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2021 Apr 26
Department of Radiology, Wayne State University, Detroit, MI, United States
An Overview of Venous Abnormalities Related to the Development of Lesions in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/33981281/

Abstract

The etiology of multiple sclerosis (MS) is currently understood to be autoimmune. However, there is a long history and growing evidence for disrupted vasculature and flow within the disease pathology. A broad review of the literature related to vascular effects in MS revealed a suggestive role for abnormal flow in the medullary vein system. Evidence for venous involvement in multiple sclerosis dates back to the early pathological work by Charcot and Bourneville, in the mid-nineteenth century. Pioneering work by Adams in the 1980s demonstrated vasculitis within the walls of veins and venules proximal to active MS lesions. And more recently, magnetic resonance imaging (MRI) has been used to show manifestations of the central vein as a precursor to the development of new MS lesions, and high-resolution MRI using Ferumoxytol has been used to reveal the microvasculature that has previously only been demonstrated in cadaver brains. Both approaches may shed new light into the structural changes occurring in MS lesions. The material covered in this review shows that multiple pathophysiological events may occur sequentially, in parallel, or in a vicious circle which include: endothelial damage, venous collagenosis and fibrin deposition, loss of vessel compliance, venous hypertension, perfusion reduction followed by ischemia, medullary vein dilation and local vascular remodeling. We come to the conclusion that a potential source of MS lesions is due to locally disrupted flow which in turn leads to remodeling of the medullary veins followed by endothelial damage with the subsequent escape of glial cells, cytokines, etc. These ultimately lead to the cascade of inflammatory and demyelinating events which ensue in the course of the disease.

Free full text: https://www.frontiersin.org/articles/10 ... 61458/full

From E. Mark Haacke et al.

Conclusion:
All this evidence of venous vascular abnormalities in MS leads to a critical hypothesis as to one potential cause of MS: “Local disrupted venous flow leads to remodeling of the medullary veins followed by a breakdown of the endothelium with the subsequent escape of glial cells, cytokines, etc. that in turn lead to the autoimmune demyelinating process and subsequent tissue death and atrophy.” There are several key features in MS that can be understood in the context of this review. Whether or not venous flow disruption occurs first, the pathological course of MS is consistent with the continual feedback loop of constantly reducing blood flow over time. This is consistent with all findings in the literature. There are multiple mechanisms by which demyelination could occur at the cellular level but the source likely remains the extravasation of various cells and how they might precipitate demyelination. Abnormal flow is also consistent with generating an endothelial response in the form of inflammation first. This then leads again to the conventional wisdom on how the endothelium responds to inflammation. However, in the scenario outlined here, we show the effects of continued flow reduction because of processes such as fibrin deposition and collagenosis. This can then create a feedback loop as shown in Figure 4 where vascular insufficiency leads to venous hypertension and other flow effects that then lead to a breakdown of the BBB. Further, the return to normal flow may, in fact, predict why lesions can recover as the usual nutrients and conditions required for endothelial health return to normal as well. In summary, this comprehensive overview of vascular effects in MS should open the door to study abnormal flow and its temporal relationship to the development of MS lesions using a variety of in vivo imaging methods. We encourage further research to study the microvasculature in MS as it relates to lesion formation and the development of chronic lesions.




Figure 4. Flow chart of hypothesized effects of abnormal flow in multiple sclerosis related to the neurovascular unit. In this scenario, abnormal medullary vein flow not only initiates the process of vessel wall damage and vasculitis but also can cause remodeling where the brain attempts to overcome the flow abnormalities and, in the process, can create complicated drainage pathways including very small or micro venous angiomas by recruiting anastamotic veins connecting the medullary veins. A recovery of flow may then lead to the resolution (disappearance) of the lesion. Continued slow flow or obstructed flow is likely to exacerbate the conditions leading to blood brain barrier breakdown and worsening of the flow creating a negative feedback loop that eventually leads to cell and tissue death. On the other hand, at early stages of the lesion, the pro-inflammatory cytokines can induce endothelial impairment through increased levels of vascular endothelial growth factor (VEGF), VEGF receptors and endothelial adhesion molecules that lead to a recursive loop that promotes vascular remodeling, angiogenesis and inflammation; especially as the lesion progresses to a late neurodegenerative stage with chronic hypoperfusion. Note that the numbers listed in the blocks refer to the different sections in this paper associated with that stage of the disease process: (1) inflammation and vascular damage; (2) venous collagenosis; (3) role of venous ischemia; (4) cerebral venous infarction; (5) dural sinus flow effects, abnormal CSF flow, and increases in venous pressure; (6) changes in perfusion of MS lesions; (7) fibrin deposition; (8) retinopathic vascular abnormalities; (9) medullary vein flow; (10) central vein sign; (11) evidence of dilated veins; (12) endothelial dysfunction; (13) loss of medullary vein density; (14) developmental venous anomalies; (15) early vascular changes as a marker for new lesions; (16) advanced microvascular MRI using ultra-small superparamagnetic iron oxides (USPIO); and (17) imaging indications of venous abnormalities.


All of this begs the question, if MS is primarily a vascular disease of the brain, and not an autoimmune disease, then how do we treat it? Clearly, the lack of efficacy of immune modulating treatments in slowing the progression of long term disability has demonstrated the futility of that approach.

Very good video. Albeit the presenter won't get an Oscar for a riveting performance.
The content is worth taking in.