Studies looking at PEM - have they measured PEM or just the response to the challenge used?

[Jonathan Edwards]

Does caffeine actually reduce the mechanism of fatigue, or does it just counter the perceptions of fatigue, while the actual basis of fatigue (excess or deficiency of a chemical in certain cells) might remain the same?

But the questionnaire is not designed to test 'the actual basis of fatigue'. It is designed to elicit the symptom the ordinary people call fatigue. That may be very woolly but it gives consistent results that correlate remarkably well with the effect of a TNF inhibitor or rituximab on their biological mechanism targets.

We can be pretty sure that there are dozens of 'actual bases of fatigue', from antibody production to heart failure to TNF production. The value of asking about fatigue is that it addresses a real life problem directly - what you feel like. And the point I was making is that it does that usefully and reliably.

Caffeine reduces the feeling of fatigue so it reduces fatigue. It might have little impact on factors contributing to fatigue like TNF production, but that wouldn't make it any less a reduction of fatigue.

 

[Jonathan Edwards]

And that is what you want to measure, because doing what you need to do, not the feelings, is what matters at the end.

agree with Trish. This is completely wrong. Feeling awful matters in its own right. People with late stage rheumatoid arthritis are often very cheerful despite not being able to do much because they no longer have any nausea or fatigue and others around them see their plight and treat them as as valuable friends as they ever were.

PWME idon'thave that luxury. I would much rather be in a wheelchair with RA than have ME. And my patients would have agreed. They would often laugh and indicate that I was trying too hard to make their joints move. What mattered was that they were surrounded by a family and friends who adjusted their lives to fit them.

 

[poetinsf]

agree with Trish. This is completely wrong. Feeling awful matters in its own right.

Nobody said feeling doesn't matter. But measuring feeling just for the sake of the feeling gets into the psychology domain. And Trish's objection was about fatigue measure not capturing non-physical (read/listen/chat) ability, as far as I can tell. In the end though, it may not matter since how awful you feel will likely be proportional to your disability that stops you doing what you need to do. So the measure that properly capture your disability will also capture how bad you feel.

I did measure both over the period of a month back in 2015-16 and found R value of 0.89 between my feelings/perception score and the actual time I spent lying down. (Again, not scientific since I was both subject and observer). If that or some other physical measure generally hold, there is need to measure feelings which suffers from both drift and elasticity.

 

[Jonathan Edwards]

In the end though, it may not matter since how awful you feel will likely be proportional to your disability that stops you doing what you need to do. So the measure that properly capture your disability will also capture how bad you feel.

That sounds terribly like psychology to me.

I annoyed one of my rheumatology colleagues over the years by refusing to allow my patients to be recruited to psychology studies. The problem with psychology is not the subject matter-feelings, which do matter for their own sake - but the theorising, and pseudo-philosophising, including the idea that you cannot get reliable indicators of people's distress. The problem is that psychologists are incompetent, not that mind does not matter.

It matters a lot whether you measure objective things or subjective things, end results or indicators of process, and so on. But the right measure is different for every different circumstance. The reason for not trying to measure symptoms ME is chiefly that most treatment options are unblindable, so one needs something more objective. We have no idea of process so process markers are not much use so far.

I am very much an advocate for measuring outcome with altimetry in many practical situations, but that is not Andy's question. He asked people are really measuring PEM.

 

[Sid]

at onset, it was an instantaneous recognition that something had gone very, very wrong. Subjectively it felt systemic: deeply cellular and metabolic

You took the words right out of my mouth. This feeling was like nothing I had ever experienced and it was accompanied by a sense of something being profoundly wrong, doom. There’s no conventional vocabulary that can explain it. It’s not tiredness, fatigue, malaise, or any of this. It also had nothing to do with objective activity levels because in the early days I was still maintaining a very high step count while feeling like every cell in the body was poisoned and like I was LITERALLY DYING.

 

[Eddie]

I think we can be fairly certain that Vo2 max and other CPET measures are not analogous to PEM. If a healthy control experiences a reduction in CPET parameters for whatever reason, it seems unlikely that they are in a state of PEM.

For me PEM has always been more of a neurological phenomenon. Feeling poisoned but in a way that produces sensitivity to noise and light, ringing in the ears, headaches, pressure behind my eyes and other similar symptoms. I think if we aren't measuring something in the brain it is likely not what PEM really is. Perhaps the cause is peripheral. However, PEM almost certainly has to be changing something in the brain. Are there any studies that look at what happens in the brain during PEM? Seems like the most reasonable place to search for a way to measure it.

 

[Sean]

My first degree was in History of Art...

I think Wessely's first degree was in art history too.

I'll particularly echo the feeling of having been "poisoned". I had no prior equivalent experience of this feeling (even with a hangover in my youth) and at onset, it was an instantaneous recognition that something had gone very, very wrong. Subjectively it felt systemic: deeply cellular and metabolic. The recognition that this was something new and terrible was augmented by the immediate knowledge that nothing in medical training or clinical practice had prepared me for this possibility.

This. Both the 'poisoned' feeling, and the deep immediate recognition that something was very seriously fundamentally wrong, all happened on the first day I was sick, and has never gone away.

 

[Ravn]

As per title. Have research studies that, in theory, are meant to be looking at PEM in pwME actually tried to measure PEM or have they only measured the response to the challenge (typically CPETs) that are intended to trigger PEM? Is there a difference between this response and PEM and, if there is, can we currently say what it is?

That is one tough nut of a question @Andy. The more I think about it the more I'm struggling to disentangle everything in my mind, there are so many strands to it

Because of writing these posts I haven't been able to read this thread yet so I may be repeating what others have said

Thoughts in no particular order

We can look at PEM at the observed outcome level or the mechanistic level

For the observed outcome level, i.e. symptoms experienced and signs observed, we have a number of studies trying to measure these in various ways. On top of my head I can recall questionnaires, repeat CPETs, cognitive testing, actimetry. There's certainly room for further rigorous studies but at observed outcome level we have at least some reasonable evidence

For the mechanistic level, i.e. the underlying molecular/cellular/signalling changes, I can only think of a few studies on top of my head. Hanson's recent CPET one, the minuscule good day bad day one by Tate's team and I have a vague feeling there's another one underway (maybe by Younger?). There were probably others but the fact I can't recall them suggests their findings weren't memorable

Some of the studies could be viewed as a sort of hybrid, notably the repeat CPETs. They are clearly measuring the outcome of PEM, i.e. the inability to repeat workload on day 2. What is less clear if they also measure (part of) an underlying mechanism. They might, to some degree, if the hypothesis about an early switch to anaerobic respiration being a driver - rather than just the outcome - of symptoms is correct but the jury's still out on that one

 

[Ravn]

Complications abound

We still don't know what PEM is at the mechanistic level. It follows that we don't know how to measure something we don't know what is

There are many open questions about the nature of PEM. Are rapid fatiguability and PEF sometimes forms of PEM, on the PEM spectrum so to speak? Does PEM driven by physical exertion have the same underlying mechanism as PEM driven by mental exertion or by sensory stimulation? Some people have strong opinions on these questions but I don't think any of them are settled yet. Which means keeping the potentially different forms of PEM and PEM-like conditions separate for research purposes for now. Ideally they should all be studied so findings can be compared but this is rarely done and would require larger cohorts than are commonly available, to retain statistical power. Where large cohorts aren't possible priority should be given to clearly defined cases of delayed onset PEM, simply because the delay is the most distinctive feature, but even that is too rarely done. Often not even understood it seems to me

 

[Ravn]

More complications:

The underlying driver of PEM may in itself be asymptomatic - cue the delay in PEM - until it crosses some threshold of dysregulation where it directly triggers symptoms or indirectly triggers them by setting of some downstream cascade of other stuff going wrong

Also, the fact that the delay varies so much may be diluting any findings. If a study measures a certain molecule say at 24 hours post-exertion but participants include people whose PEM sets in at 12 hours and others whose PEM sets in at 48 hours that has the potential to confuse things. Yet it's conceivable that the rise & fall pattern of that molecule is actually the same in all cases, just more compressed in some people and more drawn out in others

I'd really like to see a serious deep-dive, even on a relatively small number of people - because costs - with very well-defined delayed-onset PEM. Take blood samples at as many time points as is feasible over the whole PEM period (plus a bit before including during the exertion period, and also after), plus urine, plus saliva, plus activity recording, plus everything else you can get your hands on while the participants are at home resting and recovering (so scans would be out). Not sure what the most suitable controls would be

Obviously a fishing expedition like this can only serve as a starting point for developing hypotheses that can then be tested but we really need data from more time points over the course of PEM than the limited data we have to date

 

[CRG]

Whenever you talk about whether something is true, it can quickly devolve into metaphysics. In science though, only what predicts, not explains, something correctly is what matters.

Prediction is a reductive of Popper, like EBM this reduction removes any significance of prior plausibility and so long as a proposition produces a predictable/repeatable result it is deemed, metaphysics or not - to be true. Simplistic prediction is fine for basic chemistry and physics but complex science including medical research is dependent on sophisticated and often opaque statistical analyis which in itself can serve as faux plausibility and which is precisely the cul de sac ME/CFS research was led into by the UK BPS school.

 

[Creekside]

Call it whatever you want, fatigue or sickness, we are talking about the same thing:

I'd prefer that they call it something other than "fatigue". There are so many different interpretations of "fatigue" that one study's measurements will likely be misapplied for someone else's interpretation of "fatigue". If a study--using questionnaires--is measuring some factor reproducibly, call it Xrqzyl, or Slognification; anything but the undefined "fatigue". Maybe the study's Xrqzyl can be applied reproducibly to some other study, and maybe it will fail to apply to some other study's "fatigue". I object to patients being subjected to harmful treatments based on a factor that can't even be properly defined.

 

[poetinsf]

I am very much an advocate for measuring outcome with altimetry in many practical situations, but that is not Andy's question. He asked people are really measuring PEM.

The conversation then predictably devolved into what PEM really is, obviously because you have to know what it really is before you can really measure it. (It's feeling! It's symptom!). It's like philosophers debating what sensation really is and then inventing a concept like qualia.

What I'm advocating is that what's important about disease in general, and MECFS in particular, is that it prevent you from living life that you want to live. If we view MECFS/PEM as a disability, then measuring the disability will measure the severity of PEM. And feelings conveniently happened to be proportional to that measure. Understanding the underlying mechanism will be required to find the solution, but that's not required in order to measure.

 

[poetinsf]

I'd prefer that they call it something other than "fatigue".

Dully noted I myself prefer to call PEM post-exertional sickness, or CFS chronic flu-like sickness. We should stick to sickness rather than fatigue.

 

[poetinsf]

Prediction is a reductive of Popper, like EBM this reduction removes any significance of prior plausibility and so long as a proposition produces a predictable/repeatable result it is deemed, metaphysics or not - to be true. Simplistic prediction is fine for basic chemistry and physics but complex science including medical research is dependent on sophisticated and often opaque statistical analyis which in itself can serve as faux plausibility and which is precisely the cul de sac ME/CFS research was led into by the UK BPS school.

Medical research predicts in the form of (testable) hypothesis. It's rather annoying to me when I see a paper that philosophize and sensationalize but doesn't propose anything testable. (MECFS as hibernation, anyone?) Or something that is no more than a correlation study and then extrapolate to sensationalize.

 

[poetinsf]

I think we can be fairly certain that Vo2 max and other CPET measures are not analogous to PEM. If a healthy control experiences a reduction in CPET parameters for whatever reason, it seems unlikely that they are in a state of PEM.

Not sure what you meant by "not analogous", but we can be also fairly certain that the result of 2-day CPET test is a manifestation of PEM. I'm not aware of any other disease, let alone a healthy control, that results in a dramatic reduction of VO2MAX the day after an exercise. I think VO2MAX reduction meets "if and only if PEM" condition. It could serve as a marker if it weren't so brutal.

 

[B_V]

Has anyone tried to measure PEM at all? Eg the NIH intramural study must have had its participants in PEM for some of the time.

Yes, intramural study tried to study PEM after CPET. IIRC, we had blood drawn before, during, 1 hour, 3 hours, 12 hours and 24 hours after the exercise. Something like that. I don't know exactly what the plans were for the blood draws...some kind of immune profiling, proteomics, etc.

 

[Binkie4]

Yes, intramural study tried to study PEM after CPET. IIRC, we had blood drawn before, during, 1 hour, 3 hours, 12 hours and 24 hours after the exercise. Something like that. I don't know exactly what the plans were for the blood draws...some kind of immune profiling, proteomics, etc.

Thank you @B_V. We look forward to reading the results when they are published.

 

[Eddie]

Not sure what you meant by "not analogous", but we can be also fairly certain that the result of 2-day CPET test is a manifestation of PEM. I'm not aware of any other disease, let alone a healthy control, that results in a dramatic reduction of VO2MAX the day after an exercise. I think VO2MAX reduction meets "if and only if PEM" condition. It could serve as a marker if it weren't so brutal.

Yes I worded that incorrectly, I think the decline on a 2-day CPET is likely to be associated with PEM in people with ME. However, I'm not convinced that a decline in Vo2 max is unique to PEM in general as you can also see declines from dehydration and detraining (obviously over a larger period of time). This doesn't mean that the two day CEPT doesn't reflect PEM just that more work needs to be done to ensure that this decline matches whatever pathology is going on during PEM. I also don't know what other conditions with exercise intolerance show on a two day CPET to determine if this decline is really unique to ME/CFS.

I also find it interesting that Systrom's invasive CPET finds abnormalities during a single test. Perhaps the lower filling pressures and left to right shunting contributes to the worsening CPET results on the two day test but does not reflect whatever drives the feeling of PEM. I wonder if there have been ME/CFS cases in which the two day CPET normalized (or was never abnormal) but the feeling of PEM remained?

 

[poetinsf]

I wonder if there have been ME/CFS cases in which the two day CPET normalized (or was never abnormal) but the feeling of PEM remained?

Havana Syndrome may qualify. It has similar neurological symptoms, but I'm not sure if it includes PEM as a symptom even though it includes fatigue. There are only a few cases, that they are called "weird ailment" rather than a disease, let alone MECFS.