Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

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.

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.
 
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.

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.
 
I don't really know much about either
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.
 
Perhaps orexin is involved in ME/CFS in some way but I’m skeptical that it would be T cell mediated like in narcolepsy.

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.
 
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.
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.

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.

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.
 
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.

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.

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.

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.
 
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.
I would be careful here. Making sweeping generalizations is seldom wise, but where it concerns pwME, it is even less so.
 
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.
Many patients have also problem with thermoregulation. I think hypothalamus is responsible for thermoregulation so maybe it also fit together with your thinking.
 
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

Yes, but if you take individual papers in any field where the popular idea is to look for T cell responses to specific antigens you will find papers that find that. It has been going on for rheumatic fever and multiple slcerosis for decades. Presumably they found proteinsfromorexin cells because that is what they were looking for. How did they demonstrate that these were pathogenic or even active in vivo? Normally that is something beyond current technology. People move sideways to animal models. But all you can do in an animal model is show causation in that model, not that it also applies to the human disease.

You can always find T cell responses to anything if you are dedicated to doing so. I wait for the day when the finding is reliable enough to base a diagnostic assay on it.

And having one particular antigen is not irrelevant because the reason people are looking for specific T cells is the DQ genetic linkage and there is no reason why one DQ allele should confer risk on developing T cell responses to a range of proteins from a particular cell type unless of course DQ alleles are involved in something else-maybe trafficking to hypothalamus.

I am perfectly happy to believe that in the case of narcolepsy/cataplexy there are T cells killing orexin producing cells through peptide recognition but I have learntto be very sceptical about these stories.
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.

You are beginning to sound very much like the people in 1997 who told me I was a fool to suggest that B cells might be a good therapeutic target in rheumatoid, lupus, MS, myositis... Several tens of billions of dollars of useful healthcare further on ... I have been right in the past by saying maybe there are other ways things might happen. So I am entitled to think that I do not need to stick to received dogma 'throughlines'!!

What is this 'throughline'? Isn't it a tautology. Where we see T cells causing damage they are always causing damage? If T cells were involved and not causing damage we wouldn't see it. We would have to infer it. What about T cell immunity to tumours that manifests purely as the absence of tumours? And what about feeling ill with 'flu'? Whatever the process is that makes us feel ill with flu doesn't damage anything at the site where it does that - likely the hypothalamus. That might not beTcell derived cytokine but itmight well be. So there is no story that T cells only work through damage. (I can think of half a dozen other examples but this would then go on for ever!)

And we already have something that the standard dogma does not explain. Why are there very few T cells in most brain tissue but quite a few in these hypothalamic regions in the normal state. Isn't it likely that T cells are doing something there other than causing damage? And why is narcolepsy pretty much the only CNS disease where T cells seem to target one specific anatomical structure? MS goes everywhere. Isn't it a bit of a coincidence. that this is a place where T cells normally do something else that does not involve cell injury?

(I also have some other information that is not generally available and that is partly why I am following this line of thought.)
 
there is no reason why one DQ allele should confer risk on developing T cell responses to a range of proteins from a particular cell type unless of course DQ alleles are involved in something else-maybe trafficking to hypothalamus.
There may well be "something else" that the DQ allele does, but I don't see remotely any reason to believe that HLA is somehow involved in trafficking to specific areas of the body. That is not a finding that needs to be observed under very specific conditions--I can think of a dozen various experiments that would have already shown even the hint of that possibility. Again, it's positing a completely unobserved mechanism of T cells that (in the absence of positive evidence in any other context) must somehow only happen in a particular region of the brain, based on speculation that T cells in the brain might do something in other cases where we have no details.

What about T cell immunity to tumours that manifests purely as the absence of tumours?
I don't think that's an example to the contrary when T cells are targetting cancerous tissues, and you can see the T cell infiltration as well as cell debris from those dead cancer cells. It's still a case of targetted tissue damage, just to the "tissues" we want to be targetted.

And what about feeling ill with 'flu'? Whatever the process is that makes us feel ill with flu doesn't damage anything at the site where it does that - likely the hypothalamus. That might not beTcell derived cytokine but itmight well be.
We know that direct administration of interferon causes flu-like symptoms on its own. Sure, one could speculate that there are multiple ways to end up with the same presentation or that this specific case operates through some T-cell dependent mechanism. But that would be picking one option out of dozens without evidence to consider it more likely than any other candidate. The same amount of evidence exists for receptors detecting circulating levels across the BBB, or any other interferon-producing cell type. Which happens to be all cell types.

We actually have more evidence against T cells being causative for those symptoms since I know several colleagues doing viral infection studies on congenitally T-cell deficient mice and there is no lack of observable symptoms or sickness behavior in those cases. Is it possible that the generation of flu-like symptoms occurs via two completely different mechanisms between mice and human? Sure, there's always a chance. But it seems far from likely.

So the two examples given are not evidence of T cell activity in the absence of targeted tissue damage. Perhaps the other unlisted examples would be helpful here.

You are beginning to sound very much like the people in 1997 who told me I was a fool to suggest that B cells might be a good therapeutic target in rheumatoid, lupus, MS, myositis... Several tens of billions of dollars of useful healthcare further on ... I have been right in the past by saying maybe there are other ways things might happen. So I am entitled to think that I do not need to stick to received dogma 'throughlines'!!
Sure, everyone's entitled to speculation. But even if the case of B cells in those autoimmune diseases, there were hints of evidence in that direction before it was proven. You yourself said that the answer came in a previous paper from your group that you had not viewed in the correct light at the time.

I just simply don't see a comparable case here--and there is a difference between a theory simply challenging "dogma" and a theory that relies on multiple consecutive unevidenced leaps based on only the possibly of unobserved phenomena without any supporting positive indications from any similar context.

Like I've said before, I'd be happy to be proven wrong. I can only judge on what's available to me, and I don't think anyone on this forum is particularly inclined to take anyone's word on the basis of a track record, even from someone with as robust a track record as you.

(I also have some other information that is not generally available and that is partly why I am following this line of thought.)
I would be happy to make judgements when that evidence becomes available. If this happens to be a reference to HLA allele associations, I will note that HLA associations don't mean that T cells are causative in an illness. It could just as likely be an indication of increased susceptibility to certain infections which are more likely to trigger post-viral sequelae via a currently unknown HLA-independent mechanism.

Which may well be the case in narcolepsy too given the association with influenza A, or perhaps it is also the case in anklyosing spondylitis, or other contexts where specific antigens have yet to be identified--as you imply, we simply don't know for sure. The evidence for T cell involvement in narcolepsy is not any stronger than the specific evidence for T-cell recognition and damage of orexin neurons, so T cells may well be completely irrelevant.

As for ME/CFS, if you have anything more definitive than an HLA association, I'd be excited to see it.
 
Sure, everyone's entitled to speculation. But even if the case of B cells in those autoimmune diseases, there were hints of evidence in that direction before it was proven. You yourself said that the answer came in a previous paper from your group that you had not viewed in the correct light at the time.

I see very parallel hints here.
Let's wait and see.
 
Just anecdotally, I have episodes of temporary paralysis when I crash, and I know others do too. 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. She has never been evaluated for narcolepsy.
I've never had paralysis myself, but I have known several others -- a few in person (support group) and many more online -- who have reported intermittent paralysis.
 
FYI, purportedly there is acquired periodic paralysis. This is - as is the case with typical pp - supposedly temporary or intermitant.

Not much, relatively speaking, is known about it because no money is thrown at it because it effects so few and, for the most part, we are a selfish and uncaring lot until the pain is ours, i.e., it's not so much about the lack of science as it is character.
 
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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.
This smacks of opinion but it is framed as fact. Please remember this is a science forum.
 
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