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A neuroglial hypothesis of ME/CFS from a pediatrician with ME/CFS and a leading glial cell researcher

Yet another fascinating hypothesis has come our way. Produced by a German researcher/pediatrician/author with chronic fatigue syndrome (ME/CFS) in collaboration with an internationally known glial cell researcher it’s yet another example of how richly the creative juices in our community run. Where else in the medical field are individuals so apt to buckle down, dig into the studies, puzzle things out for themselves – and come up with novel ideas?

Here is Dr. Herbert Renz-Polster’s story:

Dr. Herbert Renz-Polster

Dr. Herbert Renz-Polster

Six years ago Dr. Herbert Renz-Polster came down with ME/CFS. This year he published a hypothesis paper on it that’s received more views – almost 12,000 – than 92% of the papers published in that journal.

I am a German pediatrician, trained in the US, first @ Maine Medical Center, then @OHSU, Portland OR, where I did a fellowship in pediatric pulmonology. Back then I published my first scientific paper, on the relationship between mode of delivery and subsequent development of allergies (()). That was back in 2005.

Back in Germany, I worked at an academic public health institute (part of the University of Heidelberg), where we built up a pediatric section. Ten years ago I left academia and worked part-time as a pediatrician but also published popular parenting books, mostly based on evolutionary ethology, which I also explored scientifically. 

At the end of 2016, I came down with a severe case of influenza from which I slowly recovered. Three months later after strenuous exercise, I literally crashed to a point where I could only walk a few steps, which brought me to the ER – and later an uneventful work-up with many specialists including neurologists, cardiologists, internists, etc…

Thereafter I had better days with hope and worse days with despair – I knew that I was ill but I did not know from what. To pay the bills I still went to conferences and talks etc. and crashed for days afterward. Eventually, I put 1 and 1 together and finally suspected ME/CFS (which before I had heard of but – to my now never-ending shame – had smugly thought of as “something psychosomatic”).

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In the fall of 2017, I had deteriorated to a point that I could not drive a car anymore, couldn´t even tolerate the light of the moon, and spent more and more days in bed, with especially insomnia and anxiety being big issues. I then contacted Prof. Scheibenbogen who saw me at the Charite in Berlin and diagnosed me with ME/CFS.

I then dragged through the months, still working on and off, part-time. With better pacing, a lot of sleep and a lot of support from my wife, grown-up children and twin brother I gradually improved. The pandemic helped a lot because I inadvertently realized how much I really suffered from the talks I gave in other cities and how much each travel set me back. Now I am doing talks only online, which is a smoother ride.

From the beginning of my illness, I researched whatever pieces I could get a hold of on ME/CFS. I wanted to understand what was going on in my body! My feeling was always: yes, my whole body is affected, the immune system is activated, I am low on energy – yet at the deepest level I felt: that a substantial part of all this is in my brain which apparently does not do its business of proper regulation anymore.

Glial Cells

Glial cells in the central nervous system (Version 8.25 from
OpenStax Anatomy and Physiology, Wikimedia Commons)

How often did I say to my wife: “This is in my head!” This deeply felt notion of “something wrong in my head” made me curious about how the pathology of the central nervous system may be connected to all the things I knew about ME/CFS – including the symptoms and the many findings reported in the literature (like mitochondrial dysfunction, endothelial dysfunction, etc.)

So about 2 years ago, when pondering again about how the brain may possibly be involved – or even “cause”? –  of so many dysfunctions, I ventured upon a group of cell populations that I didn´t know much about, the glia. What I found out was that CNS function (and dysfunction) is closely tied to the proper work of these cell populations (which include microglia and astrocytes). This got me, and the more I read about these co-regulatory brain cells the more I became convinced that they may play an important role in the whole mess of ME/CFS.

So I started an “Occam razor” project, listing all that is known about ME/CFS (signs, symptoms but also pathomechanisms) and tried to understand for every single entry on that list how it could possibly be explained by glial dysfunction.

I worked on this for a year, then sent it to my cousin who happens to be a veterinary neuropathologist and holds a research chair at the University of Guelph, Canada. We refined the hypothesis and published it as a preprint, aptly termed “Broken Connections – The Evidence for Neuroglial Failure in ME/CFS”.

Shortly thereafter I came across a major publication on the role of glia in COVID 19. As it turned out, the main author, Marie-Eve Tremblay, is one of the leading neuroscientists and glia researchers. I at once understood that she might appreciate our approach, e-mailed her to make her aware of our work – and so, in mid-2021, our collaboration began.

It ended in our publication of “The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure” in May 2022. During this time I learned an incredible amount about glial regulation from my collaborators (and I think they learned a lot about ME/CFS from me ;-).

I continue to read every piece of research on ME/CFS and am convinced that we now have a critical mass of knowledge that we will have both biomarkers and therapies in the very near future (my own bet would be on immunomodulatory therapies including BC-007,  and “trained immunity” approaches as well as other therapies that may be able to silence activated endogenous viruses (here I am an eager follower of Prusty´s work).

Also, I am now part of the medical advisory board to the German ME/CFS Society, and I now work with my former ME/CFS physician Carmen Scheibenbogen. So the loop has closed in a certain sense and I now benefit from the immense knowledge and insight into super interesting research ideas in this group.

The Paper – A Brief Summary

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial failure by Herbert Renz-Polster*, Marie-Eve Tremblay, Dorothee Bienzle, Joachim E Fischer

Our work on the role of glia in ME/CFS is now published in Frontiers of Cellular Neuroscience. In this publication, we explain why ME/CFS research may benefit from a closer look at the role of neuroglia. The term “neuroglia” or “glia” describes a network of cell populations mainly in the central nervous system which is important for brain health and brain function. At its core, this network constitutes the immune system of the brain.

Why should we take this network into focus in ME/CFS?

Many biological systems are affected in ME/CFS. There is, for example, evidence for immune dysfunction (including autoimmunity), for metabolic, mitochondrial, and possibly peroxisomal dysfunction, for endothelial or vascular dysfunction, for inflammatory activation, and for dysfunction of the autonomous nervous system (and the central nervous system in general).

But it is still unclear how these dysfunctions fit together and how they conspire to cause the symptoms of ME/CFS.

We think that these processes can directly or indirectly affect a very important regulatory system of our biology: the neuroglia, and thus the innate immune system of our central nervous system (CNS). This non-neuronal system is mainly based on cells called microglia, which cooperate with other glial cells, called astrocytes and oligodendrocytes (the latter are responsible for maintaining the myelin sheaths of the nerve cells). The main task of this glial network is to protect the functionality and integrity of the brain. Whenever the health of the brain is challenged this cell population will be called to action. The glial cells are also very important for cooperation with the immune system outside the brain.

In a more detailed look, the neuroglial network plays an important role especially in the regulation of cerebral blood flow, protecting the blood-brain barrier, and maintaining functional connections within the brain. The glial cells are thus very important for motor functions, autonomous regulation, sleep, sensory gating, memory, mood, and cognition – all functions that are to some extent “broken” in ME/CFS. Also, glial cells work in close concert with mast cells.

Therefore, theoretically, the glial network could play an important role in the pathobiology of ME/CFS.

The GIST

  • Dr. Renz-Polster’s neuroglial hypothesis of ME/CFS brings us yet another contribution to the ME/CFS field from Germany. 
  • Dr. Renz-Polster came down with ME/CFS in 2016 when a strenuous workout following a severe case of influenza left him unable to walk more than a few steps at a time. 
  • With better pacing, a lot of sleep, and a lot of support from my wife, grown-up children, and twin brother he gradually improved.
  • Feeling that the brain must be involved he asked himself if damage or perturbations to the immune cells of the brain – the microglia or neuroglia cells – could explain his symptoms. 
  • He developed a hypothesis and produced a preprint“Broken Connections – The Evidence for Neuroglial Failure in ME/CFS”. Then when an internationally known glial cell expert- Dr. Marie-Eve Tremblay – published a paper on long COVID, he contacted her.  Together they published a follow-up paper  “The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure” which has proved popular. 
  • The extensive neuroglial (microglial) network plays an important role in many processes in the brain including cerebral blood flows, the blood-brain barrier, motor functioning (movement),  autonomic nervous system regulation, sleep, sensory gating (problems with stimuli), memory, mood, and cognition. Plus glial cells work in close concert with mast cells to boot. 
  • The authors found that post-exertional malaise, reduced brain blood flows, endothelial dysfunction, immune dysfunction, and mitochondrial/metabolic dysfunction could all be explained by glial cell issues. 
  • So could the brain findings in ME/CFS – the altered connectivity or messaging occurring between different parts of the brain, the difficulty the brain has in sending blood to the correct places, the increased intracranial pressure, the altered cellular metabolism in parts of the brain, and the vagus nerve problems – can all be explained by glial cell dysfunction. 
  • They propose that the glial cells and the network they’re embedded in have become hyperactive – and are responding to the slightest stimuli – even possibly to stimuli that are evoked doing something seemingly innocuous like reading or watching a movie. 
  • They noted that glial cells could be producing neuroinflammation but could also simply be interfering with the proper flow of blood across the brain. 
  • Finally, they produced an “apple graph” which shows how the many different pieces of ME/CFS may fit together
  • Dr. Renz-Polster is convinced that we’re getting closer and believes that we’ll see biomarkers and therapies in the very near future.

Our Work Step by Step

We, therefore, reviewed the whole ME/CFS literature for details about a possible contribution of glia in the many pathways that are dysregulated in ME/CFS. Here, we put the main focus, especially on two features of ME/CFS: post-exertional malaise, and the reduced cerebral blood flow.

We picked these two features for two reasons: both are present in all ME/CFS patients (at least if stringently diagnosed and examined), and they have been exceptionally well studied. Also, they seem to somehow jive together (for example, exercise leads to reduced cerebral blood flow).

What we found is that both of these features can be plausibly explained as a manifestation of malfunctioning glia (some more details below).

We then examined through which ways the other pathobiological features of ME/CFS (e.g., endothelial dysfunction, immune dysfunction, mitochondrial/metabolic dysfunction) could affect the functionality of this biological hub between brain and body. Endothelial dysfunction, for example, can alter the permeability of the blood-brain barrier so that peripheral immune cells can enter the brain and cause inflammation. This in turn activates the glia. Mitochondrial dysfunction (or any other cause of metabolic dysfunction) goes along with abnormal metabolites; these can also activate the glial cells (which are especially vulnerable to many toxic substrates).

The same aggravation can happen from severe inflammation (which also floods the body with abnormal metabolites) or from signals from a revved-up immune system. Autoantibodies, for example, may not only act on the blood vessels but may also directly or indirectly influence the immune system outside and inside the brain (for example, if the blood-brain barrier is not working properly).

Finally, we reviewed the ME/CFS experimental record for evidence from e.g. imaging studies or from laboratory studies (proteomics, transcriptomics, metabolomics, etc.) that may point to glial dysfunction in ME/CFS. Here, we identify and present many findings from different fields and different research teams which suggest that the function of glia may indeed be affected in ME/CFS. For example, all the findings of abnormal brain function in ME/CFS can plausibly be explained as manifestations of glial dysfunction:

  • broken neurovascular coupling
  • decreased cerebral blood flow
  • altered functional connectivity between brain areas
  • raised intracranial pressure
  • altered cellular metabolism in several brain areas and nuclei
  • vagal dysfunction.

The Jekyll and Hyde face of the Glia

In our explanation of why glia may be central in the regulatory disaster of ME/CFS we especially highlight a unique property of this group of cells: they can shift between an “aggravated” (= hyperreactive) and a more “quiescent” state.

  • Aggravation happens by any form of stress (including inflammation)
  • As already mentioned, glia can also become activated by abnormal metabolites and also by oxidative or nitrosative stress
  • If repeatedly or pervasively aggravated, the glial cells become ever more reactive, i.e. prone to overreaction. This creates a vicious circle.
  • This also means that the threshold for becoming aggravated can fluctuate and differ over time.

We propose that this flexible response of glia could explain the typical PEM features, i.e., the delayed onset, the typical duration of days (to weeks), and also the different thresholds for PEM between patients. We also think that the central role of glia in PEM could explain why PEM can happen even without any muscular exertion (i.e., alone from thinking hard or from watching a movie).

No “Alternative” Theory

Dr. Marie-Eve Tremblay

Dr. Marie-Eve Tremblay’s microglial findings have opened new avenues of research.

Our explanations are not meant to replace or contradict the many theories about ME/CFS, like mitochondrial dysfunction, endothelial dysfunction, the role of autoimmunity, the role of reactivation of endogenous microbes, etc.

On the contrary: With our theory, we try to add a layer that may provide a better or finer-grained understanding of the many broken pieces in ME/CFS. Also, this added piece may be valuable when it comes to understanding how some drugs may work for ME/CFS, or which drugs or interventions may be hopeful candidates.

Also, with this work, we were able to benefit from the knowledge of a world expert on glia, Marie-Eve Tremblay, who co-authored this publication (so far ME/CFS research has not had that much access to this field of neuroscience). What she could highlight, for example, was that we may need to think more stringently about the concept of *neuroinflammation* (which some ME/CFS researchers embrace and others dismiss).

Glial dysfunction can be caused by many processes, some of which may not necessarily be inflammatory*. Also, glial dysfunction may not necessarily cause an inflammatory response. For instance, dysfunctional glia may “just” disrupt neurovascular coupling, i.e., the process which matches local perfusion in the different brain areas to local demand. We should probably become less zealotic in this regard.

And, finally, we have used this review of the ME/CFS literature to, again and again, regard ME/CFS from a system’s perspective: how may the pieces fit together? How may they be orchestrated? This gave rise to an “apple graph” which is part of the publication and shows how interwoven and resonant the many aspects of ME/CFS are.

Dr. Renz-Polster has been communicating with Jarred Younger about his hypothesis and neuroinflammation. Dr. Younger’s Solve M.E. Webinar on neuroinflammation and ME/CFS is today from 10-11 pm PDT.

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