An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Wirth et al)

SNT Gatchaman

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An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Klaus J. Wirth, Carmen Scheibenbogen and Friedemann Paul

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Abstract
There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.
 
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I replied to @Consul in the other thread but you're right it's probably worthwhile to make a separate one for this.

I said: Very interesting, thank you. Shame that they don't provide any theoretical ways to repair endothelial tissues (peptide therapies? ARA-290, GHK-Cu, BPC-157?) or restore a2ar/b2ar functioning (periodic use of agonist/antagonist drugs?).
 
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I replied to @Consul in the other thread but you're right it's probably worthwhile to make a separate one for this.

I said: Very interesting, thank you. Shame that they don't provide any theoretical ways to repair endothelial tissues (peptide therapies? ARA-290, GHK-Cu, BPC-157?) or restore a2ar/b2ar functioning (periodic use of agonist/antagonist drugs?).
Im a bit behind on the biochem unfortunately ;)
 

nerd

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Wirth, Scheibenbogen do good work when it comes to research on endothelial dysfunction and serology. They've modeled specific pathomechanisms such as endothelial dysfunction quite well in that these are thorough and detailed. This paper, unfortunately, doesn't even attempt to give a complete neuropathological submodel. There are many more subjects that are simply overlooked by this paper. It's rather a review and overview of their own research and how it fits together.

Even though they reference one paper from Van Elzakker, they don't completely reflect his work. They draw dysautonomia as an unexplained phenomenon. They speculate about sleep disturbances in a causal manner. But all of this could be explained much better and more complete via the model from Van Elzakker, by neural and glial homeostasis, and especially stem brain pathology. They scratch the topic by attributing stem brain pathology to stress- and noradrenergic-mediated desensitization. I get it - adrenergic pathology is one of their key foci. I also get that it's almost impossible to keep track of all the research while tracking one's own. But whenever they leave an open end that connects to the stem brain, it could be completed by Van Elzakker's theory.

Receptor homeostasis also seems to have been overlooked in their recent paper on endothelial dysfunction. I hope that they will look into this subject more in-depth. Because I'm personally not convinced by the microclotting theory yet. I think Scheibenbogen and colleagues have a better lead if they only follow it.
 

Pyrrhus

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The third paragraph in the introduction is what raised my eyebrows:

Wirth et al 2021 said:
Many symptoms are, however, not obviously explained by neurological pathology including the cardiovascular situation with orthostatic intolerance, hypovolemia and a low activity of the renin–angiotensin–aldosterone system (RAAS), or the impaired muscle function (reduced handgrip strength and fatigability) and energetic disturbance. This co-occurrence of seemingly unrelated symptoms and findings prompts to look for a unifying explanation (the most parsimonious explanation).
Most of these symptoms can, in fact, be "obviously explained" by neurological pathology:
  • the cardiovascular situation with orthostatic intolerance ("obviously explained" by the well-documented dysautonomia of the nerves controlling the dilation/constriction of blood vessels)
  • hypovolemia and poor fluid retention ("obviously explained" by the long-discussed hypothalamic dysfunction)
  • the impaired muscle function - reduced handgrip strength and fatigability ("obviously explained" by dysfunction of the motor nerves and associated spinal tracts, etc.)
 
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SNT Gatchaman

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Agree with @nerd that there are gaps in the explanation with the above paper. I personally think aspects from these key papers will all contribute to the explanation in due course (esp. Pretorius, Wirth/Scheibenbogen, VanElzakker, Younger). The findings demonstrated by other researchers are hopefully downstream features which I hope will self-correct when the fundamental problem is able to be reversed.

I'm extremely keen on the micro-clot theory for LC and either some ME or possibly most/all early-stage ME. A related mechanism of endothelial dysfunction might otherwise explain other ME sub-types.

As soon as widespread endothelial dysfunction is demonstrated, that becomes a mechanism for neuro-inflammation, due to disruption of the blood-brain barrier. Common neurological symptoms might reflect particularly vulnerable brain regions. Regional cerebral hypoxia may also contribute.

VanElzakker's brainstem studies and theories could explain the dysautonomia. I do think though that orthostatic intolerance, being so common in ME (with or without HR/BP changes) may have a more direct explanation. I would consider the effect of venous under-filling from chronic, variable micro-circulation impairment or adrenergic receptor dysfunction could play a role in this.

In LC at least, the micro-clots are being shown to contain inflammatory mediators. They, along with activated platelets might induce vascular receptor dysfunction, perhaps in some cases via an intermediary auto-antibody.
 

nerd

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hypovolemia and a low activity of the renin–angiotensin–aldosterone system (obviously explained by the long-discussed hypothalamic dysfunction)
Not only that. Wirth and Scheibenbogen focus on alpha-adrenergic function. Renal function, the RAAS, and the UTI are also regulated (or potentially regulated) by alpha-2 receptors.

Alpha-adrenoceptors and the kidney (1988) [pmid: 2906696]

De Leeuw et al. said:
Sympathetic nerves may modify various aspects of renal function including renal haemodynamics, renin secretion and sodium output. In a series of experiments we found that within the human kidney alpha 2-adrenoceptors are of greater importance than alpha 1-receptors in mediating the adrenergic effects. For instance, intrarenal infusion of an alpha 1-antagonist has a small effect on renal perfusion, whereas blockade of alpha 2-receptors increases renal flow profoundly. There is evidence that the relevant receptors are located at a postjunctional site. Alpha 2-receptors also play an inhibitory role in renin secretion. Recent data suggest that the alpha 2-receptor, which reduces renin release, is located presynaptically. Thus, stimulation of this receptor reduces noradrenaline overflow, and hence diminishes beta-adrenoceptor mediated increases in renin.

I do think though that orthostatic intolerance, being so common in ME (with or without HR/BP changes) may have a more direct explanation.
These are just different regions in the stem brain. Given Van Elzakker's theory, it's unlikely that every patient will exhibit the same manifestation of dysautonomia. It depends on microglia involvement, neural homeostasis, vagal activity, potential monocyte migration, potential cytokine influx, potential infection of the stem brain, metabolic signaling/status (GABA/glutamate). It doesn't mean that it all has to be the same denominator though. It might as well be how you describe, or because of hypovolemia, endothelial dysfunction, cardiomyopathy, etc.
 
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SNT Gatchaman

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That's an interesting comment @SlamDancin. Of course it's highly unlikely that researchers might read any of our comments here and signal to noise ratio would be very low for them. Also, I can't see any of them directly interacting here or on similar boards as they would be so vulnerable to our inevitable frustrations. I do appreciate the limited interactions on Twitter, however.

Perhaps we might envisage a moderated system of flagged discussions/points that could be edited and communicated to the researchers monthly, at arms' length. A bit like the "questions for Ron Davis" thread, but to a group and not requiring them to respond, merely a "for your consideration".

Doubt it could work in practice, which is a shame, because there are patients who clearly have high-level knowledge across a broad field of ME theory. Suspect we all might end up arguing over what should be included, as we've all got our pet theories :woot:.

@Martin aka paused||M.E.'s NGO sounds like a good potential interface between researchers and patients, with fund-raisers/celebs and other interested parties also intermixed - all of whom have a high bar to entry to keep things manageable.
 
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NGO sounds like a good potential interface between researchers and patients, with fund-raisers/celebs and other interested parties also intermixed - all of whom have a high bar to entry to keep things manageable.
Thank you for mentioning me.
I would like everyone to become a member internationally. We are thinking about how we can make the membership fees as low as possible, so that everyone can afford it. Maybe a monthly fee instead of a yearly fee.

However, I have to mention that the requirements to become an ACTIVE member are high. So that means, since this is about medical discussions about the disease, one would have to have an academic degree in a health profession (doctor, biologist, pharmacist ...) and professional experience.
That should ensure the quality of the NGO.

What every member (including passive members) can do, however, is to submit an application to the annual general meeting (which will of course take place online), e.g. aimed at financing a specific research project.

But we don't do any research ourselves. Whether a constant exchange with scientists makes sense would have to be discussed.
Scientists usually have very little time. That's why they don't visit forums or reply to posts there.

You can write good theories to some on Twitter or contact the respective secretariat.
 
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Can this desensitization of adrenergic receptors be potentially reversed? It sounds like it could be core problem in sympathetic hyperactivity. Sorry I don't understand how biology works, please correct me
 

Oliver3

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The third paragraph in the introduction is what raised my eyebrows:



Most of these symptoms can, in fact, be "obviously explained" by neurological pathology:
  • the cardiovascular situation with orthostatic intolerance ("obviously explained" by the well-documented dysautonomia of the nerves controlling the dilation/constriction of blood vessels)
  • hypovolemia and poor fluid retention ("obviously explained" by the long-discussed hypothalamic dysfunction)
  • the impaired muscle function - reduced handgrip strength and fatigability ("obviously explained" by dysfunction of the motor nerves and associated spinal tracts, etc.)
To me that's called having eds.
I hope that collagen and tissue matrices are looked into. I still think crispr is the way out of this mess
 

SlamDancin

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I’ll just say this, I’m nowhere near some of y’all in terms of scientific knowledge or understanding but a few years ago I wrote up the best hypothesis I could based on my understanding of what might cause the nature of how patients tend to fall ill with ME/CFS after a trigger, as if there is a switch that gets broken. I sent it to Ron Davis and he sent it to Rob Phair and we worked together a little pre-metabolic trap. You never know what could come from just reaching out to any researcher who will listen.
 

Oliver3

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I’ll just say this, I’m nowhere near some of y’all in terms of scientific knowledge or understanding but a few years ago I wrote up the best hypothesis I could based on my understanding of what might cause the nature of how patients tend to fall ill with ME/CFS after a trigger, as if there is a switch that gets broken. I sent it to Ron Davis and he sent it to Rob Phair and we worked together a little pre-metabolic trap. You never know what could come from just reaching out to any researcher who will listen.
I often message Rebecca at the open medicine foundation. She's really good at passing even the smallest ideas along. Everyone should try if they feel they have smthg to offer
 

SlamDancin

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For example, OMF is open to testing new hypotheses. This hypothesis needs more evidence and they’re equipped at Ron’s lab to figure out how to design novel experiments.
 

nerd

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Can this desensitization of adrenergic receptors be potentially reversed? It sounds like it could be core problem in sympathetic hyperactivity. Sorry I don't understand how biology works, please correct me
For that, the real mechanism would have to be known. Otherwise, you'd try to resolve the issue as per multiple theories in parallel. I currently use an adrenergic agonist, Butcher's Broom. It's not reverse but rather a compensation of the issue. If it even works at all, I can't tell because I'm taking so many things.

I dont think scientific knowledge is the most important thing. Insight is.
Overview is key. And it's not specific to this subject either. I had the same issue with the papers I've written in my own discipline. It sometimes happens so fast that your paper can be outdated before it's completed. If you don't keep yourself updated, you might publish something that already shows a contradiction right away.

I have the impression that certain members of this forum have the best overview among all scientists out there (I know - it might just be my own bias). It's good for us forum members to have such experienced minds available. Because we have time to figure out who to trust and in which regards. But the members of the scientific community who actively work on their own tasks don't have this time. How can they get an overview?

Normally, you'd expect overview papers that do this job. It's not that such overviews don't exist. Even this paper from Wirth and Scheibenbogen is supposed to give an overview. But which one really goes into depth?

I collaborated on a rolling overview project on COVID-19 for a short time because I had the impression that certain aspects of the disease pathology were commonly overlooked. You can imagine how much has been published on COVID-19. It's a full-time job and you're supposed to approve the whole paper in the end. That wasn't the reason I opted out though. Bias from the lead author was when it came to poor quality control of the contributions.

I'm wondering why such a project isn't possible with CFS/ME. I think it's necessary. We have MEpedia. But to medical folks, this isn't even a source, worse than Wikipedia. You need scientists behind such a project. Many and not a single author. And you need to eventually publish the updated versions so that they go through peer-review to give them credibility. I think the necessity for such a project is more valid than ever.

After Christmas, I'll write a post from my recent personal experience why I have the impression that the medical community is completely lost and that they are lost because they can't get an overview either. Not by reading a single paper. They don't know where to start, so they don't start at all but come up with their own unfounded ideas, based on personal anecdotal experience, that aren't helpful to any patient.
 

Violeta

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Oh gosh this paper is so good. Makes me wish I would get to the conclusion and it would say, okay, do this and you will feel much better. But I read the spoiler.


With respect to:
  • hypovolemia and poor fluid retention ("obviously explained" by the long-discussed hypothalamic dysfunction)
I wonder if that also is also an alpha adrenergic receptor issue.

Although it doesn't answer the question of whether there is a lack of chemical (epinephrine/norepi) or if the receptors for some reason aren't responding.

I am having good luck with Butcher's Broom. Sometimes I get restless leg and one night I took some Butcher's Broom to see if it would help, and not only did it help with the restless leg but also helped me sleep.

Maybe everyone already realizes this and I am late to the party.

Adrenergic receptors in the hypothalamus
https://pubmed.ncbi.nlm.nih.gov/6122645/

Oh my, if I understand this study, blood coagulation can be involved, too.
https://pubmed.ncbi.nlm.nih.gov/1964643/
 
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