The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Abstract

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.