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

[Andy]

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?

 

[Trish]

Can you clarify what you mean by measuring PEM?

 

[Andy]

Can you clarify what you mean by measuring PEM?

Any kind of measurement of the participants in the time following the challenge that is presumed to trigger PEM. It might be by simply recording activity levels in some way (diary form, activity trackers, etc) or be more involved with any form of biological testing (blood test, brain scans, gut microbiome tests, etc).

 

[Creekside]

I think there's a good chance that many of the studies are measuring things other than actual PEM. Someone should probably do a study measuring various factors of PEM that is triggered in different ways. For example, PEM from socializing, emotional stress, strenuous physical exertion, and less strenuous physical exertion. Measure for 4+ differently triggered PEM and see which factors correlate. It would be useful to have an actual marker for PEM.

If we had a marker for PEM, that might throw out all those studies on mice that are claimed to have ME.

 

[Binkie4]

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.

I'm sorry because I feel I should know this but it feels as if I am remembering less. PEM is so crucial.

edit: @Andy- in everyday life, it isn't always easy to know what challenge produced the PEM. For me on Fri, was it walking a few more steps than usual or was it singing along to my life music? I have no idea. Both felt great at the time but today, I have huge PEM. I may not write any more because of said PEM but will read any responses. Thanks.

 

[poetinsf]

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

I don't understand the question. What is PEM other than the response to the "challenge" of exertion? 2-day CPET only measures VO2MAX the day after, true. I don't think you can do more than that without virtually killing the patients. I suppose they could do 6MWT throughout the following days, but I don't see that showing anything that 2-day CPET haven't. I think some biological tastings have been done, like looking at lactates and cytokines, but nothing turned up. They also did muscle biopsy, but they didn't find any damage.

 

[Jonathan Edwards]

I have three thoughts about this.

The idea of 'measuring PEM' is quite complicated. You might measure something that actually reflects symptoms - maybe spontaneous activity. You might also measure something that you think might be responsible for the symptoms - like a cytokine on a blood test. You might measure something that reflects the cause but is not responsible for the main symptoms - like some change in muscle chemistry. And you might measure something that reflects accumulated past change but is a red herring in terms of the process of PEM production at the time.

I think there might be a good argument for deliberately trying to establish what is normal despite the occurrence of PEM. Either induce PEM or wait for it to occur and then look for what is normal despite the symptoms actually being there. I am not too happy with exercise studies that claim to be studying PEM because the subjects may report some degree of feeling worse that will tick a PEM box but I think the interest is only in subjects who feel really awful - maybe too awful to have tests done.

Linked to that, I would like to see people with PEM studies under complete rest - despite feeling awful. I would like to see a comparison of several measures during a period of relative stability and then a measure in complete rest despite symptoms of PEM. Normal measurements at that time would indicate things that were not the cause of feeling awful and also things that were not influenced by whatever did cause it. Normal pulse rate, muscle oxygen or lactate content, blood flow, CRP, creatine kinase or whatever would tell us that the symptoms were due to something else.

The power of negative data on what stays normal is greatly underrated.

 

[Jonathan Edwards]

What is PEM other than the response to the "challenge" of exertion?

I think the point is that there may be a variety of responses, and, as indicated above, some may relate to the symptoms PEM and others may not. A recent study claims to show muscle necrosis in Long Covid cases after exertion. But PEM in ME isn't local muscle pain. Historic 2 day CPET tests showed reduced O2 consumption during further strenuous exercise, but PEM is something that occurs at rest some time after exertion. The changes in O2 consumption might reflect a shift in muscle response to injury programmed over months by having ME but nothing actually to do with the process that generates PEM.

 

[poetinsf]

PEM is something that occurs at rest some time after exertion.

If you meant feelings by "at rest", I'll have to say, at the risk of being repetitive, feelings aren't something we can measure. Fatigue, or worsening of it, is something that can be measured only by its physical effect on you. If you meant something physiological, nothing has turned up so far, as far as I know. Looking at the blood or muscle is a low hanging fruit; plenty of that has been done already, I would think.

The changes in O2 consumption might reflect a shift in muscle response to injury programmed over months by having ME but nothing actually to do with the process that generates PEM.

CPET test had similarly deconditioned subjects as control. If you meant some sort of damage from just having MECFS, that would be a pure speculation.

 

[Jonathan Edwards]

If you meant feelings by "at rest", I'll have to say, at the risk of being repetitive, feelings aren't something we can measure. Fatigue, or worsening of it, is something that can be measured only by its physical effect on you.

You have obviously not been involved in much clinical research. Rheumatologists have been measuring fatigue for decades. It is not measured in physical units, for sure, but it is reproducibly quantified. The idea that you cannot use feelings for scientific research is a pet idea of philosophers of science who don't know much about science!!

If we did not have subjective sensations like sight and hearing there would never have been any science at all. My first degree was in History of Art and I have never forgotten how much more rigorous the connoisseurs were than biomedical scientists. Mistakes were more costly.

 

[poetinsf]

The idea of 'measuring PEM' is quite complicated.

Measuring (the severity of PEM) should be quite simple: just measure your symptoms, not causes, post-exertion and then compare it with pre-exertion. Now, investigating what PEM really is entirely different story and what you are suggesting pertains that. But then, that could be what Andy was really referring to rather than just measuring the severity.

Normal pulse rate, muscle oxygen or lactate content, blood flow, CRP, creatine kinase or whatever would tell us that the symptoms were due to something else.

Hasn't this been done already? Despite recent studies indicating anomaly (like the muscle study which I'm highly skeptical of), no abnormality really stuck over the years.

 

[Jonathan Edwards]

CPET test had similarly deconditioned subjects as control. If you meant some sort of damage from just having MECFS, that would be a pure speculation.

I don't think we have any evidence for controls being 'similarly deconditioned'. All we know for some studies is that controls were relatively inactive individuals too. I think it is very plausible that the limitation of activity in PWME iso a very different sort from people who just do not do much. PWME that I know from committee work are permanently judging their activity and working with certain limits. People who don't do much may well do something strenuous now and again.

So, for sure, the idea that CPET results might be the result of accumulated physiological change is speculative but so is everything here, and there is actually as much logic to there being an ME specific shift in muscle fibre structure a anything.

 

[Jonathan Edwards]

Measuring (the severity of PEM) should be quite simple: just measure your symptoms,

I thought you said we couldn't do that!!

But then, that could be what Andy was really referring to

I think Andy was opening up a very important and complex discussion.

Now, investigating what PEM really is

But that gets back to the semantic confusion - whether 'really is' refers to the causal process or the clinical state. This is the oldest chestnut in clinical science.

 

[Jonathan Edwards]

Hasn't this been done already? Despite recent studies indicating anomaly (like the muscle study which I'm highly skeptical of), no abnormality really stuck over the years.

Studies were done in the 1980s, many by close colleagues of mine - Richard Edwards, who was my chief at the time, Joan Round, David Jones and Di Newham. We worked on the same floor in the Rayne Institute in University Street London WC1. Jo Cambridge (who now works on ME) and I even got involved in some collaboration - she was an expert on dermatomyositis in those days.

But a lot of people have been critical of the work in Richard's group - partly because he made it clear he thought CFS was all psychological. I think some very good work led to negative data but it is pretty hard to find the sort of reliable evidence base we want. MR imaging was done but I am not sure how much actually on CFS.

I do tend to agree that if something obvious was to be found it might well have been found but the old studies are rarely cited now and I am not sure they were as exhaustive as one might think. I have no idea what patients were used since the hospital had not CFS or ME specific service at the time. Goodness knows if they had ME as we now understand it.

 

[poetinsf]

Rheumatologists have been measuring fatigue for decades. It is not measured in physical units, for sure, but it is reproducibly quantified.

Can you elaborate on that? If you are talking about fatigue surveys asking feelings, we have different opinions. Feelings suffer from sensation drift that may change over time; they may be reproducible in a short term, but may not be in the longer term. And that is why I gave up on the feelings measure in my work.

If you are referring to something else, maybe we are talking over each other's head.

If we did not have subjective sensations like sight and hearing there would never have been any science at all.

I'd love to talk about metaphysics, but that would be off topic, I'm afraid.

 

[Jonathan Edwards]

Can you elaborate on that? If you are talking about fatigue surveys asking feelings, we have different opinions. Feelings suffer from sensation drift that may change over time; they may be reproducible in a short term, but may not be in the longer term. And that is why I gave up on the feelings measure in my work.

Rheumatologists mostly use visual analogue scales for fatigue. And for drugs like TNF inhibitors and rituximab for diseases like RA you get slam dunk reliable shifts in cohorts. The bar charts can be predicted from the pharmacology, as I pointed out in what was billed as the most expensive patent case in the history of the drug trade - which the side employing me won.

There is no doubt that you have to use VAS with care. Subjects need to be trained repeatedly on how to use them and there are systematic biases that show up in unblinded trials like a sore thumb. But under adequate blinding the reproducibility shows through very clearly. In ME, fatigue scales were used in the blinded phase II rituximab study, the unblinded extension and the blinded phase III. The blinded studies showed consistently no effect. The unblinded study showed a huge apparent effect. But that is part of the methodology that needs to be taken into account.

I'd love to talk about metaphysics, but that would be off topic, I'm afraid.

Don't be shy. We have had discussions of Leibniz, Dennett, Descartes and more on these threads. My 'day job' is writing about the biophysics of phenomenal perception in the context of metaphysics and philosophy of mind.I am currently writing a paper on possible psychophysical laws linking dendrite length proportions to primary and secondary quality percepts. Maybe it should go on another thread but the fallacy of not being able to measure subjectives is very relevant to Andy's query here.

 

[poetinsf]

PWME that I know from committee work are permanently judging their activity and working with certain limits. People who don't do much may well do something strenuous now and again.

I'd agree with that. From my own experience in recovery, I could testify that deconditioning in PWME is at another level. If the degree of deconditioning is the question though, they could always use other patients, like COPD or MS, as the control.

 

[Trish]

I'd like there to be more longitudinal studies that follow patients over a year or more, with continuous monitoring of everything that can be monitored using wearables. That includes motion/steps, heart rate, HRV, and any biochemical wearables like glucose and sweat. Also daily record keeping using an app of symptoms and activities, mental, physical, social, emotional, and symptoms. Ideally it would also include say a weekly visit to take blood and urine samples which sometimes over the year will coincide with PEM and sometimes without.

All we have at the moment is either retrospective accounts of what PEM feels like, and 2 day CPET and other methods for inducing PEM. The large study led by Maureen Hanson and the Workwell people's studies have done biomedical testing with blood and urine sampling before and after, and keeping records of how long patients take to recover to pre exercise challenge severity level.

 

[Kitty]

PEM is something that occurs at rest some time after exertion

My experience: that's quite true to the extent that I'm no longer doing whatever caused the reaction. I'm at rest from that.

But I'm not at rest in the way I would be without the PEM. I'm fidgety, I can't focus, I can't sleep, and I need to visit the loo every 20 to 30 minutes. There's an all-over tension that seems to be in the smallest muscle fibres, which isn't under voluntary control.

I realise that's not what you were getting at, but some types of PEM, at least in the first 24 to 48 hours, are definitely a state of unrest. It might not be very complicated physiologically (some kind of overstimulation), but it's part of the pattern.

 

[poetinsf]

I thought you said we couldn't do that!!

Only if you equate symptoms to feelings.

I looked at VAS, and it is no different that the 1-9 scale I've been using. It still suffered from perception drift over the years when it comes to fatigue. The key was to anchor the middle and never change it, I found. It's much easier said than done, I'm afraid.