Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis

Abstract

Background: It has been proposed by Zamboni and colleagues that multiple sclerosis is caused by chronic cerebrospinal venous insufficiency, a term used to describe ultrasound-detectable abnormalities in the anatomy and flow of intra- and extracerebral veins. We conducted a meta-analysis of studies that reported the frequency of chronic cerebrospinal venous insufficiency among patients with and those without multiple sclerosis.

Methods: We searched MEDLINE and EMBASE as well as bibliographies of relevant articles for eligible studies. We included studies if they used ultrasound to diagnose chronic cerebrospinal venous insufficiency and compared the frequency of the venous abnormalities among patients with and those without multiple sclerosis.

Results: We identified eight eligible studies: all included healthy controls, and four of them also included a control group of patients with neurologic diseases other than multiple sclerosis. Chronic cerebrospinal venous insufficiency was more frequent among patients with multiple sclerosis than among the healthy controls (odds ratio [OR] 13.5, 95% confidence interval [CI] 2.6-71.4), but there was extensive unexplained heterogeneity among the studies. The association remained significant in the most conservative sensitivity analysis (OR 3.7, 95% CI 1.2-11.0), in which we removed the initial study by Zamboni and colleagues and added a study that did not find chronic cerebrospinal venous insufficiency in any patient. Although chronic cerebrospinal venous insufficiency was also more frequent among patients with multiple sclerosis than among controls with other neurologic diseases (OR 32.5, 95% CI 0.6-1775.7), the association was not statistically significant, the 95% CI was wide, and the OR was less extreme after removal of the study by Zamboni and colleagues (OR 3.5, 95% 0.8-15.8).

Interpretation: Our findings showed a positive association between chronic cerebrospinal venous insufficiency and multiple sclerosis. However, poor reporting of the success of blinding and marked heterogeneity among the studies included in our review precluded definitive conclusions.

Figure 1:

Results of literature search and identification of eligible studies.

Figure 2:

Meta-analysis of diagnosis of chronic cerebrospinal venous insufficiency (presence of at least two parameters) in patients with multiple sclerosis (MS) versus healthy controls (top panel) and controls with other neurologic diseases (bottom panel). An odds ratio greater than 1.0 indicates an increased likelihood of a diagnosis of chronic cerebrospinal venous insufficiency in MS patients versus controls. CI = confidence interval, OR = odds ratio.

Figure 3:

Meta-analysis of individual parameters of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis (MS) versus healthy controls. (1) Reflux in internal jugular veins or vertebral veins; (2) flow reversal in deep cerebral veins; (3) stenoses of internal jugular vein; (4) flow not detectable in internal jugular veins or vertebral veins; and (5) reverted postural control of main cerebral venous outflow pathway (internal jugular veins). An odds ratio greater than 1.0 indicates an increased likelihood of the parameter being present in MS patients versus controls. CI = confidence interval, OR = odds ratio.

Figure 4:

Meta-analysis of individual parameters of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis (MS) versus controls with other neurologic diseases. (1) Reflux in internal jugular veins or vertebral veins; (2) flow reversal in deep cerebral veins; (3) stenoses of internal jugular vein; (4) flow not detectable in internal jugular veins or vertebral veins; and (5) reverted postural control of main cerebral venous outflow pathway (internal jugular veins). An odds ratio greater than 1.0 indicates an increased likelihood of the parameter being present in MS patients versus controls. CI = confidence interval, OR = odds ratio.