Blood Brain Barrier Compromise with Endothelial Inflammation may Lead to Autoimmune Loss of Myelin during Multiple Sclerosis

Abstract

Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammation and demyelination within the central nervous system. The mechanism that triggers the disease remains elusive. However, recent findings may indicate that multiple sclerosis, at its source, could be a hemodynamic disorder. It has been found that multiple sclerosis patients exhibit significant stenoses in extracranial veins draining the central nervous system (in azygous and internal jugular veins), which are associated with significant pressure gradients measured across strictures. Such anatomic venous abnormalities were not found in the control group of healthy subjects. In this review, it is hypothesized that pathological refluxing venous flow in the cerebral and spinal veins increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the cerebrovascular endothelium. This, in turn, could lead to the increased permeability of the blood-brain barrier. Inflamed and activated endothelium could secrete proinflammatory cytokines, including GM-CSF and TGF-beta In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells. Consequently, a potential therapeutic option for multiple sclerosis could be pharmacotherapy with either substances that strengthen the tight-junctions barrier, or with agents that reduce the expression of adhesion molecules. In addition, surgical correction could be an option in some anatomical variants of pathologic venous outflow. We are optimistic that a hemodynamic approach to the multiple sclerosis pathogenesis can open a new chapter of investigations and treatment of this debilitating neurologic disease.

Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins

“…Perhaps, locally increased CBF and CBV accompanied by a decreased MTT represents the formation of new outflow routes that employ already existing, yet rather small, veins and bypass obstructed pathways. It might be hypothesized that plaques arise preferentially along such overloaded veins (Simka, 2009). However, contrary to the currently ruling autoimmune model of MS, Barnett and Prineas (2004) showed that apoptosis of oligodendrocytes precedes the inflammatory process.…”

Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins

“…Perhaps, locally increased CBF and CBV accompanied by a decreased MTT represents the formation of new outflow routes that employ already existing, yet rather small, veins and bypass obstructed pathways. It might be hypothesized that plaques arise preferentially along such overloaded veins (Simka, 2009). However, contrary to the currently ruling autoimmune model of MS, Barnett and Prineas (2004) showed that apoptosis of oligodendrocytes precedes the inflammatory process.…”

Chronic cerebrospinal venous insufficiency and multiple sclerosis: A commentary

“…However, if the background for MS were a congenital vascular malformation, one should expect to find a peak in the incidence of this disease in young patients, similarly to obstructing malformation in the inferior vena cava. The low incidence of chronic venous insufficiency in tropical countries, retinal periphlebitis associated with MS,4 and pathologic flow patterns in perfusion MR studies5 also support the venous hypothesis. Moreover, a published review has explained how, hypothetically, an impaired venous outflow could lead to the initiation of autoimmunity in MS patients 4…”

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

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Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins

“…Perhaps, locally increased CBF and CBV accompanied by a decreased MTT represents the formation of new outflow routes that employ already existing, yet rather small, veins and bypass obstructed pathways. It might be hypothesized that plaques arise preferentially along such overloaded veins (Simka, 2009). However, contrary to the currently ruling autoimmune model of MS, Barnett and Prineas (2004) showed that apoptosis of oligodendrocytes precedes the inflammatory process.…”

Chronic cerebrospinal venous insufficiency and multiple sclerosis: A commentary

“…However, if the background for MS were a congenital vascular malformation, one should expect to find a peak in the incidence of this disease in young patients, similarly to obstructing malformation in the inferior vena cava. The low incidence of chronic venous insufficiency in tropical countries, retinal periphlebitis associated with MS,4 and pathologic flow patterns in perfusion MR studies5 also support the venous hypothesis. Moreover, a published review has explained how, hypothetically, an impaired venous outflow could lead to the initiation of autoimmunity in MS patients 4…”

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

“……”

Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins

“…Perhaps, locally increased CBF and CBV accompanied by a decreased MTT represents the formation of new outflow routes that employ already existing, yet rather small, veins and bypass obstructed pathways. It might be hypothesized that plaques arise preferentially along such overloaded veins (Simka, 2009). However, contrary to the currently ruling autoimmune model of MS, Barnett and Prineas (2004) showed that apoptosis of oligodendrocytes precedes the inflammatory process.…”

Chronic cerebrospinal venous insufficiency and multiple sclerosis: A commentary

“…However, if the background for MS were a congenital vascular malformation, one should expect to find a peak in the incidence of this disease in young patients, similarly to obstructing malformation in the inferior vena cava. The low incidence of chronic venous insufficiency in tropical countries, retinal periphlebitis associated with MS,4 and pathologic flow patterns in perfusion MR studies5 also support the venous hypothesis. Moreover, a published review has explained how, hypothetically, an impaired venous outflow could lead to the initiation of autoimmunity in MS patients 4…”

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

“……”