The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure, 2022, Renz-Polster et al

This is a popular hypothesis. Emphasis on hypothesis. It has issues to overcome. Most such hypotheses fail. One or more hypotheses wont fail over time. Its too early to accept this as certain, or even highly likely, but I think its inadvisable to automatically dismiss it.

One of the dilemmas it will face eventually if the evidence of glia involvement grows is the question of whether its a primary cause or a secondary problem. If there is a general mechanism then it might impact the brain, and the brain is vulnerable to energy deficits and many other things.

As for remote physical symptoms being linked to such a brain dysfunction, the brain helps regulate a lot of autonomic and non-autonomic functions. So its in the range of possible, with current understanding, that it might alter peripheral function through direct and secondary mechanisms, including regulation of blood vessels. Such an explanation, while possible, is clearly just hypothetical and awaiting detailed demonstrable mechanisms. Otherwise the psychobabblers should be taken more seriously, as they have similar but less detailed arguments.

So cautious skepticism is warranted I think, but not extreme skepticism. There are a lot of unanswered questions, and lots that need to be validated and tested. However medical hypotheses may often be in this state, and pursuing them means we should be able to get the data that confirms or refutes the hypothesis given enough research over time.

There is no question, in my view, that something is going on in the brain, but we still do not know if its causal, co-causal or secondary.

 

Note that Herbert Renz-Polster is a pediatrician from Germany and Dorothee Bienzle is a veterinary scientist from Canada. Neither have a prior research/publication history in ME/CFS.
https://www.umm.uni-heidelberg.de/c...n/allgemeinmedizin/team/herbert-renz-polster/
https://ovc.uoguelph.ca/pathobiology/people/faculty/Dorothee-Bienzle

Unfortunately in my reading of the manuscript, the authors make a series of assumptions that contradict both the experiences of patients and some published literature.

I'm not sure the authors understand PEM. Much of the description above diverges strongly from patient experience.

Most patients experience short term exacerbation of symptoms, particularly fatigue. But PEM is not merely an exacerbation of symptoms, it is not equivalent to exacerbation of fatigue related symptoms. PEM is special because involves a specific set of symptoms - headache, sore throat, flu-like symptoms, circulation issues, POTS etc. I currently only get POTS during PEM, for example. PEM in my experience does follow a 'dose-response' dynamic.

Secondly, many patients experience PEM or other exacerbation triggered from mental exertion *differently* to PEM triggered by physical exertion. This is a specific clue to the pathology and one that is completely overlooked by the authors.

This is flat out incorrect. Many patients report that mental and peripheral fatigue do not appear simultaneously and exacerbation of one does not necessarily lead to exacerbation (or PEM related) of the other.

While there is overlap of symptoms, I dispute this as well. Those "neuro-orthopedic" conditions have key symptoms that present differently - whether it be hypermobility or symptoms like ataxia for those with spinal or cerebellar issues. But most patients do not have these conditions.

In my experience hypersensitivity to sensory stimuli is related to my level of cognitive resources available to process the input. I don't think this is specific to ME/CFS at all. In general I do not relate at all to the claim of "hypersensitivity to sensory stimuli across sensory modalities".

The second point is flat out wrong. Studies in adults have consistently failed to demonstrate any association with arousal or adrenergic stimulation - indeed studies show normal levels of catelcolamines, and brain studies tend to show understimulation of areas of research interest.

Aside from that, the author doesn't seem to understand what central fatigue is at all, it's coupling with peripheral metabolism and it's role in cardiovascular regulation.

 

I wonder if PEM is both thresholded and dose dependent? A low dose of exertion might not exceed the threshold, but a higher dose might have increasing effects depending on how much it exceeds the threshold? There is also threshold recovery to consider. In my own case if I am already in PEM the threshold seems small or even tiny and easy to exceed, and the impact is often worse. If this is generally the case then both the thresholds and the PEM response are dependent on multiple factors and can change over time.

 

Decades ago a MD, not my regular doctor, noting my symptoms asked if I had ever hit my head. This had never happened to me in any significant way. I really wish we had pursued this avenue.

Nothing may have come from testing, but on the other hand there might have been some findings that cast doubt on my ME (cfs) being psychological.

 

Maybe some of us are always close to that threshold.

 

One hypothesis I have of the very severe pwME is they are always over that threshold, never ever recover until the threshold goes up.

 

This would follow from the CPET studies which show we have to dependent on anaerobic, inefficient respiration for much of our energy needs. If there is not enough ATP available the body prioritises the heart brain and liver so less will be given to muscles.

Low blood sugar in diabetics causes mental confusion which is helped by taking sugar so eating something probably does the same in ME. I have bad hypoglycaemic attacks (confirmed by blood machine) and I suspect that the faulty signally we experience for thermoregulation and so on also include telling the liver to facilitate release of sugars in a timely way. The brain can only produce energy from glucose so that could explain eating helping too.

 

@Snow Leopard - I'd like to better understand that difference. Has this ever been studied and/or written up anywhere? And if not, would you mind adding a little more on this?

Thanks in advance

 

It hasn't been properly studied, to my chagrin.

See poll results "physical vs cognitive PEM - same or different". Only ~22% reported that physical and cognitive induced PEM felt the same.


Also note that the idea that cognitive activity can lead to prolonged physical symptoms is one of the central reasons why many in the BPS brigade thinks ME/CFS is psychosomatic.

 

I was unaware of that. Is that written somewhere?

 

@snow

Thanks for this, @Snow Leopard - interesting poll and confirms what I thought

 

Surely the brain and its correct functioning is affected by all manner of things external to it; cognitive issues by no means indicate the root cause lies in the brain, though it conceivably could of course. The cause(s) of cognitive issues and PEM could very likely be external to the brain.

 

No acknowledgement then that cognitive effort imposes energy demand that may not be physically available. Even if that turns out to not be scientifically true, it is no less feasible than their half-baked theories, which themselves are very far from proven.

 

They do communicate with each other, and both respond to cytokines. They evolved to work together, so if one is disturbed, the other will probably be too. The other glial cells have similar interactions.

 

Hormones, which are created by or controlled by the brain? Feedback control of the muscles? Erroneous signalling to the muscles (fighting each other rather than working efficiently)? Incorrect control of breathing and bloodflow to accompany muscular action? There's so much feedback between the brain and the body that there are probably many possible explanations.

 

My PEM seemed to be just increased severity of my general ME symptoms. I didn't get any new symptoms, or any on your list above. I expect that PEM involves a common core dysfunction, but how that expresses itself downstream depends on the individual.

I agree; it varies with the individual. My legs were capable of a 40 km bike ride in hills, but my head wanted to have a soft pillow on the handlebars to just flop down on, due to mental lethargy.

I agree that the paper is far from perfect, and does have some serious errors. I still consider it a good starting point for discussion the various points brought up. Do the symptoms and responses of ME fit the hypothesis? What parts don't fit, and do they completely destroy the hypothesis? I find that this hypothesis fits my experiences with ME better than the other hypotheses I've read.

 

Lots of people with ME don't get headaches or POTS, see the following threads for different descriptions of PEM:

https://www.s4me.info/threads/pem-f...ld-sufferers-how-would-you-describe-it.12231/
https://www.s4me.info/threads/defining-and-measuring-post-exertional-malaise-a-discussion.15783/
https://forums.phoenixrising.me/threads/how-long-does-your-pem-last.36063/
https://www.s4me.info/threads/decodeme-uk-me-cfs-dna-study-underway.15604/page-14 - Discussion of different types of PEM.
https://www.s4me.info/threads/trishs-severity-scale-how-do-you-score.16605/page-7#post-315479 - Works full time but can't walk more than 200 steps.
https://www.s4me.info/threads/what-...file-and-or-b-not-in-the-me-literature.19147/
https://www.s4me.info/threads/if-yo...cfs-symptoms-which-would-they-be.19187/page-2
https://www.s4me.info/threads/analy...me-cfs-2021-ithaca-college.19252/#post-326949
https://www.s4me.info/threads/pem-timing-symptoms-and-levels-of-disability.5191/page-3
https://www.s4me.info/threads/is-fatigue-not-your-main-or-significant-symptom.23112/
https://forums.phoenixrising.me/threads/whats-your-first-last-sign-of-pem.86231/

https://www.s4me.info/threads/coini...terrelated-energy-and-time.24552/#post-405604

May be start a poll about it if you can.

This is definitely the case for me. The more I push past my injury threshold the worse the payback and damage are.

 

Now published
Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking.

Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated.

Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.

From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

https://www.frontiersin.org/articles/10.3389/fncel.2022.888232/full

 

It fits my thoughts on ME, just with higher detail.

 

But reduced cerebral blood flow is surely something suggested by Campos-Costa thirty years ago and never verified?