Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

Holy—I can’t believe we waited 8 years for this.

So, a bunch of the patients in the study ended up recovering completely, and most of them barely get PEM.. Makes me wonder if they're just studying people who can shake off a post-viral fatigue easier than others. You know, the kind who might get better with stuff like graded exercise or the Lightning Process. Where psychological intervention may be the treatment, because you’re not that sick.

They didn't even bother to look into how patients handle PEM. Plus, the participants were mild enough to go through all their tests. How does that even start to cover what it's like for those with moderate to severe ME/CFS, who are mostly bedridden and hit PEM pretty much anytime they push too hard?

I can't help feeling like this whole study misses the mark. Eight years down the drain on what feels like the wrong crowd, wrong criteria and wrong methods. Where's the 2-day CPETs, or checking out what happens during a PEM flare-up? Where is the common sense?

This just feels like a massive step backward for the community. It's frustrating to think about how much longer people will suffer because this ‘study of the decade’ completely dropped the ball on wanting to understand what ME/CFS really is about.

On a curious note, has anyone here ever mapped out what a study really should consist of, in terms of criteria and methods? And is anyone in the scientific community actually following up on this? Or are we just holding on to the long covid crowd and hoping they will find the answer? I’m struggling to see the roadmap and way forward from here.
 
dave30th said:
You're not having PEM during the exertion itself, so you can't really have the exertion intolerance during the exertion, at least as I've been understanding the term.
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I think I have a slightly different understanding. During a sustained activity I'll experience rapid muscle fatiguability, pain and OI; if I keep going there are likely to be additional symptoms, such as nausea, dizziness, breathlessness. If I was rested beforehand, it's not PEM. But I still understand it to be part of the phenomenon of exercise intolerance, as it's clearly an abnormal response to low-level effort in a person with no cardiac or respiratory disease.

My understanding isn't necessarily the same as everyone else's, of course!
 
dave30th said:
yes, the exertion intolerance isn't the wish to stop. It's the fact that people have a physical, somatic reaction afterwards. You're not having PEM during the exertion itself, so you can't really have the exertion intolerance during the exertion, at least as I've been understanding the term.
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I disagree. See my previous post.

dave30th said:
Also, just because someone can push themselves to finish a task doesn't mean their bodies can actually handle that without subsequent damage. The logic seems off.
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Again, a problem, see my last post. We can't push through every task. Symptoms increase and debility increases during tasks, nothing to do with effort whatever or deconditioning. They need to recognise the effects of fatigability/exertion intolerance during and for minutes and hours after all activity as well as delayed PEM following increased activity.
 
Hutan said:
I believe that, given the involvement of clinicians who see a lot of people with ME/CFS, at least most of the 17 participants were appropriately selected. The study has a lot bigger problems than selection, in my view.
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Of course. I was not saying there weren't. But redefining PEM as "feelings of discomfort" and then virtually ignoring PEM is a pretty big problem and the choice of method to identify PEM is just one facet of that problem.
 
tommybrand said:
On a curious note, has anyone here ever mapped out what a study really should consist of, in terms of criteria and methods? And is anyone in the scientific community actually following up on this? Or are we just holding on to the long covid crowd and hoping they will find the answer? I’m struggling to see the roadmap and way forward from here.
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Indeed they have. Every study is different but the DecodeME study put a lot of effort into getting the criteria, numbers and recruitment right for its particular purpose. There is also an ongoing project to tidy up generally applicable criteria which includes sensible people with a lot of relevant experience.

The NIH intramural study always looked to me like a camel designed by a committee. A good fMRI study on its own would have been excellent. A serious muscle study like that of Wust on a decent number would have been good. The idea that you can measure everything and solve a problem is never a good approach.
 
Trish said:
Again, a problem, see my last post. We can't push through every task. Symptoms increase and debility increases during tasks, nothing to do with effort whatever or deconditioning.
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I am sure that happens, but an increase in symptoms and increasing debility are seen in almost any condition limiting exertion capacity. It occurs in heart, respiratory, kidney and liver failure, multiple sclerosis and so on. PEM later seems to be much more specific. I guess it may never have been clear in anyone's mind whether the EI of SEID is intended to relate to this general sort of intolerance at the time, which of course applies to sound and light intolerance in ME, or the PEM payback sort of intolerance. They probably need quite different routes of investigation.
 
“This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks. Both the autonomic and central motor dysfunction result in a reduction in physical activity. With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. These features make up the PI-ME/CFS phenotype.”
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Holy hell. This is more nakedly preposterous than I could have imagined. To not define, identify, and measure the cardinal symptom of the illness properly and then conclude the paper with some vague garbage suggestive of old central sensitization theories is so far beyond unforgivable.

I’m beating a dead horse, but any preference or unconscious feelings about exercise or activity have no relation to what drives ME. We were all disabled from the moment of onset, before we even knew we were sick. Most of us became so much sicker not knowing that exercise was harmful, not having a negative association with activity.

My first experience of PEM was after climbing Mt. Washington and rock climbing a ~500 ft bluff only a day or so later. The impacts were terrible, physically, but especially cognitively. I struggled to send even basic emails in the days after, when just weeks before I could get through LSAT practice exams (even if my cognition had already measurably worsened). It was unlike anything I’d experienced, and I climbed Mount Fuji the year previously, also with no preparation and in roughly the same physical condition.

Even with those impacts, I didn’t realize exercise or activity might have any connection to my symptoms until months later. By that point the physical and cognitive impacts had worsened and it only took an hour of mixed aerobic & anaerobic exercise to leave me significantly more disabled the rest of the evening and in the days after. And even then, I didn’t stop exercising entirely. I continued rock climbing, but switched to bouldering, where I would climb a route (10-20 seconds activity) and then rest for 10-15 minutes until my heart rate came down to baseline. I continued to do this even after I had to leave work, my mom driving me to the facility. The PEM it produced grew over time and I eventually stopped. I never did expand my energy envelope even as my skill improved.

edit: I should add that once I left work, I rested for days before and after for this to be even remotely sustainable.
 
dave30th said:
They state clearly, if I remember, that CBT and exercise are "downstream" treatments not likely to have any impact on the immune-related causal factors--so that's a positive message at least.
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Is it a positive message?

FND and BPS have never had any issue being internally inconsistent and filled to the brim with hypocrisy and cryptic terms that have different meanings depending on the context. Saying the illness is real and organic, or that nothing is wrong with the patient and everything is imagined based on the context and their political needs.

If the issue is the unwillingness to put in effort, CBT is the obvious treatment. And even if doctors get the memo that CBT/GET doesn't work (instead of thinking it was a result of political pressure by patient orgs) the fact that the illness is described in these terms will solidify what everybody already thinks: that it is mostly just false perceptions about one can do and that there is no real need to drive resources and talent to this area when people are suffering and dying from "real" diseases.

ME is competing for funding with thousands of deadly and horrible illnesses. With a study like this one reinforcing these kind of stereotypes, it becomes increasingly unlikely that ME will get significant funding in the years to come.

This study was supposed to set the record straight and leverage on the authority of the NIH to make the world understand what ME really is. It did the opposite, it reinforced the pre existing stereotypes, only with a sprinkle of "we had to write this is organic and CBT doesn't work otherwise the patients would complain". Journalists might get fooled, the neurologists and medical professionals in charge of managing disease funding won't.
 
Jonathan Edwards said:
I am sure that happens, but an increase in symptoms and increasing debility are seen in almost any condition limiting exertion capacity. It occurs in heart, respiratory, kidney and liver failure, multiple sclerosis and so on. PEM later seems to be much more specific. I guess it may never have been clear in anyone's mind whether the EI of SEID is intended to relate to this general sort of intolerance at the time, which of course applies to sound and light intolerance in ME, or the PEM payback sort of intolerance. They probably need quite different routes of investigation.
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I wasn't suggesting exertion intolerance/fatiguability are unique to ME/CFS. I was responding to the suggestion by @dave30th and others that the only thing stopping us exerting is anticipation that it might trigger later PEM. I experience both exertion intolerance and PEM. I agree they need to be recognised as different and researched as such.
 
Mfairma said:
Holy hell. This is more nakedly preposterous than I could have imagined. To not define, identify, and measure the cardinal symptom of the illness properly and then conclude the paper with some vague garbage suggestive of old central sensitization theories is so far beyond unforgivable.

I’m beating a dead horse, ....
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@Mfairma If you think about it more clearly, you will find you aren't beating a dead horse, it's just that the horse is not preferring effort to its current state.
;)
 
RaviHVJ said:
I think this is the politically smart response to the paper - skate over its conclusions and serious flaws, and use it to call for proper funding from the NIH.

The truth is that an $8 million study looking at 17 patients wouldn’t be expected to make serious inroads in any other field. The paper has taken on such intense significance because the NIH provides virtually no funding for ME research. We need to get to a place where it doesn’t hugely matter that an individual study has significant flaws because enough well-funded research is happening that the field builds a momentum of its own.
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Isn't this wishful thinking though?

Action is a consequence of will. Or should we say, effort follows effort preference...

In the past 40 years, the medical establishment has had very little effort preference towards studying and funding ME. Mostly because it was perceived as an issue of the patients having a preference towards not doing things that require effort, instead of a real illness. Laypeople would call it being lazy. You know, "we are all tired when we don't wanna do something".

Given that this paper did not dispel that stereotype, and in fact reinforced it, do we seriously expect that cheering on the NIH with this study will magically give us that $200 million a year other diseases have, after decades of disrespect, contempt and neglect?
 
It's interesting to go back to the Phoenix Rising threads. Here's some excerpts from one of my posts in March 2017, complaining about including Walitt and a number of other overtly psychosomatic believers in the trial staff. It looks like, to start with, the NIH were suggesting that Walitt was just managing the admin of the trial, the logistics of getting people places. Then he was collecting patient data.

It's a matter of trust.

The NIH knows patients are very wary of more patient blaming and findings that suggest that if people just stopped focusing on their symptoms and instead slept better, ate better, exercised more, they could be well. They know that much of the community has problems with a number of the NIH staff who have made statements along those lines.

So I really don't understand why they would put those distrusted NIH staff in direct contact with ME trial participants.

...

I therefore think it is very likely that the quality of the data recorded during this NIH screening process will be affected by the choice of the NIH personnel.

And yes, I get that this is only a screening process, but I don't believe that data collected in the interviews will just be thrown in the bin once the participants are selected. Of course it will be used in subsequent analyses.

Remember that Walitt believes Shorter has something of so much value to say to the NIH that he arranged for him to travel from Canada to give a talk. I thought we were assured that Walitt would simply be organising the admin for this trial, ensuring patients got to the various data collection locations. Instead we find that he has a big part to play in interpreting and recording patient's symptoms.

Why on earth, if you were trying to run an investigation into ME that will be both useful and accepted as useful by the ME community, would you not choose staff for the face-to-face data collection who don't have a record of publicly denigrating ME patients?
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And now it turns out that Walitt wasn't just the admin person at all, or even the person just collecting initial data from participants. Here he is, first named author on a paper that is exactly as full of psychosomatic vagueness and misrepresentation of data as we might have expected from him.
 
Trish said:
I was responding to the suggestion by @dave30th and others that the only thing stopping us exerting is anticipation that it might trigger later PEM.
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I don't think I said that, and if I implied it, I didn't mean to. I certainly don't think that the only thing preventing it is a mental anticipation. What I said was that even if patients could do push through, it doesn't mean there's not damage--I criticized the logic of their claim. I also said that the main payback seems to be after exertion, not during, given that the performance on CPET tests tends to be similar on Day 1. That's not saying that patients can't get depleted during the activity and be unable to continue. Of course they can. If what I wrote implied otherwise, I'm sorry!
 
Hubris said:
If the issue is the unwillingness to put in effort, CBT is the obvious treatment. And even if doctors get the memo that CBT/GET doesn't work (instead of thinking it was a result of political pressure by patient orgs) the fact that the illness is described in these terms will solidify what everybody already thinks:
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I agree the impacts of the language are likely to be very problematic. But yes, I do think it's a positive--in the relative sense--that they have pegged the causes on immune dysfunction and dismiss CBT as curative even if they use very, very unhelpful and ambiguous terms.
 
Trish said:
We can't push through every task
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I agree! I didn't say that people could push through every task. The point I was trying to make was that even if someone is able to push through a task, it doesn't mean it's a good idea. I wasn't saying anything about all the times that people can't push through.

But that reminds me of a review I once read about a new but apparently not good Toni Collette movie. (I love her!). The review started out something like this: "Toni Collette is the kind of actress who can probably play anything she wants. But that doesn't mean that she should."
 
Jonathan Edwards said:
Indeed they have. Every study is different but the DecodeME study put a lot of effort into getting the criteria, numbers and recruitment right for its particular purpose. There is also an ongoing project to tidy up generally applicable criteria which includes sensible people with a lot of relevant experience.

The NIH intramural study always looked to me like a camel designed by a committee. A good fMRI study on its own would have been excellent. A serious muscle study like that of Wust on a decent number would have been good. The idea that you can measure everything and solve a problem is never a good approach.
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@Adam pwme you have some contacts in the Lyme & Log covid communities i.e. via Twitter. Since Nath [NIH] reckons ME/CFS, Lyme & Log covid are basically the same then there may be an opportunity to join forces to lobby for a "good fMRI study" & "serious muscle study like that of Wust". The NIH ME/CFS Research Roadmap may be a useful vehicle to propose those.
 
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