Broken Connections: The evidence for neuroglial failure in ME/CFS, by Herbert Renz-Polster, MD, Dorothee Bienzle, PhD 31 Aug 2021 [doi:10.31219/osf.io/ef3n4]
In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified – including immune abnormalities, inflammatory activation, mitochondrial dysfunction, endothelial dysfunction, muscular dysfunction, cardiovascular dysfunction, and dysfunction of the autonomous nervous system.
Yet, it remains unclear how these pathways are related, which of them may be upstream or downstream, and which ones may be explanatory of the symptomatology of ME/CFS (and thus possibly targets for therapeutic interventions).
A similar uncertainty is currently experienced by thousands of researchers who struggle to understand Postacute Sequelae of Covid (PASC, “Long Covid”), a condition with many similarities to ME/CFS.
In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS. i.e., we suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.
For this “histological” approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.
Through this search we have identified the CNS neuroglia – microglia and astroglia – as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the
neuroimmune basis of ME/CFS.
After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.
We feel encouraged in this “histological” concept by recent findings from fibromyalgia research. After 50 years of unsuccessful investigations this “sister disease” of ME/CFS has been unraveled – through a “histological” approach. As ingenious human-mouse transfer experiment have shown, fibromyalgia is based on a neuroimmune process directed against the glial cells in the dorsal root ganglia of the spinal cord.
The theoretical leads that we are presenting in this review point in a
similar direction: the final pathogenetic pathway of ME/CFS is likely to consist of a neuroimmune reaction – directed against the glial cells of the CNS connectome.
‘The neuroglial unit orchestrates the many physiological functions that have so far been implicated in ME/CFS’
Of note, this is not a unifying theory about the etiology, the triggers or the inception process of ME/CFS. This approach is focused solely on finding the final pathogenetic pathway(s) which may underlie the clinical manifestations of ME/CFS. It does not question existing theories about the inception of ME/CFS, be they based on autoimmunity, persistent infection, mitochondrial or metabolic failure or any other assumption.
The profound dysregulation underlying ME/CFS is seated in the central nervous system
. Anyone who has worked through this working paper may understand why this is the only plausible assumption for me: ALL the phenomena of ME/CFS can be most directly explained as a consequence of dysfunctions in the central nervous system. There is just no other location in the human body in
which the deep seated, archaic regulatory units affected in ME/CFS are to be found.
For me, ME/CFS is not a dysfunction that ALSO affects the CNS, it is a dysfunction that is DRIVEN by the CNS. For me, this “central” explanation also covers the general mitochondrial dysfunction seen in ME/CFS, the
muscular dysfunction and the “enigmatic cardiovascular situation in ME/CFS – “peripheral” as all these features may appear, they all can be explained as consequences of central regulatory dysfunctions.
Bluntly, in an “Occam’s razor” investigation, there is just no need for a “peripheral” explanation. Also, the “central” hypothesis is also the only explanation that fits with the specific “coupling” of symptoms in ME/CFS (see [2.5]). And it is also the only explanation for the multi-trigger, threshold driven, delayed and prolonged stress response after exercise (see [3.0]).
Here, I need to add a disclaimer: This is a functional description of how the clinical cascade of ME/CFS may be best explained. This does NOT imply that influences outside the CNS may not play a role in ME/CFS or may not be appropriate targets for therapeutic interventions. Similarly, the “central”
argument does also not imply that there may not be more profound, general processes that inaugurate, prime, sustain or otherwise influence this central pathological matrix (to be revisited below).
The pathophysiology of ME/CFS affects completely disparate physiological processes. It is a “dauer state” and it is “sustained arousal” – at the same time. It is vagal dysfunction and sympathetic dysfunction – at the same time. It is adrenergic stimulation and adrenergic failure – at the same time.
It is hyperarousal and under arousal – at the same time (for details on the “paradoxical” nature of ME/CFS, see [4.11]). ME/CFS just does not fit into any single regulatory unit. I therefore doubt that what is broken in ME/CFS can be found in a single brain nucleus (like a “fatigue nucleus”) or a single transmitter system or a single receptor system. I rather suggest that the core pathology of ME/CFS is a diffuse one that affects a matrix that contributes to many regulatory units and spans many regulatory levels.