The idea of MS being a vascular disease is not new. In the 1930s T.J. Putnam proposed venous obstruction as the primary alteration in MS [
7]. Given the venotopic localization of MS plaques, this hypothesis has been discussed on and off ever since. In 2007 an Italian group headed by P. Zamboni added new fuel to the fire by demonstrating that venous blood flow alterations can be found at a high frequency in MS patients [
5]. The initial study on 89 MS patients and 60 control subjects was soon followed by a second one by the same investigators addressing venous hemodynamics in 65 patients with clinically definite MS and 235 controls [
1]. Using high resolution echocolor Doppler sonography (ECD) and transcranial color Doppler sonography (TCCS). Zamboni et al. defined five parameters that-if at least two are present-allow diagnosis of CCSVI i.e. (1) reflux in the internal jugular and/or vertebral veins; (2) reflux in the deep cerebral veins; (3) B-mode evidence of internal jugular vein stenosis; (4) flow not Doppler-detectable in the internal jugular and/or vertebral veins; (5) reverted postural control of the main cerebral venous outflow pathways. He reported that the presence of venous outflow anomalies was dramatically associated with the diagnosis of MS [
1]. This finding was confirmed by another study of the same group who detected CCSVI in all of 109 MS subjects but none of the 177 controls (sensitivity 100%, specificity 100%) [
6]. Iron-driven inflammation was proposed as the mechanism by which CCSVI contributes to MS pathogenesis (see below). Analogous to chronic venous insufficiency of the lower legs, venous congestion is assumed to cause a higher transmural venous pressure that impairs the endothelial barrier leading to local erythrocyte extravasation. Extravascular hemolysis then may lead to iron deposition that attracts immune cells and kicks off an inflammatory cascade that culminates in MS plaque pathology [
8,
9].
During the last years, other groups have tried to reproduce the pioneering work of Zamboni with variable success (Table
1). Simka et al. reported the presence of CCSVI in 90% of 70 MS patients under investigation [
10]. In line with that, Al-Omari and Rousan found 84% of MS patients (n = 25) to test positive for CCSVI but none of the controls (n = 25) [
11]. However, other groups have failed to detect this high prevalence of CCSVI in MS questioning the concept of CCSVI as the underlying cause of the disease [
12‐
14]. In a study by Doepp et al., none of the participants (n = 56 MS patients, n = 20 controls) fulfilled the CCSVI Doppler criteria proposed by Zamboni et al. Lack of CCSVI was also reported in a German cohort of 20 MS patients, with only one out of 20 control subjects fulfilling the CCSVI criteria [
13]. Very recent data derived from a large population of MS patients does indeed suggest a higher prevalence of CCSVI in MS compared to controls, but at substantially lower numbers than those found in the original publication by Zamboni et al. 56.1% of MS patients (n = 289), 38.1% of CIS patients (n = 21) and 22.7% of healthy controls (n = 163) fulfilled the sonography criteria for CCSVI [
15]. Yet, the presence of CCSVI was also high in patients with other neurological diseases (42.3%, n = 26) questioning the specificity of CCSVI in MS [
14]. Of note, the prevalence of CCSVI was highest in patients with progressive MS suggesting that CCSVI may be a consequence rather than a cause of disease [
15]. A possible cause-effect relationship was also challenged in a study on CIS patients: If CCSVI played a major role in MS pathogenesis, one could argue that it should be present at disease onset. However, only 16% of CIS patients tested positive for CCSVI [
12]. While demographic factors like disease duration, age and sex may account for the divergent findings between the groups, methodological issues, operator-dependant differences in the interpretation of sonography findings and difficulties in operator-blinding may also play a role. Recognizing the shortfalls of venous Doppler sonography, other methods for detection of CCSVI and surrogate markers of cerebrospinal venous congestion have been evaluated. It has been hypothesized that if CCSVI was present in MS, one can assume an elevated intracranial venous pressure reflected by an increased intraocular venous occlusion pressure in MS patients [
16]. Yet, a recent study on 29 MS patients and controls failed to detect such differences in venous occlusion pressure [
16]. Others have argued that if MS pathophysiology was related to iron deposition in venous congestion, this should be reflected by higher ferritin levels in the cerebrospinal fluid as observed in siderosis or subarachnoidal hemorrhage. However, CSF ferritin levels were largely normal in the MS population studied [
17]. Magnetic resonance venography and flow quantification was performed in a limited numbers of MS patients again demonstrating no significant differences in the extracranial venous system of MS patients and healthy controls [
18‐
21]. Although this may argue against the vascular hypothesis of MS, one has to consider that MR may just be an inadequate method for detecting CCSVI [
3,
21]. Selective venous angiography is considered the gold standard among the diagnostic tests for extracranial venous stenosis (EVS). To confirm his ultrasound findings, Zamboni et al. performed invasive venography in 65 MS patients demonstrating multiple significant extracranial stenoses in all patients but in none of the 45 control subjects [
1]. In contrast, the rate of EVS as shown by selective venography was significantly lower in a study by Yamout et al. [
22] who pointed out several pitfalls in performing invasive extracranial venography that may lead to overestimation of venous outflow anomalies: The caliber of the internal jugular veins depends on patient's position, breathing (inspiration vs. expiration), compression by nearby structures (i.e. sternocleidomastoid muscle, esophagus, pulsating carotid arteries) and prominent valves, all of which can give a picture of pseudostenosis [
22]. Accordingly, a high operator-dependency of the method can be assumed and it is not surprising that again some authors report venous stenoses in up to 97% of patients previously diagnosed with CCSVI by sonography [
23], whereas others fail to do so [
12]. Despite the obvious difficulties in establishing an operator-independent diagnosis of CCSVI, the vascular hypothesis of MS has recently gained a lot of attention in the media. Balloon dilatation of venous stenosis or stent implantation would in theory cure CCSVI and a number of interventional-radiologists have already started to actively promote the so-called "liberation treatment" as a therapeutic option in MS. Zamboni and colleagues have performed transluminal angioplasty in 65 patients observing a significant improvement of clinical and MRI outcome measures in an uncontrolled, unblinded trial with a mean follow-up of 18 months that lacked a sham control to assess placebo effects [
3]. Safety and tolerability of endovascular treatment was recently addressed in a large trial in which balloon angioplasty was performed on 192 cases and additional stenting in another 152 cases of MS patients [
23]. The procedure was reported as relatively safe with major complications (thrombotic stent occlusion, surgical removal of angioplastic balloon from the femoral vein) occurring in 1.5% of patients. Stent migration was observed in 2.3% of patients and few cases of pseudoaneurysms, gastrointestinal bleeding and atrial fibrillation were reported [
23]. However there is also anecdotal evidence of stent dislocation to the right ventricle and death from cerebral hemorrhage following peri-procedural anticoagulation [
24]. Up to now, there is no scientific proof of efficacy of any endovascular treatment in MS and patients should not be treated outside of randomized, controlled trials [
25].
Table 1
Comparison of CCSVI studies
TCCS | 89 MS | 60 | alterations of intracranial venous haemodynamics in MS patients | + | Zamboni et al. | 2007 | |
TCCS-ECD (+ selective venography) | 65 MS (65 MS) | 235 (48) | high association of venous outflow anomalies with MS (OR43). Selective venography: multiple extracranial venous stenoses in all MS but none of the control subjects | + | Zamboni et al. | 2009 | |
TCCS-ECD | 109 MS | 177 | presence of CCSVI (≥ 2 criteria) in all MS patients but none of the controls | + | Zamboni et al. | 2009 | |
ECD | 70 MS | n/a | extracranial signs of abnormal venous outflow in 91,4% of MS patients | + | Simka et al. | 2010 | |
ECD | 25 MS | 25 | extracranial signs of CCSVI (≥ 2 criteria) in 84% of MS patients but none of the controls | + | Al-Omari and Rousan | 2010 | |
TCCS-ECD | 56 MS | 20 | absence of CCSVI (≥ 2 criteria) in all MS and control subjects | - | Doepp et al. | 2010 | |
TCCS-ECD | 20 MS | 20 | absence of CCSVI (≥ 2 criteria) in all MS and 95% of controls | - | Mayer et al. | 2011 | |
TCCS-ECD | 289 MS 21 CIS | 189 | Higher prevalence of CCSVI (≥ 2 criteria) in MS (56,1%) compared to healthy controls but low sensitivity/specificity | +/- | Zivadinov et al. | 2011 | |
TCCS-ECD (selective venography) | 50 CIS (7 CIS) | 170 | Ultrasound criteria for CCSVI in 8 CIS patients, no venous anomalies detected by venography. | - | Baracchini et al. | 2011 | |
selective venography | 31 MS 11 CIS | n/a | extracranial venous outflow anomalities infrequent in early MS, more prevalent in late MS | +/- | Yamout et al. | 2010 | |
selective venography | 342 MS | n/a | venous stenoses detected in 97% of patients previously diagnosed with CCSVI by ultrasound | + | Ludyga et al. | 2010 | |
In conclusion, the prevalence of CCSVI in MS patients was reported to range between 0% to 100% depending on the study centre and the method of detection employed. The initially proposed specificity of CCSVI detection in MS has been challenged by demonstrating its presence in healthy controls and other neurological diseases. In particular both doppler sonography and selective venography are operator-dependent and it may be difficult to ensure operator-blinding which is a major pitfall in all positive studies to date. A standardized technique, rigorous blinding and quality control of all procedures in multicenter studies are necessary to finally clarify the role of CCSVI in MS. This approach is mandatory before any attempts should be made to treat CCSVI in MS patients which at present cannot be recommended.