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

[bobbler]

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 suspected it was based on 'rolling wave'. I've tried googling but there is so much on it being a type of agile planning that I've no chance

My suspicion is based on a faint memory that with waves then a 'faster' wave moves through and collects other waves and gets bigger/faster and so on - so the picture in my mind is of if PEM is Mon-Wed but I am exerting on Monday then I'm adding an eg Tues-Thurs PEM-wave on top of that and so on. By the time you (as in Kitty's analogy of working full time) end up flat on your back at the weekend then the cumulative PEM might need 3 weeks to recover (say 3 days acute) and you get 2 days absolute rest, just enough to be able to force yourself half-recovered into the cycle again.

But for someone new who doesn't know what it is then ... it just feels like you are really ill - and the rolling PEM problem with eg questionnaires (without giving people tests, like having a week off work, see if total rest means you spot patterns afterwards) is of course anyone ill feels relieved when they finally rest but still ill and blinking awful when they are giving a presentation with flu.

But yes it would be helpful if things that people just think they 'get' (it's only when you mention it that I even think that isn't one of those that describes it well) test it, and plus we have the international and other elements too.

 

[Kitty]

The question is, can you predict how able you will be tomorrow based on objective measures?

Given that I can't predict how able I'll be 20 minutes from now, I doubt it.

I might have an attack of IBS, or my leg muscles might go dead, or I might feel too dizzy to stand up, or I might have retinal migraine in one of my eyes so that I can't see to read, or I might feel pretty much fine. All of these have happened in the last three hours, and may or may not recur.

 

[poetinsf]

Given that I can't predict how able I'll be 20 minutes from now, I doubt it.

I might have an attack of IBS, or my leg muscles might go dead, or I might feel too dizzy to stand up, or I might have retinal migraine in one of my eyes so that I can't see to read, or I might feel pretty much fine. All of these have happened in the last three hours, and may or may not recur.

Not sure about IBS or migraine, but I can reliably reproduce PEM, and you probably can too. All I had to do was to walk just 5% faster on my bi-daily walk. It's just that you can't reliably prevent PEM. You need to account for all cumulative exertion for several days to make any kind of prediction. At least that is how it appears to work in my case.

 

[poetinsf]

Not familiar with the acronym MET

Metabolic equivalent of tasks. It's a calorie expenditure measure relative to resting state.

 

[NelliePledge]

Metabolic equivalent of tasks. It's a calorie expenditure measure relative to resting state.

Ok thanks I imagine that’s not one many are familiar with

 

[Kitty]

You need to account for all cumulative exertion for several days to make any kind of prediction.

But you still couldn't make any kind of prediction, because PEM isn't a thing on its own.

You might work out a way to predict theoretical energy capacity, but it would bear no relation to real life if it didn't take account of other symptoms. My energy capacity last night was actually okay, but it didn't mean I could function. You can try to make ME conform to standards and follow logic, but it won't.

 

[Eddie]

How similar is PEM to how one might feel after they exerted themselves during a bad infection? I'm trying to think back to when I had an infection pre-ME/CFS, but it is hard for me to think of an example where I didn't try to rest when quite sick. There differences like fever which don't typically happen during PEM, but I'm more curious about the response to exertion when sick, not the response to the virus/bacteria/etc itself.

 

[Kitty]

How similar is PEM to how one might feel after they exerted themselves during a bad infection?

I think one of the differences might be sleep. I haven't many memories of this because I got ill in my teens, but I do remember a couple of things—going to a family funeral when I was really unwell with bronchitis, and getting out of bed with a 'flu-like illness to sit an exam. Both times I went back home and slept heavily for hours.

In PEM I struggle to sleep much at all, and even when I do it's light, fitful, and I wake often needing the bathroom.

 

[Mij]

How similar is PEM to how one might feel after they exerted themselves during a bad infection?

I contracted COVID in 2022 and it didn't resemble M.E PEM at all, not even close. No cognitive issues or other symptoms of delayed ME PEM.

But, it was similar to PVFS over exertion I experienced during sudden viral onset in 1992. It affected legs muscles only, the only muscles I used for exertion, I couldn't walk or stand for very long until I recovered 6 months later.

Sleep doesn't make a difference for me. I slept like a baby.

 

[Eddie]

I contracted COVID in 2022 and it didn't resemble M.E PEM at all, not even close. No cognitive issues or other symptoms of delayed ME PEM.

Did you try to exert yourself while you were infected? Also I presume you had ME/CFS at that point so that makes it a little hard to figure out what is related to the infection and what is related to ME/CFS. I think people certainly can have cognitive symptoms after exertion when sick, especially if the infection is bad enough. It is really hard to differentiate what is a result of infection and what is a result of exertion during infection though.

If PEM really is similar to the post exertion feeling during sickness, than that would suggest that maybe there is some sort of sickness response that isn't turning off in ME/CFS. I wish we knew more about what actually drives the feeling of being sick in the brain. I don't think ME/CFS can be the whole sickness response as things like fever are pretty rare or don't occur in PEM. However, if there is no infectious agent, perhaps only parts of the sickness response are engaged. Especially those parts that respond to exertion when sick.

 

[Mij]

Did you try to exert yourself while you were infected?

Yes, but I couldn't stand for more than 2 minutes. I rested for 3 1/2 weeks and felt I had recovered and gone back to my baseline after one month so went out for a very nice 50 minute walk only to get up the next morning unable to stand up on my legs again. I had to crawl around and eat out of cans for another 3 weeks. My cognitive function was fine but it took another 5-6 months to get back to my baseline. I'm fine now.

Also I presume you had ME/CFS at that point so that makes it a little hard to figure out what is related to the infection and what is related to ME/CFS.

I've had ME/CFS for 32 years. I understand the differences very well. I've also had reactivation/relapse from HHV6 and EBV at the same time from taking immune modulators and it never affected my cognitive processing, speech . . . It is a completely different experience from M.E

I had exertion issues for the last 2 days, sore ears, mild sore throat and tired legs. Whether it's an infection or not I don't know, but this occurs off and on for the last 20+ years. M cognitive energy was fine.

Eddie, the delayed PEM that I experience is very distinctive and has a very distinctive onset and process in my case. It affects brain, ANS, every muscle, gait, speech, balance, cognitive energy, hormones et My 'battery' is dead and takes 3 days to 'recharge'. It is not similar to immediate over exertion PEM.

My personal view is that my immune system is exhausted.

 

[EndME]

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.

I know little about biology but aren't there a tremendous amount of things where symptomology occurs delayed?

For example Iwasaki suffers from Alpha-Gal-Syndrome (which didn't even exist before 2002 and was discovered purely by coincidence) and which is an allergic reaction to meat caused by a tick bite and follows a delayed-onset anaphylaxis (3-8 hours). Similarly people with coeliac also very often have delayed symptomology (sometimes even days later). I would image the list goes on...

 

[duncan]

I understand the differences very well. I've also had reactivation/relapse from HHV6 and EBV at the same time from taking immune modulators and it never affected my cognitive processing,

May I ask, expressed how?

 

[Mij]

@duncan I'm not sure what you're asking.

I was explaining to Eddie that over exertion PVFS in my case feels very different from delayed M.E PEM from going over my energy limits. If I have a viral infection over exertion I would experience immediate PEM but that does not include the same symptoms as delayed PEM.

 

[duncan]

I'm sorry. How did you decide you'd HHV6 and EBV reactivation? I'm not disputing this; I'm asking to the metric.

Why I'm asking is because I distrust current standards across many infections. I respect your interpretation.

 

[poetinsf]

But you still couldn't make any kind of prediction, because PEM isn't a thing on its own.

Not sure what you meant by this. PEM is defined as worsening of symptoms after an exertion, and there is a specific exertional threshold for it. At least mine does. Maybe yours don't and that could be where the disagreement is.

We can easily do a thought experiment. You put a PwME through a 2-day CPET test. Instead of going all the way to 100W in 10 min, however, you stop at each 10w interval and see he/she develops PEM next day. You repeat it and then stop when he/she does. That would be the threshold.

Now, the trick is to translate that into a number that is comparable across all activities. The simple work measure of sum(Watt*min) doesn't work since you can avoid PEM by reducing the power and increasing the duration. So we need an f(intensity, duration) that yields a same number for (sum of all) activities that trigger the PEM.

I won't get into the detail for now, but one measure using the sum of exponential metabolic decay as the accumulative stress that you work against has shown some promise in my fitbit data going back to 2015. There are limitations through, because MECFS is super-sensitive to exertion intensity and fitbit is not. So, once I'm satisfied with the model, I'll need to find a way to compliment it with manual data. Stay tuned. I'm back on the road to escape my PEM, so it will be forever before I have something for the public, if ever. (I'm typing this on my phone in the back of my car.)

 

[SNT Gatchaman]

PEM is defined as worsening of symptoms after an exertion, and there is a specific exertional threshold for it.

I don't believe there is such a specific threshold for most pwME, it's just too variable and our biology has too many moving parts: not least being whether the immune system is activated for any reason at the time of exertion.

We can easily do a thought experiment. You put a PwME through a 2-day CPET test. Instead of going all the way to 100W in 10 min, however, you stop at each 10w interval and see he/she develops PEM next day. You repeat it and then stop when he/she does. That would be the threshold.

That would be the threshold for that iteration. But then repeat the entire process another five times over the next five weeks. Do you think you'd get the same threshold each time?

 

[Mij]

I'm sorry. How did you decide you'd HHV6 and EBV reactivation? I'm not disputing this; I'm asking to the metric.

I had very sudden symptoms one morning but not bad enough to stay home. I was feeling very well during that time period, about 90% improved in 2001. I had a doctors appt that day so went to see my doc who asked how I was doing and I said 'great', when I really wasn't sure why I feeling so weird. Decided to go shopping after and within the hour I was being helped into a cab by total strangers b/c I couldn't walk. My blood circulation just stopped and my legs felt like rubber. It was that sudden. I emailed my doctor and he was stunned b/c he just saw me earlier and I told I was 'fine' and asked why I didn't tell him, I told him that I didn't have time to assess how I was feeling.

So went back to my doc, got tested and both EBV and HHV6 had very high titers. My doc told me I looked like death and was really stunned at how fast I changed. Glad he saw that for the record Not making it up, eh?

 

[duncan]

So went back to my doc, got tested and both EBV and HHV6 had very high titers. My doc told me I looked like death and was really stunned at how fast I changed. Glad he saw that for the record Not making it up, eh?

Understood. Thank you.

For the first time in about a decade, I just had my EBV and HHV6 levels tested. I feel like crap and likely look like death as well, but am unsure what my high titers signify other that past exposure - that's why I asked.

 

[Mij]

I was tested for many viruses via PCR/DNA/RNA but nothing ever showed up, even when I felt 'viral' or bad. The testing was done about one year after that EBV and HHV6 reactivated episode. It's difficult to test for I think unless you're very symptomatic? Dunno

I hope they find something to treat so you can feel better