Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

V.R.T. said:
My partner who is also a pwME has episodes where she falls asleep very quickly in the daytime that do not feel to her like the regular feeling of getting sleepy and taking a nap.
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I get daytime sleepiness, too. The important thing is that I HAVE to fall asleep to recover. If I just rest for hours on end, the sleepiness doesn't go away. But if I fall asleep, and usually I only fall asleep for 5 minutes, I wake up and it's like my system has been reset and the sleepiness is gone. Unless I've really overdone it just short of PEM then the sleepiness persists throughout the day.
 
OrganicChilli said:
I get daytime sleepiness, too. The important thing is that I HAVE to fall asleep to recover. If I just rest for hours on end, the sleepiness doesn't go away. But if I fall asleep, and usually I only fall asleep for 5 minutes, I wake up and it's like my system has been reset and the sleepiness is gone. Unless I've really overdone it just short of PEM then the sleepiness persists throughout the day.
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Hers she says feels like she's been drugged. Like it doesn’t feel like normal falling asleep. And she sleeps for a couple of hours typically when it happens.

It's been the case since I met her, 2 years before we got ME but she had had post viral illness before then after glandular fever.
 
V.R.T. said:
I don't really know much about either
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There was a school of thought out of Australia that suggested ME/CFS was in at least some cases a channelopathy, or involved a channelopathy.

I am struggling so excuse this layperson's attempt to describe:
Channelopathies refer to ion channels in muscle cells that fail to one degree or another due to one of three elements being off (sodium, calcium or potassium.) The cells misfire and the result is abnormal weakness or even paralysis. The condition is broadly referred to as periodic paralysis.

Not much is known about it.
 
I am not sure T cell involvement in narcolepsy/cataplexy would be relevant to ME/CFS, iirc a Swiss group showed pretty definitively that it is mediated by antigen-specific T cells that target orexin-producing neurons. The damage to that neuron cluster was also quite visible in neurological studies.

In general, every piece of evidence I’ve come across involving T cells in neurological disease has evidence of antigen specificity and detectable damage to a part of the brain. Other examples of location specificity of T cells are mediated by local interferon signaling calling the T cells there (eg psoriasis).

Perhaps orexin is involved in ME/CFS in some way but I’m skeptical that it would be T cell mediated like in narcolepsy.
 
jnmaciuch said:
Perhaps orexin is involved in ME/CFS in some way but I’m skeptical that it would be T cell mediated like in narcolepsy.
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For sure it is not gong to be the same error of T cells recognising an orexin-related antigen but that does not stop there being another error making use of the same window in the brain's exclusion of T cells.

My reading of the literature just this last week suggests that despite claims it is not clear that anyone has nailed a specific antigen though.
 
Jonathan Edwards said:
For sure it is not gong to be the same error of T cells recognising an orexin-related antigen but that does not stop there being another error making use of the same window in the brain's exclusion of T cells.
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I’m not sure what this refers to? If this is a reference to the idea that the CNS is protected from lymphocyte infiltration I think that concept has been disproven over and over again in multiple different healthy and disease contexts. Meaning that we know T cells traffic through the brain, but the only evidence of them contributing to any pathology is in contexts when they are recognizing something specific in the brain itself.

Jonathan Edwards said:
My reading of the literature just this last week suggests that despite claims it is not clear that anyone has nailed a specific antigen though.
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Could you share what you’re referring to? All the most recent studies I could find have a pretty solid consensus on T cell recognition of orexin neurons, though the specific proteins being recognized may not be the same in all cases.
 
jnmaciuch said:
I’m not sure what this refers to? If this is a reference to the idea that the CNS is protected from lymphocyte infiltration I think that concept has been disproven over and over again in multiple different healthy and disease contexts.
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I am not aware that it has. For a lot of tissues T cells migrate through on a regular basis -muscle and skin for instance. You see a few T cells in normal tissues on immunochemistry. I am not aware of evidence for such regular transit in brain. T cells will certainly enter inflamed brain, either. in MS or brain abscess, but we always knew that.

I am also not sure that in MS we know they recognise something specific. Sure, that has been the dogma for nearly fifty years. because everyone is sidetracked by inappropriate animal models like EAE but is there really good evidence for T cells recognising anything specific in human disease? You can find T cell responses to anything if you encourage the cells enough. In rheumatoid there is good evidence for all the T cells either being inactive or being stimulated by non-antigen specific signals (the work by Brennan and Feldman). MS is explainable on the basis of inappropriate B cell clonal survival in CNS - the hallmark of the disease.T cells may well be passers by.

jnmaciuch said:
Could you share what you’re referring to? All the most recent studies I could find have a pretty solid consensus on T cell recognition of orexin neurons, though the specific proteins being recognized may not be the same in all cases.
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No,I don't remember but I did a PubMed search and looked at reviews. There is always a 'solid consensus' about finding specific T cells in these situations because that is the received wisdom. But over the decades nothing proves to be reproducible. Which sounds as if it may apply here if the 'specific proteins being recognised' are inconsistent.

It seems pretty certain that T cell interactions with MHC Class I are involved in ank spond (it could be NK KIR interaction but people tried to get that story to fly and it never really did. But we have no good evidence for involvement of any specific antigen. The recent review by Matt Brown flagged up here made it clear that that is still the case. Why shouldn't T cell interactions in brain be independent of any specific antigen recognition if that is so for RA and AS (and quite likely MS)?

One thing that strikes me as significant about ME/CFS is that it leaves almost all brain functions completely intact, unlike MS, Altzheimer's or even Parkinson's. Members here may be severely disabled and may have brain fog but their intellect is completely unimpaired. Maeve Boothby O'Neill died with her intellect as sharp as a razor. And nobody has upper motor neuron signs or blindness etc. That means that if there is any involvement of brain,'neuroinflammation' even, it is very tightly localised and presumably to an area that deals with fatigue and sleep etc. Which is around the hypothalamus and brain stem. Moreover, since all sorts of other crucial functions occur within a millimetre or two there cannot really be any (vessel-based) inflammation because it would spill over.

It seems that the subfornical area does allow regular T cell traffic and it seems a pretty good candidate. Maybe for narcolepsy there really isa canonical loss of T cell tolerance to a specific antigen but I have heard that story without convincing evidence too many times. Even if so, Isee no reason why there should not be a problem in the same brain area with T cells being activatedbut not by local antigen - as for RA.
 
I was looking at papers not reviews, where the “inconsistency” was due to finding T cells reactive to multiple proteins, but all from orexin neurons. Which just means you can end up at the same place with T cells recognizing slightly different proteins so long as those proteins come from the HCRT neurons. That’s where the specificity comes from, having one particular antigen is irrelevant

And the throughline from other diseases is that if T cells get involved, regardless of how they get activated, you see tissue damage. The idea of tissue-specific T cell involvement that does not also involve damage is completely unsubstantiated.

The only justification for arguing that something completely new and unobserved is happening with T cells in ME/CFS would be if you already had proof that T cell localization to the brain is necessary for disease. Which we definitively don’t have, that’s just speculation. In the absence of evidence of T cell involvement or tissue damage, the much more logical conclusion is that T cells simply aren’t causative here.
 
Jonathan Edwards said:
One thing that strikes me as significant about ME/CFS is that it leaves almost all brain functions completely intact, unlike MS, Altzheimer's or even Parkinson's. Members here may be severely disabled and may have brain fog but their intellect is completely unimpaired.
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I would be careful here. Making sweeping generalizations is seldom wise, but where it concerns pwME, it is even less so.
 
Jonathan Edwards said:
One thing that strikes me as significant about ME/CFS is that it leaves almost all brain functions completely intact, unlike MS, Altzheimer's or even Parkinson's. Members here may be severely disabled and may have brain fog but their intellect is completely unimpaired. Maeve Boothby O'Neill died with her intellect as sharp as a razor. And nobody has upper motor neuron signs or blindness etc. That means that if there is any involvement of brain,'neuroinflammation' even, it is very tightly localised and presumably to an area that deals with fatigue and sleep etc. Which is around the hypothalamus and brain stem. Moreover, since all sorts of other crucial functions occur within a millimetre or two there cannot really be any (vessel-based) inflammation because it would spill over.
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Many patients have also problem with thermoregulation. I think hypothalamus is responsible for thermoregulation so maybe it also fit together with your thinking.
 
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