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

If PEM was called next-day malaise it would help. In these situations you never know if the other person is confusing PEM with feeling tired after exertion or with delayed malaise that's different.

 

In the Discussion, they say:

"Moreover, testing of effort preference and the participants’ own words are consistent with this finding [on central and peripheral fatigue]. Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.

Consistent with this observation, with strong encouragement during CPET, all but one of the PI-ME/CFS participants reached a respiratory exchange ratio of 1.1." (bold added)​

I read this as their explanation that pwME only overcame their "effort preference" through strong encouragement from those conducting the test.

But in my personal experience with CPET as a HV, it's standard practice in CPET testing to strongly encourage all participants, not just pwME.

To state this for the pwME participants only is a biasing statement to bolster their argument.

 

I recall that Nath is on record as saying re Lyme, ME/CFS & long covid - if you solve one then you solve them all. So this is the "great unifying theory" -- post infection your brain tells you that you can't do stuff & in some cases that persists i.e. a biological abnormality.

So is this hypothesis reflected in the (NIH) ME/CFS Research Roadmap Priorities- e.g. is there a suggested topic which reflects this hypothesis? Or do we just suggest the fMRI study Jonathan alluded to ?[https://www.s4me.info/threads/deep-...me-2024-walitt-et-al.37327/page-9#post-516621]

 

And if they only gave 'strong encouragement' to the patients then they purposefully biased their results.

Additional (rhetorical) question, how do they know that the encouragement was an influence either way? Did they have the patients do a CPET with and without encouragement, in order to be able to compare?

 

The question of whether PEM was present or not is a nuanced one.

They note the cases were adjudicated by experts and the supplemental data said all 17 pwME met IOM criteria

BUT
They used the CDC Symptom Inventory to evaluate symptoms. The question for PEM in that tool is "unusual fatigue after exertion." Not PEM

Also, the IOM criteria require that core symptoms be present at least ½ the time and be at least moderately severe. But the study's source data for the CDC symptom Inventory responses show that 10 of 17 pwME experienced this "unusual fatigue after exertion" only "a little of the time.” The other options were a) Some of the time, b) A good bit of the time, c) Most of the time, or d) All of the time.

So based on what I've read so far, the question asked and the low frequency rate accepted do not satisfy the IOM criteria for PEM in my opinion. And I haven't seen any explanation for why they lowered the frequency rate accepted

As far as there being expert adjudicators who would have been able to recognize PEM - I'm guessing they did not see the participants but rather reviewed summaries of information collected by study staff - basically in this case a check that PEM was present.

 

its not useful PEM, nor did they do any day after or longitudinal stuff. useless

 

The more I think about it, the more problematic it becomes that they speculated "conscious or unconscious pacing" as the cause of the effort preference. It seems more logical to speculate that it was due to the central fatigue given that the physical correlation between catechol and the effort preference. Yet, there is nothing about catechol in the section where they discuss the grip test and rTPJ. The catechol anomaly is discussed in its own section apart from the grip test discussion and left as "an area to be further investigated". It's as if they minimized the physical finding in favor of qualitative speculation. Why?

This is problematic because the effort preference would be apparent even in the PEM state: you fail to exert harder/longer not because of the peripheral fatigue, but because you *feel* weak and fatigued. It is same as other sick patients: flu or hay fever patients cannot exert harder/longer because they feel weak and fatigued, not because their muscles fail. So, if you dismiss the MECFS fatigue as effort preference or a product of pacing, then you end up dismissing PEM fatigue as effort preference as well. The end result would be an assertion that "you are tired because you are afraid of being tired".

Maybe the central fatigue itself is an effort preference problem. But the term "effort preference", whether intended or not, connotes volition whereas central fatigue does not. A big difference to an average reader. Their speculation about pacing as the cause does not help. Not sure if their discussion about MECFS as a central fatigue problem at the end of the paper would remedy that.

 

Bloody hell.. so this whole study is a wash.

 

Decided I'd ask NIH whether they'd follow through with this paper i.e. in the (NIH) ME/CFS Research Roadmap Priorities?
Thanks for the insight & suggestions @JonathanEdwards

https://twitter.com/user/status/1760673753711911223

 

I fail to understand how so many intelligent and well-versed people have thought, and to a degree still think we will get a fair shot at the NIH. I honestly don't say this to put people down, but it needs a real change in attitude towards this institute. The NIH put a person in charge of this study that is on the record for saying that Fibromyalgia is nothing but the figment of vivid imaginations. Why are we even sitting down with them?

How on earth could NIH leadership maintain 'ME/CFS is a real biological disease' with straight faces while also putting Walitt in charge, without being (excuse my English) full of shit? I don't think that's possible.

The whole communucation, as far as I am concered, of NIH leadership in regards to ME/CFS is an rather obvious front for 'act like and say that this is a real biological disease, just keep saying it, but we all know it's going nowhere, so win us some time'.

Sure, one can try fighting small battles leading to incremental success, on a plain scientific playing field, but honestly, this will get us not very far as we can see. We need a much bigger, in terms of constant pressure, more aggressive politcal advocacy to get to a btter place.

I wonder if a forum like this one, but specifically for political action could be useful towards that end, any thoughts?

 

I recall writing on this forum multiple times about how my body, when not in PEM, appears to be unable to fully sense whatever problem it is that leads to PEM. The brain feels as if it's capable of doing a thing, and motivation and interest surge, but then the actual ability to do things is vastly lower. It fails to predict the consequences and overestimates its abilities. We cannot trust that feeling good and motivated in the moment actually means being able to complete the task that we feel good and motivated about. This is a very consistent pattern.

The behaviour that we patients learn to compensate for this comes across as anxious, overly passive, lacking motivation, negativity, etc. Other people think the cure is to get us to enter into a more positive mental state but that doesn't help at all in the log term.

If anything the perception problem is that we think we can, but actually can do much less (especially in a sustained manner).

 

@EndME & @Braganca - you highlighted WASF3 - this Tweet was brought to my attention
https://twitter.com/user/status/1760374518701236298

 

They make our symptoms sound like a minor nuisance, an annoying itch or something.

 

Is there any mention of the drugs that they have said might benefit studying?

I seem to recall they said they had candidates.

 

Yes.. but what does the WASF3 study even really mean if 10/17 patients had ‘fatigue after exertion” “a little of the time”?

 

And ironically, the real problem is that with PEM, we all keep underestimating how much effort things take and hit the wall. We all forget just how punitive it all is, how much it hurts to go over that limit, and still we go over that limit again and again. They got is so completely backwards it would be hilarious if it didn't set back research and was the only shot the NIH would bother doing for a long time.

At least there's LC research, but this is truly "Youth in Asia" level of not understanding the problem on an essay that is about euthanasia.

 

Which might very well be the case, if they selected mild patients that had fatigue after exertion "a little of the time" and had no POTS.

This whole study is an insult to the severe patients that can't even feed themselves. "Effort preference" my ass.

We need to realize that the whole thing was set up like a psych study from the start.

Yes, they did lots of tests looking for the organic cause but this is done in psychiatry as well. Schizophrenia had a GWAS done many years ago, and in most mental illnesses the immune system is being studied.

So what's the problem? The problem is that if you start with the assumption that ME is a mental illness (it isn't), you will not be able to study it properly. Patient selection, interpretation of findings, the focus of the whole study will be wrong.

The reason they didn't pay attention to PEM and the 2 day CPET is that they don't think it's real. Simple as that. They start from the assumption that the symptoms are subjective and look at the muscles "just in case" there might be something there. Same with the cognitive tests. The focus is completely wrong. They didn't seek to find what was wrong, just validate their pre existing assumptions that ME is a subjective illness without any real impairment.

Yes, they concede that maybe the "subjective sensation" might be immune mediated but that doesn't help us if they are so biased that they can't even be bothered to study PEM, or select the proper patients.

How would you feel if you had treatment resistant depression or bipolar disorder and the researchers were hell-bent on studying the composition of your toenail? Yes, it's "organic" but it doesn't mean it's the right focus.

This is what happens when you put pressure on them to do an "organic study". Organic study and psychiatry are not mutually exclusive. They do deep phenotyping in mental illness too.

As @butter. Says, we need to start demanding studies that have a proper focus on what the illness actually is. If the science is not focused on ME, it will keep being a waste of time and money in the following decades.

 

Medscape 'Deep Phenotyping' Identifies Abnormalities in ME/CFS by Miriam Tucker

quotes:
Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

"To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that's a question that needs an answer," VanElzakker said.

...

Nath told Medscape Medical News, "I think the most important thing is not to discount these patients…They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don't have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them."

 

There are different levels of cognitive inability to do tasks. Your example is high-level, involving prediction and judgement. There also seems to be a lower level, what I think of as hidden machine code, where some neurons are involved in a feedback loop from muscle sensory nerves and maybe other pain-sensing nerves, and maybe nutrient sensors (glucose, lactic acid, etc) that affect the strength of signals sent back to the muscles. That level of inhibition is beyond psychology; it's hardware (wetware?). I think ME affects that level of body functions.

 

Reminder - When the study protocol first came out advocates demanded it be improved and to reflect the physiological nature of ME. We DID demand a proper study.
NIH did amend it.
But as we can see from this article, adjudication may have been required for participation, but that didn't mean much (I am not denigrating the work of the adjudicators - I feel the investigators overrode the adjudicators) and NIH used the instruments they wanted to use rather than using instruments that truly capture ME. And so on....
Remember also that stakeholder participation in study conception, design, execution, was NOT part of this.
Knowledgeable stakeholders HAVE to be involved from start to finish!