Post-exertional malaise in daily life and experimental exercise models in patients with [ME/CFS], 2023, Vøllestad and Mengshoel

[Hutan]

Yes, but that study was self-reported symptoms. And we all know that GET proponents and the people who believe them only consider reports of improvements to be worth listening to, not reports of harm. And, honestly, even I have some doubts about the accuracy of the reports in terms of them being a measurement of the impact of the CPETs.

I have participated in a 2 day CPET study (2 days between tests, not 1 day though). I really had no idea how long it took me to recover, and the instances of what I call PEM were quite short. Things were greatly complicated by the effort involved in getting to the study site (it involved a plane trip) but also by the fact that I was staying away from home and so wasn't doing my usual activity (I did quite a lot less while away). And then I had more to do when I got home after the second CPET, catching up on housework. I guess that is part of the reason why I think a residential study where people are required to do a standard number of steps for a day, where other activity is also standardised, and where people are in that environment for days before, during and after the exercise is necessary.

 

[Kitty]

I guess that is part of the reason why I think a residential study where people are required to do a standard number of steps for a day, where other activity is also standardised, and where people are in that environment for days before, during and after the exercise.

A slightly idle thought, but it's a shame some researchers can seemingly accept patients' reports of how they feel, but not their advice on what would be likely put them into an uncomfortable (but not extremely high-risk) level of PEM on a given day.

If we could do that, we wouldn't need everybody to go somewhere and do all the same things for some studies. Almost anyone who's been managing ME for two or three years will be able to come up with something that will provoke the PEM response the researchers need, and they will do it more accurately because they know better than anyone else roughly how far into their energy overdraft they are.

It doesn't seem much less scientific than failing to account for people having endured travelling varying distances, time-spans, and levels of comfort to get to a centre.

 

[Ravn]

I guess that is part of the reason why I think a residential study where people are required to do a standard number of steps for a day, where other activity is also standardised, and where people are in that environment for days before, during and after the exercise is necessary.

A residential study to control as many factors as possible would be ideal. However, rather than doing 3 or 4 or 5 CPETs in a row I think a safer option would be to stick to 2 but do a heck of a lot more testing at many more time points. In a residential setting you could draw blood every hour or two, maybe less often at night, plus collect urine and saliva and do some very small cognitive test, say a reaction time test every 4 hours, etc etc
Doing this after day 1 and day 2 should give us enough of an inkling of where to look further re cumulative exertion.

Another reason I wish many more tests would be done per CPET performed is that it would reduce the number of pwME put at risk. At the moment one cohort does their CPET and 1 or 2 things get measured at 1 or 2 time points, another cohort has a couple of different things measured, a third cohort... you get the picture, and then any finding from any of the cohorts has to be replicated in yet more cohorts. Would be better if all those different things could be measured in the first cohort, using cohort 2 and maybe 3 for replication if anything really significant was found in the first and you wouldn't need all the others after that to go through CPET as well

on what would be likely put them into an uncomfortable (but not extremely high-risk) level of PEM on a given day
[...]
It doesn't seem much less scientific than failing to account for people having endured travelling varying distances, time-spans, and levels of comfort to get to a centre.

I've wondered that, too. The current protocol is supposed to deliver a standardised dose of exertion but in reality that's unlikely to be the case so the outcome is, potentially, a very different level of PEM for different individuals. I don't know how that affects results compared to instructing experienced patients to put themselves into their minimum level of PEM

 

[Andy]

I understand why they are used but the problem with standardised doses of exertion in research of pwME is that different levels of exertion will have different effects, depending on how seriously, or not, each participant is affected and their normal activity level. Particular towards the mild end, there is potential for huge variation in activity in individuals.

In order to get the cleanest results the participants would need to be assessed for a period in a normal setting - at least number of steps per day, activity logs, 24hr heart rate monitoring, as well as getting baseline results for anything else that will be measured during the testing phase.

 

[Kitty]

I don't know how that affects results compared to instructing experienced patients to put themselves into their minimum level of PEM

I wouldn't suggest a minimum, it'd be too difficult to gauge. They'd need to aim for the upper half of the amber zone whilst trying to stay out of the danger area.

The protocols used in many studies are likely to put some patients into the red zone even if it wasn't intended; they're doing a structured set of activities different to what they'd normally do, and some will feel a strong incentive to complete them. A few of us have talked about unfamiliar patterns of muscle use having an order of magnitude more PEM potential than things we're used to doing. No one knows how common it is, but it's a reasonable enough proposition that it should be considered.

Of course it's unrealistic to have a study where people do their PEM-provocation unobserved at home, but it might be realistic to take their advice on what is most likely to provoke it reliably but safely. If it's acceptable that none of them can start the study with the same level of energy and quality sleep debt, it ought to be acceptable that differing levels of effort can be used to trigger their PEM.

 

[bobbler]

I understand why they are used but the problem with standardised doses of exertion in research of pwME is that different levels of exertion will have different effects, depending on how seriously, or not, each participant is affected and their normal activity level. Particular towards the mild end, there is potential for huge variation in activity in individuals.

In order to get the cleanest results the participants would need to be assessed for a period in a normal setting - at least number of steps per day, activity logs, 24hr heart rate monitoring, as well as getting baseline results for anything else that will be measured during the testing phase.

I'd add in having a 'control group' who just do 'everything but the CPET' ie so that the journey, sitting around, questions and finding building etc exertion are factored in, as well as the set an alarm to be somewhere the next day stuff. And make sure they underline that isn't 'a control' like a control for those who were healthy would be therefore but just a sense of the exertion from logistics and so on. But I guess if that is where they are taking the baseline measures then that is the baseline. Which is a bit of a potential issue for certain measures I can imagine.

I can't think of a way that our environment can be that well controlled (building work, knock on door, whatever meaning the night's sleep is a bust) that there wouldn't be a need for logging so that the cumulative factors are at least there when they are trying to work out some strange patterns. And I'm not sure making something residential wouldn't add strain from not being in your own bed and set up etc.

The neatest thing I liked this year was the piece of research a few months ago which had Bateman Horne involved I think where they used time with feet down (or something similar) as a measure. And said it was one of the measures that correlated best. I mention this because it could be one of the neater ways to correlate whether some cut down on other exertion for the time period of the CPET vs the weeks before and who has gone into it with PEM about to hit from something two days before or cumulated load from those prior weeks etc.

If the aim is to focus on the 'once triggered, what happens' phase that is all very well but they will need a sense of what could be variable inputs contributing to different triggers at different timings when looking at the data patterns.

 

[Mij]

I've said it before, but I would really like to see a proteomic study with multiple CPETs (more than 2, maybe 5, one per day ) done in people with relatively mild ME/CFS (with very careful control of activity levels before and between the tests, and frequent testing of blood and reaction time .I've said it before, but I would really like to see a proteomic study with multiple CPETs (more than 2, maybe 5, one per day ) done in people with relatively mild ME/CFS (with very careful control of activity levels before and between the tests, and frequent testing of blood and reaction time.

I'm sorry but I don't agree with this. When my improvement reached 90% many years ago I would have considered myself 'mild' and I didn't experience OI. Any type of continuous activity or mild exercise over the course of more than 2-3 days brought on uncomfortable symptoms, not so much PEM, but it was 'building" when I wasn't aware whether it would start. I feel we don't need to go beyond our limit to measure PEM? Not sure.

When you say blood levels, what levels are you referring to? Lactate? My lactate levels during PEM 'normal'.

 

[Andy]

I feel we don't need to go beyond our limit to measure PEM?

I think that most of us identify PEM as being something that occurs when we have gone beyond our limits, so it would be hard to study PEM without doing so.

 

[Mij]

The process of measuring PEM might start even before we actually feel the delayed symptoms.

I don't know what they are measuring exactly.

 

[Mij]

The Workwell Foundation measured a high functioning M.E female athlete before and after she trained for a marathon for six months. Her results showed her functioning level was lower and yet she didn't experience PEM that I'm aware of or she wouldn't have been able to train and run the marathon.

So in her case there was a process that led to her final results.

 

[Andy]

The process of measuring PEM might start even before we actually feel the delayed symptoms.

The process of measuring what ends up being up PEM when we go beyond our limits certainly could start before the patient participants experience symptoms, but without evidence that the process ends up being PEM then claiming the process is PEM could well be misleading.

The Workwell Foundation measured a high functioning M.E female athlete before and after she trained for a marathon for six months. Her results showed her functioning level was lower and yet she didn't experience PEM that I'm aware of or she wouldn't have been able to train and run the marathon.

So in her case there was a process that led to her final results.

In most case definitions of ME/CFS, PEM is a required symptom. I'm not sure there would be much benefit in studying this athlete for those of us who do experience PEM and who can't run marathons.

 

[Mij]

 

[Mij]

In most case definitions of ME/CFS, PEM is a required symptom. I'm not sure there would be much benefit in studying this athlete for those of us who do experience PEM and who can't run marathons.

I agree, but I'm assuming this athlete's health improved just like mine did when I didn't experience PEM for the first 10 years of illness. She thought she could retrain herself but it made her 'worse'. There is no mention of PEM symptoms in her case though so not sure.

 

[bobbler]

I think that most of us identify PEM as being something that occurs when we have gone beyond our limits, so it would be hard to study PEM without doing so.

And indeed I agree that most never get adjustments (maybe with the exception of the odd good year) that mean they aren’t above their limits - cumulatively at least over a week or many weeks - just by their standard commitments /life.

such as work (pretty rare to be able to get adjusted hours or commute or avoid walks between buildings or peak times when you’ve an illness where you are trying to explain payback and cumulative rather than v it doubly can’t).

I do think doing one each day for five days is pushing it as in real life you end up desperately sneaking in naps or having to go home ill when you have that in natural setting. And because it’s that lack of break and recovery I think is the most permanently damaging va a one off PEM you might get some way to resting off

 

[bobbler]

The process of measuring PEM might start even before we actually feel the delayed symptoms.

I don't know what they are measuring exactly.

The issue we have there is I’m not sure I could reliably produce ‘rested’ even if I was mild. Because of things impacting sleep and so on. So without being able to differentiate ‘no residual or cumulative PEM’ then I think it would need something that definitely did do ‘enough PEM’ we knew we were measuring something different as milder must be a pig for many to get to know where you stand with whether you body is ok or over-threshold’ etc


I’m not keen on the constant re-triggering after a big exertion though from a safety perspective. But on the other hand that’s what natural environments like work are doing at which point the ethics of just monitoring that become the opposite because it’s checking/showing whether what someone is made to do anyway is safe.

 

[Trish]

The Workwell Foundation measured a high functioning M.E female athlete before and after she trained for a marathon for six months. Her results showed her functioning level was lower and yet she didn't experience PEM that I'm aware of or she wouldn't have been able to train and run the marathon.

So in her case there was a process that led to her final results.

I think we need to be very careful not to misquote what he said. I've just listened. He says she had previously been a marathon runner before she got sick. When she got sick she did their CPET testing. Then she spent six months doing aerobic training, needing to cut out a lot of other activities to do the training. He doesn't say she didn't suffer PEM as a result of the training, nor that she was able to run another marathon. He doens't specify what the training involved, but it was some sort of aerobic exercise. It might have been quite short bursts with lots of rests and lots of crashes. Her aim being to increase her aerobic fitness. Then when she was retested after 6 months, she was less aerobically fit.

 

[Andy]

I agree, but I'm assuming this athlete's health improved just like mine did when I didn't experience PEM for the first 10 years of illness. She thought she could retrain herself but it made her 'worse'. There is no mention of PEM symptoms in her case though so not sure.

I'm of the opinion that basing research strategy on individual anecdotes or assumptions, especially when they run counter to the experiences of so many other people, is not what we need to do at this time. If PEM is to be researched, and it should be, then lets research PEM, then we can understand what 'pre-PEM' looks like. We don't need a partial job done - stopping before PEM could potentially lead to some unhelpful assumptions being made and precious research funding being wasted.

 

[Mij]

Back to Hutan's suggestion, pushing pts through multiple days of CPETs might just be the nail in the coffin for a 'highly functional" "mild" M.E over time. I'm not in agreement with this. We don't know why some recover from EBV/viruses and lose stamina over time but don't develop M.E/PEM while others do.

Early in the illness there was a period of time when I had PVFS with delayed symptoms, 7-8 years to be exact, over time it developed into M.E/PEM. Was this the result of exercise, recovering and continuing the cycle? Or is there a genetic component, an early indicator, an 'off switch' that occurs early on and predicts the end result of lowing aerobic threshold before delayed PEM symptoms are reached?

 

[Andy]

We don't know why some recover from EBV/viruses and lose stamina over time but don't develop M.E/PEM while others do.

So how do you then suggest we study it?

Early in the illness there was a period of time when I had PVFS with delayed symptoms, 7-8 years to be exact, over time it developed into M.E/PEM.

Please could you describe how "PVFS with delayed symptoms" was different to "ME/PEM"?

 

[bobbler]

I think we need to be very careful not to misquote what he said. I've just listened. He says she had previously been a marathon runner before she got sick. When she got sick she did their CPET testing. Then she spent six months doing aerobic training, needing to cut out a lot of other activities to do the training. He doesn't say she didn't suffer PEM as a result of the training, nor that she was able to run another marathon. He doens't specify what the training involved, but it was some sort of aerobic exercise. It might have been quite short bursts with lots of rests and lots of crashes. Her aim being to increase her aerobic fitness. Then when she was retested after 6 months, she was less aerobically fit.

indeed I read into this that as an experienced marathon runner said person would indeed have been getting PEM but perhaps pushing through it and trying (just like all the ‘can’t accept exercise and bullying/‘coaching’/msnipulation isn’t the cure gang ) every which way as an ‘adjustment’ each time it didn’t work eg ‘maybe I just need to increment more slowly’ and all those other kind-tricks of maybe I’m feeling awful because of other things.

all that story spoke to me on is how it takes years and years for even those with the condition to go through that process because the world and ourselves is so fixated on these ideas so you think you can cheat it. And the best you get is done really wonky lifestyle you both have to hide from others and is ‘sustainable’ only in the sense you can appear gif the big you needed to whilst everything else is sacrificed and in pain (exhausted evenings, weekends, annual leave to do it). And you still are just getting slowly worse riding that tightrope.

it’s a framing that mightnt emphasise PEM explicitly - and indeed until it became well-defined recently if people tried to say they couldn’t wake up for three days after one big x for a few hours people just taunted them so they couldn’t get that language and insight right etc

so I think you’d need far more to say ‘not PEM’ from historical testimony for that reason too