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

I'm not sure if there is a logical flaw. I believe they are saying is that effort preference is a brain-related issue, not a muscle-deconditioning one. Whether or not effort preference is a meaningful concept is another matter. But I'm still trying to wrap my mind around the whole effort preference thing.

 

@B_V A huge thank you for taking part in the study, and for sharing insider scoops along the way. It sounds gruelling, and I’m sure it, the massive wait and community expectations have taken/take their toll. I’m so grateful to you and the other participants. Take care of yourselves.

 

Thought I'd mention here that the proposal for adding a new code for PEM to ICD-10-CM, first discussed at the March '23 ICD-10-CM Coordination and Maintenance Committee and re-presented with significant modifications in Sept. '23, is back on the agenda for discussion at the forthcoming March meeting, according to the Tentative Agenda:

https://www.s4me.info/threads/updat...-terminology-systems.3912/page-38#post-517208

 

Thank you so much for that deep-dive into the catechols, Hutan! I have printed it out so that I can read and reread it.

You mentioned Parkinson's and multiple system atrophy as two conditions with low levels of one of the catechols we may have low levels of. Certainly people with Parkinson's can have marked orthostatic hypotension, often immediately on standing or very quickly thereafter.

And it sounds like orthostatic hypotension may be even more severe in multiple system atrophy.

Walitt et al. say that some catechols correlated with cognitive symptoms, and you might expect worse cognitive symptoms in those with more orthostatic intolerance. I'm not sure if Walitt & co checked directly whether orthostatic symptoms correlated with the catechols - ie does not mentioning it mean they didn't correlate or weren't checked?

Agreed on all counts. I think we're much more likely to see what's problematic by looking at more severe cases, but Nath was very keen to get people as close to the infection as possible instead. Given what came next - the pandemic - they're now spoiled for choice for the latter. Follow-up studies with more severe cases would really interest me. Not necessarily the most severe, but those who would have self-selected themselves out of this study knowing that there was no way they would ever manage it.

This was so helpful, Hutan.

 

But deconditioning is primarily about fitness and is measured by aerobic capacity, specifically by CPET - and the study demonstrated deconditioning. It would be odd if a group of people with ME were not. Grip strength and muscle mass are measures more of strength than fitness.

The problem for the paper is claiming that deconditioning causes the illness or its phenotype. First, as you point out, there are no signs of severe deconditioning (such as lower strength and muscle mass, change in type IvsII fibre ratio) - and if you are going to say an illness as severe as ME is down to deconditioning, you need to show evidence of severe deconditioning. Then, as I said above, you also need to explain why other limiting illnesses - as well as severely deconditioned people after coma - do not have the same symptoms, especially PEM.

I am shocked that an NIH team assembled to understand ME at a deep level could publish such a flawed, illogical hypothesis.

 

+ 1 (thanks and printing for later)

 

Regarding CPET, they do say

That's relevant, right?

And in a blow to women, they found what they interpret as more evidence of deconditioning in females, if I've understood correctly:

I edited to add something and took it out again because it was a brain fog metabolite.

 

The low catechol levels were measured in the CSF, is that correct?

Let's assume low catechol levels are a real signal, the authors seem to indicate they might be, wouldn't it be a bit odd not to specifically mention that despite low central catechols the patients suffered from sympathetic overdrive according to HRV results?

I think they talk about how low catechols could lead to negative cardio-pulmonary downstream effects without explaining any details, but, how could the HRV findings fit into this more specifically would be really interesting, mechanistically speaking.

 

That's a nice summary and echoes my sentiments. I don't understand half of this paper or any others, but I did feel that most of the things mentioned were already done and done better. The effort preference bit sounds very vague and unhelpful so I'd immediately attributed that to Walitt as his particular niche in science specializes in the vague and the unhelpful. But I might be wrong. From reading through the comments no one seems to have found out what is meant by it exactly, which I have to figure is the exact point by now.

 

I'm not sure I'm following the logic here (patient burden aside):

Point 1)
We don't need to do CPET the second day, we'll start doing other tests to measure PEM.
Point 2)
The primary community use of the 2-day CPET is for establishing a ME/CFS diagnosis, we didn't need it because we have an expert panel. Plus, a replication is not necessary because other groups have already done so.


The above makes sense, but:

Conclusion:
We didn't find anything therefore -> effort preference, disability caused by deconditioning.

My questions:

1) if the 2 day CPET worsening is such an established truth that it doesn't even need replication, why did this paper conclude that the disability is caused by deconditioning? If your CPET performance gets worse on the second day, that's objective evidence going against the effort preference + deconditioning theory.

2) are we even really sure the patients had PEM the second day? And deduce that it can't be objectively measured (with things other than CPET), despite all the red flags in the study? When I have PEM, my POTS gets objectively worse as well as other measurable things.

This was a missed opportunity to do a deep dive on PEM and see if any other marker or measurement would correlate with the CPET worsening. I don't see how their response can be considered acceptable given the stakes and how this study was hyped as the ultimate deep dive into ME.

They are so superficial about things that they couldn't measure anything indicating PEM and concluded the illness is deconditioning, while at the same time claiming they didn't do the 2 day CPET because supposedly the 2nd day was so packed with deep dive tests and measurements they couldn't fit the CPET in. I'm sorry but I don't buy it.

 

A study with 300 well selected patients just with a 2 day CPET from the NIH would basically prove that ME is real. It will be unpleasant for those 300, but I'd say that's a better outcome than having millions doomed to an eternity of malpractice.

 

Agree but one of the things I like about this forum is the suggestions re methodology - if the methodology is sound then that removes the scientists bias. So e.g. if the studies are large enough, and have appropriate controls - other diseases as well as health controls - then it'll test the theory that fMRI can actually measure this.
The smart money, AKA Jonathan, is that the fMRI signal is just an artifact.
I think it'd be amazing if the fMRI signal is picking up sickness behaviour (signalling) and a really big step forward.

 

I do not doubt `Cochrane's ability to bias their output, but my point was that in this particular case I don't see it as being obvious how these particular data could be used, or by whom.

 

"Study offers clues into chronic fatigue syndrome"
https://www.pulsetoday.co.uk/news/c...y-offers-clues-into-chronic-fatigue-syndrome/

Unfortunately Walitt gets quoted in this media outlet for UK GPs.
In the comments, two of the GPs pick up on his spin suggesting many other readers will do likewise

 

So what does this add up to? Deconditioning they cannot find evidence of. Functional deconditioning? But it's also physical and sets over time? Even though it sets in rapidly early in the illness? And fluctuates? And what is physical about it then, if the usual findings for deconditioning aren't found? And how does that physical deconditioning set in so early on, including in very fit people which they can't find evidence of? They really didn't think that through. At all.

 

@Dolphin I think the "nothing we didn't know" comment could be interpreted in ways other than having swallowed Walitt's spin.

As a standalone comment in this piece, Walitt's quoted comment is ambiguous - it could mean people can do more than they think or less than they think. If the commenting GP has only read this piece, not the paper, then I suspect the GP is more likely to have interpreted Walitt's comment to mean "People think they can do more than they actually can". GPs would be constantly hearing people reporting things like "I went back to work and now I can't get out of bed."

 

99% of doctors will laugh at the notion of 2 day CPET proving PEM Is real so yes, we do need a study with a few hundred people done by an authoritative institution to change their mind.

Either that, or we give up and decide 2 day CPET is not relevant to the illness.

I don't see how remaining in this weird limbo where some of the patient and researchers swear by it and others don't, helps us. If everyone has a different opinion what's the point? Isn't science supposed to help us find the truth?

Nobody uses the 2 day CPET (or thinks it is relevant in any way) aside from an extremely niche selection of US physicians.