Post-Exertional Malaise - a discussion including defining and measuring PEM

I'm working on that fuel gauge for PEM. You list all activities you've done and will do, either automatically or manually, and the gauge will tell you when to stop. Am I smoking something? I guess we'll find out. I'd also make it a platform so that people can plug in their own variables to experiment.

 

The trouble with that will be the fairy folk, who swap our fuel tank every night for a different one.

We wake up with no idea whether we've got a moped, a bus, a car, or a toy train that only moves if somebody pushes it.

 

To me it just means we don't know yet what these early symptoms are a manifestation of. Some or all could be part of PEM or they could be the same sort of exertion intolerances people with all manner of other conditions get and pwME are just unlucky to get both. Because we don't know and because the early symptoms are shared with other conditions it is currently unhelpful to label them PEM. For a label to be helpful it has to do something useful like distinguishing between groups of patients with different treatment responses.

It may be helpful to conceptualise the label PEM in an analogous way to the IOM or NICE diagnostic criteria. Neither the label ME/CFS nor the label PEM say anything about underlying mechanisms.

[Side note for those who have questioned the presence and/or nature of underlying mechanisms: I use the term mechanism in a very broad sense to indicate something that works differently in some way in pwME and healthy people. That something may be a pathway broken or gone wrong, it may be some otherwise normal process activated at the wrong time or intensity, or something else entirely. For the purpose of my argument what the something is is irrelevant and, at any rate, we don't know]

Back to the labels. The purpose of the diagnostic criteria and, in my view also an important purpose of the PEM label, is to distinguish one group of patients from other groups of patients in some meaningful way. In this case we particularly want to separate people who deteriorate from increasing exercise/activity from people who ultimately benefit (even if they get some temporary symptoms like DOMS in the process). We want to do this for diagnostic purposes, for pragmatic management reasons (e.g. don't refer the wrong people to GET) and to get more homogenous research cohorts so we might learn something about those elusive underlying mechanisms, eventually. In the meantime syndromic labels aren't perfect, more of a current best guess, liable to change as we learn more, but the best tool we have to meaningfully distinguish between groups of patients.

Both the diagnostic criteria and the PEM label work by honing in to what we currently think are the core features or patterns that, taken together, distinguish one group of patients from other groups of patients. They don't - can't - list all the many symptoms a pwME may have and we all know we have a heck of lot more symptoms than the few mentioned in the diagnostic criteria. But all those extra symptoms aren't helpful for the purpose of the label - to distinguish between groups of patients. There's too much uncertainty around them. Some of those extra symptoms may eventually turn out to be directly attributable to ME (or PEM), some may be due to comorbidities pwME are particularly susceptible to, others may just be unlucky individual comorbidities. No one knows. So for the purpose of the labels the extra symptoms only confuse matters because they don't distinguish anything from anything else. In the case of PEM, if we label every symptom after exertion as PEM just because it happens after exertion we end up with a lot of false positives.

At the individual level the additional symptoms are of course highly relevant and should absolutely be taken note of and addressed appropriately by and for each individual. But it's not helpful for every symptom after exertion to be labelled PEM just as it's not helpful for all chronic fatigue to be labelled as ME. With syndromic labels we're looking for what distinguishes our fatigue and our reaction to exertion from other patient groups' fatigue and reaction to exertion.

Boy, that was hard to get down into even approximately clear language! I hope it clarifies at least a little rather than confuses even more
TLDR:
When discussing PEM it's helpful to separate

• underlying mechanisms
• symptom constellations that are most likely PEM because different from symptom constellations in other illnesses (helpful to call these PEM)
  
• symptoms which may or may not turn out to be PEM but which can't be differentiated from symptoms common in other illnesses (unhelpful to call these PEM at this stage of our knowledge)
  
• labels, which are not the same as the thing they're labelling but a linguistic and conceptual tool to try to make sense of things

 

Picking on exactly 12 hours is indeed arbitrary. However, a delay in onset and/or peaking of a weird constellation of symptoms is common. There's some confusion because some people talk about delayed onset and others about delayed peaking. Personally I think looking for symptom peaking rather than onset is more informative when it comes to distinguishing between ME-PEM and other forms of exertion intolerance.

I can walk 50m without feeling any change whatsoever. I have the same level of background symptoms after the walk as I had before it. Zero immediate indication of having done too much. After 4-6 hours I get a little uptick in symptoms. This lasts for just a couple of hours before they settle back to where they were pre-walk (this temporary uptick seems to be unusual, so may be just an individual quirk). Then, 24 hours after the walk all hell breaks loose. This happens even if I immediately returned to rest after the walk. So despite the complete lack of early symptoms there's no stopping the PEM train once it gets rolling.

If I walk 100m I do get early symptoms like weak legs and excessive exhaustion (which I call 'weak legs' and 'excessive exhaustion', not PEM). Followed by full-blown PEM 24 hours later. Again, no amount of rest after the walk wards off next-day PEM.

The effect of orthostatic exertion is different for me. There always are early symptoms typical of OI (which I call OI symptoms, not PEM). If I stop early enough after symptom onset there won't be any PEM the next day. But if I push on too long though there will be PEM.

 

For me, OI and ME/PEM have always run along side each other at the same level. My ME is now a managed moderate and so is the OI.

I remember my early years of mild when trying to keep working too, but the crashes were still not as bad as what I was about to experience at very severe and severe ME years.

The severity of my ME and PEM severity entirely depends on the level of my ME. And I must say that my mild to very severe was different from coming out the other side to a now managed moderate. (I will try to explain this in a post another day).

I've been through all the stages, from onset to very severe (unmanaged to the point of very severe), then spent around 10 years trying to rest manage my way out of the severe years and the hardest hitting PEMS I've ever experienced with ME were in those very severe and severe years.

Now at a managed moderate level I don't get those severe PEM intensities. I still have symptoms and the tell tale warning signs that I have overdone and need to cut back and rest.

I find it hard to understand if a mild ME was getting very severe PEMs especially if experiencing them fairly often. It would sound more to me like a spiraling down to severe level if not pulling back from exertion drastically.

I know I have to remember that everybody can experience ME differently though.

 

I think I still don't understand the difference between PEM and an ME flare in my own body.

 

In a way it’s one of the few where it can be both/isn’t an issue having those two as long as clarified when needed.

I see rolling PEM as when you basically never get out of PEM and so rolling means you are having to push through and thereby probably exacerbating and exacerbating things. Maybe eventually you just explode and pass out sleep. If you are allowed.

but this phenomenon is most mentioned by me as being an issue before people know what they have - which is to be considered when describing the illness - and might well be having no choice but to try and keep pushing thru commitments with all the tricks in the book (caffeine etc setting alarm earlier and earlier to scrape and cajole body into action using the adrenaline to complete things and so on)

 

This is such a weird quirk of the disease. If I cross some invisible threshold I get slammed later. It's a massive clue.

I previously knew of only one bodily system with a delay built in - the development of antibodies to a novel pathogen. But recently I became aware of another - the end point of an unfolded protein response.

Unfolded protein response is the reaction the body unleashes when the endoplasmic reticulum gets overwhelmed. Now, this goes on for a while and ends in one of two ways. At the end the endoplasmic reticulum gets on top of things and the cell is fine, or it doesn't and the cell starts a process to die. It can die in an orderly or messy fashion: apoptosis or necrosis.

The canonical cause of UPR is an accumulation of unfolded proteins (they've found other triggers too), and in response the body ramps up protein folding capacity while reducing protein demand.

It is extremely difficult to find online how long the body gives the endoplasmic reticulum to sort things out before giving up and killing the cells but the references I've found hint it's hours. It's also unclear just how long it takes the apoptotic / necrotic processes to fire up. But it is certainly plausible that it adds up to the 12h-36h window in which PEM arrives.

So the way it would work is this: when we exercise we overwhelm our endoplasmic reticulums. They start the UPR but for some reason it doesn't work. They can't recover. After a certain number of hours a lot of cells will die. If a lot of cells in a muscle are overwhelmed and die off in a short period (or maybe all the cells along a blood vessel?), it could release a lot of damage-associated cytokines and purines into the body and basically set off every alarm in the whole house. All sorts of systems, including central systems and immune responses could turn a local problem into a global one.

This model would also explain why our pem thresholds are so variable and hard to judge - we presumably aren't aware of the things that are pushing our enodplasmic reticulums close to the edge.

The only direct evidence we have that this could be what's happening in PEM is the new Hwang study where he finds the overwhelmed ER pumping WASF3 into mitochondria, and finds one arm of the UPR response (PERK) signalling strongly but another arm (BIP) quiet. What he describes is certainly not a classic UPR, but it could be what one looks like in a broken system. The recent Wust work on muscle necrosis is not, on its own, evidence for UPR activation but it certainly fits the pattern.

I can imagine a scenario where a virus or viral fragment is in our endoplasmic reticulums occupying the machinery for its own purposes, and so there's not enough capacity left for doing much. If we push ourselves the endoplasmic reticulum sets off UPR, and then, perhaps because of the non-standard signalling Hwang found, it doesn't work. So we end up with mass apoptosis and necrosis, which makes us feel very sick.

A weakness of this theory is how modest the metabolomic findings have been - you'd expect what I described to show up very clearly. Still I'm excited to see what Hwang finds, and I hope he does investigations with exercise provocation.

 

This is intriguing. One point, however: channelopathies can also manifest with delays.

 

Yes, hi !
Not currently but in my most mild periods this is how my mecfs used to remind me it was still lurking. I'd come home from a bike ride all sweaty and full of endorphins, carry on with my day like normal, go to bed, wake up and 24 hours later realise, oh no...

The longer i've been sick and the worse I've got the less clear PEM is - i feel kinda rubbish a lot. But it used to be real bright line.

 

Interesting!! One of the non-canonical causes of UPR (alluded to above) is a failure of calcium homeostasis in the endoplasmic reticulum.
https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-023-01062-y

 

I don't think the terminology or the usage is at all fixed.

What I describe as PEM is the routine reaction to previous activity. It's fairly predictable, though the mildness or severity of it is sometimes surprising; the symptom pattern varies with severity, but it's always within a familiar range.

What I describe as an ME flare is very different. It's sometimes the result of long-term accumulated PEM (particularly when I was working), but it can also—like remissions—be unexpected.

It's more active than day-to-day PEM. Whereas PEM feels flu-like, this is more like a real infection, with a whole procession of symptoms rapidly flaring, subsiding, and switching. I'm so parched that I need to drink eight to 10 litres of water a day, I have the 'poisoned' feeling, I'm completely confined to bed, and I have almost no cognitive capacity (it can be really difficult even to find out what day of the week it is).*

I've had this level of active illness for several months at a time, but also for just a week or two. It's followed by a long and frustrating collapse in function, which is much quieter symptom-wise. It usually lasts about two years, then I gradually recover all or most of my previous function.

So to me, there's a very clear difference between a flare and PEM, but I don't know whether anyone else has this pattern.


* I've also symptoms that, looking back, were really odd. They include out-of-body experiences, which started with a strange grinding sensation going down my spine, then all the muscles in my back going into spasm and making me arch up in bed. Whilst it was happening, I'd have the feeling of being on the ceiling looking down on myself. The muscle spasms were painful, but at the same time it was incredibly exhilarating, like being on some kind of drug trip. It's only happened to me three times in nearly 50 years of illness, but there was never any medication involved; whatever was going on, my own brain was doing it!

 

Yes and these are the pwME who eventually reach the point of no return when they might have had a small chance of returning to work part-time or having a small social life early in the illness if they paced properly and didn't exercise. I continued to run for 2 yrs, but in 1998 didn't understand what delayed PEM was, I thought I was the only person who experienced this and that it would eventually go away on it's own. The more I continued to exercise, the more amplified my symptoms became during delayed PEM.

I could still run today on a "good day" w/o symptoms, but I fear I would end up in the ER with delayed PEM. The last episode I had a few yrs ago was the scariest ever.

 

The fairy won't bother you as long as you stick to an objective measure. MET, for example, is always fixed for the same activity. The question is, can you predict how able you will be tomorrow based on objective measures? That's what I'm working on.

 

I can buy that. I've been using the term "permanent PEM" but I can see rolling PEM meaning something similar, as in "rolling sum". In general though, I think the terminology is important. I understand human language is context-sensitive, but it's difficult to come to common understanding, in science in particular, if we mean different things with same words.

 

I think this is an appealing idea. I don't think it will apply to cognitive/emotion/focus-based PEM, though.

Still cool to try.

 

100% agree on the terminology. It seems one of the most straightforward and fair asks for us to fix to get a terminology that does what it says on the tin vs the 'new/accurate' understanding of ME/CFS ,

EDIT to add: actually a 'terminology framework' so it almost pre-defines the next one to add and so on, avoiding people making up names.

and also as we then add new ones they probably can slot into the same 'does what it says on the tin' if we have considered writing these in the context of a process (ie so they match and layer in a way that makes sense, like a nesting doll)

Humans prospered as they say when we had the ability to communicate. I can't help but thinking the continual undermining of vocab is a deliberate attempt at hobbling pwme and putting a rift between them and any bystanders who need to understand how to keep them safe and basics on the condition. Getting us all talking at cross-purposes wondering whether someone used a certain term because they've different ideas what the condition is or just because they've been taught it's an OK term (I personally hate 'flare') and playing into making it look like pwme are inconsistent with each other and 'maybe is a label where fakers can hide' etc. (that's one of the big old tropes)


We deserve terms that we can all use being sure they say the same thing and aren't divisive. And ones that have logical 'next steps' if people need to 'add to it' or guess at it and be near. Particularly given the nature of the condition and its symptoms, plus how many we might need to learn if a newbie.

And that includes 'healthies' - if we really want to have allies who aren't all good intentions but think they get it and are genuine in spirit but can't quite keep up on the ins and outs. Plus if my noticing the difference in language style across different subject's literatures, the type of people that we want looking into ME/CFS and working on it won't like fuzzy ambiguous (interpret what you like) terms and be more attracted to and able to 'get into' something that is logical, crisp and clear and descriptive of what you see.

Importantly I think it is a complex condition to describe and so we need language to do the basics for us. And scientists or medics who might find it is a pretty interesting 'process' of a condition with some distinct patterns that look nothing like the hysteria/witchtrial-type nonsense some spout instead. At the moment if we have to explain every word we mention we don't get past the first sentence (and need to layer on ten for the penny-drop) not to mention how many have been misinformationed

And we can then do a trope list and include - which is a reasonable ask - 'old terms to be dropped please as they are offensive and/or inaccurate'

It seems a reasonable ask we get basic nomenclature signed off along with a glossary to stop horrible people attempting to pre-bunk and bias any word a pwme might need to say in front on an HCP to be something for derision

I can't help but think if we managed to achieve that list. And that isn't an unusual request. It would change a lot about how the condition 'looks' (because it would change how we looked to rather than floundering speaking a different language to the HCPs)