Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank, 2024, Huang et al

Perhaps the OI/hypertension discussion might benefit from my experience. I am not alone, but I have BOTH hypertension and NMH, neurally mediated hypotension. My hypertension is constant, my OI is usually suppressed except when very tired, such as my two and a half days without sleep earlier this week. During my Tilt Table Test maybe twenty odd years ago, my blood pressure crashed to zero and my cardiologist was about to call the crash cart when his treatment restored my bp enough to regain consciousness.

Given that maybe most of us have a new type of OI (eighty percent if I recall correctly), if it can be called that, with hypoperfusion of the brain, that does not show up on conventional TTT, we still do not know nearly enough to answer these questions. This is the kind of complicated that makes it no surprise that researchers still have not figured it out.

To me, metabolomics data is critical in our path forward. Of course I am biased, my background is in biochemistry.

For the record I consider I have ME, if pacing well I have minimal fatigue (but it takes only tiny amounts over my limit to have it crash back), I have been diagnosed with CFS four times (ME was not being used much back then), and may have been sick 56 years now after measles encephalitis as a child, though it really kicked up several notches after a stomach flu in 1985, several years before I was diagnosed as having antibodies to a coxsackie virus (1989).

 

I developed OI after reactivation of both HHV6 and EBV 11 years after PVFS/ME onset. I'm referring it OI because it's the only term we have at this time. We don't have a proper term for what we're experiencing for that either. It certainly exacerbates the pathophysiology of delayed PEM and we don't understand that yet either.

 

I understand what you're saying and wasn't trying to diminish anyone's experiences. The severity of the patient is very important. What I was trying to convey was that focusing more on the distinctive set of symptoms that we all share in common such as delayed PEM.

I think we'll find that there are different types of ME, like there are with MS, in which there are 4.

 

I have seen lipid homeostasis issues in cells from multiple tissues from pwME (some of these are experiments with Chris) and I do want to specifically look at membranes in a future project

 

Hypertension is in reference to ongoing elevated blood pressure at rest.

Orthostatic hypotension is the dramatic drop and sustained drop of blood pressure upon standing outside of a normal range. POTS is the dramatic rise and sustained rise of heart rate upon standing outside of a normal range.

Hypertension had no significance to ME/CFS, this isn't related to orthostatic issues.

 

Depends on the study, certainly severity matters if you were to develop an objective marker for clinical trials. It remains an important need for this disease.

In terms of studying the pathology of the disease or developing a diagnostic. It may not matter but it also may matter, the cause of severity is unknown.

One might simply think a severe patient has a more severe pathology of ME/CFS, but that may not be the case. A severe patient may have an accumulation of undefined co-morbidities that exacerbate their physical condition and remain unaccounted for.

 

The delay in PEM is very likely related to RNA, there are many processes in the body that take 24-48 hours to alter path.

The exacerbation that occurs in response to this new path is of course interesting.. what is biologically happening.

 

From what I hear, delay in PEM changes to nearly immediate when people are very severe. If this is actually the same phenomenon, then a process that only occurs consistently after over 24 hours wouldn't make sense.

 

That would be interesting to know. The delay differs between people (see DOMS as an example) but I think the fact that people say the delay in PEM becomes immediate when they become severe. That's an interesting piece of knowledge.

Is there a paper on this or is this from your experience in discussion with patients?

 

I don’t think we can say either way if the delay in PEM changes as people become more severe.

For example with my gluten intolerance there is a twenty four hour delay in the emergence of symptoms, but when I was eating gluten everyday I was neither aware of the gluten issues or the delay. The symptoms were mixed up in the general confusion of my ME. I had previously found that a raw food vegan diet seemed to help my ME symptoms when I was at the trying anything and everything stage, so later trying this again I found when I broke my diet with a sandwich my ME symptoms got worse along with a migraine twenty four hours later. Looking at gluten more systematically I identified my intolerance, but the clear pattern of the delay was only apparent when I was generally gluten free. Similarly if someone is in rolling PEM it is not at all clear if there is or is not a delay in the symptoms being triggered because they are present all the time.

The issue is further confused if one accepts that there is a distinction between PEM and rapid fatiguability. I find when I am more severe in general and/or when I am in PEM that rapid fatiguability becomes more rapid and more marked. So if someone is very severe and in rolling PEM it would be near impossible without some biomarker of PEM to sort out what is ongoing PEM and what is rapid fatiguability.

 

I think it is more likely that the more severe a patient is, the lower the level of over-exertion needed to trigger PEM and, as Peter says, for some it is quite possible that they are in a state of rolling PEM.

 

As far as I remember, it's just from what people have said on forums. I'll try to search to find these anecdotes.

The way I understand "rolling PEM" is you're constantly overexerting, so even as the PEM from one activity ends, new PEM is beginning, and you're always in PEM.

Again I'll have to search to confirm I remember right, but I think this is different from if someone could clearly tell PEM was beginning based on an activity that only happened an hour ago.

 

After some searching and some thought, I think it's very possible that when people say "immediate PEM", they're experiencing rapid fatigability, like @Peter Trewhitt said.

I immediately get very tired after eating, but it only lasts a few hours so I wouldn't consider it PEM. I can see how if this immediate fatigue lasted a day or two and overlapped with "real" PEM starting, it would seem like PEM was immediate.

But just to get a taste of what people say, there are lots of anecdotes if you search online for "immediate PEM" or "immediate PEM severe". Nothing I saw from a quick search was very convincing that it's the same thing.

Wikipedia does say "PEM usually starts 12 to 48 hours after the activity,[34] but can also follow immediately after. PEM can last hours, days, weeks, or months.[10]: 6

This long German PDF is citation 10. Maybe someone who speaks German can figure out what it says about immediate PEM.

 

There are a few mentions of immediate PEM in research as well, for example:

Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome, 2023, Vøllestad et al

What I remember about delay decreasing with increasing severity may have just been based on one or two people, I'm not sure.

 

I have heard from patients that experience immediate PEM such that they describe this red flush that starts in the face and spreads.

I am particularly interested in the concept that a mild patient may experience a delay but if they were to become more severe with time they notice their PEM has less delay. I'd be keen to know of PEM delay inversely correlated to severity.

That is something I haven't heard but would be a worthwhile area to investigate if that was happening.

 

My mind could have been playing tricks with remembering hearing that delay decreased as people got more severe. I'll keep an eye out, but maybe some of the severe members here can confirm or deny it happening to them.

 

I'm very severe, and I still experience my PEM on a delay of about 24 hours, with the peak in symptoms at roughly 48 hours.

There are some symptoms that I experience an uptick in immediately after an activity (e.g. muscles in my scalp fasciculate if I raise my head a little bit off the pillow) but that usually feels like I'm already in a state of aggravating my condition (perhaps this is "rolling PEM", but it's not the flu-like feeling of entering a sickness state, or the headache and fatigue I mostly associate with PEM).

 

Interesting discussion on PEM.

What is the range of time before PEM do you recognise its coming?

 

For me (moderately ill) I often wake up with it the day after exertion.

There appears to be some kind of relationship with sleep, but I don't know how common it is or whether it means anything. For instance, overactivity can cause so much overstimulation that I can't sleep at all. On Wednesday evening I went to a new session at a pub 35 minutes' drive away, I played for longer than I'm used to, and felt a bit nervy due to not knowing most of the people. After that I was awake for 28 hours (so I felt okay on Thursday), and the PEM has only kicked in this morning, Friday. Ugh.