditioning in some cases. The 'true PEM' symptoms come later. Otherwise it's difficult to explain how many pwME can skip the so-called 'early PEM' stage altogether but still get the delayed PEM symptoms.

Two, sometimes - but not always - it sounds as though Workwell consider the early aerobic/anaerobic switch they find in CPETs as the direct cause of all the other signs & symptoms. Other times it sounds as though they consider it, as I do, as just one manifestation of the underlying PEM mechanism, but one which if ignored and pushed through can cause additional symptoms.

In both cases there appears to be a failure to clearly distinguish between underlying mechanism and signs & symptoms experienced. At any rate, mighty confusing (to me at least)

 

[Hutan]

Trying to get my head around to what degree the discussion about PEM and CPET is about semantics or differences in substance.

I think what's happening is people are discussing PEM at two different levels but don't always identify clearly which one they're referring to, and sometimes the two levels get mixed up. The two levels being

1) an underlying PEM mechanism: some unknown molecular/cellular/neurological/whatever mechanism which in itself isn't directly perceptible by us but which via unknown pathways eventually manifests as

2) PEM signs & symptoms: the very peculiar constellation of signs & symptoms we experience; some of them are subjective (e.g. sore throat, heavy legs), some of them can be measured (e.g. increased resting HR, reduced ventilatory threshold at day2 CPET)

So PEM mechanism vs PEM signs & symptoms.

To my mind this means the 2day CPET measures one element out of the many PEM signs & symptoms PEM manifests as. It's unclear how that relates to the underlying mechanism.

I think there is quite a bit of semantics, which is not to say that it's unimportant.

I define things a bit differently to you. I'd say
1) an underlying abnormal response to exertion:some unknown molecular/cellular/neurological/whatever mechanism which in itself isn't directly perceptible by us but which via unknown pathways manifests as more fatigue, lower threshold for muscle fatiguability, worse CPET measures, increased resting heart rate, an infection of some sort. If there isn't enough rest it manifests as

2). PEM signs and symptoms - the crash, it's the 'I can't do anything else right now but lie in bed and wait to get through this'. It's as if my body is saying 'enough! you absolutely must rest'. It's the pain, the fatigue, chills, it's the malaise.


It is a bit of a problem that the definition of PEM is so variable. I hadn't realised it was understood in so many different ways.

 

[Jonathan Edwards]

1) an underlying PEM mechanism: some unknown molecular/cellular/neurological/whatever mechanism which in itself isn't directly perceptible by us but which via unknown pathways eventually manifests as

2) PEM signs & symptoms: the very peculiar constellation of signs & symptoms we experience; some of them are subjective (e.g. sore throat, heavy legs), some of them can be measured (e.g. increased resting HR, reduced ventilatory threshold at day2 CPET)

Like Hutan, I agree with you that there are two aspects here, mechanisms and manifestations.

The problem is that, with my rheumatoid hat on, I don't see any likelihood of there being 'an underlying mechanism'. Things are going to be more complex.

Diseases involving misbehaviour of regulation systems, which RA and ME almost certainly both are, arise from causal chains that look a bit like the inside of Swiss watches. For RA we identified 55 steps that could contribute. The 'underlying mechanism' is in a sense all quite normal. The disease occurs because that underlying mechanism has a bug in it that can spin off various effects. Some of those effects may be normal compensatory effects that nevertheless generate symptoms of different sorts or abnormal blood results. It all gets very complex.

It may be fair to say that there is some underlying error of regulation in ME but if anything we would call it the ME mechanism. One result is the symptom pattern of PEM. Another may be a shift in muscle physiology shown on CPET day 2. But that muscle shift might be a manifestation of some normal compensatory process quite unrelated to the PEM pathway.

For instance, it might be that as a result of symptoms, PWME tend to regularise their activity such that variation from day to day is in a narrower range. They may do as much as a sedentary control and not be significantly 'deconditioned' but avoid sudden shifts in activity level. This might lead to a shift in muscle homeostatic mechanisms such that if the muscle is suddenly exposed to maximal effort it generates danger/repair signals more forcefully. That might be because of a shift in fibre type predominance or in a lack of repair events in recent past making connective tissue or muscle cells more vulnerable to sudden use. A deterioration in function after muscle use due to repair signals is normal for some forms of exercise and is a reason for increasing activity gradually during training.

If this were the case then paradoxically the habit of avoiding PEM might be the reason for muscles failing on day 2. The result would be indirectly related to PEM but not a measure of an underlying PEM process.

 

[Snow Leopard]

Here I meant in the "best currently available" sense, not definitive. For "always the case" I note in Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment (2014, JTM) fig 4 that "Subjects’ whose VO2 @VT did not decrease during Test 2 showed a decrease in VO2 peak." So the ventilatory threshold measure alone isn't AUC 1.0.

VO2 at VT is the wrong measure! It is the power at the VT that is the sensitive measure, not the VO2!

Side note, addressing a general point being discussed, the 2 Day CPET measures persistent fatigubility (primarily due to central fatigue induced by muscle afferent feedback), not PEM in general.

 

[Medfeb]

Great discussion in this thread, especially separating out mechanisms from symptoms and change in function

Side note, addressing a general point being discussed, the 2 Day CPET measures persistent fatigubility (primarily due to central fatigue induced by muscle afferent feedback), not PEM in general.

Just to clarify - How do you define fatiguability and differentiate that from PEM?
The 2-day CPET studies have shown CPET is not measuring deconditioning and I agree it does not "measure" PEM per se. But I understand it's measuring a physiological change that is associated with/corresponds with the worsening of symptoms and function that is PEM.

On the second point, in my experience individual PEM signs & symptoms have different timelines. For example a sore throat and unquenchable thirst are only prominent on the first couple of days of the PEM experience while the heavy legs persist much longer

One, they describe symptoms immediately after exercise as different from symptoms the next day. That much I agree with. But then they name those symptom 'early PEM', a claim I don't think can be supported at this stage. Yes, the underlying PEM mechanism is very likely already busily at work under the bonnet but I would argue that at this early stage it's asymptomatic and that any symptoms experienced at that early stage are due to fatiguability or even, dare I say it, deconditioning in some cases.

Is this a semantic issue? Leaving aside the labeling for a moment, I think Workwell's timeline slide is useful if it helps teach patients to watch for early signs of overexertion. In one case I know of, the pwME recognized head pressure as an early sign of overexertion, that then escalated to headaches and if those symptoms were ignored, would end up in a full crash the next day. But if the pwME stopped the triggering exertion (in this case, browsing on a phone) when head pressure was first recognized. that would prevent the full crash. So at least in that case, learning to recognize the early signs was essential for this person to learn to pace and lessen the occurrence of PEM.

So are those early symptoms of the process(es) turned on by overexertion that result in PEM? And should those early symptoms be called "early PEM symptoms"? Or would they be better referred to as "early signs of overexertion"?

Depending on the definition of fatiguability, I wouldn't think that head pressure would be a typical symptom of either deconditioning or fatiguability

Complicated further because different triggers could result in different symptom profiles over time and different patients could experience different symptom profiles for the same trigger.

 

[Ravn]

Is this a semantic issue? Leaving aside the labeling for a moment, I think Workwell's timeline slide is useful if it helps teach patients to watch for early signs of overexertion. In one case I know of, the pwME recognized head pressure as an early sign of overexertion, that then escalated to headaches and if those symptoms were ignored, would end up in a full crash the next day. But if the pwME stopped the triggering exertion (in this case, browsing on a phone) when head pressure was first recognized. that would prevent the full crash. So at least in that case, learning to recognize the early signs was essential for this person to learn to pace and lessen the occurrence of PEM.

So are those early symptoms of the process(es) turned on by overexertion that result in PEM? And should those early symptoms be called "early PEM symptoms"? Or would they be better referred to as "early signs of overexertion"?

Being on the lookout for "early signs of overexertion" is sensible. I'm not advocating for ignoring or downplaying any sort of symptom, just for naming and describing them with care and precision to reduce misunderstandings. We simply don't know yet if some of the early signs are manifestations of PEM or not but most of the ones on the Workwell list of 'early PEM' symptoms are also symptoms of garden-variety exercise intolerance. So for now, while the matter is unclear, your term "early signs of overexertion" is preferable because a) it doesn't mix up mechanism and symptoms, b) it comes with a low risk of causing misunderstandings and c) it still serves the practical purpose of people being on the lookout for them.

The danger with calling any early symptoms 'early PEM' is that it opens the door wide to people being told they have PEM and ME when they actually have garden-variety exercise intolerance

I guess my main point is that semantics matter, especially when operating on muddy territory like the field of ME-PEM. There are many different understandings of the term PEM, as this thread makes abundantly clear. And that's just here within the forum. Now imagine the semantic Wild West out there in the wider world. To have fruitful discussions we need to be clear what exactly each of us is talking about; we can't just assume all participants in the discussion are sharing our personal understanding of the term PEM

 

[Snow Leopard]

Just to clarify - How do you define fatiguability and differentiate that from PEM?

PEM is the experience of a variety of symptoms, rather than merely locomotor fatigubility (causing central fatigue due to afferent feedback). While this can be a PEM symptom, one can in principle experience this without any other PEM symptoms.

 

[Jonathan Edwards]

I agree. PEM would still be just as much PEM even if the CPETs had been plumb normal.
Fatiguability is a distinct concept.

 

[Medfeb]

We simply don't know yet if some of the early signs are manifestations of PEM or not but most of the ones on the Workwell list of 'early PEM' symptoms are also symptoms of garden-variety exercise intolerance.

Another question to clarify - is there a standard definition for exercise intolerance? I ask because it seems that some LC clinical guidance and research studies equate PEM to exercise intolerance and then use that to leap to exercise as treatment. Of course, assuming they mentioned PEM at all

Would it be correct to say that PEM is a distinct form of exercise intolerance, presumably with other forms as well? If so, what are the different types? Are they laid out anywhere? Or is all exercise intolerance treated as one clinical entity that can be reasonably be treated with exercise, with potentially some warnings about risks or approach to be used in certain conditions?

And if PEM is not a form of exercise intolerance, can the case be made for that? Is it enough to point to the range of types of triggers (not just exercise), delayed onset, range of worsened symptoms, the worsened function, etc?

 

[Mij]

Depending on the definition of fatiguability, I wouldn't think that head pressure would be a typical symptom of either deconditioning or fatiguability

Being upright for too long brings on head pressure. It's related to OI in my experience. I also feel head pressure during delayed PEM but it feels more like a clamp wrapped around my forehead.

 

[Medfeb]

Being upright for too long brings on head pressure. It's related to OI in my experience. I also feel head pressure during delayed PEM but it feels more like a clamp wrapped around my forehead.

Thanks for that and good to remember that OI can be playing an overlapping role. I don't know if this person would describe head pressure like that or not but they were laying down the whole time so in that case, it was not related to OI

 

[Mij]

I don't know if this person would describe head pressure like that or not but they were laying down the whole time so in that case, it was not related to OI

Diagnosing dysautonomia is often partly a process of elimination. It also involves determining how and when symptoms occur and finding patterns that connect them. It could be caused by many other issues that haven't been diagnosed that brings on fatigability.