The initial study by Zamboni et al. (2009a
) proposing the entity of CCSVI and the relationship of it to the pathogenesis of MS is based on ECD and TCCS evaluation. Basing the theory of CCSVI and MS on this measurement modality has drawn criticism due to several limitations including the ability to measure intracranial venous blood flow, operator dependence, and a lack of standardized values for diagnostic criteria (Doepp et al., 2010
; Wattjes et al., 2011
The theory of CCSVI in relation to MS holds that venous outflow is obstructed leading to venous congestion with the goal of endovascular therapy to alleviate the stenosis and thus the congestion. The proposed treatment for CCSVI is percutaneous transluminal angioplasty (PTA) as described by Zamboni et al. (2009b
) in a subsequent series of endovascular treatment for CCSVI in MS patients. In their series, they defined six different malformation morphologies, including “septum/valve malformation” which indicated an anomalous valve apparatus causing flow obstruction. This was the most common type of malformation and was present in 30 right IJVs and 28 left IJVs. Angioplasty of a stenotic valve would seem to alleviate obstruction of flow, however it would also seem to induce valve incompetence that would result in reflux and thus retrograde flow and venous congestion. Whether this result is present was not described, and evaluation with selected angiography post-procedure and subsequent sonographic evaluation may provide clarification.
An important character of a novel scientific finding is reproducibility. Several investigators have unsuccessfully attempted to reproduce the findings of Zamboni’s group. An independent group was unable to reproduce an association between venous outflow obstruction and MS using sonography (Doepp et al., 2010
). This group performed transcranial color-coded sonography on 56 patients with MS and 20 control patients and found only a single patient with abnormal blood flow direction, and none of the patients fulfilled more than one criteria for CCSVI. Differences in studies including an unblinded design, a different profile of MS patients, and different sonography techniques may have contributed to the discrepancy to the findings of Zamboni et al. (2009a
). A recent report using MRV to evaluate the craniocervical venous anatomy, drainage pattern, and flow, found anomalies present in MS patients and healthy controls without abnormal flow (Wattjes et al., 2011
). Although limited by a small number of subjects (20 MS patients and 20 healthy controls), this also challenges the hypothesis that CCSVI is important in MS. Another study compared 21 patients with MS and 20 healthy control patients who underwent contrast enhanced MRI and found no difference regarding internal jugular venous outflow (Sundstrom et al., 2010
). Additionally, early results from a study looking at prevalence of CCSVI in MS with venous Doppler identified the entity in 63% of MS patients, 26% of healthy controls, and 45% of patients with other neurological disorders (Zivadinov et al., 2010
). While variability is inherently present in study designs and the technique-dependent nature of sonography, the lack of reproducibility of Zamboni’s original findings remains a criticism of the hypothesis.
Radical neck dissection is performed in patients with extensive head and neck cancer and has been reported with bilateral jugular vein ligations (Ensari et al., 2008
). Additionally, a small series of patients with an IJV obstruction due to various causes were studied angiographically and showed prominent channels from the sigmoidal, jugular, and vertebral systems (Cook et al., 1958
). Following the vascular model of MS, this would seem to cause venous congestion resulting in the proposed inflammatory response and demyelination, but this has not been reported. An alternative explanation may be that an autoimmune predisposition or propensity to be sensitized to myelin is also needed and was not present in these patients. Furthermore, preferential cranial venous outflow may be dependent on posture, with preferential flow through the jugular system in the supine position and through the vertebral system in the erect position (Valdueza et al., 2000
). If venous outflow patterns are dependent on posture in this way, then congestion from jugular obstruction may be most relevant in the supine position.
Other conditions of venous rerouting including cerebral venous thrombosis and venous embolization in treatment of vascular abnormalities such as arteriovenous malformations have not been reported to be associated with the development of MS type plaques. More recently, idiopathic intracranial hypertension (IIH) has been considered to arise from dural sinus narrowing and venous outflow obstruction. This also may result in a more restricted region of venous congestion that causes no evidence of MS type plaques due to compensation by collateral venous outflow. Additionally, venous outflow obstruction from IJV incompetence has been associated with transient global amnesia (Lewis, 1998
), however this has not been associated with MS.
The venous outflow from the head may in fact be predominantly through the vertebral venous system. A postural dependence on venous outflow has been demonstrated (Valdueza et al., 2000
). In healthy subjects, ultrasonography demonstrated vertebral venous outflow to be the dominant system in the erect position, while jugular venous drainage was more predominant in the supine position. The diagnostic criteria for CCSVI relies more on anterior venous outflow, which may be only partially involved in cranial venous drainage.
A comparable physiologic model may also be considered in pregnancy. Near the end of pregnancy, there is often considerable pressure on the vena cava. Venous blood is likely then shunted into the vertebral plexus, which would translate to increased cerebral venous pressure as well. Following the vascular model of pathogenesis in MS, it would seem that pregnant women exposed to extended venous outflow rerouting and possibly congestion, would develop sclerotic plaques. However, interpretation of this finding differently may in fact support the theory that the vascular model contributes to MS and that venous rerouting in pregnancy explains MS exacerbations.