Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies

Abstract

Objectives: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been implicated in the pathogenesis of multiple sclerosis (MS). This comprehensive meta-analysis of case-control studies investigates the association of CCSVI with MS.

Methods: Through Medline, EMBASE and Cochrane database searches, case-control ultrasound studies comparing CCSVI frequency among patients with MS and healthy controls were identified.

Results: We identified 19 eligible studies including 1250 patients with MS and 899 healthy controls. The pooled analysis showed that CCSVI was associated with MS [odds ratio (OR) 8.35; 95% confidence interval (CI) 3.44-20.31; p < 0.001) with considerable heterogeneity across studies (I (2) = 80.1%). This association was substantially attenuated in sensitivity analyses excluding studies that were carried out by the group that originally described CCSVI, included investigators who had also been involved in publications advocating endovascular procedures for CCSVI treatment, or were conducted in Italy. Our most conservative sensitivity analysis combining different exclusion criteria yielded no association of CCSVI with MS (OR 1.35; 95% CI 0.62-2.93; p = 0.453) without any heterogeneity (I (2) = 0%).

Conclusion: There is considerable heterogeneity across different case-control studies evaluating the association of CCSVI and MS. The greatest factor contributing to this heterogeneity appears to be the involvement of investigators in other publications supporting endovascular procedures as a novel MS treatment.

Keywords: chronic cerebrospinal venous insufficiency; meta-analysis; multiple sclerosis; ultrasound.

Figure 1.

Flow chart presenting the selection of eligible studies.

Figure 2.

Forest plot describing the overall association between multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI). CI, confidence interval; OR, odds ratio.

Figure 3.

Forest plot describing the results of sensitivity analysis 3 (modifying role mediated by the involvement with the Liberation procedure). Upper panels: studies conducted by investigators not involved in the Liberation procedure (n = 13); Lower panels: studies conducted by investigators involved in the Liberation procedure (n = 6). CI, confidence interval; OR, odds ratio.

Figure 4.

Forest plot describing the results of the combined sensitivity analysis (modifying role mediated by recruitment of Italian patients or involvement with the Liberation procedure). Upper panels: studies conducted by investigators not involved in the Liberation procedure and not recruiting Italian patients (n = 8); Lower panels: studies conducted by investigators involved in the Liberation procedure or recruiting Italian patients (n = 11). CI, confidence interval; OR, odds ratio.

Supplemental Figure 1.

Forest plot describing the association between Ultrasound Criterion 1 and multiple sclerosis. Apart from the overall analysis, the results of the combined sensitivity analysis are shown. Upper panels: studies conducted by investigators not involved in “Liberation procedure” and conducted outside Italy. Lower panels: studies conducted by investigators involved in “Liberation procedure” or conducted in Italy.

Supplemental Figure 2.

Forest plot describing the association between Ultrasound Criterion 2 and multiple sclerosis. Apart from the overall analysis, the results of the combined sensitivity analysis are shown. Upper panels: studies conducted by investigators not involved in “Liberation procedure” and conducted outside Italy. Lower panels: studies conducted by investigators involved in “Liberation procedure” or conducted in Italy.

Supplemental Figure 3.

Forest plot describing the association between Ultrasound Criterion 3 and multiple sclerosis. Apart from the overall analysis, the results of the combined sensitivity analysis are shown. Upper panels: studies conducted by investigators not involved in “Liberation procedure” and conducted outside Italy. Lower panels: studies conducted by investigators involved in “Liberation procedure” or conducted in Italy.

Supplemental Figure 4.

Forest plot describing the association between Ultrasound Criterion 4 and multiple sclerosis. Apart from the overall analysis, the results of the combined sensitivity analysis are shown. Upper panels: studies conducted by investigators not involved in “Liberation procedure” and conducted outside Italy. Lower panels: studies conducted by investigators involved in “Liberation procedure” or conducted in Italy.

Supplemental Figure 5.

Forest plot describing the association between Ultrasound Criterion 5 and multiple sclerosis. Apart from the overall analysis, the results of the combined sensitivity analysis are shown. Upper panels: studies conducted by investigators not involved in “Liberation procedure” and conducted outside Italy. Lower panels: studies conducted by investigators involved in “Liberation procedure” or conducted in Italy.

Supplemental Figure 6.

Forest plot describing the results of the sensitivity analysis #1 (modifying role mediated by Zamboni’s group). Upper panels: studies which did not include authors coming from Zamboni’s group or coming from groups that have previously cooperated with Zamboni (n=15); Lower panels: studies related to Zamboni’s group (n=4).

Supplemental Figure 7.

Forest plot describing the results of the sensitivity analysis #2 (modifying role mediated by completeness of the neurosonology protocol). Upper panels: studies with complete neurosonology protocol regarding CCSVI screening (n=15); Lower panels: studies with incomplete protocol (n=4).

Supplemental Figure 8.

Forest plot describing the results of the sensitivity analysis #4 (modifying role mediated by recruitment of studies conducted in Italy). Upper panels: studies conducted outside Italy (n=11); Lower panels: studies conducted in Italy (n=8).