What Mistakes are Being Made in ME Research?

I recently read a news item about static electricity research, and how the experimental results were confusingly unreliable, with test results being radically different each time the same test was done. One researcher decided that was interesting, and did a series of experiments, paying attention to the differences. That revealed that contact history (how many times the surfaces were put into contact then pulled apart) was important. Changes to the surface at the nanometer level was likely involved.

So, what similar mistakes might be being made with ME research, which similarly has conflicting experimental results? Seems like a good topic for brainstorming.

My first thought was that the standard stationary bicycle test is a very unusual activity for most PWME, which might give unusual results. I'm not sure what to replace it with, but maybe simply walking up an incline is more common.

Another thought: the various activities involved with going to a lab for an experiment might be causing physiological effects that aren't being taken into account properly. Just the stress of worrying about getting PEM from it might produce some changes that researchers will mistake as ME causes or effects.

Of course, comparing PWME against "healthy controls" is a mistake if you're trying to identify factors specific to ME, rather than just inactive, unwell people.

 

No one is accounting for the trip to the lab/hospital, which is a huge extra exertion for ME patients and its variable per patient and how severe they are. The assumption up to this point is they are taking samples from people before and after exertion, they may just be taking them from over exerted and very over exerted ME people. As far as I recall no one has gone into an ME persons home where no extra exertion has been done to take samples to compare. Its likely a huge area of error for determining baseline.

 

@DMissa does home visits in Australia.

 

There's lots of known unknowns in this space like plasma vs serum; pbmcs vs skeletal muscle; sample storage; collecting samples at different times of day, after different amounts of exertion, etc.

There's also biological sex and disease duration which muddle things up. And severity.

All of these mean we might be looking where the signal isn't, or burying signal under a load of noise.

So what are the unknown unknowns that hopefully we will look back on one day like ?

I'm not sure experimental techniques are even consistent enough to expect a common error that explains the issue. Probably the error is a more fundamental error, something we are not looking for, because the problem related to something in the body we just don't properly understand, like maybe the role of irisin or peroxisomes, or maybe how cerebral blood flow is linked to central control of innate immunity?

The space of unknown unknowns is a dark one of uncertain dimensions!

 

We need a test to document the inability to sustain exertion over time. Something that can show that in comparison to an average person of the same age, people with ME struggle to keep going.

Exercise testing has focused on short and intense sessions and maximal performance. But the problem is the impairment to sustain low intensity exertion over the course of the day and to recover from it over nigh. This is also what matters more in daily life for most people than the ability to perform well on an exercise test for 10 minutes.

Also, has anyone looked at delayed heart muscle inflammation and various other measures of heart health and delayed autonomic dysfunction?

 

The root of the misunderstanding of ME is this: normal people can comprehend difficulty with intense exertion because of their experience with sports, but struggle to understand difficulty with sustained exertion because they can't reach the same state of exhaustion that we experience, and confuse ordinary fatigue from daily life, that they can push through and recover from easily, with pathological exhaustion that only occurs in illness. The combination of difficulty understanding, easy misinterpretation, and lack of objective test then leads to widespread disbelief. We get called lazy and crazy for experiencing and describing an abnormally low tolerance of exertion.

If we had some ability to show a decline in performance in ME, in comparison to a healthy person, over the course of the day with trivial activities of daily living, it would help.

 

For that, I hope it would include a way to distinguish between muscle limitations and neurological ones. Electrostimulation of muscles would avoid the possible neurological factors. Hmmm, even that doesn't rule out some sort of neurological feedback system that affects the muscle cells. I think the main point is that it's important to be aware of the complexity of factors and the assumptions being made. The assumption that "Exercise is good for you!" might apply to some healthy, normal people, but not all of us fit in that category. Drugs wrok well and safely ... for people who match the test subjects closely enough, but not everyone does.

 

Yes, a lot of those tests are based on the results from healthy people. Molecule X breaks down at this rate <in healthy individuals>, but that doesn't mean that it will have the same rate in an unhealthy person.

My Tsh usually tests elevated, but taking T4 or T3 doesn't seem to make any noticeable difference in how I feel, so I'm not convinced this is standard hypothyroidism. If ME alters the kynurenine pathway, it might elevated picolinic acid, which elevated Trh which elevates Tsh, so elevated Tsh is normal for someone with a disorder that elevates picolinic acid. That's the sort of mistake I'm talking about: there might be an easily observed abnormality that is dismissed because "doctors know what causes that". Is the failure to uncover ME's cause due to what is known that is false, rather than what isn't known?

 

Studying mild/moderate people as the default.

There may be signals in blood or tissue that are much more clearly expressed when people become severe.

 

They should locate all the people that could NOT comply with the GET and CBT and were not counted in the results of these studies, and research them.

 

Lack of replication and lack of publication of negative results would be 2 substantial things.

Lack of open source data another, but things seem to be slowly improving in some places.

I also worry that rigorous recruitment might be a lot rarer than we sometimes think.

I would also like more longitudinal data. If we look at the intramural study are the results any different if we look at those people that recovered at a later time point etc? Which of the patients are recovering, which ones have gotten worse a year later etc?

The search for biomarkers trying to seperate ME/CFS from HC's with high precision often using machine learning techniques. This largely seems like nonsense. For example combining cortisol together with a handful of other randomly connected things to get a high separation doesn't seem like it will lead anywhere when these things haven't ever been "biomarkers" anywhere else. What is it supposed to tell us?

Another thing would be the application of tools from elsewhere without thinking about what might be happening in ME/CFS. For example there's hundreds of studies using all sorts of different cognitive tests all getting a range of different results but has the question "what do cognitive problems in ME/CFS" entail been asked?

Exercise studies claiming to study PEM but not recording how people felt before the different exercise tests, afterwards, in the days following or even asking whether "PEM" was even induced.

There also seem to be quite a few researchers working so far outside of their area of expertise that some claims in certain studies become rather dubious. More collaboration seems useful in those scenarios.

 

Using weak inclusion criteria. Not using questionnaires that measure PEM duration / Severity or crucially how easy PEM is triggered. Using ill suited outcome measures such as the Chalder Fatigue Scale which wouldn't register a permanently lower PEM threshold if baseline symptoms remained the same.

 

Doing research that produces data of low value. Not understanding the data. Misrepresenting data.

 

But people do understand and relate to sick fatigue and exhaustion that comes with, say, flu or COVID, don't they? They also understand how difficult it is to push through with even a common cold. I think the most relatable way to describe ME/CFS is "chronic flu-like sickness that gets worse after exertion".

And this is why I object to exotic description of ME/CFS with plethora of exotic symptoms in the news media. ME/CFS may be multi-systemic, multi-whatever with all kinds of neurological and functional problems, but we need a simple description of it that people can relate to.

To me, ME/CFS makes perfect sense when viewed as some sort of hypersensitivity to low-grade inflammation that triggers the sick fatigue and neurological problems. People understand allergy, so people should be able to relate to that. The actual mechanism may turn out to be something entirely different, but it still could serve as a way to communicate ME/CFS to non-patients as long as it fits the pattern of ME/CFS sickness.

 

Having the flu every now and then is sufficiently different from having ME all the time.

The flu doesn't give you delayed reaction to exertion, although the reaction can feel similar.

 

Yes, but people can relate to how lousy they felt having a flu, and how good it feels when it passes. Then you can say that ME is like having that flu for years or decades, miserably waiting for it to pass. It's not a perfect analogy, but there aren't any better ways to communicate it.

 

The acute flu is worse than my ME and obvious. My ME is insidious and, at low activity levels, causes only mild symptoms that aren't visible. It is aggravated by exertion in a delayed manner and I'm continuously learning to do less than I would like to. This leads to a lifestyle that invites negative judgments because from the outside it looks like I'm lazy, not motivated do achieve more than little, and holding back out of irrational fears and avoiding responsibilities... because after all, I look okay most of the time, and sometimes do as much as a normal person, so how bad can the ME I claim to have really be?

Others think that being able to do something once means not having limitations because they lack the experience of abnormal fatigability and PEM. They notice that I'm holding back and seem concerned and worried about doing something or doing too much, and they may decide that the key problem I suffer from is a psychological resistance to doing things. If PEM is unknown to a person, they lack the knowledge to correctly interpret the behaviour of ME patients.

It's this what is so misunderstood.

If we could show that ME patients cannot maintain normal activity levels without problems, it would help a lot.

Since my ME has improved, I'm spending more time with other people and the three main differences that can be observed are:

• They can keep going the whole day! They don't tire as quickly and as profoundly as I do. They do get tired, but remain functional and don't seem to suffer as much when tired, unlike me.
• They don't get exhausted by sensory stimuli in busy places.
• They recover well from exertion and don't have PEM. Needing to reduce activity on one day to recover from the previous day is something they seem to experience only in extraordinary circumstances, and not as badly as I do.

 

Does having the flu not feel at least similar to abnormal fatiguability? People with the flu don't feel like going for a run, or doing a lot of housecleaning. It's not identical to ME, but they can't maintain normal activity levels either.

I can't really understand your experience either. I don't have that abnormal fatiguability, or sensitivity to stimuli, and even when I had PEM, my recovery from exertion (normal fatigue) was normal. I'm not sure how we can communicate the experience of brainfog to people who haven't had that either. Yes, the experiences of ME aren't properly understood by healthy people, but neither are the experiences of migraines, ADHD, and a whole host of other conditions. I can't experience PMS or other female symptoms. If the problem of communicating that to men hasn't been solved, doing it for ME isn't going to happen either.

I agree that the misunderstanding of ME symptoms does affect research. How much ME research funding has been wasted by mistaking ME's fatigue-like symptom for normal fatigue?

 

This one particularly relates to the NIHR type nonsense, therapist-based and other psychosomatic misleading research I have seen far too much of lately trying to tell people who have been taught to switch off their empathy and curiosity to then 'fake it' (lots of reasons there including them having no idea how bad it is/they are, or worse it is just training people to carry on doing it but in such a way 'you can't get caught' ie faked it just enough you can argue that you weren't disrepectful)

I saw this one pop up on a social media reel with the following exerpt

"there is no reason to learn how to show you are paying attention if you are in fact paying attention" (3.26 in)

the video is: Celeste Headlee: 10 ways to have a better conversation | TED Talk

The list then begins at 4.25

and early in says "you want to enter into every conversation assuming that you have something to learn"

and whilst the whole list might not be exactly contextualised to understanding an illness they have misunderstood, or wish to expand their understanding of (and many don't know which of those they fall into or which pieces they think 'they know' are actually 'unknown unknowns') it has some very good points to bring people hopefully back to earth a bit.

I particularly thought the point about asking open questions that mean people give open answers is important (and shows respect and humility, and isn't 'bounding' people). I'd add in that doing this tends to differentiate the type of person you are talking to when you are on the patient side and a lot of therapists seem to be heading towards the closed survey stuff.

The catch with this of course is that someone isn't being predatory when the person answers and just looking to pick out what they want to hear or argue with out of context, when someone has gone to the effort of describing it in context often for a reason (not because they are dumb)

Another one that hit home in this was "don't equate your experience with theirs".

I'm taking this slightly into a different context here when I think of the x-type error (wish I could remember the name for it but I think it would be useful to compile a list of these) the underlies nearly all of the BACME-type misinformaiton and poor advice.

because it is based on them being a person who suffers from no illness and certainly not ME/CFS believing they can give advice on what their concept of when they were tired that one time after a busy weekend and how a cup of coffee and forcing themselves to get up at the right time helped them.

And how it contrasted with eg @PhysiosforME and their approach and why it was such a relief when they first came on the scene (and confirmed we weren't in a complete dystopia where noone heard what we said)