Preprint A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome 2023 Stussman et al

Background
A central feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM), which is an acute worsening of symptoms after a physical, emotional and/or mental exertion. PEM is also a feature of Long COVID. Dynamic measures of PEM have historically included scaled questionnaires which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semi-structured qualitative interviews (QIs) at the same intervals as Visual Analog Scale (VAS) measures after a Cardiopulmonary Exercise Test (CPET).

Methods
Ten ME/CFS and nine healthy volunteers participated in a CPET. For each participant, PEM symptom VAS (7 symptoms) and semi-structured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each patient. QI data were used to determine the symptom trajectory and peak of PEM. Performance of QI and VAS data were compared to each other using Spearman correlations.

Results
QIs documented that each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time, and most bothersome symptom. No healthy volunteers experienced PEM. Scaled QI data were able to identify PEM peaks and trajectories, even when VAS scales were unable to do so due to known ceiling and floor effects. QI and VAS fatigue data corresponded well prior to exercise (baseline, r=0.7) but poorly at peak PEM (r=0.28) and with the change from baseline to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=.0.77, 0.42. and 0.54 respectively) and reduced the observed VAS scale ceiling and floor effects.

Conclusion
QIs were able to capture changes in PEM severity and symptom quality over time in all the ME/CFS volunteers, even when VAS scales failed to do so. Information collected from QIs also improved the performance of VAS. Measurement of PEM can be improved by using a quantitative-qualitative mixed model approach.

https://www.medrxiv.org/content/10.1101/2023.04.24.23288821v1

 

I doubt that qualitative interviews of vague symptoms qualifies for two decimal point precision in their results. I think my judgement of my PEM symptoms was coarser than single digit precision.

 

I agree that studying PEM properly needs to be one of the priority areas. And definitely that it needs to be for more than 3 days (particularly as I can't imagine a set-up where all paricipants might be guaranteed to not have PEM re-triggered at some point e.g. from noisy or uncomfortable set-up). I don't think that just measuring activity is good enough however for it. I've had to be forced up doing things whilst in PEM so much over my life and I think focus on behaviours really doesn't cut it. And where it does measure these contextualising them and measuring the intensity is pretty important (e.g. someone might power through for a bit then crash out really hard).

Such a hard job I guess, but important that it isn't ducked because it needs to be filtered down to 'the measure' really.

The issue is, how on earth we measure the 'illness' aspect of it given how both ill we are in it and how even just writing or describing (and thinking to do so) would in itself be exertion of the person in PEM. I'd quite like to see some small-scale exploratory stuff - which is why I liked the heart-rate in the home type stuff - that works out maybe what kind of physical measurables like breathing gases, heart rate, bloods and blood pressure, foot raising, inability to sleep due to pain or discomfort and so on, how on earth PEM might be identified and described and even we can not when it has ended/passed. Just see if there are cycles and changes in these things that plotted over the ;enght of a PEM episode might help to show what it is/is going on.

And yes I sort of don't mind exploratory using interviews etc but get a bit concerned if scales or leading questions rather than qualitative are being used if these haven't been heavily informed by prior exploratory research to make sure that list is actually complete and good and relevant. I want to see PEM defined well and worry we could easily end up red-herringed when it begins with a scale or a list and of course the same underlying thing going on sort of might result in different symptoms in different people or not.

 

Yes. I am going off memory here, but after the CPET, I had blood work done at 1 hour post, 4 hours, 12 hours, 48 hours and 72 hours. Something like that. The blood work was done at the same time as the structured questionnaires.

 

Also, these are the final numbers of patients screened for the NIH Intramural study:

"Study recruitment occurred between December 2016 and February 2020. Of 484 ME/CFS inquiries for NCT02669212, 217 individuals underwent detailed case reviews, 27 ME/CFS and 25 HVs underwent in-person research evaluation. Of these, a subgroup of 10 participants with ME/CFS and 9 HVs completed the CPET experiment. All ME/CFS participants met 2015 IOM ME/CFS criteria and were determined to have ME/CFS by a panel of clinical experts by unanimous consensus. Additional recruitment was terminated due to the COVID-19 pandemic. The study was approved by the NIH IRB. Informed consent was obtained from all participants."

I know a lot of people annoyed that the screening was so rigid.

 

We already spent a loooooooooooooong time at the Clinical Center. Longer followup would've been nice but I was happy to get out when I did and fly home.

 

I hope that didn't come across as a 'you should have' , but it is useful to contextualise any methods or results whatever the subject area in the spirit of wanting to one day put the big picture together of these things.

That's why I said it is a difficult job: PEM's going to be a tricky one to measure directly but building up that picture is very important to some day get there and put these pieces that might need to come from different angles together.

And probably there are lots of exploratory parts to putting the picture together, and the heartrate in the home type thing is interesting because even just being out of one's home environment with everything set-up to minimise exertion (including eccentric bed layouts, really little things etc). I'm not sure I could properly, fully recover from a large amount of PEM until I got to my own bed.

But all far better than the past approach of people trying to 'reframe' the condition or simplify things so we ended up with fatigue scales etc.

 

I didn't take it that way. I still think 3 day followup with bloodwork is very valuable. Sure, longer would be better, but PEM is almost always triggered within 72 hours.

 

I still disagree. It would be like an in vitro test for sneezing: it's unlikely to lead to a dramatic new understanding of colds, or a treatment that reduces sneezes (but not the other cold symptoms). Yes, a treatment for sneezing or PEM would be appreciated by those suffering from that, but it doesn't solve ME. Solving the core dysfunction of ME solves all the ME symptoms.

 

Yes, but that's just one possibility for a test for ME. A test for ME is an important goal; much more important than a test for just one ME symptom. A test for PEM might not be the easiest route to a test for ME. A qualitative test for brainfog or lethargy might be even more useful for ME, and also useful for other diseases.

I admit I am biased, since I no longer suffer from PEM. The fact that I have ME without PEM means that PEM is a downstream effect of ME, rather than a core part of it. Also, a test for PEM wouldn't work for me, and neither would a new treatment. Increased brainfog and lethargy were main symptoms of my PEM, and those symptoms didn't vanish when I didn't have PEM. I'd definitely vote for studying brainfog or lethargy rather than PEM.

 

and that we don't know what symptoms are 'rolling PEM' or being above threshold in the 'perform but don't do yourself much good' zone vs are what .. constant something or other .. unless we have a way of really knowing when PEM actually ends. For all we know, as we eventually even if just for our own sanity have to get up and start doing when PEM has relieved to a certain point (if we could or did rest in the first place), PEM could continue a lot longer in the body that we think and we are just distracting ourselves from it + the nature of it being long-term and all the usual challenges means we've no idea what normal feels like anymore.

I mean there is a big difference in how someone moderate who might have just had 9 days solid in bed as a planned recovery-break feels on that first morning they wake up naturally and following how their body feels only do what they know they are up to, and how we feel when we just aren't over-threshold or in PEM but plugging on.

And that sort of matters for research when there has been some implicit bar of homogeinity inserted into methodology and results that say 'x% should all show the same things/differences' to know who is 'pre-PEM over-threshold' who is 'in PEM (and know it)' who is 'in the trails of PEM/after-affects' vs who is 'rested'. Given all these things are reactions to exertion so might involve certain measures going in different directions to each other.

I slightly wonder about over-arduous conditions that are lab-based when measuring PEM, because I have a question (a real one - genuinely putting it out there as I don't know) about whether when you've overdone it, but aren't in a position where your body can rest e.g. above threshold but can't yet 'down-regulate' or body is in 'up-regulation' maybe because you've really overdone it and it needs to rest to rest, or maybe because you are somewhere that is antagnoising you with discomfort or still having to exert. Well then is that PEM yet, should it be noted as a different stage of 'PEM' but noted separately because it might show different features?

 

A new title came up on my alert for this paper:
A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome

They seemed to have dropped the ‘myalgic’ all together.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187342/

Here is a screenshot.