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An observation and general hypothesis for cfs/me

ash0787

Senior Member
Messages
308
So there's obviously some sort of problem on a cellular level at least within the muscles if not throughout the body, the metabolic pathways are altered in some way which is resulting in less energy outcome, its not obvious as to why but this seems to be the case right from the start, people experience heavy feeling legs and slowed large scale motor function activation, and when they try to exercise they perform less well particularly in endurance, and feel sleepy etc. There is also a problem with more severe patients where lactic acid builds up quickly when the muscles are used, which seems to have been demonstrated in lab tests. so it seems fair to assume there is some baseline level problem there which does not disappear during times of relative health. Who knows what causes this, antibodies, DNA methylation ? could be anything.

The observation I made is that individual muscles are not particularly damaged by heavy usage during times of relative health, but when in an overall crash state, the same muscles are very susceptible to inflammation, it seems to happen simultaneously with the activity, can go from feeling completely normal to an intense ache within about 1 hour.

What this makes me think is that the 'crash' is likely a form of mode switch by the body or immune system,
in response to toxins which are produced by the underlying problem with the cells which I described, or possibly some sort of stress signalling molecules being sent out by the exerted cells, effectively the crash would seem to be the body going into some sort of 'sepsis' like state, anxiety rises, stress vulnerability, heart rate etc. Now when this happens it seems to compound the underlying / original problem, the bodies energy output seems to drop even further, maybe 50% or 60% more and we are forced to lie very still for a while and move as little as possible, or rather don't particularly feel like moving.

I think when we enter that state we are more susceptible to damage, the immune system seems to be overactive at that time, which is what then causes that instantaneous muscle inflammation that I mentioned.

The worst state I personally got into was shortly following a period where I was easily entering crashes,
some lasting over 1 week, and at the same time there was clear auto-immune activity.
 

Mohawk1995

Senior Member
Messages
287
@ash0787 Good thoughts though and you are right in mentioning the similarities in symptoms across people with ME.

There is no question that based on the work that Dr. Ron Davis, Dr Ian Lipkin, Drs Luge and Mella as well as others have done that there is a biochemical, metabolic and immune basis for what we are seeing clinically in ME. The next big question is what is it that starts the cascade of responses that then result in Mitochondrial shut down, Neuro-inflamatory issues, autonomic dysregulation, changes in CSF and changes in immune markers.

Is it molecular as you note? Is it viral? Purely autoimmune? Bacterial? Some as yet undetermined process?

The next big question to me is what is the involvement of the control centers in the body namely Neurophysiology. I tread into dangerous waters, but clearly there is a neurophysiological component. It is certainly a systemic one.

My theory is an over-reactive and over-protective response that is systemic, but is activated by a neuro-immune response to a "threat" (Virus, Bacteria, Severe Trauma or stress, Reaction to medication or Vaccine or any other potentially threatening event). It then stays on too long and is often too strong.

However, no one as of yet has been able to clearly define what specifically triggers it or how the initiation of this triggering occurs.
 
Messages
15,786
I tread into dangerous waters, but clearly there is a neurophysiological component. It is certainly a systemic one.
Why is it certain? I'm pretty sure most things regarding the pathology of ME are still uncertain to a large extent.

... Severe Trauma or stress ....
Good news, you can rule this one out as a cause of ME, based on a large prospective study.

It then stays on too long and is often too strong.
The idea that we continue to react to a threat which no longer exists is not a new one. It's the basic foundation of psychobabble, and calling it neurological instead of psychological is no less babble. The basic foundation is still that there is no ongoing lack of health, aside from the brain thinking there is. And the quacks pushing these theories still propose CBT and GET to cure them - because, after all, the muscles are presumed healthy, and we accordingly just need to convince the brain of that.

But this central sensitization model doesn't make much (if any) sense in light of objective abnormalities such as the CPET. How could the malfunctioning brain plausibly make our VO2max tank 24 hours after an earlier bout of maximal exercise? How would it cause lymph nodes to ache and swell?

Central sensitization is a very poor hypothesis for explaining ME, with no support shown for it (beyond musings like yours) and a complete failure to account for anything which is known about the biology of ME thus far.
 
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ash0787

Senior Member
Messages
308
The virus theory is interesting, but it runs counter to what I'm theorizing, I'm saying that the immune system is operating near normally most of the time, and that it is only overactive during PEM / crashes

I don't know whether its actually the immune system that is causing the underlying metabolic issue, via auto-antibodies etc, it could be that virus have changed the genetic code interpretation or something, 'injecting' a new code which is turning off the mitochondrias ...

My main point is that I think we often view CFS as a sliding scale based on one factor, so essentially the underlying problem is scaling up during times of increased symptoms, I think theres an alternative interpretation, there are two fundamental problems going on, the underlying problem which remains relatively static although likely can be exacerbated by various factors, and the immune response to that underlying problem, the latter is producing the more acute changes in symptoms.

The main implication of this is that theres a possibility that the Rituximab responders are not actually fixing the underlying problem, they are just taking out half of the equation.
 

TiredSam

The wise nematode hibernates
Messages
2,677
Location
Germany
The idea that we continue to react to a threat which no longer exists is not a new one. It's the basic foundation of psychobabble ...
But if water is able to retain a memory of substances previously dissolved in it even when molecules of the substance no longer exist, are you seriously telling me our minds are not capable of a similar feat?
 

Murph

:)
Messages
1,799
My main point is that I think we often view CFS as a sliding scale based on one factor, so essentially the underlying problem is scaling up during times of increased symptoms, I think theres an alternative interpretation, there are two fundamental problems going on, the underlying problem which remains relatively static although likely can be exacerbated by various factors, and the immune response to that underlying problem, the latter is producing the more acute changes in symptoms.

The main implication of this is that theres a possibility that the Rituximab responders are not actually fixing the underlying problem, they are just taking out half of the equation.

I think this is a really good point. CFS is a chronic problem with acute flares. (In severe people the two seem to merge. They are chronically in the acute phase.) There is no guarantee the two problems are in the same system, nor that solving one will solve the other. They could be linked very tangentially or very closely.

I've been through long remissions where I could do a lot with no PEM but I still had that chronic problem. I could trigger PEM if I did the wrong things.

We have a fair bit of research on how people are on average, but researchers rarely ask subjects if they are in PEM when their blood is drawn. I'd like to see much more examination of the process of PEM: measurements taken every 8 hours for, say 72 hours as people go through an exercise test and payback.

I'm not sure I agree that Rituximab is only fixing the PEM system however. It could be temporarily blocking the higher order problem.
 

Mohawk1995

Senior Member
Messages
287
How could the malfunctioning brain plausibly make our VO2max tank 24 hours after an earlier bout of maximal exercise? How would it cause lymph nodes to ache and swell?

In the same manner that a malfunctioning Nervous System can create the "right physiologic environment" for an anaphylactic response to routine allergy testing. You are stuck on the Psychiatric interpretation of "Central Sensitization" which is completely bogus in my thinking. Just as you and others feel like you are banging your head against a wall, I feel the same because I am telling you ME is completely physiological and beyond the person's ability to control and you still think I am saying psychosomatic. I just have a different explanation for the physiology.

As for lymph nodes, it causes swelling in them in Migraines which are clearly "neuro-physiological" in addition to nasal congestion and histamine responses. It is not a far leap at all to say that this could not be the same or very similar processes occurring in ME. AND I don't think for one second that a Migraine is "psychosomatic".
 

Mohawk1995

Senior Member
Messages
287
The main implication of this is that theres a possibility that the Rituximab responders are not actually fixing the underlying problem, they are just taking out half of the equation.

I would agree for the most part. If we are treating the Biochemical/Biomolecular substances like B-cells, we are probably not treating the underlying cause of why there is the large systemic release of these agents. Still can be an effective treatment and potentially part of a cure, but not directly aimed at the cause.
 

Eastman

Senior Member
Messages
526
There is this post from another thread.

Bacterial Lipopolysaccharides (LPS), like from a leaky gut, can cause an increase in HIF1, a decrease in oxygen consumption, an increase in PDK1 and therefore an inhibition of PDH.

Upon stimulation with Th1 cytokines or bacterial lipopolysaccharides, resting macrophages shift their phenotype toward a pro-inflammatory state as part of the innate immune response. LPS-activated macrophages undergo profound metabolic changes to adapt to these new physiological requirements.

One key step to mediate this metabolic adaptation is the stabilization of HIF1α, which leads to increased glycolysis and lactate release, as well as decreased oxygen consumption. HIF1 abundance can result in the induction of the gene encoding pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) via phosphorylation.

LINK
 
Messages
15,786
I just have a different explanation for the physiology.
Your explanation is still completely central, and you conveniently have failed to address how any central theory, be it psychological or neurological, cannot possibly account for many ME symptoms.
As for lymph nodes, it causes swelling in them in Migraines which are clearly "neuro-physiological" in addition to nasal congestion and histamine responses.
At best that shows that those conditions are also not central. But I'm pretty sure migraines don't cause swollen lymph nodes - rather there are conditions which can cause both migraines and the swelling. So I really don't see the relevance to your argument.
 

lansbergen

Senior Member
Messages
2,512
Forget the spychobabbles but the brain and spinalcord form the central nervus system. All over the body are sensors which send informaton to the .CNS. The CNS is involved in the immune response.

I can agree with most of what Mohawk1995 says but I am pretty sure the threat is not gone .
 

Mohawk1995

Senior Member
Messages
287
Your explanation is still completely central, and you conveniently have failed to address how any central theory, be it psychological or neurological, cannot possibly account for many ME symptoms.

This statement is made on conjecture just as mine are. We don't know the mechanism of how ME starts, nor do we know how it physiologically impacts the body. We especially do not know that much about Neurophysiology and are just beginning to understand the complexity by which it regulates and protects the body.

I agree with you that ME is not pscychosomatic. I agree with you that there are significant physiological process and pathophysiology at work in ME. I agree with you in that these process create metabolic and biochemical "fallout" in the body and that these are the markers that Dr. Davis, Dr Lipkin and others are now being able to isolate and identify. I especially agree with you that CBT and GET will not treat the primary mechanisms of this disease.

The only thing I say for certain is that we disagree on what is at the core of the ME mechanism. From what I can tell (and please correct me if I am wrong) you believe the primary mechanism is a peripheral physiology issue such as chronic viral or bacterial or other. I believe that the primary mechanism is Neuro-Immune/Neuro-protective. To be clear this is not Central Sensitization (neuro-physiological phenomenon that can create increased sensitivity to many things). You could be right. I could be right. We both could be mostly right.

The thing that matters is we both want solutions to the ME conundrum that bring real and lasting help and recovery to people who suffer with ME. I am pretty sure everyone here will agree on that.