Make PEM central to ME research [blog post by me]

[Peter T]

I agree with @Trish. Under current definitions, research without participants displaying PEM is not research into ME/CFS.

That research into ME/CFS requires ME/CFS participants to display PEM is surely self evident. There may be reasons to compare people with ME/CFS with others displaying overlapping symptoms but not experiencing PEM, but that is a completely separate question to that addressed by this thread.

There is also the issue implicit in the header for this thread that though research into ME/CFS will require participants experience PEM, the target of that research may or may not relate to PEM, that depends on the research question.

I think it is worth while giving thought to people who drop by the wayside as definitions of ME/CFS are refined, and if we develop clinically useful diagnostic testing or biomarkers yet more people may drop by the wayside. However that does not justify watering down patient selection criteria for research purposes. Clinical criteria for planning symptom management needs also to take into account PEM, but there may be significant overlap in management for those displaying overlapping symptoms without PEM. So there may be some research questions that don’t necessarily require PEM, but surely that needs to be made explicit and it would make sense to know which participants did or did not have PEM if we are not to repeat previous mistakes in generalising inappropriately between different clinical groupings.

 

[Jonathan Edwards]

I find this discussion disconcerting. If PEM isn't a necessary feature for diagnosing ME/CFS, then what is ME/CFS?

For me it is a name used to describe a pattern of illness that maybe 0.5% of the population have. That pattern includes disabling symptoms that get called fatigue but are more complicated and unpleasant. These symptoms follow a time course that does not seem to make sense in terms of standard physiological explanations, with variations that may be called worsenings, relapses, crashes, or whatever. People report a link between exertion and worsenings but the link seems variable and is hard to use as objective evidence. The symptoms are also not explainable by some known disease such as RA or MS.

I don't know of people who have similar symptoms with this level of disability who should be excluded just because they do not report a clear link between exertion and worsening. There are a. lot of people with fatigue that is not in itself so disabling and there are people with recognised diseases that are complicated by fatigue. PACE was initially criticised for having too wide inclusion criteria but I would be surprised if there are really many people who would fit the above who should be excluded from a diagnosis of ME/CFS purely because they do not recognise themselves as having PEM.

There is also the problem that PEM is probably pretty easy to misdiagnose. When I had post Covid fatigue I could easily have agreed that I had PEM but I sensed that there was nothing comparable to what members here describe. There was nothing out of proportion or specifically delayed. There was no roller-coaster over the weeks, just a sense of not being able to get going again.

 

[Kitty]

PEM isn't a thing in itself

Yep.

We use PEM as shorthand for worsening that is linked to activity (including sensory input), is disproportionate to the level of activity, is delayed in onset, and often includes symptoms that are absent or diminished when activity is reduced.

But those are all characteristics of ME/CFS. PEM is the pattern they typically take, which is important in distinguishing ME/CFS from other conditions.

The reason it can't be separated from ME/CFS is that it is ME/CFS.

ETA: cross-posted with Jo.

 

[Jonathan Edwards]

The reason it can't be separated from ME/CFS is that it is ME/CFS.

I don't think that quite works.

The problem is that there will always be activity, especially the 'normal levels of activity' that are claimed to be able to provoke PEM. I agree that the pattern of PEM is the pattern of ME/CFS but that pattern includes an unpredictability that at times PEM has to be shoehorned into at best.

And what actually matters is the existence of maybe 250,000 people in the UK who are ill. That is a fact of reality rather than a theory of what is most characteristic of those people that depends on a causal attribution.

 

[Utsikt]

The problem is that there will always be activity, especially the 'normal levels of activity' that are claimed to be able to provoke PEM. I agree that the pattern of PEM is the pattern of ME/CFS but that pattern includes an unpredictability that at times PEM has to be shoehorned into at best.

Are you saying that the episodes of worsening might not just be caused by exertion, or that the relationship between exertion and the episodes might be influenced by other factors? Perhaps both?

 

[NelliePledge]

Problem with this is that PEM may be so mild and subtle that for some patients, some of the time, it may not impact them enough to be consciously detectable. Milder patients with no experience of the more severe end of the spectrum might even not recognise PEM in the first place, they simply lack the experiential reference frame to judge it accurately.

Definitely the case during gradual onset when I was undiagnosed for probably a decade. What was almost certainly undiagnosed PEM I read as flu/viral illness. I wouldn’t use subtle as a description though I was ill but not at a severity level that seemed particularly concerning

 

[Jonathan Edwards]

Are you saying that the episodes of worsening might not just be caused by exertion, or that the relationship between exertion and the episodes might be influenced by other factors? Perhaps both?

Yes, both would be possible.

 

[Creekside]

Are you saying that the episodes of worsening might not just be caused by exertion, or that the relationship between exertion and the episodes might be influenced by other factors?

I couldn't tell the difference between PEM and food intolerance, aside from delay difference. I see ME's symptom-producing mechanism as a black box that responds to different inputs: immune signals, cognitive exertion, food responses, etc. Individuals have different responses to each of the possible factors.

 

[Mij]

Could there be distinctive PEM differences between LC and ME/CFS "PEM"? I've experienced both, and my experience with both were similar during my early ME-viral onset. I recovered from Covid-type PEM after six months, but the ME- delayed PEM worsened over the years.

I am very interested in Mark Painters research in specific CD8 T cells and performing advanced sequencing to define changes that might occur.

 

[Creekside]

The reason it can't be separated from ME/CFS is that it is ME/CFS.

I managed to completely block my PEM by taking cumin. Does that mean that taking cumin switched me from having ME and having an unrelated disease with exactly the same symptoms except for PEM, and that other disease would vanish if I forgot to take my dose?

As a thought experiment, assume that PEM is caused by a change in production of chemical z23, which maybe 12 steps downstream, results in lethargy, brainfog, etc. What if cumin didn't interfere with z23, but blocked step 4. So, in that case, I still have the PEM mechanism working, but its effects are no longer observable. Meanwhile, step 12 is still being triggered by foods and by whatever is responsible for the baseline lethargy and brainfog. If that's the case, how many people still have that z23 problem, but have their own blockage downstream of step 1, and thus don't display standard PEM responses?

I think the definition of PEM--and of ME--is presently too precise for something we don't understand and can't measure. You wouldn't claim that your local storm was 13.174% stronger due to global warming, since we don't understand global warming--or even local weather--well enough to make accurate predictions.

I have no objection to a definition of PEM to standardize ME studies. It's important to limit variables for such studies. I object to applying that definition beyond its purpose as a study restriction. What's helpful for a limited set of studies might be harmful when used as a diagnostic criteria for determining disability support. It might be a hindrance for some ME studies that are following a different theory than "ME is PEM, and PEM is ME".

 

[Felis Catus]

and severe chronic brainfog sounds like a worse fate than PEM.

I couldn't tell the difference between PEM and food intolerance, aside from delay difference.

I'm wondering if your and my views differ due to different experiences, in particular different severities of ME/CFS.

 

[Peter T]

I managed to completely block my PEM by taking cumin. Does that mean that taking cumin switched me from having ME and having an unrelated disease with exactly the same symptoms except for PEM, and that other disease would vanish if I forgot to take my dose?

We have also had this discussion in relation to a possible very mild early stage of ME with less than 50% deficit and for people who have recovered to a level of less than 50% impairment.

I personally would be happy for someone who had ME and experienced PEM but who managed to eliminate PEM by whatever means, including cumin, to be included within a pragmatic or clinical definition of ME/CFS, even though they do not meet the exact, and potentially arbitrary, definition of the syndrome, but I would be concerned in such participating on research on ME/CFS, without that being explicitly accounted for within the research questions and research design.

Until we establish some sort of biomarker there will be arbitrary cut off points, however that is necessary to avoid research becoming impossibly vague. However we also need to keep in mind that some people maybe inappropriately excluded, so have a looser clinical definition.

 

[Creekside]

Especially when the quote below trivialized PEM as not a worse fate than brain fog.

I wasn't trivializing PEM; I was pointing out that other ME symptoms can be as bad or possibly worse. It's not mild brainfog vs severe "can't even move" PEM. There's incapacitating chronic brainfog and "just feeling a bit worse than usual" PEM, and everything in between. I wouldn't want someone with disabling chronic ME symptoms to be denied support just because they didn't match some overly (without supporting evidence) specific criteria. What if the criteria for ME required a >1C temperature rise starting at 22.3 hrs +/- .1 hrs after exertion? That may be a a ridiculously restrictive criteria, but there's no reliable clinical evidence for the requirement for PEM either. Until we have a reliable marker for ME, we can't know how many PWME do or don't have observable PEM.

 

[chillier]

I find this discussion disconcerting. If PEM isn't a necessary feature for diagnosing ME/CFS, then what is ME/CFS?

We'd be back to the Fukuda or Oxford criteria of chronic disabling fatigue, with or without a few other random symptoms, and back to being lumped together with all other fatiguing conditions.

And the idea of PEM being so mild the person doesn't notice it is wierd to me. Even when my ME/CFS was at its mildest, I had identifiable times several times a year when I couldn't go to work for a week or two because I was too sick and they always followed doing more than usual physical activity in the previous day or two. PEM was a significant move between severity levels and disability, not just feeling a bit sicker or more tired.

I agree with you Trish I think it's absolutely necessary. The causes of crashes and worsenings are multifactorial and murky; I suspect randomness is the biggest factor in mine, followed by getting a bug and exertion. But this is because pwME try to keep inside their energy capacity. If I were to go for a run then the cause effect relationship would be very obvious. I agree it's quite intractable and hard to pin down in practice, but it's 100% a real thing.

For research purposes especially it needs to stay to keep the cohorts as well defined as possible. I think it should stay for general diagnosis too although I see the problem that this leaves a group of people for whom a general diagnosis of 'chronic fatigue' is not quite right.

Whatever biological mechanisms are really driving our illnesses could I guess correlate really poorly with ME/CFS as a human defined category. Maybe IBS, FM, Chronic pain, ME/CFS, post concussion syndrome and other things that are currently poorly represented with names like functional movement or functional seizure disorders could be driven by similar mechanisms. Or maybe not, but I wouldn't be surprised if the mechanisms line up wonkily with the syndrome.

 

[Creekside]

I'm wondering if your and my views differ due to different experiences, in particular different severities of ME/CFS.

Absolutely. Don't we all think, at least to some degree, that our personal experience of ME is the gold standard?

My ME experience:

1) My ME did not noticeable affect my physical performance (strength, endurance, etc).
2) I could do lengthy exertion (biking, hiking, digging) without triggering PEM, yet <1 minute of unaccustomed physical exertion would.

So, just from those non-standard experiences, I'm skeptical about theories involving muscle dysfunction or ATP production as being core to ME. Suffering from PEM for 15+ years, and then having it cured, makes me think much differently about the theory of PEM as a core part of ME.

If someone triggers PEM from a short walk, and their muscles feel weak, and read 100 other people having the same response, they'll likely support a theory about core-PEM and mitochondrial dysfunction. However, a theory isn't proven by 100 "me too"s; it's disproven by one or more counterexamples. That's science.

 

[chillier]

go straight to the blog post

Post-exertional malaise (PEM) is the defining feature of Myalgic Encephalomyelitis (ME). But often it doesn’t take center stage in research on ME and is instead treated as an afterthought, or even ignored altogether. If we really want to make progress on ME, research should make PEM central in ME research.

What I’m talking about here is not the common problem that a up to 89% of research still uses broad inclusion criteria that do not make PEM necessary to be included as a patient in the study. I am also not talking about all the Long Covid research that fails to assess their subjects for PEM and other subtypes like orthostatic intolerance and hyperallergicity/MCAS. No, this is about going beyond those minimal requirements.

I’m talking about the fact that many studies are theoretically impoverished. They tend to study ME without any design specific to the disease besides inclusion criteria. They run a panel of tests, compare for any differences between patients and controls, report significant findings, and that’s it. You can swap out ME for any other disease and the research design could stay the same. Better ME research uses some method to provoke PEM and then measure any changes in the subjects, but this is also not sufficient.

In my latest blog post, I discuss 9 questions that every ME hypothesis needs to be able to answer, and the difficulties that PEM poses to studying ME.

https://viralpersistence.substack.com/p/make-pem-central-to-me-research

As you say in the blog PEM is slippery and I wonder if it could be too slippery to reliably aim research at in a way that isn't unethically intentionally induced. The enormous variability between patients in how PEM manifests for them, catching them at the right time, the inability to know whether the worsening is due to activity or something else - these all muddy things so much.

There's a compromise I think maybe Ian Lipkin is attempting with good day, bad day studies. I wonder if anything could be learned just looking at the fluctuating relapses and remissions of a signal individual in detail with the right set of assays.

 

[duncan]

After 30 years or so, my PEM seems to have devolved, i.e. it appears more randomly at time and more intense. I used to be able to forecast when PEM would kick in. Too much of any exertion, basically - but I had a pretty good feeling for what that threshold was.

These days it's more sensitive, or at least it seems so. I can no longer necessarily understand the cause of a given episode. Maybe my PEM has developed a hair trigger? I don't know. But it no longer seems as formulaic or predictable. I sure hope I'm not alone in this - but I know my cognitive issues are worse than most, so who can say.

Not sure of the implications of non-static PEM.

 

[AliceLily]

I have no objection to a definition of PEM to standardize ME studies. It's important to limit variables for such studies. I object to applying that definition beyond its purpose as a study restriction.

This is what is important to me for research.

As for diagnosis of ME/CFS I certainly agree we need to catch those who do not recognize PEM because there will be many still trying to get to understand their symptoms and what they actually have wrong with them. It took me until very severe ME/CFS to even recognize the severe PEM bouts I was having in my early ME/CFS.

Also, sorry Creekside for my emotional response last night.

 

[Kitty]

As you say in the blog PEM is slippery and I wonder if it could be too slippery to reliably aim research at in a way that isn't unethically intentionally induced.

That's my feeling.

We don't even know that PEM is a observably different state to not-PEM. It could be the same signal responding to more stimulation, and just because it makes us feel so much worse it doesn't automatically follow that it'll be easier to see.

The worry is that people could spend a lot of time and money performing a whole series of diligent studies, and still only come up with the Bellman's Map of the Ocean.

 

[jnmaciuch]

We don't even know that PEM is a observably different state to not-PEM. It could be the same signal responding to more stimulation, and just because it makes us feel so much worse it doesn't automatically follow that it'll be easier to see.

Though if someone feels much worse in "PEM", something has to be changing somewhere. The goal would be to hypothesize what specifically is changing in magnitude and design an experiment specifically to see it across those fluctuations