Evaluating case diagnostic criteria for ME/CFS: toward an empirical case definition, 2022, Conroy, Jason et al

I don't really understand what this paper is trying to do.

Diagnostic criteria are designed to distinguish people with a condition from those without it. To judge the usefulness of criteria you presumably need to look at both groups and see what the sensitivity and specificity is.

As far as I can see this paper makes use just of people who not only have a diagnosis but have responded to questionnaires etc.

Diagnostic criteria do not necessarily bear any relation to a description of 'typical case'. They relate to discriminating features. These might be trivial. For instance, Reiter's syndrome can be diagnosed reliably by the presence of skin changes on the soles of the feet that may not even have been noticed by the patient.

 

Ironically, PEM is perhaps/maybe more unique and obvious when ME is milder - because you don't have the lack of function day-to-day/same symptoms all the time in the same way? I can't be sure as I try and think about it. However such people are also like to be in situations where they aren't 'resting' or 'low activity' so actually have rolling PEM - which is a situation that is very very hard to spot certainly in yourself. I'd say inability to wake up for 2 weeks barring the odd strangely lazarus few hours at probably weird times in the middle of people 'trying to keep up and be normal or not upset normal people they are with that want to understandably do normal things' is kind of the red flag.

It's terrible that the cardinal symptom hasn't yet been probably unpicked and understood across the various populations - Workwell has done a great job on proving it and physiology - I think that potentially these guys might do better taking a set defined by Workwell (and some severe they wouldn't dare put through it but more obvious) and doing some ethnography to really hone how PEM 'shows'.

By that I mean - when 'experimenting and being defined' ie once someone actually thinks they have PEM and tests it, and ALSO 'in daily life' ie what is the initial presentation going to likely look like that makes the former 'worth a try'?

If we can get rocking and rolling on that it would make an extraordinary difference to people's lives. Goodness knows what I wouldn't have had to go through if that had been nailed, or someone wanted to listen and didn't think what I described 'made no sense' to them and sounded whatever.

 

i don't understand the first paragraph [cognitive issues] but the sleeping for 2 weeks thing popped out at me.

i never connected this with m.e. or pem but fwiw:

As a teenager, for two weeks, I had to sleep 23 hours per day, with no oher correlated symptoms. Could not stay awake. I was fully awake and normal for 1 hour each day. I ate then.

There was no sleepwalking, altered behavior, or altered mood. It did not recur. It was in an infirmary at a location where i lived in a dormitory. Nurse diagnosed mono. Is this Kleine-Levin? Is this a possible mono symptom?

 

I've tried an amend on first para - but let's see whether I've made it better or worse lol!

That is for me glandular fever and ME the hr a day. I don't know on KL but haven't failed to notice the similarities in certain ways (though I don't think that comes with any of the other symptoms I also have/had). DO wonder whether it would be worth a similar researcher from K-L exploring - I don't know whether it has been not explained well enough to drag them in based on the similarities?

I remember over the years, and certainly when I knew I had something like ME Kleine-Levin being on he TV with documentaries and wondering what my family's response would be (let's just say the sleeping bit has been a major thing for individuals, I think that is upbringing-related for them rather than ME). I suspect they came to a similar journey as I. It was the closest thing I'd seen to what I had. But the documentary seemed to have to try and wake the kids (in the doc) up for their hour a day and they seemed out of it, whereas the strangest thing was - certainly back over most of the years I've been ill - is that there was nearly always an hr where it was like awake and great.

Of course not many conclusions to come to from there given it could have been that the parents were waking them - maybe for the film, maybe because they'd been told to and indeed if I'd been treated in that way would have been similar. Vice versa who knows if they were left whether they'd have naturally had a good hour at a really awkward time?

The other distinctive difference was that according to the documentary it seemed to have specific 'cycles' like 'every 6 weeks for 2 weeks solid'. Of course looking back at my last 'throws' when trying to sustain work whilst poorly I was booking a week off every 6-7 weeks. I'd make it to that 7th week if schedule meant it wasn't precise it was my physical body screaming out on me as I forced it through. And the more ill I was the more I was 'in pain' and unrefreshing sleep for several days before it became refreshing and deep. The impression I was given from the documentary was that the cycle for K-L was clockwork and just 'switched them off' sort of thing.

 

I think that these phenomena are exactly the things that someone like Jason should be studying, unbundling and describing - hopefully then with business-like nomenclature for each of the different types (by which I mean like the business literature trying to find a 'does what it says on the tin' term that would catch on and not get manipulated by BPS into somethng that means something that isn't a real symtpom - like when they try and rename PEM into post-exercise tiredness of fatigue, as if we don't realise normal people get that for a little bit to a little extent to and will read this as bunch of whingers).

I reckon some of these exact things vary within and across individuals. I'd say unrefreshing sleep is a key indicator I've been doing too much over time. Whether that is the 'cumulative PEM' where you either can't name an incident or special day or are just rolling it because you've no choice and then slowly get more and more treacly.

I get immediate muscle stuff e.g. arms go shaky after too much on those and sometimes that is relieved by rest (I can't lift a cup to mouth at that point and can't 'hold my own arms so have to have pillows under them anyway) but I suspect that depending on what I managed to do to make them that way I think it adds to the PEM total later on - though of course that combines in with 'other stuff' in that space of time.

I can trigger cognitive PEM worst with talking, noise/flashing lights and sound stuff and exercise ie physical (I wouldnt say I could exercise as normal people would think that term means currently) than strangely 'thinking'. But I can't read many pages of a book even on a good day anymore. SO physical and orthostatic, talking (which is thinking but the speaking bit feels like energy - phone is the worst, like seeing face takes some energy out of it) more congitive PEM immediately than cognitive work gives cognitive PEM. BUT the bit I can't work out is whether DELAYED PEM is due to cognitive worse ie so the cognitive is bad but delayed more, less of a 'kill switch' (I feel I'm collapsing on phone calls, have to lie down and eventually am quite sick if I push through).

Some days I'd just not be able to wake my brain, but couldn't tell you which day or what tasks because each different one cumulates differently. etc

 

agree that the more rest the better your sleep. That is why I find the sleep hygeine stuff so devious and misinformed and misleading. worse thing you can do is force people to go 'through the wall' and then think you'll make them sleep better when they get to bedtime. rest for long periods when you are really ill and hypersomnia is a necessary stage to ever get to the more normal stage etc. it just seems so dumb a thing and so obvious from my position yet it is like banging head against the wall however you explain it to most as they deliberately do the non-listen thing, v strange.

 

PEM according to the IOM is basically the same as in NICE 2021, although some of the descriptions are in different places and we use our own wording.

In essence, we described PEM as being caused by physical, cognitive or emotional exertion, and being disproportionate, often delayed and with prolonged recovery times.

We also noted that, for instance, cognitive exertion can worsen physical symptoms, and so on; that there isn't always a clear pattern for triggering PEM; and that some or all of a patient's symptoms can worsen, or new symptoms can emerge.

That's almost identical to the IOM version you've outlined but, again, the two criteria have the details in different places.

The DSQ description of PEM, which Jason uses and which is used with the CCC, seems more focused on the subjective experience of exhaustion to me. The IOM and NICE 2021 are less focused on what PEM feels like and more focused on what observable patterns there may be to help guide diagnosis.

For me, the DSQ section on PEM is about fatigue, fatigability and long-term exhaustion than PEM. And they could be said to cover delayed onset muscle soreness too.

 

@Adam pwme - Thank you. This is especially helpful.

Do you know of any existing instrument that comes close to assessing PEM in this way? I'm asking because we have researchers new to the field, including Long COVID researchers, and it would be helpful to have a common method to identify the presence of PEM.

In a 2021 study, Jason published an expanded PEM questionnaire that asks questions about onset, types of triggers, symptoms that result, duration, recovery, and pacing. For resultant symptoms, his used a different list of questions than the original PEM questions. This may get at some of the points you raise. But I expect it is longer than researchers would want use for the purpose of identifying PEM in their subjects (although it might be useful for better characterization of PEM).

Any suggestions on a shorter questionnaire and/or recommendation for researchers?

Edited to add: This might more appropriately be in this thread on case selection criteria for research.
Edited to add: @adambeyoncelowe I meant to tag you in response to your post above.

Also, I'd appreciate thoughts from everyone, including recommendations for how we deal in the interim with the lack of a biomarker or a robust questionnaire

 

Thread on that paper here, The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and CFS (2018) Jason et al.

 

I think you meant to tag @adambeyoncelowe

 

@Adam pwme - Thank you for the message. And yes, I did

 

The 2021 questionnaire looks like it's in alignment with the IOM and NICE 2021. So I think this could be used. Though, I'm not sure how it's scored, as that will be crucial.

The key points seem to be covered, as well as some welcome additions, such as cumulative subthreshold PEM leading to worsening as well (which definitely captures part of the patient experience, IMO).

ETA: This questionnaire seems quite different to the previous one. So I guess this is the result of the patient input last time he announced a PEM questionnaire. If so, I think that's to be commended.

 

> In essence, we described PEM as being caused by physical, cognitive or emotional exertion, and being disproportionate, often delayed and with prolonged recovery times.

thanks that's clear but after all this time i do not feel i understand pem. to me, it seems any insult to the body, orthostatic, noise, light, chemical, mold, cognitive, physical, jostling, interpersonal, etc. can cause worsening. sometimes permanent. the above limits to 3 things.

i do not get why those 3 are focused on. it seems those 3 and other insults can produce same results. [worsening would be somehting like a subset of symptoms common in m.e. like stamina, oi, stim overload. but i am trying to distinguish causes here and not describe worsening.]

what am i missing? [or adding? or substituting?] are we eliminating the fact that [specifically] lifting my arm is a problem for me at the time and also requires recovery? exertion also does that but lifting is different from say pushing into my chest.

p.s.

fwiw i have posts on this topic [not just the operner] on this thread also: https://www.s4me.info/threads/does-...at-exertion-is-the-correct-focus-concept.6059

 

Arguably, the things you list ('orthostatic, noise, light, chemical, mold, cognitive, physical, jostling, interpersonal, etc') could be covered by the three listed domains (physical, cognitive and emotional).

E.g., orthostatic triggers could be seen as physical exertion (you are moving, after all), light and chemical triggers could be seen as physical (perhaps via immune) and cognitive (perhaps via central processing), mould could be seen as physical (immune again), and so on.

It's just how you slice up the pie. Some people will lump and some people will separate. In the NICE 2021 criteria, you'll note that OI and sensitivities are listed separately, but they could reasonably also be included under the listed PEM triggers if you interpret physical, cognitive and emotional broadly. Clinicians will therefore have some discretion there.

I will also note that there is considerable debate within our own community about lumping and splitting different triggers for symptom worsening, such as whether orthostatic stress causes PEM or OI, and whether those are the same thing.

And there is even more disagreement about whether chemicals, light and mould, for example, are necessarily triggers for PEM or are triggers for something else (e.g., sensitivities that cause a physical immune response or a central processing crash). Many severe patients have told me that, for them, a 'crash' from sensory input is different to what we would normally call PEM, for instance.

You could also argue that even if sensitivities are another process going on (an immune reaction, a processing issue), they still use up energy in that process, which might be more than the body had to spare, and so PEM may be a secondary outcome to whatever else is going on...

So it's certainly not easy and I don't think we can say for certain what PEM is and isn't yet. It may be necessary to be as clear as possible until we do know, so that we don't assume everything has the same cause and consequence.

Personally, I think sensitivities are slightly different and have different consequences than talking or walking, but those consequences can also lead to PEM.

Likewise, I think OI has some different features to PEM and is probably distinct, but it can also trigger PEM, causing a double whammy (e.g., OI that impacts immediately, leading to PEM that kicks in later and lasts much longer).

 

My subjective sense is that sensory hypersensitivities and orthostatic intolerance result in their own specific short term negative responses that is distinct to PEM if exposure is not too long. Recovery from these if exposure is stopped soon enough is quite rapid, and does not seem to have the paradoxical effect of negative symptoms continuing to get worse once exposure has stopped, which often is a feature of PEM.

However that is not to say they do not contribute to triggering PEM if exposure continues. For example accompanying my god daughter on perfume shopping, resulted it headache, dizziness and confusion, that disappeared rapidly once I took myself out of the shop, whereas using a scented soap that leaves a residue on the skin, means having a bath is more likely to trigger PEM than the same exertion but with hypoallergenic shower gell.

A rock band playing on the Green outside my house was by itself a nightmare, but it continuing for four hour resulted in PEM with all the ME symptoms twentyfour hours later.

This interaction between PEM and hypersensitivities/OI also is seen in that when in PEM the threshold for them is considerably lowered.

To clarify, my personal belief is that PEM and hypersensitivities/OI are distinct phenomenon, but interact in that the latter can contribute to triggering PEM and PEM involves lowering the threshold for experiencing the latter.

 

I'm a bit confused with regard to which version of the DePaul Questionnaire we discussed already on the forum? Has the latest version already incorporated some of the forum's and others' feedback? Or are Jason's team working on another update?

I think it depends on the purpose - clinical care or research on pathomechanisms/ epidemiology?

I realize that it may not be easily practicable for the recruitment of study participants, but I think in general a good activity and symptoms diary, both for cognitive and physical activities, could be useful. An app that doesn't need much cognitive effort to use -- ideally pwME or their carers only have to check some boxes for cognitive activities and the most common symptoms, while physical activity is automatically measured by an apt device?

The discussion has been controversial with regard to the question whether mildly and moderately affected pwME can avoid PEM, but I think most pwME usually experience PEM often enough so that in most cases, such an app/ device would capture at least one episode of PEM in a fortnight?

In general, I think the focus should be on developing a good actimeter/ accelerometer measurement in addition to an activity/ symptoms diary, maybe also special cognitive testing (also done at home, daily at the same time), so that the questionnaire could be validated (against a control group) using objective measurements.

Another point is that assessments that exclusively rely on patients' reports in questionnaires may not be a good diagnostic instrument if patients have brain fog, rapid cognitive fatigability or other cognitive issues.

Edited for clarity.

Edit 2: Not sure if it's even necessary to assess / monitor more symptoms if both quantity and intensity of cognitive and physical activities could be reliably monitored and a clear decline after an increasing quantity or intensity of activities can be shown? (Even if there are additional declines in activities due to other PEM triggers.)

 

Slightly off topic, but I think devices documenting PEM could not only be worthwhile as a diagnostic instrument but also give clues to pathomechanisms.

 

I agree. You don't need to do any activity at all to know that you have PEM, because you feel ill.

I'd also replace 'unrefreshing sleep' with 'much more difficulty than usual initiating and maintaining sleep'. There's no mention of the wired feeling, the extreme clumsiness, the inability to remember simple words...

 

Good question and probably my fault as my question above took it outside the scope of this thread so some of the following responses belong in this thread about Jason's expanded PEM assessment that @Andy posted above.

 

In case others are confused, too, Jason's website lists all questionnaires here:

https://www.leonardjason.com/cfsme_measures-2/

Here is a forum dicussion on Defining and Measuring Post-Exertional Malaise. (from 2020).

From February 2018 is the S4ME Submission to the public review on Common Data Elements for ME/CFS: Concerns with the proposed measure of post-exertional malaise

And here are two papers taking into account patient input:

Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Holtzman et al. (2019) | Science for ME

https://www.s4me.info/threads/asses...atigue-syndrome-cfs-holtzman-et-al-2019.8460/

Factors Affecting the Characterization of Post-Exertional Malaise Derived from Patient Input, 2020, Holtzman, Jason et al | Science for ME

https://www.s4me.info/threads/facto...atient-input-2020-holtzman-jason-et-al.16700/