AliceLily
Senior Member (Voting Rights)
Thanks for this.
Make PEM central to ME research [blog post by me]
- Thread starter Siebe
- Start date
The ME/CFS criteria requiring PEM seems to be cutting out a good cohort for research. And I'd like more research into PEM specifically (it would be good to collect what little we have into a thread, if we haven't already?).
Even before mentioning PEM I do think people with ME/CFS look pretty distinctive. I don't know of another group of patients featuring all 3 of the following:
Studies in the 80s and 90s didn't explicitly require PEM but seem to have been inadvertently studying a cohort at least somewhat relevant to us. It could be that they selected somewhat for high disability (often many of their cohort would be unable to work, or have people being cared for by their parents) and this served as a proxy for PEM? At first they thought these patients had depression, and then discovered that they didn't actually seem depressed by any measure. They thought the 'fatigue' stemmed from allergies or low grade inflammation but their RCTs showed that neither antihistamines nor steroids (nor a bunch of other things) help. And it seems increasingly possible they found an actual biological difference between this group of 'CFS' patients and healthy controls (e.g. buspirone-prolactin) and just never followed up on it at all.
The fibromyalgia GWAS showed interesting overlap with the DecodeME results. Maybe the delta between the two can tell us more about PEM and/or the particularly high disability level of pwME/CFS.
[ Edited to reduce rambling chaos ]
Even before mentioning PEM I do think people with ME/CFS look pretty distinctive. I don't know of another group of patients featuring all 3 of the following:
- A set of symptoms skewed towards feeling ill, pain, OI, IBS, sensory and cognitive problems etc.
- No other diagnosis explaining these symptoms.
- A shockingly high degree of net disability. (Be it from a severe baseline, or milder baseline + periods of being much worse, or the worst of both.)
Studies in the 80s and 90s didn't explicitly require PEM but seem to have been inadvertently studying a cohort at least somewhat relevant to us. It could be that they selected somewhat for high disability (often many of their cohort would be unable to work, or have people being cared for by their parents) and this served as a proxy for PEM? At first they thought these patients had depression, and then discovered that they didn't actually seem depressed by any measure. They thought the 'fatigue' stemmed from allergies or low grade inflammation but their RCTs showed that neither antihistamines nor steroids (nor a bunch of other things) help. And it seems increasingly possible they found an actual biological difference between this group of 'CFS' patients and healthy controls (e.g. buspirone-prolactin) and just never followed up on it at all.
The fibromyalgia GWAS showed interesting overlap with the DecodeME results. Maybe the delta between the two can tell us more about PEM and/or the particularly high disability level of pwME/CFS.
[ Edited to reduce rambling chaos ]
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Kitty
Senior Member (Voting Rights)
I worry about the rationale of investing resources and capacity in a search for a small beep when there's a giant foghorn already sounding—the one that shuts some people down so much they have to live in darkness and silence. Have we got our priorities right?
jnmaciuch
Senior Member (Voting Rights)
To be honest, if there was such a foghorn, I think it would have been seen consistently on all the untargeted screens that have been done already. The most likely time for there to be anything to pick up on seems like when symptoms would be worst. If we’re grasping at straws in either direction this is the most fruitful place to look
[edit: and looking at mild/moderate people in PEM is going to be either equally or less logistically strenuous as going right to severe ppts. Part of the problem with zeroing in on severe is the question of what are you going to compare to. You end up with endless confounders due to the facts of life as severe. Good day/bad day isn’t perfect but it does let you control for a lot by comparing the same individual at different moments]
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jnmaciuch
Senior Member (Voting Rights)
Re: PEM and activity I think the obvious solution is just to say there is some process X that causes worsening of symptoms/new symptoms which, for many pwME, can be pretty predictably induced by some event Y that happens during “exertion”. But X (or maybe Y->X) can also be induced by other things besides exertion.
Like the relationship between abdominal cramps and menstrual cycle phase. Abdominal cramps aren’t exclusive to periods, but menstrual cycle does give some valuable information for what might be going on at the biological level in specific instances of the symptom.
Like the relationship between abdominal cramps and menstrual cycle phase. Abdominal cramps aren’t exclusive to periods, but menstrual cycle does give some valuable information for what might be going on at the biological level in specific instances of the symptom.
At the same time the question would still be why one would find it so hard to see any differences between healthy people and pwME/CFS, if one isn't looking at sampling at specific time points. Exercise studies looking at metabolites etc have come out with nothing, they might not have been ideal in the type of setup that is proposed in the blog and we've discussed various issues about 2-day CPET studies not capturing PEM at all, but I'll still be surprised if someone was to find answers to ME/CFS first with the approach proposed in the blog. If someone has a hypothesis on what specifically changes in magnitude after exertion, will they not also have an hypothesis for what is different before that?
I think the obvious solution is to do a long term activity tracking study to finally get some data on all of this. Once that is done one can begin postulating things and designing studies as proposed in the blog.
chillier
Senior Member (Voting Rights)
I think there's two things that are reasonable and practical to look at which are:
1) Response to exertion, which include CPET and hand grip strength.
2) Differences over a time course of health fluctuations.
I think both of them are completely valid and reflect dynamics that are relevant to ME/CFS, but neither of them are PEM and I think that's ok. Maybe a bigger issue than all that though - as maybe you are alluding to - is that the techniques being applied are probably fundamentally looking in the wrong place.
I feel in particular that ME/CFS pathology is probably not observable in the blood (though who knows maybe with the right perturbation of populations of neurons something might show up there like the prolactin stuff?). The answer is maybe somehow in the assaying of neurons.
This might also be the way to quantify and measure PEM directly in the natural course of someone's illness. By seeing if an exertion spike preceeds a health dip more often than you would expect by chance.
V.R.T.
Senior Member (Voting Rights)
Yes ways to look at neurons should be a major focus going forward.
V.R.T.
Senior Member (Voting Rights)
If there is immune pathology it is probably hidden away in tissue. For that reason I think immune researchers need to get a bit less squeamish about biopsies, and/or do some therapeutic experiments to test their theories if safe and feasable. If we're going to settle whether there is immune pathology we can't just keep testing blood over and over without ever looking at the other places that might have observable immune signalling pathology.
But if it is visible in the blood with the right test, it is quite likely to only be so during PEM, or in the most severe. So good day bad day studies would be valuble but it is still inexcusable how little research looks at the most severe patients. It makes no sense not to look at the most affected.
But if it is visible in the blood with the right test, it is quite likely to only be so during PEM, or in the most severe. So good day bad day studies would be valuble but it is still inexcusable how little research looks at the most severe patients. It makes no sense not to look at the most affected.
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V.R.T.
Senior Member (Voting Rights)
In general I find the questioning of whether exertion actually causes PEM uncomfortable. I know all too well it isn't the only factor and it is a slippery concept. But when you take away that fact you take away the reason for all of the adjustments pwME need. If we wouldn't get worse from it, why shouldn't we try and get our own lunch or sit up on a chair in the waiting room or talk to a doctor for an hour straight? If it's just uncomfortable in the moment? And of course we have all tried this and had to stop.
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Yann04
Senior Member (Voting Rights)
I’ve never heard this term before. Interesting alternative for the cluster of symptoms called “MCAS”. Did you come up with it?
In my opinion problematically, if I recall correctly, the CCC doesn’t actually require PEM it just counts as points towards the diagnosis.
Yann04
Senior Member (Voting Rights)
I think it’s worth seperating two things. Exertion -> long term worsenings, it’s far harder to establish causality for long term worsenings. And I could imagine a sort of confirmation bias confounding. Y makes illness worse -> person gets more PEM when exerting because Y made illness worse -> Person realises their illness is now worse and blames it on the exerting that made them notice.
But at the same time I feel like looking back on my permanent worsenings they sort of clearly followed a period of more exertion than before.
As for non-permanent worsenings, what we might call PEM episodes. Having been so severe that there is essentially no variation in day to day routines. When I couldn’t communicate essentially at all, spend 24/7 lying in the dark and not hearing a sound, it was pretty obvious to me that X extra stimulus/exertion, caused a pretty predictable Y worsening over the next days. I feel like being in that situation removed all the noise (pun intended) and made it pretty clear to me my worsenings followed extra stress, exertions, or sensory stimulus. Though of course could partially be confirmation bias. And I’m not pretending I can explain everything. There is some PEM that hits me unexpectedly, I can’t predict my illness course entirely based on yesterday/week/year’s exertion.
I also wonder if it would actually be possible to have an objective study confirming this. PEM has no objective markers, but we can probably get some objective proxies. Many symptoms people tend to report in PEM are objectively measurable, diarrhea/constipation, acid reflux, tachycardia, lack of sleep/oversleeping. I feel like that could be objectively measured for symptoms someone says they get during PEM and a “symptom score” could be compared over time to see if there seems to be a causative relationship between activity increases and symptom score.
Same. I recognised I had short term exertion intolerance. (Vomiting/Feeling Weak/Quasi-fainting after intense exercise; I can’t believe my doctors didn’t take these symptoms more seriously). But when I felt worse for a week or so I just assumed flu/virus. Even though this was happening super often and I never seemed to fully recover from these “flus”.
Yeah there’s also that. If you’re pacing well your over exertions will be minor and thus cause and effect might be harder to untangle than big overexertions.
Same, and as a very severe person I already face so much day to day scepticism from people who are supposed to be allies that “that small thing” “can actually trigger PEM”.
jnmaciuch
Senior Member (Voting Rights)
Yeah, I see your point. Though just speaking for myself, the lack of foghorn findings in all the other studies helps make it obvious that the constant mechanism must be something tricky to measure for some reason. Hidden in particular tissues or producing only some but not all of the typical signs people look for to indicate XYZ happening…
Unfortunately the way most funding bodies and ethics review boards work, you already need to have data to show why you want to do a particular complicated/invasive/unconventional/resource intensive study. At least some concrete indication that any part of your theory is true. Other diseases can check that box from animal models, even if the model is less than ideal. We’re at a disadvantage on that front.
[Edit: whoops just scrolled up, I’m just repeating some things @chillier already said]
Sure, I agree.
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V.R.T.
Senior Member (Voting Rights)
This seems to be a real catch 22 to me, and I'm not sure how we get around it other than crowdfunding/getting private donors to fund small studies looking at whatever unconventional/complicated/invasive thing we need to look at. And that doesn't solve the ethics board problem...
Yep, that would be the goal.
I agree, but the way I see it is not as questioning but rather as getting some data on things before setting off on the things that are proposed in the blog.
I agree that testing blood is likely fruitless, especially if the pathogen - which I think you are talking about? - is sequestered in some sort of reservoir in the brain.
One possible avenue might be looking for antibodies in CSF during PEM. You'd have to involve a fairly exhaustive antibody panel.
Other than that, if the agent is holed up in the brain, trying to do a PCR would be hit or miss, and extremely invasive for the patient. Autopsies would be an obvious solution but you can't involve PEM at that point.
V.R.T.
Senior Member (Voting Rights)
I'm actually talking about erroneous immune cell or cytokine signalling rather than latant virus or bacteria.
We haven't had many CSF studies iirc.
jnmaciuch
Senior Member (Voting Rights)
I don’t think it’s impossible it just requires ME/CFS researchers to go the extra mile…or extra several miles (and, unfortunately, for reviewers to be somewhat flexible on what kind of supporting evidence theyre willing to accept. Most will not be evaluating a theory on its own merit)
I was in a Baruniak one several years back where they tried to induce PEM. They performed a lumbar puncture for that, as well as a fMRI, if I recall correctly.