DOES CHRONIC VENOUS INSUFFICIENCY PLAY A ROLE IN MS PATHOGENESIS (YES)?
P. Zamboni
Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by flow blockages in the internal jugular and/or azygous veins (IJVs-AZ) with opening of collaterals and insufficient drainage proved by reduced cerebral blood flow and increased mean transit time in cerebral MRI perfusional study. As far as the origin of venous narrowing is concerned, phlebographic studies of the IJVs and AZ systems demonstrated that venous stenoses were likely to be truncular venous malformations. CCSVI condition has been found to be strongly associated with multiple sclerosis (MS), a disabling neurodegenerative and demyelinating disease considered autoimmune in nature. In several epidemiological observations performed at different latitudes on patients with different genetic backgrounds the prevalence of CCSVI in MS ranges from 56% to 100%. In this particular moment the status of the research cannot clarify at all if CCSVI should play a role in MS pathogenesis. There are 3 main research fields producing findings partially supporting this idea.
1. Brain pathophysiology assessed by non conventional MRI measures.
Brain pathophysiology is significantly modified by the presence of extracranial venous obstruction. Cerebrospinal fluid dynamics is the mirror of CCSVI, since reabsorption is of course hampered at the level of the dural sinus in consequence of the slight but significant increase of venous pressure. Redistribution of cerebrospinal fluid and brain volume in the skull is associated with the hemodynamic severity of CCSVI.
The vascular community is familiar with the increased iron deposition in the distal part of the territory not properly drained in consequence of chronic venous insufficiency. There are several papers describing the higher iron levels in the basal ganglia of patients affected by CCSVI and MS, the more distal territory drained by the parenchymal veins. A role for CCSVI in MS is consistent not only with the well known perivenular distribution of MS lesions, but also with recent studies that have found a central vein in the long axis of inflammatory MS lesions using ultra-high field MRI and abnormally high levels of redox active metals,
particularly iron, identified with an MRI technique called susceptibility-weighted imaging (SWI). This is a new and sophisticated MRI technique developed by Mark Haacke in Detroit, capturing the interest of the neuroradiologists in this new field.
2. Pathology of the venous wall in course of CCSVI-MS
Specimen coming from jugular vein wall were analyzed and compared with control specimen. CCSVI-MS seems to be a peculiar disease, reinforcing the idea to be cause rather than product of MS due to the following:
No T-cells infiltration in the vein wall
Prevalence of type 3 collagen respect to type 1, normally constituting the jugular wall in controls
Poor distribution of smooth muscle cells in the media with abnormal distribution in the adventitia, with arrangement in clusters rather than in longitudinal layers
Abnormal presence of intraluminal septum, flap, double channel, malformed valves clearly indicating problems in the development of the vein.
3. Genetics of CCSVI MS.
MS is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors, which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. It has been investigated in such region if a genotype-phenotype correlation might exist in MS people with evidence of the adjunctive CCSVI venous blockages phenotype. This was highly suspected due to the abnormal architectonics and molecular constitution of the jugular vein wall, above
described. In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the numbers of known CNVs found in the HLA region and the number of CCSVI-venous stenosing malformations identified in patients. (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). Pathway analysis revealed common
routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, 15 patients, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in
susceptibility to this novel MS/CCSVI plus phenotype, and perhaps even other types of the disease.
DOES CHRONIC VENOUS INSUFFICIENCY PLAY A ROLE IN MS PATHOGENESIS? “NO”
O. Stüve
Recent studies suggested that venous insufficiency (CCSVI) may be causally related to the etiology of multiple sclerosis (MS). Patterns of venous obstruction were also associated with clinical disease phenotypes. Using percutaneous transluminal angioplasty (PTA) and stenting, one group of investigators
demonstrated that vascular hypoplasia can be successfully treated. There was also a significant benefit with regard to numerous clinical outcomes in patients with MS who underwent PTA.
Based in these observations, the following hypotheses have been stated: (1) Blocked extracranial veins causes cerebral venous reflux in patients with MS. (2) A stasis of venous blood flow, or a reversal of flow, or a lack of laminar flow results in iron overload in pervascular tissue and initiates an inflammatory
cascade within the central nervous system. While results from these open-label uncontrolled trial is compelling at first glance, there are significant concerns with regard to their biological plausibility. First, Published data on the effects of iron-overload does not support its pathogenic role in autoimmunity. Also, chronic venous insufficiency has not been associated with inflammatory disorders in other parts tissues or organs. Importantly, the observations on CCSVI also do not explain other epidemiological findings, namely the latitudinal gradient of MS, or the preponderance of female patients with MS. It also does not explain some of the clinical or paraclinical disease activity associated with this disorder: (1) How does a fixed anatomical defect result in a relapsing-remitting disease course in most patients? (2) Why is there a decrease in disease activity
during pregnancy? (3) Why is there a decrease in gadolinium-enhancing (Gd+) lesions in the brain on magnetic resonance imaging during progressive forms of MS, when the sequelae of venous reflux should be amplified? (4) How does CCSVI explain spinal cord disease? (5) How does the presence of CCSVI
explain the beneficial response of many patients to currently approved immunomodulatory and immunosuppressive pharmacotherapies?
Some of these concerns should be addressed in blinded, multi-center randomized trials.