MS appears to be related to venous flow abnormality of the brain with secondary brain autoimmunity
I read the article by Zomboni (1) with interest, with respect to the interaction of the cerebral venous system and central nervous system in development of multiple sclerosis (MS).
An interaction between the central nervous system and venous system has been observed previously in MS lesions by F. A Schelling (2) who initially observed “striking widening of the main venous passageways in the skulls of victims of multiple sclerosis”, and observed venous involvement in the development of cerebral lesions of multiple sclerosis. His supposition was lesions of MS are due to venous back jets from intermittent rises in pressure in the large collecting veins of the neck and especially the chest (2) and noted that Beno Schlessinger, in 1939, while injecting the straight sinus under heavy pressure, noted the extravasations produced around the lateral ventricles “closely stimulate the distribution and even shapes of plaques in multiple sclerosis”.
Certainly venous involvement is distinctive in MS plaques, which usually are perivenous in location, especially in the brain.
The venous outflow obstructions noted by Zamboni (1) appear significant in the development of multiple sclerosis, however their origin remains uncertain. Possibly they are developmental, although an underlying abnormality of the venous wall could also lead to development, especially since MS more commonly develops during adult life, and possibly there is more than one etiology since MS is variable in symptomatology.
Venous obstruction may lead to decreased cerebrospinal fluid reabsorption with subsequent toxicity to neuronal structures from retained CSF components. Additional injury would occur subsequent to breakdown of the blood brain barrier from intermittent elevation of venous pressure injuring capillary and venule endothelium, with secondary development of autoimmunity to brain components following exposure to the systemic immune system, which is ordinarily barred from the central nervous system. After autoimmunization to brain components, MS could transition from a initial abnormality of venous drainage to a secondarily progressive autoimmune disease.
1. P Zamboni, R Galeotti, E Menegatti, et al.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
J Neurol Neurosureg Psychiatry 2009; 80: 392-399.
2. F Alfons Schelling MD
Multiple sclerosis: The image and its message. The meaning of the classic lesion forms.
Available on line at URL: http://www.ms-info.net/ms_040504.pdf
No conflict of interest.
Chronic cerebrospinal venous insufficiency: a potential weakening factor of the blood-brain barrier
Multiple sclerosis is believed to be an autoimmune pathology, yet the mechanisms triggering the disease remain elusive. Therefore, I read with great interest the paper by Zamboni and his team who investigated the venous hemodynamics in patients with multiple sclerosis. His findings that this disease might be attributable to venous refluxes shed new light on the facts that have been known for decades (1), but have been mostly ignored by the scientific community. It should be answered, however, how this pathological outflows in the extra- and intracranial veins could trigger autoimmune reaction.
The loss of integrity of the blood-brain barrier, which is primarily built by tight-junction complexes between adjacent endothelial cells of the cerebrovascular endothelium, is a hallmark of multiple sclerosis. In this context, parallels between multiple sclerosis and chronic venous insufficiency of lower extremities (which is also an endotheliocyte- focused pathology) could be helpful. Yet, it should be remembered that endotheliocytes building the blood-brain barrier highly differ from those in the periphery. Moreover, venous hypertension in cerebral and spinal veins is unlikely to disassemble the cerebrovascular endothelial barrier (2). Indeed, although Zamboni has found increased venous pressure distally of venous stenoses, these pressure gradients were rather small. Thus, it is more likely that not venous hypertension, but pathological pattern of the blood flow-associated forces, decreased level of shear stress in particular, disassembles the blood-brain barrier and increases the transendothelial permeability. It has been found that an enhanced expression of pivotal tight junction proteins: occludin and ZO-1 in the cerebrovascular endothelium was associated with reduced transendothelial permeability and it has been shown, moreover, that an increased shear stress, especially with pulsatile flow characteristics, upregulated these proteins (3). By contrast, loss of shear stress after flow cessation enhanced the blood-brain barrier permeability (4). Therefore, a reduced shear, for instance as a result of the refluxing venous blood flow, could potentially result in the weakening of the blood-brain barrier. This in turn could initiate an autoimmune attack against nervous tissue.
Several questions, though, should have been answered before multiple sclerosis was recognized as a fundamentally hemodynamic disorder. First, if intracranial reflux is indeed the trigger of multiple sclerosis plaques, and not an innocent bystander. This will require additional studies in a much larger cohort of multiple sclerosis patients. Second, if these refluxes only bypass an occlusion and affect exclusively large cerebral and spinal veins, or they extend also into smaller veins (probable, damage of the blood-brain barrier can occur on condition that a decreased shear stress influence the cerebrovascular endothelium in the postcapillary venules). Third, mechanistic links between venous refluxes and cellular and molecular pathways that are responsible for autoimmune reaction should be determined, since such a discovery could result in the development of novel effective pharmacologic agents. Regarding these mechanisms, it should be suspected that the low shear-induced expression of ICAM-1 (adhesion molecule, which is responsible for the firm adhesion of leukocytes to endothelia) by cerebrovascular endothelium, could be a critical point in the initiation of multiple sclerosis plaque, since the crosslinking of ICAM-1 with integrins expressed on the leukocytic surfaces leads to a weakening of the blood-brain barrier and facilitates the transendothelial leukocyte migration (5).
Furthermore, consequently to Zamboni’s findings it may be speculated that at least for some anatomical variants of pathological venous outflow, surgical correction of steno-occlusions can be a therapeutic option in addition to or instead of pharmacotherapy.
In conclusion, investigations of the extra- and intracranial hemodynamic disturbances in multiple sclerosis patients appear to be a challenging avenue and may open a new chapter of therapeutic approach to this debilitating disease.
1. Schelling F.
Damaging venous reflux into the skull or spine: relevance to multiple sclerosis.
Med Hypothes 1986;21:141-8.
2. Simka M.
Evidence against the role for dural arteriovenous fistulas in the pathogenesis of multiple sclerosis.
Med Hypothes 2008;71:619.
3. Colgan OC, Ferguson G, Collins NT, et al.
Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress.
Am J Physiol Heart Circ Physiol 2007;292:H3190-7.
4. Krizanac-Bengez L, Mayberg MR, Cunningham E, et al.
Loss of shear stress induces leukocyte-mediated cytokine release and blood-brain barrier failure in dynamic in vitro blood-brain barrier model.
J Cell Physiol 2006;206:68-77.
5. Lyck R, Reiss Y, Gerwin N, Greenwood J, Adamson P, Engelhardt B.
T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells.
There is no conflict of interest regarding this letter.
Visit the full archive of podcasts for JNNP here >>
This recent issue is free to all users to allow everyone the opportunity to see the full scope and typical content of JNNP.
View free sample issue >>
Don't forget to sign up for content alerts so you keep up to date with all the articles as they are published.