Arguably, this phenomenon first described by Uhthoff represents a modern paradigm to model the impaired integrity of axonal conduction after demyelinating injury as being affected by both abnormal voltage-gated sodium channels, as well as current leak from potassium efflux from uncovered potassium channels.
There are 4 types of cortical lesions seen in patients with MS including: leukocortical, intracortical, subpial, and cortex spanning types. Leukocortical lesions are at the grey matter and white matter junction. Intracortical lesions are characterized by perivascular demyelination expanding from a cortical vessel. Subpial lesions show demyelination along the outer surface of the gyri. Last, some lesions span the entirety of the cortex (20). In progressive MS, subpial lesions are the most common (8). All cortical lesions are associated more prominently with either primary or secondary progressive stages of MS as opposed to relapsing-remitting MS (21). Furthermore, several studies have shown that cortical demyelination and neurodegeneration are relatively specific to MS. The proposed mechanism to explain these changes relates to local inflammatory infiltrate and oxidative stress, and not simply to white matter damage with a dying back axonopathy culminating in grey matter degeneration (22).
Cortical demyelination is more pronounced in areas associated with meningeal inflammation within the sulci (23), suggesting that at least part of the pathophysiology is related to local flow of cerebrospinal fluid (CSF) and circulating factors in the subarachnoid space. However, it remains unknown whether or not cortical injury is being driven by a diffusing autoantibody or cytokine being produced in the CSF compartment and penetrating into the cortex; or, if cortical injury could be due to secondary tissue destruction from oxidative injury as a byproduct of overlying inflammation (23).
Patients with higher synthesis of CSF IgG oligoclonal bands at onset of disease have been shown to have worse disability and more severe grey matter pathology (24). In some selected populations, there is an increase in peripheral B-cell activity related to cytokine variance, in particular B-cell activating factor. This upregulation is possibly why therapies targeting B-cells are beneficial in MS (25). The benefits of plasma exchange in some patients with MS also underscore the prospects that soluble factor(s) (e.g., antibody, cytokine, chemokine, etc.) may figure prominently in both disease pathogenesis and course perpetuation (e.g., secondary progressive MS).
Demyelination of axons drastically increases their metabolic needs. For instance, Na+/K+ ATPase pump leak out into the ambient environment in the absence of myelin. Energy is needed to maintain homeostasis in this context (25). Recent studies have shown that demyelinated axons have a large increase in mitochondrial content, and remyelinated axons have a modest increase in mitochondrial content (26). These observations likely reflect compensatory mechanisms aimed to protect against the increased energy needs of the axon. However, mitochondrial content is susceptible to oxidative stress, and patients with progressive MS exhibit mitochondrial DNA deletions, which leads to respiratory-deficient neurons. The end effect is self-propagating injury: not only are axons destroyed in the acute demyelinating attack, but those that remain have a higher metabolic need, constituting a mismatch between supply and demand. Accordingly, therapies that target mitochondrial dysfunction are potential future avenues of treatment (27).
Within the past decade, we have found evidence of a lymphatic system for the CNS, which may play a role in either initiating or perpetuating an inflammation (28). This observation has countered one of the tenets of a traditional dogma that has long held that the brain is immunologically privileged. Many systemic autoimmune diseases, such as Crohn disease, are characterized by ectopic lymphoid follicles. These are produced by the locally activated B-cells undergoing clonal expansion because of antigen presentation from dendritic cells as well as interactions with T-cells. Ectopic germinal follicles are also found in the meninges in MS, and may serve as a reservoir of cells that proliferate an inflammatory response (29). Evidence that these follicular structures are not just the byproduct of a larger inflammatory response is that subpial cortical lesions that are associated with B-cell follicle structures demonstrate a gradient of cell loss in the adjacent underyling cortex. There is greater cell loss in cortical layers I and II, with decreasing cell loss further from the cortical surface (30).
An emerging cardinal hallmark of MS is that of meningeal inflammation and its associated subpial demyelination. The extent of this meningeal inflammation corresponds to a severe MS clinical phenotype, including both primary and secondary progressive disease subtypes (20,31,32). Inflammatory meningeal infiltrates are detected by MRI in 33% of patients with progressive MS compared with historical rates seen on histopathology postmortem of 40% (20). The development of improved brain MRI techniques (high-resolution 3T postcontrast T2 FLAIR sequences with delayed image acquisition, and 7T sequences) now shows these structures in vivo (33). Continued improvement in MRI technology will allow for the detection of more subtle leptomeningeal enhancement on a longitudinal basis, and allow for observation of treatment response.
Proof to date regarding the role of B-cell activity in MS, is the successful application of B-cell depleting therapy in patients with progressive disease (34). There is a germinal center-like reaction and clonal expansion by the intrathecal presence of somatic hypermutation of IgM, which can be found in the CSF. This supports the theory of antigen-driven affinity maturation within the protected compartment of the CNS (35). The production of oligoclonal IgM bands (both lipid-specific and to sperm-associated antigen 16, a protein expressed on astrocytes) is associated with higher disability (36). A self-sustaining inflammatory process contained behind the walls of the blood-brain barrier could also be the cause of the limited success for other systemic therapies in the treatment of progressive MS.
What tips the balance from the early relapsing-remitting course, to the unrelenting, and more treatment-recalcitrant progressive phase of the disease remains an enigmatic question in MS. Early in the course of MS, a peripheral immune response is likely focal; with chronicity an expanded repertoire of potential targets becomes established (i.e., epitope spreading), resulting in a much more formidable disease state to treat (37). Ongoing inflammatory mechanisms seem to be inextricably linked with evidence of demyelination, neurodegeneration, brain atrophy, and the corresponding set of clinical manifestations that are a derivative of these processes. In fact, patients without ongoing inflammation exhibit rates of neurodegeneration which match those of control subjects (38). These phases are not fully independent. For instance, patients with poor early relapse recovery exhibit a shorter latency for the onset of a predominantly progressive disease course. This observation implicates constitutive disease activity as the principal catalyst for the perpetuation of both the clinical and paraclinical facets of disease progression (39,40). Continuous atrophy, axonal loss, and ultimately neurodegeneration progress, even in the latest epochs of the disease course, corroborating findings from postmortem studies of patients with MS showing chronic plaques with on-going axonal injury (41).
The overarching pathophysiology of chronic axonal loss is based on a chronic energy imbalance between supply and demand. Demyelination causes a shift from saltatory, to membrane conduction of electrical propagation along “lengths” of segmental demyelination. This, in turn, leads to a redistribution of Na+ channels along the length of the axon, in contrast to the normal and strategically localized concentration of Na+ channels being distributed at the nodes of Ranvier and at the paranodal interface (42). In the face of chronic demyelination, there occurs a highly relevant diminution of intra-axonal adenosine triphosphate (ATP). This bioenergetic derangement impacts the necessary reversal of the Na+/Ca2+ channel needed to reestablish normal ionic concentrations, after the insertion of new sodium channels as an adaptation to restore axonal conduction. Although the process of recalibrating ionic concentrations is imperative, it is also very expensive in terms of energy utilization. Furthermore, the pathophysiologic consequences of this biochemical reorganization of the intra-axonal milieu, is also attended by excessive concentration of intra-axonal calcium. The escalation of intracellular levels of Ca2+ induces proteolytic enzymes and impairs mitochondrial function, in conjunction with the liberation of excitatory amino acids such as glutamate. This cascade of events accelerates tissue damage and disorganization, making repair and recovery increasingly more formidable in the CNS (18). In addition, the impaired mitochondria that remain are more susceptible to both ionic and hypoxic insults, creating a “currency” deficit, and an inability to maintain normal homeostasis. This eventually increases the vulnerability of demyelinated axons to undergo deconstruction (e.g., breakdown of intra-axonal microtubules and neurofilaments) and consequent degeneration (43).
The retina represents the front of the brain and can now be interrogated noninvasively with objective methods of assessment. A potential overview of how the mechanistic heterogeneity in MS plaque pathogenesis in the brain can be “seen through the eye” is outlined in Table 1 (44,45). With this approach, the eye represents a window through which we can characterize pathophysiologic signatures that correlate with changes in other discrete functional CNS systems, and with whole brain structure. Accordingly, the interrogation of structure–function relationships within the eye will provide deeper insights into mechanisms of CNS injury and repair, in MS and other degenerative disorders. In the field of MS, there is a great need for better biomarkers that are sensitive to subclinical manifestations of the disease, which ultimately govern disability. Interrogating the visual system with multiparametric modeling techniques that couple the most robust assessments of retinal architecture with physiological processing metrics will provide objective, valid, and reproducible means to elucidate pathophysiologic signatures of brain dysfunction in MS. Ultimately, exploring the link between eye and brain will enhance our understanding of subtle aspects of disease progression, and ultimately refine our ability to test the efficacy of new treatments in patients with MS.
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