RedFox
Senior Member (Voting Rights)
I strongly agree with you, Ravn. We need to shift the research from why fatigue happens, to why PEM happens. It's the cornerstone of this disease.
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If you had to guess ME/CFS cause, what'd you say?
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Kitty
Senior Member (Voting Rights)
I can't even remember many groups systematically taking the really basic measurements (urine volume, makeup and frequency; skin & core temperature; sweat makeup; heart rate and variability; blood pressure & gases; blood sugar; stress hormones) whilst rested and then during the onset of PEM triggered by a significant overstretch of capacity.
Anyone who's had a bad bout of PEM knows that at least some of the readings will be different, but unless the work is done, nobody will be able to gain insights by analysing the changes and comparing them with other data.
+1
Yes, the immune system(s), and their interactions with each other and with various other parts of the body (microbiomes, vagus nerve, etc) is still so poorly understood. A real problem is that doctors assume that it's better understood than it is, and that the basic diagnostic tests cover all possible problems, and all treatments work exactly the way they are supposed to in the textbooks, for all patients. If a mechanic trained on a Model-A Ford popped the hood on today's typical car, he'd say that he had no idea what all that stuff did. Doctors, facing the same lack of knowledge of how the body works, seem fine with the equivalent of changing the oil and blaming the car owner if that doesn't fix the problem.
I'm less enthusiastic about that approach. I think that the delay from physically-induced PEM is explained by the immune response to muscle usage (and damage): The immune cells have to detect the signals of damage, communicate that to other cells, then there's an orchestrated response, which in turn triggers a response from glial cells, after another delay. Cognitive exertion could trigger the same response from glial cells without several of those delay steps. My physically-induced PEM had a consistent 24 hr delay, while cognitively-induced had a shorter (<1 hr) and more variable delay, probably dependent on the magnitude of the exertion. I'm still impressed by type IV sensitivity responses: a precise and consistent delay of 48 hrs +/- maybe 5 minutes. What sort of timing mechanism is at work for that?
The other reason I'm not in favor of focusing on PEM is that I managed to cure my PEM, but I still have the other ME symptoms: lethargy, brainfog, aches, sleep problems and some other minor symptoms. So, curing PEM does not cure ME; it's just one symptom. Figuring out the mechanism of PEM could possibly provide a clue to whatever dysfunction is triggering it, but I don't think it's likely to be so important of a clue that it will quickly solve ME.
I still favor the black-box approach: try a lot of different inputs, such as chemicals, and look for any reliable responses, positive or negative. If they stumble across a reliable beneficial factor, maybe some slight modifications might make it a useful treatment. I'm fine with a treatment that they can't explain why it works.
A factor could narrow down where to look; if it doesn't cross the BBB when swallowed, but does work sublingually, focus on the brain rather than the gut or muscles. If a chemical does have a reliable response, try to find cofactors, which can narrow down how it's doing whatever it's doing. If there's a consistent delay, that too helps narrow down how it's working. IF ME is caused by a slight change in some ratio of certain molecules, and limited to a small area of the brain (the ratio is blurred out only mm from the cells), then it's going to take a very very long time to find it by looking for differences between patients. My ME has responded (mostly negatively) to quite a few factors, and I expect that's common for PWME. I wouldn't be surprised if the typical PWME responded to at least a few dozen common chemicals (herbs&spices, etc). The problem is reliability and consistency. I respond badly to cinnamon, but others find that it helps. However, if they tested enough people, there might be some reliable common factors, which could be useful clues.
No, it's just a very common symptom, but you can get rid of PEM but still have ME. I expect there is a group of people with ME who fail the diagnosis because they don't show that one symptom, which is not essential for ME.
Ravn
Senior Member (Voting Rights)
You're misinterpreting my argument @Creekside
I'm not saying PEM is the only phenomenon that needs looking at and I'm certainly not saying curing PEM is the same as curing ME. I'm not even claiming the current diagnostic criteria requiring PEM are necessarily right. However, for now, PEM is the one thing every pwME diagnosed according to current criteria has in common and which at the same time is uncommon in other diseases. Even if it eventually turns out that there's a variant of ME without PEM, there will still be a very large number of pwME who do get PEM. Therefore any serious ME-hypothesis has to be able to provide a credible explanation, backed by empirical data, for a mechanism that can at least enable downstream delayed PEM in susceptible people.
My key argument is nothing more than that shifting the research focus from fatigue and/or general lack of energy to investigating the delayed aspect of PEM serves to a) focus the mind and b) narrow the field of investigation. The usual focus on fatigue and/or general lack of energy has given us decades of muddled thinking including confusion about the nature of PEM. Importantly, fatigue and/or general lack of energy can be caused or impacted by about a trillion things. The potential causes for delayed PEM are, probably, still rather numerous but there'll be fewer than a trillion. So searching in this narrowed field increases the chances of finding that crucial thread on which to pull to hopefully unravel (some of) the rest of the ME mystery
And now that I've spent almost an entire day trying to write a single post that's precise enough to not also be misunderstood I realise there's another mystery: why is it that the more brainfog I have the longer and more complicated my sentences become (trust me, the draft versions were a lot more convoluted than what you've just read)? This is almost as weird as the delayed PEM thing. Anyway, back to bed for me, again. Sigh
I'm not saying PEM is the only phenomenon that needs looking at and I'm certainly not saying curing PEM is the same as curing ME. I'm not even claiming the current diagnostic criteria requiring PEM are necessarily right. However, for now, PEM is the one thing every pwME diagnosed according to current criteria has in common and which at the same time is uncommon in other diseases. Even if it eventually turns out that there's a variant of ME without PEM, there will still be a very large number of pwME who do get PEM. Therefore any serious ME-hypothesis has to be able to provide a credible explanation, backed by empirical data, for a mechanism that can at least enable downstream delayed PEM in susceptible people.
My key argument is nothing more than that shifting the research focus from fatigue and/or general lack of energy to investigating the delayed aspect of PEM serves to a) focus the mind and b) narrow the field of investigation. The usual focus on fatigue and/or general lack of energy has given us decades of muddled thinking including confusion about the nature of PEM. Importantly, fatigue and/or general lack of energy can be caused or impacted by about a trillion things. The potential causes for delayed PEM are, probably, still rather numerous but there'll be fewer than a trillion. So searching in this narrowed field increases the chances of finding that crucial thread on which to pull to hopefully unravel (some of) the rest of the ME mystery
And now that I've spent almost an entire day trying to write a single post that's precise enough to not also be misunderstood I realise there's another mystery: why is it that the more brainfog I have the longer and more complicated my sentences become (trust me, the draft versions were a lot more convoluted than what you've just read)? This is almost as weird as the delayed PEM thing. Anyway, back to bed for me, again. Sigh
AliceLily
Senior Member (Voting Rights)
I've had PTSD from my experience of the ME PEM. I've had ME for over 25 years and been to all levels of ME except needing tube feeding. PEM is the very worst ME can throw at you. At very severe ME, PEM it is a never ending repeat circuit of hell on earth day in and out. The hundreds of symptoms it produces at that level of ME is something I never want to experience again.
I should add that PEM to me is a collection of symptoms. Some are always there or regular, some are new, some come and go. So there is much going on within this collection during PEM from hour to hour, day to day.
I should add that PEM to me is a collection of symptoms. Some are always there or regular, some are new, some come and go. So there is much going on within this collection during PEM from hour to hour, day to day.
I can agree with shifting the focus from fatigue (which they can't measure anyway). In this thread ( https://www.s4me.info/threads/has-s...-normal-post-viral-fatigue.35699/#post-498829 ) I made this comment "A quick look showed several papers along the lines of "Specialized neurons that are activated after infection have been identified in the brain. These neurons orchestrate an array of sickness behaviours that help the body to cope with disease and to fight infection."" I'd like to see more research along those lines: is there a clump of neurons whose activation correlates with ME symptoms, and maybe a different clump correlating with PEM?
I feel that PEM delay, even if it's precise and consistent, is easily explained by immune system delays, and thus not really leading to anything specific to ME. If, for example, the delay for physically-induce PEM was found to correlate with the rise in IFN-g, that wouldn't narrow the possibilities down by much, since IFN-g has so many effects in the body. If you're looking for changes in the brain, injecting one specific cytokine would reduce the number of changes you'd get from general immune activation, so it would have some value. I just don't think it's the best path to follow, since finding the cause of PEM delay isn't likely to be easy.
A major point in favour of studying PEM is that it's probably the most reliable symptom among PWME. With some subjects, you can have them lift a weight 3 times or pedal a bike 5 minutes, and know that 23.45 hours later, they will reliably show certain measurable symptoms (temperature rise, lower grip strength, or whatever). That means that you can look for changes at that specific time, whether it's serum cytokines, neural activation in the hypothalamus, or whatever your specialty is. I think that's way more efficient than studying hundreds of PWME and hoping that some factor is going to jump up and down waving a flag. There are just too many differences between individuals. So, I'm less in favour of studying the delay of PEM, and more in favour of exploiting that reliable delay.
Our thought processes depend on interaction between neurons, glia, and other factors. When we compose text, some cells are offering possibilities, while others are pruning them back, and others judging how we think they'll be perceived by other people. If ME is altering the balance between those cell functions, it's reasonable to expect that it will affect how we write.
As an ME test, I think there are too many non-ME factors affecting composition style for it to be useful.
the problem with this is that provocation studies is not without risks. While I agree we need to shift away from the concept of ‘fatigue’ and it is not useful, I tend to think 5at metabolic pathways is where the answer may be, but I am not stuck on any particular pathway as the explainer to each one of us. There may be several pathways present in our patient population, with each individual having a particular signature.
I hope that researchers find the cause in my lifetime. I have a vivid memory of a researcher telling me they would have treatments within 7 years. That was 10 years ago.
Dysfunction of the anterior cingulate cortex (ACC), whose job (part of executive functioning) is to filter out unnecessary information.
I have noticed many pwME have this problem, me included.
In Younger's RMS study, the part of the brain which showed the most abnormalities was the ACC.
I did this test on myself and it showed a far greater abnormality than anyone's on Younger's study - probably because of how severe my illness is while he only likes to study moderate or mild patients like 95% of researchers.
Of course, if this was a normal illness, neuroscientists would have rushed to replicate this on 1000 people and study the ACC in ME. But because of extreme prejudice and discrimination, it has been crickets since Younger's study which was published like what 4 years ago?
I think this is one of the most solid findings we would have, possibly a biomarker, but literally nobody gives a shit.
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Society trying to reduce risks to 0.000000% is certainly hampering science. Some PWME crash badly from exertion, so you shouldn't do provocation testing on them. However, others get reliable, consistent PEM that lasts a short time, with no longer-term effects, so if it would speed up finding a solution for ME, I think there would be plenty of volunteers.
Do you mean 5-HTP pathway? A search for 5at led me to rocket propellant. I don't think my "fatigue-like symptom" is due to a lack of rocket propellant, but that's an interesting explanation.
Hoopoe
Senior Member (Voting Rights)
Lately I'm thinking that PEM must involve neuroinflammation, and that's why there is malaise. Maybe some proof-of-concept experiment could mitigate PEM in a provocation study by temporarily blocking neuroinflammation.
And the neuroinflammation is presumably a response to some elusive peripheral signals.
And the neuroinflammation is presumably a response to some elusive peripheral signals.
No sorry, that was a typo. The iPad screen keyboard sometimes switches from letters to numbers without warning
leokitten
Senior Member (Voting Rights)
Immune system dysregulatiom triggered by viral infection. Caused chronic immune overactivation for many months that set in motion a cascade of negative consequences, particularly areas of my brain, that my body now can’t seem to come out of. The symptoms felt exactly like that in the beginning.
AliceLily
Senior Member (Voting Rights)
Change in brain function was my earliest debilitating symptom of ME long before the PEM got significant. The earliest symptom before that was two days of very severe vertigo-like lightheadedness, the third day I went down with a nasty cold. I'd never experienced anything like in my life before.
I have a feeling that we can carry the ME for years without obvious PEM but perhaps getting colds and flu and other things might be what spirals us into the advanced PEM ME? Which makes the ME chronic?
AliceLily
Senior Member (Voting Rights)
Interesting what you have written here @Creekside Excuse me though, even though I have had ME for over 25 years I am still trying to get my head around all the nuances of ME.
I think I understand what you are saying here. But I think really what is happening with you is that you have tamed down the ME flaring PEMs. I would like know how long it took you and how severe things had been for you previous. I personally think what you are experiencing now is still PEM but at a much lesser degree. All those symptoms to me are symptoms of PEM that can still exacerbate with having really overdone or with accumulation if you are not careful.
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Well, that constellation of symptoms has been with me since 2001, even on days when I did no significant exertion. I see PEM as an exacerbation of those symptoms. I could do some triggering exertion, and 24 hrs later, those symptoms would abruptly flare up, with a slight but reliable temperature increase. PEM-phase vs non-PEM-phase seemed quite distinct. My PEM was fairly mild (I'd have a crappy day, not doing much, but not bedridden) and usually passed by the next day or two. I never had a "crash". or even lengthy mild PEM.
I had fairly reliable PEM for 10+ years. Then one day I did some heavy exertion (chainsawing a big tree), knowing that I'd have bad PEM the next day. To my amazement, the expected PEM didn't show up. My journal showed that I'd taken a tsp of cumin the previous day (one of my occasional experiments, because cumin gave me temporary remission years previous). I experimented with that, and found that taking a level tsp of ground cumin reliably blocked my PEM 100% for three days. Taking I think it was 5 full tsps of cumin extended the blocking to 5 days, but that seemed to be minimal improvement and risked losing effectiveness by overdosing. If I forgot my dose, PEM would trigger as usual, but taking cumin once the symptoms flared up would block them after an hour or so. After taking cumin every 3 days for 2.5 years, with occasional intentional missing a dose or taking a smaller dose (to see what would happen), I found that I no longer had PEM, regardless of my level of physical exertion. Cognitive exertion didn't trigger PEM either. I also lost the worsening of symptoms if I didn't take my regular T2 dose. That should mean something too, but T2 has so many different effects on cells that it's hard to guess how it was doing what it was doing, and why curing PEM might affect that.
I don't think so. I have the symptoms that I had when I wasn't in PEM-phase. My ME symptoms don't increase even if I dig 20 wheelbarrow loads of soil or swing an 8-lb sledgehammer until I'm exhausted. If I had PEM at a lesser degree, it should increase with exertion.
There are dietary triggers that increase my ME symptoms. That's very similar to PEM, but I take that to mean that PEM's mechanism triggers the same brain changes that some other factors do.
A few people have reported a reducing in ME or PEM symptoms, but nowhere near the extent that it had for me. Why did it work so well for me and not for anyone else? I think it's such a shame that the medical research system doesn't have an option for really unusual cases to be studied (without a huge amount of effort for the patient). I did offer to the OMF to provide some before/after blood or other samples or scans, to see if they could find a difference before/during PEM and with/without cumin, but no one took me up on that. An opportunity lost.