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

[alex3619]

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).

 

[Mij]

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.

 

[Mij]

It matters to me insofar as:
1) More severely ill people may have more of whatever is wrong in their bodies, which may be important for detecting whatever it is
2) Most research up to this point has excluded us, and has found very little
3) researchers invent totally whackadoodle definitions of severity and publish misleading writing on it, like those ones that defined "severe" as people who would pass multiple sets of diagnostic criteria for ME/CFS
4) when researchers misunderstand severity as symptom burden/frequency, they haven't understood the condition or its classic defining feature (PEM), and that carries over into other assumptions they make, and doesn't bode well for them looking in the right direction.

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.

 

[DMissa]

What would be the next steps to try and confirm that there are actual changes in cell membranes - do you know of anyone working in that area?

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

 

[MelbME]

They found 1/4 of people with ME/CFS had hypertension as did 1/4 of the people in the Comparison group.
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I've been led to believe for many years by the media, papers, and advocacy that people with ME/CFS have orthostatic intolerance and a major cause of that is hypotension. In fact it is my understanding that orthostatic intolerance has been thought to be almost universal in ME/CFS. If that is the case I would have thought this data would show that there was a significantly lower % of PwME with hypertension which is not the case.

That makes me wonder what is the reason for orthostatic intolerance for those with hypertension, and why have we not seen more research asking that question. I feel that could hold an important clue to this disease.

I don't think I mentioned POTS. By definition POTS has a definition of an increase in heart rate WITHOUT a drop in blood pressure. However it seems clinicians and patients use POTS as a name for any sort of increase in heart rate above 30ppm, regardless of blood pressure. That muddies the water.

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.

 

[MelbME]

Does severity matter at this point when mildly and severely affected patients all experience severe delayed PEM when we go over our own personal energy threshold?

I didn't experience severe delayed PEM for 8 years until I started exercising again when I became very mild almost symptom- free. I didn't have OI during that time period.

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.

 

[MelbME]

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.

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.

 

[forestglip]

there are many processes in the body that take 24-48 hours to alter path.

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.

 

[MelbME]

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?

 

[Peter T]

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.

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.

 

[Andy]

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.

 

[Sean]

for some it is quite possible that they are in a state of rolling PEM.

I think this is a serious confounder.

 

[forestglip]

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?

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.

 

[forestglip]

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?

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.

 

[forestglip]

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

The US Committee on the Diagnostic Criteria for ME/CFS describes PEM as having an immediate onset or occurring within 30 h, but it is outlined that PEM may also develop hours or days after the trigger has ceased (Locher and IOM, 2015). Moreover, the committee describes an unpredictable duration of PEM as it may last for hours, days, weeks, and even months.

In accord, a survey demonstrated a large variability in reported onset and duration of PEM, and most of the respondents reported that they sometimes experienced an immediate onset and sometimes a delayed onset (Holtzman et al., 2019). The delay ranged from 1 h to a week, and the duration could last from 1 day to several months. Similar results have been reported by others (Chu et al., 2018; Stussman et al., 2020).

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

 

[MelbME]

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.

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.

 

[forestglip]

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.

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.

 

[horton6]

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).

 

[MelbME]

Interesting discussion on PEM.

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

 

[Kitty]

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.