If you had to guess ME/CFS cause, what'd you say?

My early experiences of ME convinced me that it was neuroimmunological. I didn't have any physical limitations from it. So far I haven't seen any "sound science" to change my bias.

That's what I mean about judging hypotheses on whether they "feel right". We factor in the "sound, proven science part" (which is presently pretty much zero) and out personal experiences, which we give great weight to since we "know it's true", and yes, we factor in misremembered facts and facts that we're missing the proper perspective on, and some non-applicable factors, such as mood, and we end up with "That hypothesis makes sense" or "That's total rubbish!!!". I hope that whoever does decide ME research funding has a stronger medical science background and weighs all the available evidence properly (I don't have a lot of confidence in that; politics and fame/popularity are involved), but there's no reason why I can't decide to read one paper whose summary "feels right" to me and chose to not read another that "doesn't feel right".

 

The idea was a 'glial cell reaching into different parts of the brain'. There aren't any.
As Trish says, we would do better to stick to science.

ME might be due to the effect of tap water on the nucleus caeruleus but probably isn't.

We have no evidence that there is anything much wrong with glia in ME anyway. The data did not pan out, unsurprisingly.

I welcome out of the box suggestions, though, certainly as things go they might be more interesting than a word salad derived from unreproducible data!

 

FWIW, the million $ question for me is whether ME/CFS reflects pathogen persistence or immune dysfunction (including autoimmune responses).

It could be something else, I know, like an acquired channelopathy, but my money rests on one of those two.

Science is paramount, but I try not to lose sight of politics and history and embedded vested concerns (e.g. patents and legacy and liabilities, etc).

 

For myself, I've always felt that it was the antibiotics that I was put on for a very bad tooth infection that caused my ME. Second guess would be the fact that I had a very bad cough and cold for six months until it was discovered that I had a very bad tooth infection that was stopping my immune system from dealing with the cold. Or maybe it was a combination of the both.

 

My early ME was similar in that I was still able to work full time, though I was having some symptoms. Unfortunately, I didn't know I had ME back then and if I'd known what I know now I would have stopped working straight away and begun a resting routine and access things from there. PEM was very subtle in those earlier years until I started the downward spiral.

I personally think the focus needs to be on PEM because the suffering is so great with it. We do need to know more about the earlier ME but early ME like symptoms could still be other illnesses that need to be ruled out.

There is a lot to unpick in this illness and understand. For example the levels, are there stages in each level? Then how do you categorize the managed MEs where they have managed to have less severe PEMs? I would call myself moderate but also a managed severe, meaning I could easily become severe again if I didn't continue my resting routine. I am not a cured severe ME patient, I am a managed severe that is now at moderate after decades of resting.

 

Simon McGrath's comment came to mind - years of hypothesis testing hasn't got us very far.
I'm hoping GWAS [DecodeME] will give us clues.
Think Jonathan suggested a potential immune cause -- new class of immune cells. Pathway we don't know e.g. TPPP gene -- turned up in very small Norwegian GWAS.

 

That was based on a mis-memory. Skimming lots of research papers (while suffering from brainfog) does not lead to perfect recall of details. I read something about long-range reach in the brain, and maybe that was about neurons in some part of the brain. Also "In humans, a single astrocyte cell can interact with up to 2 million synapses at a time." Okay, that's over millimeters rather than across brain regions, but some of those 2 million neurons might have long reach.

While trying to verify glial reach, I came across a paper on astrocyte involvement in longer-ranged timing signals in the brain: "These findings identify a previously unknown role of astrocytes as active cells that might distribute long-range signals to synchronize the brain clocks, thus further strengthening the importance of reciprocal interactions between glial and neuronal cells in the context of circadian circuitry."

Well, as the above quote points out, astrocyte functions are not fully understood, so tests based on what's known about glia functions may have missed something important. The present state of glial testing might be the equivalent of testing a computer by checking that the "on" LED is lit. If you know anything about computer chip timing, you'll be aware of what can go wrong if the timing signals don't arrive at the proper places at the proper times. It's possible that this newly-discovered role of astrocytes in transmitting timing signals across the brain could explain some aspects of ME.

 

I agree that anything might cause ME but if we are going to discuss brain cell function it would be good to get it roughly right.

2 million synapses in the pyramidal cell layer of cortex is about 50 neurons worth - so pretty local.

The papers on glia in ME all refer to microglia as far as I know - which are unrelated to astro yes, even if they are classed under 'glia' which just means 'other parenchymal cell types than neurons'.

I guess the basic point to make maybe is that getting messages rapidly right across brain - say a hundred times a second, is what neurons do all the time so we do not need to think of glia of any sort. The astrocyte people are constantly writing papers on 'hitherto unknown functions of astrocytes' to sound smart but the real problem is that we have no idea how neurons manage thinking of any sort. They are helped by astrocytes, certainly, but EEG traces make it look unlikely that timing as controlled primarily by atrocities rather than neurons themselves. Moreover, the specific messages are not much to do with timing, but which particular cells fire.

I am sorry to nitpick but there is so much dross about on 'neuro-inflammation' that doesn't actually seem to exist.

 

Clearly, I missed something...

 

sorry, the predictive text changed 'anything' or maybe '.nything'

 

I don't take the lack of obvious signs of neuroinflammation as being complete proof of lack of involvement of the brain's immune system. We don't really know how neurons function, and we also really don't know how glial cells function, so it's hard to trust the existing methods for identifying neuroimmune abnormalities.

When my ME started, apparently as a type IV food sensitivity, I had the standard ME neurological symptoms triggered by t-cell activation. To me that implies a neuroimmunological mechanism. Several treatments were more effective when taken sublingually, which again implies a neurological mechanism. I lacked any observations of a cause elsewhere in my body, aside from triggering from the digestive tract. So I was, and still am, biased towards neuroimmunological mechanisms. I've read papers supporting this hypothesis, and I admit I rate them higher than I do papers about liver or viral causes.

 

ME/CFS is an umbrella term for various problems. Some day we will be able to understand how different causes can lead to a similar presentation.

The assumption that there's only one ME/CFS is maybe a reason we haven't made much progress. Let's not search for that one perfect biomarker or explanation that fits all cases, let's search for subgroups that make sense and fit into a coherent picture.

That recent study about a structural DNA variant that led to a ME/CFS-like phenotype is not going to get as much attention as it should in my opinion just because it doesn't fit neatly into the existing assumptions. The patient had some signs of subtle hormone dysregulation which is not that uncommon. Maybe we could learn a lot from it. In this case, the authors proposed a problem with regulation of neurosteroids leading to inappropriate activation of GABA receptors. I read this as "constant sedation of the patient's CNS".

The WASF3 discovery also started with a patient that had a ME/CFS-like illness but also maybe did not fit the existing view of how proper ME/CFS should look like.

 

What DNA study?

 

@Ash https://www.s4me.info/threads/long-...e-akr1c2-severe-fatigue-2023-oakley-et.35423/

 

I think in my case of ME it was an immune reaction to an antibiotic which caused permanent metabolic change in homeostasis which then set of pro inflammatory symptoms causing a cascade of symptoms that was made worse by other hits like flu tipping me into ME.

I have no deep knowledge of all these processes so this is a wild guess.

 

This is the conclusion researchers have come to in regards to the rare autoimmune disease I have called "Relapsing Polychondritis" (RP). Researchers now believe it to be a syndrome rather than a single disease entity and they believe that there are multiple disease pathways causing similar symptoms. It would explain why RP patients vary so much in presentation, progression, and response to treatments. Unfortunately it also likely means it will be that much harder to find more effective treatments and/or cures. Right now there is research being done at the NIH that is aimed at trying to tease out some different 'types' of RP (sub-groups). This to me seems to be a smart move, albeit it might not be so straightforward or simple. Like ME/CFS no biomarker exists for Relapsing Polychondritis and the diagnosis is based on symptoms.

* For those who don't know my story, before being diagnosed with RP I was misdiagnosed by the Open Medicine Clinic as having ME/CFS.

 

Hi all,

I guess I'm a bit late to the party. For what it's worth, I think MECFS is a hypersensitivity to low grade inflammation. Typical PEM that lasts a few days, for example, tracks inflammation response to maximal exercise in healthy people. MECFS people could be responding to low grade inflammation caused by minimal exertion as if it were a maximal one. And severely ill patients could be so sensitive that they are in permanent state of PEM just from the inflammation of the baseline metabolism. Intolerance to alcohol and flu shot also could be explained by the same hypersensitivity.

Internally, microglial cells could be the one that becomes hypersensitive. That could explain brain fog and other neurological symptoms as well as fatigue and ache. Microglial activation has been implicated in other chronic fatigue/neurological problems, such as concussion fatigue, GWI as well as age-related ones.

The innate immune cells could be becoming hypersensitive from the stress of novel virus that they don't have adaptive immunity for. That could explain the high rate of MECFS prevalence in COVID19, and also explain the likes of vaccine, Paxlovid and metformin drastically cutting down the chance of long COVID. For non-viral MECFS cases, prolonged inflammation from stress could be triggering the hypersensitivity.

And yes, this probably is more of my imagination than science. A working theory does help though, to comprehend and predict so that I can deal with the problem. I'm not married to any theory, however; I'm always ready to drop any theory at any evidence that is to the contrary.

 

I actually think it is the other way around. The idea that MECFS has multiple subtypes have been hindering the progress, imo, as such notion allows people to propose and explore theories that does not explain all phenomena. They look at a subset of MECFS symptoms of severely ill patients and call it mitochondrial dysfunction, for example. Or hibernation. Or persistent viral infection. Or blood clot. You ask them, how do they explain PEM? Or brain fog? Or light sensitivity? Or fully functioning mild/recovered patients with PEM only in specific circumstances? The answer typically is: maybe it is a different subtype. Or some convoluted explanation like metabolic dysfunction triggering dormant virus which in turn triggers some kind of trap, etc, etc. I think we'll be able to focus and make the better use of the limited resources if we dismiss theories that does not explain all key symptoms and phenomena. A theory worthy of pursuing should at least explain the hallmark symptoms in a straightforward manner. Many theories out there don't, imo.

 

I've had C-reactive protein testing done at different times but there's no indication of inflammation in my case. The testing at one time was 3-4 days after recovering from delayed PEM- nothing.

I feel like I'm dealing with a viral infection but there is no virus. I've had RNA/DNA testing for viruses and an immune phenotyping profile done and all it shows is that my CD4, CD8 et are all below normal range, but that doesn't point to anything specific. Dunno. I don't have blood clots either b/c I've had testing for that.