PEM discussion thread - post-exertional malaise

[Peter T]

Careful observation, careful language.

I second that.

 

[OrganicChilli]

A question for those who experience immediate PEM, does your immediate PEM include the features that don’t occur as part of normal fatigue, such as swollen glands, symptoms unrelated to the triggering activity, etc?

My immediate PEM symptoms change every few weeks, but at the moment I get body chills, a sore throat and painful legs. If I have a headache the next day, I definitely overdid it, but I count the immediate and the delayed onset as PEM. I don't have symptoms when I'm not in PEM apart from occasionally feeling tired.

 

[AliceLily]

If you experience a worsening of orthostatic intolerance with nausea and headache while you are still involved in some exertion does that have to be excluded from the topic of PEM? If you experience these things the next morning for just one day is that to be excluded?

Thanks for this. This has helped me to understand my immediate PEM which was most intense naturally in my severer years. I would get an immediate headache, nausea, exhaustion came with it. I don't know whether OI has the exhaustion as well as PEM. I also got immediate aching of sinuses, flu like symptoms (maybe that one was immediate PEM). There were other so many other symptoms but I cannot remember them all right now.

So the immediate headache and nausea sounds like it mostly came from the OI. I remember I got different types of nausea throughout my overall ME, which might explain that I was experiencing not only OI nausea but PEM nausea at other times. I wonder if I even was getting a double up of different types of nausea on top of each other. What I mean by different types of nausea was that one type my stomach felt like it had gravel in it. Another type was straight feeling of nausea. There was 3rd type but I can't remember how I described it. I did record it, but need to find it.

 

[Jonathan Edwards]

What may be useful to remember is that doctors devise clinical terms for two quite different purposes. They may use the term as a diagnostic pointer or they may use it as an indicator of ill-health or disability. Unfortunately, most doctors who devise such terms forget that there are two different purposes and things get muddled.

As an example: the GALS screen for rapid assessment of joint problems was in set up by four doctors, ostensibly with the aim of being diagnostic screen for joints not being entirely normal in the context of a complaint in one joint or some other body part. But some of the doctors also wanted the screen to indicate how disabled the person was, for that joint. They ended up testing the shoulder by asking the person to put their hand up and behind their head. This is an indicator of a shoulder being significantly difficult to use. But a much more sensitive test of whether a shoulder is at all abnormal - maybe just a bit restricted from an old episode of inflammation - is to ask the person to put their hand down and round behind the back to touch the spine.

PEM seems to have been devised as a diagnostic term for recognising ME/CFS as opposed to fatigue from anaemia or heart failure or whatever. It is like nail pitting or lifting, which distinguishes psoriatic arthritis from rheumatoid. Nail lifting can be a real nuisance but for 80% of people is trivial in comparison to their arthritis and nail pitting causes no trouble.

So I think any fact sheet needs to separate two quite different issues. One is why doctors have this term PEM, which they use for diagnosis. The other is what it is like to suffer worsening from exertion or other things in ME/CFS.

 

[Evergreen]

The Institute of Medicine report in 2015 (now National Academy) does not emphasise delay they way the CMO report (UK, 2002) did. Here’s how they describe PEM:

PEM is an exacerbation of some or all of an individual’s ME/CFS symptoms that occurs after physical or cognitive exertion and leads to a reduction in functional ability (Carruthers et al., 2003). As described by patients and supported by research, PEM is more than fatigue following a stressor. Patients may describe it as a post-exertional “crash,” “exhaustion,” “flare-up,” “collapse,” “debility,” or “setback.”2 PEM exacerbates a patient’s baseline symptoms and, in addition to fatigue and functional impairment (Peterson et al., 1994), may result in flu-like symptoms (e.g., sore throat, tender lymph nodes, feverishness) (VanNess et al., 2010); pain (e.g., headaches, generalized muscle/joint aches) (Meeus et al., 2014; Van Oosterwijck et al., 2010); cognitive dysfunction (e.g., difficulty with comprehension, impaired short-term memory, prolonged processing time)(LaManca et al., 1998; Ocon et al., 2012; VanNess et al., 2010); nausea/gastrointestinal discomfort; weakness/instability; lightheadedness/vertigo; sensory changes (e.g., tingling skin, increased sensitivity to noise) (VanNess et al., 2010); depression/anxiety; sleep disturbances (e.g., trouble falling or staying asleep, hypersomnia, unrefreshing sleep) (Davenport et al., 2011a); and difficulty recovering capacity after physical exertion (Davenport et al., 2011a,b). In some cases, patients experience new symptoms as part of the PEM response. [A patient quote follows]

They go into more detail about the onset of PEM on p.79:

Onset
Although PEM may begin immediately following a trigger, patients report that symptom exacerbation often may develop hours or days after the trigger has ceased or resolved.4 Likewise, some studies have shown that PEM may occur quickly, within 30 minutes of exertion (Blackwood et al., 1998), while others have found that patients may experience a worsening of symptoms 1 to 7 days after exertion (Nijs et al., 2010; Sorensen et al., 2003; Van Oosterwijck et al., 2010; White et al., 2010; Yoshiuchi et al., 2007). The delayed onset and functional impairment associated with PEM also is supported by actigraphy data. ME/CFS participants enrolled in a walking program designed to increase their steps by about 30 percent daily were able to reach this goal initially, but after 4 to 10 days their steps decreased precipitously (Black and McCully, 2005).

And here’s what they say about duration/how prolonged PEM is, also p.79:

Duration
PEM is unpredictable in duration, potentially lasting hours, days, weeks, and even months (FDA, 2013; Nijs et al., 2010). After maximal exercise tests, ME/CFS patients experience greater fatigue compared with healthy controls (Bazelmans et al., 2005; LaManca et al., 1999b), and their fatigue and other symptoms last much longer relative to healthy active (Bazelmans et al., 2005) and sedentary controls (Davenport et al., 2011a,b; LaManca et al., 1999b; VanNess et al., 2010). In several studies, healthy controls declared themselves recovered within 24 to 48 hours after physical or cognitive exertion, whereas fewer than 31 percent of ME/CFS subjects had returned to their prestressor baseline state by this time, and as many as 60 percent were still experiencing multiple symptoms after 1 week (Cockshell and Mathias, 2014; Davenport et al., 2011b; VanNess et al., 2010).

The word “delay” does not appear in the Summary or Key Facts documents, but I found one mention of “delay” in the Clinicians’ Guide (not prominent):

PEM may be delayed related to the trigger.

Edited to fix formatting in quotes.

 

[Evergreen]

I looked at Moore et al. 2023 again - this is the study from Hanson's group called "Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)" available here https://www.mdpi.com/1648-9144/59/3/571.

It's relevant for this discussion because it focuses on symptoms of PEM rather than physiological correlates of PEM following a 2-day CPET in people with ME/CFS (well assessed by a physician, met CCC criteria and were not doing any regular exercise) and sedentary controls.

The issue of delayed onset only comes up in the limitations part of the discussion (I added the bolding):

there were very many subjects with ME/CFS and a few CTL subjects whose SSS scores peaked, declined and then went back up again. In such individuals, it is very difficult to ascertain whether or not there is truly a bi-phasic peak in SSS scores in response to a 2-day CPET stimulus. Other patterns we occasionally observed were what appeared to be a delayed onset of PEM symptoms, with symptoms not increasing until days after the 2-day CPET. Such phenomena are difficult to explain with the known acute physiologic responses to acute exercise. One issue could well be that subjects feel recovered, but are not, and thus increase their activities and unwittingly provoke a worsening of symptoms. In addition, external variables beyond our control could increase stress and bring about such symptoms. Controlling rest more rigorously after a 2-day CPET would be difficult and costly. Thus, while there were unquestionably subjects whose SSS scores were higher several days after the 2-day CPET, we conclude that these response curves were most likely noise and variability in external stimuli. Neither the spline curves nor either of the pharmacokinetic models shows even a trace of bi-phasic behavior. If there are such persons, it seems likely that they are reflecting more external variables and personal behaviors rather than normative traits of persons with ME/CFS.

So while they saw delayed onset of PEM, it was not the norm. The average pattern was this:


I'm actually not sure if the two CPETS were done on days 0 and 1 or days 1 and 2, but I think it was days 0 and 1. I may have missed this in the paper.

 

[Utsikt]

I looked at Moore et al. 2023 again - this is the study from Hanson's group called "Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)" available here https://www.mdpi.com/1648-9144/59/3/571.

It's relevant for this discussion because it focuses on symptoms of PEM rather than physiological correlates of PEM following a 2-day CPET in people with ME/CFS (well assessed by a physician, met CCC criteria and were not doing any regular exercise) and sedentary controls.

The issue of delayed onset only comes up in the limitations part of the discussion (I added the bolding):


So while they saw delayed onset of PEM, it was not the norm. The average pattern was this:
View attachment 25606

I'm actually not sure if the two CPETS were done on days 0 and 1 or days 1 and 2, but I think it was days 0 and 1. I may have missed this in the paper.

I wonder if the intensity or nature of the exertion might impact the delay. Exercise with a CPET is pretty extreme, and might on average produce a quicker response in terms of PEM compared to less intense exertion. Maybe there is some kind of dose response relationship here.

 

[Trish]

Thanks, @Evergreen, those are useful resources. It's a while since I read the IOM report. The Moore one I have on my list for factsheet refs. I agree it's useful.

I think the confusion over when PEM starts is partly because some people have referred to every effect of exertion even short lived symptoms that start during an exertion and are quickly eased by rest within minutes, so for example someone who has OI and starts to feel unwell and is able to lie down straight away may find the feel back to their normal within a few minutes. To me that's not PEM.
Also someone whose leg muscles start feeing weak and heavy after walking 2O metres if they are able to sit down those symptoms may ease off after a few minutes.
If we called those transient minor increases PEM, many of us would be straight into in PEM every time we move.

On the other hand if someone continues with activity and the immediate symptoms build up to the extent we can't ease them with rest, and instead become the lead in to much worse symptoms for hours or more, then it makes sense to call that PEM.

 

[Trish]

I wonder if the intensity or nature of the exertion might impact the delay. Exercise with a CPET is pretty extreme, and might on average produce a quicker response in terms of PEM compared to less intense exertion. Maybe there is some kind of dose response relationship here.

There is the added complication with interpreting the CPET studies that participants may have already gone over their PEM threshold in the days before the CPET, and in their journey to the test centre. So they may be building PEM on PEM already triggered.

 

[Evergreen]

A question for those who experience immediate PEM, does your immediate PEM include the features that don’t occur as part of normal fatigue, such as swollen glands, symptoms unrelated to the triggering activity, etc?

Today I went out for lunch with my goddaughter and her family. I drove there myself (30 min each way). This is much more activity than I would normally undertake. When I got back I fell asleep for three hours and at present I feel tired, a little achy including a mild headache, a little bit befuddled but no more than I was before setting of this morning, and have a runny nose (however I have just had tea and a runny nose often follows eating). It would not occur to me to call this PEM.

At present I could just be exhausted from the increased activity, especially if it goes away with further rest and/or sleep.

However if in the morning I still feel like this or worse I would then consider if I am experiencing PEM, particularly if other symptoms emerge or reemerge over night. Does that mean for me some degree of delay is necessary for me to regard something as PEM and I am defining PEM differently to others, or do others go into the weird and wonderful symptom tangents of PEM without delay?

Really good question.

I experience both immediate and delayed PEM. I had a visit yesterday - I only manage a few a year - where I talked to someone I love very much and am very familiar with for 45 mins. While lying down in my own bed. A small bit of having to multitask - talk and listen through noise - at the end of the visit, but no exposure to perfume or levels of light or movement that can be difficult in other PEM-triggering events. During the visit, I started getting worse brainfog, headache, a very wired/revved up feeling, increased pain all over, increased sensitivity to noise. Those symptoms continued and intensified and those are still my symptoms now. Eventually, I will come down from the wired feeling, but the others will persist. When the symptoms abate (these daysusually within a week), I will think I'm OK, but then do something that I can usually tolerate and get fired straight into the PEM hellpit again.

So I think that's different from your experience, where you described that you feel crappy, but no more than you were before.

I definitely call what I'm currently experiencing PEM in all its weird and wonderful glory. And I shouldn't be posting but that's wiredness for you.

 

[Evergreen]

Thanks, @Evergreen, those are useful resources. It's a while since I read the IOM report. The Moore one I have on my list for factsheet refs. I agree it's useful.

I think the confusion over when PEM starts is partly because some people have referred to every effect of exertion even short lived symptoms that start during an exertion and are quickly eased by rest within minutes, so for example someone who has OI and starts to feel unwell and is able to lie down straight away may find the feel back to their normal within a few minutes. To me that's not PEM.
Also someone whose leg muscles start feeing weak and heavy after walking 2O metres if they are able to sit down those symptoms may ease off after a few minutes.
If we called those transient minor increases PEM, many of us would be straight into in PEM every time we move.

On the other hand if someone continues with activity and the immediate symptoms build up to the extent we can't ease them with rest, and instead become the lead in to much worse symptoms for hours or more, then it makes sense to call that PEM.

I agree, if something is quickly eased by rest within a few minutes then that is not PEM. It doesn't meet the prolonged criterion.

For me, though, if my legs start feeling sore and stiff after walking too much, they're going to be sore and stiff for the next week or so. If I'm upright to the point of really triggering OI, then I'm going to have PEM. But if I just briefly get black in front of my eyes as soon as I stand up, I'll often be fine (though it happens more when not fine, so it may just be a more subtle less-fine). OI in people without ME/CFS causes fatigue, i.e. people do not just bounce back from dizziness without any consequences. But what Physios for ME and physiologists like Workwell point out is that they can't train us, and that that stands out as something they only see in ME/CFS and long COVID. So ultimately, I expect studies will show differences between us and people with other conditions in what looks similar on paper.

 

[Jonathan Edwards]

for example someone who has OI and starts to feel unwell and is able to lie down straight away may find the feel back to their normal within a few minutes. To me that's not PEM.

But (assuming this is exertion induced) isn't it not PEM because it got better quickly, not because it came on quick?

 

[Trish]

But (assuming this is exertion induced) isn't it not PEM because it got better quickly, not because it came on quick?

Yes, that's what I meant. Sorry I wasn't clear.

 

[Kitty]

But (assuming this is exertion induced) isn't it not PEM because it got better quickly, not because it came on quick?

I'd say it's more positional than exertional, and it's not PEM because there's no delay.

PEM isn't necessarily long lasting—sometimes the worst of it can be over inside a day—but it's always delayed.

Do you think it's useful to stick to this separation? I've assumed the delay's important because it could help with diagnosis (people with most pain and fatigue conditions are likely to get rapid onset worsening), and it might be a clue in research. But I don't actually know.

ETA: cross-posted with Trish

 

[poetinsf]

A question on how you interpret prolonged.

We could define "prolonged" means "not relieved by rest". I don't know if immediate PEM is same as rapid fatiguability since I don't have an experience with immediate PEM. But the rapid fatigue is usually relieved by rest in my case, even if that doesn't necessarily prevent PEM the next day.

I wouldn't know where to put my half-day PEM though. It is delayed, disproportionate to the exertion and not relieved by the rest. That's probably why I've been calling it a PEM. But it certainly is nothing compared to other patients who are dispatched to the bed for days or weeks after similar exertion.

 

[Yann04]

I don't know if immediate PEM is same as rapid fatiguability

Definitely isn’t for me. It changes something deeper. It’s like getting an allergic reaction or getting food poisoning when the PEM is immediate. (By that I mean showing up within an hour of overrexertion).

 

[poetinsf]

Definitely isn’t for me. It changes something deeper. It’s like getting an allergic reaction or getting food poisoning when the PEM is immediate. (By that I mean showing up within an hour of overrexertion).

Thank you. I'll keep in mind that immediate PEM != rapid fatiguability from now on.

 

[Jonathan Edwards]

I'd say it's more positional than exertional, and it's not PEM because there's no delay.

PEM isn't necessarily long lasting—sometimes the worst of it can be over inside a day—but it's always delayed.

It seems fairly clear to me that different people have different concepts of PEM here. Not surprisingly, perhaps.

The OI in question was OI induced by exertion so we were talking exertional.
I don't see any value in insisting on delay if only because activities may be spread out over long enough for the problem to start while still exerting.

I agree that the fact that PEM is often delayed may be telling us something crucial about mechanism and it may also be a good diagnostic discriminator. But I think readers are going to get confused if they are told that PEM is only what we call delayed worsening.

From the mechanistic point of view, my current thought about how all this works would allow for worsening with and without delay to both be features of a more complicated picture. Some PEM may require cell migration and activation in tissue such as muscle, which may fit well with building up over 24-48 hours. But the same signalling mechanism could be activated straight away on other tissues such as lymph node where the right cells are already in place and just need to make some RNA or even just phosphorylate some proteins, which could take a few minutes.

 

[Evergreen]

There is the added complication with interpreting the CPET studies that participants may have already gone over their PEM threshold in the days before the CPET, and in their journey to the test centre. So they may be building PEM on PEM already triggered.

Moore et al. 2023 did something interesting on that score - they told subjects to rest, and it seemed to work, in that they had less PEM before they did the first CPET than they did when initially assessed:

Subjects were instructed to rest prior to their 2-day CPET studies. Examining the baseline SSS scores to the pre-CPET1 scores, a prominent finding was that ME subjects were substantially more fatigued at baseline in their normal day-to-day lives than at the pre-test assessment prior to CPET1. Mean SSS scores—the mean of a subject’s SSS scores for all nine domains—at baseline were significantly higher than at pre-CPET1 (5.70 +/- 0.16 vs. 4.02 +/- 0.18, p < 0.0001).

But of course even in that semi-rested state prior to CPET, their symptom/PEM scores were still high compared to controls (eyeballing it from the figure in my post above, about 4.5 for pwME compared to about 0.3 for controls on a scale of 0 to 10).

Here's what Moore et al. say about it in the discussion (my bolding):

The phenomenon of being deconditioned yet overtrained is supported by the striking observation that, at baseline in
their home environment, our ME subjects reported significantly higher symptoms on the SSS than they did prior to the first CPET. Using the quartile thresholds for the pre-CPET1 SSS survey (as in Figure 5), 52 of 80 subjects–fully two-thirds–exceeded the threshold to be in the “High” symptom group at their baseline survey. Twenty-seven of 80 were in the “Mid” pre-CPET1 symptom category (vs. 36 at the pre-CPET1 survey), and only one of 80 was in the “Low” pre-CPET1 symptom category (vs. 24 at pre-CPET1). We advised subjects to rest in the days prior to the 2-day CPET protocol, largely so that the ME subjects would not arrive at the study site already exhausted. While we do not believe any of our subjects typically exert themselves at home as vigorously as we had them do during the CPETs, it is likely that persons with ME constantly live in the long tail of the recovery response. While activities of daily living are not as stressful as the 2-day CPET, recovery from less intense activities of daily living is likely to follow a similar decay curve. Such a response to physical activity would be consistent with the ubiquitous complaint from persons with ME that they have constant and persistent PEM. Most persons with ME would constantly experience exertion falling on an incompletely recovered decay curve, and thus their symptoms would increase to a high steady-state level.

 

[Kitty]

I agree that the fact that PEM is often delayed may be telling us something crucial about mechanism and it may also be a good diagnostic discriminator. But I think readers are going to get confused if they are told that PEM is only what we call delayed worsening

I can see the potential confusion, of course. I spent years in PEM before I even realised it was delayed, and pre-internet—when patients very rarely got to talk to one another—that was probably common.

One of the things I'm trying to get clear in my head (and not succeeding) is whether we need more than one term, or if that would just make things worse.

Personally, I found Trish's descriptions of rapid fatiguability and PEM as different concepts really helpful, but of course I saw it through the eyes of an experienced ME/CFS patient. It might have been a lot less helpful before I'd understood PEM as a consequence of previous exertion—which is delayed, but can both catch up with itself and compound.